Compr. Heterocyclic Chem. III Vol. 4 Five-membered Rings with Two Heteroatoms

4.01 Pyrazoles L. Yet Albany Molecular Research, Inc., Albany, NY, USA ª 2008 Elsevier Ltd. All rights reserved. 4.01.1 ...

Author: Katritzky A.R. | et al. (eds.)

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4.01 Pyrazoles L. Yet Albany Molecular Research, Inc., Albany, NY, USA ª 2008 Elsevier Ltd. All rights reserved. 4.01.1 4.01.1.1 4.01.2

Introduction

3

Survey of Possible Structures

5

Theoretical Methods

5

4.01.2.1

Structure and Reactivity of Pyrazoles

5

4.01.2.2

Structure and Reactivity of Indazoles

7

4.01.3

Experimental Structural Methods

8

4.01.3.1

X-Ray Diffraction

8

4.01.3.2

Microwave and Photoelectron Spectroscopy

4.01.3.3

l

H and 13C NMR Spectroscopy

4.01.3.3.1 4.01.3.3.2

9 10

Aromatic systems Nonaromatic systems

10 12

4.01.3.4

I9

4.01.3.5

15

N NMR Spectroscopy

4.01.3.6

13

C and 15N CP/MAS NMR Spectroscopy

4.01.3.7

UV and IR Spectroscopy

15

Mass Spectrometry and Ion Cyclotron Resonance Studies

16

4.01.3.8 4.01.4 4.01.4.1

F NMR Spectroscopy

17

Stability and Stabilization

17

Thermochemistry

17

Tautomerism

4.01.4.2.1 4.01.4.2.2

4.01.5

14

Thermodynamic Aspects

4.01.4.1.1

4.01.4.2

13 13

17

Annular (ring) tautomerism Substituent (chain) tautomerism

17 19

Reactivity of Fully Conjugated Rings

21

4.01.5.1

Thermal and Photochemical Reactions

21

4.01.5.2

Electrophilic Attack at Nitrogen

22

4.01.5.2.1 4.01.5.2.2 4.01.5.2.3 4.01.5.2.4 4.01.5.2.5 4.01.5.2.6 4.01.5.2.7 4.01.5.2.8 4.01.5.2.9

4.01.5.3

Proton acids on neutral compounds Metal ions Azacrown ethers and porphyrinogens Alkyl halides and related compounds: Compounds with a free NH group Aryl halides and related compounds Acyl halides and related compounds Michael addition to double and triple bonds Aminating and nitrating agents Alkenylation

Electrophilic Attack at Carbon

4.01.5.3.1 4.01.5.3.2 4.01.5.3.3 4.01.5.3.4 4.01.5.3.5 4.01.5.3.6

22 23 28 28 30 31 32 33 33

34

Nitration Sulfonation Halogenation Acylation Amination Diazo coupling

34 34 35 36 36 37

1

2

Pyrazoles

4.01.5.3.7 4.01.5.3.8

Reaction with aldehydes and ketones Miscellaneous

37 37

4.01.5.4

Nucleophilic Attack at Carbon

38

4.01.5.5

Nucleophilic Attack at Hydrogen

39

4.01.5.5.1 4.01.5.5.2

4.01.5.6

Reaction with Radicals and Electron-Deficient Species

4.01.5.6.1 4.01.5.6.2 4.01.5.6.3

4.01.5.7 4.01.6 4.01.6.1

4.01.7

Carbenes and nitrenes Free radical attack at the ring carbon atoms Electrochemical reactions and reactions with free electrons

39 40

40 40 40 41

Reactions with Cyclic Transition States

41

Reactions of Nonaromatic Compounds

42

Dihydro Derivatives

4.01.6.1.1 4.01.6.1.2 4.01.6.1.3 4.01.6.1.4 4.01.6.1.5

4.01.6.2

Metallation at a ring carbon atom Hydrogen exchange at ring carbon in neutral pyrazoles

Aromatization Reduction Thermolysis, photolysis, and pyrolysis Acylation reactions Other reactions

Tetrahydro Compounds Reactions of Substituents Attached to Ring Carbon Atoms

42 42 43 44 46 46

47 47

4.01.7.1

Indazoles

47

4.01.7.2

Other C-Linked Substituents

48

4.01.7.2.1 4.01.7.2.2 4.01.7.2.3

4.01.7.3

N-Linked Substituents

4.01.7.3.1 4.01.7.3.2 4.01.7.3.3 4.01.7.3.4

4.01.7.4

Alkyl groups Alkenyl groups Carbonyl groups and derivatives Aminopyrazoles and -indazoles Imines Nitro and nitroso groups Azo-, diazo-, and azidopyrazoles

O-Linked Substituents

4.01.7.4.1 4.01.7.4.2 4.01.7.4.3

3-Hydroxypyrazoles 4-Hydroxypyrazoles 5-Hydroxypyrazoles

48 50 50

53 53 55 56 56

57 57 57 57

4.01.7.5

S-Linked Substituents

59

4.01.7.6

Halogen Atoms

60

4.01.7.6.1 4.01.7.6.2 4.01.7.6.3 4.01.7.6.4

4.01.8

Nucleophilic substitution reactions: Neutral pyrazoles and indazoles Metal–halogen exchange substitution reactions Metal-catalyzed cross-coupling reactions Metal and metalloid-linked substituents

Reactivity of Substituents Attached to Ring Nitrogen Atoms

60 61 62 64

65

4.01.8.1

Aryl Groups

4.01.8.2

Alkyl Groups

66

4.01.8.3

N-Acyl and Carbonyl Derivatives

67

4.01.8.4

N-Oxides

68

4.01.8.5

N-Amino Groups

68

4.01.8.6

N-Nitro Groups

68

4.01.9

Syntheses Classified by Number of Ring Atoms in Each Compound

65

68

Pyrazoles

4.01.9.1

Ring Synthesis from Nonheterocycles

4.01.9.1.1 4.01.9.1.2

4.01.10 4.01.10.1

Formation of one bond Formation of two bonds

Ring Synthesis by Transformation of Another Ring Ring Transformations

4.01.10.1.1 4.01.10.1.2 4.01.10.1.3 4.01.10.1.4 4.01.10.1.5 4.01.10.1.6 4.01.10.1.7 4.01.10.1.8 4.01.10.1.9 4.01.10.1.10 4.01.10.1.11 4.01.10.1.12

4.01.11

Benzimidazole and imidazole systems Cyclopropanes Furandiones Oxazoles and oxadiazoles Oxazolium olates Pyranones Pyridines and pyridones Sydnones Tetrazoles Triazines Other five-membered heterocycles Other six-membered heterocycles

68 68 74

102 102 102 103 103 103 104 104 106 106 106 107 107 108

Synthesis of a Particular Class of Compounds and a Critical Comparison of the Various Routes Available: Pyrazoles, Indazoles, and Their Derivatives as Starting Materials for the Syntheses of Fused Ring Systems

109

4.01.11.1

Synthesis of Fused Ring Systems

109

4.01.11.2

Nucleosides and Amino Acids

110

4.01.11.3

Labeled Compounds

111

4.01.12

Important Compounds and Applications

112

4.01.12.1

Pyrazoles in Supramolecular Chemistry

112

4.01.12.2

Pharmaceuticals and Agrochemicals

113

4.01.12.2.1 4.01.12.2.2 4.01.12.2.3 4.01.12.2.4 4.01.12.2.5 4.01.12.2.6 4.01.12.2.7 4.01.12.2.8

4.01.12.3

Other Applications

4.01.12.3.1 4.01.12.3.2 4.01.12.3.3 4.01.12.3.4 4.01.12.3.5

4.01.12.4 4.01.13

Anti-inflammatory agents Cardiovascular agents CNS applications Infectious diseases Metabolic diseases Oncologytic agents Estrogen receptor Agricultural uses Pyrazole ligand applications Pyrazoles as catalysts Pyrazoles as reagents Metal pyrazole complexes Pyrazole industrial applications

Natural Products Further Developments

References

113 114 115 115 116 117 118 118

119 119 119 120 121 121

121 121 122

4.01.1 Introduction Five-membered ring systems containing two double bonds and two nitrogen atoms adjacent to each other are called pyrazoles. Previous chapters on pyrazoles have been presented in CHEC(1984), covering the literature up to 1981 , and CHEC-II(1996), covering the literature from 1982 to 1995 . This chapter covers the literature on pyrazoles during the 10-year period, 1996–2006. The previous two chapters of this series on pyrazoles dealt more with theoretical, experimental structural, and thermodynamic methods, and less with the

3

4

Pyrazoles

reactivity, synthesis, and applications of pyrazoles. During the last 10 years, more reports have appeared on the synthesis and reactivity of pyrazole ring systems. Furthermore, the medicinal chemistry applications of pyrazoles and fused-ring systems have found numerous applications in drug discovery. This chapter focuses on these current developments. Many reviews have been written on the synthesis and reactivity of pyrazoles (Table 1) as well as reviews where pyrazoles are presented in the context of other topics (Table 2). Table 1 Reviews on pyrazoles and related topics Main author

Title

Reference

A. P. Sadimenko K. Makino S. A. Shevelev K. Makino K. N. Zelenin C. Pettinari

Organometallic complexes of heterocycles II. Complexes of pyrazoles Synthesis of pyrazoles Advances in nitropyrazole chemistry Synthesis of pyrazoles and condensed pyrazoles 5-Hydroxy-4,5-dihydropyrazoles Organotin(IV) derivatives of imidazoles, pyrazoles and related pyrazolyl and imidazolyl ligands Coordination chemistry with pyrazole-based chelating ligands: Molecular structural aspects C-Phosphorylated azoles Synthesis and properties of acetylenic derivatives of pyrazoles Product class 1: Pyrazoles Synthetic utility of N-acylpyrazoles Photochemical isomerizations of some five-membered heteroaromatic azoles Pyrazol-3-ones Flash vacuum pyrolysis of isoxazoles, pyrazoles and related compound Structural revision in pyrazole chemistry

1996CCR247 1998JHC489 1998RJO1071 1999JHC321 1998THS(2)207 1999MGM661

R. Mukherjee A. M. Pinchuk S. F. Vasilevsky B. Stanovnik C. Kashima J. W. Pavlik G. Varvounis G. I. Yranzo D. Kumar

2000CCR151 2001PJC1137 2002AHC1 2002SOS(12)15 2003H(60)437 2003PHC(15)37 2004AHC141 2004COR1071 2004H(63)145

Table 2 Reviews on pyrazoles discussed in the context of other topics Main author

Title

Reference

S. A. Lang M. A. Walters K. Turnbull K. Turnbull E. S. El Ashry

Five membered ring systems: With more than one N atom Five membered ring systems: With more than one N atom Five membered ring systems: With more than one N atom Five membered ring systems: With more than one N atom Carbohydrate hydrazones and osazones as organic raw materials for nucleosides and heterocycles Five membered ring systems: With more than one N atom Five membered ring systems: With more than one N atom Five membered ring systems: With more than one N atom The retro Diels–Alder reaction as a valuable tool for the synthesis of heterocycles Five membered ring systems: With more than one N atom Annulated heterocyclo-purines. 1. Fused five-membered heterocyclo-purinediones, –purinones, and –purineimines 4-Alkoxy-1,1,1-trichloro-3-alken-2-ones: Preparation and applications in heterocyclic synthesis Cyclic 1,3-diones and their derivatives as versatile reactive intermediates in the synthesis of condensed fused ring heterocycles Five membered ring systems: With more than one N atom Five membered ring systems: With more than one N atom Stereoselective cycloadditions of nitrilimines as a source of enantiopure heterocycles 1,3-Dipolar cycloadditions in aqueous media Cross-coupling reactions on azoles with two and more heteroatoms Five membered ring systems: With more than one N atom

1996PHC(8)146 1997PHC(9)148 1998PHC(10)153 1999PHC(11)163 2000COR609

L. Yet L. Yet L. Yet G. Stajer L. Yet A. Rybar M. A. P. Martins B. C. Sekhar

L. Yet L. Yet G. Molteni G. Molteni P. Stannety L. Yet

2000PHC(12)161 2001PHC(13)167 2002PHC(14)180 2003COR1423 2003PHC(15)206 2004AHC85 2004CSY391 2004JHC807

2004PHC(16)198 2005PHC(17)172 2005H(65)2513 2006H(68)2177 2006EJO3283 2006PHC(18)218

Pyrazoles

4.01.1.1 Survey of Possible Structures Pyrazole 1 is an aromatic molecule and, like its structural isomer imidazole, contains a pyrrole-like and a pyridine-like N atom, but in the 1- and 2-positions (1,2-diazole). This survey of possible structures follows the convention adopted in CHEC(1984) . Aromatic compounds with two double bonds include the core structures such as pyrazole 1, indazole 2, and isoindazole 3 along with their nonaromatic isomers, pyrazolenine or 3H-pyrazole 4, isopyrazole or 4H-pyrazole 5, and 1H-pyrazol-2-ium salts 6. Other pyrazole structures containing carbonyl groups include 1H-pyrazol-5(4H)-one 7, 1H-pyrazol-3(2H)-one 8, 3H-pyrazol-3-one 9, and 4,5-dihydro-3H-pyrazol-3-one 10. Pyrazolines such as 4,5-dihydro-3H-pyrazole or 1-pyrazoline 11, 4,5-dihydro-1H-pyrazole or 2-pyrazoline 12, and 2,3-dihydro-1H-pyrazole or 3-pyrazoline 13 are also represented. Pyrazolidine 14 and pyrazolidin-3-one 15 are representative structures with no ring double bonds. All of these structures can have substitution on any of the carbon atoms. Many other structures such as those with fused pyrazole rings are also possible, but those mentioned above are the most common core types discussed in this chapter.

4.01.2 Theoretical Methods 4.01.2.1 Structure and Reactivity of Pyrazoles N-Unsubstituted pyrazoles can have N–H N hydrogen bonds present in their crystals, which can lead to at least six motifs such as monomers, dimers, trimers, tetramers, hexamers, and catemers. Hydrogen-bonding motifs for pyrazoles have been examined in the Cambridge Structural Database (CSD) . The accessible surface of the N-atoms has been found to be useful as a discriminator to divide structures into dimer and catemer motifs. Low accessibility favors dimers and tetramers and high values favor catemers and trimers. Empirical rules were successfully applied to predict the motifs of eight new structures in the subsequent release of the CSD. A search in the CSD for NH-pyrazoles lacking other hydrogen-bond donor and acceptor sites identified 49 compounds that crystallized in 47 structures forming dimers (16), tetramers (13), trimers (8), a hexamer (1), and catemers (10) using N–H N hydrogen bonds . These structures were divided into two classes (dimers and tetramers vs. trimers and catemers) using the accessible surface to an atom with good results. The method has been extended to new pyrazoles by means of theoretical calculations (B3LYP/6-31G* ) of the geometry of the monomers. Aspects like the conformation of phenyl substituents, the additivity of substituent effects, and buttressing effects have been approached theoretically.

5

6

Pyrazoles

The supramolecular structure of 1H-pyrazoles in the solid state was investigated by crystallographic and ab initio studies . Harmonic force fields were calculated at the corresponding optimized geometry for pyrazole at the Hartree–Fock (HF), B3LYP, MP2, CCSD (coupled-cluster singles and doubles), and CCSD(T) (coupled cluster with perturbative triples) levels using the 6-31G* basis set and at the HF and B3LYP levels using the ccpVTZ basis set . Ab initio coupled gauge-independent atomic orbital (GIAO) calculations were carried out on 21 1-substituted pyrazoles using four different ab initio methods which led to the final selection of the hybrid B3LYP/6-311þG(2d,p)//B3LYP/6-31þG(d) basis set . Comparison with experimental chemical shifts in solution (taking into account the calculated shieldings of the corresponding references) showed an excellent agreement between both sets, allowing for a factor of proportionality of about 0.96. The infrared (IR) spectra and quantum-mechanical calculations of vibrational spectra and structure of pyrazole and 3,5-dimethylpyrazole in solution, gas phase, and solid state have been investigated over a wide range of concentrations and temperatures . It was found that in the gas phase, both pyrazole and 3,5-dimethylpyrazole exist in an equilibrium between monomers, dimers, and trimers. In solution, the equilibrium between monomers and trimers dominated and no bands which could be attributed to dimers were detected. 3,5-Dimethylpyrazole retained the trimer structure in the solid state, while in the case of pyrazole, formation of the crystal provided another type of association. Geometrical and spectral characteristics of dimers and trimers, obtained by ab initio calculations, were presented and compared with experimental data. Molecular dynamics of the self-organizing strong hydrogenbonded 3,5-dimethylpyrazole was studied by quasi-elastic neutron scattering (QENS) . Hindered pyramidal inversion and restricted rotation in N-propyl-N-(4-pyridyl)-1-amino-1H-pyrazoles 16 were studied by dynamic nuclear magnetic resonance (NMR) spectroscopy and molecular modeling methods . A coupled-cluster study of the structure and vibrational spectra of pyrazole has been reported. The structure of 5-tert-butyl-4-nitro-1H-pyrazol-3-ol 17 consisted of molecules that pack in a linear hydrogen-bonded ribbon motif . This hydrogen-bonding arrangement was constructed through two dimer formations, one that is atypical of pyrazoles (N–H N) and the other via an interaction from the hydroxy group to one of the nitro oxygen atoms. The molecular structure of a novel monohydrated 3-p-nitrophenylpyrazole was found to exist as the 3-tautomer 18 rather than the corresponding 5-tautomer 19 using NMR spectroscopy, single crystal X-ray diffraction, and ab initio calculations (Equation 1) .

Pyrazoles

ð1Þ

C–H and N–H bond-dissociation energies (BDEs) of pyrazole were calculated using composite ab initio CBS-Q, G3, and G3B3 methods (Table 3) . It was found that all these methods provided very similar BDEs, despite the fact that different geometries and different procedures in the extrapolation to complete incorporation of electron correlation and complete basis set limit were used. Table 3 Bond dissociation energies of pyrazole (kcal mol1) Bond

CBS-Q

G3

G3B3 recommended

B3LYP

Charge

Spin

Bond angle ( )

N(1)–H C(3)–H C(4)–H C(5)–H

112.0 118.7 122.6 121.1

111.3 118.7 122.2 121.1

109.2 117.8 121.0 119.9

107.6 115.5 118.9 117.9

0.401 0.201 0.221 0.210

0.967 0.953 0.948

113.3 112.1 104.5 106.1

4.01.2.2 Structure and Reactivity of Indazoles Nuclear quadrupole resonance (NQR) frequencies were determined on the 35Cl isotope for several chloroindazoles and for two chloroindazole nucleosides at liquid nitrogen temperature . The influence of the site of substitution and type of substituent on the resonance frequency was analyzed and the electron density distribution and electrostatic potential in the molecules were calculated by the B3LYP/6-31G(p) method and the results were correlated with experimental data. The aqueous-phase physicochemical properties of some 3-substituted indazoles (H, Me, Br, Cl) were computed using semi-empirical methods and the results obtained were evaluated by searching for a possible correlation with the previously obtained experimental properties . The aqueous-phase geometries, relative stabilities, acidity constants, tautomerism, proton affinities (PAs) and dipole moments for the tautomeric forms of some 3-substituted indazoles and their fixed forms (model compounds in which proton migration is eliminated by replacing the mobile hydrogen atom with a methyl group) were calculated with full geometry optimization using AM1, PM3, and modified neglect of diatomic overlap (MNDO) methods. The results of aqueous-phase semiempirical calculations indicate that 1H-form 20 of the studied molecules is more stable than the 2H-form 21 (Equation 2).

7

8

Pyrazoles

ð2Þ

Ab initio and density functional theory (DFT) methods have been used to study the five tautomeric forms of indazole in gaseous and aqueous phases . The tautomers in the gas phase were optimized at MP2/6-311G(2d,2p), B3LYP/6-311G(2d,2p), and B3PW91/6-311G(2d,2p) levels of theory. Computational studies on the three tautomeric forms of four 1,5,6,7-tetrahydro-4H-indazol-4-ones, 1,5,6,7-tetrahydro-4H-indazol-4-one, 6,6dimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one, 3-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one, and 3,6,6-trimethyl1,5,6,7-tetrahydro-4H-indazol-4-one, were performed at different levels, ranging from semi-empirical AM1, ab initio HF/6-31G* and HF/6-31G** , to B3LYP/6-31G** density functional calculations . These calculations were used to establish the most stable tautomer, which in all cases was in agreement with the experimental data.

4.01.3 Experimental Structural Methods 4.01.3.1 X-Ray Diffraction The structure of 3(5)-phenyl-4-bromo-5(3)-methylpyrazole in the solid state was detemined by X-ray crystallography and showed both tautomers to be present in the crystals, forming cyclic tetramers (Equation 3) . The molecular and crystal structure of 3(5)-nitropyrazole was determined by X-ray analysis . The triclinic unit cell contained 12 molecules which form four hydrogen-bonded (N–H N) trimers. Each trimer comprised a pseudo-ring in a flattened envelope, distorted towards a chair conformation. The crystal packing consisted of layers formed by centrosymmetric-related trimers joined through C–H O interactions. The X-ray molecular structure of 4-methylpyrazole 22 showed it to exist as a hydrogen-bonded trimer in the solid state at 100 K . The X-ray molecular structure of the important molecule 3,5-bis(trifluoromethyl)pyrazole 23, determined at 120 K, revealed crystals belonging to the triclinic P1 space group . The compound formed tetramers through N–H N hydrogen bonds. Some proton disorder was necessary to explain the geometric features of the monomers. The X-ray crystal structure of 1H-pyrazole-3-(N-tert-butyl)-carboxamide 24 was determined . In the solid state, the 13C and 15N cross-polarization/magic angle spinning (CP/MAS) NMR spectra corresponded to this tautomer. In solution, both tautomers were present in a ratio that depended on the temperature (at 293 K, 90% 3-substituted/10% 5-substituted). Some unusual 1H,1H-couplings involving the NH proton were observed. DFT (GIAO) calculations were carried out. The conformation and distortion of flexible pyranoid rings in 1-(2-hydroxy-iminopyranosyl)pyrazole carbohydrates were discussed in the light of crystal structure analysis of nine compounds and the results of semi-empirical calculations of 16 model compounds were presented . Conformational similarities of several modified sugars studied by X-ray methods suggested that the presence of intramolecular C–H N hydrogen bonds between the aglycone (pyrazole ring) and axial hydrogen atoms at C-3 and/or C-5. Results from the PM3 method showed that ring puckering was also dependent on weak interactions between the aglycone group and the pyranoid ring. Conclusions from both methods converge. The crystal structures of two NH-pyrazole derivatives forming intermolecular N–H N hydrogen bonds were reported: 5-methyl-4-(3-methylpyrazol-5-yl)pyrazol-3-ol and 3-methyl-5-dihydro-1H-naphtho[1,2-d]pyrazole hemihydrochloride . Other structures were surveyed in order to obtain a deeper insight into the ways in which NH-pyrazoles self-assemble by means of intermolecular N–H N hydrogen bonds in molecular crystals. The single crystal X-ray structures of 3(5)-(2,5-dimethoxyphenyl)pyrazole and the hemihydrate of 3(5)-(3,4-dimethoxyphenyl)pyrazole have been determined (Equation 4) . The first compound exists purely as the 5substituted prototropomer in the crystal; the pyrazole pyrrolic N–H proton is involved in a three-way hydrogen bond, involving an intramolecular contact with a methoxy oxygen donor and an intermolecular interaction to the pyridinic N-atom of a neighboring molecule, forming discrete hydrogen-bonded dimers. In the second molecule, however, the

Pyrazoles

pyrrolic proton is disordered over both N-1 and N-2 via hydrogen bonding to the solvent water molecule. The structure of 3(5)-[(4-diphenylphosphinoyl)phenyl]pyrazole has been determined by X-ray crystallography as the 1H3-substituted tautomer (monoclinic, space group P21/c) .

ð3Þ

ð4Þ

X-Ray crystal structures of 1-(nitrophenyl)-2-pyrazolines 25 and 26 have been determined . The differences in conformation between both molecules and between the solid and gas phases were explained in terms of steric effects. The structure of 1-formyl-3-phenyl-2-pyrazoline 27 in the gas phase (DFT calculations), solution (NMR), and solid state (X-ray crystallography) was evaluated . The crystal and molecular structure of 1,1,3-trimethyl-2-pyrazolinium perchlorate 28 has been determined and compared with those of other pyrazolinium salts (both 1,1- and 1,2-disubstituted) . Reported 13C and 15N chemical shifts for a series of related pyrazolines have been compared with GIAO/DFT calculations, with excellent agreement. The correlation of the biological properties of pyrazolines with those of the perchlorate anion in the same molecule was also discussed.

X-Ray crystallography showed that 7-nitroindazole crystallized as an N(1)–H tautomer dimer and adopted a planar conformation assisted by intramolecular hydrogen bonding .

4.01.3.2 Microwave and Photoelectron Spectroscopy The electronic structure and gas-phase thermolysis of 4-substituted 3,3,5,5-tetramethyl-3,5-dihydro-4H-pyrazoles has been studied by photoelectron spectroscopy and the first evidence for an alkylideneselenirane was obtained . The 351.1 nm photoelectron spectrum of the 1-pyrazolide anion has been measured . The 1-pyrazolide ion 29 is produced by hydroxide deprotonation of pyrazole in a flowing afterglow ion source and a small amount of the 5-pyrazolide ion 30 was also detected and studied by photoelectron spectroscopy.

9

10

Pyrazoles

4.01.3.3 4.01.3.3.1

l

H and 13C NMR Spectroscopy Aromatic systems

The 1H and 13C NMR spectra of pyrazoles derived from chiral cyclohexanones (3-methylcyclohexanone, menthone, pulegone, dihydrocarvone, and carvone) were measured and assigned . Thirteen C- and N-trimethylsilylpyrazoles were studied by 1H and 13C NMR spectroscopy . A complete model for the prediction of 1H and 13C NMR chemical shifts and torsional angles in phenyl-substituted pyrazoles has been reported . A correlation between torsion angles calculated by molecular mechanics and differences in 13C chemical shifts of the ortho- and meta-carbon atoms of the phenyl groups in 29 N-phenyl-substituted pyrazole derivatives and 11 C-phenyl-substituted pyrazoles has been identified. Three N-substituted pyrazoles and three N-substituted indazoles, 1-(4-nitrophenyl)-3,5-dimethylpyrazole 31, 1-(2,4-dinitrophenyl)-3,5-dimethylpyrazole 32, 1-tosylpyrazole 33, 1-p-chlorobenzoylindazole 34, 1-tosylindazole 35, and 2-(2-hydroxy-2-phenylethyl)indazole 36, have been studied by NMR spectroscopy in solution (1H, 13C, 15N) and in the solid state (13C, 15N) . 3-Methyl and 5-methyl tautomers of 3(5)-methylpyrazole in a ratio of 54:46 were found in methanol by the use of 13C NMR spectroscopy . The chemical shifts and coupling constants of 23 pyrazoles bearing different substitutents at position 1 have been studied by 1H, 13C, and 15N NMR spectroscopy in solution (Table 4) . Variable-temperature 1H NMR studies of a range of 1,3,5-trisubstituted-4-nitrosopyrazoles (R1, R2, R3 ¼ Me, CF3, Ph, or t-Bu) have led to the identification of individual rotational isomers at low temperatures arising from the slowing down of the rotation of the nitroso function with respect to the pyrazole ring (Equation 5) . The coupling constants of eight N–R-pyrazoles 37 have been calculated and compared with their experimental values . The agreement was good and could be used to estimate new couplings; the whole collection was statistically analyzed. 1-Hydroxymethylindazole 38 has been studied in solution by 1H, 13C, and 15 N NMR spectroscopy .

Pyrazoles

Table 4

1

H and 13C NMR parameters of 1-substituted pyrazoles

1-Substituent

H-3

H-4

H-5

C-3

C-4

C-5

[HBPz2] Me Et 1-Adamantyl Bn CPh3 Ph COMe CONH2 NH2 NHMe NHCHO (E) NHCHO (Z) NHCOMe (Z) NTCHPh NTCHPh NTPPh3 NO2 OBn ONa TMS P[NMe2]2 SO2CF3

7.36 7.49 7.49 7.54 7.56 7.67 7.72 7.70 7.63 7.36 7.38 7.53 7.49 7.47 7.64 7.56 7.07 7.77 7.25 6.62 7.79 7.70 7.99

6.05 6.22 6.23 6.23 6.28 6.24 6.46 6.43 6.42 6.14 6.09 6.39 6.34 6.31 6.49 6.38 5.97 6.66 6.15 5.74 6.33 6.30 6.66

7.24 7.35 7.38 7.52 7.38 7.37 7.87 8.25 8.23 7.39 7.34 7.90 7.72 7.44 8.04 7.71 7.17 8.65 7.53 6.80 7.60 7.53 8.08

141.9 139.0 138.5 137.7 138.9 139.6 140.9 143.6 142.3 136.6 137.2 138.4 137.6 137.3 137.9 137.4 132.9 141.6 133.1 126.1 143.1 142.2 148.1

106.0 105.3 104.8 104.3 105.4 104.3 107.8 109.3 108.6 103.9 103.7 106.2 105.4 105.1 106.7 105.9 102.1 109.8 102.9 99.3 106.0 106.2 111.6

135.7 129.6 127.7 125.3 130.1 132.2 127.6 127.8 128.8 129.0 127.8 131.3 130.8 130.9 129.3 128.7 125.8 126.8 122.3 117.3 133.7 132.2 133.8

ð5Þ

The orientation of the substituent groups in 1,2,4-oxadiazole substituted pyrazoles 39, formed by reaction of benzonitrile oxides with an unsymmetrically substituted hydrazine, has been determined by 13C NMR assignments . The scope and limitations in the regioselective synthesis of 1,3,5-trisubstituted pyrazoles from -amino enones and hydrazine derivatives were investigated by 13C chemical-shift prediction rules for 1,3,5-trisubstituted pyrazoles .

1

H, 13C, and 15N NMR chemical shifts of 10 substituted pyrazolo[1,5-a]pyrimidines 40 were assigned based on double quantum filtering (DQF) 1H,1H correlation spectroscopy (COSY), pulsed field gradient (PFG) 1H,13C

11

12

Pyrazoles

heteronuclear multiple quantum correlation (HMQC), and PFG 1H,X (X ¼ 13C and 15N) heteronuclear multiple bond correlation (HMBC) experiments and on literature data . The 1H and 13C NMR chemical shifts and J(H,H), J(H,F), and J(C,F) coupling constants of 3-amino-9-methyl-1H-pyrazolo[3,4-b]-4-quinolone derivatives 41 were characterized and assigned on the basis of 1H, 13C, and 13C–1H (short- and long-range) correlated spectra . The assignments of 1H and 13C NMR spectra of 1H-pyrazolo[3,4-b]pyridine derivatives 42 based on one-dimensional (1-D) and 2-D NMR techniques were reported . The 13C NMR data of a series of 1H-pyrazolo[3,4-c]pyridine derivatives have been reported .

4.01.3.3.2

Nonaromatic systems

1

H and 13C NMR studies of 1-hydrazino-2,3-dihydro-1H-pyrazolo[1,2-a]pyridazine-5,8-diones 43 and -1H-pyrazolo[1,2-b]phthalazine-5,10-diones 44 and their ring–chain tautomerism were reported . The unequivocal structural elucidation of a new kind of 2-pyrazoline derivatives 45 was carried out by means of monodimensional 1H and 13C NMR spectra, as well as HMBC and HMQC experiments, and nuclear Overhauser effect difference (NOEDIFF) effects . The stereoisomerism and ring–chain tautomerism in 1-hydroxy-2,3-dihydro-1H-pyrazolo[1,2-a]pyridazine-5,8-diones and 1-hydroxy- and 1-amino-2,3-dihydro-1H-pyrazolo[1,2-b]phthalazine-5,10-diones were investigated using 1H and 13C NMR spectroscopy and all were found to exist in cyclic forms in solution . The reaction of triarylideneacetylacetones with hydrazine hydrate in acetic acid afforded excellent yields of (E)-s-trans-1-acetyl5-aryl-3-styryl-2-pyrazolines 46 via decinnamoylation . The structures of these compounds were elucidated using 1H, 13C, and 2-D NMR techniques such as H,H COSY, C,H COSY, nuclear Overhauser enhancement spectroscopy (NOESY), and HMBC. 15N NMR data for these compounds were also obtained and the results were discussed.

The 13C NMR spectra of a series of 3,5-dialkyl- and 3-alkyl-5-phenyl-4-oxo-4H-pyrazole-1,2-dioxides 47 were determined . Signals for the carbonyl carbon, C-4 of the pyrazole, appeared at 186.2–188.1 ppm, while the C-3 and C-5 signals were found in the region of 105.8–112.8 ppm. The effect of structural variation of the alkyl groups on the chemical shift of C-3 in a selected series of these compounds was investigated using published electronic and steric parameters. Strong correlations were observed with electronic parameter sets * and E when augmented with a variety of published steric parameter sets. 1H and 13C NMR investigations of 4-acyl-5-methyl-2phenyl-1,2-dihydro-3H-pyrazol-3-ones showed these compounds to exist predominantly as hydroxypyrazoles 48 in CDCl3 or benzene-d6 solution, whereas in dimethyl sulfoxide (DMSO-d6), a considerable amount of NH tautomer 49 was present (Equation 6) . X-Ray crystal analyses revealed that in the solid state the 4-propionyl compound is present as the hydroxypyrazole, the 4-(2-thienyl) derivative as the NH isomer, and the 4-cinnamoyl product to have an exocyclic double-bond structure stabilized by an intramolecular hydrogen bond.

Pyrazoles

ð6Þ

4.01.3.4

I9

F NMR Spectroscopy

The spin–spin coupling constant 3JH,F of the H(CF2)2 group varied within 1.6–3.5 Hz for 5-RF- and 3.8–4.5 Hz for 3-RFtautomeric-pyrazoles 50–53 in CDCl3 and can serve as a reliable criterion for recognition of regioisomeric and tautomeric structures of H(CF2)2-containing pyrazoles . The 19F NMR chemical shifts of 5-trifluoromethyl-1,2-dimethyl-1H-pyrazolium chlorides 54 have been investigated . Detailed analysis of the 19 F NMR spectra of the boat-shaped complexes (NBu4)2[Pd2(-LL)2R4] (R ¼ 3,5-C6Cl2F3; LL ¼ pyrazolate (pz); dimethylpyrazolate (dmpz)), HH- (head-to-head) and HT- (head-to-tail) (NBu4)2[Pd2(-LL)2R4] (LL ¼ 3-methylpyrazolate (mpz); indazolate (indz)), (NBu4)2[Pd2(-dmpz)(-LL)R4] (LL ¼ mpz, indz), and (NBu4)2[R2Pd(LL)2Pd(C6F5)2] (LL ¼ pz, dmpz) afforded valuable structural information in solution .

4.01.3.5

15

N NMR Spectroscopy

Substituent effects on the 15N NMR parameters of a large collection of pyrazoles have been compiled in tabular form from a variety of literature sources . The 13C and 15N chemical shifts of pyrazole and indazole (and compared with 10 other parent azoles and benzazoles) have been determined in the solid state at room temperature and in methanol solution at 178 K . The experimental values were compared with the absolute shieldings calculated at the GIAO/B3LYP/6-31G* level. These comparisons showed that some signals, 13C NMR but especially 15 N NMR, have to be corrected for hydrogen bonds present in certain solvents and in the solid state. The linear regressions are good enough to be used to predict some missing values. The results of various 15N solid-state NMR experiments performed on solid samples of doubly 15N-labeled 3,5-dimethylpyrazole, 5-methyl-3-phenylpyrazole, and

13

14

Pyrazoles

3,5-diphenylpyrazole were reported . In the solid state, these compounds form various hydrogen-bonded complexes. The principal values of the 15N chemical-shift tensors (CSTs) of amine and imine nitrogen atoms are derived by line-shape analysis of the 15N NMR spectra of the static powders obtained under the conditions of 1H–15N cross-polarization and 1H decoupling. An examination of a variety of common nitrogen-containing systems, which included nine structurally different pyrazole examples, was undertaken to optimize parameters for observation of 1 H–15N long-range correlations . Because of the diversity of coupling constants encountered with 1 H–15N correlations, a modified accordion-based sequence was used to provide the best results. The synthesis of a series of 1H-pyrazolo[3,4-b]quinoxalines (flavazoles) 55 by acylation, alkylation, halogenation, and aminomethylation of the parent compound was reported and their structures were investigated by 1H, 13C, and 15 N NMR spectroscopy . Restricted rotation about the partial C–N double bond of the N-acyl derivatives was studied by dynamic NMR spectroscopy and the barriers to rotation were determined. 15N NMR data of a series of 3-alkyl[aryl]-substituted 5-trichloromethyl-1,2-dimethyl-1H-pyrazolium chlorides 56 (where the 3-substituents are H, Me, Et, n-Pr, n-Bu, n-Pent, n-Hex, (CH2)5CO2Et, CH2Br, Ph, and 4-Br-C6H4) were reported . The 15N substituent chemical shift (SCS) parameters were determined and these data were compared with the 13C SCS values and data obtained by molecular orbital (MO) calculations.

4.01.3.6

13

C and

15

N CP/MAS NMR Spectroscopy

Two desmotropes, 3-phenyl-1H-pyrazole 57 and 5-phenyl-1H-pyrazole 58, were isolated and the conditions for their interconversion were established . The X-ray structure of 58 was determined and both tautomers 59 and 60 were characterized by NMR in the solid state (13C and 15N CP/MAS). In the case of 3-phenyl-1H-indazole 59 and 5-phenyl-2H-indazole 60, two concomitant polymorphs of 59 were analyzed by X-ray crystallography, and their NMR spectral properties were determined.

The molecular and crystal structures of the hydrochloride and hydrobromide salts of 3(5)-methyl-5(3)-phenylpyrazole of 61 and 62 and the hydrobromide salt of 63 were determined by X-ray analysis and 13C CPMAS NMR methods . A structural study of pyrazole-1-carboxamides 64 was made by X-ray crystallography and 13C CPMAS NMR spectroscopy .

Pyrazoles

A study of the residual dipolar 15N and 14N coupling observed in 15N CPMAS NMR spectra at variable temperature and variable field in 1-aminopyrazoles 65 and 66 and 1-nitropyrazoles 67 and 68 has been reported . The structure of pyrazole-4-carboxylic acid 69 as a solid was obtained from high-resolution solid-state 15N CPMAS NMR, X-ray crystallography, and ab initio calculations . Using dynamic solid-state 15N CPMAS NMR spectroscopy, the kinetics of the degenerate intermolecular double and quadruple proton and deuteron transfers in the cyclic dimer of 15N-labeled polycrystalline 3,5-diphenyl-4-bromopyrazole (DPBrP) 70 and in the cyclic tetramer of 15 N-labeled polycrystalline 71 have been studied over a wide temperature range with different deuterium fractions in the mobile proton sites . Mixtures, prepared either by mechanical grinding or by evaporation of equimolar amounts of 3,5-dimethylpyrazole and five carboxylic acids, four benzoic acids, and a pyrazole-4-carboxylic acid, were studied by 13C and 15N CPMAS NMR spectroscopy . In general, most pairs behaved as physical mixtures of both components, the spectrum of the mixture being the sum of the individual spectra. The influence of a 1-adamantyl group on the structure and the proton-transfer dynamics of N-unsubstituted pyrazoles were determined; four compounds were labeled with 15N and studied by variable-temperature 15N CP/MAS NMR spectroscopy: 3(5)-(1-adamantyl)pyrazole, 4-(1-adamantyl)pyrazole, 3,5-dimethyl-4-(1-adamantyl)pyrazole, and 3,5-di(1-adamantyl)pyrazole . The X-ray structure and the solid-state NMR measurements, mainly 15N CP/MAS of the labeled compounds, allowed the determination of the static and dynamic properties of 3(5)-ethyl-5(3)-phenyl-1H-pyrazole . The compound is a tetramer formed by three 5-ethyl-3-phenyl-1H-pyrazole and one 3-ethyl-5phenyl-1H-pyrazole tautomers in dynamic equilibrium with the complementary situation.

4.01.3.7 UV and IR Spectroscopy The pyrazol-5-ones exist in three basic tautomeric forms whose relative stabilities depend on the influence of the substituents and on the medium. In the solid state, such compounds exist mainly in the OH or the NH forms with the latter predominating. As a rule, both OH and NH forms and more rarely CH tautomers are stabilized through intramolecular hydrogen-bond formation or complexation with the assistance of suitable substituents in the 3- and 4-positions, respectively. A comparative IR spectroscopic study of 3-phenyl-(DPhP)- and 3-methyl-(MPhP)-substituted 1-phenyl-pyrazol-5-ones both in solution and in the solid state was performed . It was shown that aprotic solvents stabilize the oxo (CH) tautomers 72, but in protic solvents the tautomeric equilibrium shifted to the hydroxy forms (73). A zwitterionic structure of MPhP exists in the solid, rather than the CH tautomer, DPhP. In addition, accompanying quantum-chemical calculations (at the HF level of theory and with the 6-31G** basis set) suggested that the last phenomenon is a result of a steric hindrance caused by the bulky phenyl substituent at the 3-position of the pyrazolone ring. The stereostructural characterization of 1-phenyl-3-methyl (MPhP)- and 1-phenyl3–phenyl (DPhP)-pyrazol-5-ones 74 was investigated by means of linear dichroic infrared (IR-LD) spectroscopy of samples dissolved in a nematic liquid crystal . The results thus obtained, in both cases, indicated a coplanar disposition of the 1-phenyl substituent and the pyrazole fragment; however, the benzene ring attached at the 3-position in DFP deviated significantly from the pyrazolone plane. 1-Phenyl-3-methyl-5-pyrazolone (PMP) derivatives of monosaccharides were analyzed by electrophoresis on a quartz microchip with whole-channel ultraviolet (UV) detection .

15

16

Pyrazoles

Five Schiff bases 75 derived from 4-aminoantipyrine and benzaldehyde derivatives were prepared, and their ultraviolet–visible (UV–Vis), IR, 1H NMR, and fluorescence spectra were investigated and discussed . The IR spectra of 3,5-bis(trifluoromethyl)pyrazole 76 was recorded in the gas phase (monomers) and in the solid state (tetramers) and these were analyzed by comparison with the calculated normal frequencies . Ethyl 4-formyl-1,3-dimethylpyrazole-5-carboxylate 77 showed coloration upon irradiation at 366 nm, in the solid state at room temperature . The red color disappeared on melting or dissolving in a solvent. The initiation of coloration is most likely based on a photochemical intramolecular hydrogen abstraction by the formyl oxygen from the methyl group on C-3. This compound also exhibited coloration in a 2-methyltetrahydrofuran matrix at low temperature. A series of donor-substituted 1,3,5-triaryl-2-pyrazoline fluorophores 78 were structurally characterized by X-ray analysis, and their photophysical properties studied by steady-state UV absorption and emission spectroscopy . Excitedstate intramolecular proton transfer in 2-pyridyl pyrazole (79) hydrogen–bonding systems has been investigated . The effect of nonspecific solvation on the long wavelength absorption band in the UV spectra of isomeric nitropyrazoles was studied .

Charge-transfer (CT) molecular complexes of some pyrazole donors (pyrazole, 4-methylpyrazole, 3-methylpyrazole, and 3,5-dimethylpyrazole) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tetracyanoethylene (TCNE) as p-electron acceptors have been studied in methylene chloride at 25 C by UV spectroscopy . CT complexes of some pyrazoles with iodine as a -electron acceptor and with DDQ, TCNE, and chloranil (CHL) as p-electron acceptors were also investigated spectroscopically . In both reports, the spectral characteristics and stability constants of the CT complexes formed were discussed in terms of the nature of donor and acceptor molecular structure, as well as in relation to solvent polarity. The thermodynamic parameters (H, G, and S) associated with CT complex formation were also examined. The stability of the two pyrazole tautomers monosubstituted at a C-3(5) position by various substituents was investigated by theoretical IR spectroscopy and at the MP2/6-311þþG** level . For each substituent studied, the energy difference between the two tautomers, expressed in terms of E and G, was calculated. The F and OH substituents significantly stabilized the N(2)–H tautomer, whereas CFO, COOH, and BH2 favored the N(1)–H tautomer.

4.01.3.8 Mass Spectrometry and Ion Cyclotron Resonance Studies The gas-phase reactivity of the classical ionized N- or C-methylpyrazoles and the corresponding distonic pyrazolium N-methylide ions 80 and distonic-like pyrazolium C-methylide ions 81, generated from several pyrazole derivatives, was investigated through the use of mass spectrometric techniques and a B3LYP DFT approach . Mass spectra of mono-, bis-, and tris(trimethylsilyl)pyrazoles were investigated and criteria for reliable identification of isomeric trimethylsilyl-substituted pyrazoles were formulated . The collisionally induced loss of NO2 of protonated nitropyrazoles was investigated for the possible generation of hydrogen-shift isomers of pyrazole radical cations . Ab initio calculations at the B3LYP/6-31þG(d,p) level have been used to rationalize the experimental findings. The gas-phase basicities of 3,4,5-tri-tert-butylpyrazole 82 and 1,3,4,5-tetratert-butylpyrazole 83 were measured by Fourier transform ion cyclotron resonance spectrometry . The X-ray molecular structures of both compounds were determined. A clear lack of planarity is present in the pyrazole rings because of the steric effects of the tert-butyl substituents. The Csp3 atom bonded to N-1, C-3, C-4, and C-5 atoms deviated significantly from the pyrazole plane, as expected on the basis of semi-empirical AM1 calculations. In the hydrochloride salt of 3,4,5-tri-tert-butylpyrazole, the molecules formed dimers through symmetry centers in which the chlorine atom and the water molecules play an important role.

Pyrazoles

The mass spectra of five pharmacologically interesting substituted pyrazolo[1,2-a][1,2,4]triazole hydroiodides were measured using electron impact and chemical ionizations . The nature of the matrix used in fast atom bombardment (FAB) mass spectrometry analyses of pyrazolo[1,2-a]pyrazoles was found to influence significantly their positive and negative ions mass spectra . The use of glycerol as a matrix provided an abundant ion corresponding to the protonated molecule (M þ H)þ, while meta-nitrobenzyl alcohol favored the formation of the radical ion Mþ?. A compound library consisting of 144 pyrazole carboxylic acids and six sublibraries consisting of 24 components were analyzed using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) . The structures of some new carboxamide, thiocarboxamide, nicotinoyl, and isonicotinoyl pyrazoline derivatives have been related to their mass spectra . The ions produced under electron impact showed both the characteristic pyrazoline ion and unusual azete fragmentation patterns. These results suggested that the mass spectra of these pyrazoline derivatives are both position and substituent dependent. The PMP derivatives of monosaccharides, maltooligosaccharides, and oligosaccharides enzymatically released from asparagine-linked sites in ribonuclease B and fetuin have been investigated using matrix-assisted laser desorption/ ionization time-of-flight mass spectrometry (MALDI-TOF-MS) . Derivatization using PMP was selected among a number of reported methods for labeling carbohydrates since it gives a quantitative yield, proceeds through a rapid reaction and involves a simple clean-up procedure . Moreover, PMP derivatives provided an increase in sensitivity with UV and mass spectrometric detection relative to native neutral sugars.

4.01.4 Thermodynamic Aspects 4.01.4.1 Stability and Stabilization 4.01.4.1.1

Thermochemistry

Enthalpies of 12 pyrazole species including neutral, anions, cations, and radicals have been calculated at the G3B3 level . The MP2(FC)/6-31G* energy calculation, with complete optimization geometries at restricted Hartree–Fock (RHF)/6-31G* level, was carried out on the neutral and protonated forms of C- and N-monosubstituted pyrazoles . The heats of formation (using an isodesmic reaction), the PAs, and the gas basicities (GBs), were determined for pyrazole derivatives. The results were consistent with the experimental evidence and provided a better understanding of the structures and energies for monosubstituted pyrazoles. The ab initio heats of formation of aromatic heterocycles including pyrazole and indazole were compared with calculated semi-empirical (MNDO, AM1, PM3) heats of formation .

4.01.4.2 Tautomerism 4.01.4.2.1

Annular (ring) tautomerism

There has been much interest in the study of the prototropic tautomeric equilibria of heterocyclic compounds since tautomerism influences their chemical/biological properties. The phenomenon of tautomerism is related to such important questions as aromaticity and lone pair–lone pair repulsions. Experimental studies in tautomerism are still a challenge to the theoretical studies. The annular tautomerism of pyrazoles, that is, the tautomerism involving exclusively the ring proton attached to the nitrogen, has been thoroughly studied both experimentally and theoretically . Sometimes one tautomeric form is dominant. Pyrazoles unsubstituted in the 1,2-position 84 and 85 undergo tautomerism (Equation 7). In solution, equilibrium is attained so rapidly that the existence of tautomers can only be demonstrated by means of 13C and 15N NMR spectroscopy. Other than for R ¼ CH3, the equilibrium lies to the left where the 3-substituted isomer predominates. Theoretical calculations on a wide variety of NH pyrazoles clearly show a Mills–Nixon relationship between ring strain and annular tautomerism where the most stable tautomer is that

17

18

Pyrazoles

having the largest single-bond character in the C-3–C-4 bond . To check if this geometrical dependence is related to the Mills–Nixon effect, parallel AM1 calculations on the tautomerism of -ketoaldehydes and 3(5),4-disubstituted NH pyrazoles were carried out confirming the influence of the Mills–Nixon effect on the enol/enol tautomerism of -dicarbonyl compounds . A computational study of [1,5]-sigmatropic migrations of hydrogen and related phenomena was examined for 1,2-proton shifts in pyrazoles and cyclopentadiene .

ð7Þ

Indazoles can also show tautomeric forms. MP2-6-31G** calculations on 1H- and 2H-indazole annular tautomers showed that the 1H-tautomer 86 is more stable the 2H-tautomer 87 by 3.6 kcal mol1 . This result was further confirmed by the fact that the microwave rotational constants were reproduced with great accuracy. Also, electronic spectra recorded at 80 C provided experimental evidence for the clear predominance of 1H-indazole in the gas phase. The relative stabilities, PAs, and dipole moments for the tautomeric forms of some 3-substituted indazoles were calculated with full geometry optimization using AM1, PM3, and MNDO methods in the gas phase . When the annular tautomerism is taken into account, the results of the semi-empirical AM1, PM3, and MNDO calculations confirmed that the 1H-form 88 of the studied molecules is more stable than the 2H-form 89 as stated in the previous literature.

Theoretical calculations at semi-empirical AM1 and density functional B3LYP/6–31G* levels were carried out on 52 NH-indazoles . Although in most cases the 1H-tautomer is the most stable, there were several indazoles for which the 2H-tautomer was more stable than the 1H-tautomer. The differences in energy between the 1H- and 2H-tautomers were interpreted in terms of substituent effects with the use of a Free–Wilson (presence– absence) matrix. The tautomerism of 4,5,6,7-tetrahydroindazoles, also known as tetramethylenepyrazoles, bearing a trifluoromethyl group at the 3-position were found in all cases to exist as 1H-3-CF3 tautomers . Ab initio theoretical calculations have been performed on the structure and tautomerism of pyrazole cyclic dimers, trimers, and tetramers as well as on linear oligomers . The ground state and a wide variety of transition states, corresponding to different pathways for intermolecular proton transfer, have been explored and the results compared with experimental data from crystallography and solid-state NMR spectroscopy. For the simplest case of the dimer, the reaction path corresponding to a double proton transfer has been explored as well as the effect of relaxing the geometry. DFT calculations (B3LYP/6-31þG) have been carried out on tautomers and conformers of 3(5)-substituted pyrazoles and 3-substituted indazoles (1H and 2H), bearing CO2H and CO2CH3 groups . The crystal and molecular structures of five 3(5)-amino-5(3)-arylpyrazoles differing in the nature of the substituent at the paraposition of the phenyl ring (X ¼ H, Me, OCH3, Cl, Br, and NO2) have been determined by X-ray analysis and by NMR studies in the solid and solution states . Three situations were detected in the crystal structures: the 3-tautomer was present in 90, 92, and 93; the 5-tautomer was only found in 95; and both tautomers (1:1) were observed in 94. The spin–spin coupling constant 3JH,F of the H(CF2)2 group varies within 1.6–3.5 Hz for 5-RF- and 3.8–4.5 Hz for 3-RF-pyrazoles in CDCl3 and can serve as a reliable criterion for recognition of regioisomeric

Pyrazoles

and tautomeric structures of H(CF2)2-containing heterocyclic compounds 96 and 97 . The crystal and molecular structures of eight N-unsubstituted 3-ethoxycarbonylpyrazole derivatives 98 and 99 were determined by X-ray analysis . The molecules are linked by bifurcated N–H N/O bonds, giving rise to two hydrogen-bonding motifs: catemers and tetramers that are further joined by weak interactions. Their annular tautomerism was studied by 13C NMR spectroscopy. The dipole moments of 3(5)-nitropyrazole, its methylsubstituted derivatives, and the complex of 3(5)-nitropyrazole with a dioxane molecule were measured experimentally and estimated by 6-31G* ab initio calculations . Comparison of the experimental and calculated dipole moments suggested a shift of the tautomeric equilibrium toward the 3-nitro isomer. A number of 7-substituted pyrazolo[3,4-c]pyridine derivatives were synthesized in order to investigate the N-1/N-2 tautomerism within this class of biologically interesting compounds . Tautomeric equilibria were studied using 13C and 15N NMR chemical shifts and heteronuclear 1H–15N and 1H–13C spin–spin couplings, in conjunction with X-ray crystallography. The N-1 tautomer predominated in dimethylformamide (DMF) solution in all the compounds tested.

4.01.4.2.2

Substituent (chain) tautomerism

The tautomerism of pyrazolones is an old problem of pyrazole chemistry and thus it has been the subject of a considerable number of investigations. A comprehensive theoretical study of substituted 5-pyrazolones has been presented . The tautomeric equilibrium and acidity constants of these compounds have been investigated both in the gas and aqueous solution by AM1 method. AM1/COSMO solvation method was employed in the case of aqueous solution calculations. The predicted tautomeric equilibrium constants of the compounds exhibiting the tautomeric equilibrium were in good agreement with the existing experimental data, indicating that the oxo tautomers were predominant in aqueous solution whereas the hydroxy tautomers predominated in the gas phase. Pyrazol-5-ones are widely used in medicine, color photography, analytical chemistry, and agriculture. The tautomeric equilibria between the CH, OH, and NH forms in a series of 4-substituted-1-phenyl-3-methyl-pyrazolin-5-ones 100–102 have been studied using ab initio calculations at various levels of theory and comparison made with the experimental results obtained from 13C NMR measurements . The tautomerism of 4-acyl-2-phenyl2-pyrazolidin-3-ones 103 and 104 was studied by 13C NMR spectroscopy . The tautomerism of

19

20

Pyrazoles

1-(2,4-dinitrophenyl)-3-methyl-2-pyrazolin-5-one 105 was investigated by MO calculations, solid and solution 13C CPMAS NMR studies, and X-ray crystallography . It was found that the CH tautomer was the most stable in the gas and solid states. The tautomerism of pyrazolones unsubstituted at position 3(5) has been investigated by 13C and 1H NMR spectroscopic methods . Apart from chemical-shift considerations and nuclear Overhauser effects (NOEs), the magnitude of the geminal 2J[pyrazole C(4),H3(5)] spin coupling constant permitted unambiguous differentiation between 1H-pyrazol-5-ol (OH) and 1,2-dihydro-3H-pyrazol-3-one (NH) forms. Whereas 1H-pyrazol-5-ols and 2,4-dihydro-3H-pyrazol-3-ones (CH form) exhibited 2J values of approximately 9–11 Hz, in 1,2dihydro-3H-pyrazol-3-ones this coupling constant was considerably smaller (to 4–5 Hz). This can be attributed mainly to the removal of the lone pair at pyrazole N-1 in the latter due to protonation or alkylation. The effect of hydration on the stability of tautomeric forms of 1-methyl-4,5-dihydro-1H-pyrazol-5-one 106, 1-methyl-4,5-dihydro-1H-pyrazole-5-thione 107, and 1-methyl-4,5-dihydro-1H-pyrazole-5-selenone 108 was analyzed by nonempirical quantumchemical methods at different theory levels . The results of the calculations by all these methods, including DFT with two types of model (continuum and discrete), showed stronger stabilizations of the NH tautomers of all the examined heteropyrazolones in water, when compared to their CH and XH tautomers. The relative stabilities of tautomeric forms of 3-methyl-1-phenylpyrazol-5-one and its 5-thioxo and 5-selenoxo analogs, as well as their acid/base properties in the gas phase, were estimated in terms of nonempirical calculations and DFT . According to the results of both calculation methods, the CH tautomer of 3-methyl-1-phenylpyrazol-5-one is the most stable. The stabilities of the XH and CH forms of its heteroanalogs (X ¼ S, Se) are comparable; the relative stability of the SeH (SH) tautomers increases when thermal corrections, zero-point energy, and electron correlation effects are taken into account.

The structure of acylamino derivatives of 1-(2,4,6-trichlorophenyl)-4,5-dihydropyrazol-5-one was studied by X-ray diffraction . 3-Acetylamino-1-(2,4,6-trichlorophenyl)-4,5-dihydropyrazol-5-one 109 and 3-benzoylamino-1-(2,4,6-trichlorophenyl)-4,5-dihydropyrazol-5-one 110 are present in the crystal as CH tautomers. A single crystal X-ray diffraction study showed that 1-phenyl-3-methyl-4-formyl-4,5-dihydropyrazol-5-one occurred in the solid phase as two conformers of the NH tautomer . The acidity and basicity constants of 1-phenyl3-methyl-4-formyl-4,5-dihydropyrazol-5-one 111, and its 5-thione analog, in 50% aqueous dioxane were measured. PM3 calculations qualitatively explained the differences in the tautomerism and acid-base properties of 4-formylpyrazolone (-pyrazolethione) and the corresponding compounds without the formyl substituent. The coexistence in solution of tautomeric pyrazoline forms of 1,3-alkanoylhydrazonoximes of acetylacetone has heen detected and investigated by 1H and 13C NMR spectroscopic methods . These compounds lose hydroxylamine under the action of acid catalysts forming 1-acyl-3,5-dimethylpyrazoles.

Pyrazoles

4.01.5 Reactivity of Fully Conjugated Rings 4.01.5.1 Thermal and Photochemical Reactions The photochemistry of phenyl-substituted 1-methylpyrazoles was investigated using deuterium labeling methods . The photochemical isomerization of 1,5-dimethylpyrazole and 1-methyl-5-phenylpyrazole were investigated using ab initio methods . The photochemical behavior of 1-methylpyrazole, 1,3,5trimethylpyrazole, and 1-methyl-3-cyanopyrazole were investigated using PM3-RHF-CI semi-empirical calculations . Different types of prochiral dialkyl 3,3-dialkylcyclopropene-1,2-dicarboxylates have been obtained by photochemical methods from their corresponding pyrazole-3,4-dicarboxylates and their X-ray crystallographic structures were obtained . The spectral kinetic characteristics of the triplet states of 1-(4nitrophenyl)-3-methylpyrazole and 1-ethyl-3-(4-nitrophenyl)-5-chloropyrazole were studied by the laser nanosecond photolysis technique in different solvents . 3,3-Dimethyl-3H-pyrazoles were photolyzed in the presence of 2,4,6-triphenylpyrylium tetrafluoroborate or 9,10-dicyanoanthracene as sensitizers in acetonitrile; cyclopropenes and 2H-pyrroles were obtained as solvent adducts to the 1,3-radical cation intermediate . The photochemical isomerization of pyrazoles was studied using ab initio methods. The excited singlet state could evolve to give the Dewar isomer and the corresponding triplet state . The latter showed a lower energy and probably can be obtained with higher efficiency. The triplet state could evolve to give the corresponding 1,2-biradical and, then, the isomerization product. The same behavior was noted using 1,5-dimethylpyrazole. However, 1-methyl-5-phenylpyrazole gave a different behavior. The triplet state could not evolve to give the corresponding biradical. The isomerization product can be obtained only from the Dewar isomer. Irradiation of 3,3-cyclopentyl-3H-pyrazole 112 yielded spiro[2,4]hept-l-ene 115, vinylidenecyclopentane 116, and 1-vinylcyclopentene 117 by direct intramolecular rearrangements from the excited diazoalkene 113 and by competitive formation and subsequent rearrangement of the corresponding vinylcarbene 114 (Scheme 1) .

Scheme 1

Flash vacuum pyrolysis (FVP) reactions of pyrazole itself and DPP 63 were investigated in the presence of anionic clays having a hydrotalcite structure . Solid catalysts with Mg:Al ratio equal to 2:1 containing carbonate, nitrate, and silicate as interlayer anions were employed. Between 400 and 600 C, compound 1

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Pyrazoles

remained almost unchanged and only unidentified volatile products were detected in small amounts. In contrast, 63 afforded benzonitrile 118 and phenylacetonitrile 119 by a ring-fragmentation reaction at 450 C (Scheme 2). At a higher temperature (660 C), the same products were obtained in homogeneous FVP reactions, that is, 2-phenylindene 120 and 3-phenylindene 121 were isolated. A mechanistic explanation for the thermal rearrangement of 1,19dipyrazolylmethane to 4,49-dipyrazolylmethane has been given . A novel ring expansion and novel cases of sequential 1,5-shifts were noted in the thermal rearrangements of 3,3-spiro-(cyclopentyl)pyrazole containing electron-withdrawing ester groups .

Scheme 2

4.01.5.2 Electrophilic Attack at Nitrogen 4.01.5.2.1

Proton acids on neutral compounds

The effects produced on 1H, 13C, and 15N chemical shifts by protonation and by hydrogen-bonding solvents on pyrazole, 3,5-dimethylpyrazole, and 4,5-dihydro-3-methyl-2H-benz[g]indazole have been determined experimentally . Phase effects on the 13C chemical shifts of the C-4 atom of pyrazole were discussed based both on empirical models and on GIAO calculations of absolute shieldings in different complexes. The special case of the chemical shifts of pyrazoles in the solid state, where they form multiple N–H N hydrogen bonds, has also been studied. The diiodine basicity (a soft Lewis basicity) of pyrazoles and indazole was measured by means of the formation constant of the diiodine–azole complexes in heptane at 298 K . The preferred sites of diiodine fixation were the N-2 nitrogens in pyrazoles and indazole. The double-proton-transfer reactions between carboxylic acids and pyrazole were studied by computational methods up to the coupled-cluster level and the double-proton-transfer reactions between some substituted pyrazoles and guanidine were studied by ab initio calculations up to the CCSD(T) level . Protonated 3- and 4-nitropyrazoles were subjected to collisional activation and neutralization– reionization mass spectrometric studies using a large-scale tandem mass spectrometer . These and other neutral and protonated molecules were studied by ab initio methods up to and including the CCSD(T)/6-31þG* level. This information was used to assess the site of protonation of 3-nitro- and 4-nitropyrazoles in the gas phase: at equilibrium, these compounds were protonated on the ring nitrogen rather than on the oxygen of the nitro group. The basicity of simple 4,5-dihydropyrazoles (2-pyrazolines) has been discussed on the basis of protonation at N-1 in the case of 1-unsubstituted, 1-methyl, and 1-phenyl derivatives . The pKa values of 15 4,5dihydropyrazoles substituted at N-1 by p-nitrophenyl, 2,4-dinitrophenyl, and 2,4,6-trinitrophenyl groups were determined. After examining some linear free energy relationships, to discuss these pKa values further, DFT calculations, including temperature effects, were carried out on the parent compounds (no C-substituents) for the 1-unsubstituted, 1-methyl, 1-phenyl, 1-p-nitrophenyl, and 1-(2,4,6-trinitrophenyl) series. These calculations predicted an inversion of N-1 and N-2 basicities between 1-phenyl- and 1-( p-nitrophenyl)-4,5-dihydropyrazoles. Since there were no experimental data for the protonation of 4,5-dihydropyrazoles in the gas phase, chemical ionization mass spectrometry was used to try to determine the structure of protonated 1-methyl- and 1,3-dimethyl-5-phenyl-4,5-dihydropyrazoles. The substituent effects and protonation sites of 1-phenyl-3-methyl-5-N-benzylideneaminopyrazoles were studied by NMR and ab initio (6-31G* ) MO calculations .

Pyrazoles

4.01.5.2.2 4.01.5.2.2.(i)

Metal ions Simple complexes

4.01.5.2.2(i)(a) Chromium, molybdenum, and tungsten complexes

A series of carbonylchromium, -molybdenum, and -tungsten complexes containing ferrocenylpyrazole ligands, (M(CO)5L) (M ¼ Cr, Mo, or W; L represents ferrocenylpyrazole), have been prepared by the photochemical reactions of ferrocenylpyrazole ligands with M(CO)6 . A series of carbonylchromium and -tungsten complexes containing substituted pyrazole ligands, (M(CO)5L), have been synthesized by the photochemical reactions of substituted pyrazoles with M(CO)5L (M ¼ Cr or W) . Dioxomolybdenum and -tungsten compounds containing sterically demanding pyrazolate ligands have been synthesized by treatment of dioxometal halides with the potassium salts of 3,5-di-tert-butylpyrazole (t-Bu2pzH) and 3,5-di-tert-butyl-4-bromopyrazole (t-Bu2-4-BrpzH). The products [MoO2Cl(2-t-Bu2pz)], [MoO2(2-t-Bu2pz)2], [MoO2(2-t-Bu2-4-Brpz)2], [WO2(2-t-Bu2pz)2], and [WO2(2-tBu2-4-Brpz)2] were characterized by spectroscopic techniques . Michael addition of substituted pyrazoles to 1-alkynyl Fischer carbene complexes (CO)5MTC(OEt)(CUCPh) (M ¼ Cr, W) afforded (pyrazolyl)alkenyl Fischer carbene complexes (CO)5MTC(OEt)(CHTC(R1R2R3pz)Ph) (R1R2R3pz ¼ pyrazolyl; M ¼ Cr, W), with an exclusive (E)-configuration, in moderate to excellent yields . 4.01.5.2.2(i)(b) Cobalt complexes

A review covers the recent advances in the chemistry of cobalt–dioxygen and related complexes supported by hydrotris(pyrazolyl)borate ligands (Tp) . Cobalt(III) complexes, of two pyrazole-derived bidentate ligands (with one ambidentate donor site), 3,5-dimethyl-1-(N-methyl/ethyl)thiocarbamylpyrazole (HL1 for N-methyl, HL2 for N-ethyl), have been synthesized and characterized . Potentiometric, spectrometric, thermal, and conductimetric studies on some 3-phenyl-4-(arylazo)-5-pyrazolones and their complexes with divalent cobalt metal ion were investigated . The coordinating properties of the ligand 5-methyl-3-formylpyrazole 3-hexamethyleneiminyl thiosemicarbazone (HMPz3Hex) in cobalt(III) complexes, [Co(MPz3Hex)2]X?nH2O (X ¼ Cl, Br, NO3, ClO4 or BF4; n ¼ 1 to 2), have been characterized by spectroscopic and X-ray structural techniques . The coordination behavior of the novel ligand, HMPz4Cy, has been reported, together with the isolation of its diamagnetic cobalt(III) complexes, [Co(MPz4Cy)2]X?nH2O (X ¼ Cl, Br, NO3, ClO4, and BF4) in the solid state . 4.01.5.2.2(i)(c) Copper complexes

A dodecanuclear copper(II) cage containing phosphonate and 3,5-dimethylpyrazole ligands has been reported . The copper(II) complexes [(3-AMP)(3-Ac-AMP)Cu](ClO4)2 and [(3-Ac-AMP)Cu](ClO4)2 were obtained by the reactions of Cu(ClO4)2, with 3-amino-5-methylpyrazole (3-AMP) and 3-acetamido-5-methylpyrazole (3-Ac-AMP), respectively, in acetonitrile . Reaction of Cu(O2CMe)2?H2O with HL1 [3-(2-pyridyl)pyrazole] or HL2 [6-(3-pyrazolyl)-2,29-bipyridine] and NH4PF6 followed by crystallization of the crude products from DMF–ether afforded [Cu4L16(DMF)2][PF6]2 and [Cu4L24(DMF)4][PF6]4, respectively, in which the deprotonated pyrazolyl groups act as bridging ligands and the 2 2 grid-like architectures are a result of the preference of the Cu(II) ions for elongated square pyramidal coordination geometries . Reaction of CuX2 (X ¼ Cl, Br, NO3), sodium hydroxide, and 3(5)-tert-butylpyrazole (HpzBut) in a 1:1:2 molar ratio in methanol at 293 K for 3 days afforded [{Cu3(HpzBut)6(3-X)(3-OH)3}2Cu]X6 (X ¼ Cl, Br, NO3), in moderate yields . Trinuclear Cu(II)-pyrazolates of the general formula (Bu4N)2[Cu3(3-Cl)2(-4-R-pz)3Cl3] (pz ¼ pyrazolato anion; R ¼ Cl, Br, I, Me) have been prepared and characterized by spectroscopic and X-ray diffraction methods . The synthesis, crystal structure, and properties of three copper(II) complexes with different axial ligands and substituted pyrazoles [Cu(pzR)4(X)2] (X ¼ Cl and R ¼ Bun; X ¼ ClO4 and R ¼ Bun; pzR ¼ 3-substituted pyrazole) have been reported . The synthesis, characterization, and crystal structures of 3,5-bis(4butoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazole and 3,5-bis(4-phenoxyphenyl)-1-(pyridin-2-yl)-1H-pyrazole and a study of their coordination behavior toward Cu(I) and Cu(II) were investigated . The preparation and crystal structure determination of adducts of copper(II) chloride with 3-aryl-1-(imino-pyridin-2-ylmethyl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles have been reported . Electron spin densities of pyrazolato-bridged complexes [Cu(pz)2]n and [Cu2(pz)2(NO3)(H2O)(phen)2]NO3 (Hpz ¼ pyrazole; phen ¼ 1,10-phenanthroline) were elucidated by solid-state high-resolution NMR to elucidate the magnetic interaction paths with the help of molecular orbital theory . The compound [Cu2Cl9H20N6O7Cl]2 is a copper(II) complex, in which each bicationic moiety is bridged by two pyrazolate ligands . The structures and characterization of reaction products of [Cu(hfac)2] (hfac ¼ 1,1,1,5,5,5,-hexafluoropentane-2,4-dionato) with 3-methyl- and 3,5-dimethyl-1H-pyrazoles have

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Pyrazoles

been published . The synthesis, structure, and properties of {N,N9-bis[2-(1-pyrazolyl)ethyl]pyridine2,6-dicarboxamido}copper(II) have been reported . The synthesis and characterization of the copper complexes with the ligand Hbpzbiap (1,5-bis(1-pyrazolyl)-3-[bis(2-imidazolyl)methyl]azapentane) and its dehydrated form have been described . Reaction between 4-methyl-2,6-bis(pyrazol-1-ylmethyl)phenol (HL1) or its 3,5-dimethylpyrazole derivative (HL2) and Cu(ClO4)2?6H2O afforded [CuII2(L1/L2)2(OClO3)2] . The synthesis and coordination chemistry of the tetradentate ligands 6,69-bis(3-pyrazolyl)-2,29-bipyridine in complexes of Cu(II) have been described . Using a bidentate heterocyclic ligand with a mixed hard–soft nitrogen donor set (L ¼ 2-(3,5-dimethylpyrazol-1-ylmethyl)pyridine), two types of copper(II) complexes were synthesized and characterized: (1) [Cu(L)2][ClO4]2?H2O and (2) [Cu(L)2X][ClO4] (X ¼ Cl, NCS, and N3) . The reaction of copper(I) oxide and the fluorinated pyrazoles [3-(CF3)Pz]H, [3-(CF3)-5-(Me)Pz]H, and [3-(CF3)-5-(Ph)Pz]H led to the corresponding trinuclear copper(I) pyrazolates, {[3-(CF3)Pz]Cu}3, {[3-(CF3)-5-(Me)Pz]Cu}3, and {[3-(CF3)-5(Ph)Pz]Cu}3, respectively, in high yields . 4.01.5.2.2(i)(d) Gold/silver complexes

New Au(I)/Ag(I) complexes containing one or two substituted pyrazole ligands [Au(Hpzbp2)(PPh3)](p-CH3C6H4SO3) (Hpzbp2 ¼ 3,5-bis(4-n-butoxyphenyl)pyrazole) and [M(HpzR2)2]nX (HpzR2 ¼ Hpzbp2, M ¼ Au, n ¼ 1, X ¼ pCH3C6H4SO3, NO3; n ¼ 2, X ¼ 1,5-naphthalenedisulfonate (1,5-nds); HpzR2 ¼ Hpzbp2, M ¼ Ag, n ¼ 1, X ¼ BF4, CF3SO3; HpzR2 ¼ HpzNO2 (3,5-dimethyl-4-nitropyrazole), M ¼ Ag, n ¼ 1, X ¼ BF4, CF3SO3], have been prepared and characterized . Trimeric Ag(I) adducts of 3,5-di(isopropyl)pyrazole, 3,5-di(isopropyl)-4-bromopyrazole, and 3,5-di(isopropyl)-4-nitropyrazole have been synthesized by reacting the corresponding pyrazoles with silver(I) oxide . Multinuclear NMR solution studies on complexes of hexakis(pyrazol-1yl)benzene (hpzb) with Ag(I) were explored . The syntheses, spectroscopic, and structural characterization of silver(I) complexes containing tris(isobutyl)phosphine and poly(azol-1-yl)borates have been reported . 4.01.5.2.2(i)(e) Iridium complexes

Reactions of the cationic complex [(5-C5Me5)2Ir2(2-H)3]þ with pyrazole and 4-methypyrazole in aqueous solution gave bispyrazolo complexes . The synthesis of binuclear cyclopentadienyl Ir(III) pyrazolylbridged complexes and their rhodium analogs have been investigated . A series of heteroleptic Ir(III) metal complexes bearing N-phenylpyrazole ligands 1-(2,4-difluorophenyl)pyrazole (dfpzH), 1-(4-fluorophenyl)-pyrazole (fpzH), 1-(2,4-difluorophenyl)-3,5-dimethylpyrazole (dfmpzH), and 1-(4-fluorophenyl)-3,5-dimethylpyrazole (fmpzH) were synthesized and were shown to display blue phosphorescence in solution and solid states at room temperature . Various iridium complexes consisting of phenylpyrazole (ppz) ligands as ancillary ligands were designed by energy band-gap calculations via ab initio calculations and synthesized to give rise to various emission wavelengths . 4.01.5.2.2(i)(f) Iron/nickel complexes

The bidentate coordination of pyrazolates in low-coordinate iron(II) and nickel(II) complexes has been investigated . Very stable complexes of general formula [FeCp(CO)xPh2P(Me2Pz)]BF4, where x ¼ 1, 2, were prepared by room temperature reaction of the 3,5-dimethylpyrazolylphosphine ligand with [Fe2(CO)2(C5H5)2] . The synthesis and structural studies of dimetallic and trimetallic cyclopentadienyl nickel pyrazolates has been reported . A variety of stereorigid ansa-ferrocenes with o-phenylene-type bridges have been obtained by the reaction of 1,19-diborylferrocenes (1,19-Fc(BBrR)2; Fc ¼ ferrocenyl; R ¼ CH3, Br, OEt, NC4H8) with selected pyrazole derivatives . A number of iron(II) compounds containing the poly(1-pyrazolyl)methane ligands bis(1-pyrazolyl)methane (BPM), bis(3,5-dimethyl-1-pyrazolyl)methane (dmBPM), and tris(1-pyrazolyl)methane (TPM) were synthesized and characterized: cis-[Fe(BPM)2Cl2], trans-[Fe(BPM)2(NCS)2], [Fe(BPM)2Cl]þ(BPh4), [Fe(dmBPM)2Cl2] (Ph4B), [Fe(dmBPM)2Cl]þ(BPh4), [Fe(TPM)2]2þ(Cl)2, and [Fe(TPM)(NCS)2] . 4.01.5.2.2(i)(g) Lead/tin complexes

The synthesis, spectroscopic, and X-ray structural characterization of tin(II) and lead(II) 4-acyl-5-pyrazolonates have been reported . New organotin(IV) derivatives containing the anionic ligand bis(3,5-dimethylpyrazolyl)dithioacetate [L2CS2] have been synthesized by reaction of SnRnX4n (R ¼ Me, Ph, Bun, or Cy; n ¼ 1–3) acceptors and Li[L2CS2] . Novel heteroscorpionate-containing tin and organotin(IV) complexes, [SnRnX3n(L)] (R ¼ Me, Bun, Ph, or cy; X ¼ Cl, Br, or I, n ¼ 0–3; L ¼ bis(pyrazol-1-yl)acetate (bpza) or bis(3,5-dimethylpyrazol-1yl)acetate (bdmpza)), have been synthesized and characterized by spectroscopic methods . Tin(IV) and organotin(IV) compounds containing tetrakis(4-methyl-1H-pyrazol-l-yl)borate (pzTp4Me),

Pyrazoles

RnSnCl94n1?pzTp4Me (4Me ¼ tetrakis(4-methyl-1H-pyrazol-1-yl)borate; R ¼ Me or Ph; n ¼ 0–2) have been synthesized and characterized by 1H, 13C, 119Sn NMR and 119Sn Mossbauer spectroscopies . The reaction of diphenyltin(IV) dichloride with pyrazole (HPz) afforded [SnPh2Cl2(HPz)2] . 4.01.5.2.2(i)(h) Mercury/zinc/cadmium complexes

The synthesis as well as the structural and vibrational characterization of the HgL2Cl2 complex (L ¼ 3,5-dimethyl-1thiocarboxamide) have been reported . New metal chelates of Zn(II) and Cd(II) (ML2) based on (4Z)-3-methyl-1-phenyl-5-thioxo-1,5-dihydro-4H-pyrazol-4-one quinolin-8-ylhydrazone (HL1) and (4Z)-5-methyl-2phenyl-4-[(quinolin-8-ylimino)methyl]-2,4-dihydro-3H-pyrazole-3-thione (HL2) were synthesized . 4.01.5.2.2(i)(i) Palladium and platinum complexes

Palladium and platinum polyfluorophenyl complexes were prepared with these N-donor chelate ligands: bis(pyrazol-1yl)(anisol-2-yl)methane (bpzmArOMe), bis(3,5-dimethylpyrazol-1-yl)hydrocarbylmethane (bpz* mArOMe), cyclohexyl (bpz* mCy), bis(3,5-dimethylpyrazol-1-yl)ferrocenylmethane (bpz* mFec), bis(pyrazol-1-yl)(2-hydroxyphenyl)methane (bpzmArOH), bis(3,5-dimethylpyrazol-1-yl)(phenol-2-yl)methane (bpz* mArOH), 2-(pyrazol-1-yl)pyridine (pzpy), and 2-(pyrazol-1-yl)pyrimidine (pzpm) . Novel pyrazoles containing 3-[4-n-hexyloxyphenyl] (hp), 3-[4-n-octyloxyphenyl] (op), and 3-[4-n-decyloxyphenyl] (dp) substituents, HpzR (R ¼ hp, op, dp), and their corresponding Rh(I) compounds [Rh(Cl)(LL)(HpzR)] (LL ¼ 2,5-norbornadiene (NBD), 1,5-cyclooctadiene (COD), 2CO; R ¼ hp, op, dp) have been prepared and characterized . Protonation reactions of [Pt(DPPE)(pz-N)2] carried out either with HBF4(aq.) or with [18-crown-6?H3O][BF4] afforded the new pyrazole adduct [Pt(DPPE)(Hpz-N)2][BF4]2 characterized by analytical, IR, and multinuclear NMR data (DPPE ¼ bis(diphenylphosphino)ethane) . A new family of linear Pd(II) complexes based on pyrazoles containing long-chain substituents at C-3 has been prepared and their mesomorphic properties studied . Treatment of the ligands 1-(3-thia-5-hydroxypentyl)-3,5-dimethylpyrazole (thpd) and 1-(3-thia-6hydroxyhexyl)-3,5-dimethylpyrazole (thhd) with [PdCl2(CH3CN)2], [PtCl2(CH3CN)2], and NiCl2?6H2O produced the complexes [MCl2(L)] (M ¼ Pd, L ¼ thpd, thhd; M ¼ Pt, L ¼ thpd, thhd; M ¼ Ni, L ¼ thpd, thhd), which were characterized by elemental analyses, conductivity, IR, electronic spectra, and NMR spectroscopy . The mesomorphic properties of Pd(II) complexes of new long-chain 3,5-(4-n-alkoxyphenyl)pyrazoles HpzR2 (R ¼ C6H4OCnH2nþ1; n ¼ 4, 6, 8, 10, 12, 14) of the formula [Pd(3-C3H5)(-pzR2)]2 have been studied . Novel cationic 3-allylpalladium-pyridinylpyrazole complexes were synthesized from 3-alkyl5-(2-pyridinyl)pyrazole and 3-allylpalladium chloride dimer in the presence of silver tetrafluoroborate . The ligands 4,6-bis(pyrazol-1-yl)pyrimidine (bpzpm) and 4,6-bis(4-methylpyrazol-1-yl)pyrimidine (Me-bpzpm) were synthesized and their reactions with some palladium derivatives explored . The structure and conformational analysis of eight complexes derived from hexakis(pyrazol-1-yl)benzene (hpzb) with Pd(II), Pt(II), and Cu(I) metals have been carried out by means of X-ray crystallography and NMR spectroscopy . Treatment of the ligands 1,6-bis(3,5-dimethyl-1-pyrazolyl)-2,5-dithiahexane (bddh), 1,7-bis(3,5dimethyl-1-pyrazolyl)-2,6-dithiaheptane (bddhp), 1,8-bis(3,5-dimethyl-1-pyrazolyl)-3,6-dithiaoctane (bddo), and 1,9bis(3,5-dimethyl-1-pyrazolyl)-3,7-dithianonane (bddn) with [PdCl2(CH3CN)2] produces [PdCl2(L)] or [Pd2Cl4(L)] complexes, depending on the stoichiometry . The synthesis of Pd(II) complexes containing a thioether-pyrazole hemilabile ligand along with a structural analysis by 1H and 13C NMR spectroscopy and the crystal structure of [PdCl(bdtp)]BF4 (bdtp ¼ 1,5-bis(3,5-dimethyl-1-pyrazolyl)-3-thiapentane) have been reported . The stereochemically nonrigid motions and structural characteristics of (3-2-methallyl){tetrakis(3-t-butylpyrazolyl)borato}palladium(II) were investigated by variable-temperature 1H NMR spectroscopy . Tri(allyl)- and tri(methylallyl)arsine complexes of palladium(II) and platinum(II) with the formulas [MX2L2] (M ¼ Pd, Pt; X ¼ Cl, Br, I) such as [Pd2Cl2(m-Cl)2L2], [PdCl(S2CNEt2)L], and [Pd2Cl2(-dmpz)2L2] (L ¼ As(CH2CHTCH2)3 (L9), As(CH2CMeTCH2)3 (L0); dmpz ¼ 3,5-dimethylpyrazolate) have been prepared, characterized, and their photochemistry explored . Mononuclear palladium(II) complexes containing both pyrazole-type ligands and thiocyanate, of general formula [Pd(SCN)2(L)2] (L ¼ pyrazole (HPz) and 1-phenyl-3-methylpyrazole (phmPz)) have been prepared and characterized by spectroscopic and by single crystal X-ray diffraction methods . Detailed crystallographic and NMR measurements are reported for several Pd(II) allyl complexes containing chiral ferrocene-based phosphinopyrazole ligands . MePdCl[3-methyl-5-(2-pyridinyl)pyrazole], PdCl2[3-methyl-5-(2-pyridinyl)pyrazole], and bis{MePd[3-methyl-5-(2pyridinyl)pyrazole]} were synthesized, and structural assignment was performed by 1H, 13C, and 15N NMR spectroscopy . New cationic 2-Me-allylpalladium complexes were prepared with the N,N-donor chelate ligands bis(pyrazol-1-yl)(R)methane (R ¼ anisol-2-yl, bpzmArOMe; 2-hydroxyphenyl, bpzmArOH) and

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Pyrazoles

bis(3,5-dimethylpyrazol-1-yl)(R)methane (R ¼ anisol-2-yl, bpz* mArOMe; cyclohexyl, bpz* mCy; and ferrocenyl, bpz* mFc) . Pyrazoles (dimethyl 2-methyl-4-oxo-4H-chromen-3-yl-phosphonate and methyl 4-oxo-2-methyl-4H-chromene-3-carboxylate) were used as ligands (L) in the formation of ML2Cl2 complexes with platinum(II) or palladium(II) metal ions (M) . Palladium(II) complexes with bis(pyrazol-1-yl)alkanes have been synthesized . The characterization of dinuclear pyrazolato-bridged Pd(II) complexes, [{Pd(-dmpz)Cl(Hdmpz)}2] and [{Pd(-dmpz)(dmpz)(Hdmpz)}2] (Hdmpz ¼ dimethylpyrazole), has been reported . The cytotoxic, pyrazolato-bridged dinuclear platinum(II) complex [(cis-{Pt(NH3})2(-OH)(-pz)]2þ (pz ¼ pyrazolate) has been found to cross-link two adjacent guanines of a double-stranded DNA decamer without destabilizing the duplex and without changing the directionality of the helix axis . 4.01.5.2.2(i)(j) Rhenium complexes

The first mononuclear Re(V) complexes with four pyrazole ligands, [Re(O)(OMe)L4]Br2 (L ¼ 3,5-dimethylpyrazole) and [Re(O)(OMe)L4]Br2?L?4H2O, were synthesized . The structures of these adducts were established by X-ray diffraction analysis. New receptors fac-[Re(CO)3(pz)3]BAr94 (pz ¼ 3,5-dimethylpyrazole or 3(5)-tertbutylpyrazole; Ar9 ¼ 3,5-(CF3)2C6H3), synthesized from [Re(OTf)(CO)5] and the pyrazoles, have been found to show a high affinity for chloride . The behavior of the receptors [Re(CO)3(Hdmpz)3]BAr94 (Hdmpz ¼ 3,5dimethylpyrazole) and [Re(CO)3(HtBupz)3]BAr94 (HtBupz ¼ 3(5)-tert-butylpyrazole; Ar9 ¼ 3,5-bis(trifluoromethyl)phenyl) toward the anions fluoride, chloride, bromide, iodide, hydrogen sulfate, dihydrogen phosphate, nitrate, and perrhenate was studied in CD3CN solution . Mono- and dinuclear Re(IV) and Re(V) complexes with 3,5-dimethylpyrazole (Me2pzH) were synthesized . The cis-[Re2O3Cl4(3,5-Me2pzH)4] complex was prepared by the reaction of NH4ReO4 with K[HB(Me2pz)3] in concentrated HCl or by refluxing of [ReCl3(MeCN)(PPh3)2] with Me2pzH in air. The pyrazolate-bridged complex [Re2O3Cl2(-3,5-Me2pz)2(3,5Me2pzH)2] was prepared from (Et4N)2[ReOCl5] or Cs2[ReOCl5] and Me2pzH. The synthesis and UV properties of rhenium carbonyl complexes of ,9-bis[(1-pyrenyl)pyrazol-1-yl]alkane ligands were explored . 4.01.5.2.2(i)(k) Rhodium complexes

Novel pyrazoles containing hp, op, and dp substituents, HpzR (R ¼ hp, op, dp), and their corresponding Rh(I) compounds [Rh(Cl)(LL)(HpzR)] (LL ¼ NBD, COD, 2CO; R ¼ hp, op, dp) have been prepared and characterized . 3,5-Disubstituted pyrazoles HpzR2 containing long-chain 4-n-alkyloxyphenyl substituents (R ¼ C6H4OCnH2nþ1; n ¼ 4, 6, 12, 14) have been prepared and were used as ligands toward [RhCl(CO)2] and [Rh(CO)2] . The tris(pyrazolyl)amine ligands such as tris[2-(1-pyrazolyl)methyl]amine (tpma), tris[(3,5-dimethyl-1-pyrazolyl)methyl]amine (tdma), tris[2-(1-pyrazolyl)ethyl]amine (tpea), tris[2-(3,5dimethyl-1-pyrazolyl)ethyl]amine (tdea), and bis(pyrazolyl)amine ligands such as bis[2-(1-pyrazolyl)ethyl]amine (bpea) and bis[2-(3,5-dimethyl-1-pyrazolyl)ethyl]amine (bdea) reacted with [RhCl(COD)]2 in presence of NaBF4 (tpma, tdma, and bdea) or AgBF4 (tpea, tdea, and bpea) to lead to [Rh(COD)L] (BF4) (L ¼ tpma, tdma, bdea, tpea, tdea, and bpea) . Rh(I) compounds [Rh2Cl2(COD)2L] (L ¼ tpma, tpea, tdea, bpea, and bdea) and [Rh3Cl3(COD)3tdma] were prepared and characterized by spectroscopic and conductivity experiments . The bidentate N,N-ligands 1-[2-(ethylamino)ethyl]-3,5-dimethylpyrazole (L1) and 1-[2(diphenylphosphanyl)ethyl]-3,5-dimethylpyrazole (L2) reacted with [Rh(COD)(L1)(THF)2][BF4] to give [Rh(COD)][BF4] and [Rh(COD)(L2)][BF4], respectively (THF ¼ tetrahydrofuran) . 4.01.5.2.2(i)(l) Ruthenium/osmium complexes

Ruthenium complexes containing the dihydridobis(3,5-bis(trifluoromethyl)pyrazolyl)borate ligand Bp(Cf3)2 have been prepared and structurally characterized (Bp ¼ dihydridobis(pyrazolyl)borate ligands) . The synthesis and X-ray crystal structures of several dinuclear ruthenium cymene complexes based on the tetradentate ligand, 2,29(1H-pyrazole-3,5-diyl)bis(6-methylpyridine) (Me2dppzH), has been reported . The tetradentate ligands, 2,29-(1H-pyrazole-3,5-diyl)bis(4-methylpyridine) (4,49-Me2dppzH), 2,29-(1H-pyrazole-3,5-diyl)bis(6-methylpyridine) (6,69-Me2dppzH), 3,5-di(pyrid-2-yl)pyrazole (dppzH), and dipyridyloxadiazole (dpo), reacted with either Ru(trpy)Cl3 or trans-Ru(trpy)Cl2(NCCH3), where trpy is 2,29,20-terpyridine, to form a variety of Ru(II) complexes . The reactions of RuCl2[P(C6H5)3]3, RuCl2(TMEDA)2, and RuCl2(1,5-COD)(TMEDA) with polybasic amines such as pyrazole have been studied (TMEDA ¼ tetramethylethylenediamine) . The synthesis and structural studies of cationic bis- and tris(pyrazol-1-yl)methane acyl and methyl complexes of ruthenium(II) have been published . Mononuclear and binuclear ruthenium(II) complexes containing pyrazole-3,5bis(benzimidazole) have been prepared and characterized by spectroscopy and their proton-coupled redox activity investigated . The complex [RuII(dcbpyH2)(bdmpp)NCS](PF6) (dcbpyH2 ¼ 2,29-bipyridine-4,49-

Pyrazoles

dicarboxylic acid; bdmpp ¼ 2,6-bis(3,5-dimethyl-N-pyrazoyl)pyridine) has been synthesized and characterized by 1H and 13C NMR, mass spectrometry, cyclic voltammetry, and UV and IR spectroscopy . 4.01.5.2.2(i)(m) Sodium/potassium complexes

The first structurally documented 2-pyrazolato coordination by a main group metal such as potassium has been synthesized and its reactivity explored . Sodium and potassium tetrakis(3,5-di-tert-butylpyrazolato)lanthanoidate(III) complexes [M{Ln(t-Bu2pz)4}] were prepared by reaction of anhydrous lanthanoid trihalides with alkali metal 3,5-di-tertbutylpyrazolates at 200–300 C, and a 1,2,4,5-tetramethylbenzene flux for M ¼ K . The syntheses and solid-state structures of tris(pyrazolyl)methane complexes of sodium, potassium, calcium and strontium and a comparison of their structures with analogous complexes of lead(II) have been reported . 4.01.5.2.2(i)(n) Titanium/zirconium/hafnium complexes

Twenty 4-acyl-5-pyrazolonato titanium derivatives of varied nuclearity have been synthesized from Ti(OR)4 or TiCl4 and their oligomerization, hydrolysis, voltammetry, and DFT properties were investigated . Complexes of titanium tetrachloride with 3,5-di-tert-butylpyrazole, 3(5)-methylpyrazole, 4-bromopyrazole, and 4-iodopyrazole led to the corresponding TiCl4L2 binary adducts . Zirconium and hafnium complexes containing four 3,5-dimethylpyrazole, 3,5-di-tert-butylpyrazole, or DPP ligands (2-pyrazolato ligands) have been synthesized and their physical properties investigated .

4.01.5.2.2(ii) Polypyrazolylborates Poly(1-pyrazolyl)borates (‘scorpionates’) are well-established, versatile, and easily accessible ligands in coordination chemistry, which have found widespread applications ranging from analytical chemistry to homogeneous catalysis and materials science . Table 5 shows many of the polypyrazolylborate complexes with different metals published in the last decade. Table 5 Coordination chemistry of polypyrazolylborates Metal

Ligand

Content

References

Ba, Ca, Sr Ca Cr, V, Fe, Co, Ni Co(II)

Tp* Tpi Tp

Barium/calcium and strontium complexes Calcium 2-ligand complexes Mixed-sandwich Cp complexes/electronic and magnetic properties Cobalt complexes

1996POL3453 2000IC2377 2003IC4366

Co(II)

Tp, Tpii, Tpiv, Tpv Tpii Tp Tp* Tp Tpiii, Tpv Tpv Tp Tpvi, Tpvii Tp Tp Tpviii Tp Tp Tp* Tpix

Cobalt/copper complexes Cobalt triamine complexes Cu(I) chemistry of bis(dipyrazole)-diphenylborate ligands Fluorinated complexes Fluorinated copper/silver complexes Sodium/copper(I) perfluoro complexes Carbene-transfer kinetics Copper complexes Indium complexes Iridium/rhodium ethylene triphenylphospine complexes Iridium hydride complexes Cubane-type iron clusters Bis(pyrazolyl-1-yl)ferrocene complexes Tetrafluoroborate complexes 3-, 5-, 6-, and -binding metal modes

2001POL2551, 2002EJI754 2003EJI89, 2003EJI2475 2002POL2743 1997POL4087 2001IC165 2001IC667 1996IC2317 1996OM5374 1999OM2601 2000JCD133 1999MRC867 1997OM467 1999JA346 2002IC958 2005JOM(690)1971 2001IC1508 2006CC1872

Tp Tp Tp* Tpx

Oxo-bridged dimanganese complexes Carbon nucleophilic additions Dioxomolybdenum complexes Molybdenum oxo hydrolase model

1998IC3714 1998TL6273 1999JA10035 2000JA2946

Co(II), Cu(II) Co(III) Cu(I) Cu/K Cu(I), Ag(I) Cu(I)/Na(I) Cu(II) Cu(II) In Ir, Rh Ir(IV) Fe/Mo/V Fe Fe(II) Li, Na, K, Tl, Ca Mn(II) Mo Mo(IV) Mo(IV)

Tp*

Cobalt complexes

(Continued)

27

28

Pyrazoles

Table 5 (Continued) Metal

Ligand

Content

References

Mo(VI) Nd, Y Ni(II) K K/Li Os(II) Os(III) Os(V), Re(V) Re Re Re Rh(I) Rh(I) Rh(I) Ru(I) Ru Ru Ru Ru, Os Ru Ru Ti/Zr Ti Tl Tl(I) Tl W W Zn Zn

Tp, Tp* Tp Tp/Tpxiv Tpxi, Tpxii Tp Tp Tp Tp, Tp* Tp Tp Tp Tp* Tp Tp* Tp Tp Tp Tp Tp Tp Tp Tp, Tp* Tp/Tp* Tp Tp Tp Tp* Tp* Tpii Tpxiii

Molybdenum dioxo complexes Ytterium/neodymium halide complexes Organometallic complexes Potassium complexes Bitopic ligands Osmium trinitrosyl complexes Osmium chloro complexes/redox chemistry Rhenium/osmium oxo, amido, nitride complexes Rhenium carbonyl 2-aromatic complexes Rhenium bipyridyl complexes Olefin/carbonyl complexes Photochemistry of rhodium complexes Rhodium dicarbonyl complexes Complexes with CO2 or COD Ruthenium chelating complexes Ruthenium silane complexes Organometallic complexes Alloxy(carbene) complexes Ruthenium/osmium complexes Ruthenium amido complexes Ruthenium hydride/dihydrogen complexes Amido complexes Photochemistry Chemical shift anistropy Tl(I) complexes–review Multinuclear solid/solution studies Alkyne redox pair bonding cis-Oxothio/bis(thio) complexes Zinc alkoxide complexes Carbonic anhydrase

2001JCD1332 2000IC4476 1998JOM(551)215 1997IC5589 2004OM2107 1999IC3329 1999POL1587 1999JOM(591)96 1999JA6499 2000IC6127 2001OM3876 1999HCA1454 2002ICA268 2003OM1072 1999M363 1999OM2484 1998OM4249 1999OM2275 1999OM1504 2001IC6481 2005OM3088 2003IC3008 2005JOM(690)2071 1998JA10416 1998MGMC33 2004JOM(689)463 1999CC2403 2001IC4563 2004IC6054 2003JA3768

Tp ¼ HB(pz)3, Tp* ¼ HB(3,5-Mepz)3, Tpi ¼ HB(3,5-But), Tpii ¼ HB(3-Ph, 5-Mepz), Tpiii ¼ HB(3-CF3), Tpiv ¼ HB(3,5-Ph), Tpv ¼ HB(3-C2F5), Tpvi ¼ HB(Cy), Tpvii ¼ HB(3,5-Ph), Tpviii ¼ HB(2-Me), Tpix ¼ HB(3-(2-methoxy-1,1-dimethylethyl), Tpx ¼ HB(3Pri), Tpxi ¼ HB(5-Me-3-pyridyl), Tpxii ¼ HB(5--picolyl, 3-Me), Tpxiii ¼ HB(But, Me), Tpxiv ¼ HB(3-t-Bu).

4.01.5.2.3

Azacrown ethers and porphyrinogens

Mannich reaction of N,N9-bis(methoxymethyl)diaza-18-crown-6 with 4-chloro-2-(1H-pyrazol-3-yl)phenol gave the N-linked bis(3-(5-chloro-2-hydroxy)pyrazol-1-ylmethyl)-substituted diazacrown ether, which interacted with various metal ions and was evaluated by calorimetric titration . Intramolecular nitrilimine cycloadditions were exploited in the preparation of a number of azacrown ethers having a medium or large ring annulated to pyrazole units . The cystal structure of [Cu2(H1L](ClO4)3?2H2O of the dopamine interaction with a polyamine cryptand of 1Hpyrazole in the absence and presence of Cu(II) ions has been investigated . The crystal structure of the complex [Cu4(H2L]2(H2O)2(ClO4)2](ClO4)2?2H2O, where L is a new pyrazole ligand containing 1,5-diaminopentane spacers, represented a new way of obtaining metal ion-induced inorganic–organic cages . Selfassembly of [5-(pyrazol-4-yl)-10,20-bis(p-tolyl)-15-(2-ethoxycarbonylphenyl)porphyrinato]zinc(II), designed to have both a coordination site and a hydrogen-bonding site, led to a stable cyclic trimer array where coordination of the pyrazole nitrogen to the zinc(II) ion as well as hydrogen bonding between carbonyl oxygen and pyrazole NH each held zinc(II) porphyrin .

4.01.5.2.4

Alkyl halides and related compounds: Compounds with a free NH group

Pyrazole 1 can be successfully alkylated with benzyl halides using cesium fluoride–Celite in acetonitrile to give pyrazoles 122 (Equation 8) . Under the same conditions, indazole was alkylated in 90% and 81%, respectively, with benzyl chloride and benzyl bromide. Pyrazole 1 underwent fast N-alkylation with various alkyl

Pyrazoles

halides under microwave irradiation to give pyrazoles 123 (Equation 9) . The use of sodium hydrogen carbonate under microwave irradiation without solvent was found to be a good method for N-alkylation of pyrazoles . The synthesis of 2,2-dichlorotrifluoromethyl pyrazole derivatives 125 from pyrazoles 124 by the interaction of the N-sodium salts with Freon-113 has been carried out in the presence of tetrabutylammonium iodide (TBAI) as the catalyst (Equation 10) . N-Alkyl-3-substituted-5-(2-pyridyl or phenyl)pyrazole ligands were synthesized by reaction between 3-substituted-5-(2-pyridyl or phenyl)pyrazoles and the appropriate haloalkane in toluene or THF using sodium ethoxide or sodium hydride as the base . Microwaveassisted organic synthesis in nonpolar solvents was investigated utilizing cylinders of sintered silicon carbide (SiC) as chemically inert and strongly microwave absorbing materials as passive heating elements (PHEs) for the alkylation of pyrazole 1 with phenylethyl bromide to give pyrazole 126 (Equation 11) .

ð8Þ

ð9Þ

ð10Þ

ð11Þ

HY zeolite is a highly active catalyst for the vapor-phase N-methylation of pyrazoles 127 with methanol to give for example N-methylpyrazoles 128 (Equation 12) . Pyrazoles reacted with 1-adamantanol in a mixture of phosphoric acid/acetic acid (4:1 v/v) to give the corresponding 1-(1-adamantyl)- or 1,4-di(1-adamantyl)pyrazoles . The involvement of Mannich bases derived from ortho-hydroxyacetophenones 129 in amineexchange reactions with pyrazole and methyl- and/or halogen-substituted pyrazoles 130 gave the corresponding -(pyrazol-1-yl)ethyl ketones 131 in moderate to excellent yields (Equation 13) . Pyrazole 1 reacted with styrene oxide 132 under high pressure or promoted by a silica catalyst to give product 133 (Equation 14) . -Hydroxyethylpyrazoles were efficiently prepared by the regioselective ring opening of propylene and styrene oxide with various substituted pyrazoles . Nucleophilic ring opening of epoxycyclohexane with a variety of pyrazoles afforded racemic 2-(1-pyrazolyl)cyclohexan-1-ols in high yields . The kinetic resolution of these 1,3-diamino alcohols was achieved by enantioselective acylation with isopropenyl acetate in the presence of lipase B from Candida antarctica and separation of the enantiomerically pure alcohol and the ester by either medium-pressure liquid chromatography (MPLC) or crystallization.

29

30

Pyrazoles

ð12Þ

ð13Þ

ð14Þ

The sodium salt of indazole 2 interacts with dibromodifluoromethane to afford a mixture of 1- and 2-bromodifluoromethylindazoles 134a and 135a, respectively, which were not separated (Equation 15) . Similarly, the sodium salt of indazole reacted with carbon disulfide and methyl iodide under the same conditions to give a mixture of methyl 1- and 2-indazoledithiocarboxylates 134b and 135b, respectively, which were separated. Efficient and regioselective syntheses of 2-methyl- and 2-ethyl-2H-indazoles were accomplished with trimethyloxonium tetrafluoroborate or with triethyloxonium hexafluorophosphate, respectively, as alkylating agents in ethyl acetate at room temperature . The regioselective benzylation of an indazolyl-substituted pyrazole under the influence of KOH/Al2O3, KF–Al2O3, or CsF–Al2O3 was investigated .

ð15Þ

4.01.5.2.5

Aryl halides and related compounds

Many N-aryl pyrazoles are currently synthesized by metal-catalyzed cross-coupling reactions under basic mild conditions with either arylboronic acids or aryl halides. Arylboronic acids have been exploited in these types of reactions by copper-catalyzed methods. One of the first reports was of a mild C–N bond cross-coupling reaction via the arylboronic acid 136 with copper(II) acetate; arylation of pyrazole itself at room temperature in air provides good yields of N-arylated pyrazoles 137 (Equation 16) . When p-tolylboronic acid was coupled with indazole under these conditions, a 9:2 ratio of 1-aryl- and 2-arylindazoles was obtained in 88% yield. A combination of copper(I) oxide and chelating oxime-type ligands in the presence of cesium carbonate in acetonitrile was found to be effective under very mild conditions for the N-arylation of pyrazoles with aryl or heteroaryl bromides or iodides with great functional tolerance . L-Proline was used as an additive in the copper-catalyzed N-arylation of pyrazole with aryl iodides . Copper(II) acetate-mediated N-arylation with aryl boronic acids proceeded to form the N-2-substituted derivatives of 3-dimethylaminopropyloxypyrazoles . Copper(I) iodide-catalyzed N-arylation of various pyrazoles with aryl bromides and iodides was performed effectively in the presence of diamine ligands . 3-Trimethylsilylindazoles 138 underwent regioselective copper(II)-catalyzed cross-coupling to give 1-aryl-3-trimethylsilylindazoles 139, which were deprotected to 1-arylindazoles 140 under basic conditions (Scheme 3) . Copper-catalyzed

Pyrazoles

coupling of pyrazole 1 with aryl iodides was accomplished under mild conditions to give N-arylpyrazoles 142 in the presence of an oxime phosphine oxide ligand 141 (Equation 17) . Copper-catalyzed N-arylation of pyrazole can be accomplished using air-stable copper(I) iodide as a copper source and 1,10-phenanthroline in the presence of potassium fluoride/alumina as a base . Using the catalytic system Pd(OAc)2/PPh3, coupling of 2,6-dibromopyridine and substituted pyrazoles afforded the monosubstituted compounds as the major products when potassium tert-butoxide was used as the base . Without the catalyst, the disubstituted compounds were formed as the major products in yields up to 93%.

ð16Þ

Scheme 3

ð17Þ

An activating group such as a nitro substituent on a pyrazole or the aryl halide can assist N-arylation via an SNAr mechanism. For example, 3-aryl-5-ethylpyrazoles 143 underwent a highly regioselective arylation at N-1 with 4-fluoronitrobenzene 144 in the presence of base to yield the corresponding 1-(4-nitrophenyl)pyrazoles 145 (Equation 18) . N-Arylation of 3,5-disubstituted pyrazoles with 4-fluoro- or 2-fluoronitrobenzene under microwave irradiation conditions with or without solvent, compared to classical heating, afforded N-arylation regioisomers in yields depending on the method used . The electrolytic reaction of 1,4-dimethoxybenzene with 4-nitropyrazole in the presence of a Pt-electrode gave 2-(4-nitropyrazol-1yl)-1,4-dimethoxybenzene .

ð18Þ

4.01.5.2.6

Acyl halides and related compounds

Alkyl pyrazole-1-carboxylates 146, which were readily prepared from an alkyl chloroformate and pyrazole 1, are useful alkoxycarbonylating agents towards Grignard reagents for the synthesis of carboxylic esters 147 or towards

31

32

Pyrazoles

amines for the synthesis of the corresponding urethanes 148 (Scheme 4) . Ethyl 1-aroyl/aroylmethyl5-methyl-3-methylthiopyrazole-4-carboxylates have been synthesized via highly regioselective acylation of ethyl 3methyl-5-methylthio-1H-pyrazole-4-carboxylate with aroyl chlorides .

Scheme 4

4.01.5.2.7

Michael addition to double and triple bonds

N-Unsubstituted pyrazoles can add to compounds containing activated double and triple bonds. Double Michael addition of pyrazole to methyl propiolate yielded 3,3-bis(pyrazol-1-yl)propionates 149 as potential polydentate ligands . Only one isomer, 5-methyl-3-phenyl-1-pyrazolylsuccinic acid 150, was formed on addition of 3(5)-methyl-5(3)-phenylpyrazole to the double bond of maleic anhydride . Pyrazole underwent microwave-assisted Michael addition to methyl -acetamidoacrylate 151 with base to afford alanine pyrazole derivative 152 substituted at N-1 (Equation 19) . This reaction, performed under microwave irradiation, but with silica-supported Lewis acids gave mixtures of N-1- and N-2-substituted pyrazole alaninyl derivatives in different ratios. 5-Amino-3-methylpyrazole reacted chemoselectively in a Michael addition at N-1 with acrylonitrile to give the -adduct . Pyrazole 1 could be N-alkylated with trans-3,3,3-trifluoro-l-nitropropene 153 without addition of a catalyst, regioselectively with regard to the trifluoromethyl-substituted carbon atom to give 1-(1-trifluoromethyl-2-nitroethyl)pyrazole 154 (Equation 20) . 3(5)-Methylpyrazole 155 reacts with vinyl acetate 156 in the presence of a catalytic amount of mercury(II) acetate at room temperature to give addition product 157 in 80% yield (Equation 21) . Stable crystalline phosphorus ylides were obtained in excellent yields from the 1:1:1 addition reaction between triphenylphosphine and dialkyl acetylenedicarboxylates, in the presence of strong NH acids, such as pyrazole, indazole, and 5-nitroindazole . These stable ylides existed in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon–carbon partial double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group.

ð19Þ

ð20Þ

Pyrazoles

ð21Þ

4.01.5.2.8

Aminating and nitrating agents

N-Amination of 3-amino-5-tert-butylpyrazole 158 with hydroxylamine-O-sulfonic acid gave the 1,5-diaminopyrazole 159 with good regiochemical control (Equation 22) . The reactions of 159 with certain electrophiles (acetic anhydride, dimethylformamide dimethyl acetal (DMFDMA), aromatic aldehydes, methoxymethylene Meldrum’s acid) took place at one (or both) of the amino groups and no cyclized products were obtained. A number of substituted N-nitropyrazoles 160 were prepared by direct nitration of substituted pyrazoles . Pyrazole was easily N-nitrated with nitrogen dioxide in the presence of ozone in methylene chloride .

ð22Þ

4.01.5.2.9

Alkenylation

Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxide 161 with isopropylmagnesium chloride at 78 C in toluene, with N-lithioindazole 162 (or pyrazole) gave N-alkenylated indazole 163 in moderate yield (Scheme 5) . Reaction of lithiopyrazole gave the N-alkenylated pyrazole but in a lower yield.

Scheme 5

33

34

Pyrazoles

4.01.5.3 Electrophilic Attack at Carbon 4.01.5.3.1

Nitration

A review has been written on the synthesis and reactions of the nitropyrazoles . Pyrazole 1 on treatment with fuming nitric acid/trifluoroacetic anhydride gave 3,4-dinitropyrazole 164 (Equation 23), while N-methylpyrazole under the same reaction conditions gave 3-nitropyrazole (Equation 23) . 1-Methylpyrazole-3-ones were treated with aqueous nitric acid to give 1-methyl-4-nitropyrazol-3-ones, which could be reduced by catalytic hydrogenation with palladium on carbon to give 1-methyl-4-aminopyrazole-3-ones . 1,4-Dimethylpyrazole 165 was converted into 3,5-dinitro-1,4-dimethylpyrazole 166 in the presence of 2 volumes of concentrated nitric acid and 20 volumes of sulfuric acid at reflux to ensure acceptably reproducible yields of the product (Equation 24) . Pyrazole 1 could be converted into 1-nitropyrazole 167 immediately with dinitrogen pentoxide, which can then slowly be transformed to 1,4-dinitropyrazole 168 in the presence of H-faujasite zeolite F-720 or with nitrogen dioxide in ozone (Scheme 6) . The nitration of 5-chloropyrazoles 169 with a mixture of 100% concentrated nitric acid and 65% oleum or a mixture of 60% nitric acid and polyphosphoric acid (PPA) gave substituted 5-chloro-4-nitropyrazoles 170 (Equation 25) . 4-Chloropyrazoles failed to undergo nitration under these conditions and the nitration of 3-aryl-5-halopyrazoles was accompanied by introduction of a nitro group into the benzenoid aromatic ring.

ð23Þ

ð24Þ

Scheme 6

ð25Þ

4.01.5.3.2

Sulfonation

Pyrazoles 171 were sulfonated with concentrated sulfuric acid in the presence of acetic anhydride to give pyrazolesulfonic acids 172 (Equation 26) .

Pyrazoles

ð26Þ

4.01.5.3.3

Halogenation

Many methods have been reported for the direct halogenation of pyrazoles for they are very useful intermediates for metal-catalyzed cross-coupling reactions (see Section 4.01.7.6.3). Aqueous potassium dichloroiodate has been found to be a general iodinating agent for pyrazole 1 to 4-iodopyrazole 173 (Equation 27) . 4-Iodopyrazole derivatives 175 were efficiently synthesized in high yields from 174 at room temperature by the combined reagents iodobenzene diacetate (or polymer-supported (PS) iodobenzene diacetate) with iodine (Equation 28) . 3,5-Dimethylpyrazoles were efficiently halogenated via ultrasound irradiation using N-halosuccinimides . 1-Methylpyrazol-3-ones were iodinated with iodine monochloride to give 1-methyl-4-iodopyrazol-3-ones . The reagent obtained from iodine monochloride and silver(II) sulfate in sulfuric acid iodinated 1-methyl-3-nitropyrazole to give 4-iodo- and 4,5-diiodo-1-methyl-3-nitropyrazoles, while 1-methyl-4nitropyrazole gave 3-iodo-1-methyl-4-nitropyrazole . Iodination of NH or N-benzylpyrazoles 176 with iodine in the presence of cerium(IV) ammonium nitrate (CAN) provided a mild and efficient method to prepare 4-iodopyrazoles 177 even from pyrazoles containing electron-withdrawing substituents (Equation 29) . A one-pot synthetic route that allowed functionalization of the 2,6-bis(pyrazol-1-yl)pyridine backbone 178 in the 4- and 49-pyrazole positions by direct pyrazole 4-halogenation of 179 has been described (Equation 30) . The diiodo derivative in particular provided easy access to additional functionalities through both Sonogashira and Grignard exchange reactions.

ð27Þ

ð28Þ

ð29Þ

35

36

Pyrazoles

ð30Þ

1-Hydroxypyrazole 180 was selectively N-alkylated to the corresponding 2-alkyl-pyrazole-1-oxides 181, which could be subsequently deoxygenated and C-halogenated forming 1-alkyl-5-halopyrazoles 182 (Scheme 7) .

Scheme 7

4.01.5.3.4

Acylation

Reaction of 1-(4-methoxybenzyl)-1H-pyrazol-5-ol 183 with carboxylic acid chlorides/calcium hydroxide in 1,4dioxane afforded 4-acyl-5-hydroxy-1-(4-methoxybenzyl)-1H-pyrazoles 184 and the p-methoxybenzyl (PMB) protecting group could be conveniently removed from the pyrazole nucleus by treatment with trifluoroacetic acid to give the N-unsubstituted pyrazolones 185 (Scheme 8) . Pyrazolo[1,5-a]-1,3,5-triazine 186 was acylated with acyl chlorides in the presence of tin(IV) chloride without solvent to give 8-acylpyrazolo[1,5-a]-1,3,5-triazines 187, where phenylmethylamine could be readily displaced by other amines to give amino ketones 188 (Scheme 9) .

Scheme 8

Scheme 9

4.01.5.3.5

Amination

5-Aminopyrazoles 189 were readily converted into 4,5-diaminopyrazoles 190, via nitrosation and reduction, which were selectively condensed with isocyanates to yield 5-amino-4-pyrazolyl ureas 191 (Scheme 10) .

Pyrazoles

Reaction of 1-methyl-4-nitropyrazole with 1,1,1-trimethylhydrazinium halides in the presence of sodium methoxide or potassium tert-butoxide afforded 5-amino-1-methyl-4-nitropyrazoles . Specifically, the primary radical anions of substrate in the vicarious nucleophilic substitution of hydrogen in 1-methyl-4-nitropyrazole 192 with 1,1,1-trimethylhydrazinium iodide yielded 5-amino-1-methyl-4-nitropyrazole 193, which was studied by electron spin resonance (ESR) (Equation 31) . Reaction of 3,5-dinitropyrazole 194 with trimethylhydrazinium iodide in DMSO afforded 4-amino-3,5-dinitro-1H-pyrazole 195 via another vicarious nucleophilic substitution (Equation 32) .

Scheme 10

ð31Þ

ð32Þ

4.01.5.3.6

Diazo coupling

4-Amino-3,5-dinitropyrazole underwent diazotization to afford 4-diazo-3,5-dinitropyrazole, which reacted with active methylene compounds to give azo coupling products .

4.01.5.3.7

Reaction with aldehydes and ketones

Polyfluorinated aliphatic aldehydes reacted with 1-phenyl-3-methylpyrazol-5-one, 1-phenyl-3-methyl-5-amino (N,Ndimethylaminomethylenamino)pyrazole, and 1-phenyl-3-aminopyrazol-5-one at room temperature in the absence of catalyst with formation of 4-(1-hydroxypolyfluoroalkyl)pyrazoles . Dehydration of the 4-(1hydroxypolyfluoroalkyl)pyrazoles with morpholinosulfur trifluoride generated 4-polyfluoroalkylidenepyrazoles, which were active dienophiles and reacted with 2,3-dimethylbutadiene and cyclopentadiene forming spirocyclic pyrazole derivatives.

4.01.5.3.8

Miscellaneous

Reaction of 3,5-dimethylpyrazole 196 with chloral 4-chlorophenylsulfonylimine yielded addition products of C-amidotrichloroethylation at position 4 of the pyrazole ring giving 4-(1-amidotrichloroethyl)pyrazole 197 (Equation 33) . 1-Ethylpyrazole-4-carbaldehyde 199 was prepared from 1-ethylpyrazole 198 by the Vilsmeier reaction; reaction of 199 with various primary amines afforded the corresponding Schiff bases (Equation 34) .

37

38

Pyrazoles

ð33Þ

ð34Þ

4.01.5.4 Nucleophilic Attack at Carbon 2-Pyrazolin-4-oximes 203 were synthesized by reaction of 4-nitropyrazoles 200 with organolithium or Grignard reagents (Scheme 11) . This transformation can be interpreted by initial coordination of the metal at the nitro group as in 201; addition of an alkyl group at C-5 in conjugate fashion, would then give 202, the nitronate intermediate then being reduced to oxime by reaction with the excess organometallic. 1,3,5-Trisubstituted-2methylpyrazolium iodides 204 reacted with dimethylphenylsilyl- and tert-butyldiphenylsilyllithium to give 5-silyl3-pyrazolines 205, which underwent thermal ring opening with silicon rearrangement to afford -silylated -diimines (Equation 35) . The silyl group could be easily substituted by electrophiles to give 5-functionalized 3-pyrazolines. The use of indazolium and isoindazolium iodides led to 3-silylindazolines .

Scheme 11

Pyrazoles

ð35Þ

4.01.5.5 Nucleophilic Attack at Hydrogen 3-Chloropyrazolo[3,4-c]quinoline, 3-chloropyrazolo[3,4-c]isoquinoline, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin3-one, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one were obtained by acid-induced nucleophilic aromatic substitution (SNH) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline and N-hydroxypyrazolo[3,4-c]isoquinoline, representing the first cases of nucleophilic aromatic substitution of a fused pyrazole .

4.01.5.5.1

Metallation at a ring carbon atom

Pyrazoles can be selectively lithiated at different carbons and subsequently react with electrophiles depending on the substitution patterns. 1-Methyl-5-(trifluoromethyl)pyrazole underwent deprotonation and subsequent carboxylation mainly or exclusively at either the 4-position of the heterocycle or at the nitrogen-attached methyl group . Similarly, 1-phenyl-5-(trifluoromethyl)pyrazole and 3-methyl-1-phenyl-5-(trifluoromethyl)pyrazole were selectively attacked by lithium diisopropylamide (LDA) at the heterocyclic 4-position and by n-butyllithium concomitantly at the 4-position and the ortho-position of the phenyl ring. In contrast, metallation of 1-methyl-3(trifluoromethyl)pyrazole occurred only at the 5-position, whatever the organometallic or metal amide base. 1-Methylpyrazole 206 can be regioselectively alkylated with benzaldehyde to give 5-substituted or 1-substituted pyrazoles 207 and 208, respectively, depending on the base used (Equation 36) . Indazole can be regioselectively protected at N-2 by a 2-(trimethylsilyl)ethoxymethyl (SEM) group using novel conditions (Scheme 12) . The SEM group of 209 efficiently directed 3-lithiation and the resulting nucleophile reacted with a wide range of electrophiles to generate indazole derivatives 210 after the SEM group was removed by treatment with tetrabutylammonium fluoride in THF or by aqueous hydrochloric acid in ethanol. 1-( p-Methoxybenzyl)pyrazole, when treated with either butyllithium or LDA, underwent metallation at the exocyclic -position but this equilibrated to the 5-lithio species in the course of few minutes . Trapping the intermediates with a rapidly reacting electrophile such as chlorotrimethysilane or carbon dioxide offered selective access to either of the two possible regioisomers.

ð36Þ

Scheme 12

39

40

Pyrazoles

Pyrazoles can also undergo lithium–hydrogen exchange followed by transmetallation to give active species, which then can participate in a myriad of cross-coupling reactions. Ethyl 3-methoxy-1-methyl-1H-pyrazol-4-carboxylate 211 underwent efficient lithiation and quenching with various reagents to give intermediate halides, zincates, or boronic acids, which can then be cross-coupled (palladium-catalyzed) with various electrophiles to give tetrasubstituted pyrazoles 212 (Equation 37) . Site-selective functionalization of trifluoromethyl-substituted pyrazoles was explored with bromine additions or with lithiation followed by carboxylation . Palladium(0)catalyzed cross-coupling of 1-(benzyloxy)pyrazol-5-ylzinc halides, prepared by transmetallation of 1-(benzyloxy)-5lithiopyrazole, with acyl chlorides produced 5-acyl-1-(benzyloxy)pyrazoles in high yields . Similar coupling of the pyrazol-5-ylzinc halide with amino-, hydroxy-, methoxy-, fluoro-, nitro-, or formyl-substituted iodobenzene gave the corresponding 5-aryl-1-(benzyloxy)pyrazoles, while coupling with 2-iodothiophene, 2-iodopyrazole, or 2-bromopyridine provided the corresponding 1-(benzyloxy)-5-heteroarylpyrazoles.

ð37Þ

4.01.5.5.2

Hydrogen exchange at ring carbon in neutral pyrazoles

Pyrazole was selectively C-arylated via catalytic C–H bond functionalization using iodobenzene and palladium(II) acetate in the presence of triphenylphosphine and magnesium oxide to give 3(5)-phenyl-1H-pyrazole 213 (Equation 38) .

ð38Þ

4.01.5.6 Reaction with Radicals and Electron-Deficient Species 4.01.5.6.1

Carbenes and nitrenes

Pyrazolium-3-carboxylates, which belong to the class of pseudo-cross-conjugated heterocyclic mesomeric betaines, undergo decarboxylation to give nucleophilic carbenes, which could be trapped as pyrazolium salts . An aldol addition, a Knoevenagel reaction, and a Cannizzaro-type reaction were presented, which were initiated by the strong basicity of the pyrazol-3-ylidene generated in situ. The role of conformation and electronic structure in the chemistry of the ground and excited states of 2-(1-pyrazolyl)- 214a and 2-[1-(3,5-dimethyl)pyrazolyl]phenylnitrene 214b has been studied in EtOH solution at room temperature, in EtOH glasses at 90 K, and in Ar matrices at 12 K .

4.01.5.6.2

Free radical attack at the ring carbon atoms

The behavior of the 3-alkylidene-1-pyrazoline radical cations generated by photoinduced electron transfer was examined . The nitrogen-retained radical cations were detected using laser flash photolysis.

Pyrazoles

The photochemical products indicated that (E/Z)-isomerization, intramolecular cyclization, and solvent addition (acetonitrile) occurred. A density functional study of the radical reactions of 3-methyl-1-phenyl-2-pyrazolin-5-one was carried out .

4.01.5.6.3

Electrochemical reactions and reactions with free electrons

The electrochemical reactions of 1,4-dimethoxybenzene with pyrazole, 3,5-dimethylpyrazole, 4-nitropyrazole, and 3,4-dinitro-5-methylpyrazole on a platinum electrode in acetonitrile, methylene chloride, and methanol gave 2-pyrazolyl-1,4-dimethoxybenzenes . An electrochemical study related to the electrooxidation of the 3-hydroxy- and 3-methyl-derivatives of 1-phenyl-4-butyldithiocarboxylate-5hydroxypyrazole in aqueous ethanol solutions covering a wide pH interval was performed . The redox characteristics of some substituted pyrazoles and azopyrazoles were investigated in acetonitrile at platinum and gold electrodes .

4.01.5.7 Reactions with Cyclic Transition States Many Diels–Alder reactions of pyrazole-type compounds have led to ring-fused pyrazole derivatives. Alkylideneaminopyrazoles underwent microwave-assisted Diels–Alder cycloaddition reactions with nitroalkenes to give good yields of pyrazolo[3,4-b]pyridines . 5-Aminopyrazoles have been employed as dienophiles in inverse demand Diels–Alder reactions of 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine in the synthesis of pyrazolo[3,4-d]pyrimidines . N-Acetyl-styrylpyrazoles underwent Diels–Alder cycloaddition reactions with N-methylmaleimide under solvent-free conditions to give the corresponding tetrahydroindazoles in good yields and high selectivity . Oxidation of the tetrahydroindazoles with DDQ gave the expected indazoles and was accompanied by N-deacylation. Regioselective anionic [3þ2] cyclization reactions between 3-aminopyrazoles 215 and oxaldiimidoyl dichlorides 216 provided convenient access to biologically relevant 3H-imidazo[1,2-b]pyrazoles 217 with high regioselectivities, which were explained with the aid of semi-empirical computations (Equation 39) . A tandem decarboxylation/Diels–Alder reaction of 5-amino-1-phenyl-4-pyrazolecarboxylic acid with various 1,3,5-triazines has been reported . The dienophile, 5-amino-1-phenylpyrazole, was generated in situ via decarboxylation and immediately trapped by 1,3,5-triazines leading to 4,6-disubstituted 1-phenylpyrazolo[3,4d]pyrimidines in one step. Diels–Alder reaction of 4-iminopyrazoles 218 with maleimide afforded pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)dione 220 via elimination of dimethylamine and air oxidation of intermediate 219 (Scheme 13) . 3(5)-(2-Hydroxyphenyl)-5(3)-styrylpyrazoles underwent Diels–Alder cycloaddition with o-benzoquinodimethane followed by oxidation with DDQ in dioxane to give naphthylpyrazoles . Diarylpyrazole derivatives were treated with dibenzoylacetylene to give pyridazine derivatives via Diels–Alder reactions .

ð39Þ

Scheme 13

41

42

Pyrazoles

ortho-Quinodimethane intermediates from pyrazoles can undergo cycloaddition to give various fused ring pyrazole derivatives. Thus thermolysis of N-(acryloyloxy)alkylpyrazolo-3-sulfolenes provides the corresponding o-quinodimethanes which simultaneously undergo intramolecular Diels–Alder reactions to form two- and three-atom-bridged tricyclic pyrazoles . For example, pyrazolo-3-sulfolenes 221 were thermolyzed and sulfur dioxide was extruded leading to the corresponding o-quinodimethanes 222, which underwent simultaneous intramolecular Diels–Alder reactions to form two- and three-atom-bridged tricyclic pyrazoles 223 (Scheme 14) . Microwave irradiation provided a general methodology for the generation of o-quinodimethanes derived from dibromopyrazole 224 in the presence of excess sodium iodide in DMF (Equation 40) . The cycloaddition reactions of such compounds with electron-deficient dienophiles such as N-methylmaleimide allowed the synthesis of corresponding heteropolycyclic adducts 225. Dimethyl acetylenedicarboxylate, diethyl azodicarboxylate, and p-benzoquinone were other dienophiles successfully employed in this way.

Scheme 14

ð40Þ

Stereoselective Diels–Alder reactions have been reported in several cases. Enantioselective Diels–Alder reactions of 1-phenoxycarbonyl-1,2-dihydropyridine with 1-alkylated acryloyl-pyrazolidin-3-ones using a chiral cationic palladium–phophinooxazolidine catalyst afforded chiral isoquinuclidines with excellent enantioselectivity . Bismuth(III) chloride-mediated diasteroselective intramolecular [4þ2] cycloaddition reactions of S-allyl derivatives of pyrazole aldehydes led to fused sulfur-containing pyrazole heterocycles . A highly diastereoselective intramolecular hetero-Diels–Alder approach toward tetracyclic pyrazoles from 5-(3methyl-2-butenylthio)-3-methyl-1-phenyl-4-pyrazolecarboxaldehyde has been reported .

4.01.6 Reactions of Nonaromatic Compounds 4.01.6.1 Dihydro Derivatives 4.01.6.1.1

Aromatization

Several aromatization methods have been published for the conversion of pyrazolines 226 into pyrazoles 227 and conditions are presented in Table 6.

Pyrazoles

Table 6 Aromatization conditions for conversion of pyrazolines into pyrazoles Conditions

Reference

Iodobenzene diacetate Chloranil, toluene Zr(NO3)4, HOAc 1,3-Dibromo-5,5-dimethylhydantoin, silica gel supported O2, activated carbon

1997SC2683 2000EJO2593 2003S1267 2004S1744 2002OL3955 2004S1015 2004TL2181 2004TL4143 2005H(65)865 2005SC2581 2006T2492 2006TL833 2006H(968)1209

Trichloroisocyanuric acid, solvent free Cu(NO3)2, clay supported, ultrasound irradiation NBS silica gel supported, microwave irradiation, solvent free Bi(NO3)3?5H2O, HOAc, microwave irradiation N-Hydroxyphthalimide (10 mol%), Co(OAc)2 (0.5 mol%), O2, CH3CN 4-(p-Chloro)phenyl-1,2,4-triazole-3,5-dione, CH2Cl2 Ca(OCl)2, CH2Cl2

3-Cyanospiro[2-pyrazoline-5,19cyclopropane] 228 underwent unusual transformations into 3(5)-cyano-5(3)-(2hydroperoxyethyl)pyrazoles 229 in the presence of atmospheric oxygen, and these were converted into (2-hydroxyethyl)pyrazoles 230 with sodium pyrosulfite in aqueous methanol (Scheme 15) .

Scheme 15

4.01.6.1.2

Reduction

The reduction of a variety of highly functionalized N-acylated dihydropyrazoles 231 with borane–pyridine to tetrahydropyrazoles 232 has been described (Equation 41) . Many functional groups that might have been reduced were tolerated in these reaction conditions. Raney nickel-catalyzed hydrogenation of 5-substituted spiro[cyclopropane-3(1-pyrazoline)]-5-carboxylates 233 occurs with N–N bond cleavage and simultaneous cyclocondensation to give 3-aminopyrrolidin-2-ones 234 containing a spirocyclopropane fragment (Equation 42) . The presence of the second ester group in the pyrazoline side-chain, in a position ensuring the formation of a five-membered ring, results in 6,11-diazadispiro[2.1.4.2]undecane-7,10-dione 235, the product of double cyclocondensation of the intermediate diamine (Equation 43).

ð41Þ

ð42Þ

43

44

Pyrazoles

ð43Þ

4.01.6.1.3

Thermolysis, photolysis, and pyrolysis

The majority of thermolysis, photolysis, and pyrolysis reactions with pyrazolines give cyclopropane products. Photolysis of chiral trisubstituted pyrazolines 236 afforded cyclopropanes 237, in which the mechanism and stereospecificity were studied in detail (Equation 44) . Protoporphyrin reacted with diazomethane to give pyrazolines which at long wavelength (630 nm) extruded nitrogen to give the corresponding cyclopropyl derivatives . The photorearrangement of some 4-arylazopyrazolin-5-one derivatives to give cyclopropane products was studied .

ð44Þ

Flash vacuum pyrolysis of cyclobutyl pyrazoline 238 afforded 3-cyclopropyl-1,1,2,2-tetrafluorobutane 239 in excellent yield (Scheme 16) . Palladium-catalyzed diazomethane addition to 1,1,2,2-tetrafluoro-3vinylcyclobutane 240 also provided 239 under much milder conditions. 1,3-Dipolar cycloaddition of 2-diazo-1,1,1trifluoro-3-nitropropane to acrylic acid or methacrylic acid derivatives gave 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles and 5-trifluoromethyl-4,5-dihydro-3H-pyrazoles with high (E)-stereoselectivity; the latter could be pyrolyzed to give the corresponding cyclopropanes with the same configuration . FVP reactions of DPP and 3(5)methyl-5(3)-phenylpyrazole were carried out as an alternative method for studying vinylcarbenes .

Scheme 16

FVP experiments were carried out between 500 and 800 C on 3(5)-phenyl- and 3(5)-methylpyrazolinones and on 3(5)-methoxy-5(3)-phenylpyrazole . The origin of the isolated products (mainly indanone, hydroxyalkynes, and ,-unsaturated aldehydes) were explained as arising from the hydroxy tautomers of pyrazolinones. Temperature effects on the tautomeric equilibrium of 1-phenyl-3-methylpyrazolinone in solution show that the percentage of the CH tautomer increased with increasing temperature. Thermolysis of enantiopure sulfonyl pyrazolines 241 afforded sulfonyl cyclopropanes 242 in a completely stereoselective manner (Scheme 17) . Both cyclopropanes 243 and alkylidenecyclopropanes 244, containing one or two chiral carbon atoms, one of them being quaternary, were obtained by hydrogenolysis of the C–S bond and under Julia conditions, respectively. Thermal dediazotization of 3-(1-fluorovinyl)-3-methylpyrazoline 245 at 250 C afforded 1-(1-fluorovinyl)-1-methylcyclopropane 246, which was capable of isomerizing further, at 600 C, to

Pyrazoles

give 1-fluoro-2-methylcyclopentene 247 (Scheme 18) . Triethyl 4-R-4,5-dihydro-1H-pyrazole3,5,5-tricarboxylate 248 reacted with chlorine to yield triethyl 4-R-5-chloro-4,5-dihydro-3H-pyrazole-3,3,5-tricarboxylate 249, which on thermolysis provided the corresponding 2-chlorocyclopropanetricarboxylic ester 250 (Scheme 19) . The same ester reacted with bromine in dichloromethane at room temperature to give a mixture of esters of the corresponding 1H-pyrazole-3,5-dicarboxylic acids and 5-bromo-4,5-dihydro-3,3,5-tricarboxylic acids. Thermal decomposition of spiro pyrazolines 251 resulted in ring enlargement and afforded ring-fused alkylidenecyclobutanes 252 in high yields (Equation 45) . Substituted bicyclic 1-halogeno-1-cyclopropanecarboxylates have been prepared by elimination of molecular nitrogen from 4-halogeno-7-aryl-1-methyl-2,3,7-triazabicylo[3.3.0]oct-2-en-4-carboxylates, which were obtained by the reaction of 7-aryl-1-methyl-2,3,7-triazabicyclo[3.3.0]oct-3-encarboxylates with chlorine and bromine . Substituted ethyl 1,2,3,4,49,59-hexahydrospiro[naphthalene-2,59-pyrazole]-39-carboxylates reacted with chlorine or N-bromosuccinimide to give spirocyclic substituted 3-halo-4,5-dihydro-3H-pyrazoles which expelled nitrogen on heating with the formation of substituted spirocyclic 1-halocyclopropane-1-carboxylates . Heating of the title compounds with bromine in acetic acid resulted in opening of the spiro-fused six-membered ring to afford ethyl 4-aryl-5-[2-(2-carboxyphenyl)ethyl]pyrazole-3-carboxylates.

Scheme 17

Scheme 18

Scheme 19

45

46

Pyrazoles

ð45Þ

4.01.6.1.4

Acylation reactions

3-Methyl-1-phenyl-2-pyrazolin-5-one and 1-dodecyl-3-methyl-2-pyrazolin-5-one reacted with carbon disulfide and 1,5-dibromopentane in the presence of sodium acetate in DMF or n-butyllithium in THF to afford 1,5-bis(4dithiocarboxylate-5-hydroxypyrazolyl)pentane derivatives . 3-Hydroxy-1-phenyl-2-pyrazolin-5-one 253 reacted with primary, secondary, and allylic alcohols in the presence of molecular sieves and concentrated sulfuric acid to give 3-alkoxy-1-phenyl-2-pyrazolin-5-ones 254 (Equation 46) . Reaction of 3-amino-, 3-hydroxy-, and 3-methoxy-1-phenyl-2-pyrazolin-5-one 255 with carboxylic acid chlorides/calcium hydroxide in 1,4dioxane afforded mainly the corresponding 4-acyl-2-pyrazolin-5-ones 256 (Equation 47) . 3-Methoxy-1-phenyl-2-pyrazolin-5-one reacts with dimethylformamide diethyl acetal to give an (E)/(Z)-mixture of the 4-dimethylaminomethylene product. With TCNE, the 4-dicyanomethylene product is obtained. With nitrous acid, the 4-hydroximino derivative results. Addition of alkyl or aryl isocyanates, or addition of triphosgene followed by treatment of amines to 3,5-dihydropyrazoles 257, provided dihydropyrazolyl ureas or amides 258 in good yields (Equation 48) . Direct acylation with dimethylcarbamoyl chloride or sulfonylation of 257 were unsuccessful; however, N-acylation with butyryl and benzoyl chlorides did succeed. 3-Methylpyrazol-5-ones reacted by O-acylation with acyl isothiocyanates in the presence of ethanol/dioxane to give 5-acyloxy-3-methyl-1H-pyrazoles .

ð46Þ

ð47Þ

ð48Þ

4.01.6.1.5

Other reactions

3-Heterocyclyl-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazoles 259 on thermal elimination of water from the 3-(thien-2-yl), 3-(pyridin-2-yl), and 3-(pyridin-4-yl) compounds readily gave the corresponding pyrazoles but acid catalysis was required to form 3-(benzothiazol-2-yl)-5-trifluoromethylpyrazole and 3-(1-methylbenzimidazol-2-yl)-5trifluoromethylpyrazole 260 (Equation 49) . Thienopyrazole and thienopyrazolothiazepine

Pyrazoles

derivatives were prepared via the reaction of 5-amino-2,4-dihydro-2-phenyl-3H-pyrazol-3-one with carbon disulfide and different molar ratios of a variety of halo compounds having an active methylene under phase-transfer catalysis conditions .

ð49Þ

4.01.6.2 Tetrahydro Compounds Pyrazolidinediones 261 were oxidized with manganese(III) acetate in the presence of alkenes 262 at elevated temperatures to produce 4,4-bis(alkenyl)pyrazolidinediones 263 in good yields (Equation 50) . The reactions of 1-acetyl-2-phenyl-5-hydroxypyrazolidines with pyrazol-5-ones led to the corresponding 4-(pyrazolidin-5yl)pyrazolones , with amino acid esters affording the corresponding N-pyrazolidin-5-yl amino acids under mild conditions and with oxindoles on the surface of potassium-fluoride alumina giving 3-(5-pyrazolidinyl)oxindoles .

ð50Þ

Copper-catalyzed 1,3-dipolar cycloaddition of azomethine imine 264 with ethyl propiolate 265 with a chiral ferrocenyl bidentate ligand efficiently generated dihydropyrazol[1,2-a]pyrazolones 266 in very good yields and ee (Equation 51) .

ð51Þ

4.01.7 Reactions of Substituents Attached to Ring Carbon Atoms 4.01.7.1 Indazoles Functionalized 5,6-dihydro-4-hydroxy-2-pyrone 269 was formed via a novel formal cycloaddition reaction between 3-indazole carbaldehyde 267 and pyrandione 268 for which a pericyclic and aldol-like pathway have been proposed (Equation 52) . Various 4,6-dinitro-1-phenyl-1H-indazoles 270 substituted at position 3 were prepared via transformations involving the formyl group of 3-formyl-4,6-dinitro-1-phenyl-1H-indazole . 3-R-4,6-Dinitro-1-phenyl-1H-indazoles (R1 ¼ CHO, CN, 1,3-dioxolan-2-yl) 270 reacted regiospecifically with anionic O-, S-, and N-nucleophiles, with replacement of only the 4-nitro group to give 271 in good yields (Equation 53) . The regioselectivity of nucleophilic displacement was the same when R1 ¼ H.

47

48

Pyrazoles

3-Methylindazole 272 was t-butoxycarbonyl (BOC)-protected followed by radical bromination with N-bromosuccinimide to give bromoindazole 273, which then underwent nucleophilic substitution by the carbanion of diethyl acetamidomalonate followed by decarboxylation and hydrochloride salt formation to provide a synthesis of 2-azatryptophan 274 (Scheme 20) .

ð52Þ

ð53Þ

Scheme 20

4.01.7.2 Other C-Linked Substituents 4.01.7.2.1

Alkyl groups

4-Chloromethylpyrazoles 275 underwent substitution with sodium azide or with potassium phthalimide to give 4-azidomethylpyrazoles 276 and 4-phthalamidomethylpyrazoles 277, which were then reduced with Raney nickel or cleaved by hydrazinolysis, respectively, to give 4-aminomethylpyrazoles 278 (Scheme 21) . The preparation of 4-(2-aminoethyl)-3,5-dimethylpyrazole from 4-(2-chloro and iodoethyl)-3,5-dimethylpyrazoles followed the same route . 4-Chloromethylpyrazoles 275 also reacted with triphenylphosphine to yield the triphenyl(4-pyrazolylmethyl)phosphonium chloride, which underwent Wittig reactions with aromatic or heteroaromatic aldehydes to furnish 4-[2-aryl(heteryl)ethenyl]pyrazoles . The N-THP-protected 3,5-bis(chloromethyl)pyrazole 279 permitted efficient attachment of various N-donor side arms through nucleophilic substitution reactions to give pyrazoles 280 (THP ¼ tetrahydropyran-2-yl; Scheme 22) . 3-Aryl-1phenyl-4-mercaptomethylpyrazoles reacted with monochloroacetic acid to give 3-aryl-1-phenyl-4-pyrazolylmethylsulfanylacetic acids whose oxidation with hydrogen peroxide in acetone or acetic acid solution led to 3-aryl-1-phenyl-4pyrazolylmethylsulfinyl- and sulfonylacetic acids, respectively . A simple and efficient protocol for the

Pyrazoles

synthesis of 3-methoxy-4-arylmethylene- and 3-methoxyheteroarylmethylenepyrazoles 282 involved the reaction of 4-pyrazolylmethyl alcohols 281 with either alcohols or thiols (aryl and heterocyclic (furanyl, indolyl, and pyrrolyl)) in the presence of camphorsulfonic acid (CSA) (Scheme 23) . These reactions are believed to proceed via a Friedel–Crafts-type carbocation mechanism. Reaction of 5-trichloromethylpyrazoles 283 with amines provided pyrazole-5-carboxamides 284 efficiently (Equation 54) .

Scheme 21

Scheme 22

Scheme 23

49

50

Pyrazoles

ð54Þ

4.01.7.2.2

Alkenyl groups

Oxidative addition of N-aminophthalimide with lead tetraacetate in the presence of 1,5-diaryl-3-[(E)-2-arylethenyl]1H-pyrazoles 285 gave adducts at the side-chain double bond, giving the corresponding phthalimidoaziridinylpyrazoles 286 (Equation 55) . The reaction of 1,4-dimethyl-3,5-dinitropyrazole 287 with DMFDMA gave (E)-N,N-dimethyl-2-(1-methyl-3,5-dinitropyrazol-4-yl)ethenylamine 288 (Scheme 24) . Acid hydrolysis of the latter afforded (1-methyl-3,5-dinitropyrazol-4-yl)acetaldehyde 289, and reaction with sodium nitrite in hydrochloric acid led to 2-hydroxyamino-2-(1-methyl-3,5-dinitropyrazol-4-yl)acetaldehyde 290, precursors for other reactions leading to bicyclic pyrazoles. Bromination of 3-(3-arylpyrazol-4-yl)acrylic acids 291 led to the formation of 2-bromo-3-(3-arylpyrazol-4-yl)acrylic acids 292 which were converted into 3-(3-arylpyrazol-4-yl)propionic acids 293 by treatment of potassium hydroxide in an alcoholic solution (Scheme 25) .

ð55Þ

Scheme 24

Scheme 25

4.01.7.2.3

Carbonyl groups and derivatives

Oxidation of the pyrazole carboxaldehydes 294 using potassium permanganate in aqueous pyridine gave satisfactory yields of the carboxylic acids 295 (Equation 56) . Condensation of N-alkylpyrazole-4-carbaldehyde 296 with 2,3-bis(hydroxyamino)-2,3-dimethylbutane sulfate, then sodium periodate oxidation of 1,3-dihydroxyimidazolidine 297 afforded pyrazolyl nitronyl nitroxides 298 (Scheme 26) . Another approach to

Pyrazoles

the synthesis of polyfunctional pyrazolyl-substituted nitronyl nitroxides was developed based on presynthesized pyrazole derivatives prepared by 1,3-dipolar cycloaddition . 3-Aryl-1-phenyl-4-pyrazolecarbonyl isothiocyanates reacted with 3-amino-5-methylisoxazole to afford 3-aryl-N-(3-acetonyl-1,2,4-thiadiazol-5-yl)-1-phenylpyrazole-4-carboxamides . N-Sulfinyltrifluoromethanesulfonamide reacted with 3-methyl-1-phenyl1H-pyrazole-4-carbaldehyde 299 to afford the corresponding N-pyrazolylmethylidenetrifluoromethanesulfonamide 300 (Equation 57) . Derivatives of N-benzyl[3-aryl(heteroaryl)-4-pyrazolyl]methanimines, prepared from 1-phenylpyrazole-4-carbaldehydes 301 and benzylamine, reacted with diethyl phosphite to afford diethyl benzylamino[3-aryl(heteryl)-4-pyrazolyl]-4-methylphosphonates, which, on hydrolysis with 20% hydrochloric acid, yielded the corresponding aminophosphonic acids 302 (Scheme 27) . An expedient synthesis of 1,3-diaryl-4-(3,39-diindolyl)methylpyrazoles has been developed using Amberlyst 15-catalyzed condensation of 1,3diaryl-4-formyl pyrazoles with indoles .

ð56Þ

Scheme 26

ð57Þ

Scheme 27

5-Fluoro-1-phenylpyrazole-4-carboxamides 304 have been formed by condensation of the 5-fluoro-1-phenylpyrazole4-carboxylic acid 303 with amines (Equation 58) . 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole3-carboxylic acid 305 was converted via reactions of its acid chloride with alcohols or N-nucleophiles, into the corresponding ester or amide derivatives 306 (Equation 59) . Resin-bound pyrazole-4-carboxylic

51

52

Pyrazoles

acid 307 was transformed into the corresponding azide using diphenylphosphoryl azide (DPPA) followed by Curtius degradation, protection with 9-fluorenemethanol (FmOH), and acidic cleavage from the resin to give 3-amino-4-Fmocprotected pyrazole 308 in moderate yield (Fmoc ¼ 9-fluorenylmethyloxycarbonyl group; Scheme 28) . 4-Oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxamides 310 were prepared from pyrazoloketo acids 309 using a modified Ugi condensation with isocyanides and amines (Equation 60) . 1H-Pyrazole-3-carboxylic acid was converted via reactions of its acid chloride with various binucleophiles like 1,2-diaminoethane, 1,2-diaminopropane, and 2-amino-2-methylpropanol into the corresponding bis(1H-pyrazole-3-carboxamides) in good yields . 4-Benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid 311 can be converted into its rather stable intermediate acid chloride, which can react with various alcohols or N-nucleophiles to give pyrazoles 312 (Equation 61) . Reaction of 312 with hydrazines afforded pyrazolo[3,4-d]pyridazines 313.

ð58Þ

ð59Þ

Scheme 28

ð60Þ

ð61Þ

Pyrazoles

1,3-Disubstituted 1H-pyrazole-4-carbaldehyde N,N-dimethylhydrazones 314 reacted with the Vilsmeier–Haack reagent, utilising the aza-enamine concept, in an electrophilic substitution reaction at the azomethine C-atom yielding the 1,4,5-triaza-pentadienium salts 315 (Scheme 29) . These were hydrolyzed to give 2-hydrazono-2-(1H-pyrazole-4-yl)ethanals 316. The electrophilic attack did not take place at the vinylogous position 59 of the pyrazoles.

Scheme 29

4.01.7.3 N-Linked Substituents 4.01.7.3.1

Aminopyrazoles and -indazoles

4.01.7.3.1(i) Various reactions 3- and 5-Aminopyrazoles are very useful as starting materials for the syntheses of various fused ring systems. Many specific examples of these pyrazole fused ring systems can be found in Section 4.01.11. Selective protection of 3-aminopyrazoles can lead to a variety of 3-acylaminopyrazole derivatives. 3-Aminopyrazole 317 could be selectively protected at N-2 giving BOC-protected pyrazole 318, which reacted with various acyl chlorides followed by BOC removal to provide 3-acylated pyrazoles 319 (Scheme 30) . Other protecting groups such as carbobenzyloxy (Cbz), benzyl (Bn), and SEM could be introduced at the N-2 position with biphasic conditions using potassium hydroxide as the base. A simple procedure for the BOC protection of H-1 of 3-aminopyrazoles has been described where 3-acylaminopyrazole derivatives could be prepared in good yields .

Scheme 30

Various interesting reactions of 5-aminopyrazoles have been reported. Reaction of 5-amino-3-methyl-1-(Ar-substituted)pyrazoles 320 with 2-acetyl-1-phenyl-3-pyrazolidinol 321 in the presence of a five-fold excess of alumina in warm benzene selectively formed products of substitution at the 5-amino group to give pyrazoles 322 (Equation 62) . 5-Amino-1-aryl-4-methylpyrazoles 323 readily added to methyl 1-aryl-2,2,2-trifluoroethylidene carbamates 324 to give the corresponding methyl 1-aryl-2,2,2-trifluoro-1-(5-pyrazolylamino)ethyl carbamates 325, which underwent fragmentation to afford N-(5-pyrazolyl)-1-aryl-2,2,2-trifluoroethanimines 326 (Scheme 31) . 5-Aminopyrazole is known to be a highly reactive heterocyclic C-nucleophile. For example, 5-aminopyrazoles 327 reacted with N-benzyl-3-cyanopyridinium chloride 328 to give 1-benzyl-3-cyano-4-(5-aminopyrazol-4-yl)-1,4-dihydropyridines 329 with high regioselectivity via C-nucleophilic additions (Equation 63) . A rearrangement product 332, not the anticipated 333, was obtained when 5-N-(benzotriazol-1ylmethyl)amino-3-tert-butyl-1-phenylpyrazole 331 was treated with electron-rich alkenes using a protic or Lewis acid catalyst . Attempts to form 333 in the presence of silver nitrate led to pyrazolic Tro¨ger’s base 334 (Scheme 32).

53

54

Pyrazoles

ð62Þ

Scheme 31

ð63Þ

Scheme 32

Condensation of 5-amino-3-(2-pyrrolyl)pyrazoles with 1-vinyl(ethyl)-2-formylimidazoles afforded complex heterocyclic ensembles; Schiff bases containing pyrrole, pyrazole, and imidazole rings were the products with various cis/ trans-ratios . Starting from 1,3-dimethyl-5-aminopyrazole and p-substituted benzaldehydes (R ¼ H, Me, NO2), four different compounds were obtained: the Schiff bases, a bis-pyrazolyl Schiff base (R ¼ H), the expected bispyrazolo[3,4-b;49,39-e]pyridine (R ¼ Me), and the carbinol derived from the Schiff base (R ¼ NO2), depending on the starting benzaldehyde . The mechanisms of the cascade reactions of aminosubstituted pyrazoles with 1,3,5-triazines have been studied using first principles MP2/6-311þþG** //B3LYP/6-31G*

Pyrazoles

calculations in both the gas and solution phases . The interaction of 3,5-diamino-4-nitropyrazole with electrophilic reagents such as acetic anhydride, DMFDMA, orthoformic esters and ketones were investigated . The use of 3-aminopyrazole derivatives as -sheet templates was investigated using a series of ferrocenoyl (Fc)-dipeptides (Fc-Gly2-OEt, Fc-Ala2-OBzl, Fc-Leu-Phe-OMe, Fc-Val-Phe-OMe, Fc-Phe2-OMe, Fc-Leu2-OMe, Fc-Val2-OMe). Synthetic, spectroscopic, structural, and electrochemical studies were reported .

4.01.7.3.1(ii) Diazotization Diazotization of 4-amino-5-alkynylpyrazole 335 followed by intramolecular cyclization gave 7-chloro-1H-pyrazolo[4,3-c]pyridazines 336; the amino and alkynyl positional isomers at the C-3 and C-4 positions were also cyclized to give other pyrazolopyridazines (Equation 64) . Diazotization of 4-aryl-5-aminopyrazoles (aryl ¼ 4,5-dimethoxyphenyl and indol-3-yl) followed by intramolecular azo coupling reactions led to the corresponding pyrazolo[3,4-c]cinnolines or pyrazolo[39,49:6,5]pyridazino[3,4-b]indoles .

ð64Þ

Diazotization of 5-aminopyrazole 337 in acetic acid afforded 3H-pyrazolo[3,4-c]cinnoline 338 via intramolecular azo coupling while diazotization in sulfuric acid in the presence of arenes resulted in the formation of 5-arylazopyrazoles 339 (Equation 65) .

ð65Þ

4.01.7.3.1(iii) Oxidation Substituted 3-anilino-1,5-diphenylpyrazoles were oxidized with lead(IV) tetraacetate in benzene or methylene chloride solution . ESR measurements confirmed the formation of aminyl radicals from para-CH3-substituted pyrazoles. The radical intermediates from unsubstituted pyrazoles were recognized by their transformations to triarylaminium cation radicals. These were generated by consecutive oxidation of the dimeric products the structures of which were proved by NMR spectroscopy and 15N labeling.

4.01.7.3.2

Imines

6-Azido-1H-pyrazolo[3,4-b]pyridine-5-carbaldehydes reacted with aromatic amines to give the corresponding N-arylimines which cyclized in refluxing toluene to give 6-aryl-1,6-dihydrodipyrazolo[3,4-b]pyridines .

55

56

Pyrazoles

4.01.7.3.3

Nitro and nitroso groups

A review covers the synthesis and reactions of the nitropyrazoles . 3- or 5-Substituted-1-methylpyrazole-4-carbonitriles were obtained from reactions of isomeric 1-methyl-3-nitro- and 1-methyl-5-nitropyrazole-4-carbonitriles with sulfur, oxygen, and nitrogen nucleophiles in the presence of potassium carbonate or sodium methoxide . Pyrazole amino acid oligoamides were prepared on polyethylene glycol starting from 3-nitro-1Hpyrazole-5-carboxylic acids or protected 3-aminopyrazole amino acids . A polymer support facilitated product isolation during synthesis and made the target oligoamides soluble in chloroform and water. Alkaline hydrolysis of mono- and dinitro derivatives of pyrazole is accompanied by the elimination of the nitro group as a nitrite anion . The hydrolysis kinetics were studied by polarographic and photometric methods.

4.01.7.3.4

Azo-, diazo-, and azidopyrazoles

Azo-, diazo-, and azidopyrazoles have been employed as useful starting points for syntheses of pyrazole-fused ring systems. A one-pot and convenient synthesis of multisubstituted pyrazolo[3,4-b]pyridines 342 has been achieved by a two-step reaction: diazo transfer of 5-azido-1-phenylpyrazole-4-carboxaldehydes 340 with ketones 341 in ethanolic potassium hydroxide to give 5-amino-1-phenylpyrazole-4-carboxaldehyde and subsequent Friedla¨nder reaction of 5-amino-1-phenylpyrazole-4-carboxaldehyde with ketones (Equation 66) . Cycloaddition of 5-azidopyrazoles with methyl prop-2-ynoate afforded 1-(pyrazol-5-yl)-1,2,3-triazoles, which on FVP gave 5-methoxypyrazolo[1,5-a]pyrimidin-7-ones . 5-Azido-3-benzyl-4-formyl-1-phenylpyrazoles 343 extruded dinitrogen upon heating in toluene to give the corresponding nitrenes, which immediately rearranged via a ring-opening–ring-closure sequence to produce an equimolar mixture of 4-cyano-2-phenyl-3-phenylazofurans 344 and 3-benzyl-4-cyano-1phenylpyrazoles 345 (Equation 67) . Ethyl 5-diazopyrazole-4-carboxylate 346 participated in a C-azo coupling reaction with resorcinol to give 5-azopyrazole-4-carboxylate 347, which under acidic conditions cyclized to benzo[e]pyrazolo[5,1-c][1,2,4]triazine 348 (Scheme 33) . -Naphthol, N,N-dimethylaniline, 1,3,5trimethoxybenzene, and 1,3-dimethoxybenzene also were azo-coupled to 346 and cyclized further to other products.

ð66Þ

ð67Þ

Scheme 33

Pyrazoles

4.01.7.4 O-Linked Substituents 4.01.7.4.1

3-Hydroxypyrazoles

Heating dipolarophiles with 4-alkyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide inner salts 349 resulted in [3þ2] cycloaddition across positions 3a and 5 of the aromatic system to give the [3þ2] cycloadducts 350 in good yields (Equation 68) .

ð68Þ

4.01.7.4.2

4-Hydroxypyrazoles

An efficient route to 4-aryloxy pyrazoles 353 bearing a trifluoromethyl group has been developed from 4-hydroxypyrazole 351 and 3,5-dicyanofluorobenzene 352 under basic conditions, with concomitant removal of the silyl group (Scheme 34) . Removal of the N-hydroxyethyl group was achieved by a two-step protocol involving mesylation followed by treatment with sodium cyanide at elevated temperatures, resulting in the formation of the dealkylated compound 354.

Scheme 34

4.01.7.4.3

5-Hydroxypyrazoles

5-Hydroxypyrazoles can be converted into their corresponding sulfonates, which can then be used in Suzuki crosscoupling reactions. For example, palladium-catalyzed cross-coupling of pyrazolyl triflates 355 with aryl boronic acids afforded highly substituted pyrazoles 356 (Equation 69) . The new bifunctional reagent 1-methyl-3bromo-pyrazol-5-yl nonaflate 357 underwent highly chemoselective Pd-catalyzed couplings to the nonaflate, followed by Suzuki couplings to the bromide, allowing sequential, regioselective introduction of the two aryl substituents to give coupled products 358 and 359 (Scheme 35) .

ð69Þ

57

58

Pyrazoles

Scheme 35

Attempted O-arylation of 5-hydroxypyrazole 360 resulted in aryl migration from the initially formed ether 361 to give 4-arylpyrazole-1H-5-ol derivatives 362 (Scheme 36) . 1-Acyl-5-hydroxy-1H-pyrazoles are useful acylating agents for alcohols, phenols, amines, and hydrazines .

Scheme 36

4-Keto-5-hydroxypyrazoles have been utilized as intermediates in the synthesis of fused pyrazole ring compounds. 4-Acetyl-5-hydroxy-1-phenyl-1H-pyrazole 363 reacted with benzoyl chloride and lithium bis(trimethylsilyl)amide to give an intermediate diketone, which was cyclized in the presence of acid to yield 1,6-diphenyl-1H-pyrano[2,3c]pyrazole-4-one 364 (Equation 70) . Similarly, Claisen condensation of 4-acetyl-5-hydroxypyrazoles with esters followed by acid-catalyzed ring closures provided a route to 1H-pyrano[2,3-c]pyrazol-4-ones . 4-Benzoyl-3-chloropyrazoles 366, prepared from 4-benzoyl-5-hydroxypyrazoles 365 with phosphorus oxychloride, were converted into oximes followed by intramolecular base-promoted cyclizations to give 3-phenyl-6H-pyrazolo[4,3-d]isoxazoles 367 (Scheme 37) .

ð70Þ

Scheme 37

Pyrazoles

Rearrangement of 5-acylpyrazole derivatives can occur if there is no substituent at the 4-position of the pyrazole depending on the reaction conditions. Substitution by phase transfer-catalyzed alkylation of 5-hydroxy 3-substituted1H-pyrazoles 368 by different alkyl halides in the presence of tetrabutylammonium bromide (TBAB) gave O-alkylated pyrazoles 369, whereas in the presence of carbon disulfide, 5-hydroxy-3-substituted-1H-pyrazole-4-carbodithionate 370 was formed (Scheme 38) . 5-Hydroxy-1-phenyl-3-pyrazolones 371 can be converted, with a number of aromatic acid chlorides, into their enol esters 372 which rearrange in the presence of potassium cyanide, triethylamine, and 18-crown-6 as catalyst to yield 5-hydroxypyrazolonyl aryl ketones 373 (Scheme 39) . 4-Benzoyl-3trifluoromethyl-5-p-toluenesulfonyloxypyrazole derivatives were synthesized by the rearrangement of the benzoyl groups in 5-benzoyloxy-4-bromo-3-trifluoromethypyrazole to 4-benzoyl-5-hydroxy-3-trifluoromethylpyrazoles via lithium–bromide exchange using tert-butyllithium . 4-Acyl-5-hydroxy-1-phenyl-3-trifluoromethylpyrazoles 376 were prepared by reaction of 1-phenyl-3-trifluoromethyl-1H-pyrazol-5-ol 374 with trimethyl orthoacetate, triethyl orthopropionate, and triethyl orthobenzoate, respectively, followed by hydrolytic cleavage of the first formed condensation products 375 (Scheme 40) .

Scheme 38

Scheme 39

Scheme 40

An electrochemical study related to the electrooxidation of the 3-hydroxy and 3-methyl derivatives of 1-phenyl-4butyldithiocarboxylato-5-hydroxypyrazole in aqueous ethanol solutions covering a wide pH interval was performed .

4.01.7.5 S-Linked Substituents There are only a few reports in this area. Reaction of a pyrazolyl disulfide 377 with bromotrifluoromethane and ethyl bromide in the presence of sodium dithionite at room temperature afforded pyrazolyl sulfides 378. Oxidation of these with hydrogen peroxide in trifluoroacetic acid afforded sulfenylpyrazoles 379 in excellent yields (Scheme 41) . Pyrazole-4-carbaldehyde 380 has been utilized in the efficient synthesis of

59

60

Pyrazoles

thiopyrano[5,6-c]coumarin/[6,5-c]chromones through intramolecular domino Knoevenagel hetero-Diels–Alder reactions with 4-hydroxycoumarin and its benzo analogs and a rapid synthesis of mono- and bistetrahydropyrazolo[49,39:5,6]thiopyrano[4,3-b]quinolines via imino Diels–Alder reactions .

Scheme 41

4.01.7.6 Halogen Atoms 4.01.7.6.1

Nucleophilic substitution reactions: Neutral pyrazoles and indazoles

Many reactions have been reported in this area since the last report . 5-Chloropyrazoles have been utilized in a myriad of nucleophilic substitution reactions. Various nucleophilic heteroaromatic substitutions on 5-chloropyrazoles 381 occur readily in warm DMF to give 5-substituted pyrazoles 382 (Equation 71) . Nucleophilic substitution reactions of 5-chloropyrazoles 383 with amines and thiols under mild conditions provided 5-alkylamino- and 5-alkylthiopyrazoles 384 (Equation 72) . Fluoride-mediated nucleophilic substitution reactions of 1-(4-methylsulfonyl(or sulfonamide)-2-pyridyl)-5-chloro-4-cyanopyrazoles with various amines and alcohols occurred under mild conditions to provide 5-alkylamino- and 5-alkoxypyrazoles in moderate to high yields . Substitution of 5-chloro-4-formyl-1-phenylpyrazole 385 with prenyl thiolate gave -chloropyrazole-4carbaldehye 386, which is a synthon for the synthesis of polycyclic heterocycles (Equation 73) . Examples include the efficient synthesis of thiopyrano[5,6-c]coumarin/[6,5-c]chromones through intramolecular domino Knoevenagel hetero-Diels–Alder reactions with 4-hydroxycoumarin and its benzo analogs , and a rapid synthesis of mono- and bis-tetrahydropyrazolo[49,39:5,6]thiopyrano[4,3-b]quinolines via imino Diels–Alder reactions . The reaction of 5-chloro-1,3-dimethyl-4-nitropyrazole 387 with ethyl cyanoacetate in DMSO in the presence of potassium carbonate led to ethyl 2-cyano-2-(1,3-dimethyl-4-nitro-1H-pyrazol-5-yl)acetate 388 (Equation 74) . 3-Chloro-5,7-dinitroindazoles 389 and 391 underwent nucleophilic displacement with morpholine in refluxing 1,4-dioxane to give 3-morpholinoindazole 390 (Scheme 42) . 5-Aminopyrazoles 393 were obtained by direct reaction of the ester 392 with lithium arylamides (Equation 75) .

ð71Þ

Pyrazoles

ð72Þ

ð73Þ

ð74Þ

Scheme 42

ð75Þ

4.01.7.6.2

Metal–halogen exchange substitution reactions

Several reports have been published where lithium or Grignard derivatives of halopyrazoles have been reacted with various electrophiles. The synthesis of 4-substituted-1-(benzyloxy)pyrazoles 395 has been accomplished via iodine– magnesium exchange of 1-(benzyloxy)-4-iodopyrazole 394 (Equation 76) . Regioselective introduction of electrophiles to the 4-position of 4-bromo-1-[(tert-butyldiphenylsilyl)oxy]pyrazoles 396 via bromine–lithium exchange yielded 4-substituted-5-(tert-butyldiphenylsilyl)-1-hydroxypyrazoles 397 with silyl group migration (Equation 77) . Reaction of iodopyrazol-3-one 398 with diisopropylmagnesium provided the intermediate magnesium pyrazole, which was converted to functionalized pyrazol-3-ones 399 with various electrophiles

61

62

Pyrazoles

(Equation 78) . 3-Arylated 1-hydroxypyrazoles were synthesized via 3-metallated pyrazole-1-oxides . 4-Silicon- or 4-tin-metallated pyrazoles were prepared from silyl- or stannylcupration from 4-halopyrazoles . 1-Hydroxypyrazole glycine derivatives 402 were prepared from iodopyrazoles 400 via Grignard addition to N-BOC-iminomalonate 401 as an electrophilic glycine equivalent (Scheme 43) .

ð76Þ

ð77Þ

ð78Þ

Scheme 43

4.01.7.6.3

Metal-catalyzed cross-coupling reactions

The number of palladium-catalyzed cross-coupling reactions of halogen-substituted pyrazoles and indazoles has increased greatly in recent years. However, protection of the nitrogen is required for cross-coupling reactions to work. In the first reports of this kind of chemistry, it was found that substituents at the 1-position on the pyrazole ring affected the yields and that a dimethylsulfamoyl group, as an electron-withdrawing group, gave the highest yield as seen in the synthesis of 5phenyl-1-dimethylsulfamoylpyrazoles 403 and 404 (Equations 79 and 80) . The cross-coupling reaction of 1-aryl-5-bromopyrazoles 405 with alkynes, vinyltin reagents, and arylboronic acids promoted by a palladium catalyst afforded unsymmetrical 3,5-disubstituted-1-arylpyrazoles 406 (Equation 81) . 4-Iodopyrazole 407 was protected with ethyl vinyl ether to give pyrazole 408, which underwent palladium-catalyzed cross-couplings with substituted alkynes and deprotection affording 4-alkynyl-substituted pyrazoles 409 (Scheme 44) . 3-Iodoindazole 410 underwent combined N-1 and C-3 arylations with boronic acids in a one-pot palladium-catalyzed reaction to give 1,3-diarylindazoles 411 (Scheme 45) , and 410 also participated in a Heck cross-coupling reaction with methyl acrylate to give indazole 412, which is a useful precursor to 2-azatryptamines . 3-Iodoindazole 410 also underwent Sonogashira-type cross-coupling reactions with various terminal alkynes, thus providing a general route to 3-alkynylindazoles 413 (Scheme 45) . 7-Iodopyrazolo[1,5-a]pyridines 414 underwent palladium-catalyzed Stille cross-coupling reactions to afford 7-substituted pyrazolo[1,5-a]pyridines 415 (Equation 82) . Suzuki cross-coupling of 3-iodoindazoles with arylboronic acids provided a general and flexible route to 3-arylindazoles . The reaction of functionalized 3-iodoindazoles with a higher-order cuprate provided polyfunctional 3-cuprated indazoles which were readily acylated with various acid chlorides giving 3-ketoindazoles . 4-Arylpyrazoles could be synthesized either by palladium-catalyzed reactions of N-trityl-protected 4-tributylstannylpyrazoles with aryl iodides or N-trityl-protected 4-iodopyrazoles with aryltributylstannanes . 4-(5-iodo-3-methylpyrazolyl)phenylsulfonamide 416 served as an efficient template for the preparation of Suzuki-coupled

Pyrazoles

products 417 using catalytic palladium on carbon with arylboronic acids (Equation 83) . 1-Benzyl-4(1H)pyrazole can be cross-coupled with 3-pyridine-boronic acid in excellent yield .

ð79Þ

ð80Þ

ð81Þ

Scheme 44

Scheme 45

63

64

Pyrazoles

ð82Þ

ð83Þ

Several pyrazoloquinolines and pyrazoloisoquinolines were halogenated, and the utility of these halides was demonstrated by a series of palladium-catalyzed cross-coupling reactions . 4-Substituted and 3,4-disubstituted indazole derivatives were obtained by palladium-catalyzed cross-coupling reactions , and these compounds were further elaborated into other indazoles . !-Functionalized-3-alkylpyrazolo[1,5-a]pyrimidines were prepared by Sonogashira couplings of 3-iodopyrazolo[1,5-a]pyrimidines with propargylic and homopropargylic compounds . 3-Chloro-1-phenyl-2-pyrazoline underwent Suzuki cross-coupling reactions efficiently with arylboronic acids in good yields under microwave irradiation . 5-Bromo-3-iodoindazole has been employed in sequential Sonogashira and Suzuki cross-coupling reactions .

4.01.7.6.4

Metal and metalloid-linked substituents

The Stille reaction of tributylstannylpyrazoles and the Suzuki reaction of pyrazole boronate esters or boronic acids have found several applications in cross-coupling reactions. The palladium-catalyzed cross-coupling reactions of aryl iodides and 5-tributylstannyl-4-fluoropyrazole 419 prepared from fluoro(tributylstannyl)acetylene 418 proceeded smoothly to give the corresponding 5-aryl-4-fluoropyrazole 420 in good yields (Scheme 46) . Furthermore, N-methylation at the pyrazole ring by sequential treatment of 5-tributylstannyl-4-trifluoromethylpyrazole 419 with LDA and iodomethane regioselectively provided the N-methylpyrazole 421 (Scheme 47) . The addition reaction of 5-lithiated-4-trifluoromethylpyrazole with a wide range of aldehydes or ketones allowed easy and high-yielding introduction of substituents at C-5 to give pyrazoles 422. N-1-Substituted pyrazole boronic acids could be cross-coupled with chloro- and bromobenzene efficiently with a palladium catalyst .

Scheme 46

Scheme 47

Pyrazoles

Efficient preparation of 3-aryl-1H-pyrazoles 424 by reaction of 1-protected-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1H-pyrazoles 423 with (het)aryl halides has been described (Scheme 48) . The SEM protecting group was difficult to remove in the presence of a carboxylate group and often required drastic refluxing conditions and excess tetrabutylammonium fluoride. Using a THP protecting group was found to alleviate these shortcomings. Starting from 1H-pyrazole, a large number of 1-alkyl-1H-pyrazol-4-yl and 1-alkyl-1H-pyrazol-5-ylboronic acids and their pinacol esters were synthesized . The key step in the methodology was the regioselective lithiation of the pyrazole ring; the pinacolates were stable to prolonged storage and were convenient as organic reagents.

Scheme 48

4.01.8 Reactivity of Substituents Attached to Ring Nitrogen Atoms 4.01.8.1 Aryl Groups 1-Phenylpyrazole 425 can undergo palladium-catalyzed arylation of the phenyl ring, ortho to the pyrazole, via C–H functionalization to give biphenylpyrazoles 426 (Equation 84) . Comparable arylations can utilize aryl tosylates or aryl chlorides, with a ruthenium catalyst, ortho to the heterocycle in 1-phenyl- or 1-(p-tolyl)pyrazoles 427 to give pyrazoles 428 (Equation 85) . CAN in methanol–water gave a new N-dearylation of a series of substituted 1-( p-methoxyphenyl)pyrazoles 429 producing p-benzoquinone and the parent azole 430 when used in a mole-for-mole ratio (Equation 86) .

ð84Þ

ð85Þ

ð86Þ

65

66

Pyrazoles

4.01.8.2 Alkyl Groups Fused pyrazole compounds have been prepared from N-alkyl-substituted pyrazoles. For example, a palladiumcatalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C–H functionalization as the key step has been described, in which an alkyl–aryl bond and an aryl–heteroaryl bond are formed in one pot. A variety of highly substituted six-membered annulated pyrazoles 433 were synthesized in a one-step process in moderate yields from N-bromoalkyl pyrazoles 431 and aryl iodides 432 (Equation 87) . An intramolecular cyclization version has also been reported. Exposure of 2 equiv of n-butyllithium to 1H-pyrazole-1-alkanoic acids 434 afforded the cyclic ketones 435 via a Parham-type cyclization process (Equation 88) .

ð87Þ

ð88Þ

N-(Cycloalken-1-yl)pyrazoles 438 were synthesized via elimination of benzotriazole from the corresponding 1-[1(pyrazolo)cycloalkyl]benzotriazoles 437, prepared from 1-(benzotriazolylmethyl)pyrazole 436 (Scheme 49) . The reaction of 1-(3,5-dimethylpyrazol-1-yl)acetone 439 with phenyldiazonium chloride afforded the corresponding phenylhydrazone 440, which was converted into pyridazines 441 and 442 by condensation with active methylene nitriles and DMFDMA, respectively (Scheme 50) .

Scheme 49

Scheme 50

Pyrazoles

1-Benzylindazole and 1-benzyl-4-bromo-3,5-dimethylpyrazole were efficiently debenzylated with potassium tertbutoxide in DMSO and oxygen at room temperature . Alkylation of pyrazoles 443 with 2,2-dichloroethyl ether under conditions of phase-transfer catalysis gave N-[2-(2-chloroethoxy)ethyl]pyrazoles 444, which underwent dehydrochlorination with potassium hydroxide in DMSO giving N-(2-vinyloxyethyl)pyrazoles 445 (Scheme 51) .

Scheme 51

4.01.8.3 N-Acyl and Carbonyl Derivatives N-Acyl pyrazoles have been employed as versatile intermediates in some reactions. Indium-mediated coupling of allylic bromides 447 with N-acyl-pyrazoles 446 in aqueous media provided an efficient regioselective synthesis of the corresponding ,-unsaturated ketones 448 in good yields (Equation 89) . Various -keto esters 450 were prepared either by the alcoholysis of N-(4-oxoalkanoyl)pyrazoles or the Grignard replacement of the pyrazole moiety of 4-(N-pyrazolyl)-4-oxoalkanoic esters 449 (Equation 90) . By using 3-phenyl-l-menthopyrazole as a chiral auxiliary, -substituted -keto esters were obtained enantioselectively. 1-(N-Arylthiocarbamoyl)amidino-3,5-dimethylpyrazoles on reaction with -haloketones or hydrazine afforded 2,4-diaminothiazoles and 3,5-diamino-1,2,4-triazoles, respectively .

ð89Þ

ð90Þ

A series of 2-(5-aryl-3-styryl-4,5-dihydro-1H-pyrazol-1-yl)-4-(trifluoromethyl)pyrimidines 453 were synthesized by the cyclocondensation of 5-aryl-1-carboxamidino-3-styryl-4,5-dihydro-1H-pyrazoles 451 with 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones 452 (Equation 91) .

ð91Þ

67

68

Pyrazoles

4.01.8.4 N-Oxides Sequential functionalization of pyrazole-1-oxides via regioselective metallation led to the synthesis of 3,4,5-trisubstituted-1-hydroxypyrazoles . 3-Acylated-2-(4-methoxybenzyl)-2H-pyrazole 1-oxides were formed by the reaction between a 3-magnesium 2H-pyrazole-1-oxide and acid chlorides . 3-Arylated-1hydroxypyrazoles were synthesized from 3-metallated-pyrazole 1-oxides . The reaction between hexafluorobenzene and the anion of 1-hydroxypyrazole affords a mixture of the products of bis-, tetrakis-, and hexakis-substitution . In the case of hexakis(bromomethyl)benzene, its reaction with 1-hydroxypyrazole leads to the hexakis-substituted product.

4.01.8.5 N-Amino Groups N-Aminopyrazoles 454 were found to react with nitric oxide in the presence of oxygen to afford deaminated products 455 in high yields (Equation 92) . This reaction was also performed successfully on 1-amino- and 2-aminoindazoles and on 6-nitro-1-aminoindazole. The anion of 1-aminopyrazole and hexafluorobenzene afforded only the product of monosubstitution at the amino group, probably due to the acidity of the remaining NH .

ð92Þ

4.01.8.6 N-Nitro Groups Electrochemical reduction and chemical reduction by cysteine or potassium ferrocyanide of N-nitropyrazoles provided a new source of nitric oxide .

4.01.9 Syntheses Classified by Number of Ring Atoms in Each Compound 4.01.9.1 Ring Synthesis from Nonheterocycles 4.01.9.1.1 4.01.9.1.1(i)

Formation of one bond Via hydrazones

4.01.9.1.1(i)(a) Cyclization under basic conditions

The reaction of enolizable ketones 457 with 1-alkyl-1-cyanohydrazine 456 led to cyanohydrazones 458, which cyclized under mildly basic condtions to give the corresponding 5-aminopyrazoles 459 (Scheme 52) . Aminohydrazones 460 underwent base-promoted heterocyclization at room temperature to produce 1-aminocarbonyl1H-pyrazol-5(2H)-ones 461, which on thermal solvolytic cleavage afforded 1H-pyrazol-5(2H)-ones 462 (Scheme 53) . Base-mediated synthesis of 1,4-dihydrobenzopyranopyrazoles 466 was achieved with bromovinyl hydrazones 463 via [2þ3] intramolecular cycloaddition in a diazo intermediate 464 (Scheme 54) .

Scheme 52

Pyrazoles

Scheme 53

Scheme 54

4.01.9.1.1(i)(b) Cyclizations via acidic conditions

Hydrazone 1,4-adducts 467, prepared from thiocarboxylic acids and conjugated azoalkenes, reacted with trifluoroacetic acid in refluxing chloroform to give 1-alkoxycarbonyl-3-methyl-4-acylthio-5-alkoxypyrazoles 468 (Equation 93) . Reactions of 468 with sodium hydride afforded pyrazolone-type products, while in acidic media hydrolysis products were observed. 1,4-Diazabicyclo[2.2.2]octane (DABCO)-catalyzed aza-Michael additions of hydrazones 469 to activated alkenes 470 gave products 471, which underwent cyclization to 4,5-dihydropyrazoles 472 upon treatment with acid (Scheme 55) . Cyclization of hydrazones 473 with PPA gave substituted indazoles 474 (Equation 94) .

ð93Þ

Scheme 55

69

70

Pyrazoles

ð94Þ

4.01.9.1.1(i)(c) Cyclizations via Vilsmeier–Haack conditions

Condensation of -keto-ester hydrazones 475 with the Vilsmeier reagent yielded a general synthesis of 1,3-diaryl-4pyrazoleacetic acid esters 476 (Equation 95) . Regioselective addition of lithiated -hydrazonophosphino oxides 477 to isocyanates afforded functionalized hydrazonoamides 478, which were then cyclized to 5-aminopyrazoles 479 with phosphorus oxychloride in the presence of triethylamine (Scheme 56) .

ð95Þ

Scheme 56

4.01.9.1.1(ii) Intramolecular cyclization of nitrogen-containing groups with unsaturated systems Thermolysis reactions have also been investigated as methods for preparing pyrazoles. Thermolysis of azido imines 480 led to 2-substituted-4,6-dinitro-2H-indazoles 481 (Equation 96) . High-temperature intramolecular cyclization of N,N-diethyl-N9-(4-substituted-2-ethynylphenyl)triazenes 482 under neutral conditions provided both 5-substituted isoindazoles 483 and 6-substituted cinnolines 484 (Equation 97) . 3-Substituted1H-indazoles 487 were prepared from the cyclocondensation of (2-chloroaryl)acetylenes 485 with hydrazine via 486 in refluxing n-butanol (Scheme 57) . Lewis-acid promoted ‘coarctate’ cyclization of 10 2-(phenylazo)benzonitrile derivatives furnished isoindazoles .

ð96Þ

Pyrazoles

ð97Þ

Scheme 57

Treatment of resin-bound -arylazobenzhydryl 488 with a Lewis acid at room temperature followed by acidic cleavage furnished indazole 489 in quantitative yield, the reaction being monitored by single bead IR microspectroscopy (Equation 98) . Unsymmetrical azines 490 thermally cyclized to fused pyrazoles 491 (Equation 99) . Indazoles 493 were obtained from thermal cyclizations of (2-alkynylphenyl)triazenes 492 in the presence of methyl iodide as a solvent; other solvents were tested where either no reaction or complex mixture of products was obtained (Equation 100) .

ð98Þ

ð99Þ

ð100Þ

71

72

Pyrazoles

4.01.9.1.1(iii)

Intramolecular palladium-catalyzed reactions

4.01.9.1.1(iii)(a) Cyclization via hydrazines

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. N-Aryl-N-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2H-indazoles 495 (Equation 101) . Palladium-catalyzed intramolecular C–N bond formation of N-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[1,2-b]indazoles 498 via intermediate 497 (Scheme 58) . 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of N-tosyl-N-(1-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposure of the reaction mixture of the cyclization to potassium tert-butoxide . N-Aryl-N9-(o-bromobenzyl)hydrazines 499 or [N-aryl-N9-(o-bromobenzyl)hydrazinato-N9]-triphenylphosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl1H-indazoles 500 (Scheme 59) .

ð101Þ

Scheme 58

Scheme 59

4.01.9.1.1(iii)(b)

Cyclization via hydrazones

An efficient method for the preparation of 3-substituted indazoles 503 was developed using a palladium-catalyzed intramolecular amination reaction of 2-bromophenyl hydrazone derivatives 502 (Equation 102) . Good functional group compatibility was observed under mild reaction conditions and various 3-substituted indazoles were obtained in moderate to excellent yields. Palladium-catalyzed cyclization of arylhydrazones of 2-bromoaldehydes and 2-bromoacetophenones to give 1-aryl-1H-indazoles has been studied in detail. The cyclization of the arylhydrazones of 2-bromobenzaldehydes 504 can be performed with good to high yields using Pd(DBA)2 and chelating phosphines (DBA ¼ dibenzylideneacetone), of which the most effective is bis[2-(diphenylphosphino)phenyl]ether (DPEphos) in the presence of potassium phosphate as a base to give indazoles 505 (Equation 103) . Two-step one-pot microwave irradiation of 2-halobenzaldehydes or 2-haloacetophenones 506 with phenylhydrazine yielded the aryl hydrazones, which were further cyclized to give 1-phenyl-1H-indazoles 508 via copper(I) diamine-catalyzed N-arylation reactions in the presence of ligand 507 (Equation 104) .

Pyrazoles

ð102Þ

ð103Þ

ð104Þ

4.01.9.1.1(iv) Miscellaneous cyclizations Hydrogenation of methyl 2-Cbz(hydrazine)-3-hydroxy-4,4-dimethoxybutanoate 509 followed by cyclization in the presence of trifluoroacetic acid afforded the first asymmetric synthesis of the (4S,5R)-5-carbomethoxy-4-hydroxy-2pyrazoline 510 (Equation 105) . Reaction of allylhydrazines with phenylselenenyl sulfate, produced from diphenyl diselenide and ammonium persulfate in the presence of trifluoromethanesulfonic acid, afforded phenyselenyl-substituted pyrazolidines, which underwent dehydrogenation and oxidative deselenenylation to give pyrazole derivatives . Pyrazolidine, 1-pyrazoline, and 2-pyrazoline derivatives were prepared by selenium-induced cyclizations of homoallylhydrazines . An electrochemical methodology for an efficient access to orthonitrosobenzylamines 512 from ortho-nitrobenzylamines 511 has been developed; these products were cyclized to produce the desired 2-substituted indazoles 513 in high yields (Scheme 60) .

ð105Þ

Scheme 60

73

74

Pyrazoles

4.01.9.1.2 4.01.9.1.2(i)

Formation of two bonds Hydrazines and 1,3-difunctional reagents

4.01.9.1.2(i)(a) From -ketoketones

Pyrazoles can be prepared by the solventless condensation of diketones and hydrazines in the presence of catalytic amount of sulfuric acid at ambient temperature . 1,3-Diketones were synthesized directly from ketones and acid chlorides and were then converted in situ into pyrazoles by the addition of hydrazine . This method is extremely fast, general, and chemoselective, and permits the synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole-containing fused rings. Efforts have been made to investigate the intermediates formed by the reaction of arylhydrazines and 1,3-dicarbonyl compounds in the preparation of pyrazoles; the isolable hydroxy-pyrazoline intermediates, subtle regioselectivity, the relative reaction rate variations observed during acid-catalyzed and neutral pyrazole cyclizations were all discussed . The factors affecting regioselectivity during the formation of 1,5-diarylpyrazoles from arylhydrazines and 1,3-diketones were identified and the regioisomers were characterized by 1-D NOESY, liquid chromatography–nuclear magnetic resonance (LC–NMR), and X-ray analyses . New bis-pyrazole derivatives were synthesized from aryl- and xylyl-linked bis(-diketone) precursors . Pyrazoles and tetrahydroindazoles can be prepared by condensation of 1,3-diones and hydrazines with layered zirconium sulfophenyl phosphonate catalysis, in solvent-free conditions . Dehydration of the hydroxydihydropyrazoles can be effected with sulfuric acid in acetic acid to give 3-substituted-l-(4-methylquinolin-2-yl)-5-trifluoromethylpyrazoles. 2,6-Bis-hydrazinopyridine has been prepared and used for the preparation of a wide variety of 2,6-bis-pyrazolylpyridines by reactions with 1,3-diketones . This approach represented the most efficient preparation to date of sterically crowded 2,6-bispyrazolylpyridines, and the only method for the preparation of pyrazolylpyridines containing unsymmetrically 3,5-disubstituted pyrazoles with the larger groups in the 5-positions. The interaction of 3,5-dichloro-2-pyridylhydrazine with 1,3-diketones gave 1,3,5-trisubstituted pyrazoles; however, with an acetoacetic ester, a 1,3-disubstituted pyrazol-5-one containing a 3,5-dichloropyridyl residue was obtained . Regioselective preparation of pyrazoles in high yields from 1,3-diketonatoboron difluorides with methylhydrazine and phenylhydrazine has been reported . Reactions between cinnamoyl(2-hydroxybenzoyl)methanes and hydrazine hydrate in acetic acid gave 3-(2-hydroxyphenyl)-5-styrylpyrazoles, while the corresponding reactions with phenylhydrazine yielded 5-(2-hydroxyphenyl)-1-phenyl-3-styrylpyrazoles as the major products and 3-(2-hydroxyphenyl)-1-phenyl-5-styrylpyrazoles as by-products . The synthesis of a series of trimethoxysilyl-tethered N-substituted 3,5-dialkylpyrazolylpyridines from 1,3-diketones bearing a tethered alkoxysilyl group at the 2-position has been reported . A simple alteration in the usual reaction conditions was reported, which allowed the exclusive formation of 1,5-diarylpyrazoles. 1-(1-Carboxy-2-R-4-methylcyclohex-4-enyl)carbonyl- and 1-(2-R-4-methylcyclohex-4-enyl)carbonyl-3,5-dimethyl(diphenyl)pyrazoles were obtained from the reaction of monohydrazides of 2-Rmethyl-4-cyclohexene-1,1-dicarboxylic acids and hydrazides of 2-R-4-methyl-4-cyclohexene-1-monocarboxylic acids with acetylacetone or dibenzoylmethane . Primary aliphatic and aromatic amines 514 underwent electrophilic amination with oxaziridine 515 to give the corresponding N-BOC hydrazides which reacted further with 3,5-heptadione 516 to give pyrazoles 517 in a one-pot synthesis (Scheme 61) .

Scheme 61

Various groups substituted between the two carbonyl groups of 1,3-ketones give highly substituted pyrazoles on reaction with hydrazine. For example, 4-alkoxypyrazoles 519 were synthesized from 3,5-heptadiones 518 with

Pyrazoles

hydrazines (Equation 106) . Diketooximes 520 reacted conveniently with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 521 (Equation 107) . 3-Arylhydrazono-4-polyfluoroalkyl2,4-dioxobutanoates reacted with hydrazines to give ethyl 4-aryldiazeno-3-polyfluoroalkyl-1H-pyrazole-5-carboxylates . Reactions of 1,6-disubstituted 3,4-dihydroxy-2,4-hexadiene-1,6-diones with hydrazine hydrate, or hydrazine hydrochloride, afforded heterocyclization products, 3,39-bipyrazoles . Similarly, the chemoselective reaction of 1,6-diaryl-3,4-dihydroxy-2,4-hexadiene-1,6-diones with arylhydrazines gave rise to 1,19,5,59-tetraaryl-3,39-bipyrazoles and 1,5-diaryl-3-aroylacetylpyrazoles.

ð106Þ

ð107Þ

The use of 1,3-dicarbonyl compounds containing strong electron-withdrawing substituents (perfluoroalkyl, 4-nitrophenyl) attached to one of the carbonyl groups in reaction with hydrazine or its monosubstituted derivatives (4-nitro- and 2,4dinitrophenylhydrazines) produces stable intermediates for the synthesis of pyrazoles (5-hydroxy-2-pyrazolines) or their linear tautomers have been reported . Selected 1,3-diketones having a trifluoromethyl group and/or a fluorine at the 2-position were condensed with aromatic hydrazines to provide aryl-, heteroaryl-, and alkyl-substituted trifluoromethyl phenylpyrazoles . Reaction of 2-hydrazino-4-methylquinoline with a series of trifluoromethyl--diketones gave 3-substituted-5-hydroxy-l-(4-methylquinolin-2-yl)-5-trifluoromethyl-4,5-dihydropyrazoles and, in some cases, 5-substituted-l-(4-methylquinolin-2-yl)-3-trifluoromethylpyrazoles, depending on the substitution pattern of the diketone . The reaction between 2-trifluoroacetylcycloalkanones and methylhydrazine or phenylhydrazine afforded exclusively 3-trifluoromethylpyrazoles . The application of microwave heating to a silicaassisted solution-phase synthesis technique has been utilized to develop a rapid and efficient two-step protocol for the preparation of pyrazoles 526 from aryl methyl ketones 522 and ethyl trifluoroacetate 523 with aryl hydrazine 525 via trifluoroketo enol 524 (Scheme 62) . Fluoroalkyl-containing 1,2,3-triketone 2-(2,3-dimethyl-5-oxo-1phenyl-1,2-dihydropyrazol-4-yl)- and 2-(4-ethoxycarbonylpyrazol-3-yl)hydrazones were synthesized by the azo coupling reactions of fluorinated 1,3-diketones with the corresponding hetaryldiazonium chlorides, and the hetarylhydrazones thus synthesized were subjected to cyclocondensation with hydrazines at the 1,3-dicarbonyl fragment to give 3-fluoroalkyl-4hetarylazopyrazoles . Lithium salts of fluorinated -diketones have been employed as fluorine-containing synthons for the preparation of fluoro-substituted pyrazoles . 3-Hydroxyimino-1,1,1-trifluoromethyl-4methyl-2,4-butanedione reacted with hydrazine monohydrate to form the corresponding 4-hydroxyiminopyrazole . Fluorinated 2-arylhydrazones of 3-oxoesters and 1,3-diketones reacted with hydrazine hydrate or phenylhydrazines to give the corresponding pyrazole derivatives .

Scheme 62

75

76

Pyrazoles

The polymer-assisted solution-phase (PASP) synthesis of a 192-member group of 1,5-biaryl pyrazoles from 1,3diketones and 4-hydrazinobenzoic acid as precursors has been reported . Condensation of aromatic or aliphatic esters with resin-supported sulfonamides 527, followed by cyclization with hydrazines, activation with trimethylsilyldiazomethane, and cleavage using amines, provided highly substituted, isomeric pyrazoles 528 and 529 (Scheme 63) .

Scheme 63 4.01.9.1.2(i)(b) From -enaminoketones (esters)

Reaction of 2-bromoacetophenone 530 with DMFDMA to give the intermediate enaminoketones followed by reaction with various arylhydrazines afforded diarylpyrazoles 531, which underwent palladium-catalyzed Mizoroki–Heck intramolecular couplings to give pyrazolo[1,5-f ]phenanthridines 532 (Scheme 64) . A small library of 1,4,5trisubstituted pyrazoles was prepared in solution using a three-step procedure starting from Meldrum’s acid, which was acylated with different acyl chlorides, and the products opened with different alcohols and amines to give substituted -keto esters and -keto amines; further reaction with DMFDMA to the -enaminoesters or amines and the final cyclization were effectively carried out under microwave irradiation in the presence of substituted hydrazines . (Z)-3-Benzoylamino-4-dimethylamino-2-oxo-3-butene, prepared from 1-benzoylamino-2-propanone and DMFDMA, was converted regioselectively by reaction with a series of hydrazines into 1-substituted-4-benzoylamino-5-methyl-1H-pyrazoles . Microwave-assisted condensation of aromatic ketones with N,N-dimethylformamide diethyl acetal yielded 1-aryl-3-dimethylaminoprop-2-enones, which in the presence of hydrazine afforded the corresponding 3-arylpyrazoles .

Scheme 64

-Aminoenones react with monoalkyl hydrazines to give 1,3,5-trisubstituted pyrazoles regioselectively . The mechanism and level of regioselectivity depend on both the substitution pattern of the substrates and the reaction conditions. When the least bulky substituent is attached at the -position of the enone, a high regioselectivity is obtained, usually higher than that from equivalent -diketones. Reactions of -acylenaminoketones with hydrazines afforded various substituted pyrazoles . Aqueous one-pot synthesis of pyrazoles from enaminoketones promoted by microwave irradiation has been reported . A convenient method to obtain 3-amino-5-trifluoromethyl-1H-pyrazoles by cyclocondensation of 4-amino-4ethoxy-1,1,1-trifluorobut-3-en-2-ones with hydrazine and phenylhydrazine has been reported . Trifluoromethylated pyrazoles were synthesized from trifluoromethylenaminones and monosubstituted hydrazines . 5-Amino-3-phenylpyrazoles 534 were prepared from -oxoketene O,N-acetals 533 using montmorillonite K-10 under sonication conditions (Equation 108) . 3-Amino-1-(p-phenyl-substituted)-2-buten-1-ones

Pyrazoles

and ethyl 3-amino-1-(p-phenyl-substituted)-2-propenoates were employed in the synthesis of pyrazoles and pyrazolinones on solid-support K-10 using ultrasound conditions and in a homogeneous medium . Related to this chemistry, a comparison of the 13C NMR spectra of 70 pyrazoles allowed the evolution of a 13C chemical shift prediction rule for 1,3,5-trisubstituted pyrazoles, with deviations of less than 1 ppm .

ð108Þ

4-Acetyl-3-amino-5-oxo-hexenenitrile 535 reacted with hydrazines to give pyrazolyl enaminonitriles 536 in moderate yields (Equation 109) . Reaction of -[(dimethylamino)methylene]--oxoarylpropanenitriles with hydrazines gave a mixture of the 4-aroyl-5-aminopyrazoles and 5-aryl-4-cyanopyrazoles . Reaction of hydrazines with dimethyl 2-pyrrolidino-4-oxo-2-pentenedioate 537 in the presence of acid provided N-substituted pyrazole-3,5-dicarboxylates 538, which could be further elaborated to bicyclic pyrazoles 539 when R was an alkylamine or alcohol side-chain (Scheme 65) . Treatment of -diketones and the corresponding -enaminoketones, having modified carane (2-ethyl-6,6-dimethylbicyclo[3.1.0]hexane) and p-menthane (3-ethyl-1-isopropylcyclopentane) skeletons, with aryl- and alkylhydrazines resulted in regioselective formation of N-substituted pyrazoles or stable pyrazolinols depending on the nature of the substituent at the hydrazine nitrogen . Silyl -enaminones, synthesized by reductive cleavage of 5-silyl, 3-, 4-, and 5-silylmethylisoxazoles, are versatile synthons bearing different silyl groups in various positions of the enaminoketonic system; they are of great interest in the regioselective synthesis of 3- or 5-silylpyrazoles and 3-, 4-, or 5-silylmethylpyrazoles, which can serve as building blocks . Protected N(19)-substituted (S)-3-(4-methoxycarbonyl-1H-pyrazol-5-yl)alanines were prepared by acidcatalyzed cyclocondensations of a chiral enaminone, available from L-aspartic acid, with hydrazine hydrochloride . (E)-N-Methoxy-N-methyl--enaminoketoesters were employed for regioselective condensations with hydrazines in a microwave-assisted synthesis of ethyl 1,5-disubstituted-4-pyrazole carboxylates .

ð109Þ

Scheme 65

New germanium-based linkers 540 have been utilized for the preparation of regioisomeric polymer-supported pyrazoles 541 and 542, which were cleaved upon reaction with hydrazines to give pyrazoles 543 and 544 (Scheme 66) . Aniline cellulose-bound enaminones 545 reacted with phenylhydrazine under microwave irradiation to produce pyrazolocarboxylic acid derivatives 546 in high yields (Equation 110) . Resin-bound enamino keto diesters 547 reacted with hydrazines followed by acidic cleavage to give pyrazole– dicarboxylic acid derivatives 548 (Scheme 67) .

77

78

Pyrazoles

Scheme 66

ð110Þ

Scheme 67

4.01.9.1.2(i)(c) From -ketoesters

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound -keto esters 549 has been described (Scheme 68) . Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene--oxo esters with phenylhydrazines . 2-(Pyrazol-1-yl)pyrimidine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazine with aromatic aldehydes . Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones . Reactions of hydrazines with N-acetoacetyl derivatives of (4S)-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety .

Scheme 68

Pyrazoles

4.01.9.1.2(i)(d) From -keto or enol trichloro(trifluoro)methylketones

Reactions of trichloromethyl-substituted 1,3-dielectrophiles 551 with hydrazine afforded hydroxy pyrazoles 552 (Equation 111) . Cyclocondensation of alkenones 553 with phenylhydrazine under microwave irradiation furnished 5-trichloromethyl-substituted pyrazoles 554 in excellent yields (Equation 112) . 4-Alkoxy-1,1,1-trichloro-3-alken-2-ones were useful precursors for the regiospecific synthesis of 5-trichloromethylpyrazoles using hydrazines . 1,1,1-Trifluoro-4-ethoxy-3-buten-2-one, 3-trifluoroacetyl-3-buten2-one, 4-dihydro-2H-pyran, or furan reacted readily with pentafluorophenylhydrazine or per(poly)fluoroacetylhydrazines to give N-substituted 5-hydroxy-5-trifluoromethylheterocycles, which were dehydrated by treatment with phosphorus pentoxide or thionyl chloride to form N-substituted 5-trifluoromethyl pyrazoles in good yields . 3-Amino-5-trifluoromethyl-1H-pyrazoles were synthesized by cyclocondensation reactions of 4-amino-4-ethoxy-1,1,1trifluorobut-3-en-2-ones with hydrazines . -Alkoxyvinyl trifluoromethyl ketones 555 reacted with methylhydrazine to yield 3-(trifluoromethyl)-1-methylpyrazoles 556 (Equation 113) .

ð111Þ

ð112Þ

ð113Þ

4.01.9.1.2(i)(e) From -ketonitriles, -cyanoaldehydes, and malonitriles

5-Aminopyrazoles were prepared from the reaction of hydrazines with a resin-supported -ketonitrile . Cyanoacetophenone has been employed as a synthon for the assembly of 1,4,5-trisubstituted pyrazoles . 2-Tosylethylhydrazine 559 could be condensed with either -ketonitriles 557 or -aminoacrylonitriles 558 to give 5-aminopyrazoles 560, which were deprotected with sodium ethoxide to give 3(5)-aminopyrazoles 561 (Scheme 69)

Scheme 69

79

80

Pyrazoles

. Rink amide-linked resin 562 reacted with hydrazines followed by acidic cleavage to give 4-(4-carboxaminophenyl)-5-aminopyrazoles 563 (Scheme 70) . 1,3-Oxonitriles reacted with alkylhydrazines to give 1-alkyl-5-aminopyrazoles . A one-pot three-step procedure from acid chlorides, malonitrile, and alkylhydrazines yielded 1-alkyl-5-amino-3-aryl-4-cyanopyrazoles .

Scheme 70

4.01.9.1.2(i)(f) From -haloaldehydes, esters, ketones, oximes, and nitriles

The reaction of o-fluorobenzaldehydes 564 or their O-methyloximes 565 with hydrazine has been developed as a new practical method for synthesis of indazoles 566 (Scheme 71) . -Chlorovinyl aldehydes 567 and 569 were converted into pyrazolo[3,4-b]quinolines 568 and pyrazolo[3,4-c]pyrazoles 570, respectively, in the presence of hydrazine hydrate and p-toluenesulfonic acid under microwave irradiation (Scheme 72) . Reactions of -trifluoromethylated -arylacetates 571 with excess hydrazines in refluxing dioxane afforded the corresponding 5-fluoropyrazolin-3-ones 572 (Equation 114) . 1-Aryl-3,4,4-trichloro-3-buten-1-ones reacted with hydrazine to give pyrazole derivatives, in which two pyrazole molecules underwent coupling to give 3-arylpyrazole-5-carbaldehyde azines . -Chloro--trifluoromethyl ketones reacted with phenylhydrazine to give regioisomeric 3- and 5-trifluoromethylpyrazoles . A series of 4-fluoro-5-(perfluoroalkyl)pyrazoles 574 have been prepared by heterocyclization of hemiperfluoroenones 573 with methylhydrazine (Equation 115) . These same pyrazoles could also be prepared in a one-pot reaction from their respective acylsilanes and this general procedure was applied to aryl, aliphatic, and carbohydrate derivatives. 1H-Pyrazolo[3,4-b]pyridines 575 were obtained from copper(I) iodide-catalyzed cyclizations of 2-chloro-3-cyanopyridines with hydrazines .

Scheme 71

Scheme 72

Pyrazoles

ð114Þ

ð115Þ

2-Bromobenzaldehydes 576 reacted with arylhydrazines in toluene in the presence of a catalytic amount of a palladium catalyst and chelating phosphorus ligands to afford 1-aryl-1H-indazoles 577 in good yields (Equation 116) . Cyclic -bromovinyl aldehydes 578 are cyclized with phenylhydrazine in toluene in the presence of palladium(II) acetate and a chelating phosphorus ligand together with sodium tert-butoxide to give 1-aryl-1Hpyrazoles 579 in moderate to good yields (Equation 117) . This method can also be applied to acyclic aldehydes and other arylhydrazines.

ð116Þ

ð117Þ

4.01.9.1.2(i)(g) From -hydroxy-enones, esters and aldehydes

Reactions of the trifluoroacetyl enol ethers 580 with hydrazines afforded 3-(2-furyl)- or 3-(2-thienyl)pyrazoles 581 (Equation 118) . A regiospecific one-pot synthesis of trifluoromethyl-substituted heteroaryl pyrazolyl ketones has also been disclosed . A one-pot procedure, utilizing -alkoxyvinyl trichloro(fluoro)methyl ketones with methyl- and phenylhydrazines, provided methyl and ethyl 1-phenylpyrazole3(5)-esters in different ratios of 3- and 5-ethyl esters . 1-Acetyl-2-methoxyazulene 582 reacted with arylhydrazines in refluxing ethanol to give 1-aryl-3-methylazuleno[1,2-d]pyrazoles 583 in moderate to high yields (Equation 119) . Methyl 3-methoxy-2-trifluoromethylacrylate 584, readily prepared by a Wittig reaction of methyl 3,3,3-trifluoropyruvate, has been treated with a number of aryl- or hetarylhydrazines to give

81

82

Pyrazoles

3-hydrazinoacrylates 585, which undergo consecutive hydrogen fluoride elimination and intramolecular nucleophilic addition via 586 to afford methyl 1-(het)aryl-5-fluoropyrazole-4-carboxylates 587 under mild base catalysis (Scheme 73) . The interaction of the sodium salts of 3-(1-adamantyl)-1-hydroxy-1-propen-3-one and 4-(1-adamantyl)-1-hydroxy-1-buten-3-one with hydrazine or phenylhydrazine led to the synthesis of 3-(1-adamantyl)- and 3-(1-adamantylmethyl)pyrazoles and 3-(1-adamantyl)-2-phenylpyrazole . 4-Alkyl(aryl)substituted pyrazoles were prepared from ethoxy- or dimethylaminoacrolein with hydrazine hydrochloride . Quenching a -lithiated benzotriazolylvinyl ether with acid chlorides provided the corresponding -keto vinyl ethers which were condensed with hydrazines to give 4-benzotriazolylpyrazoles . 1,1,1Trifluoropentane-2,4-dione and 1-(thien-2-yl)-4,4,4-trifluorobutane-1,3-dione reacted readily with per(poly)fluorophenylhydrazines to give N-per(poly)fluorophenyl-5-methyl(or thien-2-yl)-3-trifluoromethylpyrazoles and 3-methyl(or thien-2-yl)-5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazoles, respectively . Treatment of the latter with phosphorus pentoxide afforded the dehydrated products, N-per(poly)fluorophenyl-3-methyl(or thien2-yl)-5-trifluoromethylpyrazoles, in good yields.

ð118Þ

ð119Þ

Scheme 73

4.01.9.1.2(i)(h) From -hydroxyketones

Tetrasubstituted pyrazoles 589 were synthesized regioselectively in good yields from the reaction of Baylis–Hillman adducts 588 with various hydrazine hydrochlorides in 1,2-dichloroethane (Equation 120) . Baylis– Hillman adducts 591, derived from aldehydes and 2-cyclohexen-1-one 590, reacted with hydrazines to give pyrazoles 592, which could be dehydrogenated to 2H-indazoles 593 (Scheme 74) .

ð120Þ

Pyrazoles

Scheme 74

4.01.9.1.2(i)(i) From -sulfonylketones

The preparation of pyrazoline derivatives 595 was accomplished by reaction of phenylhydrazine with a traceless solid-phase sulfone linker 594 (Equation 121) .

ð121Þ

4.01.9.1.2(i)(j) From -ketoamides

5-(Substituted-amino)pyrazoles 597 were synthesized from -ketoamides 596 with hydrazines and Lawesson’s reagent (Equation 122) . Resin-immobilized -ketoamides 598 reacted with hydrazines in the presence of Lawesson’s reagent followed by acidic cleavage to give 5-N-alkyl(aryl)amino pyrazoles 599 (Scheme 75) .

ð122Þ

Scheme 75

4.01.9.1.2(i)(k) From 1,3-dihalides

Microwave-assisted cyclocondensation of arylhydrazines 600 with alkyl dihalides or ditosylates 601 in aqueous media afforded 4,5-dihydropyrazoles 602 (Equation 123) . Reaction of phenylhydrazine 603 with 1,3-dibromo2-propanol 604 under the same conditions afforded the 1-phenyl-1H-pyrazole 605 (Equation 124) .

83

84

Pyrazoles

ð123Þ

ð124Þ

4.01.9.1.2(i)(l) From -oxo(thio)ketene acetals

Condensation of -oxoketene N,S-acetals 606 with arylhydrazines provided 1,3,5-trisubstituted pyrazoles 607 (Equation 125) . Novel ketene N,S-acetals 608 were reacted with hydrazine to give 3,4,5-trisubstituted pyrazoles 609 (Equation 126) . Phosphonyl-substituted pyrazoles have been synthesized through cyclization of ,-dicyano (-cyano--ethoxycarbonyl)phosphonyl/S-methyl ketene acetals with hydrazines . Efficient regiocontrolled synthesis of highly substituted and annulated indazoles from -oxoketene dithioacetals has been reported . An efficient highly regioselective protocol for the synthesis of isomeric 1,3-diaryl (or 1-aryl-3-alkyl) and 1,5-diaryl (or 1-aryl-5-alkyl)-5 (or 3)-(N-cycloamino)pyrazoles has been reported by cyclocondensation of common -oxoketene N,S-acetal precursors with arylhydrazines by variation of reaction conditions . 1,1-Dimethoxy-4,4-di(methylthio)-3-buten-2-one has been shown to be a useful three-carbon synthon via cyclocondensation with hydrazine for the efficient regiospecific synthesis of a variety of pyrazole derivatives with a masked aldehyde functionality at the 3-position .

ð125Þ

ð126Þ

4.01.9.1.2(i)(m) Miscellaneous reactions

Allyl amines 611 and pyrazoles 612 could be obtained by hydrazinolysis of 2-ketoaziridines 610 (Equation 127) . A variety of aziridines, including N-unprotected, N-substituted, as well as bicyclic enamine and aminal types, were transformed into diversely substituted linear or cyclic products. The hydrazinolysis of homochiral aziridines proceeded without racemization and usually allylamines are obtained in greater yields than the pyrazoles in each case. Addition of hydrazines to -hydroxy acylsilanes 613 afforded 3-trimethylsilyl pyrazoles 614 (Equation 128) (TMS ¼ trimethylsilyl group) .

ð127Þ

Pyrazoles

ð128Þ

4.01.9.1.2(ii)

Hydrazines and ,-unsaturated systems

4.01.9.1.2(ii)(a) From ,-unsaturated ketones

Treatment of -benzotriazolyl-,-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring afforded unsymmetrical 1,3,5-triaryl-4-alkylpyrazolines and -pyrazoles . One-pot reactions of ,-unsaturated ketones 615 with hydrazinediium dithiocyanate gave 1-thiocarbamoyl-2-pyrazolines 616 or 1-formyl-2-pyrazolines 617, in different ratios, depending on the structure of the ketone (Equation 129) . Electrochemical reaction of 2,2,2-trichloroethylideneacetophenones 618 yielded 2,2-dichlorovinylacetophenones 619 which reacted with methylhydrazine to give 3-aryl-5-dichloromethyl2-pyrazolines 620 (Scheme 76) . Reaction of -trifluoromethyl-,-unsaturated ketones with hydrazine produced 3-trifluoromethylpyrazoles . 2,2-Difluorovinyl ketones reacted with monosubstituted hydrazines to give 5-fluoropyrazoles in a regioselective manner . The reactions of 4-amino3-phenylamino(thio)carbonyl-3-penten-2-ones and ethyl 3-amino-2-phenylamino(thio)carbonyl-2-butyrates were investigated in reactions with hydrazine hydrate and hydrazine hydrochloride to evaluate the 1,3-electrophilic centers of these compounds by the formation of pyrazole rings . Nafion-TMS-mediated Mukaiyama aldol reaction of silyl enol ethers with aldehydes, obtained from mild oxidation of alcohols with polymer-supported perruthenate (PSP), yielded ,-unsaturated ketones, which upon treatment with hydrazines allowed the clean synthesis of 4,5-dihydro-1H-pyrazoles . The asymmetric induction in the synthesis of 3,4,5-trisubstituted-4,5-dihydropyrazoles with ferrocenyl substituents, starting from the (E)- and (Z)-isomers of ,-unsaturated ketones, was studied .

ð129Þ

Scheme 76

4.01.9.1.2(ii)(b) From ,-unsaturated esters

The one-pot three-component reaction of polyethylene glycol-supported acrylate 623 with aldehydes 621 and hydrazines 622 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 624 in good yields and high purities (Scheme 77) . 1,3-Dipolar cycloaddition of resin-supported acrylic acid 625 with the nitrilimines generated in situ by oxidation of the aldehyde phenylhydrazones with (diacetoxy)iodobenzene under microwave irradiation gave 626, which was converted into 1-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 627 (Scheme 78) .

85

86

Pyrazoles

Scheme 77

Scheme 78 4.01.9.1.2(ii)(c) From alkynyl ketones or esters

Cyclocondensation of diacetylenic ketones 628 with hydrazines afforded alkynyl-substituted pyrazoles 629 (Equation 130) . Highly regioselective syntheses of 1,3,5-trisubstituted pyrazoles were achieved using acetylenic ketones and hydrazines . -Hydroxyalkynyl ketones were useful precursors for the preparation of combinatorial libraries of pyrazoles . Thus, chiral -acetylenic ketones 630 reacted with hydrazines to yield pyrazolyl oxazolidine derivatives 631, which were further elaborated to novel enantiomerically pure pyrazolyl--amino alcohols 632 (Scheme 79) . Similarly, optically active pyrazolyl -amino acids were prepared from chiral -acetylenic ketones . 5-Silylpyrazoles were prepared from condensation of silylalkynones with hydrazines . Linked bis-pyrazoles, a pyrazolyl-isoxazole, a pyrazolyl-pyrimidine, and a pyrazolyl-triazole were synthesized starting with commercially available 1,4-bis(trimethylsilyl)-1,3-butadiyne or readily available bis-acetylenic diketones . A stepwise approach allowed the synthesis of nonsymmetrically substituted bis-pyrazoles and linked heterocycles with two different cores, whereas a symmetric approach based on the use of bis-acetylenic diketones allowed a very short synthesis of symmetric bis-pyrazoles.

ð130Þ

Scheme 79

Pyrazoles

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, N-alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocondensation process (Equation 131) . N-Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition–decyclization–cyclocondensation process (Equation 132) .

ð131Þ

ð132Þ

Phosphazenes, derived from hydrazines and acetylenic esters, were employed in the regioselective synthesis of 5-pyrazolones and pyrazoles . Reactions of isocyanides 637 and dialkyl acetylenedicarboxylates 638 in the presence of 1,2-diacylhydrazines 639 led to highly functionalized pyrazolines 640 (Equation 133) .

ð133Þ

4.01.9.1.2(ii)(d) From acrylonitriles

A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-1H-pyrazoles by reaction of -chloro-arylacrylonitriles with hydrazine hydrate . Reaction of 2-(3,3-dicyano-2-propenylidene)-4,4,5,5-tetramethyl-1,3-dioxolane 641 with hydrazine afforded 3-(2-hydroxy-1,1,2-trimethylpropoxy)pyrazole 642 (Equation 134) . Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic, and sulfonyl hydrazines led to the synthesis of N-1-substituted 3-acyl-4-cyano-5-aminopyrazoles, which are versatile intermediates for the synthesis of many biologically active scaffolds . 2-Hydrazinothiazol-4(5H)-one reacted with a variety of cinnamonitrile derivatives and activated acrylonitriles to yield annelated pyrazolopyrano[2,3-d]thiazole .

ð134Þ

4.01.9.1.2(ii)(e) From chalcones

The addition of hydrazines to chalcones gives dihydropyrazoles, which can be functionalized further. For example, ,-unsaturated ketones 643 were condensed with arylhydrazines to yield dihydropyrazoles 644; these can be further alkylated and oxidized to 1,3,5-triaryl-4-alkylpyrazoles 645, which are novel ligands for the estrogen receptor (Scheme 80) . A parallel solution-phase synthesis of an N-substituted 2-pyrazoline library 648

87

88

Pyrazoles

resulted from hydrazine addition to chalcones 646 to give the unstable pyrazolines 647, which were trapped with various electrophiles in the presence of polymer-bound base (Scheme 81) .

Scheme 80

Scheme 81

Dihydropyrazoles can be prepared under microwave irradiation conditions. -Alkyl chalcones 649 reacted with hydrazines under microwave conditions followed by addition of acid chlorides to yield 1-acyl-3,5-diaryl-5-alkyl-4,5dihydropyrazoles 650 (Scheme 82) . 1,3,5-Trisubstituted-2-pyrazolines 652 were obtained from chalcones 651 and phenylhydrazine on silica gel and with microwave irradiation (Equation 135) .

Scheme 82

ð135Þ

An efficient and convenient synthesis of 3,5-diphenyl-1H-pyrazoles from chalcones by the action of hydrazine hydrate on chalcone epoxide followed by simultaneous dehydration has been reported . The reaction of bis(chalcones) and bis(chalcone) tetrabromo derivatives with hydrazine hydrate gave bis(pyrazolines) and bis(pyrazoles), respectively . 1,3,5-Trisubstituted pyrazoles were synthesized from chalcones and hydrazines in the presence of iodine . The reaction of 1,5-diaryl-3-methyl-1,4-pentadien-3-one with arylaldehyde phenylhydrazones in the presence of chloramine-T proceeded regiospecifically in methanol and regioselectively in acetic acid, leading to mono- and bis-pyrazolines . The condensation of substituted hydrazines with diarylmethylidenecyclopentanones afforded 2,3-disubstituted-6-arylmethylidenecyclopenta[1,2-c]pyrazoles . Reactions of (E,E)-cinnamylideneacetophenones with hydrazines yielded 3-aryl-5-styryl-2-pyrazolines, which were converted into their corresponding pyrazoles by oxidation with chloranil (CHL) . Methylhydrazine reacts in an alkaline

Pyrazoles

medium, in a regioselective mode, with chalcones to yield 2-pyrazolines, which can be oxidized by DDQ to the corresponding 1H-pyrazoles . From oligo(chalcone)s this reaction yields cross-conjugated compounds with an alternating sequence of 1,4-disubstituted benzene rings and 3,5-disubstituted 1H-pyrazole rings. Isomeric 2pyrazolines were synthesized from 29-hydroxy-59-chlorochalcones . 4.01.9.1.2(ii)(f)

Miscellaneous ,-unsaturated systems

-Acyl--heterosubstituted vinylphosphonates reacted with hydrazine to give phosphono-containing pyrazoles . Reaction of 1-aroyl-2-arylsulfonylethenes with hydrazine hydrate afforded 2-pyrazolines, which were then subjected to dehydrogenation, pyrolysis, nitrosation, and acylation reactions . N-Ary1-1per(poly)fluoroalkyl acetylenic imines 653, the cross-coupling products of N-aryl per(poly)fluoroalkyl imidoyl iodides with acetylenes, were used as precursors to synthesize fluorinated heterocycles such as pyrazoles 654 in the presence of hydrazine hydrate (Equation 136) .

ð136Þ

4.01.9.1.2(iii) Hydrazines and unsaturated systems 3-Trifluoromethylpyrazoles were conveniently prepared in two steps via the radical addition of fluoroalkyl iodides to alkynes followed by condensation with hydrazines . Photochemical reactions of perfluoroalkyl iodide 655 and -chlorostyrenes 656 in the presence of hydrazine and acetic acid afforded 5-aryl-3-perfluoroalkylpyrazoles 657 (Scheme 83) .

Scheme 83

Tandem sequences involving metal catalysis have yielded some interesting pyrazole structures. Four-component coupling, in the presence of a palladium catalyst, of terminal alkynes 658, hydrazines 659, carbon monoxide, and aryl iodides furnished pyrazoles 660 (Equation 137) . A novel one-pot synthesis of 3,5-disubstituted-2pyrazolines 663 has been achieved with an unexpected coupling–isomerization sequence of haloarene 661, propargyl alcohol 662, and methylhydrazine (Scheme 84) . A palladium-catalyzed cascade involving an intermolecular quenching–cyclocondensation reaction of o-iodophenol 664 with dimethylallene and arylhydrazines provided pyrazolyl chromanones 665 (Equation 138) . Novel -polyfluoroalkoxy vinamidinium salts reacted with hydrazines to give pyrazoles regiospecifically in good yields . Domino coppercatalyzed coupling/hydroamidation of iodoenynes 666 with bis(BOC)hydrazine led to a highly efficient synthesis of 3,4,5-trisubstituted pyrazoles 667 (Scheme 85) .

ð137Þ

89

90

Pyrazoles

Scheme 84

ð138Þ

Scheme 85

4.01.9.1.2(iv)

Via hydrazones

4.01.9.1.2(iv)(a) Via acid- and base-promoted cyclizations

A versatile synthesis of pyrazoles from benzophenone hydrazones was demonstrated with a variety of 1,3-bifunctional substrates under acidic conditions . Hydrazones 668 and 671, prepared from palladium-catalyzed heteroaryl halides with benzophenone hydrazone, reacted with 1,3-bifunctional substrates 669 and 672 under acidic conditions to yield pyrazoles 670 and 673, respectively (Equations 139 and 140) . Enolates of -chloro--oxoaldehydes react with arylhydrazines in the presence of acetic acid or -oxo--chlorenamines react with arylhydrazines to produce osazones of carbonyl-substituted glyoxals, which under conditions of acid catalysis undergo intramolecular heterocyclization to the corresponding functionalized pyrazoles .

ð139Þ

Pyrazoles

ð140Þ

Dilithiated C-,N-phenylhydrazones were condensed with ethyl oxanilate, ethyl 4-chloroxanilate, or ethyl oxamate, followed by acid-catalyzed cyclizations to afford 1H-pyrazole-5-carboxamides . Polylithiated 29-phenylacetohydrazide was condensed with aromatic esters followed by acid-catalyzed cyclizations to yield 1,2-dihydro-3Hpyrazol-3-ones . Various C-,N-phenylhydrazones were dilithiated with excess LDA followed by condensation with methyl 2-(aminosulfonyl)benzoate; acid cyclization then afforded new pyrazole benzenesulfonamides . The preparation of 2-(1,5-diphenyl- or 5-substituted-phenyl-1H-pyrazole-3-yl)phenols 675 from trilithiated 29-hydroxyacetophenone phenylhydrazone 674 and aromatic esters was reported (Equation 141) . Dilithiated 2-tetralone phenylhydrazone and aromatic esters were employed in the synthesis of 4,5-dihydro-2H-benz[e]indazoles . (3E)-4-Phenyl-3-buten-2-one hydrazones 676 were treated with excess LDA and condensed with several aromatic esters followed by acid cyclization to afford 3-(2-phenylethenyl)-1H-pyrazoles 677 (Equation 142) . 1,3,5-Trisubstituted pyrazoles 679 were obtained by reaction of esters or acid chlorides with the 1,4-dianion of methyl 2-thienyl ketone N-ethoxycarbonylhydrazone 678 (Equation 143) .

ð141Þ

ð142Þ

ð143Þ

Base-promoted reaction of nitrobenzenes 680 with aryl imines 681 afforded arylindazoles 682 (Equation 144) . -Tosylhydrazono phosphonates 683, novel and bifunctional reagents, were employed in a concise approach to give polysubstituted pyrazoles 684 in the presence of aromatic and aliphatic aldehydes under basic conditions (Equation 145) .

ð144Þ

91

92

Pyrazoles

ð145Þ

4.01.9.1.2(iv)(b)

Via intramolecular [3þ2] cyclizations

Pyrazolidine derivatives 687 were obtained from the intermolecular [3þ2] cycloaddition between hydrazones 685 and alkenes 686 (Equation 146) . Reaction of N-monosubstituted hydrazones with nitroalkenes led to a regioselective synthesis of substituted pyrazoles . Base treatment of hydrazonoyl chlorides with polyethylene glycol monomethyl ether (MeOPEG)-supported acrylates and acrylamides gave the corresponding MeOPEGsupported 4,5-dihydropyrazoles . Basic hydrolysis of the cycloadducts caused the removal of the MeOPEG pendant giving 5-carboxy- or 5-aminocarbonyl-4,5-dihydropyrazoles, respectively. 1,3-Dipolar cycloaddition of hydrazonoyl chlorides with alkynes over alumina and under microwave irradiation afforded 3,4,5-trisubstituted pyrazole derivatives . Enamine 688 reacted with hydrazonoyl halides 689 to yield 3,4-disubstituted pyrazoles 690 (Equation 147) . 1,3-Disubstituted-pyrazole-4-carbonitriles were prepared from enaminonitriles and hydrazonyl halides . Structurally novel chiral glycopyrazoles were obtained in good yields from the intramolecular [3þ2] nitrilimine cycloaddition reactions of phenylhydrazone groups on carbohydrate-derived substrates . The 1,3-dipolar cycloaddition of four hydrazonoyl chloride derivatives with the sodium salt of an unsymmetrical -diketones (benzoylacetone) offered a versatile method for the regioselective synthesis of 2H-pyrazoles in a fashion similar to the cycloaddition of the nitrilimides with ,-unsaturated ketones and esters .

ð146Þ

ð147Þ

Enantioselective [3þ2] cycloaddition of halohydrazones 692 with dipolarophile 691 in the presence of ligand 693 under Lewis acid conditions, followed by reduction, provided an entry to chiral dihydropyrazole scaffolds 694 in excellent yields and good ees (Scheme 86) . Highly enantioselective synthesis of pyrazolidines 698 was achieved by the [3þ2] acylhydrazone–enol ether cycloadditions of 695 and 696 in the presence of a chiral silicon Lewis acid 697 (Equation 148) .

Pyrazoles

Scheme 86

ð148Þ

4.01.9.1.2(iv)(c) Miscellaneous cyclizations

Treatment of hydrazones 699 with 2,4,6-trichloro[1,3,5]triazine and DMF gave iminium salts 700, which were converted into 3-aryl-4-formylpyrazoles 701 (Scheme 87) . A versatile and efficient synthesis of 3-substituted-1H-indazoles 703 from aryl mesylates 702 and hydrazines through the intermediate hydrazone was disclosed (Equation 149) . Access to the 1H-pyrazolo[4,3-c]pyridine core 704 was obtained from bisacetylenic-N-benzoylhydrazones with aqueous ammonia . Reaction of N-aziridinylimino carboxamides 705 with triphenylphosphine in carbon tetrachloride provided access to pyrazole-fused heterocycle 707 via thermal rearrangement of N-aziridinylimino ketenimines 706 (Scheme 88) . A one-pot preparation of 3(5)substituted-lH-pyrazoles employed a Horner–Emmons reaction of aldehydes with the dianion of diethoxyphosphorylacetaldehyde tosylhydrazone followed by intramolecular cyclization upon warming, via [1þ4] cyclization . 3,3,3-Trifluoro-2,2-dihydroxypropanesulfonamides are useful building blocks for the synthesis of 4-trifluoromethyl-5-pyrazolesulfonamides via hydrazone intermediates . A regioselective synthesis of 5-(trifluoromethyl)pyrazoles has been reported from the [1þ4] cyclization of phenylhydrazones with N-aryltrifluoroacetimidoyl iodides . -Halogenoketone hydrazones 708 reacted with isocyanides in the presence of sodium carbonate to give 5-aminopyrazoles 709 (Equation 150) . Several 3-aryl-1-(4,6-dimethyl-2pyrimidinyl)-4-formylpyrazoles were prepared from 4,6-dimethyl-2-pyrimidinyl hydrazones with various acetophenones using the Vilsmeier–Haack reagent . Phosponyl hydrazones reacted with Vilsmeier reagent to afford 3-phosphonylpyrazoles . -Ketosulfone 710 reacted with hydrazonyl halides 711 in refluxing ethanol, thus achieving a synthesis of 3-acyl-4-sulfonylpyrazoles 712 (Equation 151) .

Scheme 87

93

94

Pyrazoles

ð149Þ

Scheme 88

ð150Þ

ð151Þ

4.01.9.1.2(v) 4.01.9.1.2(v)(a)

Azo (azido, diazo) compounds with various systems [2þ3] Dipolar cycloadditon of alkenes

Reaction of a range of 1-bromocyclopropenes with diazo compounds led to pyrazoles, which ring-opened to pyridazines in reasonable yields . 2H-Azirine-3-carboxylate unsubstituted at C-2 acted as a dipolarophile in the reaction with diazomethane to give 4,5-dihydro-3H-pyrazoles . Methyl diazoacetate regioselectively added to N-substituted imides 713 of itaconic acid to afford spiro-2-pyrazolines 714 (Equation 152) . ()-8Phenylmenthol-derived pentacarbonylalkenyl(alkoxy)chromium carbene complexes reacted with diazomethane derivatives to give only one diastereomer of enantiomerically pure 4,5-dihydro-1H-pyrazoles via [3þ2] cycloaddition; the one-pot synthesis of the corresponding esters was also described . The 1,3-dipolar cycloadditions of

Pyrazoles

diazoalkanes with diethyl trans-glutaconate yielded 1-pyrazolines, which isomerized to 2-pyrazolines or were oxidized to pyrazoles on standing in air . Regioselective 1,3-dipolar cycloadditions of captodative alkenes 1-acetyl-1aroyloxyethene with nitrile imines or diazoalkanes provided the corresponding 5-acetylpyrazoles . Reaction of diazo compounds with derivatives of 3,3,3-trifluoropropene afforded trifluoromethyl-substituted pyrazolines and pyrazoles .

ð152Þ

1,3-Dipolar cycloaddition of diazomethane and ethyl diazoacetate to -(diethoxyphosphoryl)vinyl p-tolyl sulfoxide furnished 3-phosphorylpyrazoles . Reactions of diazomethane or diazoethane with activated sulfoxides 715 in the presence of Yb(OTf)3 produced a stereocontrolled synthesis of bicyclic pyrazolines 716 (Equation 153) . Cycloaddition of excess diazomethane to 1-aroyl-2-arylsulfonylethenes gave 1-methyl-3-benzoylpyrazole . Cycloaddition of diazomethane to bis(arylsulfonylethenyl)sulfones and 1-styrylsulfonylethenes led to 2-pyrazolines, which were dehydrogenated to pyrazoles with CHL . Diazomethane was added to enyne sulfones 717 in a regio- and stereospecific manner to give 4-alkynyl-5-phenylsulfonyl-4,5-dihydro-3H-pyrazoles 718, which were converted to 4-alkynyl-1H-pyrazoles 719 on reaction with methyllithium (Scheme 89) .

ð153Þ

Scheme 89

Diazomethane reacted regioselectively with peripheral vinyl substituents of pyropheophorbide a and purpurin-18 N-methylimide to produce the corresponding 10-pyrazolinyl-substituted derivatives as main products . Similarly, treatment of protoporphyrin IX gave a mixture of mono- and disubstituted pyrazolinyl analogs. Thermolytic decomposition of the pyrazolinyl derivatives produced cyclopropyl-substituted chlorins and porphyrins. -Nitro-mesotetraphenylporphyrin reacted with diazomethane to give a pyrazoline-fused chlorin as the main product, which was then converted into the corresponding pyrazole-fused porphyrin, by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and into a methanochlorin by refluxing in toluene . [60]Fullerene-fused pyrazolines were prepared by the reaction of C60 with alkyl diazoacetates under solid-state high-speed vibration milling conditions, as well as in toluene solution . 4.01.9.1.2(v)(b)

[2þ3] Dipolar cycloadditon of alkynes

Intermolecular 1,3-dipolar cycloaddition of -diazoarylacetates with alkynes in the presence of indium(III) chloride in water gave 3,5-disubstituted pyrazoles . 1,3-Dipolar cycloaddition of 2-diazopropane with propargyl alcohols led to the regioselective synthesis of 3,3-dimethyl-5-substituted pyrazoles . The [3þ2] cycloaddition of various -substituted ethynyliodonium salts with ethyl diazoacetate resulted in single regioisomeric pyrazoles in moderate yields . Addition of a solution of trimethylsilyldiazomethane in hexanes to

95

96

Pyrazoles

chromium or tungsten alkynyl complexes 720 in THF presumably afforded metallahexatriene carbenes 721, which decompose rapidly and were trapped by tert-butyl isocyanide to give indazole derivatives 722, isolated as single regioisomers, in good yields (Scheme 90) . 3-Trimethylsilyl-1,2-pyrazole-4-carboxaldehydes were prepared in quantitative yields from the hydrolysis of 4-arylaminomethyl-3-trimethylsilylpyrazoles, obtained from the reaction of ,-acetylenic aldimines with diazomethane . Microwave-assisted preparation of a wide range of 5-ethoxycarbonylpyrazoles and 3-substituted pyrazoles by 1,3-dipolar cycloaddition of diazo compound to acetylenes has been reported .

Scheme 90

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3(5)-phenyl- or 3,5-disubstituted pyrazoles 725 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-pyridylacetylene with diazo compounds 724 generated in situ from aldehydes 723 has been reported (Scheme 91) . Cyclization of ortho-(arylethynyl)benzene diazonium salts 727, prepared from alkynyl aniline 726, having substituents at the para-position of the aryl ring furnished indazoles 728 (Scheme 92) .

Scheme 91

Scheme 92

Pyrazoles

4.01.9.1.2(v)(c)

Cyclizations via allenes

Diazomethane reacted with 3-methyl-1-vinyl-1,2-butadienylphosphonates 729 by [3þ2] cycloaddition at the 1,2double bond of the allenic fragment to give 3-phosphinoyl-4-isopropylidene-3-vinyl-4,5-dihydro-3H-pyrazoles 730 (Equation 154) . The reaction with diphenyldiazomethane involved the vinyl fragment and yielded substituted diphenylcyclopropane. Tandem Michael addition/cyclization of the anion of 2-phenylazo-1,3-dicarbonyl substrates to 1,2-diaza-1,3-butadienes gave 1-phenylpyrazoles . Reactions of polymer-bound 1,2diaza-1,3-butadienes with triphenylphosphine provided convenient entry to 4-triphenylphosphoranylidene-4,5-dihydropyrazol-5-ones .

ð154Þ

4.01.9.1.2(v)(d)

Cyclizations via enones

The synthesis and relative stability of 3,5-diacyl-4,5-dihydro-1H-pyrazoles prepared by dipolar cycloaddition of enones and -diazoketones has been published . 3-Acyl-4-aryl-2-pyrazolines have been synthesized by the reaction of ,-unsaturated ketones with diazomethane . Ethyl diazoacetate added to 1,3diarylpropenones in a regioselective fashion to give the intermediate 4,5-dihydro-3H-pyrazole derivative; 1,3-hydride shift in the latter led to the formation of the isomeric ethyl 4-aryl-5-aroyl-4,5-dihydro-1H-pyrazole-3-carboxylate and ethyl 4-aryl-3-aroyl-4,5-dihydro-1H-pyrazole-5-carboxylate in a ratio of 5:1 . 1,3-Dipolar cycloaddition of 2-diazopropane with diarylideneacetones afforded diastereomeric bis-2-pyrazolines . 4.01.9.1.2(v)(e)

Cyclizations via 1,3-diketones

Substituted 2-diazopentane-1,3,5-triones have been transformed into 3,5-disubstituted-4-hydroxypyrazoles . Disubstituted pyrazoles were obtained by the reaction of 4-aryl-2,4-oxobutanoic acid aryl amides with diazomethane or diazoethane . The reaction of 2-methylene-1,3-dicarbonyl compounds with ethyl diazoacetate gave 4,5-dihydro-1H-pyrazole derivatives in good yields, which were stable for several months at room temperature . 4.01.9.1.2(v)(f)

Cyclizations via azodicarboxylates

Optically active pyrazolidine derivatives have been synthesized by the copper- and palladium-catalyzed asymmetric one-pot tandem addition–cyclization reactions of 2-(2,3-dienyl)--ketoesters, organic halides, and dibenzyl azodicarboxylate . Reaction of the Huisgen zwitterion, derived from triphenylphosphine and dialkyl azodicarboxylates 731, with allenic esters 732 afforded highly functionalized pyrazoles 733 (Equation 155) . Pyrazole formation is believed to proceed via a novel nitrogen-to-carbon migration of the carboalkoxy group.

ð155Þ

4.01.9.1.2(v)(g) Miscellaneous cyclizations

1-Substituted-4-alkoxy-, -4-alkylthio-, and -4-aryloxy-lH-pyrazol-5(2H)-ones have been prepared by the reaction of conjugated azoalkenes with alcohols, thiols, and phenols . [( p-Sulfonamidophenyl)azo]malononitrile reacted with hydrazine or phenylhydrazine in refluxing ethanol to give 3,5-diaminopyrazole or 1,4-diphenyl-3,5-diaminopyrazole, respectively . 1-Aryl-4,6-dinitro-1H-indazoyl-3-methylcarboxylates 735 were prepared from 2,4,6-trinitrotoluene 734 and arenediazonium chlorides (Equation 156) . 1-Aryl-4-hydroxy-1H-pyrazoles were prepared

97

98

Pyrazoles

from the reaction of 4-chloroacetic acid and aryldiazonium salts . 2-Cyanoaryldiazonium bisulfates 736, obtained by treatment of 3-hydrazones of isatin and its 5-bromo- or 5-nitro derivatives with nitrosylsulfuric acid, underwent an in situ condensation reaction with malonic acid dinitrile to give (2-cyanoaryl)hydrazones 737, which reacted with hydrazine to afford 3,5-diamino-4-(2-cyanoarylazo)pyrazoles 738 (Scheme 93) . [3þ2] Cycloaddition of lithium trimethylsilyldiazomethane with benzynes, generated from halobenzenes 739, gave the corresponding 3-trimethylsilylindazoles 740 and 741 in various ratios (Equation 157) . These trimethylsilylindazoles reacted with aryl aldehydes in the presence of cesium fluoride to give 3-(arylhydroxymethyl)indazoles in good to moderate yields . The effect of lithiation on the reactivity of diazo derivatives with sulfonylalkynes on the synthesis of three isomeric trisubstituted pyrazoles was studied .

ð156Þ

Scheme 93

ð157Þ

Substituted pyrazoline derivatives 744 were synthesized in high yields through the cycloaddition reactions of azides 742 with acrylates 743 under Baylis–Hillman reaction conditions (Equation 158) .

ð158Þ

Pyrazoles

4.01.9.1.2(vi)

Other reactions

4.01.9.1.2(vi)(a) Cyclizations via azomethine imines and nitrilimines

A short review has been published on the utilization of chiral enaminones and azomethine imines in the synthesis of functionalized pyrazoles . Azomethine imines, generated from -silylnitrosamines via a 1,4-silatropic shift, underwent 1,3-dipolar cycloadditions with dipolarophiles to give pyrazole derivatives . Synthesis of pyrazoles can be achieved by azomethine imine cycloaddition to a polymer-supported vinyl sulfone . Reactions of aroyl-substituted heterocyclic ketene aminals with nitrile imines give fully substituted pyrazoles via 1,3-dipolar cycloaddition . Acetylacetone reacted smoothly with nitrilimines, generated in situ by the catalytic dehydrogenation of aromatic aldehyde phenylhydrazones with chloramine-T, to afford, regioselectively, 1,3-diarylpyrazoles . Solid-phase cycloaddition of nitrilimines to resin-bound enamines afforded 1,4-diarylpyrazoles after acidic cleavage . A cycloaddition reaction of nitrilimines with aryl styryl sulfones led to tetrasubstituted pyrazolines, which were dehydrogenated with CHL in xylene to give the fully aromatic pyrazoles . CAN oxidation of the cycloadducts gave 4-(pyrazol-5-yl)carbonyl-2-azetidinone and 4-(pyrazol-4yl)carbonyl-2-azetidinone, respectively. 1,3-Dipolar cycloaddition of diphenylnitrile imine, generated in situ from N-phenylbenzohydrazonoyl chloride in the presence of triethylamine, with methyl (E)-2-(acetylamino)-3-cyanoprop2-enoate yielded methyl 4-cyano-2,5-diphenylpyrazole-3-carboxylate by elimination of benzamide from the primary cycloadduct . Regioselective 1,3-dipolar cycloaddition of bis-nitrilimines with the benzylidene derivatives of chroman-4-one and thiochroman-4-one afforded the corresponding bis-spiropyrazoline derivatives . A number of 1-aryl-5-substituted-4,5-dihydropyrazoles have been synthesized by 1,3-dipolar cycloaddition of variously substituted nitrilimines to the appropriate alkenyl dipolarophiles in aqueous media and in the presence of a surfactant . Clean and fast cycloadditions were observed between electron-rich nitrilimines and electron-poor dipolarophiles, while reversal of the electronic features of the reactants gave poor results. Oxidation of aldehyde 4-chloro-2,3,5,6-tetrafluorophenylhydrazones with [bis(acetoxy)iodo]benzene leads to the formation of nitrilimines, which reacted in situ with ethyl acrylate to produce 3-substituted-1-(4-chloro-2,3,5,6tetrafluorophenyl)-5-ethoxycarbonyl-4,5-dihydropyrazoles in moderate to good yields . Syntheses of enantiomerically pure 3,3a-dihydropyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones from stereoselective intramolecular cycloadditions of homochiral nitrilimines were investigated . The first example of asymmetric induction in intramolecular nitrilimine cycloadditions was identified in the synthesis of enantiopure 3substituted-6-oxo-2,3,3a,5-tetrahydro-4-methoxycarbonylfuro[3,4-c]pyrazoles . A (1R,2S,5R)-()-menthyl chiral auxiliary was used for the first time in an intramolecular nitrilimine cycloaddition, in syntheses of enantiopure pyrazolo[1,5-a][4,1]benzoxazepines and pyrazolo[1,5-a][4,1]benzodiazepines . Asymmetric induction by the (S)-1-phenylethyl group in intramolecular nitrilimine cycloadditions gave enantiopure 3,3a-dihydropyrazolo[1,5a][1,4]benzodiazepine-4(6H)-ones . A highly stereoselective nitrilimine cycloaddition to 3(R* )-phenyl4(S* )-cinnamoyl-2-azetidinone gave 4-(4,5-dihydropyrazol-5-yl)carbonyl-2-azetidinone as the major and 4-(4,5-dihydropyrazol-4-yl)carbonyl-2-azetidinone as the minor product . The diastereoselective cycloaddition of a nitrilimine with enantiopure acrylamides was exploited to obtain enantiopure 4,5-dihydropyrazoles . The diastereoselective cycloadditions of enantiopure nitrilimines with ethyl acrylate were exploited in dry toluene and in aqueous sodium hydrogen carbonate as reaction media . Shorter reaction times and improved diastereoisomeric ratios of the resulting 5-ethoxycarbonyl-4,5-dihydropyrazoles were observed in aqueous media. The first highly regio- and diastereoselective synthesis of 2-pyrazolines by [3þ2] cycloaddition of chiral nonracemic Fischer carbene complexes with nitrilimines has been described . A series of isoindazole-C60 dyads based on pyrazolino[60]fullerene were prepared by 1,3-dipolar cycloadditions of the nitrilimines, generated in situ from hydrazones, to C60 . 4.01.9.1.2(vi)(b)

Cyclization via nitroarenes

Reaction of 2-nitrobenzyl triphenylphosphonium ylide 745 with aryl isocyanates afforded 2-aryl-2H-indazoles 746 (Equation 159) . Reductive cyclization of o-nitroketoximes 747 in the presence of catalytic iron dimer in dioxane under a carbon monoxide atmosphere furnished 1H-indazoles 748 (Equation 160) .

ð159Þ

99

100

Pyrazoles

ð160Þ

4.01.9.1.2(vi)(c) Cyclization via iminium salts

Vilsmeier-type reagent 749 reacted with imines 750 to afford enaminoimine hydrochlorides 751, which were transformed to pyrazoles 752 upon addition of hydrazine (Scheme 94) . A variety of vinylogous iminium salts 753 were useful precursors for the regiocontrolled synthesis of heterocyclic appended pyrazoles 754 (Equation 161) .

Scheme 94

ð161Þ

4.01.9.1.2(vi)(d)

Cyclizations via aminopyridinium intermediates

Reaction of 1-amino-3-benzyloxypyridinium mesitylenesulfonate 755 with methyl propiolate in the presence of potassium carbonate in DMF at room temperature gave a mixture of methyl 4-benzyloxy- 756 and 6-benzyloxypyrazolo[1,5-a]pyridine-3-carboxylates 757 (Scheme 95) . Treatment of 756 and 757 with 48%

Scheme 95

Pyrazoles

hydrobromic acid afforded 4-hydroxypyrazolo[1,5-a]pyridine 758 and 6-hydroxypyrazolo[1,5-a]pyridine 759, respectively. Ethyl 2,2-dihydropoly(per)fluoroalkanoates reacted with N-aminopyridinium iodide to give poly(per)fluoroalkyl-substituted pyrazolo[1,5-a]pyridine in the presence of triethylamine and potassium carbonate in DMF . 4.01.9.1.2(vi)(e) Miscellaneous reactions

An expeditious, four-step procedure has been described for the conversion of bulk-scale accessible D-xylose into 5-hydroxymethyl-1-phenylpyrazole-3-carboxaldehyde, which in turn was converted into various pyrazole building blocks with versatile application profiles, such as the 1-phenylpyrazole-3,5-dicarboxylic acid and 3,5-bis(aminomethyl)-1-phenylpyrazole . N,N9-Diarylbisnitrile imides add regioselectively to -(benzothiazol-2-yl)cinnamonitriles and -(l-methylbenzimidazol-2-yl)cinnamonitriles to yield exclusively the cycloadducts 5,59-dicyano-4,49,5,59-tetrahydro[3,39-bi-lH-pyrazoles], which underwent aromatization via thermal elimination of hydrogen cyanide under basic conditions to afford the corresponding 3,39-bi-lH-pyrazole derivatives, respectively . A stereospecific synthesis of 1-(aryl)-3,5-diphenyl-4,5-dihydro-1H-pyrazoles (chiral pyrazolines) with the N-arylhydrazones of the Michael adduct from the ring-closure reaction, which occurred by a stereospecific intramolecular nucleophilic substitution of thiophenoxide, has been investigated . Reaction of 2-nitroenamines and 2-nitroalkenyl sulfides with ethyl isocyanoacetate provided a novel synthesis of ethyl 1-hydroxpyrazole-3-carboxylates . The prepared aldazines (aldehyde azines) 760 were allowed to react with 2 equiv of dimethyl acetylenedicarboxylate 761 in a 1,3-dipolar reaction to give N-allyl pyrazoles 762 (Equation 162) . The first products formed were pentalene azine derivatives, which in some cases underwent skeletal rearrangment to acyclic tetraene azines, which underwent further skeletal rearrangment to N-allylpyrazoles. A general and highly convenient procedure for the synthesis of 3-heteroaryl- and 3-aryl-substituted 1H-indazoles 764 has been developed. These compounds 764 were synthesized in good yield by refluxing the sodium bisulfite adduct of heteroaromatic and aromatic aldehydes 763 and phenylhydrazine in DMF (Equation 163) . Cyclocondensation of -alkoxyvinyl trifluoromethyl ketones 765 with thiosemicarbazide in methanol under mild conditions gave 3-aryl[alkyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-pyrazoloethiocarboxyamides 766, which were easily dehydrated with concomitant thiocarboxyamide group hydrolysis in concentrated sulfuric acid to give 3-aryl[alkyl]-5-trifluoromethyl-1H-pyrazoles 767 (Scheme 96) . A convenient method for the synthesis of 1H-pyrazole-4-carboxylic acid esters 769 from -ketaminoesters 768 uses conventional or microwave-assisted Vilsmeier reactions (Equation 164) . Cyclization of ,-unsaturated phenyl ketones with aminoguanidine under neutral conditions afforded 5-aryl-4,5-dihydro-1H-pyrazole-1-carboximidamides . 1,3-Dipolar cycloaddition of polymer-supported -silylnitrosoamides 770 with dimethyl acetylenedicarboxylate 761 gave pyrazole derivatives 771 without the necessity for a cleavage operation (Equation 165) . Polymer-bound 1,2-diaza-1,3-butadienes have been employed in the solid-phase syntheses of 4-triphenylphosphoranylidene-4,5-dihydropyrazol-5-ones and 4-methoxy-1H-pyrazol-5(2H)-ones . Methoxyvinyl trifluoromethyl ketones 772 underwent regiospecific cyclization with aminoguanidine to give trifluoromethyl alcohols 773, which were dehydrated to give trifluoromethylated 2-[1H-pyrazol-1-yl]pyrimidines 774 (Scheme 97) .

ð162Þ

ð163Þ

101

102

Pyrazoles

Scheme 96

ð164Þ

ð165Þ

Scheme 97

4.01.10 Ring Synthesis by Transformation of Another Ring 4.01.10.1 Ring Transformations 4.01.10.1.1

Benzimidazole and imidazole systems

Cycloadditions of (5Z)-1-acyl-5-(cyanomethylidene)-3-methylimidazolidine-2,4-diones 775 with arylhydrazonyl chlorides proceeded regio- and stereoselectively under basic conditions to give pyrazole-5-carboxamides 776 (Equation 166) . Acylation of arylhydrazones of 2-acetonyl- and 2-phenacylbenzimidazoles with aroyl chlorides or acetic anhydride proceeded, in a new heterocyclization reaction, via opening of the benzimidazole ring to give 5-(o-acylaminophenyl)aminopyrazoles . Unexpected ring opening of benzimidazoles with nitrilimines led to pyrazole derivatives .

Pyrazoles

ð166Þ

4.01.10.1.2

Cyclopropanes

Regioselective ring opening of 3-aryl-2-benzoyl-1,1-cyclopropanedicarbonitriles 777 with hydrazine provided a synthesis of 3-aryl-5-phenylpyrazoles 778 (Equation 167) .

ð167Þ

4.01.10.1.3

Furandiones

Furan-2,3-diones 779 reacted with various hydrazines to yield pyrazole-3-carboxylic hydrazides 780 in moderate yields (Equation 168) . 4-Benzoyl-1-(4-nitrophenyl)-5-phenyl-1H-pyrazole-3-carboxylic acid 782 was obtained from the furan-2,3-dione 781 and N-benzylidene-N9-(4-nitrophenyl)hydrazine (Equation 169) .

ð168Þ

ð169Þ

4.01.10.1.4

Oxazoles and oxadiazoles

2,3-Dihydropyrazol[3,2-b]oxazoles were employed as intermediates in the preparation of 1-methyl-3-hydroxypyrazoles . A series of 6-substituted fluorinated indazoles 784 were obtained through an ANRORC-like rearrangement (addition of nucleophile, ring opening, and ring closure) of 5-tetrafluorophenyl-1,2,4-oxadiazoles 783 with hydrazine (Equation 170) .

ð170Þ

103

104

Pyrazoles

4.01.10.1.5

Oxazolium olates

5-Trifluoromethyl-3-hydroxypyrazoles 786 were obtained selectively through the regioselective attack of phenylhydrazine on mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates 785 in refluxing benzene; the same reaction in DMF and 1,2-dichloroethane at room temperature, respectively, gave 6-trifluoromethyl-1,2,4-triazines and 3-trifluoromethyl-5-pyrazolones (Equation 171) .

ð171Þ

4.01.10.1.6

Pyranones

The most common method for the preparation of pyrazoles from other heterocycles is from pyranone-type compounds. Condensation of 2,3-dihydro-4H-pyran-4-ones 787 with various aryl hydrazines in the presence of montmorillonite KSF clay under mild conditions proceeded rapidly to afford enantiomerically pure 5-substituted pyrazoles 788 (Equation 172) . Comparable results were obtained when arylhydrazines were reacted with 2-formyl glycals under microwave irradiation . Phenylhydrazine and hydrazine were reacted with 3-acetyl-4hydroxy-6-methyl-2H-pyran-2-one to afford 4-acetoacetyl-3-methylpyrazolin-5-ones, which were employed in the synthesis of bipyrazoles and pyrazoloisoxazoles . Reaction of 3,3-dialkyl-6-(trifluoromethyl)-2,3-dihydro-4-pyrones with hydrazine hydrate afforded 3-(trifluoromethyl)-5-substituted-pyrazoles .

ð172Þ

3-Aryloxychromone 789 was condensed with hydrazine to give 4-aryloxy-3-(2,4-dihydroxyphenyl)pyrazole 790 (Equation 173) . Treatment of 5,7-dimethyl-2-trifluoromethyl-8-azachromone 791 with hydrazine afforded pyridonyl pyrazole 792 (Equation 174) . The reaction of chromenethione or chromene 793 with hydrazine occurred readily to afford pyrazoles 794 in good yield (Equation 175) . Treatment of 3-(3-aryl-3-oxopropenyl)chromen-4-ones with hydrazine yielded pyrazolyl-2-pyrazolines . Reaction of 3-formylchromenes with phenylhydrazine or with tosylhydrazine under solvent-less microwave irradiation afforded 4-(2-hydroxybenzoyl)pyrazoles in a single step . The synthesis of 3- or 5-o-hydroxyphenol-4-benzylpyrazoles was accomplished by treatment of 3-benzylchromones, 3-benzylflavones, or their 4-thiochromone analogs with hydrazine hydrate in hot pyridine . 3-(2-Benzyloxy-6-hydroxyphenyl)-5-styrylpyrazoles were prepared via the reaction of 2-styrylchromones and hydrazine hydrate . Treatment of 3-aroyl-5benzyloxyflavones with hydrazine afforded 3,5-diaryl-4-(2-benzyloxy-6-hydroxybenzoyl)pyrazoles together with 4-aroyl-5-aryl-3-(2-benzyloxy-6-hydroxyphenyl)pyrazoles as minor products .

ð173Þ

Pyrazoles

ð174Þ

ð175Þ

-Halosubstituted chromenes can undergo a variety of reactions to give substituted pyrazoles. 3-Chloro-2-polyfluoroalkylchromones 795 reacted with hydrazine hydrochloride in refluxing ethanol to give 4-chloro-3(5)-(2-hydroxyphenyl)5(3)-polyfluoroalkylpyrazoles 796 (Equation 176) . 3-Halo-4-methoxycoumarins 797 were transformed into 4-halo-5-(2-hydroxyphenyl)-3-oxo-2,3-dihydropyrazoles 798 with hydrazine hydrate in ethanol at room temperature (Equation 177) . However, excess hydrazine in refluxing ethanol afforded 4-hydrazono-2-pyrazolone 799. A one-pot process to form 3,4-diarylpyrazoles 801 by Suzuki coupling of arylboronic acids to chromone 800, followed by condensation with hydrazine, has been reported (Scheme 98) .

ð176Þ

ð177Þ

Scheme 98

105

106

Pyrazoles

4.01.10.1.7

Pyridines and pyridones

The 3-cyano-4-trifluoromethyl-6-aryl-2(1H)-pyridones 802 reacted with hydrazine hydrate to give exclusively 5-trifluoromethyl-3-arylpyrazoles 803 (Equation 178) . The interaction of the 3,5-diacyl-1,4-dihydropyridine 804 with hydrazine hydrate proceeded readily to give bis-pyrazolylmethanes 805 in high yields (Equation 179) .

ð178Þ

ð179Þ

4.01.10.1.8

Sydnones

Sydnones can undergo smooth cycloaddition with propargylic esters to give pyrazoles. The reaction involves a 1,3dipolar cycloaddition of the mesoionic sydnones, behaving as cyclic azomethine imines. The initially formed cycloadducts readily release carbon dioxide to produce a mixture of five-membered regioisomeric pyrazoles. For example, 3-(p-aryl)-4-cyanosydnone 806 underwent 1,3-dipolar cycloaddition to give pyrazoloesters 807 and 808 in varying ratios (Equation 180) . Further amidation and Ritter reaction led to pyrazole-based dihydroorotate dehydrogenase (DHODase) inhibitors. Condensation of 4-acetyl-3-arylsydnones with various aryl aldehydes gave the appropriate ,-unsaturated ketone precursors, which were reacted with hydrazine hydrate to give 3-arylsydnonyl-1H-pyrazoline derivatives .

ð180Þ

4.01.10.1.9

Tetrazoles

Cyanopyrazole heterocycles were easily prepared via thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines, or tetrazolo[1,5-a]pyridines . Tetrazolylacroleins 809 underwent ring transformation on reaction with fumaronitrile 810 to afford pyrazolyl derivatives 811 (Equation 181) . Mechanistically, the tetrazolylacrolein is believed to react with the dipolarophile via a 1,3-dipolar cyclization route to give a

Pyrazoles

dihydropyrazole intermediate followed by hydrogen cyanide and nitrogen elimination. 1,5-Diaminotetrazole reacted with chalcones via Dimroth rearrangement to give 5-tetrazolylhydrazine, which resulted in the formation of 1-(5tetrazolyl)-3,5-diaryl-2-pyrazolines .

ð181Þ

4.01.10.1.10

Triazines

3-Chloro-6-phenyl-1,2,4-triazines 812 react with -chlorosulfonylcarbanions giving pyrazoles 813 with halosulfonyl, sulfonamido, and sulfonyloxy groups at C-3 (Equation 182) . Trifluoromethylated 7-hydroxy-4,7dihydroazolo[5,1-c]triazines reacted regioselectively with methylhydrazine and phenylhydrazine to form 3-trifluoromethylpyrazoles . Reaction of 6-aryl-3-dimethylamino-1,2,4-triazine 4-oxides with potassium cyanide resulted in the formation of 3-amino-5-aryl-4-nitrosopyrazoles via an ANRORC mechanism . A novel route to pyrazole derivatives bearing sulfonyl, amino-, alkoxy-, and aryloxysulfonyl groups at C-3 involved an ANRORC-type mechanism from 3-chloro-6-aryl-1,2,4-triazines with -halocarbanions .

ð182Þ

4.01.10.1.11

Other five-membered heterocycles

A new general method for the synthesis of 1-acyl-3-hydroxy-1H-pyrazoles 816 starting from 4-ethoxymethylene-2phenyloxazol-5(4H)-one 814 and hydrazides in boiling dioxane has been described (Scheme 99) . The route includes a migration of an acyl group via intermediate 815. 4,5-Diaryl-1,2,3-thiadiazoles and 1,2,3benzothiadiazoles were converted into 1,2,3-thiadiazol-3-ium-3-methanide 1,3-dipoles by reactions with trimethylsilylmethyl trifluoromethanesulfonate followed by treatment of the intermediate salts with cesium fluoride . These gave in situ cycloaddition–rearrangement reactions with some alkyne and alkene dipolarophiles leading to substituted 1-(2-vinylthioethenyl)pyrazole systems. 1,2,3-Triazoles 817 underwent a Diels–Alder cycloaddition with dimethyl acetylenedicarboxylate 761 under solvent-free conditions and microwave irradiation in the presence of silica-bound aluminium chloride to afford pyrazole-3,4-dicarboxylates 819 with extrusion of the substituent on C-4 of the triazole intermediate 818 as a nitrile (Scheme 100) . A new heterocyclization of

Scheme 99

107

108

Pyrazoles

Scheme 100

4-trifluoroacetyl-2,3-dihydropyrroles 820 with hydrazines provided entry to trifluoromethylated pyrazoles 821 bearing a -aminoethyl side-chain (Equation 183) . The addition of hydrazine to functionalized furans led to a variety of 4,49-bipyrazoles depending on the structure of the starting materials .

ð183Þ

4.01.10.1.12

Other six-membered heterocycles

(Z)-3-Acetyl-2-methyl-2,3-dihydro-1,4-benzodioxin-2-ol 822 reacted with hydrazines with the formation of pyrazoles 823 substituted at C-4 with an o-hydroxyphenoxy group (Equation 184) . 1-Phenyl- or 1-methyl-5-benzamidopyrazole-4-carbohydrazide derivatives were prepared from 1-methyl- or 1-phenyl-6-phenylpyrazolo-[3,4-d]-1,3-oxazin-4(1H)-one derivatives and hydrazine hydrate . The reaction of ethyl 1-amino-6,7-difluorooxoquinolin-4-one-3-carboxylate 824 with pentane-2,4-dione in acetic acid, in the presence of air, yielded 1-(2-acetyl-4,5-difluorophenyl)-3-methyl-4-acetylpyrazole 825 (Equation 185) . Desulfurization of 3-methyl-6H-1,3,4-thiadiazine 826 with glacial acetic acid afforded 5-aminopyrazoles 827 (Equation 186) . Treatment of nitropyrimidine derivatives 828 with various hydrazines under very mild conditions gave 4-nitro-3,5-diaminopyrazoles 829 for novel efficient and insensitive explosives syntheses (Equation 187) . Thermal extrusion of sulfur dioxide or carbon dioxide from their respective heterocyclic precursors 830 or 831 generated 1,2-diaza-1,3-butadienes 832, which underwent palladium(0)-catalyzed carbonylation to yield 2,3pyrazol-1(5H)-ones 833 or a Diels–Alder-type reaction with N-phenyldiazamaleimide to afford cycloadduct 834 (Scheme 101) . Fully substituted 1H-pyrazoles 837 were prepared from the condensation/fragmentation/cyclization/extrusion reactions of thietanone 835 with 1,2,4,5-tetrazines 836 (Equation 188) . C60Tetrazine Diels–Alder adducts bearing electron-deficient dihydropyridazine groups underwent chemoselective amination and hydration reactions upon addition of primary aliphatic amines and water, respectively, to form new adducts with 4,5-dihydropyrazole groups nested atop the [60]fullerene skeleton .

ð184Þ

ð185Þ

Pyrazoles

ð186Þ

ð187Þ

Scheme 101

ð188Þ

4.01.11 Synthesis of a Particular Class of Compounds and a Critical Comparison of the Various Routes Available: Pyrazoles, Indazoles, and Their Derivatives as Starting Materials for the Syntheses of Fused Ring Systems 4.01.11.1 Synthesis of Fused Ring Systems Many kinds of pyrazole-fused ring systems, especially in applications in the medicinal chemistry area, have been published during the last decade. These include general structures such as pyrazolopyridines, pyrazoloprimidines, pyrazoloquinolines, pyrazoloisoquinolines, pyrazolopyrazines, pyrazolopyridazines, pyranopyrazoles, pyranopyrazoles, pyrazolotriazines, and pyrazolo-fused phosphorus rings. The synthesis and structures of these ring systems are presented in Volumes 9 and 10.

109

110

Pyrazoles

4.01.11.2 Nucleosides and Amino Acids A review has described the synthetic approaches, chemical properties, biological activities, and structure–activity relationships (SARs) of pyrazole nucleosides and condensed pyrazole nucleosides . Many of the references are pre-1996, and only selected post-1996 examples will be cited here. The synthesis of 1-aryl-6,7-dichloro-3--D-erythrofuranosylpyrazolo[3,4-b]quinoxaline C-nucleoside analogs and 3--D-ribofuranosyl-lH-pyrazole-4-carboxamide has been described . D-(Ribofuranosyl)pyrazole 841 was stereoselectively synthesized by cyclization of intermediate diol 840 obtained from 2,3,5-tri-O-benzyl-D-ribose 839 on reaction with the lithium salt of N,N-dimethylpyrazole-1-sulfonamide 838 (Scheme 102) . Synthetic approaches to new 4-(furanos-4-C-yl)-1H-pyrazole and 3-(furanos-4-C-yl)-1Hpyrazole derivatives are described, including its pyrazole-5-carboxylate derivative, which is a pyrazofurin analog . The solid-phase parallel synthesis of 4--D-ribofuranosylpyrazolo[4,3-d]pyrimidine nucleosides has been reported . A multistep stereospecific synthesis of two novel pyrazole C-nucleosides 842 and 843 has been achieved starting from D-glucose and both were found to be moderate inhibitors of the in vitro growth of N2a tumor cell lines . 29-Deoxy-49-thiopyrazolo[3,4-d]pyrimidine nucleosides were synthesized and tested against a panel of tumor cell lines . 19-(N)-Homocarbanucleosides (R ¼ nucleoside) based on the 1-methylcyclopenta[c]pyrazole scaffold 844 was prepared by coupling a purine or pyrimidine to, or constructing it on, a protected 1-methylcyclopenta[c]pyrazole pseudosugar synthesized from ()-(exo,exo)-1-methyl-4,5,6,7-tetrahydro-4,7-methanoindazole-5,6-diol by oxidative cleavage of the starting glycol, reduction of the resulting dialdehyde with sodium borohydride, and the protective monosilylation of the bis(hydroxymethyl) reduction product . -D-Ribofuranosyl-enaminoesters reacted with benzylhydrazine to give pyrazole C-nucleoside derivatives . The chemical synthesis and biological evaluation of some acyclic -[6-(10-carbamoylalkylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]thioalkylamide nucleosides for their antiviral and antitumor activity have been described .

Scheme 102

The synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acids from (1R,3R)and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl esters involved a regiospecific ring– chain transformation of the enaminones by attack of the hydrazines . The naturally occurring amino acid (S)--pyrazolylalanine 846 was synthesized via the nucleophilic ring opening of an optically active aziridine 845 by pyrazole (Scheme 103) . A stereospecific synthesis of optically active pyrazoles 847 as constrained amino acids, from L-proline via trimethylsilyl alkynyl ketones, has been described . Novel pyrazole-containing bicarboxylic -amino acids 848 were prepared as mimics of the cis-amide bond .

Pyrazoles

The synthetic strategy employed allowed the regio- and stereoselective preparation of 1,3- or 1,5-disubstituted pyrazolyl rings. Pyrazolyl oxazolidines, prepared from L-serine, were transformed into novel chiral -amino acids containing a pyrazole ring . The synthesis of (2S)-/(2R)-2-amino-4-(1-aryl-/1,5-diaryl-1H-pyrazol-3yl)butyric acid was prepared from carboxy lactams through ring–chain transformation reactions .

Scheme 103

4.01.11.3 Labeled Compounds 3,5-Dimethylpyrazole-d8 and DPP-d12 849 were prepared by base-induced isotope exchange in superheated deuterium oxide . The photochemistry of phenyl-substituted 1-methylpyrazoles was investigated using deuterium labeling methods .

Radiolabeled compounds are prepared frequently for the study of biological and metabolic processes. N-(Piperidin1-yl)-5-(4-methoxyphenyl)-1-(2-chlorophenyl)-4-[18F]fluoro-1H-pyrazole-3-carboxamide 850 has been synthesized as a potential radiotracer for the study of CB1 cannabinoid receptors in the animal brain by positron emission tomography . The central cannabinoid receptor antagonist SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, was synthesized from commercially available starting materials . The tritiated SR141716 851 exhibited a tritium–proton NOE, which both definitively identified the position of the tritium as well as confirmed the structure as the sought-after isomer of the diarylpyrazole. This work provided a direct method for the preparation of preferred iodinated aryl substrates that offer advantages where selectivity and high incorporation in catalytic reduction is sought. 1-(5-tert-Butyl-2-p-tolyl-2Hpyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), currently in clinical trials for the treatment of inflammatory diseases, is a potent inhibitor of p38 MAP kinase. Deuterium-, tritium-, and carbon-14-labeled BIRB 796 with stable and radioactive isotopes were prepared for metabolism, distribution, and absorption studies . Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide) is an effective inhibitor of the cyclooxygenase-2 (COX-2) enzyme. The synthesis of a no-carrier-added iodine-123-labeled analogue 852 of celecoxib was accomplished in four steps for potential use in single photon tomography .

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Pyrazoles

Pyrolysis of 13CH3-labeled 1-methylpyrazole 853 with chloroform at 550 C in a continuous flow reactor yielded unlabeled 2-chloropyrimidine 854 and 2-cyanopyrrole 855 labeled at the cyano groups (Equation 189) . However, pyrolysis of 1-benzylpyrazole with chloroform under similar conditions gave 2-chloropyrimidine 854, 2-phenylpyrimidine, and, as the major product, -carboline.

ð189Þ

4.01.12 Important Compounds and Applications 4.01.12.1 Pyrazoles in Supramolecular Chemistry A synthesis of novel 4-acylpyrazol-5-one-substituted crown ether metal-chelating reagents has been reported; crown ether 856 was found to be an effective and metal ion-selective extraction reagent . A new diaza heteroaromatic crown of 3,5-disubstituted-1H-pyrazole 857 which formed solid dinuclear complexes with lipophilic phenethylamines has been developed . Bis-(3,5)pyrazolophanes (18- to 24-membered rings annulated to pyrazole units) were synthesized by double cycloadditive macrocyclization of bis-hydrazonoyl chlorides with bis-allyl, bis-vinyl, and bis-propargyl ethers .

A simple synthesis of pyrazolo[49,59][60]fullerenes from pyrazolyl hydrazones with [60]fullerene was achieved with microwave irradiation; evidence of intramolecular charge-transfer interaction was shown . Novel C60-fused isoxazolines have been synthesized from 1,3-dipolar cycloadditions of pyrazole nitrile oxides to C60 under thermal or microwave irradiation . A new triad based on pyrazolino[60]fullerene and a conjugated

Pyrazoles

N,N-dimethylaniline group has been synthesized by a copper-free Sonogashira cross-coupling reaction using microwave irradiation as the source of energy . The electrochemical and photophysical properties of the triad were systematically investigated by techniques such as time-resolved fluorescence and transient absorption spectroscopy. The effect of cation size, charge, H-bonding, and aromatic interactions on the three-dimensional supramolecular architecture of pyrazole-4-sulfonate networks of alkali and alkaline-earth metals has been reported . Supramolecular arrays of cationic complexes containing pyrazole ligands and tetrafluoroborate, trifluoromethanesulfonate, or nitrate as counterions have been investigated along with the crystal structure of bis(3,5-dimethyl-4-nitro-1Hpyrazole- N2)silver(I)nitrate ([Ag(HpzNO2)2](NO3)) . The interaction with Cu(II) and dopamine of three polyazacyclophanes containing pyrazole fragments as spacers has been described . Formation of mixed complexes, Cu(II)-macrocycle–dopamine, has been studied by potentiometric methods in aqueous solution. In both 3-methyl-1,5-diphenyl-1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepine and 5-(4-chlorophenyl)-3-methyl-1-phenyl1,6,7,8-tetrahydropyrazolo[3,4-b][1,4]diazepine, an N–H N hydrogen bond linked six molecules to form an R66 (30) ring . A series of tridentate ligands N,N-bis-[(disubstituted-1-pyrazolyl)methyl]arylamines and benzylamines, tetradentate N,N9-bis-[(disubstituted-1-pyrazolyl)methyl]para-phenylenediamines, and hexadentate N,N,N9,N9-tetra-[(disubstituted-1-pyrazolyl)methyl]para-phenylenediamines have been prepared in good yields by condensation of arylamines, benzylamine, or para-phenylenediamine from N-hydroxymethyl-disubstituted pyrazoles. The synthesis and characterization of these various polydentate ligands as candidates for metal complex wires were discussed .

4.01.12.2 Pharmaceuticals and Agrochemicals Within the last 15 years or so, pyrazole-fused ring systems have found numerous applications in drug discovery efforts, and biological activities using these scaffolds have resulted in patented and approved drug candidates. For example, sildenafil is a selective inhibitor of phophodiesterase 5 (PDE5) and is the first agent with this mode of action for the treatment of male erectile dysfunction . This new drug was approved for prescription use within the United States and the European Union during 1998 and has become one of the fastest-selling drugs of all time. Celecoxib has been approved for the inhibition of the COX-2 enzyme pathway for the treatment of rheumatoid arthritis . Rimonabant is a drug in clinical trails that shows high affinity for the CB1 cannabinoid receptor for the treatment of obesity .

Representative examples for various therapeutic areas show how pyrazole or fused pyrazole ring systems can have varied applications in drug discovery efforts. Only nonfused pyrazole ring examples will be shown in the examples below; fused pyrazole rings systems are presented in Volumes 9 and 10.

4.01.12.2.1

Anti-inflammatory agents

Inhibition of p38 has become one of the major targets in developing anti-inflammatory drugs, due to its prominent role in regulating inflammatory cytokines such as tumor necrosis factor alpha (TNF-) and interleukin (IL-1). Pyrazole-based inhibitors of the transforming growth factor beta (TGF-) type I receptor kinase domain (TR-I) included 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues 858 . Analogs 859 of BIRB 796, a member of the N-pyrazole-N9-naphthyl urea class of p38 mitogen-activated protein kinase (MAPK) inhibitors, has been reported .

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The COX enzymes, which catalyze the first step in arachidonic acid metabolism, were identified as the molecular targets of all nonsteroidal anti-inflammatory drugs (NSAIDs). SAR studies of the novel 2-[3-di and trifluoromethyl-5-alkylaminopyrazo-1-yl]-5-methanesulfonyl(SO2Me)/sulfamoyl (SO2NH2)–pyridine derivatives 860 for canine COX enzymes have been described ; the 5-alkyloxy and 5-alkylthio analogs and 5-heteroaryl-phenyl analogs have also been reported . 1,3-Diarylcycloalkanopyrazoles 861 were identifed as selective inhibitors of COX-2 .

4.01.12.2.2

Cardiovascular agents

Thromboembolic diseases remain the leading cause of death and disability in developed countries. Factor IXa (fIXa) plays a key role in maintaining internal homeostasis in the intrinsic pathway of the clotting cascade. Inhibition of fIXa presents an alternative and viable way of treating thrombosis arising from both venous as well as arterial vascular injuries. Selective and efficacious factor IXa hydroxypyrazole inhibitors 862 have been described . Factor Xa has also become a major focus of pharmaceutical intervention in the past decade because of its central role in the blood coagulation cascade. A variety of P4 motifs have been examined to increase the binding affinity and in vitro anticoagulant potency of biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxamide-based 863 fXa inhibitors . 1-(3-Amidinophenyl)-1H-pyrazole-4-carboxamides 864 were found to be dual inhibitors of factors IXa and Xa .

The renin–angiotensin system (RAS) plays a key role in regulating cardiovascular homeostasis and electrolyte/fluid balance in normotensive and hypertensive subjects. Activation of the renin–angiotensin cascade begins with renin

Pyrazoles

secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of the octapeptide angiotensin II (AII), which then interacts with specific receptors present in different tissues. Two basic types of receptors, both having a broad distribution, have been characterized so far: the AT1 receptor, responsible for the majority of effects attributed to this peptide, and the AT2 receptor, with a functional role as yet uncertain. The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles 865 as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported .

4.01.12.2.3

CNS applications

The dopamine D4 receptor subtype has received much attention as a pharmacological target for the treatment of schizophrenia, Parkinson’s disease, depression, and attention-deficit/hyperactivity disorder (ADHD). 4-N-linkedheterocyclic piperidine derivatives 866 with high affinity and selectivity for the human dopamine D4 receptors have been reported . Aminomethyl-substituted biaryls 867 bearing a pyrazole moiety have been found to have dopaminergic partial agonism for the D4 receptor subtype .

Dopamine D2 receptor ligands have been designed for the treatment of schizophrenia. For example, 1-aryl-4(piperazinylmethyl)-1H-pyrazoles have been found to be good ligands for the dopamine D2 receptor .

4.01.12.2.4

Infectious diseases

A number of 1,5-disubstituted 4-[1H-imidazol-1-yl(phenyl)methyl]-1H-pyrazoles have been synthesized and evaluated for antibacterial activities in vitro against Candida albicans, Cryptococcus neoformans, and Staphylococcus aureus . The antimicrobial activity of 1H-pyrazole carboxylates 868 has been disclosed . The synthesis and antibacterial activity of 5-aryl- or 5-[(E)-2-arylvinyl]pyrazoles 869 of DNA gyrase inhibitors has been disclosed . 1,5-Diaryl-pyrazole-3-carboxylates 870 have been found to have improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase . A number of 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 871 were synthesized and tested for antibacterial and antifungal activity . Carbon–carbon-linked (pyrazolylphenyl)oxazolidinones 872 with antibacterial activity against multiple drug-resistant Gram-positive and fastidious Gram-negative bacteria have been developed . Some pyrazoles prepared from pyrazole-4-carboxylic acid hydrazide showed antiviral activity .

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Pyrazoles

Since the discovery of the chemokine receptor CCR5 as a co-receptor with CD4 for human immunodeficiency virus 1 (HIV-1) cell entry, there has been an intense interest to discover small-molecule CCR5 antagonists as potential agents for the treatment of HIV-1 infection. Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side-chains as in 4-substituted pyrrolidines 873 have been investigated intensely . 1,5-Diphenylpyrazole non-nucleoside HIV-1 reverse transcriptase inhibitors 874 have been reported with enhanced activity against the HIV-1 virus . Malaria remains one of the most important diseases of humanity with over half of the world population at risk of infection. It affects mainly those living in tropical and subtropical areas with an incidence of 500 million cases per year globally. The antimalarial activity of 4-(5-trifluoromethyl-1H-pyrazol-1-yl)chloroquine analogues 875 has been evaluated in vitro against a chloroquine-resistant Plasmodium falciparum clone .

4.01.12.2.5

Metabolic diseases

The physiological role of CB receptors is not yet completely understood, although they seem to be involved in certain pathophysiological processes such as asthma, pain, appetite modulation, multiple sclerosis, vomiting, immune and inflammatory diseases. In particular, selective CB1 receptor ligands might produce potentially beneficial therapeutic effects including prevention of weight gain (treatment of obesity), mediated by interaction between CB1 receptors, involved in the control of appetite. A series of 4,5-dihydro-1H-benzo[g]indazole-3-carboxamides 876 showed high affinity for the CB1 and CB2 receptors . A series of N-1- and C-5-substituted cycloalkyl and C-5 4-methylphenyl analogs of the N-(piperidin-1-yl)-4-methyl-1H-pyrazole-3-carboxamide class of cannabinoid ligands were synthesized . Other 1,5-diarylpyrazole receptor ligands, close analogs to rimonabant, such as 877 have been synthesized by various pharmaceutical companies . Novel 3,4-diarylpyrazolines 878 as potent CB1 receptor antagonists with lipophilicity are described .

Pyrazoles

Another exciting drug target for the treatment of obesity is melanin-concentrating hormone receptor 1 (MCHR-1). Optimization of a high-throughput screening hit against MCHR-1 led to the discovery of 2-(4-benzyloxyphenyl)-N[1-(2-pyrrolidin-1-ylethyl)-1H-indazol-6-yl]acetamide 879 . This compound was found to be a highaffinity ligand for MCHR-1 and a potent inhibitor of MCH-mediated Ca2þ release; it showed good plasma and central nervous system (CNS) exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHR-1 antagonist that is efficacious upon oral dosing in a chronic model of weight. Urea-substituted variations of 879 have also been tested for MCH-1 activity . The synthesis and biological evaluation of 3-aminoindazole MCHR-1 antagonists 880 have been reported .

The KATP channels present in pancreatic -cells serve to regulate glucose-mediated insulin secretion by coupling cellular glucose metabolism directly to membrane potential. The discovery and synthesis of a series of 3-trifluoromethyl4-nitro-5-arylpyrazoles as potent KATP channel agonists has been reported . The in vivo activities of a series of substituted pyrazole-4-carboxylic acids as hypoglycemic agents have been described .

4.01.12.2.6

Oncologytic agents

Inhibition of the epidermal growth factor receptor (EGFR) tyrosine kinase activity by small molecules has proved effective for the treatment of cancer. A series of 1,4-dihydroindeno[1,2-c]pyrazoles 881 were identified as potent multitargeted (VEGFR and PDGFR families) receptor tyrosine kinase inhibitors . 1-(2-Pyrimidinyl)-1H-pyrazole derivatives 882 were prepared as new antitumor agents, showed antiproliferative activity against human lung cancer cell lines; they also inhibited tubulin polymerization .

Exposure of cells to stress, such as heat shock or oxidative stress, results in the accumulation of molecular chaperones, commonly known as heat shock proteins (Hsps). Hsp90 has emerged over the last few years as being of particular interest because of its role in the evolution, development, and disease pathology of cancer. Novel piperazinyl, morpholino, and piperidyl derivatives 883 of the Hsp90 inhibitor CCT018159 and

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Pyrazoles

VER-49009 have been reported. The crystal structure of human Hsp90 complexed with dihydroxyphenylpyrazoles has also been reported . Similarly, 3-(5-chloro-2,4-dihydroxyphenyl)pyrazole-4-carboxamides were also studied as inhibitors of Hsp90 molecular chaperone .

3,5-Diphenyl-4-hydroxy-4,5-dihydro-1H-pyrazoles and 3,5-diphenyl-1H-pyrazoles were synthesized and evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines . A series of pyrazole oxime ether derivatives 884 were prepared and examined as cytotoxic agents .

4.01.12.2.7

Estrogen receptor

The estrogen receptor (ER) is a nuclear hormone receptor of pharmaceutical interest as a target for the treatment of osteoporosis, breast cancer, and other endocrine female disorders. Triarylpyrazoles with basic side-chains have also been evaluated for ER ligand-binding activity . A series of tetrasubstituted pyrazoles, embodying 1,3-diaryl-4,5-dialkyl or 3,5-diaryl-1,4-dialkyl substitution patterns, for the ER have been published . The synthesis and activity of substituted 4-(indazol-3-yl)phenols 885 as pathway-selective ER ligands, useful in the treatment of rheumatoid arthritis, have been reported .

4.01.12.2.8

Agricultural uses

The 1-phenylpyrazole core has been shown to bestow pharmacological activity in a number of areas in the pharmaceutical and agrochemical industries. In the latter field, select examples of biological activities include insecticidal, miticidal, and herbicidal. More specifically, 1-phenylpyrazoles with alkyl, acyl, thioalkyl, or cyano substituents at the 4-position exhibit potent insecticidal activity. In particular, 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulfinyl-1H-pyrazole-3-carbonitrile (Fipronil) is one of the most commercially successful insecticides. In fleas, ticks, and other arthropods, it acts as a gamma-aminobutyric acid (GABA)-gated

Pyrazoles

chloride channel inhibitor causing neuronal cell hyperexcitability and eventual death. Close analogs such as 886 and 887 have been prepared.

4.01.12.3 Other Applications 4.01.12.3.1

Pyrazole ligand applications

Biarylphosphine ligands 888 were found to have fairly broad substrate applications in palladium-catalyzed amination reactions of aryl halides . Chiral bis(pyrazolyl)methanes were employed as catalysts in the asymmetric Diels–Alder reactions of 1-acryloyl-3,5-dimethylpyrazole with cyclopentadiene in the presence of magnesium perchlorate . A series of rhodium complexes with chiral ferrocenyl chelating ligands 889 containing a tertiary phosphine and a pyrazole moiety provide up to 99% ee in the hydroboration of styrene . Pyrazole-derived bidentate ligands (P,N-donor) with bulky substituents at the 3-position of the pyrazole were used in Suzuki coupling reactions with aryl bromides and chlorides . Pyrazole-tethered Schiff base ligands 890 promoted Suzuki cross-couplings of aryl bromides and chlorides with phenylboronic acid efficiently under mild conditions . Camphopyrazole ligands (both R and S) 891 provided >93% ee in the catalytic enantioselective addition of diethylzinc to benzaldehyde .

4.01.12.3.2

Pyrazoles as catalysts

Pyrazole and 3,5-dimethylpyrazole were effective stoichiometric catalysts in the Baylis–Hillman reaction of cyclopentenone 892 with p-nitrobenzaldehyde 893 in basic media to give adducts 894 in good yields (Equation 190) . An asymmetric borane reduction of ketones catalyzed by N-hydroxyalkyl-l-menthopyrazoles has been reported . 3-Aryl-l-menthopyrazoles 895 were assessed for their catalytic activity for asymmetric Diels–Alder reactions .

ð190Þ

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Pyrazoles

4.01.12.3.3

Pyrazoles as reagents

4-Nitro-1H-pyrazole-1-[N,N9-bis(tert-butoxycarbonyl)]carboxamidine 896 has been developed as a reagent for the rapid and efficient solid- and solution-phase synthesis of bis(carbamate)-protected guanidines from primary and secondary amines . 3,5-Dimethyl-N-nitro-1-pyrazole-1-carboxamidine 897 was employed as a reagent for the preparation of a range of guanidines via nitroguanidine intermediates . A convenient one-step transformation of primary and secondary amines into the corresponding unprotected guanidines using 4-benzyl-3,5-dimethyl-1Hpyrazole-1-carboxamidine 898 and its polymer-bound variant were described . The scope and limitations of the method, the microwave assistance of amidination, as well as a recycling protocol were examined. A new cellulosesupported reagent 899 for the synthesis of guanidines in aqueous medium has been prepared starting from commercially available functionalized cellulose beads . Primary and secondary amines, anilines, and amino acids were transformed into the corresponding guanidines in high yields and under very mild conditions.

The chromium trioxide complex with 3,5-dimethylpyrazole 900 was used for the oxidation of cyclohexenecarbonitrile to 3-oxocyclohex-1-ene-1-carbonitrile . 2-Acyl-3-phenyl-l-menthopyrazoles were effective enantioselective agents employed in the resolution of secondary alcohols . A bicyclo[3.1.1]heptano[4,3-c]pyrazolederived chiral auxiliary for dipolar cycloadditions was evaluated for the 1,3-dipolar cycloadditions of nitrile oxides and nitrilimines. Diastereoselective addition of a range of nucleophiles (allyltributylstannane, the methyl acetate-derived silyl ketene acetal, and trimethylsilyl cyanide) to chiral N-acyl pyrazolines 901 gave densely functionalized building blocks for asymmetric synthesis . Basic hydrolysis of the cycloadducts gave enantiopure 5-carboxy-4,5dihydroisoxazole (S)-(þ)-5-carboxy-4,5-dihydropyrazoles .

Pyrazoles

4.01.12.3.4

Metal pyrazole complexes

Bis(pyrazolyl)borate copper complex 902 has been employed as a catalyst in homogeneous and heterogeneous styrene epoxidation reactions . Pyrazole palladacycles 903 have proved to be stable and efficient catalysts for Heck vinylations of aryl iodides . A hemilabile pyrazolyl-functionalized N-heterocyclic carbene complex of palladium(II) such as 904 has been found to be an excellent catalyst for Heck and Suzuki crosscoupling reactions in ionic liquids .

4.01.12.3.5

Pyrazole industrial applications

A series of acyclic pyrazole derivatives were covalently immobilized on silica gel through a flexible 3-glycidoxypropyltrimethoxysilane spacer arm and these materials were used as sorbents for the recovery of heavy and alkali metal ions from aqueous solutions . Two different series of N-donor pyrazole ligands have been used in the liquid–liquid extraction of Cu(II), Cd(II), and Pb(II) ions from aqueous solution using methylene chloride as a solvent . The percentage of extracted metal ion determined by atomic absorption measurements was analyzed as a function of the ligand structure. It was shown that the ligand capacity for extraction is affected by the nature of the bridge between the central nitrogen atom and the pyrazole rings. The tridentate ligand exhibits a good extractive affinity for copper(II) and lead(II).

4.01.12.4 Natural Products Natural products containing pyrazole rings are practically nonexistent. It seems that the evolution of organisms has produced few enzymes capable of forming an N–N bond. However, a methanol extract of the sponge Tedania anhelans yielded the two unusual heteroaromatic acids, pyrazole-3(5)-carboxylic acid 905 and 4-methylpyrazole-3(5)-carboxylic acid 906, which are reported for the first time as natural products .

4.01.13 Further Developments The tautomerism in the solid state and in solution of five 4-bromo-1H-pyrazoles has been studied by multinuclear magnetic resonance spectroscopy . When there is a bromine atom at position 3(5), the tautomer present in all cases in the solid state and in the solution state is the 3-bromo one. Hydrazines reacted with 4-, 5-, and 6-chloro-1-alkynylphosphonates to provide the corresponding 4,5-dihydropyrazolo-3-methylphosphonates . A novel one-pot synthesis of substituted pyrazoles from chalcones and hydrazines in a tandem cyclization–dehydrogenation approach on Pd/C/K-10 catalyst has been described . A copper(II) oxide-catalyzed regioselective synthesis of 1-alkyl- and 1-aryl-1H-indazoles from ortho-halogenated alkanoylphenones, benzophenones, and arylcarboxylic acids with hydrazines in the presence of potassium carbonate has been developed . A palladium-catalyzed C–H activation/intramolecular amination reaction sequence provided a new route to 3-aryl/alkylindazoles .

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Pyrazoles

The Wittig–Horner reaction of protected 3-formylindazoles with N-(benzyloxycarbonyl)--phosphonoglycine trimethyl ester has been developed as a new practical synthesis of dehydro 2-azatryptophans and amino acid derivatives . Nucleophilic addition of Grignard or lithiated reagents of 3-N-methoxy-N-methylamides of indazole afforded a library of 3-keto and 3-formylindazoles . A fast and efficient bromination of pyrazoles with N-bromosuccinimide in acidic media by microwave irradiation has been reported . Reaction of pyrazole with N-halosuccinimides in either carbon tetrachloride or water gave 4-halopyrazoles in excellent yields . Transition metal-catalyzed cross-coupling of pyrazoles continued. 4-Chloro-1,3,5-trimethylpyrazole underwent efficient Suzuki cross-coupling reactions with both aryl- and heteroaryl boronic acids with new air-stable PdCl2{PR2(Ph-R)} complexes . Suzuki cross-coupling of a 5-pyrazolylboronic ester with methyl 2-bromo-4-fluorobenzoate followed by cyclization with thionyl chloride led to a facile synthesis of new pyrazoloisoindolones . Indazole 2 underwent N-arylation with iodobenzene with copper(I) iodide in the presence of tetrabutylammonium bromide and sodium hydroxide in refluxing toluene . The palladiumcatalyzed cross-coupling reactions of 5-tributylstannyl-4-fluoro-1H-pyrazole with aryl iodides provided high yields of the corresponding 5-aryl-4-fluoro-1H-pyrazoles . A regiospecific synthesis of 1,5-disubstituted-1Hpyrazoles containing differentiated 3,4-dicarboxylic acid esters via Suzuki coupling of the corresponding 5-trifluoromethane sulfonates has been reported . Efficient palladium-catalyzed synthesis of 7-substituted or 3,7-disubstituted 1H-indazoles from 7-OTf-1H-indazole and 3-bromo-7-iodo-1H-indazole, respectively, has been disclosed . Pyrazole 1 and indazole 2 underwent N-functionalization with alkoxydienyl and alkoxystyryl boronates in the presence of copper(II) acetate and cesium fluoride . A variety of pyrazolo[1,5a]indole derivatives were synthesized by a copper(I) iodide-catalyzed intramolecular amination reaction .

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129

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Pyrazoles

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2004BML813 2004BML935

2004BML941

2004BML947

2004BML1221 2004BML1229 2004BML3345

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133

134

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2004BML3581

2004BML4949 2004BML5263 2004BML6035 2004CC104 2004CC394 2004CEJ1193 2004CEJ1827 2004CHC513 2004CHE183 2004CHE869 2004CHE964 2004CHE1034 2004CHE1039 2004CHE1142 2004CHE1485 2004CHE1506 2004CL106 2004CL1026 2004COR1071 2004CSY391 2004EJI3089 2004EJI3484 2004EJO695 2004EJO4348 2004EJO4672 2004GC90 2004H(63)145 2004H(63)373 2004H(63)1311 2004H(63)2537 2004IC6054 2004ICA2899 2004ICA3279 2004ICA4247 2004ICC382 2004JA11718 2004JCO332 2004JCO350 2004JCO385 2004JFC(125)1299 2004JHC285 2004JHC601 2004JHC807 2004JHC931 2004JLR847 2004JME627

2004JME6435 2004JMT(673)17 2004JMT(686)83 2004JMT(689)251 2004JOC2661 2004JOC5578 2004JOC9085 2004JOM(689)463

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137

138

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2006BML649 2006BML1202

2006BML2046

2006BML2796 2006BML2955 2006BML4266

2006BML4371

2006CC1872 2006CEJ2244 2006CEJ3741 2006EJO2344 2006EJO2417 2006EJO2825 2006EJO3283 2006H(68)1209 2006H(68)1825 2006H(68)1961 2006H(68)2177

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140

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2006TL817 2006TL833 2006TL2265 2006TL2443 2006TL3209 2006TL4655 2006TL5203 2006TL5797 2006TL7571 2006TL8761 2006TL8807 2006TL8965 2007EJO1318 2007JOC5104 2007OL525 2007OL2931 2007SC137 2007SL1203 2007SL1600 2007T419 2007T1154 2007T5062 2007T8104 2007TL245 2007TL2457 2007TL3213 2007TL4123 2007TL4595 2007TL6262

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Pyrazoles

Biographical Sketch

Larry Yet was born in Vancouver, British Columbia, Canada. After graduating with his B.Sc. degree in chemistry from the University of British Columbia working with Professor James P. Kutney on his senior thesis, he continued his graduate studies with Professor Harold Shechter at The Ohio State University, receiving his M.S. degree in 1990 and Ph.D. in 1995. He then carried out postdoctoral research with Professor Douglass F. Taber at the University of Delaware. Since 1996, he has worked at Albany Molecular Research, Inc., as a senior research scientist.

141

4.02 Imidazoles N. Xi, Q. Huang, and L. Liu Amgen, Inc., Thousand Oaks, CA, USA ª 2008 Elsevier Ltd. All rights reserved. 4.02.1

Introduction

145

4.02.2

Theoretical Methods

146

4.02.3


152

4.02.3.1

X-Ray Diffraction

152

4.02.3.2

Proton and Carbon NMR spectroscopy

156

4.02.3.2.1 4.02.3.2.2

4.02.3.3


156 160

NMR Involving Other Nuclei

162

4.02.3.3.1 4.02.3.3.2


162 164

4.02.3.4

Ultraviolet Spectroscopy

165

4.02.3.5

IR Spectroscopy

167

4.02.3.6

Mass Spectrometry

167

4.02.3.7

Electron Spin Resonance

169

4.02.3.8

Photoelectron Spectra

170

4.02.3.9 4.02.4 4.02.4.1

CD Spectra

171

Intermolecular Forces

171

4.02.4.1.1 4.02.4.1.2 4.02.4.1.3

4.02.4.2

4.02.5.1

Aromatic Stability Other thermodynamic aspects Conformations

172 174 175

176

Annular prototropic tautomerism Substituent prototropic tautomerism Ring-chain isomerism

176 178 180

182

Unimolecular Thermal and Photochemical Reactions Fragmentation Rearrangements

182 182 182


4.02.5.2.1 4.02.5.2.2 4.02.5.2.3 4.02.5.2.4 4.02.5.2.5 4.02.5.2.6

4.02.5.3

172

Reactivity of the Fully Conjugated Rings

4.02.5.1.1 4.02.5.1.2

4.02.5.2

171 171 172

Tautomerism

4.02.4.3.1 4.02.4.3.2 4.02.4.3.3

4.02.5

Melting points Solubility Chromatography

Thermochemistry

4.02.4.2.1 4.02.4.2.2 4.02.4.2.3

4.02.4.3

170


184

Introduction Proton acids: Basicity and acidity of imidazoles and benzimidazoles Metal ions Alkyl halides and related compounds: Imidazoles without a free NH group Alkyl halides and related compounds: Imidazoles with a free NH group Aryl halides and related compounds: Imidazoles with a free NH group


184 184 184 184 186 187

191

143

144

Imidazoles

4.02.5.3.1 4.02.5.3.2 4.02.5.3.3 4.02.5.3.4 4.02.5.3.5 4.02.5.3.6 4.02.5.3.7 4.02.5.3.8

4.02.5.4


4.02.5.4.1

4.02.5.5

4.02.6.1

201

203 203 203 204 204

211 211 211 214 215

216 216 222

223 223

Compounds not in tautomeric equilibrium with aromatic isomers

Dihydro Compounds Tautomerism and interconversions Aromatization Ring fission Other reactions

Tetrahydro Compounds

4.02.6.3.1 4.02.6.3.2 4.02.6.3.3

4.02.7

201

Isomers of Aromatic Derivatives

4.02.6.2.1 4.02.6.2.2 4.02.6.2.3 4.02.6.2.4

4.02.6.3

Diels–Alder reactions and 1,3-dipolar additions Photochemical cycloadditions

191 191 191 194 197 198 198 198

Reactivity of Nonconjugated Rings

4.02.6.1.1

4.02.6.2

Carbenes Free-radical attack at ring carbon atoms Electrochemical reactions and reactions with free electrons Catalytic hydrogenation and reduction by dissolving metals


4.02.5.7.1 4.02.5.7.2

4.02.6

Metallation at a ring carbon atom Nitrogen carbanion and SRN1 reactions C-Acylation via deprotonation Transition metal catalyzed coupling reactions

Reactions with Radicals and Electron-Deficient Species

4.02.5.6.1 4.02.5.6.2 4.02.5.6.3 4.02.5.6.4

4.02.5.7

Hydroxide and O-nucleophiles


4.02.5.5.1 4.02.5.5.2 4.02.5.5.3 4.02.5.5.4

4.02.5.6

Reactivity and orientation Nitration Lithium–halogen exchange followed by electrophilic attack Halogenation Friedel–Crafts type alkylation and acylation Diazo coupling Silylation Oxidation

Ring fission Aromatization Other Reactions

223

223 223 224 226 228

236 236 237 238

Reactivity of Substituents Attached to Ring Carbon Atoms

240

4.02.7.1

Reactions of Substituents Involving Ring Transformations

240

4.02.7.2

Fused Benzene Rings

242

4.02.7.3

Alkyl Groups

242

4.02.7.4

Substituted Alkyl Groups

244

4.02.7.4.1 4.02.7.4.2 4.02.7.4.3

4.02.7.5

Vinyl and arylalkyl Activated alkyl Heteroatom substituted alkyl


4.02.7.5.1 4.02.7.5.2 4.02.7.5.3 4.02.7.5.4 4.02.7.5.5

244 245 246

248

Unsaturated alkyl Alkylidene Aryl Imine and nitrile derivatives Carbonyl derivatives

248 251 256 257 259

4.02.7.6

Amino and Related Groups

261

4.02.7.7

Oxygen-Linked Substituents

264

Imidazoles

4.02.7.8

Sulfur-Linked Substituents

265

4.02.7.9

Halogen Atoms

269

4.02.7.10 4.02.8

Metals and Metalloid-Linked Substituents

Reactivity of Substituents Attached to Ring Heteroatoms

271 273

4.02.8.1

Aryl Groups

273

4.02.8.2

Alkyl Groups

273

4.02.8.3

Alkenyl Groups

277

4.02.8.4

Acyl and Aroyl Groups

278

4.02.8.5

Nitrogen Functions

280

4.02.8.6

Silicon, Phosphorus, and Related Groups

280

4.02.8.7

Sulfur Groups

280

4.02.8.8

Oxygen Groups

280

4.02.9

Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component

4.02.9.1

Formation of One Bond

4.02.9.1.1 4.02.9.1.2 4.02.9.1.3

4.02.9.2

Formation of Two Bonds

4.02.9.2.1 4.02.9.2.2

4.02.9.3

281 281 287 294

295

From [4þ1] carbon fragments From [3þ2] carbon fragments

295 307

Formation of Three or Four Bonds

323

4.02.9.3.1 4.02.9.3.2 4.02.9.3.3 4.02.9.3.4 4.02.9.3.5

4.02.10

Formation of the 1,2- (or 2,3-) bond Formation of the 1,5- (or 3,4-) bond Formation of the 4,5-bond

281

Formation Formation Formation Formation Formation

of the 1,2-, 2,3-, and 3,4-bonds of the 1,2-, 1,5-, and 3,4-bonds of the 1,2-, 2,3- and 4,5-bonds of the 1,2-, 1,5-, and 4,5-bonds of four bonds

Ring Syntheses by Transformations of Another Ring

323 325 327 327 328

332

4.02.10.1

Ring Expansions

332

4.02.10.2

Transformations of Other Five-Membered Rings

336

4.02.10.3

Ring Contractions

340

4.02.11

Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available

342

4.02.11.1

Imidazole and Benzimidazole Oxides and Radicals

342

4.02.11.2

Nitroimidazoles

344

4.02.11.3

Fluoroimidazoles

345

4.02.11.4

Selenoimidazoles

346

4.02.12

Applications and Importance

References

347 348

4.02.1 Introduction Imidazole 1 is a five-membered aromatic molecule containing two annular nitrogen atoms. One nitrogen behaves like a pyrrole-type nitrogen and the other one shows a close resemblance to a pyridine-type nitrogen. The systematic name of this structure is 1,3-diazole, which is rarely used in the chemical literature. As in the earlier editions CHEC(1984) and CHEC-II(1996), this chapter covers the following ring structures: imidazole 1 and benzimidazole 2, 2H- 3 and 4Himidazole 4, the imidazolines 5–7, imidazolidine 8, imidazo-2-yldiene 9, and imidazolidin-2-ylidene 10 (Figure 1).

145

146

Imidazoles

Figure 1 Ring structures covered in this chapter.

Reviews on the chemistry of imidazole-related molecules since 1996 include: synthesis of imidazole-containing natural products , fluorinated imidazoles , N-halogenated imidazoles , and nitroimidazoles ; imidazole derivatives as biologically important molecules ; the aromaticity of imidazole and related molecules ; synthesis, physicochemical properties, structures and applications of imidazoliumbased ionic liquids ; and characterization and applications of imidazo-2yldienes and imidazolidin-2-ylidenes .

4.02.2 Theoretical Methods Over the decade 1995–2005, ab initio quantum chemistry has become an important tool in studying imidazole derivatives. Two highly productive approaches are often utilized for the calculations: the wave function-based methods (e.g., Hartree–Fock theory and second-order Moller–Plesset perturbation theory (MP2)) and the density functional theory (DFT) based methods (e.g., gradient-corrected (BLYP) and hybrid (B3LYP) methods). For simple imidazole derivatives in gas phase and solution, ab initio quantum-chemical calculations can provide results approaching benchmark accuracy, and they are used routinely to complement experimental studies . A wide variety of molecular properties, including structures and energetics , acidity , tautomer equilibria , thermochemistry profiles , and spectroscopic quantities of various types , have been investigated. The DFT method has become increasingly popular in computing molecular properties of imidazole analogues since the publication of CHEC-II(1996). For example, Gallouj and co-workers employed the DFT method based on the B3LYP formalism to compute the vibrational modes of 4-ethylimidazole with the 6-31G(df, p)-(5d, 7f) basis set . Toyama and co-workers investigated the molecular vibrations of two tautomers of 4(5)-methylimidazole using the DFT approach . Hasegawa and co-workers performed a systematic vibrational analysis on four possible protonated forms of 4-methylimidazole employing the B3LYP-DFT method with 6-31G(df, p) basis set . Maes and co-workers demonstrated that the DFT/B3LYP/6-31þþG** method yielded the most accurate vibrational frequency predictions for monomeric imidazole among three levels of theory (the RHF and MP2 methods and the parametrized DFT method) . Mo´ and co-workers calculated the enthalpies of formation of N-substituted imidazoles using the B3LYP/6-311* G(3df, 2p)//6-31G(d) approach . For molecular properties of complex systems, especially those in solution, ab initio quantum-chemical calculations may not be able to provide accurate results. For example, the acidity of imidazole in the gas phase can be calculated to provide equivalent or greater accuracy than that obtained experimentally; however, the determination of its pKa value

Imidazoles

in solution is less satisfactory . This is mostly due to the difficulty in quantitatively calculating solvation energies with adequate accuracy. A few approaches have been investigated to deal with the solvation effects required for evaluation of acidity/basicity in solution. Using a PCM (polarized continuum model) solvation method, the pKa value of imidazole in DMSO has been calculated to be 17.6 (MP2) and 17.1 (B3LYP), as compared to the experimental result of 18.6. . At the B3LYP/6-311þG(d,p) level of theory, the computed pKa values of several substituted imidazoles in solution are within 0.8 pKa units . Better results are obtained with various force field models. Thus, calculation with fixed-charges force field model reproduces the aqueous pKa value of imidazole at 6.4 (vs. the experimental 7.0), while the polarizable force field model yields an even more accurate pKa value at 6.96 . The pKa values of complexed imidazole derivatives are not predicted accurately by ab initio or semiempirical calculations, even when combined with semiempirical solvation models. Thus, for a series of imidazol-1-ylalkanoic acid derivatives, the calculations are unable to describe the zwitterionic structure of the carboxylic monoacids series as the most stable form determined experimentally in solution (Figure 2) . Likewise, the effect of an imidazole substituent on the pKa of phenol is not well reproduced using DFT/B3LYP/6-311þG(2d, 2p) and DFT/ B3LYP/6-31G(d) calculations (Scheme 1). The computed pKa values are higher than the experimental values by ca. 4 log units. Nonetheless, the trend of increasing acidity along the series is reproduced by the calculations .

Figure 2 Imidazol-1-ylalkanoic acid derivatives (R1, R2 ¼ H or Et).

Scheme 1

Characterized by its unique pKa value in aqueous solution, the protonation of imidazole ring plays an important role in biological systems and has been investigated by combinations of dielectric, quantum mechanical, and computer simulation methods . The species involved in the protonation process, that is, imidazole and the imidazolium ion, are characterized as both individual and complexed identities. For example, the electronic spectra of imidazole and the imidazolium ion have been computed with the complete active space self-consistent field method and multireference second-order perturbation theory . The solvation free energies of imidazole and the imidazolium ion have been investigated using the Ewald method and equilibrium fluctuations of electrostatic potentials . In addition, the imidazole–imidazolium complex, a strongly hydrogen-bonded system formed in the equilibrium, has also been the subject of many theoretical calculations . Thus, the vibrational spectra of the imidazole– imidazolium complex have been computed at the B3LYP/6-311þþG** level of theory . Similar calculations have been extended to the pyrazole–imidazole system, which also forms an extensive H-bonded complex . Histamine, a biologically important imidazole derivative, is in multiple acid–base and tautomeric equilibria in aqueous solution. Tautomeric and basic center preferences for isolated neutral and monoprotonated histamine have been studied by ab initio calculations (HF, MP2, and DFT), and the polarizable continuum model (PCM) has been

147

148

Imidazoles

used to investigate the variations of the tautomeric and basicity center preferences in histamine on going from the gas phase to aqueous solution . Tautomeric equilibria and vibrational spectra of histamine in solution have also been computed by quantum-mechanical calculations . Two possible histamine conformations, that is, essential and scorpio forms, have been investigated at different semiempirical (CNDO, INDO, MINDO/3, MNDO, AM1, and PM3) and ab initio (RHF/STO-3G//STO-3G, RHF/ STO-4G//STO-4G, RHF/3-21G//3-21G, RHF/6-31G//6-31G, RHF/6-31G* //6-31G, RHF/6-31G* //6-31G* , RHF/631þþG** //6-31G* , RHF/6-311þþG** /6-31G* , RHF/6-31G** //6-31G** , RHF/31þþG** //6-31þþG** , MP2/6-31G* // 6-31G* and MP2/6-31G** //6-31G** ) levels of theory. The results indicate that the so-called ‘essential’ (trans, T1) and ‘scorpio’ (gauche, T2) conformations of the neutral histamine tautomers equilibrate through the monoprotonated histamine tautomer (MP) (see Scheme 2) . Calculations using the AM1 method have also been carried out on isolated neutral and ring-N-protonated forms of histamine and model 4(5)-alkylimidazoles . Theoretical investigations on the conformers of more complex imidazoles, such as the dipeptides HisGly and GlyHis, have been carried out with a combination of Monte Carlo search with the Amber force field and local geometry optimization at the ab initio HF/6-31G(d) level .

Scheme 2 Acid–base and tautomeric equilibria of histamine.

Theoretical calculations have been employed to study the unique structural features of the imidazole ring. The characteristic annular tautomerism of imidazoles with unsubstituted nitrogen is a fast process, leading to usually inseparable tautomeric pairs . Computed at the IEF-PCM/B3LYP/6-31G* level of theory, the 1,3-tautomerization is predicted to be feasible through the formation of an intermolecular imidazole chain in nonprotic solvents, while the 1,2-prototropic shift, as an intramolecular tautomerization path, is disfavored . The preference of one tautomer form over another is governed by four different effects: sand/or p-electron donating and/or withdrawing effects, as indicated in the theoretical studies on C-5-substituted imidazoles at the MP2/6-311þþG** level (Scheme 3) . Similar results have also been obtained from semiempirical AM1 and PM3 calculations .

Scheme 3 Tautomerism of C-5-substituted imidazoles.

Imidazoles

Imidazole derivatives undergo ring-substituent prototropic tautomerization, which is often mediated by a solventassisted mechanism. A systematic investigation of the proton transfer in the tautomerization of 2-thioimidazolone using DFT theory indicates that the barrier height for non-water-assisted intramolecular proton transfer is very high (175.8 kJ mol1) . Enol/ketone and thiol/thione prototropic tautomerism in 2-imidazolone and 2-thioimidazolone has been investigated by ab initio methods in terms of thermodynamic stability (Scheme 4) . Semiempirical methods (AM1, PM3, and MNDO) have been used to evaluate the tautomerism of 2-, 4-, and 5-imidazolones and their thio- or azo-analogues in the gas phase .

Scheme 4 Tautomerism in 2-imidazolone and 2-thioimidazolone.

Molecules such as 2-(2-hydroxyphenyl)benzimidazole (shown in Scheme 5), 2-(3-hydroxy-2-pyridyl)benzimidazole, 2-(2-hydroxy-3-pyridyl)benzimidazole and 4,5-dimethyl-2-(2-hydroxyphenyl)imidazole are characterized by having a proton donor (the OH) group and a proton acceptor (the -NT) site connected by an intramolecular hydrogen bond in the ground state. Tautomerism of these molecules has been investigated by HF/CIS/D95** , semiempirical (AM1), DFT/B3LYP/6-31þG* methods, as well as Monte Carlo simulations, continuum model, and the Onsager, SCI-PCM, and COSMO methods based on both ab initio and semiempirical Hamiltonians calculations .

Scheme 5

The structures of substituted imidazolines such as the antihypertensives Clonidine and Moxonidine have been studied with B3LYP/6-31þG(d,p) and BP86/TZ2P DFT methods (Scheme 6) . 1,3-Dialkylimidazolium-based ionic liquids (ILs) are a class of novel solvents with very interesting properties. The structures and conformational properties of 1-alkyl-3-methylimidazolium halide ionic liquids have been studied with a B3LYP parameter functional method with 6-31G* , 6-31þþG** , and 6-311þþG** basis sets. The calculated results indicate imidazolium cations can form hydrogen bond interactions with halide anions . Similarly, in the structures of the 1-alkyl-3-methylimidazolium hexafluorophosphate or tetrafluoroborate, hydrogen-bonding interactions between the fluorine atoms of the PF6 or BF4 anion and the C-2-hydrogen on the imidazolium ring are also predicated by DFT (B3LYP) and RHF calculations .

149

150

Imidazoles

Scheme 6

Ab initio calculations at the B3LYP, MP2, and CCSD(T) levels on the gas-phase ion pairs of 1-butyl-3-methylimidazolium chloride indicate that the most stable conformers are essentially degenerate and have the chloride H-bonding to, or lying above, the C-2-H bond . The ethyl side-chain in 1-ethyl-3-methylimidazolium ion had been predicted to exist in an equilibrium between planar and nonplanar Et groups versus the imidazolium ring plane, in its liquid form . The local structure of ionic liquid 1,3-dimethylimidazolium chloride has been investigated by density-functional-based Car–Parrinello molecular dynamics (CPMD) simulations. The specific CH Cl hydrogen bonds are characterized in terms of donor–acceptor interactions between lone pairs on Cl and antibonding s* CH orbitals . Imidazol-2-ylidene and related carbenes 9 and 10 are remarkably stable, and many theoretical studies have been carried out to investigate the special stabilities (see also Section 4.02.4.2.1) . According to theoretical predictions at the B3LYP level, the activation energy of the 1,2-hydrogen shift of 9 to imidazole is very high . Ab initio calculations at the MP4/6-311G(d,p)// MP2/6-31G(d) level suggest that the higher stability of 9 than that of 10 is caused by the enhanced pp–pp delocalization. Nevertheless, both carbenes (9 and 10 in Figure 1) are strongly stabilized by electron donation from the nitrogen lone pairs into the formally ‘empty’ pp orbital . On the other hand, the prototype carbenes, that is, structures with hydrogen atoms on the nitrogens (e.g., 9), have not been isolated as stable compounds. Calculations at B3LYP/aug-cc-pVDZ level of theory suggest that two molecules of imidazol-2-ylidene could form the hydrogen-bonded complex 11 initially. Complex 11 would then dimerize to form imidazole dimer 13 through transition state 12 with a low activation energy value of 4.8 kcal mol1 (Scheme 7) .

Scheme 7 Species involved in the intermolecular hydrogen transfer and dimerization of 2,3-dihydroimidazol-2-ylidene.

The gas-phase proton affinity of 1-ethyl-3-methylimidazol-2-ylidene indicates that the carbene is one of the strongest bases reported thus far. DFT calculations have been carried out at the B3LYP/6-31þG(d) level to rationalize this strong basicity . Interestingly, dilithiated imidazole 14 and benzimidazole 15,

Imidazoles

displaying similar structures to those of N-heterocyclic carbenes, are potentially accessible, as predicted by B3LYP/ 6-31G* and B3LYP/6-311þG** calculations. In these structures, the p orbitals on the central carbons are only partially occupied, as are also observed in the related carbenes, for example, imidazol-2-ylidene (Figure 3) .

Figure 3 Dilithiated imidazole 14 and benzimidazole 15.

Theoretical computations have been used to study the reactions that involve imidazole or benzimidazole analogues . For example, the ring-closure reactions of 2,4-diazapentadienyl anions and the corresponding dipoles have been investigated by quantum-chemical model calculations (RHF, MP2, SCS-MP2, G3, and DFT) (Scheme 8) , and the reactions of various functionalized imines with nitrosoalkenes giving imidazoles and imidazole N-oxides have been investigated by theoretical calculations at the semiempirical AM1 and ab initio HF/6-31G* levels of computational analysis (Scheme 9) .

Scheme 8

Scheme 9

The mechanism of imidazole-2-ylidene-catalyzed transesterification has been studied using B3LYP DFT (Scheme 10). The reaction is predicted to involve neutral tetrahedral intermediates, TS1 and ATS1, in which the catalyst imidazol-2-ylidene facilitates proton transfer from alcohol to the carbonyl oxygen by forming the tetrahedral intermediate TD .

151

152

Imidazoles

Scheme 10

The reaction of azathioprine, an immunosuppressive drug, with hydroxide anion has been investigated by means of quantum chemistry . The reaction of azathioprine with cysteine in aqueous solution has also been studied using solvation model SM5.4 with PM3 Hamiltonian. The calculations suggest that the reaction involves nucleophilic attack by the COO of cysteine on the C-5 atom of the imidazole ring, followed by a subsequent intramolecular attack by the SH group of the cysteine residue (Scheme 11) .

Scheme 11

4.02.3 Experimental Structural Methods 4.02.3.1 X-Ray Diffraction X-Ray crystallography has become ever more accessible and, as a result, routine inclusion of crystal structures of imidazoles and their metal complexes have often appeared in the literature since the publication of CHEC-II(1996). Particularly, transition metal complexes containing imidazole ligands are increasingly used in, and their X-ray structural studies are reported for, important organic reactions such as Heck (N,N9-di-(2,4,6-trimethylphenyl)imidazolidine-2-thione/PdCl2 ), Suzuki–Miyaura (1,3-bis(2,6-diisopropylphenyl)imidazolidine/Pd(0) ), Pauson–Khand (N-heterocyclic carbene (NHC)/Co ), and olefin metathesis (NHC/Ru ). Earlier work on the characterization of NHCs has been summarized in a review . In contrast to the commonly observed NHC C-2-metal complexes, major products from the reactions of pyridine-functionalized imidazoles and IrH5(L)2 (L ¼ Ph3P; R ¼ mesityl, i-Pr) shows abnormal ligand binding at the C-4/5 position of imidazolium salts. The structures of these complexes have been unequivocally established from X-ray structural analyses (16, 18, Figure 4). The hydrogenated intermediate 17 has also been isolated and characterized in the solid state .

Imidazoles

Figure 4 Abnormal Ir-imidazolium complexes.

1-Methyl-2,4,5-trinitroimidazole was first reported in 1970 but its structure in the solid state was determined only in 2001. The 2-, 4-, and 5-nitro groups are twisted out of the imidazole plane by 24.2 , 9.8 , and 39.5 , respectively . The mechanism of nucleophilic addition to 4-nitroimidazoles under basic conditions is supported by the isolation and structure confirmation of intermediate oximes such as 19 (Scheme 12) and their ring transformed products .

Scheme 12

In the synthesis of anionic amido-N-heterocyclic carbene complexes of lanthanides (22, Ln ¼ Sm, Y; N9 ¼ (TMS)2N)) from the bridged imidazolium complex 20 via carbene 21, a typical increase in the length of the C–N bond and a decrease in the N–C–N angle were observed going from 20 to 21 . The Sm– Ccarbene distance of 2.588(2) A˚ is the shortest recorded compared to those reported for monodentate Sm–NHC ˚ complexes (2.62–2.83 A). In the solid state, 4(5)-nitro-5(4)-methoxyimidazole exists as a 1:1 mixture of the two prototropic annular tautomers . However, in histidine-dipeptides, the tautomer equilibrium (N1-H vs. N"2-H) has been found to vary depending on the nature of the peptide structures . The strongly fluorescent crystals of 23 (Figure 5) show efficient amplified spontaneous emission (ASE) associated with an excited-state intramolecular proton transfer (ESIPT) process . From the X-ray crystallographic analysis and semiempirical molecular orbital calculation, it has been found that the four aromatic groups attached to the imidazole ring of 23 provide a positive steric effect towards improved fluorescence emission by limiting the excessive tight-stacking responsible for the intermolecular vibrational coupling and relevant nonradiative relaxation. The methyl group in 2-(4-methylpyridin-2-yl)-1H-benzimidazole derivative 24 assumes an anti-configuration, while significant delocalization of the charge in salt 25 is manifested in a decreased N(1)–C(2) vs. C(2)–N(3) bond length differences. The dihedral angles about C-2–C-29 correlate well with relative UV-visible properties

153

154

Imidazoles

. In the solid state the cyclic peptide based on dipeptidyl imidazole 26 organizes to a rigid molecule in which all lone pairs of the imidazole nitrogens and the hydrogens of the secondary amides point toward the center of the macrocycle. The valine side-chains all lie on the same face of the molecule and adopt axial positions. The imidazole moieties form a cone-like structure .

Figure 5

In the crystal structures of nitronyl nitroxide 27 and iminyl nitroxide 28 (Figure 6), magnetic linear chains along the c-axis have been observed when R is H. These solids exhibit strong antiferromagnetism. In contrast, Cl substitutions in both radicals result in a less favorable geometry for intermolecular spin interactions .

Figure 6

The 10-E-3 hypervalent adducts from imidazo-thione/selenone and bromine (29, X ¼ Se; 30, X ¼ S, Se; Figure 7) assume T-shaped bonding with an almost linear Br–X–Br array roughly perpendicular to the average plane of the imidazole ring. These adducts are arranged in parallel planes, showing graphite-like stacking . Similar bonding geometries have also been observed in the X-ray structures of bisimidazolines with the mixed halogen IBr .

Figure 7

Macrocyclic imidazolylboranes can exist in various structural types depending on the substituents of both the imidazole and borane component. In the crystal structure of pentameric 31, all imidazole rings are almost perpendicular to the plane of the molecule. The average N–B–N angle of 109.3(6) is very close to that of a perfect pentagon. The tetramer 32 shows that the two opposite imidazole rings lie in the plane of the molecule while the other two are perpendicular to it .

Imidazoles

The nitrogen atoms of imidazoles are excellent H-bond acceptors. As a result, hydrates of these molecules form extended H-bonded networks (see also Section 4.02.2). One-dimensional water chains have been observed in the hydrates of 33, 34 (Figure 8) , and even 35 in which a strong electron-withdrawing nitro group is present . Diverse H-bond networks have also been reported in the hydrates of oligo(thiophenes) capped with imidazole , 2,29-dimethyl-4,49-biimidazole , and human isozyme (hCA II) complex with L-histidine or histamine . Not surprisingly, Baccatin III forms a 2:1 crystalline complex with imidazole which utilizes N(1)–H in the HB to the Ac(10) group of one Baccatin and N-3 in the HB to the HO(7) of another Baccatin molecule .

Figure 8

In the structure of 1,3-dihydroxy-4,4,5,5-tetramethylimidazoline (36, Figure 9), the imidazolidine ring is highly distorted (>0.27 A˚ off the mean plane). The hydroxyl groups form intermolecular hydrogen bonds with the nitro group . The complexes between tris(4,5-dihydroimidazol-2-yl)benzene and either TFA (37, R ¼ CF3) or tetrazole form C3-symmetrical H-bond networks. The molecular network in 38 features a twisted dicarboxylate (79.5 ) bridging coplanar bisimidazolines .

Figure 9

The ethylene-bridged imidazolium chloride 39 (Figure 10) crystallizes in the monoclinic space group P21/c with an antiparallel arrangement of the two halves. The chloride anions interact with hydrogen atoms at C-2 and C-19 of the bridge. In contrast, the naphthalene analogue 40 crystallizes in the triclinic space group P1¯ with syn relationship of the imidazole rings. The water molecule forms extensive hydrogen contacts bridging both the cations and the chloride anions .

Figure 10

155

156

Imidazoles

N-heterocyclic carbenes (NHCs) catalyze the amidation of unactivated esters with amino alcohols (see Section 4.04.2). The X-ray structure of N,N9-bis(mesityl)imidazolylidene–methanol complex (41, Figure 11) reveals a nearly linear (174 ) hydrogen bonding interaction within the plane defined by the imidazolidine ring . This observation, along with solution 1H NMR, 13C NMR, and IR studies, led to the proposal of a new mode of catalysis for stable carbenes. Similar solid-state hydrogen-bonding interaction between an NHC and diphenylamine was reported earlier . Together these represent a unique type of hydrogen bond involving a carbon-based acceptor: X-H C.

Figure 11

Cross-linking between the imidazole ring of histidines and side-chains of another residue have been identified by X-ray structure studies in enzymes such as the green fluorescent protein (GFP) with a Y66L variant (His-148 to Leu66) and the O2 binding site of cytochrome c oxidase (Tyr244-His240) . In the latter case, copper(I) complexes of Tyr-His model structures have been shown to mimic the Tyr244-His240 crosslink.

4.02.3.2 Proton and Carbon NMR spectroscopy 4.02.3.2.1

Aromatic systems

A review on 1H NMR of Cu(II) complex with histidine-containing peptides has appeared . Typical examples of proton and carbon chemical shifts are given in Table 1 for compounds 42, 43, and 44 . Table 1

1

H and 13C NMR chemical shifts of 1,2-dimethylimidazole derivatives at 80 C in [d8]-THF

Atom H-1 H-3 H-4 H-5 C-1 C-2 C-3 C-4 C-5 C-6 C-7 C-8 C-9 C-10

2.95 1.6-1.2 (br) 5.99 6.06 32.42 166.7 22.16 (br) 110.8 123.7

3.54 2.25 6.64 6.88 32.62 145.1 13.10 121.0 127.4

32.3 164.1 12.93 112.7 122.9 45.50 76.83 148.9 71.16 54.1-54.3

Imidazoles

In biaryl systems containing an imidazole ring, the 1H chemical shifts of the other ring can vary over a large range depending on the conformation and resonance interactions in the imidazole ring. For example, the aromatic proton located ortho to the aryl–heteroaryl axis in the seven-membered cyclic ether 45 (Figure 12) experiences a far greater downfield shift than the analogous proton in the rotationally less restricted eight-membered cyclic ether 46 . N-Methyl isomers of 47a and 47b show very different chemical shifts for the pyridine protons due to different canonical forms induced by the N-methyl imidazoles. The signals for the protons on the pyridine ring in 47a appear over a broad range ( ¼ 2.06 ppm) compared to those for 47b ( ¼ 0.87 ppm) . In m-xylenebridged imidazolium receptor 48, the C-2 proton signal of imidazolium moiety shifts downfield (9.2–10.7 ppm) when the free receptor 48a becomes complexed with anions such as Br 48b in MeCN .

Figure 12

Metalloporphyrins having an imidazolyl group at the meso position can form a complementary dimer, where each imidazolyl group is coordinated to the metal ion of the other porphyrin in a slipped cofacial arrangement. Imidazole protons of the free ligand H2Piv3ImP were observed at 7.8 ppm as a broad single peak due to free rotation of the imidazole. In the presence of a metal ion, as in (Co(III)Piv3ImP)2, the imidazole protons were observed as two peaks, because rotation was inhibited by coordination of N-6 to the cobalt of another porphyrin . Based on the 1 H NMR spectrum of 2-(1H-imidazol-2-yl)-pyridine-Ru2þ complex, the mer/fac isomer ratio was determined to be close to the statistic ratio (3:1) due to the C3-symmetry associated with the fac isomer . The solution NMR spectrum of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide 49 at 300 K corresponds to prototropic equilibrium between tautomers (49a, 49b, Scheme 13). Addition of a small amount of TFA increases tautomerization, leading to narrower, averaged signals ascribed to 49c. At 233 K, the signals were assigned as cited in Table 2 . The average of signals obtained at 233 K is very close to the values measured in the presence of TFA. The 13C NMR spectrum of 49 also suggests that there is no tautomerization at 233 K, slow prototropy at 300 K (broad signals), and rapid exchange in the presence of TFA (Table 3). However, in the solid state 13 C NMR (with the nonquaternary suppression NQS experiment), the imidazole ring signals are similar to either the 233 K or the averaged spectra, casting doubts on the structural interpretation (see 15N NMR).

Scheme 13

157

158

Imidazoles

Table 2

1

H NMR chemical shifts of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide 49 2-Ph

4-Ph

5-Ph

400 MHz CDCl3

OH

ortho

meta

para

ortho

meta

para

ortho

meta

para

233 K Average 300 K CF3COOH

11.91

8.22 8.22 8.31 7.98

7.33 7.33 7.33 7.34

7.45 7.45 7.44 7.42

7.62 7.03 7.61 7.06

7.45 7.26 7.44 7.25

7.45 7.35 7.44 7.32

6.44 7.03 6.60 7.06

7.07 7.26 7.08 7.25

7.25 7.35 7.23 7.32

Table 3 Selected

13

C NMR chemical shifts of 1-hydroxy-2,4,5-triphenyl-1H-imidazole 3-oxide 49

100 MHz, CDCl3

C-2

C-4

C-4

233 K Average 300 K CF3COOH CPMAS, 300 K

135.4 135.4 135.7 135.5 132.5

129.5 128.0 n.o. 126.3 128.6

126.4 128.0 n.o. 126.3 126.6

In the 13C MAS NMR spectra of histidine-dipeptides, the 13C chemical shifts for C and C span a large range (up to 13 ppm) and are highly influenced by the tautomer effect and intermolecular interactions . The imidazole ring 13C chemical shifts of 50 (158.6, 123.8 (2JCF ¼ 36.0), 131.0 ppm, Scheme 14) resemble more closely those of 1-methyl-5-(p-tolyl)-4-trifluoromethyl-1H-imidazole (137.6, 128.8 (2JCF ¼ 37.4 Hz), 133.0 ppm). Based on this observation, it was proposed that in the solid state 50 most likely assumes the tautomeric form 50a rather than 50b .

Scheme 14

The 13C chemical shifts of 2-lithiated imidazoles in THF-d8 range from 195.9 ppm to 216.1 ppm for compounds 51–54 (Figure 13). Simple imidazoles such as 51–53 exist as the ring form even at 20 C, whereas benzimidazole exists as a mixture of ring 54a and chain 54b, C2 158.4 ppm) tautomers. The nature of the lithiated species (carbene, carbenoid, or simple carbanion) is not easily discerned based on the 13C chemical shifts .

Figure 13

Quaternization of imidazoles (55, Figure 14) to imidazolium salts 56 leads to low-field shifts of all the imidazole carbon signals except that of C-4, which is shielded probably by steric compression resulting from N-3 substitution. In contrast, the corresponding imidazole 1-oxides 57 show a high-field shift for all the imidazole carbons. This high-field

Imidazoles

shift is due to increased negative charge accumulated at the carbon atoms (as reflected by the resonance structures). N-Oxidation also leads to a significant increase in the one-bond C–H coupling constant (1J) and a decrease in the differences between long-range coupling constants (3J), as a result of increased delocalization .

Figure 14

The complex [Y(L){N(SiMe3)2}2] (L ¼ 1-tert-butyl-3-(2-tert-butylaminoethyl)imidazol-2-ylidene) showed a CC(carbene) resonance at 186 ppm with a 1J 89Y–C(carbene) coupling of 54.7 Hz, larger than any 1JYC value reported for an s-bound yttrium alkyl or an yttrium–NHC adduct . In comparison, the 1JYC value for Y[N(SiHMe2)2]3(N,N9-dimethyl-NHC) was 49.6 Hz . Analyses of 13C NMR of N-heterocyclic carbenes (Figure 15) seem to suggest that the chemical shift of the carbene carbon correlates to the NCN bond angle in the solid state (Table 4). 13

Figure 15 Table 4 Selected 13C chemical shifts of N-herocyclic carbenes and bond angles in the solid state Carbene

( ppm) at C-2

N-(1)–C-(2)–N-(3) angle ( )

58 59 60 61 62 63 64

211.4 219.7 213.7 244.5 238.2 231.4 240

102.2 101.4 101.5 104.7 106.4 103.5; 104.3 n.a.

The rate of deuterium exchange at C-2 of substituted imidazolium cations in buffered D2O was measured by monitoring the disappearance of the C-2 proton signal. These data enabled calculation of carbon acid pKa values of 1,3-dimethylimidazolium (23.0), 1,3-dimethylbenzimidazolium (21.6), and 1,3-bis((S)-1-phenethyl)benzimidazolium (21.2) . Solid-state 1H CRAMPS (combined rotation and multiple pulse spectroscopy) and 13C NMR studies of lyophilized L-histidine at various pH values provided valuable insights into the acid–base and tautomeric equilibria. Calculated pKa values from solid-state acid-to-base ratios (r) are similar to those measured in solution . Dynamic 1H NMR measurement of line broadening of intramolecularly hydrogen-bonded amide NH at different temperatures predicts that the strength of hydrogen bonds in N,N9-disubstituted imidazole-4,5dicarboxamides 65 is 14 kcal mol1 (Figure 16).

159

160

Imidazoles

Figure 16

In studies of the 1H NMR spectra of N-glucosylimidazoles, analyses of both J4,59 from the sugar ring and chemical shifts of the imidazolyl H-2 upon protonation discount the previously proposed reverse anomeric effect of electropositive groups at C-1 of pyranoses. Dipolar coupling of H-2 and H-4 protons of the histidine residue in L-carnosine (ß-alanyl-L-histidine) has been observed in human tissues using an in vivo 1H NMR technique .

4.02.3.2.2

Nonaromatic systems

The 1H and 13C NMR chemical shifts of the aldose reductase inhibitor 4(S)-2,3-dihydro-6-fluoro-2(R)-methylspiro[chroman-4,49-imidazoline]-29,59-dione (methylsorbinil, 66, Figure 17) and its seven synthetic intermediates have been completely assigned on the basis of DEPT, COSY, g-HSQC and g-HMBC. All the J-values for C-F (1–4 bonds), H-F (1–4 bonds), and H-H (3–4 bonds) have been determined .

Figure 17

13

C NMR spectra of a series of imidazolidines with different substitution patterns have been reported based on HMQC single bond and HMBC long-range H-C correlations. For 1,3-dialkyl (or dibenzyl)imidazolidines, 1JC–H constants reflect relative orientation to the nitrogen lone pair: C–H bonds trans to a lone pair have lower values (1JC–H 135 Hz) whereas C–H bonds cis to a lone pair have higher values (1JC–H 144–154 Hz) . In the 1 H NMR spectra of N-benzyl imidazolidines, protons trans to nitrogen lone pair have upfield chemical shifts based on the notion that trans lone pair or cis-alkyls have shielding effects on the protons . This trend also holds for the C-2 protons of N,N9-diaryl imidazolidines . Conformations of 1,3-dihydroxy-4,4,5,5-tetramethyl-2-pyridinylimidazolidines (67–69, Figure 18) have been studied using both 1H and 13C NMR techniques and HF/6-31G(d) calculations. All three molecules adopt a conformation with the OH groups trans to the pyridinyl groups at lower temperature. At T > 300 K, 69 can also adopt another conformation where intramolecular H-bonding (N-OH) is no longer viable . cis-N,N9Dialkyl-4,5-diaryl imidazolinium 70 shows symmetrical 1H and 13C NMR resonances, indicating a planar conformation of the N-CTN moiety. The large coupling constant between the two benzylic protons (J4,5 ¼ 12–12.90 Hz) suggests a small dihedral angle (0–15 ) . 1JC–H couplings are directly proportional to the fraction of scharacter in a given C–H bond. In the 13C NMR spectrum of monolithiated chiral imidazoline 71 at 69 C, a single set of well-resolved signals with C ¼ 40.2 ppm (t, 1JC–H ¼ 125 Hz) is consistent with the expected N-lithiation. Further lithiation of (C) affords a single unsymmetrical product whose 13C NMR spectrum at 69 C shows C ¼ 64.2 ppm (d, 1JC–H ¼ 157 Hz), in agreement with N,C-bislithiated structure 72. Both the (downfield) chemical shift and the increase in 1JC–H are indications of partial delocalization at the C of 72. Overall, this center is pyramidalized and renders a high degree of diastereoselectivity in alkylation reactions .

Imidazoles

Figure 18

During the C-5 lithiation–substitution of 73 (Scheme 15), it was found that the reaction yields never exceeded 50%, and that a significant amount of starting material was always recovered. Both 1H and 13C NMR measurements indicated that 73 exist as a 1:1 mixture of rotamers about the NBOC amide bond at 78 C. Upon addition of s-BuLi, only one of the rotamers undergoes deprotonation. Presumably only the conformer in which the carbonyl oxygen is cis to C-5 of the imidazolidine ring undergoes directed lithiation. Based on line coalescence of the NMR signals at various temperatures, the half-life for rotation was determined to be >100 h at 78 C and 10 min at 40 C . H/D substitution rates (kdeut) of 5-monosubstituted imidazolidine-2,4-diones were determined by 1 H NMR spectroscopy. In conjunction with the rates of racemization (krac), as determined by chiral HPLC methods, it was postulated that the deuteration and racemization of chiral 5-monosubstituted hydantoins follow general base catalysis and that the deuteration occurs with inversion of configuration .

Scheme 15

The reactions of 2-amino-2-deoxy-D-glucopyranose with 2-halo-phenyl isothiocyanates in ethanol–water produced the corresponding (4R,5R)-1-aryl-5-hydroxy-4-(D-arabino-tetritol-1-yl)imidazolidinone-2-thiones (74, Scheme 16) with J4,5 2.2 Hz. On the other hand, reaction with 2-methoxyphenyl isothiocyanate gave rise to the (4R, 5S)epimer 77 with J4,5 7.4 Hz. The 5(S)-epimer undergoes rapid epimerization in DMSO giving 78, as evidenced by 1 H NMR measurements. Per-O-acetylation of the OH groups was achieved in Ac2O-pyridine (1:1) at 15 C without altering the C-5 configuration. Rapid elimination of the 5-OAc in the (5R) epimer 75 led to the formation of the corresponding imidazoline 76. Variable-temperature 1H NMR analyses revealed that the (5S)-epimer also undergoes elimination but via the (5R)-epimer. It was concluded that the elimination reaction follows a pericyclic pathway . Dynamic NMR techniques as well as molecular mechanics were employed for the study of atropisomerism of 74–76, 78–80. The naphthylthiones 79, 80 showed the highest barrier of rotation about the C(Ar)–N bond (17 kcal mol1) and existed as mixtures of atropisomers at room temperature .

161

162

Imidazoles

Scheme 16

4.02.3.3 NMR Involving Other Nuclei 4.02.3.3.1

Aromatic systems

Spectroscopic properties of both imidazole and benzimidazole are difficult to define due to the annular tautomerism. A compilation of solid state and solution 13C and 15N NMR data at both rt and low temperature was reported along with comparisons with, and attempted correlations to, calculated absolute shieldings . Chemical shift principle values for imidazole have been reported and compared with calculated values. The 15N chemical shift tensors are very sensitive to the hybridization of the nitrogen atoms . A 2D–15N exchange NMR study of protonic conduction in 15N-labeled imidazole provided little support to the Grotthus mechanism . The 22 tensor value is a good indicator of hydrogen bond length in cationic imidazole species such as histidine . Magic-angle spinning solid-state 2D 15N NMR with the rotor synchronized sequence R1852 applied at the 1H Larmor frequency allowed for an estimate of hydrogen bond length in crystalline [U-13C, 15N]-Lhistidine?HCl?H2O [15N(1)-H: 109 pm; 15N("2)-H: 105 pm] . Computed chemical shifts (s 1H, 15N, 195Pt, 99Ru, 103Rh) of transition-metal (M ¼ Zn, Pd, Pt, Ru, Rh) complexes with a prototypical nitro-imidazole-based radiosensitizer, 1,2-dimethyl-5-nitro-1H-imidazole, were reported at the GIAO-BP86 and B3LYP levels for BP86/ECP1-optimized geometries . 1 H–15N heteronuclear multiple bond correlation NMR (HMBC) is a convenient method for locating the position of imidazole-protecting groups . A modified accordion-based sequence with an accordion delay of 3–10 Hz was used to optimize 1H-15N long-range correlations. In general, stronger correlations were observed from protons to pyrrole-like nitrogens than to the pyridine-type nitrogens of imidazoles . In N-alkylated imidazoles, the ‘pyridine-type’ nitrogen resonates at higher frequency (higher ) compared to the substituted ‘pyrrole-type’ nitrogen (>60 ppm) . Hence in the 1H–15N HMBC spectrum the cross peak between the b-protons of the histidine side-chain and the p-nitrogen would coincide with the higher nitrogen in a -protected compound (81, Figure 19). Similarly, a correlation with the lower nitrogen would indicate a p-protected compound 82. This method was applied to C-4-linked imidazole ribonucleoside 83 where the location of the POM group at the t-nitrogen was established (a 1H(C10)/15N(p) cross-peak in 1H–15N HMBC signals [ (ppm) 15N (t) 176.1, 15N (p) 247.1, and 1H (C10) 4.66]) .

Imidazoles

Figure 19

The first solid-state cross-polarization magic angle spinning 15N-CPMAS/NMR was recorded for 1-hydroxy-2,4,5triphenyl-1H-imidazole 3-oxide (84, Scheme 17). Two signals at 170.4 and 166.2 ppm (300 K) were observed. Based on GIAO/B3LYP/6-31G* calculations, the signals were attributed to the presence of two independent molecules with an averaged structure 1c in the asymmetric unit .

Scheme 17

The 19F NMR chemical shift sensitivity of fluoroimidazoles as a function of pH near the region of the pKa of the substrate was studied in an effort to develop potential probes for intracellular pH determination. As shown in Table 5, the maximum chemical shift BHþ/B (chemical shift difference between acid (HBþ) and base (B) forms) varies as a function of the F-substitution, with the 1-(4-fluorophenyl)imidazole 87 showing the largest shift. Interestingly, in 86 the 19F resonance moves downfield with increasing pH while that of 85 moves in the opposite direction .

Table 5 Acidity and

19

F NMR/pH property of 1-substituted fluoroimidazoles

Structure pKa BHþ/B

5.18 0.46

6.52 0.22

5.78 3.94

163

164

Imidazoles

4.02.3.3.2

Nonaromatic systems

For a leading reference containing multinuclei NMR data for RCM catalysts containing NHC ligands, see . Multiple-nuclei (13C, 15N, 77Se) solid-state CPMAS/NMR spectra of 1,3-imidazolidine-2-selenones have been reported . Effects of substituents and hydrogen bonding on 14N and 17O chemical shifts in 3-imidazoline 3-oxides were shown to vary over a range of 155 and 110 ppm, respectively . 2-Methyl-5-nitroimidazoles were studied by 14N NMR–NQR double resonance spectrometry to evaluate the effect of substitutions on electron density distributions . Through studies of 6Li and 15N NMR spectra of 88 and 89 in various proportions, the formation of the mixed dimer 90 was identified as the catalyst responsible for enantioselective epoxide rearrangements to chiral allylic alcohols (Scheme 18).

Scheme 18

The structure confirmation of dimethyl 1-(4-chlorophenyl)-2-methyl-5-oxo-2-imidazoline-4,4-dicarboxylate 91, synthesized via a 1,3-dipolar cycloaddition reaction between an azomethine ylide and an isocyanate, was based on an nOe (7.5%) between the 2-methyl group and the 29-aromatic H, and the fact that there was one sp2 nitrogen at 72 ppm (N3) in the 14N NMR and one sp3 nitrogen at 212 ppm (N1) in the 15N MMR (Figure 20).

Figure 20

The characterization of transient intermediates during photosensitized oxidation of 2-13C-4,5-diphenylimidazole was made possible by following the change of the 2-13C label as a function of temperature. The 13C and 15N spectra data for the intermediates are shown in Table 6 . Lithiation of 1,2,2,5,5-pentamethyl-3-imidazoline 3-oxide 92 leads to the formation of the dipole-stabilized organolithium 93 (Scheme 19). Compared with 92, both C-4 and C-5 resonate at higher frequency, whereas N-3 resonates at lower frequency (Table 7). The 7Li NMR resonance appears significantly lower in frequency relative to that of s-BuLi (0.34 ppm), indicating more covalent character of the C–Li bond in 93 .

Imidazoles

Table 6 Chemical shifts of transient intermediates formed during the reaction of 2-13C-4,5-diphenylimidazole with singlet oxygen 13

Temperature ( C )

Transient intermediates

15

C ( ppm)

N ( ppm)

C-2

C-4

C-5

N-1

N-3

100

102.2

172.6

100.3

111.1

307.0

88

117.5

167.0

167.0

356.6

356.6

80

177.8

181.4

181.4

308.6

308.6

80

127.3

162.9

162.9

364.2

304.2

30

163.7

100.6

189.1

44.9

288.3

Scheme 19 Table 7 Selected 14N (MeNO2), 13C (TMS), and 7Li (LiClO4) chemical shifts for 92 and 93 (ppm) Compound

14

13

92 93

74 115

132.1 213.1

N-3

C-4

13

C-5

60.5 72.0

7

Li

n.a. 0.69

4.02.3.4 Ultraviolet Spectroscopy In MeOH, 2-(1H-imidazol-2-yl)pyridine shows two p–p* bands at 272 and 292 nm. Upon complexation with Co2þ or Ni2þ, these two bands show slight red shifts along with a new, weaker band around 340 nm (" 8000 dm3 mol1 cm1) . The UV-visible spectra of 94–98 (Figure 21) show broad and intense maxima (max) in the range of 250–340 nm (log " > 4). Quaternization at the picoline ring 96, 97 generally led to bathochromic effects relative to the neutral compounds 94, 95, in agreement with increased charge transfer. A hypo-hypsochromic shift was observed from 96 ! 98, reflecting two opposing effects: charge transfer and deviation from planarity of the rings around C(2)–C(29) .

165

166

Imidazoles

Figure 21

By analyzing the UV spectra of 4-(imidazol-1-yl)phenol complexed with b-cyclodextrin (CD) under different conditions, it was concluded that the imidazole moiety was buried deep inside the cavity of CD . The 2-(2-pyridylmethylsulfinyl)benzimidazole structure present in proton pump inhibitors is responsible for acidactivated formation of a reactive intermediate that is responsible for covalent binding to the cysteine 813 residue of the pump. The effect of the pKa of either the imidazole or the pyridine moiety on the half-life of these inhibitors was studied using pH-dependent UV spectroscopy . UV-Vis spectroscopy as well as X-ray crystallography was employed to delineate the mechanism of the green fluorescent protein (GFP) chromophore formation . The hydride transfer reaction from 2-[furyl and thienyl]-1,3-dimethylbenzimidazoline derivatives 100 to pyridinium or isoquinolinium salts giving 99 (Figure 22) has been studied in i-PrOH–H2O (4:1) using UV spectroscopy. The results were rationalized by the Marcus theory supporting the notion of a one-step hydride transfer mechanism .

Figure 22

Hydrolysis of 2,4,5-triphenyl-N-acylimidazoles, as followed by UV-Vis measurements, was found to proceed through a concerted pathway that was accelerated by steric crowding around the N-acyl bond . The pKa values were determined based on the kinetic data of the hydrolysis of 5-methyl-3,5-diarylimidazolidine-2,4dione 101 yielding 102 (Scheme 20).

Scheme 20

Binding of metal ions Cu2þ and Zn2þ to calixarene containing fluorophore and imidazole ionophore causes opposite responses to the fluorescence emission at 404 nm .

Imidazoles

4.02.3.5 IR Spectroscopy Acetylation of (4R,5R)-1-aryl-5-hydroxy-4-(D-arabino-tetritol-1-yl)imidazolidinone-2-thiones 74 first gives the OAc derivatives showing NH stretching at 3300 cm1 and then the NAc derivative, prepared by per-acetylation at 80 C, showing an amide stretch at 1700 cm1 . 4-Cyanoimidazolium-5-olate (103, Figure 23) can exist in eight different tautomeric forms (three keto-, four enol-, and one enoate). The IR spectrum of this compound shows CH and NH stretching in the 3200–2300 cm1 region. The absence of carbonyl stretching around 1700 cm1 and CO stretching around 3400 cm1 suggests the mesoionic structure 103 .

Figure 23

Triphenylimidazole on a Ag surface gives rise to Raman enhanced lines at 928, 1009, 1097, and 1380 cm1. The first three bands were assigned to ring breathing of the imidazole ring oriented perpendicular to Ag .

4.02.3.6 Mass Spectrometry The farnesyl transfer inhibitor 104 (Scheme 21) undergoes a complicated rearrangement and fragmentation upon collision-induced dissociation in the gas phase. An intramolecular SN2 reaction followed by fragmentations expels the methylene–imidazole (m/z 81), and the m/z 326 fragment .

Scheme 21

Structures of both imidazol-2-ylidene 105 and imidazol-4-ylidene 106 (Scheme 22) were generated as the corresponding ions 105?þ and 106?þ by neutralization–reionization (NR) and charge-stripping (CS) mass spectrometry from 2-formylimidazole and 4,5-bis(methoxycarbonyl)imidazole, respectively. Relative to imidazole, the collision-induced dissociation (CID) mass spectrum of 105?þ shows an intense peak at m/z 42 that is attributed to the loss of acetylene, thus supporting the 2-carbene ion structure. The CID spectra of 106?þ show a strong peak at m/z 29 and a weak peak at m/z 16 . During photosensitized oxidation of N(1)–H, C(2)–H imidazoles with molecular oxygen, the formation of CO2 was detected by GC-MS analyses of the reaction atmosphere . Electron impact mass spectrometry studies of 1,3-di- and 1,2,3-tri-substituted imidazolines show ionization preferences depending on the substitution pattern (Scheme 23). Ions corresponding to R1Nþ were detected for all substrates (path 2). In 2-substituted 1,3-diarylimidazolidines, loss of substituents at C-2 ([M-R]þ, path 3) is favored over the loss of hydrogen (path 4). In 1,2,3-trisubstituted compounds, azirinium ions (c, path 4A) were abundant, especially when R ¼ aryl. 2-Phenylimidazolidines fragment to the characteristic tropylium ion (C7H7þ, m/z 91). 1-Aryl-3-benzylimidazolidines readily lose a benzyl group as radical or cation ([M-benzyl]þ, path 1) .

167

168

Imidazoles

Scheme 22

Scheme 23

Imidazoles

N-Substituted 2-(2-bromophenyl)benzimidazoles form palladacycles by reaction with Pd(dba)2. These complexes were characterized by mass spectrometry . Cold spray ionization (CSI) mass spectrometry of tris(imidazoline) 107 (Figure 24) and tris(oxazoline) 108 in dichloromethane indicated the formation of heterodimer predominantly [m/z 614.0, (107þ108)þ] .

Figure 24

4.02.3.7 Electron Spin Resonance A series of 2-imidazoline nitroxides linked to a pyrazole either directly or through a phenylethynylic bridge show the ESR characteristics of the 2-imidazoline nitroxide moiety. An unexpected strong temperature dependence of magnetic moment eff(T) for solid 109 was discovered that agrees with the Bleaney–Bowers model for isolated two-center exchange cluster with spin 1=2 (Figure 25). In single crystals of 109, packing by pairs of molecules was observed although there were no intermolecular contacts within the range of 3 A˚ . The ESR spectrum of hydroxamic acid 110 showed a quintuplet with a high nitrogen coupling constant (aN ¼ 8.71 G) . Both solid and solution ESR of nitronyl biradicals have been reported .

Figure 25

2-(Nitrenophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole 3-oxide 1-oxyls (111 and 112, Figure 26), generated from the corresponding azido derivatives in frozen solution, show S ¼ 3/2 state ESR spectra with zero-field splitting jD/hcj 0.277 cm1, jE/hcj 0.002 cm1 for 111 and jD/hcj 0.352 cm1, jE/hcj 0.006 cm1 for 112 . These results suggest that quinonoid delocalization in the case of 111 does not result in exchange of the nitreno radical.

Figure 26

169

170

Imidazoles

A series of 2-imidazoline-1-oxyl derivatives with the general structure A-Sp-R (A: charge acceptor, luminophor; Sp: spacer; R: imidazoline) were studied in a three-spin system using optically detected magnetoresonance OD ESR and level-crossing Mary spectroscopy. In the most favorable case 113, a spin triad with 100 ns lifetime was observed and the exchange integral for the biradical anion derived from 113 was estimated to be 103 G . Upon irradiation with a Xe lamp (100 W), the typical five-line spectrum characteristic of the nitronyl nitroxide radical 114 (g ¼ 2.0066) was progressively transformed into a seven-line spectrum characteristic of an imino nitroxide radical (Scheme 24). It was proposed that during the irradiation, selective deoxygenation of the radical 114 to the radical 115 had occurred .

Scheme 24

Copper(II) ions are involved in antiferromagnetic exchanges in the ESR of imidazole-bridged Cu(II)–Cu(II) complexes with ethylenediamine . The ESR spectra of 3-imidazoline nitroxides show that the spin density localizes mostly at the NO fragment with a dominant triplet at N-1 with splitting of 14.1 G (in toluene) . pH-Dependent spin probes such as N,N-disubstituted 4-amino-2,2,5,5tetramethyl-3-imidazoline 1-oxyls with pKa values ranging from 3.5 to 6.2 have been reported . The peak-to-peak line width of the ESR spectra in the presence of paramagnetic broadening agent K3Fe(CN)6 was used to determine the pKa values of carboxyl groups remote to the nitroxide moiety. Bis-imidazole complexes of a series of Fe(III)-porphyrinates show EPR spectra with g values increasing as a function of the dihedral angles between the axial imidazole ligands: ‘large gmax’ signals are observed (3.61–3.27) for nearly perpendicular ligand plane arrangement . In the mixed-spin ferric heme cytochrome-c system, the nitrogen ENDOR reveals larger hyperfine coupling to the histidine nitrogen and smaller hyperfine coupling to the heme nitrogen than found in high-spin ferric heme systems .

4.02.3.8 Photoelectron Spectra Mo¨ssbauer electronic structure studies of imidazole ligated iron(II) porphyrinates suggest that they form a distinctly different set of electronic configurations than iron(II) porphyrinates with other axial ligands, as reflected in opposite signs for zero-field splitting constant (D) and quadrupole splitting (Eq) .

4.02.3.9 CD Spectra CD spectroscopy is useful in determining the absolute configuration of chiral imidazolines. In methanol, 116 shows a positive Cotton effect, whereas 117 shows a negative Cotton effect at 370 nm (Figure 27) .

Figure 27

Imidazoles

4.02.4 Thermodynamic Aspects 4.02.4.1 Intermolecular Forces 4.02.4.1.1

Melting points

It is well known that N-unsubstituted imidazoles have higher melting and boiling points than their N-substituted analogues. The N-H group presented in N-unsubstituted imidazoles is able to form a strong hydrogen bond, resulting in highly crystalline solids. Destroying the hydrogen-bonding network as in N-substituted imidazoles effectively lowers the melting and boiling points. Thus, imidazole and 1-methylimidazole boil at 256 C and 199 C, respectively. A dramatic decrease of the melting point (mp) is observed when 2-(4-methylpyridin-2-yl)-1H-benzimidazole 94 (mp ¼ 225–226 C ) is N-methylated to give 95 (mp 80–82 C) , due not only to the removal of hydrogen bonding but also an altered conformation (Figure 28).

Figure 28

Room temperature (rt) ionic liquids are salts composed of large organic cations and a variety of anions, and usually having a melting point at or below room temperature . In particular, 1,3-dialkylimidazoliums have been widely used as cations in rt ionic liquids. The influence of structure variation in these cations on the melting point has been extensively investigated . Qualitatively, low symmetry, weak ion interactions, and effective charge distribution over the cation and/or anion tend to reduce the crystal lattice energy of the salts, thus resulting in lowmelting salts . Hence, the crystalline 1-n-butyl-3-methylimidazolium 3,5-dinitro-1,2,4-triazolate (Figure 29), which contains an aromatic charge delocalized anion, that is, the nitro-substituted triazole, has a low melting point of 35 C .

Figure 29

4.02.4.1.2

Solubility

Imidazole derivatives generally have good solubility in protic solvents. Simple imidazole derivatives, such as 1Himidazole, 2-methyl-1H-imidazole, and 1,2-dimethylimidazole, have very high solubility in water. Their solubility in alcohol is lower than that in water and decreases with increasing molecular weight of the alcohols . The solubility of imidazoles in ethers is lower than that in alcohols and decreases with increasing chain length of the ethers . In contrast, the solubility of benzimidazoles in alcohols (C3–C6) is higher than in water and generally decreases with an increase of the alkyl chain length of the alcohols. The solubility of 2-methylbenzimidazole in alcohols (C3–C6) is higher than that of benzimidazole . Both benzimidazole and 2-methylbenzimidazole have much higher solubility in octan-1-ol than in water . Simple imidazoles are much less soluble in nonpolar solvents. For example, 1H-imidazole, 2-methyl-1H-imidazole, benzimidazole, 2-methylbenzimidazole, 2-phenylimidazole, 4,5-diphenylimidazole, and 2,4,5-triphenylimidazole have very low solubility in chloroalkanes (dichloromethane, 1-chlorobutane), toluene and 2-nitrotoluene. Among them, the solubility of phenylimidazoles is significantly lower than that of 1H-imidazole or benzimidazoles in all of the solvents .

171

172

Imidazoles

Imidazolium-based ionic liquids are characteristically soluble in water . For the ionic liquids containing butylmethylimidazolium as the cation, octanol–water partition coefficient (KOW ¼ concentration in octanol/concentration in water) values range from 0.003 to 11.1, depending on the choice of anion. The KOW values increase with increasing alkyl chain length on the cation. Nonetheless, imidazolium-based ionic liquids are polar molecules and are more soluble in low-molecular-weight alcohols. Thus, the solubility of 1-dodecyl-3-methylimidazolium chloride in primary alcohols, such as ethanol, 1-butanol, 1-hexanol, 1-octanol, 1-decanol, and 1-dodecanol, decreases with the increase in the molecular weight of the alcohol (C6 to C12) .

4.02.4.1.3

Chromatography

Reverse-phase high-pressure liquid chromatography (RP-HPLC) has become a widely applicable method for analyzing and purifying mixtures containing imidazole derivatives . Moreover, separation and analysis of racemic imidazole derivatives have been achieved using HPLC with chiral stationary phases (CSPs) . For example, HPLC with chiral columns containing carbamate of cellulose and amylase was employed to analyze and separate a mixture containing racemic becliconazole and its synthetic precursors 118, 119, and imidazole (Figure 30). The HPLC method gives good performance from both qualitative and quantitative standpoints, allowing the enantiomeric ratio of becliconazole and its impurities to be determined .

Figure 30 Becliconazole and precursors to it.

4.02.4.2 Thermochemistry 4.02.4.2.1

Aromatic Stability

Aromatic stability, also referred to as ‘aromaticity’, is not a directly measurable quantity, but rather is generally evaluated on the basis of energetic, geometric, and magnetic criteria . Different aspects of aromaticity, such as aromatic stabilization energies (ASE), resonance energies (RE), nucleus-independent chemical shifts (NICS), magnetic susceptibility exaltation (), harmonic oscillator model of aromaticity (HOMA), etc., have been fully reviewed . The absolute numerical values for these criteria are not meaningful; instead, they are useful in comparable terms . For example, ASE, arguably the most used operational criterion, gives 25.2 kcal mol1 for imidazole in one calculation , while it is 16.18 kcal mol1 in another . Nonetheless, under the same calculation criteria, the ASE value can be used to evaluate the relative aromaticity of different ring system. Thus, ASE has been calculated to be 25.2 kcal mol1 for imidazole, 26.7 kcal mol1 for benzene, 19.8 kcal mol1 for furan, and 25.5 kcal mol1 for pyrrole . The aromatic stability of imidazolyl carbene has been evaluated according to thermodynamic, magnetic, and structural criteria . Theoretical calculations indicate that there is cyclic electron delocalization in imidazole-2-ylidene 9 (Figure 1), although its aromatic character is less pronounced as compared to benzene or the imidazolium cation . In fact, the computed aromatic stabilization energy for carbene 9 is comparable to that of furan and pyrrole . The aromaticity of 4H-imidazoles 120a–d and their derivatives has been investigated in detail (Scheme 25). The electronic absorption of compounds 120a–d show bathochromic shifts of about 150 nm upon protonation, attributed to transformation of the cyclic mero-polymethine-type chromophore in 4H-imidazoles 120 into the polymethinic p-bond system of the iminium salt 121. The iminium salt 121 can also be regarded as an anti-aromatic 1,3-diazacyclopentadienylium salt 1219. Based on nucleus-independent chemical shift (NICS) calculations, the structure of compound 120 is considered to possess weak anti-aromatic bonding character .

Imidazoles

Scheme 25

The weak anti-aromaticity character of compound 120 is also demonstrated in their single crystal structures. In the ˚ crystal structures of compound 120a–c, the C–N bond lengths in the heterocyclic ring are in the range of 1.34–1.37 A. ˚ are considerably longer than typical Interestingly, the C(4)–C(5) bond lengths in compounds 120a–d (1.493–1.511 A) ˚ Theoretical calculations Csp2–Csp2 bonds found in conjugated systems (in imidazole, the length of Csp2–Csp2 is 1.358 A). [DFT RB3LYP/6-311þG** and ab initio G2(MP2)] predict a planar 5-aminoimidazol-4-imide parent structure, in ˚ in agreement with the X-ray data which the C–C bond of the 5-membered ring is exceedingly long (1.53 A), . Compounds 120 can also be oxidized regioselectively to afford aminonitrones 122. The X-ray structural analysis of 122 (Ar ¼ p-MeC6H4) shows an unexpected tautomeric fixation of the hydrogen atom and indicated that the resonance structures 1229 and 1220 participate in the stabilization of the nitrone 122. Thus, compounds 122 are unusually stable due to the contributions of anionic as well as cationic delocalized mesomeric structures (Scheme 26) .

Scheme 26

Aromaticity can be assessed by comparing the relative reactivities of imidazole derivatives and their analogues. For example, the aromatic stability of imidazolone 123 has been evaluated by the rate of base-catalyzed deuterium exchange and condensation with hexadeuteroacetone. Three compounds were used in both studies: 1-methyl-2phenyl-5(4H)-imidazolone 123, 2-phenyl-5(4H)-oxazolone 124 and 3,3-dimethyl-2-phenyl-4(3H)-pyrrolone 125 (Scheme 27). The order of the reactivity in these kinetic surveys was the same: 123 > 124 > 125. This result is explicable on the basis of the stabilization of the derived anions (e.g., 1239) by aromaticity. The higher reactivity of 123 versus 124 would arise from the lower aromaticity of oxazole relative to imidazole. In addition, the N-Me 1H NMR signal in the imidazolone 126 shows a discernible downfield shift of 0.1 ppm relative to the parent 123. This deshielding seems to indicate the presence of a ring current in 126, most likely a consequence of its aromaticity .

173

174

Imidazoles

Scheme 27

Imidazoles are generally considered to be electron-rich and stable aromatic compounds. However, with certain substituents attached to the imidazole ring, aromatic stability may alter greatly. For example, during the reaction of 2(1-chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole hydrochloride 127 with excess of N,N-dimethylamine, an addition product, 4,5-bis(N,N-dimethylamino)-1-methyl-2-(2,2-dimethylpropyl)-2-imidazoline 129, was obtained in 74% yield together with a normal SN2 product, 2-(1-N,N-dimethylamino-2,2-dimethylpropyl)-1-methyl-1H-imidazole 128 in 15% yield (Scheme 28). Compound 129 may result from a serial double nucleophilic addition of the secondary amine to the imidazole nucleus, even though it is otherwise a stable aromatic ring structure .

Scheme 28

4.02.4.2.2

Other thermodynamic aspects

Accurate experimental enthalpies of formation of N-substituted imidazoles were measured using static bomb combustion calorimetry, the ‘vacuum sublimation’ drop method, and the Knudsen-effusion method . The enthalpies of combustion, heat capacities, enthalpies of sublimation, and enthalpies of formation of 2-tertbutylbenzimidazole and 2-phenylimidazole have been reported and the experimental results compared with theoretical estimates of the enthalpies of formation, obtained in single-point calculations at the B3LYP/6-311þþG(d,p) level on B3LYP/6-31G* optimized geometries . Crystalline imidazole (mp 361–364 K) fuses autogenously after making contact at room temperature with methanol (mp 316 K) as a consequence of the hydrogen bond network alternation. Conditions have been established to grow single crystals of ionic liquids, and the structures of several commercially available low-melting ionic liquids have been determined .

Imidazoles

Thermodynamic properties of imidazolium-based ionic liquids, such as densities, heat capacities, and enthalpies of fusion of [bmim] [PF6] and [bmim] [NTf2] have been determined and a critical analysis of the effect of impurities on the measured thermodynamic properties has been carried out .

4.02.4.2.3

Conformations

Like fully conjugated imidazoles, some 2-imidazoline, hydantoin, and imidazolone ring structures adopt planar conformations. Thus, 4,5-bis(4-hydroxy/methoxyphenyl)-2-imidazolines 130a–b have a symmetric planar ring in spite of being formally asymmetric due to the typical amidine structure (Figure 31). In the 1H NMR spectra of 130a–b, only one set of signals for the aromatic protons and a singlet resonance of the benzylic protons are observed. The same effect also shows in the 13C spectrum of 130b (MeO compound) with seven signals. Such spectra can only be rationalized with a symmetric heterocyclic ring with partially sp2-hybridized nitrogens and a delocalization of the proton between the nitrogen atoms .

Figure 31

X-Ray structural analysis of 3-alkyl-5-arylimidazolindinedione 131 indicates that the central hydantoin ring is planar, with the N and C atoms adopting sp2 hybridization. Bond lengths within the ring are intermediate between single and double bond, implying electronic delocalization in the system (Figure 32). Similarly, the crystal structure of 4,4-diphenyl-5-imidazolone 132 revealed that the imidazole ring is planar (including also O-6 and H-1 and H-2) while the phenyl rings are almost mutually perpendicular. The double bond is localized between C-2 and N-3, as shown in Figure 32 .

Figure 32

A fully saturated imidazolidine usually adopts a nonplanar geometry. Semiempirical studies on 2-methyl-1,3dihydroxy-4,4,5,5-tetramethylimidazolidine 133 suggested that the imidazolidine ring assumes a half-chair conformation, as shown in Figure 33. The calculated results are in agreement with the experimental observations for 2-aryl-1,3-dihydroxy-4,4,5,5-tetramethylimidazolidines 134. Thus, the 1H NMR spectra of 134 indicated that the two methyl groups are situated in magnetically distinct environments, which means the molecule has a nonplanar conformation . X-Ray structural analysis of ethyl N-(5,5-diphenyl-4-oxo-2-imidazolidyl)glycinate 135 showed that the five-membered imidazolone ring has an open-envelope conformation with C-4 departing from the [N(3)–C(2)–N(1)–C(5)] plane by 0.044 A˚ (Scheme 29). The deviation of the imidazolone ring from planarity is caused by the sp3 hybridization of C-5. The guanidine fragment is flat and the p-electrons in this system are delocalized between all three C–N bonds. The two N-hydrogens more likely reside on N-1 and N-6, as depicted in tautomer 135b (cf. Section 4.02.2) .

175

176

Imidazoles

Figure 33

Scheme 29

Interesting conformational features were discovered in 1-methyl-2-(4-methylpyridin-2-yl)-1H-benzimidazole 95, two rotamers of which have the methyl group in a syn- or anti-configuration relative to g-picoline ring (Figure 34). X-Ray analysis of compound 95 revealed that the benzimidazole ring, the g-picoline ring, and the methyl group lie on a plane, thus allowing extensive electron delocalization in the molecule. Additionally, the X-ray data indicate the existence of C–H N hydrogen bonds .

Figure 34

4.02.4.3 Tautomerism 4.02.4.3.1

Annular prototropic tautomerism

4,5-Disubstituted 1H-imidazoles are classic examples of prototropic annular tautomerism. Depending on the nature of substituents, one tautomer may predominate over the other, as in the case of trifluoromethyl-substituted imidazole 50, where form 50A is the major component in solution in DMSO or CH3CN. In an unusual case, the two tautomers, 4-nitro-5-methoxyimidazole 136A and 5-nitro-4-methoxyimidazole 136B, were found as a 50:50 mixture in the crystal structure (Scheme 30) . Intramolecular hydrogen bonding can greatly influence the prototropic annular tautomerization. 4,29-Bi-imidazole nucleosides can exist in four roto-tautomers due to the restricted rotation about the conjoining bond (Scheme 31). With different R groups, one roto-tautomer may be favored over the other. Thus, for R ¼ CH2OH, roto-tautomer 137a dominates, while for R ¼ CH3, the 137a and 137d roto-tautomers are very close in energy, as indicated by both experimental and computational (DFT at the B3LYP/6-31G(d,p) level of theory) results. The electronic influence on N-39 by the R group affects the strength of the hydrogen bond and can thus have a marked influence on the overall energy of the structure .

Imidazoles

Scheme 30

Scheme 31

The prototropic equilibrium of a series of benzimidazole derivatives 138 with intramolecular H-bonding potential has also been investigated by NMR and IR techniques and theoretical methods. For example, tautomer 138-I, particularly structure 138-IA is found to be more stable in amide analogues (R ¼ NH2), while tautomer 138-II is predominant for esters (R ¼ OEt) (Scheme 32). The stability of tautomer 138-II over tautomer 138-I in esters could be attributed to intramolecular hydrogen bonding between the NH of the benzimidazole ring and the carbonyl group .

Scheme 32

177

178

Imidazoles

4-Cyanoimidazolium-5-olate 139 is a 5(4)-substituted imidazole-4(5)-one derivative and therefore can exist in eight different tautomeric forms because of both annular and keto–enol tautomerism as shown in Scheme 33. Spectroscopic studies (X-ray single crystal structure, NMR, IR) suggested mesoionic character (as exemplified in 139h and 139i) in solid-state and in solution (DMSO). The bond lengths indicated a p-delocalization in the ring involving also the substituents, with values in keeping with those reported for imidazole .

Scheme 33

4.02.4.3.2

Substituent prototropic tautomerism

Heteroatom-substituted imidazole derivatives have the opportunity to undergo ring-substituent prototropic tautomerization. For example, structural characterization of 1-mesityl-1,3-dihydroimidazole-2-selone by X-ray diffraction and NMR spectroscopic methods demonstrated that the compound exists as the selone rather than the selenol tautomer, a result that was confirmed by DFT calculations (Scheme 34). Specifically, the hydrogen atom attached to nitrogen was located and refined in the X-ray diffraction. The C–Se bond length of 1.845 A˚ is intermediate between the values predicted by the respective sum of the single- and double-bond covalent radii of carbon and selenium: ˚ As such, the structural data are consistent with the notion that an important d(C–Se) ¼ 1.94 A˚ and d(CTSe) ¼ 1.74 A. resonance contributor is the zwitterionic form with a C–Se single covalent bond .

Scheme 34

Aminonitrone-N-hydroxyaminoimine tautomerism in 2-substituted 1-hydroxy-4,4,5,5-tetramethyl-4,5-dihydro-1Himidazole 140 is considered to be an acid–base equilibrium with the ratio between the forms dictated by the ratio of their acidity constants. A substituent with a positive mesomeric and/or inductive effect stabilizes the nitrone form 140A more effectively than the N-hydroxyaminoimino form 140B (Scheme 35) .

Imidazoles

Scheme 35

In contrast, the tautomerization of benzimidazole N-oxide derivatives is greatly influenced by the hydrogen bonding abilities of the N-hydroxy/N-oxide moiety through either intramolecular or intermolecular modes. Thus, n-butyl-5-nitrobenzimidazole-2-carboxamide 3-oxide 141 in CHCl3 or DMSO is a mixture of tautomers, the N-oxide being the predominant one. On the other hand, ethyl 5-nitrobenzimidazole-2-carboxylate 3-oxide 142 exists in the solid phase as the N-hydroxy tautomer, unambiguously identified by an X-ray diffraction experiment. The tautomer is stabilized by a strong and linear intermolecular hydrogen bond (O–H- - -N-39) (Scheme 36).

Scheme 36

An acidic side-chain in imidazole derivatives produces a form in which the imidazole ring is protonated. This is exemplified in (S)-2-hydroxy-3-(1H-imidazol-5-yl)propanoic acid hydrate 143, which has a fully extended lactic acid side-chain oriented nearly perpendicular to the imidazole plane. The imidazole ring is protonated, and the carboxylate group deprotonated, presenting a zwitterionic structure (Scheme 37) .

Scheme 37

Ring-substituent prototropic tautomerism is predicted to exist in 3-amino-1-(2-aminoimidazol-4-yl)-prop-1-ene 144. According to the calculations at the 6-316* level of theory, the conjugated CTC bond would migrate along the side-chain, leading to four possible tautomers, as shown in Figure 35. The computed energy differences between the four tautomers are relatively small (90% to 62%. It was suggested that the addition of 1,10-phenanthroline or dba as ligands to the copper salt creates a soluble, stable, and more active copper catalyst species in situ, which in turn improves the turnover rate of the reaction and lowers the activation barrier, in comparison to the classical Ullmann-type catalysis. Though only a catalytic amount of copper is needed, a stoichiometric amount of 1,10-phenanthroline (relative to aryl halide) is required to provide efficient catalysis. Later, it was reported by the same laboratory that racemic trans-1,2-cyclohexyldiamines 211 and 212 are effective ligands (in catalytic amounts, i.e., 10% with respect to aryl halide) for the catalytic copper (1% CuI, with respect to aryl halide) mediated N-arylation of cyclic and acyclic amides with aryl bromides and aryl iodides, and N-arylation of nitrogen heterocycles, including imidazole, with aryl iodides . This class of 1,2-diamines 211 and 215 was also reported to be able to assist copper in catalyzing arylation of imidazole even between sterically hindered coupling partners, though yields were low (Scheme 52) . Imidazole and benzimidazole were arylated by arylboronic acids when catalyzed with the same catalyst system, the Chan–Evans–Lam protocol.

187

188

Imidazoles

Figure 38 Ligands for copper-mediated imidazole N-arylation.

Scheme 51

Imidazoles

Scheme 52

Salicylaldehyde Schiff bases and analogues were reported to form highly active copper catalysts with Cu2O for Ullmann-type coupling reactions. Ligands such as salicylaldoxime 208 (Salox), salicylaldhydrazone 209, and pyridine-carbaldehyde Schiff base 210 (Chxn-Py-Al) were very effective for N-arylation of imidazole and benzimidazole . The catalysts are so active that copper-catalyzed arylation of imidazole with an aryl iodide can be performed at 50 C when Salox 208 was used as ligand, giving a nearly quantitative yield. Aryl bromides were also effective coupling partners when compound 209, which is commercially available, was used as the ligand at 80 C. The difference in reactivity between an aryl bromide and an aryl iodide offers a control feature in designing a synthetic route toward a particular desired target, such as 201 (Scheme 53) .

Scheme 53

Amino acids such as L-proline 218 and N,N-dimethylglycine 219 were very effective in assisting CuI-catalyzed arylation of imidazole and benzimidazole by aryl bromides and aryl iodides . Both electron-rich and -poor aryl iodides coupled with imidazole in excellent yields, when catalyzed by CuI (10%, with respect to imidazole) with L-proline 218 (20%, with respect to imidazole) as ligand, in the presence of K2CO3 (2 equiv) as base. This catalyst system was also very effective in mediating the coupling between electron-poor aryl bromides (>90% yields in most cases) and imidazole, while electron-rich aryl bromides gave lower yields, though still fairly good (80% yields in most cases). However, N,N-dimethylglycine 219 worked well as a ligand in CuI-catalyzed arylation with electronrich aryl bromides of imidazole and benzimidazole. L-Proline 218 was also reported to promote copper(I) iodidecatalyzed Ullmann type coupling between imidazole or benzimidazole and various alkenyl bromides to give N-alkenyl imidazole and benzimidazole in ionic liquids as solvent . Common bases of choice for Ullmann type reactions are K2CO3 and Cs2CO3 that are effective in most cases. However, an organic-soluble base, tetramethylammonium carbonate (TEAC) was found to be more effective than Cs2CO3 when 8-hydroxyquinoline 221 was used with CuI for N-arylation of imidazole by aryl bromides and iodides. Aryl bromides reacted efficiently with imidazole when CuI (10%) and 8-hydroxyquinoline 221 (10%) were used. The use of TEAC as base created a near homogeneous reaction system which was very effective in forming the C–N bond between aryl halides and imidazole or benzimidazole. This catalyst system was also effective in catalyzing the coupling between aryl chlorides and imidazole or benzimidazole, though in lower yields (40–50%). Pyrrolidine-2-phosphonic acid phenyl monoester (PPAPM) 216a is readily accessible and is very effective as a ligand in copper-mediated C–O, C–N, and C–P bond formation . Though both bromobenzene and iodobenzene were effective in arylating imidazole, by controlling reaction temperature and time, selectivity was achieved for iodobenzene over bromobenzene (Table 8).

189

190

Imidazoles

Table 8 N-Arylation of imidazole Temperature ( C )

Time (h)

Yield (%)

100

24

86

110

30

85

95

24

89

Under solvent-free conditions, imidazole and benzimidazole were efficiently arylated by aryl/heteroaryl chloride or bromide, catalyzed by copper(I) bromide in the presence of 2-amino-4,6-dihydroxypyrimidine 220 as a ligand and TBAF as a base . Even sterically crowded 2-methylimidazole and 2-methylbenzimidazole were efficiently arylated with high yields. However, arylation of 2-phenylimidazole with 2-chloropyrimidine gave only a trace of product while arylation of 2-methylimidazole with the same aryl chloride afforded the product in quantitative yield. When polyethyleneglycol (PEG) was used as co-solvent, 4,7-dimethoxy-1,10-phenanthroline 214 was found to be effective in copper-catalyzed N-arylation of imidazole by aryl bromides or iodides . A critical part of this catalytic system is the inclusion of PEG. It is believed that PEG acts as a phase transfer reagent, when Cs2CO3 is used as base. Besides the much expanded scope in coupling partners, one major improvement of 4,7-dimethoxy-1,10phenanthroline over 1,10-phenanthroline is that only a catalytic amount of the ligand is needed, and the reactions can be carried out at 80–120 C. A variety of sterically hindered imidazoles and aryl halides were coupled in good to excellent yields. Intrinsic reactivity differences between aryl halides enabled coupling of aryl iodides selectively in the presence of substrates containing bromine, chlorine, or fluorine. Imidazole was selectively arylated in the presence of a free hydroxyl or an amino group. Phosphoramidite 216b was reported as an effective ligand for copper to catalyze C–N bond formation in Narylation of imidazole or benzimidazole with aryl iodides . The reaction could be carried out at 90 C and produced moderate to high yields (65–90%). Preformed, stable copper catalysts, such as aminoarenethiolate copper(I) are also effective catalysts for mediating N-arylation of imidazole and benzimidazole (Figure 39) .

Figure 39 Aminoarenethiolate–Cu(I) complexes as active catalysts for Ullmann-type couplings.

Imidazoles

It was found that N-arylation reactions could be carried out in solventless conditions with all the six catalysts 222– 227. However, with the presence of a little NMP (1 ml at a 5 mmol scale), reaction yields were higher in all cases. In the presence of NMP, the yields were 77–100%, wheareas for the neat case, the yields were 56–68% (Scheme 54).

Scheme 54

While the catalysts discussed above are all homogeneous systems, zeolite- and FAP-supported copper complexes were developed as heterogeneous catalytic systems, and are also rather effective in catalyzing the N-arylation of imidazole and benzimidazole with no additional organic ligands added. Other ligandless catalysts for Ullmann type reactions used CuO or Cu2O–Cu nanoparticles . Not only could the insoluble catalyst be easily removed via filtration after the reaction, it could also be recycled and reused with ease. The catalytic efficacy remained high after three cycles. A protocol of ligandless and solventless copper(I) bromide mediated N-arylation of imidazole and benzimidazole by aryl bromide or aryl iodide was reported .

4.02.5.3 Electrophilic Attack at Carbon 4.02.5.3.1

Reactivity and orientation

The reactivity and orientation displayed by imidazole and benzimidazole toward electrophilic attack at carbon were reviewed in detail in CHEC(1984) and CHEC-II(1996).

4.02.5.3.2

Nitration

Most widely used protocols for nitration of imidazoles still use HNO3 in conc. H2SO4 ; fuming HNO3 and conc. H2SO4 ; fuming HNO3, conc. H2SO4 with addition of Ac2O . Yields of nitration reactions are generally low to moderate. Mostly, nitration proceeds at C-4 of an imidazole. However, a mixture of 4- and 5-nitroimidazoles was also observed with a near 1:1 ratio . Though nitration of some imidazoles goes readily at ambient temperature, a trifluoromethyl substituent on the imidazole ring has a profound deactivating influence. Nitration of compound 230 did not take place at 80 C; at 100 C, nitration did not stop at mono-nitro-derivative 231 – a mixture of mono- and dinitration products (with near 1:1 ratio) was formed. Thus, a nitro substituent at C-4 does not seem to be a strong deactivating factor, since compound 231 could be completely converted into 232. On the other hand, nitration of 4-trifluoromethylimidazole 233 was much slower when compared with compound 230, taking 24 h to complete the reaction in 86% yield. A methyl group at C-2 resulted in a substantial increase in reactivity: only 4 h were needed to complete the nitration of 235 to 236 (Scheme 55) . Ozone-mediated nitration (Kyodai nitration) of imidazole under neutral condition gave poor yields of 4-nitroimidazole. However, the yield improved dramatically with the addition of methanesulfonic acid. The combination NO2– O3 is a much more reactive electrophilic reagent since a reaction temperature of 0 C was sufficient (Scheme 56), . The 4-nitro product 238 could also be converted into 1,4-dinitroimidazole 239 over a long period.

4.02.5.3.3

Lithium–halogen exchange followed by electrophilic attack

The 2-chloroimidazole 240 undergoes chlorine–lithium exchange to give the 2-lithiated species which could then be quenched by an electrophile: with benzyl chloroformate 241 the imidazole-2-carboester 242 was obtained (Scheme 57) . N-1-Protected 2,4,5-triiodoimidazole 243 was selectively lithiated at the 2-position via iodine–lithium exchange (Scheme 58) (2005S136>. The lithiated species was then quenched by a number of aryl aldehydes 244 to give unsymmetrical diarylmethyl alcohols 245 in high yields. The high yields of these reactions indicated that the iodine– lithium exchange of this triiodoimidazole is efficient and selective.

191

Table 9 N-arylation/alkenylation of imidazole and benzimidazole via improved Ullmann-type coupling reactions Substrates

Halides

1

2

Ar/Vna

X

CuX

þ þ þ

þ

Ar Ar Ar

B(OH)2 B(OH)2 B(OH)2

Ar Ar Ar Ar2 Ar Ar Ar Ar Ar Ar Ar Ar Ar Ar Ar Ar Vn Ar Ar Ar Ar Ar Ar Ar Ar Vn Ar

B(OH)2, (BF3)Kþ Pb(OAc)3 Br, I IþBF4 Pb(OAc)3 I Br Cl Br, I Br, I I Br Br, I Cl, Br, I Br, I B(OH)2 Br Br Br, I Br Br, I Br, I Br Cl, Br, I Br, I Br Br, Cl

Cu(OAc)2 [Cu(OH) TMEDA]2Cl2 CuCl, CuBr, CuI, CuCl2, CuClO4, Cu(OAc)2, Cu(NO3)2 CuI, Cu(OAc)2 Cu(OAc)2 (CuOTf)2-PhH Cu(acac)2 Cu(OAc)2 CuI CuO Cu2O-Cu (CuOTf)2–TolH Cu2O CuI (CuOTf)2-TolH CuI CuI CuI Cu(OAc)2 CuI CuSR* Cu2O CuI CuI CuBr (CuOTf)2-PhH Cu(II)-NaY CuFAP CuI CuBr

þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ a

þ þ þ þ þ þ

þ þ þ þ þ

þ þ

þ þ

Ar ¼ aryl, heteroaryl; Vn ¼ vinyl.

Ligand

Base

211 and 216a

Cs2CO3

213 and 217

Cs2CO3 K2CO3

211

K3PO4 K2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 TEAC Cs2CO3 pyridine

213 and 217 208–210 212 and 213 213 and 217 218 and 219 221 211 and 216a 218 214 213 215 216b 213 and 217

210

K2CO3 Cs2CO3 KF/Al2O3 K3PO4 Cs2CO3 Cs2CO3 K2CO3 K2CO3 Cs2CO3 TBAF

Solvent

Temp.( C)

Time (h)

Reference

DCM DCM MeOH

rt rt Reflux

24 16 3–12

1998TL2941 2000OL1233 2004CC188

DCM DCM-DMF xylene DCM DCM Dioxane DMSO DMSO DMF-xylene MeCN Dioxane,DMF xylene DMSO DMF DMF,dioxane DCM IL NMP, Neat n-PrCN,NMP xylene DMF DMF Xylene DMF DMSO MeCN No

rt 90–100 110–125 50 rt 110 150 150 115 82 110 110 60–110 110–130 95–170 rt 90–110 160 80–120 130–140 95–110 95 110 120 110 50 145–150

48 4–6 24–48 6 3–14 24 48 18 48 24–100 24 71 34–65 10–64 24–48 48 20–36 16 3–48 15–18 24–30 24 71 20–48 2–15 30 24

2005EJO1637 1992TL659 1999TL2657 2000SL1022 2000OL3055 2001JA7727 2003OL4847 2004CC778 2004BMCL1637 2004CEJ5607 2004JOC5578 2005JOC3997 2005JOC5164 2005JOC10135 2005EJO1637 2005JME6632 2005CC2849 2005OL5241 2006OL2779 2006TL5203 2006CEJ3636 2006T4435 2006EJOC693 2006SL2195 2006TL3897 2006CEJ5301 2006JOC8324

Imidazoles

Scheme 55

Scheme 56

Scheme 57

193

194

Imidazoles

Scheme 58

4.02.5.3.4

Halogenation

Benzimidazole was iodinated at the 2-position to form a copper-benzimidazole complex 246 by treatment with CuI and KI in aqueous ammonium hydroxide (Scheme 59) .

Scheme 59

Iodination of a benzimidazole was also achieved via treating a 1-alkylated benzimidazole with a strong base such as LDA or alkyllithium at low temperature then quenching with 1,2-diiodoethane, or iodine . NBS brominates benzimidazole at the 2-position . Treatment of benzimidazole with BuLi followed by quenching with carbon tetrabromide, carbon tetrachloride, or oxalyl chloride, gave 2-bromobenzimidazole or 2-chlorobenzimidazole, respectively . Oxidative iodination was first reported for iodination of arylamines using iodine and urea hydrogen peroxide (UHP) as an oxidant in moderate yields . A modified oxidative iodination with iodine and ortho-periodic acid was found to be effective in iodination of imidazole at C-2 giving 247 in 72% yield ; 5–8% of another regioisomer was observed via NMR and TLC. It was proposed that iodine was oxidized by ortho-periodic acid [I (VII)] to an Iþ species, which is capable of iodinating arenes, including imidazole (Scheme 60). It is worth noting that the only by-product of this reaction is water.

Scheme 60

Imidazoles

Aromatic nucleophilic substitution (SNAR) of a haloimidazole or halobenzimidazole with an appropriate halogen salt, that is, halogen exchange, is also a promising way of making halogenated imidazoles and benzimidazoles, especially fluoro derivatives. The 2-bromoimidazole 248 was converted in good yield into 2-fluoroimidazole 249 by treating with spray-dried KF in the presence of a catalytic amount of 18-crown-6 in diglyme under reflux (Scheme 61) . Likewise, compound 248 was converted into 250 by treatment with CuCl in diglyme under reflux in good yield. When LiCl was used as the chloride source, compound 250 was formed at 150 C and could be dealkylated to give 251 upon intense heating, with an overall yield of 72% from 248 to 251.

Scheme 61

Cesium fluoride in 18-crown-6 as solvent converted 2-chlorobenzimidazole 252 into 2-fluorobenzimidazole 253 quantitatively. The fluorine could then be displaced in situ by alkylamine 254 at room temperature with a good yield . It was also found that a catalytic amount of cesium fluoride coupled with triethyleneglycol monomethyl ether (TGME) was effective in promoting the amination of 252 with amine 254 to give 255 in high yield (Scheme 62) .

Scheme 62

When treated with TBAF in DMF, 2-bromobenzimidazole was converted into 2-fluorobenzimidazole (24% yield) . TBAF in DMSO was found to be very efficient in converting electron-deficient aryl and heteroaryl chlorides, including 2-chlorobenzimidazole 252, into their fluoro analogues, even at room temperature, in high yields (Scheme 63) .

195

196

Imidazoles

Scheme 63

Sandmeyer reaction was effective in converting an aminoimidazole into a fluoroimidazole. Zinc reduction of 4-nitroimidazole 256 followed by treatment with aqueous NaNO2 in HBF4, in one-pot, gave 4-fluoroimidazole 257 (Scheme 64) .

Scheme 64

Chlorination of imidazole and benzimidazole at C-2 has mainly been accomplished by deprotonation of an imidazole or benzimidazole with BuLi or LDA followed by quenching with a perchloroalkane . 2-Chlorobenzimidazole can also be obtained by chlorodehydration of benzimidazol-2one by heating in POCl3 . Using N-chlorosuccinimide (NCS), 4,5-disubstituted imidazoles afford 2-chloro substituted imidazoles. However, if other positions are available, chlorination goes preferentially at C-5 first, then C-4, and lastly, C-2. Selective chlorination (or halogenation in general) at the 2-position can be achieved via deprotonation using LDA, at the 2-position, followed by quenching with NCS or NBS (Scheme 65) .

Scheme 65

Imidazoles

Under basic conditions, a 1,3-disubstituted imidazole 264 was selectively brominated with benzyltrimethylammonium tribromide (BTMA Br3) in the presence of calcium carbonate to give the 5-bromoimidazole 265 in good yield (Scheme 66) .

Scheme 66

4-(1H-Imidazol-1-yl)benzenamine 266 was selectively brominated only on the phenyl ring with BTMA Br3 and Ca2CO3 (Scheme 67) , though generally speaking imidazoles are much more electron-rich than benzenes.

Scheme 67

4.02.5.3.5

Friedel–Crafts type alkylation and acylation

Ordinarily, direct Friedel–Crafts alkylation and acylation do not take place on imidazoles due to deactivation of imidazole ring after coordination to a Lewis acid catalyst (CHEC-II(1996)). Most alkylations and acylations of imidazoles have been realized via quenching of an imidazole lithium derivative with a corresponding electrophile (CHEC-II(1996)). However, the following are examples of direct electrophilic alkylation of imidazole. A two-step synthesis of marine natural product ageladine A 271 started from the commercially available histamine 269 and the pyrrole-2-carboxaldehyde 268. The entire skeleton of the alkaloid was built in one step via a Pictet–Spengler type condensation. The reaction was accelerated by Lewis acid scandium triflate, although the reaction did proceed without a catalyst but at a slower pace (Scheme 68) .

Scheme 68

197

198

Imidazoles

Likewise, electrophilic condensation of an imidazole via a Mannich protocol occurred when an imidazole 272 was aminomethylated at C-4 to give 275 in aqueous acetic acid at room temperature (Scheme 69) .

Scheme 69

The synthesis of a cyclopentadienyl-annulated imidazolium salt 282 was accomplished through a Nazarov-type cyclization as a key transformation. This annulation step was affected by toluenesulfonic acid via protonation– dehydration of the tertiary allylic alcohol 278 to form a three-centered carbocation, which was then annulated, in an electrophilic fashion, onto the C-4 position of the imidazole to form 279. The formation of the alcohol 278 was achieved via lithiation of imidazole 276 and then quenching with ketone 277 to give the 1,2-addition product (Scheme 70) .

Scheme 70

4.02.5.3.6

Diazo coupling

The coupling of diazotized p-aminoacetophenone (DPAAP) with imidazole forms the basis of the differential pulse adsorption stripping voltammetry (DPASV) method for detection of histidine and its metabolites. The absorption of azo-histidine was found to obey Frumkin absorption isotherm .

4.02.5.3.7

Silylation

Silylation at carbon can be achieved via quenching an imidazole anion with a silylating agent such as trimethylsilyl chloride, as discussed in CHEC-II(1996).

4.02.5.3.8

Oxidation

The mechanism of the oxidation of imidazoles by singlet oxygen was studied via isotope-labeled imidazole derivatives. Singlet oxygen reacts with 4,5-diphenylimidazole 283 via a [4þ2] cycloaddition to form a 2,5-endoperoxide 284. Upon warming, the 2,5-endoperoxide decomposed to form the hydroperoxide 285, which then decomposed via two pathways (Scheme 71). The hydroperoxide 285 lost water to form 286, which was rehydrated to 287. In the other pathway, the formation of carbon dioxide and benzyl diimine suggested that the oxidative decomposition went through the following mechanism: the hydroperoxide 285 was deprotonated at C-2 followed by 1,2-shift then protonation to form diol 289. The diol rearranged to amino-oxazolinone 291 by opening and reclosing the fivemembered ring. Amino-oxazolinone 291 decomposed to benzil diimine 292 and CO2 .

Imidazoles

Scheme 71

An NH in the imidazole is required for the decomposition of the initially formed endoperoxide. Otherwise the endoperoxide decomposes back to starting material. The endoperoxide product 294 from N-methylimidazole 293 was stable up to 28 C. However, it only decomposed to give back starting material 293 upon warming. On the other hand, 2,5-endoperoxide 296 of 2,4,5-triphenylimidazole gave rise to hydroperoxide 297, which was rearranged to 4,5endoperoxide 298. The latter converted to diacylamidine 299 (Scheme 72), .

Scheme 72

199

200

Imidazoles

Oxidative rearrangements of tetrahydrobenzimidazoles 300–304 on treatment with dimethyldioxirane (DMDO) provided spiro-5-imidazolones 305–311 selectively in good yields. Moderate to excellent stereoselectivity was achieved via preferential oxidation at the less sterically hindered face (Scheme 73) .

Scheme 73

One of the notable features of this rearrangement is the exclusive formation of 5-imidazolones 315 rather than the isomeric 4-imidazolones (Scheme 74). These results were attributed to two causes. Sterically, the 5-imidazolone is less crowded than the isomeric 4-imidazolone since the spirocyclopentyl ring is further away from the

Imidazoles

N-1-substituent. Second, the carbocation 314 (or electron-deficient carbon) leading to the 5-imidazolone is more stabilized than the corresponding carbocation which would lead to the 4-imidazolone.

Scheme 74

However, from substrate tetrahydrobenzimidazol-2-carbamates 316a and 316b, no spiro rearrangement products were observed. Instead, diols 317a and 317b were found to be major products, along with oxidative coupling products 318a and 318b. Less sterically congested methyl carbamate gave much better conversion than its t-butyl counterpart. Davis’ reagent (N-sulfonyloxaziridine), on the other hand, was also able to bring about oxidative rearrangement of tetrahydrobenzimidazole 319 to spiro-5-imidazolone 320 in good yield (Scheme 75) .

Scheme 75

4.02.5.4 Nucleophilic Attack at Carbon 4.02.5.4.1

Hydroxide and O-nucleophiles

4.02.5.4.1(i) Neutral imidazoles Cyclocondensation of 2-halobenzimidazole 322 (or 2-haloimidazoles) with 2-hydroxybenzyl alcohol 321 in the melt gave 85-91% of 2H-benzimidazo[2,1-b][1,3]benzoxazine 323 (Scheme 76) . Hydrazonoyl halide 325 reacted with 2-methylthiobenzimidazole 324 to furnish benzimidazo[1,2-d]-1,2,4-oxadiazole derivative 326 (Scheme 77) . This reaction proceeded in a [2þ3] fashion.

201

202

Imidazoles

Scheme 76

Scheme 77

4.02.5.4.1(ii) Acidity of C-2 hydrogen of imidazolium cation Position C-2 of an imidazole is usually electrophilic. However, a 1,3-disubstituted imidazolium cation can easily be deprotonated at C-2, thus converting the carbon atom into a nucleophilic centre (Scheme 78). Sodium hydride deprotonates 1,3-dimesitylimidazolium chloride; quenching with an electrophile such as isobutyl chloroformate then formed imidazolium-2-carboester 328 in good yield . Dimethyl carbonate N-methylated 1-methylimidazole, then an electrophilic substitution at C-2 gave imidazolium-2-carboxylate 331 (Scheme 78) .

Scheme 78

Imidazoles

4.02.5.5 Nucleophilic Attack at Hydrogen 4.02.5.5.1


N-Methylimidazole was converted into the 2-lithio-imidazole upon treatment with a stoichiometric amount of lithium in the presence of isoprene as catalyst (20 mol%) in THF at room temperature with near quantitative yield . The same lithioimidazole was obtained in high yield when butyllithium or methyllithium were used as lithiating reagents (Schemes 79 and 80).

Scheme 79

Scheme 80

Lithiated imidazoles are good nucleophiles and can easily be converted into other species by treatment with an appropriate electrophile. For example N-methylimidazole was converted into 332. Sec-butyllithium was then used to deprotonate at the 5-position for reaction with 333 leading to 334. Removal of the silyl group followed by installation of the second alkyl group at C-2, using n-butyllithium and 336, then gave the 1,2,5-trisubstituted imidazole 337 (Scheme 80) .

4.02.5.5.2

Nitrogen carbanion and SRN1 reactions

Direct C–C bond formation at the 2-position of imidazole and benzimidazole was reported when imidazole was deprotonated with potassium t-butoxide in liquid ammonia via electrochemically induced SRN1. Coupling products 340 and 341 were isolated in a 4:1 ratio when the reaction started from 4-methylimidazole 338. Only one product 343 was obtained when 2-methylimidazole was used. It was proposed that delocalization of the negative charge of 345 resulted in some carbanion character (resonance contributors 346–348), and thus subsequent SRN1 reaction with an electron deficient aryl chloride at carbon (Scheme 81) .

203

204

Imidazoles

Scheme 81

4.02.5.5.3

C-Acylation via deprotonation

Direct acylation of N-protected imidazole involves formation of an N-acyl azolium salt, which is then deprotonated at C-2 followed by rearrangement of the acylazolium ylide to the 2-acylated imidazole (for mechanism and a number of applications, see CHEC-II(1996)). An example is shown in Scheme 82: N-acylation of imidazole 350 followed by 2-deprotonation of the azolium cation, then migration of the acyl group to C-2 gives product 351 .

Scheme 82

4.02.5.5.4 4.02.5.5.4(i)

Transition metal catalyzed coupling reactions Palladium mediated coupling of N-protected imidazole halides

4.02.5.5.4(i)(a) Heck coupling

Few Heck couplings were reported associated with halogenated imidazoles. Multisubstituted 4-iodoimidazoles and 4-bromoimidazole were cross-coupled with methyl acrylate in high yields catalyzed by Pd(OAc)2 with PPh3 in the presence of TEA in DMF. Iodoimidazole 352 was cross-coupled with methyl acrylate to give product 353 under the usual Heck conditions in high yield (Scheme 83) . This iodoimidazole was also cross-coupled with styrene under similar conditions.

Imidazoles

Scheme 83

4.02.5.5.4(i)(b) Stille coupling

Imidazole-2-stannanes reacted with substituted bromobenzene in the presence of PdCl2(PPh3)2 in good yields . Imidazole-2-stannane 354 was cross-coupled with alkenyl bromide 355 (Scheme 84) . However, under the same coupling conditions, imidazole-2-stannane 354 with alkenyl iodide 357 resulted in a poor yield. It was also noted that an E-configured coupling product 359 resulted from a Z-configured alkenyl bromide 358.

Scheme 84

Arylstannanes reacted with 2-iodoimidazole under Stille conditions gave rise to cross-coupled products. The imidazole modified tetrathiafulvalene 362, synthesized via Stille coupling, formed a charge transfer complex with chloranil, which displayed metal like conductivity for the first time in a purely organic material (Scheme 85) .

Scheme 85

The 5-bromoimidazole 363 cross-coupled with an allylstannane 364 with Pd(0) as the catalyst to give allylated product 365 in good yield (Scheme 86) .

205

206

Imidazoles

Scheme 86

Sometimes, the role of the coupling partner is important for the success of a coupling reaction. Imidazole stannane 367 reacted with iodoimidazolopyridine 366 under the common Stille conditions to give product 368 in good yields. However, under the same conditions, iodoimidazole 370 and stannane 369 only produced traces of the desired product 368 (Scheme 87) .

Scheme 87

4.02.5.5.4(i)(c) Negishi coupling

Imidazole zinc reagent 372 was made from 2-iodoimidazole 371 with activated zinc dust. The organozinc reagent was cross-coupled with aryl iodides and alkenyl iodides, in good yields (Scheme 88), .

Scheme 88

Imidazole zinc reagent 376 was made via transmetallation of the 2-lithioimidazole with zinc chloride. This zinc reagent underwent Negishi cross-coupling with pyridinone triflate 377 to give the highly substituted pyridinone 378 in 51% yield (Scheme 89) .

4.02.5.5.4(i)(d) Sonogashira coupling

2-Iodoimidazole 371 coupled efficiently with TMS-acetylene 379 to produce 2-alkynyl-imidazole 380 in the presence of CuI and PdCl2(PPh3)2 at only 35 C (Scheme 90) .

Imidazoles

Scheme 89

Scheme 90

When 2-iodoimidazole 381 was treated with 382 bearing both a terminal alkene and a terminal alkyne, in the presence of copper and palladium as catalysts, only the Sonogashira product was obtained in high yield (Scheme 91) .

Scheme 91

Iodination of 384 via a Sandmeyer reaction followed by palladium-catalyzed cross-coupling with TMS acetylene and subsequent in situ treatment with ammonia in methanol in a sealed tube furnished the annulation product 387 (Scheme 92) .

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208

Imidazoles

Scheme 92 4.02.5.5.4(i)(e) Suzuki coupling

Aryl boronic ester 389 was cross-coupled with 2-iodobenzimidazole 388 under Suzuki conditions to give 2-arylbenzimidazole 390 in good yield (Scheme 93) .

Scheme 93

1-Substituted-2-iodoimidazole 391 also coupled with an arylboronic acid 392 under conventional Suzuki conditions forming 393 (Scheme 94) .

Scheme 94

Imidazoles

N-1-Substituted iodoimidazoles behave normally with arylboronic acids to give cross-coupled products . N-1-Substituted-2-bromoimidazoles also coupled efficiently with aryl boronic acids and alkenyl boronic acids to give cross-coupled products in high yields (Scheme 95) .

Scheme 95

4.02.5.5.4(i)(f) Copper-mediated cross-coupling of iodoimidazoles with allzylzinc reagents

The iodocarboxamide 397 with CuBr cross-coupled with the zinc reagent BrZnCF2CO2Et, cyclization occurred in situ to give the tetracyclic product 399 (Scheme 96) .

Scheme 96

4.02.5.5.4(i)(g) Palladium-mediated aminocarbonylation

The disubstituted imidazole 400 was brominated to give 5-bromoimidazole 401, which underwent direct aminocarbonylation in the presence of palladium acetate and 1,3-bis(diphenylphosphino)propane (1,3-DPPP) to give carboxamide 402, a selective H1 antagonist as a potential treatment for allergy (Scheme 97) .

Scheme 97

4.02.5.5.4(ii) Palladium-mediated coupling of 2-H-imidazole or 2-H-benzimidazole with aryl halides It was reported for the first time that direct palladium-catalyzed C–C bond formation could be achieved between azoles (including N-methylimidazole) and an aryl halide. Palladium-catalyzed cross-coupling with selectivity for the more electron-rich C-5 position, gave monoarylated product 403. When C-5 was already arylated, then C-2 was preferred for arylation to give 404. However, when only CuI was used in a stoichiometric amount to mediate the reaction, the cross-coupling reaction went specifically at the 2-position to give 405, although the yield was poor. When both palladium and copper were used, a mixture of 2-phenylimidazole and 2,5-diphenylimidazole were obtained in a nearly 1:1 ratio. N-Methylbenzimidazole 407 was arylated by various aryl iodides at the 2-position when catalyzed by copper(I) iodide to give excellent yields (Scheme 98) .

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210

Imidazoles

Scheme 98

1-Methylimidazole was arylated only once with solid phase bound (chloromethyl polystyrene as solid phase precursor) aryl iodide 409. Depending on the choice of catalyst, 1-methylimidazole coupled with solid phase bound aryl iodide in 67% yield at the 5-position when Pd(OAc)2 and PPh3 were used as the catalyst system. However, when CuI was added to the above catalyst system, the only product isolated was the 2-arylated imidazole 411 in 49% yield. No diarylation product was found using either reaction system (Scheme 99) .

Scheme 99

Imidazoles

1-Hydroxylimidazole, bound to a Wang resin under Mitsunobu conditions, was selectively lithiated at the 2position by butyllithium at 50 C and then transmetallated with zinc chloride to give resin bond imidazolylzinc chloride. This resin bound imidazolylzinc reagent was cross-coupled with aryl iodides under palladium catalysis to give 2-arylimidazoles (upon cleavage from resin) in moderate yields . When catalyzed by copper, imidazole itself was arylated at N-1 to give 413, a structure confirmed by X-ray crystallography. A second coppermediated cross-coupling could then be achieved at the 2-position to give 1,2-diarylimidazole 415 (Scheme 100) .

Scheme 100

Rhodium-catalyzed C-2 arylation of benzimidazole and a number of other azoles with aryl iodides was reported . Scheme 101 shows the reaction and its proposed mechanism. Benzimidazoles can undergo crosscoupling with aryl halides, though most efficiently aryl iodides, when catalyzed by a rhodium catalyst in the presence of tricyclohexylphosphine with moderate yields. It is believed that the reaction proceeds through an N-heterocyclic carbene (NHC) intermediate . A number of other coupling partners, including phenylboronic acid, phenyltrimethylstannane, and phenyl triflate, were investigated as well. Only phenylboronic acid gave 10% conversion in cross-coupled products; the other potential coupling partners did not react at all .

4.02.5.6 Reactions with Radicals and Electron-Deficient Species 4.02.5.6.1

Carbenes

Diazafulvene 424 reacts with alkenylcarbenes 425 through a formal [6þ3] heterocyclization in a regio- and stereoselective manner to afford dihydroimidazo[1,2-a]pyridines 426. When enyne carbenes are treated with diazafulvene 424, consecutive and diastereoselective [6þ2]/cyclopentannulation cyclization reactions take place affording new polycyclic complex systems 429 that can be appropriately demetallated to the corresponding imidazole-based fused systems. Finally, enyne carbenes undergo consecutive [6þ2]/[5þ1] cyclization reactions with diazafulvene 424 and tert-butyl-NC to yield tetracyclic adducts 432 (Scheme 102) .

4.02.5.6.2

Free-radical attack at ring carbon atoms

Imidazoles normally undergo free-radical reactions at the 2-position. For example, homolytic free-radical alkylation of histidines and histamines yields 2,3-disubstituted histidines and histamines. In these reactions, the free radical was generated via silver-catalyzed oxidative decarboxylation of acids with peroxydisulfate 433 (Scheme 103) . The imidazol-5-yl radical 437, on the other hand, has been generated from 5-bromo-1,2-dimethylimidazole 436 using Bu3SnH and an azo-initiator such as AIBN or 1,19-azobis(cyclohexanecarbonitrile) (ACN). The addition of the

211

212

Imidazoles

Scheme 101

imidazol-5-yl radical onto aromatic rings becomes a favorable process by keeping the concentration of Bu3SnH low during the course of the reaction. Thus, 5-arylimidazoles 439 and 440 are obtained from the nonchain reaction of imidazol-5-yl radical 436 with benzene. The reaction of 437 with 2,6-lutidine leads to the exclusive isolation of the 3-substituted isomer 441 in 35% yield (Scheme 104) . Intramolecular imidazole free-radical reactions usually afford good to excellent yields and have been used to synthesize cyclic imidazole derivatives. For example, imidazoles and benzimidazoles undergo intramolecular radical cyclization to give [1,2-a] fused derivatives. In the intramolecular homolytic substitution, N-(o-alkyl) radicals are generated using Bu3SnH from N-(o-phenylselanyl)alkyl side-chains. Phenylselanyl groups are used as radical leaving groups to avoid problems of N-alkylation (Scheme 105) .

Imidazoles

Scheme 102

Scheme 103

Xanthate 446 undergoes cyclization in the presence of camphorsulfonic acid via a radical chain reaction initiated by a small amount of lauroyl peroxide to give pyrroloimidazoles 449 in 56% yield. The use of an acid and anhydrous medium inhibits nucleophilic attack of the basic heterocycles at the xanthate moiety and allows radical reactions to occur. Fused heteroaromatic compounds can also be prepared directly from benzimidazole carrying an N-alkenyl substituent and xanthates by a tandem radical addition/cyclization to provide, for example, pyrrolobenzimidazole 453 in 57% yield (Scheme 106) . Cyclization reactions of allylic b-imidazolinonyl-b-ketoesters 454, 456 were carried out in a Mn(III)-promoted radical cascade. The reaction pathway (5-exo/6-endo or 5-exo/5-exo) can be directed to construct the cyclohexenyl 455 and central cyclopentyl 457 core skeletons with regioselectivity. In the cyclization, two C–C bonds and three or four contiguous stereogenic centers are established in one step, as shown in products 462 and 464. A plausible mechanism is depicted in Scheme 107 . The use of the Sonogashira reaction for cross-coupling between 1-iodo-2-(phenylethynyl)benzene 465 and 1-(2propynyl)-1H-imidazole 466 followed by treatment of the resulting adduct with KO-t-Bu gives an indeno-fused imidazo[1,2-a]pyridine 468 in 98% yield. Presumably the reaction proceeded through a 1,3-prototropic rearrangement to form benzannulated enyne-allenes, which then undergo either a concerted Diels–Alder reaction or a two-step process involving a Schmittel cyclization reaction to form a biradical followed by an intramolecular radical–radical coupling and prototropic rearrangement (Scheme 108) .

213

214

Imidazoles

Scheme 104

Scheme 105

4.02.5.6.3

Electrochemical reactions and reactions with free electrons

Indirect electrochemical reduction of perfluoroalkyl halides, by means of an aromatic anion mediator, in the presence of imidazole derivatives yields the corresponding C-perfluoroalkylated imidazole analogues by an SRN1 mechanism. The reaction is triggered by dissociative electron transfer and, therefore, does not involving the intermediacy of the anion radical of the substrate. Some fluoro arenes, such as 1-iodo-2-(trifluoromethyl)benzene, also react with imidazolederived ions to give the corresponding 4-(fluorinated-aryl) imidazole analogues (Scheme 109) .

Imidazoles

Scheme 106

Regioselective Michael addition of imidazole to levoglucosenone 475 is effectively catalyzed by cathodic electrolysis. The electrochemical conditions are milder and provide higher yields as compared to the base-catalyzed reactions (Scheme 110) . The reversibility of the two-electron reduction of tetraazafulvalenes 478 has been confirmed by employing cyclovoltammetric measurements, although attempts to oxidize these systems electrochemically or by chemical oxidizing agents failed. On the other hand, treatment of the systems 481 with sodium dithionite provided a new entry to quinomethides 482, which represents the SEM form of this four-step redox system and thus can finally be reduced to yield the tetraamino-substituted bisimidazoles 483 (Scheme 111) .

4.02.5.6.4

Catalytic hydrogenation and reduction by dissolving metals

Naphthalene-catalyzed lithiation of 1,3-dimethyl-2-phenylimidazolidine leads to cleavage of the benzylic carbon– nitrogen bond, with formation of an intermediate dianion. The dianion could be trapped with several electrophiles, including primary and secondary alkyl halides, as well as enolizable and nonenolizable carbonyl derivatives, affording diamines 485 in satisfactory yields (Scheme 112) .

215

216

Imidazoles

Scheme 107

4.02.5.7 Reactions with Cyclic Transition States 4.02.5.7.1

Diels–Alder reactions and 1,3-dipolar additions

Imidazoles are electron-rich heterocycless and can undergo inverse electron demand Diels–Alder reactions. Particularly, amino-substituted imidazoles are good dienophiles and cyclize with electron-poor counterparts to provide cycloadducts. For example, intermolecular cycloadditions of 2-substituted imidazole 486 with various

Imidazoles

Scheme 108

Scheme 109

Scheme 110

217

218

Imidazoles

Scheme 111

Scheme 112

1,2,4-triazines 487 produces both imidazo[4,5-c]pyridines (3-deazapurines) 490 and pyrido[3,2-d]pyrimidin-4-ones (8deazapteridines) 491. The product distribution was controlled by reactant substituents and influenced by reaction temperature . Reaction of 2-substituted imidazole 492 with 1,2,4,5-tetrazine-3,6dicarboxylate 493 produces imidazo[4,5-d]pyridazine 494 in good yield, even at low reaction temperature (Scheme 113) . Reaction of 5-amino-1-benzyl-4-imidazolecarboxylic acid 495 with 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine 496 at 80 C in DMF led to 9-benzyl-2,6-bis(ethoxycarbonyl)purine 501 in 83% yield. Presumably, 5-amino-1-benzyl-4-imidazole 497 is generated in situ from the acid and is highly reactive for the cycloaddition. The cycloadduct 498 then spontaneously undergoes retro Diels–Alder reaction with the loss of ethyl cyanoformate 499 followed by the loss of ammonia and aromatization to produce the purine in a regioselective manner (Scheme 114) . Imidazole and 2-phenylimidazole undergo intramolecular Diels–Alder reaction with 1,2,4-triazines tethered between an imidazole nitrogen and the triazinyl C-3 position to produce tetrahydro-1,5-naphthyridines. The reaction proceeds by a cycloaddition with subsequent loss of N2, followed by a presumed stepwise loss of a nitrile. Addition of antioxidant BHT inhibits aromatization to greatly improve the yield of tetrahydronaphthyridine 504 (Scheme 115) . Vinylimidazoles participate in Diels–Alder reactions with a wide variety of dienophiles . Thus, cycloadduct 508 is obtained at room temperature on reaction of compound 506 with N-phenylmaleimide 507 in 91% yield. A similar reaction occurs between natural product oroidin 509 and maleimide 510 to give cycloadduct 512 with catalysis by Y(OTf)3 511 (Scheme 116) . Homonuclear Diels–Alder dimerization of various 5-ethenyl-2-phenylsulfanyl-1H-imidazole 513 provides a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles, 514/515 as illustrated in Scheme 117 .

Imidazoles

Scheme 113

Scheme 114

219

220

Imidazoles

Scheme 115

Scheme 116

Scheme 117

Imidazoles

Reaction of a sulfonamide-protected 5-vinylimidazole 516 with 4-phenyl-1,2,4-triazoline-3,5-dione 517 in methanol gave the Diels–Alder adduct 518 in 85% yield, subequent aromatization to form the imidazole ring in 519 was achieved quantitatively by DBU treatment (Scheme 118) .

Scheme 118

The use of the p-toluenesulfonyl (Ts) and tosylvinyl (Tsv) groups as nitrogen masking groups imparts high regioselectivity in Diels–Alder reactions. The electron-withdrawing Tsv group is utilized as an electronically adjustable nitrogen-protecting group as subsequent hydrogenation provides the more electron-rich tosylethyl (Tse) group. This electronic adjustment strategy provides the desired regioisomer in good yield (Scheme 119) .

Scheme 119

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222

Imidazoles

Compound 526 undergoes an intramolecular Diels–Alder reaction providing the expected cycloadduct 527 in 48% yield, along with the aromatized congener 528 in 28% yield (Scheme 120) .

Scheme 120

4.02.5.7.2

Photochemical cycloadditions

Irradiation of a series of 4,5-bis(alkyn-1-yl)imidazoles (R ¼ Me, Bu, Ph) (450 W low-pressure Hg) induced Bergman cycloaromatization reactions providing benzimidazole derivatives. The cyclized product (R ¼ Ph) was obtained in highest yields (26–64%) with the best result obtained in THF (Scheme 121) .

Scheme 121

When a solution of 29,39-O-isopropylidenebredinin 529 in 0.1 M AcOH was irradiated with a high-pressure Hg lamp, an imidazole ring-cleavage reaction occurred to give the 2-aminomalonamide riboside 534 in 71% yield (Scheme 122) .

Scheme 122

Imidazoles

4.02.6 Reactivity of Nonconjugated Rings 4.02.6.1 Isomers of Aromatic Derivatives 4.02.6.1.1

Compounds not in tautomeric equilibrium with aromatic isomers

4.02.6.1.1(i) 2H-Imidazoles The anion 536 from a-lithiation of nitrone 535 is stabilized by the dipolar functional group. In the absence of electrophiles, 536 undergoes oxidative coupling to form dimer 537 (Scheme 123); with aldehydes or ketones, alcohols are formed in high yields. The initial alcohol 539 undergoes an intramolecular 1,3-dipolar cycloaddition process leading to the formation of the tricyclic structure 540 .

Scheme 123

4.02.6.1.1(ii) 4H-Imidazoles 5-Imino-4,4-bis(trifluoromethyl)imidazoline 542, obtained from amide 541, undergoes Dimroth rearrangement upon basic work-up giving the less congested isomer 543 that is also stabilized due to extended conjugation (Scheme 124) .

Scheme 124

4.02.6.2 Dihydro Compounds 4.02.6.2.1

Tautomerism and interconversions

2-Alkyl-2-imidazolines 544 are in equilibrium with the enediamine tautomers 545 through which carbon-bound diazenium diolates 546 are formed upon reaction with nitric oxide (Scheme 125) . Due to the electron-withdrawing nature of the pyridine rings, isomerization of cis-2,4,5-tripyridylimidazoline 547 to 548 occurs under milder conditions than those reported for non-heterocycle-substituted imidazolines (Scheme 126) .

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224

Imidazoles

Scheme 125

Scheme 126

4.02.6.2.2

Aromatization

4,4-Bis(trifluoromethyl)imidazoline 549, which contains a hydroxyl group at the 5-position, undergoes detrifluoromethylation under basic conditions to give 4-trifluoromethyl-imidazoles 551. The reaction is believed to proceed through ring opening to 550, which was isolated under milder basic conditions and subsequently converted into 551 (Scheme 127), .

Scheme 127

Dehydrogenation of 2-imidazolines to the corresponding imidazoles can be achieved with trichloroisocyanuric acid , KMnO4 absorbed on supports such as silica gel , alumina , or Montmorillonite K-10 (552, R9 ¼ H, Me) (Scheme 128). It is possible to achieve chemoselectivity during oxidation of 2-imidazolines: 2-alkylimidazolines (R ¼ alkyl) are selectively oxidized in the presence of 2-arylimidazolines (R ¼ aryl) under heterogeneous conditions. In contrast, 2-arylimidazolines are readily oxidized in DMSO at 120 C while 2-alkylimidazolines remained unchanged . This method is particularly useful for 2-arylimidazolines containing halogens where classical Pd/C dehydrogenation failed to give satisfactory results . 2-Arylimidazolines can be oxidized with molecular oxygen in the presence of activated carbon in

Imidazoles

xylene O-Iodoxybenzoic acid (IBX) and (diacetoxyiodo)benzene can also be used for the synthesis of electron-rich imidazole derivatives (cf. 553). Magtrieve in combination with microwave irradiation offers an efficient and convenient oxidation of 2-substituted imdazolines 554 . A comparison of methods for the oxidative aromatization of 2-(2-alkoxyphenyl)-1H-imidazoles 555 was reported .

Scheme 128

Substituted 2-imidazolines, especially with steric congestion at the sp3 centers, can be oxidized by air to imidazoles . Other conventional oxidations of imidazolines include BrCCl3/DBU and MnO2 . In a recent synthesis of 13C-labeled midazolam and 19-hydroxymidazolam, MnO2 was used for the oxidation of midazoline 556 (Scheme 129) .

Scheme 129

5-Aminoimidazoles 560 were selectively synthesized from trans-4,5-bisamino-1-methyl-2-alkyl-2-imidazoline 558 by heating (Scheme 130). Isotope exchange experiments suggest that the reaction proceeds through a tele-elimination mechanism via intermediate 559 (Scheme 130) .

225

226

Imidazoles

Scheme 130

2-[Furyl/thienyl]-1,3-dimethylbenzimidazoline derivatives can be oxidized by 1-benzyl-3-carbamoylpyridinium ion or 1-benzyl-5-nitroisoquinolinium ion through a one-step hydride transfer mechanism .

4.02.6.2.3

Ring fission

Hydrolysis in aqueous ethanol of 2-methyl imidazolines 561, derived from C2-symmetric diamines and the Pinner salt, leads to mono-protected 1,2-diamines 562. The latter are readily converted into N,N-disubstituted 1,2-diamines (Scheme 131) . N-protected 3-imidazolines are readily hydrolyzed under milder conditions. Thus peptidyl trifluoromethyl ketones 564 were prepared through hydrolysis of 563 .

Scheme 131

The unique resonance structure of the dihydroimidazolium cation has been studied in the context of the one-carbon transfer function of coenzyme N(5),N(10)-methenyl tetrahydrofolic acid. Reaction of 2-methyl-4,5dihydro-1H-imidazolium salt 565 with amines or water results in the formation of N,N,N9-trisubstituted ethylenediamines (566, 567) (Scheme 132). By choosing groups at N-1 and N-3 with different electronic properties, ring opening at the imidazolium carbon occurs regiospecifically as a result of protonation of the more basic nitrogen . Carbon acids such as malononitrile add to 568 to give enamines . The hydroxylamine adduct 569 undergoes a Beckmann rearrangement upon acid treatment . Compound 570 was hydrolyzed to the bisindole 571 in high yield (Scheme 133) . Ring opening of imidazoline under nitrosation is regiospecific giving nitrosoamide that is further converted to the bis-N-nitroso derivative 573. Presumably the initial product, N-nitrosoimidazolinium cation 572, undergoes hydration followed by ring opening in such a way that the NMe group is cleaved from the tetrahedral intermediate (Scheme 134). .

Imidazoles

Scheme 132

Scheme 133

Scheme 134

Under basic conditions, attempts to achieve C-5-alkylation of 574 (Scheme 135) led instead to the N-alkylated product 576 after hydrolysis. Presumably a putative initial anion underwent electrocyclic ring opening reaction to generate the more stable N-complex 575 before alkylation took place .

227

228

Imidazoles

Scheme 135

Imidazolines are often converted into the corresponding tetrahydroimidazoles prior to ring opening reactions in situ. For example, reduction of 577 with sodium offers a practical process for the conversion of carboxylic acids into the corresponding aldehydes (Scheme 136) . The reduction of dihydroimidazolium salts requires mild conditions and is applicable to complex structures. Methylation of 578 (to 579) followed by reduction with NaBH4 led to the quaternary aldehyde after work-up . Similarly, reductive ring opening of sulfonyl dihydroimidazolium salt 580 provides trisubstituted ethylenediamine derivatives 581 .

Scheme 136

4.02.6.2.4

Other reactions

4.02.6.2.4(i) 2-Imidazolines N-Alkylation of 2-methyl-2-imidazoline can be achieved under phase transfer catalysis. The reaction works best with mixed bases in the absence of a solvent (Scheme 137; R: Et, Pr, Bu, C7H15, C12H25; yields: 60–96%) .

Imidazoles

Scheme 137

When imidazolinium salts lacking a 2-substituent such as 1-(3-nitrobenzenesulfonyl)-3,4-dimethylimidazolinium iodide 582 reacted with the sodium salt of indole, 583 was formed . In contrast, 1,3-diacetylimidazolium acetate, which is derived from compound 584, reacts at the indole 3-position to give 585 (Scheme 138) .

Scheme 138

Direct C–H activation of 2-imidazolines in the addition to alkenes has been observed under rhodium catalysis as shown for the formation of 586 (Scheme 139) . The proposed intermediate was thought to be similar to that involved in metal-N-heterocyclic carbene (NHC) complexes .

Scheme 139

Difenchyl imidazolinium salt 587 when treated with a strong base (to form the putative carbene) followed by the addition of copper(II) triflate, gave the unexpected piperazin-2-one 589 and urea 588 (Scheme 140) . The formation of 589 was confirmed by X-ray structural analyses and probably results via dimerization following deprotonation of 587. The putative carbene intermediate has not been isolated. Imidazolinium salt 590 reacted with propiolate and an aromatic aldehyde to give the cyclic three-component adduct, furan 593 (Scheme 141). This reaction involves conjugate addition of the carbene to the alkyne to form 591, which undergoes cycloaddition with an aldehyde. The resulting spiroaminal 592 isomerizes to the more stable aminofuran 593 .

229

230

Imidazoles

Scheme 140

Scheme 141

Homochiral 4,5-dihydroimidazolium ylides 595 derived from chiral 1-benzyl-4-phenyl-2-imidazoline 594, undergo diastereoselective endo 1,3-dipolar cycloaddition with a range of alkene dipolarophiles to form hexahydropyrrolo[1,2-a]imidazoles 596. These reactions are best carried out in one pot by refluxing a mixture of 594, bromoacetate, and a dipolarophile in the presence of DBU (Scheme 142) . Bicyclic adducts 596 are readily converted into enantiopure pyrrolidines in a two-step procedure . An intramolecular system (597 to 598) provided a rapid assembly of 2,3,4-trisubstituted pyrrolidines .

Scheme 142

Imidazoline 3-oxides (which are nitrones) such as 599 (Scheme 143) react with dipolarophiles in an exo fashion . Depending on the substitution pattern, the adducts from electron-deficient alkynes 600 undergo a further 1,5-(C,N)-H shift 601 to form a ketone 602 or aldehyde 603. Alkene dipolarophiles react with 599 with high

Scheme 143

232

Imidazoles

regio- and diastereoselectivity, giving rise to bicyclic (604, 605) or tricyclic (606, 607) adducts in modest yields . Interestingly, the reaction with methacrylate ester gave the regioisomeric 5-substituted isoxazolidines in low yield . The imine bond in 2-imidazolines reacts with Fisher carbenes under irradiation (Scheme 144). Low yields were obtained with monosubstituted imidazolines 608a–c due to thermal decomposition of the substrates under the reaction conditions. Optically active 4,4-disubstituted 2-imidazolines 608d–e form azapenams (609d, 610e, 611) with (methoxymethylcarbene)chromium complex in good yields and high diastereoselectivity. The electronic nature of R1/R2 clearly influences the sense of diastereoselectivity (609 vs. 610, 611) .

Scheme 144

The Zwitterionic nitrogen-bonded complex 613 formed from 4,6-dinitrobenzofuroxan and imidazoline 612 (Rf ¼ (CH2)6F), undergo base-catalyzed isomerization to 613a which then undergoes a 1,3-allylic rearrangement of the N-oxide to form 613b. Extrusion of the imidazoline completes the catalytic cycle. The overall conversion is an unusual case of a formal intramolecular oxygen transfer (Scheme 145) . Reductions of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazolyl nitronyl nitroxides are discussed in Section 4.02.8.8. One of the emerging applications of imidazole-based compounds is in the area of metal complexes for novel organic transformations. 2-Imidazolines have been extensively studied as chiral auxiliary in asymmetric syntheses, such as in Scheme 146 palladium-catalyzed CO/styrene copolymerization 614 , ruthenium catalyzed Diels– Alder reaction 614 diethylzinc addition to aldehydes 615 , palladium-catalyzed allylation 616 , asymmetric intramolecular Heck reaction 617 , ruthenium-catalyzed epoxidation and Ir-catalyzed hydrogenation of imines 618 and styrenes 619 . The complex of Cu(OTf)2 with N-tethered-bis(imidazoline) 620 has been shown to catalyze asymmetric benzoylation of 1,2-diols (48% ee) and the cyclopropanation of styrenes by ethyl diazoacetate (75–83% ee) . Compared to the corresponding oxazolines, higher enantioselectivity is often observed in imdazoline-based systems. Substitution at the N-1 position offers the opportunity to fine-tune both the electronic and the steric properties of the imidazoline ring. Highly enantioselective and efficient aza-Claisen rearrangements of N-4-methoxyphenyl trifluoroacetimidates occur with the FIP catalyst 621 .

Imidazoles

Scheme 145

Scheme 146

4.02.6.2.4(ii) 3-Imidazolines Metallation of 1,2,2,5,5-pentamethyl-3-imidazoline-3-oxide 622 with s-BuLi leads to the dipole-stabilized organolithium intermediate 623 that reacts with electrophiles HgCl2, Me3SiCl, Et3GeCl, nBu3SnBr, Ph2P(O)Cl, and TsCl to give a-heteroatom substituted nitrones 624 (R ¼ HgCl, Me3Si, n-Bu3Sn, Ph2P(O), or Cl) (Scheme 147) .

Scheme 147

233

234

Imidazoles

An internal redox process took place when the alcohol 625 was treated with piperidine (but not with Et3N), leading to the formation of ketone 626 (Scheme 148) .

Scheme 148

A highly exo-selective alkylation on the amidine function of 627, possibly as a result of steric hindrance, leads to 628 the amide of which is then converted to pH-sensitive spin probe 629 via an oxidative N-demethylation (Scheme 149) .

Scheme 149

The reactions between 3-imidazoline 3-oxides (630, Scheme 150) and maleimides give rise to a mixture of endoand exo-adducts. The endo selectivity is higher in toluene than in benzene, CH2Cl2, or THF. The reaction is slower when a 2-substituent (R1) is present . Similarly, cycloadditions with isocyanate , styrene , alkenes , and alkynes give 631–634. These compounds are prone either to retro cycloaddition or fragmentations leading to the formation of imidazoles.

Scheme 150

Imidazoles

Homochiral dihydroimidazol-4-one 635 was efficiently oxidized to 2-tert-butyl-3-methyl-2,3-dihydroimidazol-4one N-oxide 636 which adds to functionalized olefins to afford the adducts 637 with high diastereoselectivity (Scheme 151) . This is an efficient method for the synthesis of chiral glycine analogues 638.

Scheme 151

4.02.6.2.4(iii) 4-Imidazolines Under irradiation conditions, imidazolines are excellent hydrogen donors. For example 1,3-dimethyl-2-phenylbenzyimidazoline 639 reduces a,b-epoxy ketones in the presence of proton donors (Scheme 152) ).

Scheme 152

Compound 639 also promotes the photoinduced reduction of ketones whereas 2-(29-hydroxyphenyl)-1,3-dimethylbenzimidazoline 640 promotes benzpinacol formation (Scheme 153) . Photoinduced single electron transfer (SET) followed by regiospecific proton transfer (PT) led to the formation of either benzhydrol or benzpinacol, depending on the 2-aryl substituent.

Scheme 153

235

236

Imidazoles

4.02.6.3 Tetrahydro Compounds 4.02.6.3.1

Ring fission

N-Alkyl and N-phenyl-2-arylimidazolidines display ring–chain tautomerism in CDCl3. The ring/chain ratios were determined based on 1H NMR spectra. Electron-withdrawing groups on the aryl ring favor the ring tautomers, whereas bulky N-substituents favor the chain tautomers. The electronic effects of the 2-aryl substituents were shown to correlate with the Hammett–Brown constants þ (log Kx ¼ þþlog KH) . Variable temperature 1H NMR studies of 2-isopropyl-1,3-imidazolidine in d6-DMSO-D2O revealed that the ring–chain equilibrium free energy G6¼ 62 kJ mol1 . Reductive cleavage of imidazolidines 641 was implicated in the one-pot synthesis of N,N,N9-trisubstituted ethylenediamines 643 from N,N9-disubstituted ethylene diamines and an aldehyde R2CHO. Presumably the intermediate iminium ion 642 is reduced by NaBH4 (Scheme 154) . Naphthalene-catalyzed lithiation of 1,3-dimethyl-2-phenylimidazoline 644 leads to benzylic C–N bond cleavage. The intermediate dianion can be trapped with electrophiles (H2O, alkyl halides, ketones, and aldehydes) to afford diamines 645 .

Scheme 154

The aminal function embedded in hexahydropyrrolo[1,2-a]imidazoles 646 (Scheme 155) renders them prone to equilibration and eliminations under basic conditions. For example 646 (E ¼ CN, CO2Me) undergoes epimerization 647 upon storage or exposure to basic alumina. In the case of chloronitrile 648, a 2,4-disubstituted pyrrole is readily formed under mild conditions .

Scheme 155

Imidazoles

N-Sulfinylimidazolidines 649 are reduced to the N-benzyl-N-sulfinyldiaminoalcohols 650 with regioselective cleavage of the aminal center. The regioselectivity is presumably due to initial reduction of the ester group and chelation of Al to both the resulting alkoxide function and the nearby aminal nitrogen atom (Scheme 156) . Acidic hydrolysis at the aminal center leads to either b-sulfinate 651 or a-benzylamine 652, depending on the reaction conditions .

Scheme 156

In the synthesis of chiral 1,2-diamines, selective hydrolysis of the aminal function group of 653 was achieved with malonic acid to give the BOC-protected diamine 654. In the presence of TFA, both aminal and BOC were cleaved to give 655 (Scheme 157) .

Scheme 157

4.02.6.3.2

Aromatization

Ethyl 2,3-a-diphenyl-5-p-tolyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3-carboxylate 656 undergoes base or thermally-induced fragmentation (formally a double cis-elimination) to imidazole 657 (Scheme 158) .

Scheme 158

237

238

Imidazoles

4.02.6.3.3

Other Reactions

4,4,5,5-Tetramethylimidazolidines 658 are oxidized to the corresponding nitronylnitroxides 659 (78%, R ¼ Ph), via a 1,3-dihydroxy intermediate (Scheme 159) . KMnO4 effects C–H oxidation of the derivative 660 to give the imidazolidinone 661 .

Scheme 159

Hexahydro-7-oxa-2,5,6a-triaza-cyclopenta[a]pentalene-1,3-diones such as 662, (Scheme 160), in the presence of a secondary amine, undergo a formal retro-[3þ2] cycloaddition to give 3-imidazoline 664 via the bisamide intermediate 663 .

Scheme 160

Unlike an N,N9-disubstituted imidazoline-2-thione, the reaction of imidazolidine-2-thione 665 itself with 2-phenyloxirane in the presence of BF3 leads to the formation of 1,3-bis[(E)-2-phenylethen-1-yl]imidazolidine-2-thione 666 (Scheme 161) . This unusual mode of reaction is presumably due to a Lewis-acid-catalyzed rearrangement of oxirane to aldehyde followed by an ene-like reaction with the iminothiol.

Scheme 161

Imidazoles

Substituted imidazolidin-4-ones can be viewed as protected glycine derivatives, thus offering versatile reactivity profiles. For example, spontaneous intramolecular reductive amination occurs upon Cbz deprotection of 667 (Scheme 162) . C-Alkylation of imidazolidinone 668 resulted in 4,4-disubstituted imidazolidinone 669 in high diastereo- and enantioselectivity (Scheme 163) . Chiral imidazolidinone organocatalysts such as 670 form iminium intermediates 671 with enals that participate in a variety of directed enantioselective organic reactions (see Section 4.02.8.3) .

Scheme 162

Scheme 163

The C-2 proton of 1,3-di-(tert-butoxycarbonyl)imidazolidine 672 is abstracted under controlled conditions with secBuLi (2.2 equiv) and the resulting anion can be quenched with various electrophiles to give 2-substituted products 673 in modest yields and, in the case of chiral 672, with low diastereoselectivity (Equation 2). Depending on the nature of substituents at C-4 and C-5, deprotonation under this protocol leads to mixture of 2- and 4-anions . In contrast to the bis-N-Boc derivative, mono-N-BOC-protected imidazolidine 674 undergoes deprotonation exclusively at the 5-position. In the presence of ()-sparteine, asymmetric lithiation occurred at the pro-S hydrogen and quenching with electrophiles (RX: Bu3SnCl, Me3SiCl, Ph2MeSiCl, Ph2CTO, MeI) afforded 675 in high optical purity (Equation 3) ; however, with allyl bromide as electrophile a racemic product was produced. The modest yield of the reaction is a result of hindered rotation about the Boc amide bond that was shown to control the extent of the deprotonation (see Section 4.02.3.3 for NMR studies).

239

240

Imidazoles

ð2Þ

ð3Þ

4.02.7 Reactivity of Substituents Attached to Ring Carbon Atoms 4.02.7.1 Reactions of Substituents Involving Ring Transformations Rarrangement of N-alkoxycarbonylimidazole acyl azides 676 led to the formation of two products (Scheme 164). Imidazo[1,5-c]pyrimidinone 677 was formed when R was either Me or Et, although it was not clear how the alkyl transfer from imidazole to the pyrimidone occurred. With higher R groups (Pr or Ph), the anticipated imidazo[4,5c]pyridinone 678 was formed .

Scheme 164

A vinyl cyclobutane rearrangement of sceptrin 679 to ageliferin 680 under microwave irradiation has been reported (Scheme 165). This reaction appeared to be specific to the 2-aminoimidazole substituted cyclobutane as a nonsubstituted model compound failed to yield any product .

Scheme 165

Imidazoles

The electron-withdrawing benzimidazole group activates nitro- or fluoro-arenes in SNAr reactions. Thus 2-(2nitrophenyl)-1H-benzimidazoles such as 681 undergo high-yielding intramolecular displacement of nitrite with N-pendant alkoxides to give tetracyclic 6,7-dihydro-5-oxa-7a,12-diazadibenzo[a,e]azulene 682 under mild conditions (Scheme 166). At elevated temperatures and in the presence of excess NaH, the initially formed product was converted into the corresponding N-vinyl-substituted 2-(2-hydroxyphenyl)-1H-benzimidazole 683 via basecatalyzed isomerization.

Scheme 166

Imidazolones 684, Fc ¼ ferrocenyl and hydantoins 686 were converted into the bicyclic 1-({9-(tert-butoxycarbonyl)3-oxo-8,9-dihydro-3H-imidazo[1,2-a][1,3]diazepin-2(5H)-ylidene}methyl)ferrocene 685 and 1,8diazabicyclo[4.3.0]non-3-ene-7,9-diones 687 , respectively, with the first-generation Grubbs’ olefin metathesis catalyst (Scheme 167). Studies on the ring-closing metathesis of substituted imidazoles were limited by the concern that N-3 ligation and the formation of stable carbene complexes from the vinylimidazole moiety potentially deactivate the catalyst. The nature of protecting groups at N-1 was not relevant to successful RCM reactions. When N-3 was protonated with TsOH, RCM with [(1,3-Mes2Im)(PCy3)Ru(CHPh)Cl2] could be applied to diallyl or vinyl allyl imidazoles 688–690, but not 4,5-allyl vinyl systems 691 .

Scheme 167

241

242

Imidazoles

4.02.7.2 Fused Benzene Rings 4,49-Dibromo-2,29-bisbenzimidazoles 692 react with aryl zincates under Negishi coupling conditions to give 4,49bisaryl-2,29-bisbenzimidazoles 693 (Scheme 168). Lower yields were obtained with heteroaryl zincates (2- or 3pyridyl) . Cross-coupling of bromides 694 with phosphonites provided an efficient synthesis of phosphonates 695 .

Scheme 168

4.02.7.3 Alkyl Groups Due to the acidic nature of the 4-methyl group, 3-hydroxyimidazoline 1-oxyl 696 condenses readily with aldehydes to give aldol products such as 697 (Scheme 169). Acetylide coupling of 697 with concurrent radical formation at N-1 results in the formation of 698 . Similarly, 4H-imidazole N-oxide 699, R ¼ Ph, 2-Py, 3O2NC6H4, Et) undergoes nitrosation with isopropyl nitrite to give oximes 700 in high yield. Treatment of 700 with TsCl yielded 4H-imidazole-5-carbonitrile 3-oxides 701 .

Scheme 169

Azolium formation from 2-alkyl imidazoles 702 renders the C-29 proton sufficiently acidic that under mild conditions the resulting anion 703 can be formed and adds to imines to form 704 (Scheme 170) .

Imidazoles

Scheme 170

Addition of the 1-benzyl-2-lithiomethyl-4,5-dihydroimidazole 705 to aldehydes or ketones, and the subsequent ‘retro–ene’ reaction to revert back to the starting material, was discussed in (Scheme 171). The reaction of 705 with nitriles results in the formation of b-amino a,b-unsaturated imidazoline 706 after in situ isomerization .

Scheme 171

Lithiated imidazoles (such as 707 (Scheme 172) are used as bulky bases in the rearrangement of cyclic epoxides to allylic alcohols in the presence of chiral lithium amides. During this process, epoxide opening by the lithiated imidazole (to give, e.g., 708) can be a competing or even an exclusive reaction pathway . The later reaction is highly sensitive to steric factors imposed by the C-2 alkyl substituents.

Scheme 172

Lateral metallation at C-2(a) of 1-tert-butoxycarbonyl-2-methylimidazoline 709 (Scheme 173) with sec-BuLi results in the formation of a bright yellow lithiated intermediate that reacts with alkyl halides, diphenyldiselenide, and phosphoryl chlorides to give 710. In the case of reaction with esters, the conjugated ketones 711 are formed . In the case of acylation with esters, conjugated enamino-ketones were the tautomer isolated. Further alkylation is also possible under similar conditions, to give 712. 2-Alkyl-2-imidazoline can exist as the enediamine tautomer, which will react with electrophiles such as nitric oxide (see Section 4.02.6.2.1).

243

244

Imidazoles

Scheme 173

4.02.7.4 Substituted Alkyl Groups 4.02.7.4.1

Vinyl and arylalkyl

When the C-2(a) bears an aromatic group 713, 715 (Scheme 174), deprotonation at this center is rapid due to the benzylic stabilization, so that it is possible to alkylate, including alkylative THF ring opening with electrophilic assistance from 9-BBN(OTf) 716, the dianions from unprotected imidazolines . Support for the N,Cdianion species is evident from the reaction with a dihalide giving 714 and from low temperature 13C NMR studies of the dilithium intermediate . With chiral imidazolines, a high level of 1,4-stereoinduction has been observed for the formation of benzylic quaternary carbon centers 716 . In the presence of an oxidant such as TEMPO, the initially formed dianion of 717 (R ¼ Me, 4-butenyl, 5-pentenyl) undergoes electron transfer to a configurationally stable radical that further reacts with TEMPO to give chiral alcohol 735 in 80% de. When TEMPO is added slowly to the dianion, dimers of 718 are formed .

Scheme 174

Imidazoles

A sequential lithiation–alkylation based on the dianion chemistry was utilized in an efficient synthesis of ()-mesembrine (Scheme 175 .

Scheme 175

4.02.7.4.2

Activated alkyl

In a vinylogous fashion, 2-o-tolyl-4,5-dihydro-1H-imidazole 719 (Scheme 176) undergoes ‘imidazole directed’ lithiation, subsequent trapping with electrophiles giving 720 and 721. The product distribution (bis- vs. mono-) can be modulated by reaction temperature and the nature/amount of base .

Scheme 176

Under basic conditions, nitrile 722 undergoes Diels–Alder [4þ2] cycloaddition with 1,3,5-triazine followed by fragmentation and concurrent deblocking of the acetate to give1-[4-(4-aminopyrimidin-5-yl)imidazol-1-yl]-1- -Dribofuranose-2,3,5-triol 723 (Scheme 177) . Direct cross-coupling approaches as between the corresponding 4-iodoimidazole and pyrimidines were less successful .

Scheme 177

245

246

Imidazoles

Electrophilic fluorination of 5-(cyanomethyl)imidazole-4-carboxamide 724 gives good yields of diastereoisomers 725, which were further transformed into a series of 3-fluoro-3-deazaguanosine analogues 726 (Scheme 178) .

Scheme 178

4.02.7.4.3

Heteroatom substituted alkyl

The anions of the 2-phosphoryl derivatives from 727 and 729 undergo Wadsworth–Emmons reactions with aldehydes or ketones to give 2-alkenyl imidazolines 728 and 730 (Scheme 179) . An alternative olefination involves alkylation of phenylselenyl derivative 731. Deprotection of 732 followed by oxidative elimination afforded N-1-unsubstituted 2-alkenyl imidazolines 733 .

Scheme 179

The Horner–Wadsworth–Emmons reagent 735 (Scheme 180) prepared through Michaelis–Becker reaction of 4-(chloromethyl)-1-tritylimidazole 734 with lithium diethyl phosphonate reacts with aldehydes or ketones to give 4-vinylimidazoles 736 .

Scheme 180

Imidazoles

3-Hydroxymethyl imidazoline 737 (Scheme 181) undergoes Mitsunubo reaction with phenols and activated amines to give 738 in high yields. Due to the instability of the imidazoline ring, coupling reactions with the corresponding bromide 739 are not successful .

Scheme 181

1-Methyl-2-(1-hydroxyalkyl)-1H-imidazole 740 is easily converted into the corresponding chloride 741 (Scheme 182). The latter undergoes SN2 reaction with less bulky nucleophiles, such as thioates, alcohols, phenols, and simple primary amines to give 742. With secondary amines or diamines as nucleophiles, tele-substitution at the imidazole ring becomes dominant, resulting in a serial double nucleophilic addition to the imidazole nucleus . Similarly, diethyl 2-methylmalonate anion adds to 741 to give direct displacement product 743, tele-, and double tele-adducts 744, 745 . The tele-reaction can be explained by the formation and subsequent reactions of intermediate 746. The carbamoyl group in 747 is replaced with soft nucleophiles under solvolysis conditions to give 748 (Nuc-H: H2O, MeOH, EtOH, AcNH2, MsNH2) .

Scheme 182

Oxidation of 2-aminomethyl-substituted imidazole 749, R ¼ Me, with either singlet oxygen or mCPBA (>2 equiv) leads to the formation of 4,4-bis(trifluoromethyl)imidazolines 750 in high yields (69–76%) (Scheme 183). Presumably chemoselective cleavage of the imidazole CTC bond (via 1,2-addition of 1O2) followed by acid-catalyzed dehydrocyclization gives rise to the rearranged product. However, when R ¼ H, 1,4-addition of singlet oxygen results in the formation of imidazolone 751, 42%) .

247

248

Imidazoles

Scheme 183

Allylic alcohol 752 undergoes a formal 1,3-allylic rearrangement upon acetylation to give 753 (Scheme 184) .

Scheme 184


Unsaturated alkyl

The unsaturated ester function in furanosyl imidazoles 754 can be converted into the corresponding aldehyde 755 either through ozonolysis or dihydroxylation/diol cleavage (Scheme 185) .

Scheme 185

Addition of ‘FBr’ to 1-trityl-4-vinyl-1H-imidazole 756 occurs with Markovnikov regioselectivity to produce 757 (Scheme 186). Elimination of HBr (giving 758) followed by fluorobromination provides 759. The bromide is converted into azide 760, which is reduced to b,b-difluorohistamine 761. In contrast, functionalization of 1-trityl-4formyl-1H-imidazole (cyanohydrin/DAST; MeNO2) does not yield useful intermediates for the preparation of 761 . The ‘FBr’ addition/HBr elimination is compatible with hydroxyl (but not carboxyl) group 762, which is employed in the synthesis of 763 en route to b-fluorourocanic acids 764 . The CTC bonds in sulfamoyl-protected imidazoles 765, 767 are electrophilic in nature and can be functionalized either through thiol radical addition 766 or palladium-catalyzed hydride reduction 768 (Scheme 187) . In the case of 768, both CTC and CTO functions are reduced. 2-Alkenyl imidazolines such as 769 (Scheme 188) behave as a,b-unsaturated esters and undergo exclusive conjugate addition of both hard (producing e.g. 770) and soft carbon nucleophiles (giving e.g. 771). In conjunction with the cleavage of dihydroimidazoles , these reactions constitute a synthesis of b-substituted carboxylic acids and ketones .

Imidazoles

Scheme 186

Scheme 187

Scheme 188

249

250

Imidazoles

Intramolecular cyclization of allylic amide 772 in the presence of strong acid gives oxazoline 773 in high yield. Hydrolysis of 773 in aqueous acid leads to the formation of 774 (Scheme 189) .

Scheme 189

2-(29-Alkenyl) substituted arylimidazoles 776 (n ¼ 1,2) undergo iodocyclization to form fused imidazoles 775, 777 (Scheme 190). The extent of iodination on the imidazole core depends on the nature of the reagents used .

Scheme 190

2-Alkynyl-4,4,5,5-tetramethylimidazolidine-1,3-diol 778 (Scheme 191), prepared from 2,3-di(hydroxyamino)-2,3dimethylbutane and an aldehyde, is prone to rearrangement to (E)-2-(1-hydroxy-4,4,5,5-tetramethylimidazolidin-2ylidene)-ketone 779 . The trimethylsilane-stabilized derivative 778 (R ¼ SiMe3) is isolable .

Scheme 191

Alkyne-substituted nitronyl nitroxide 780 reacts with diazomethane to give either 3- 782 or 4- 781 -pyrazolyl nitronyl nitroxide (Scheme 192), depending on the steric environment of the alkyne group .

Imidazoles

Scheme 192

Heterocycle-bridged enynes react with a Fischer carbene offering an easy benzannulation process. Unlike furan- or thiophene-bridged enynes, imidazole-bridged enyne 783 give a lower yield of the product 784 (Scheme 193). It has been suggested that coordination of the imidazole nitrogen to the Cr center might compete with the annulation pathway .

Scheme 193

N-Aryl and N-alkyl substituted imidazole-fused enediynes 785 undergo thermally promoted Bergman cycloaromatization to the benzimidazoles 786 at 145 C (Scheme 194). Kinetic data indicate that N-aryl substitution enhances the rate by up to sevenfold . 4,5-Bis-(alkyn-1-yl)imidazoles also undergo photoinduced Bergman cycloaromatization .

Scheme 194

4.02.7.5.2

Alkylidene

Alkylidene imidazoles are best described as either ketene acetals or enamines, depending on the positions of substitution. 2-(2-Propylidene)imidazoles such as 787 (Scheme 195) react with azides to form spiroheterocycles 788. The reaction rates vary widely depending on the hybridization of C(4)–C(5) bond of the dipolarophiles: dihydroimidazoles react in days while imidazoles take only hours .

Scheme 195

251

252

Imidazoles

The nucleophilic properties of the enaminoester or heterocylic keteneaminal in 789 can be utilized in annulation reactions with bis-electrophiles to form imidazo[1,2-a]pyridones Table 10. The reaction is thought to proceed with initial N-acylation at N-1 with either acid chloride or acylimidazolides generated in situ, followed by subsequent conjugate C-addition of the ketene acetal. With less active unsaturated esters, the reaction sequence may be reversed (e.g., azaene pathway) as supported by the isolation of a conjugated ester (entry 4). Ketoesters may lead to regioisomers (entries 5,6) while malonate or 1,3-diketones are not reactive toward 789 . Diethyl oxalate reacts with 789 to give dioxopyrrolo[1,2-a]imidazole (entry 8). In contrast to substituted aldehydes (entry 7), propenal adds to 789 to give the cyclohexene derivative in quantitative yield (entry 9, yield based on the aldehyde).

Table 10 Reactions between 805 and various nucleophiles Entry

Electrophile

Product

Yield

1

a, R ¼ H, 98% b, R ¼ Me, 89% c, R ¼ Ph, 98%

2

93%

3

82%

4

95%

5

R ¼ Me, 79% R ¼ Ph, 72%

6

21%

(Continued)

Imidazoles

Table 10 (Continued) Entry

Electrophile

9

Yield

R1 ¼ H, R2 ¼ Me, 62% R1 ¼ R2 ¼ Me, 32% R1 ¼ Me, R2 ¼ H, 32% R1 ¼ H, R2 = Ph, 27%

7

8

Product

EtO2C–CO2Et

50%

60%

The N,N-ketene acetal function in fused systems such as 790 (R ¼ H, Me (Scheme 196) undergoes easy hydration on chromatography to afford the saturated system 791 (see also 787).

Scheme 196

Bromination of enamine ketone 792 leads to the formation of 793 (Scheme 197). The Br in 793 can be replaced with hydrazine to give 2-(1-hydrazino-1,2-oxopropylidene)imidazoline 794. Cyclization between the nitrogen termini in 810 with aldehyde or acid chlorides affords 795, imidazo[2,1-d][1,2,4]triazine 796 and imidazo[2,1-d][1,2,4]triazepines 797 and 798, respectively . C-Benzylation of 799 with ethyl 2-(bromomethyl)benzoate affords 800 (Scheme 198), readily converted into azepinone 801 in the presence of base . C-Alkylated ketene aminals 802 (R ¼ phenyl, vinyl; Ar ¼ phenyl, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4) react with diethyl azodicarboxylate to give the quaternary carbon-containing adducts 803. Upon prolonged heating in THF, the latter undergo sequential intramolecular cyclization, fragmentation, and ring-fusion to yield 804, 805, and 806 (Scheme 199) . (5Z)-1-Acyl-3-methyl-5-(cyanomethylidene)imidazolidine-2,4-diones such as 807 readily undergo 1,3-dipolar cycloadditions with various 1,3-dipoles. The final products depend both on the nature of the dipoles and the dipolarophiles. Thus, spirohydantoins 808 and 809 are formed under neutral conditions with diazomethane or a nitrile oxide whereas further isomerization occurs under either basic or acidic conditions leading to acylureas such as 811 via 810 (Scheme 200) . The exocyclic methylene in thiohydantoins 812 reacts with O,O-diethyl S-hydrogen phosphorodithioate to give the conjugate adduct 813 (Scheme 201). Base-induced intramolecular cyclization, fragmentation, and ring formation gives 3,5-diaryl-3,5-dihydrothieto[2,3-d]imidazole-2(1H)-thiones 814 .

253

254

Imidazoles

Scheme 197

Scheme 198

Scheme 199

During the design of steroid mimics as potential ACAC inhibitors, the exocyclic enone functions in 2-[4,4bis(trifluoromethyl)-2-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-5-ylidene]-1-(4-fluorophenyl)-1-ethanones 815 are selectively reduced with zinc dust to the imidazolines 816 in high yields (Scheme 202) .

Imidazoles

Scheme 200

Scheme 201

Scheme 202

255

256

Imidazoles

4.02.7.5.3

Aryl

Reductive cyclization of 2-(ortho-nitro)phenyl imidazoles 817, 819 (Scheme 203) in the presence of an orthoester or a ketone is promoted by a low-valent titanium reagent TiCl4-Zn to afford imidazo[1,2-c]quinazolines 818 and 5,6dihydroimidazo[1,2-c]quinazolines 820 . Notably, halogens are not reduced under these conditions.

Scheme 203

Reductive metallation of 1,3-dimethyl-2-(4-substituted phenyl)imidazoles 821 (Scheme 204) with Li metal in the presence of naphthalene (5%) leads to either dehalogenation or benzylic dealkylation. The resulting anions are trapped with electrophiles (H2O, alkyl halides, ketones, and aldehydes) to afford diamines 822 . Cross-coupling of iodide 823 with phosphines under the conditions of Kraatz afforded the BIPI ligands 824 for asymmetric Heck reactions . SNAr reactions of the corresponding fluoride or bromide have been reported .

Scheme 204

Imidazolines are excellent directing groups in the metallation of aromatic rings. The diastereoselectivity 826/827 of ortho-metallation of chiral ferrocenyl imidazolines 825 showed a remarkable influence of LDA as an additive (Table 11).

Imidazoles

Table 11 ortho-Lithiation of 825 Product

t-BuLi (equiv)

LDA (equiv)

EX

815/816 (1H NMR)

Yield (%) (isolated )

825a 825a 825a 825a 825b 825b 825b 825b

1.10 0.95 1.10 0.95 1.00 0.95 1.00 0.95

0.00 1.50 0.00 1.50 0.00 1.00 0.00 1.00

MeI MeI Ph2CO Ph2CO MeI MeI Ph2CO Ph2CO

5: 1: 4: 1: 1: 1: 1: 1:

61 66 34 50

1 12 1 12 3 31 2 21

41 41

The directing function of the nitrogen atom of imidazolines makes it possible to prepare metallocycles of chiral imidazoline-based ligands. Cycloplatination of the Phebim ligand 828 (Scheme 205) leads to the formation of pincer complexes 829 through directed C–H bond activation . Similarly, cyclopalladation of ferrocenyl imidazolines 830 affords the FIP complexes 831 . Metallation of 2-phenylimidazoline with Pd(II) or Pt(II) reagents leads to the formation of cyclometallated complexes in which the a C–H of the phenyl ring was replaced with a C–Pd or C–Pt bond .

Scheme 205

4.02.7.5.4

Imine and nitrile derivatives

1,3-Dipolar addition of the 1,3-dipole derived from aldoxime 832 with various alkenes affords 3-(-2-butyl-4-chloro1H-imidazolyl)-substituted d-2-isoxazolines in high yields with the 5-substituted isoxazolines 833 as the major products (Scheme 206). These compounds are potent antifungal agents .

Scheme 206

257

258

Imidazoles

In the presence of sulfur, ethylene diamine adds to 4,5-dicyanoimidazole 834 (Scheme 207) to form bis-imidazoline 835 using microwave heating . In contrast, 4H-imidazole-5-carbonitrile 3-oxides 836 react with primary or secondary amines at the 5-position resulting in displacement of the activated CN group 837 .

Scheme 207

In 4-cyanoimidazole 838, the nitrile group undergoes addition to Grignard reagents to afford 4-acyl-1H-imidazoles 840, presumably via intermediate 839 . Controlled reduction of the nitrile group on an imidazole ring 841, 842 to an aldehyde function is achieved either by LiAlH(OEt)3, generated in situ from LAH and EtOAc in THF , or by hydrogenation in dilute sulfuric acid (Scheme 208) .

Scheme 208

a-Iminocarbonyl derivatives of 2,5-dihydro-1H-imidazole nitroxides 843 undergo heterocyclization reactions in the presence of a base to give oxazoles 847. In the presence of an amidine, 1,3,5-triazines 846 are formed as well. These reactions have been shown to proceed through the homodimer 844 that under basic conditions fragments to intermediate 845. Cyclization of 845 leads to the formation of the oxazole. On the other hand, addition of amidine to intermediate 845 followed by extrusion of PhCHO and subsequent oxidative cyclisation, perhaps by air, leads to triazines (Scheme 209) . The reactions of 1-aryl-5-amino-4-cyanoformimidoyl imidazoles 848 can take different courses depending on the nature of the reagents and the sites of reaction at the cyanoformimidyl function. Methyl cyanoacetate reacts at the imidyl carbon to give intermediates 849 which then cyclize to 3-aryl-6,7-dicyanoimidazo[4,5-b]pyridine-5-one 851 as the salt form 850 (Scheme 210) . The high chemoselectivity of this reaction is presumably due to intramolecular hydrogen bonding that leads to the initial intermediate 849. Compound 851 is a strong acid such that neutralization of the salt 850 requires strong acids like TFA (pKa 0.23). Similarly, 853 reacts with ethoxymethylenemalononitrile to give 854 . Acetylacetone, which has similar pKa to methyl cyanoacetate, reacts

Imidazoles

Scheme 209

with 848 at the imine nitrogen under similar conditions to give, after a series of rearrangements, 6-carbamoyl purine 852 . Isocyanates react at the imine nitrogen of 5-amino--imino-1H-imidazole-4-acetonitriles 853 via intermediates 855 and 857 to give either 4,49-bi-1H-imidazol-2-ones 856 or 2-oxopurines 858, depending on the nature of the isocyanates: tosyl isocyanate favors the formation of 858 , whereas alkyl and aryl isocyanates favor 856 . The ambident 1,3-dipolar 2-arylthiocarbamoyl imidazolium salts 859 are readily prepared from the corresponding carbenes and phenyl isothiocyanate as crystalline solids. Reaction of 859 with DMAD leads to the formation of spiro[imidazoline-2,39-dihydrothiophenes] 860, indicating that 859 acts as a C–C–S dipole. In contrast, the reaction of 859 with ethyl propiolate proceeds slowly to form spiro[imidazoline-2,39-dihydropyrroles] 861, indicating a C–C–N dipolar reaction being thermodynamically driven (Scheme 211) .

4.02.7.5.5

Carbonyl derivatives

In the Schmidt rearrangement of imidazolyl aryl ketone 872, Ar ¼ 4-FC6H4), the reaction appears to favor the imidazolyl migration 864 over the aryl migration 863 (Scheme 212) . A Baylis–Hillman product 865 has been observed for 2-formylimidazole with excess methyl acrylate in the presence of DABCO . In situ protection of the vinylogous ester-aldehyde of imidazole 866 as triazine 867 allows for the selective conversion of the ester group into amide 881 . An improved dissymmetrization of imidazole-4,5-dicarboxylic acid 869 for the synthesis of N,N9-disubstituted dicarboxamides 872 involves the preparation of pyrazine-dione diphenyl ester 870. Selective amide formation at the pyrazine carbonyl at low temperatures affords the mixed amide ester 871, which is subsequently converted into 872 (Scheme 213) . Electron-rich heterocycles (Ar-H: indoles, furans, and pyrroles) react with a,b-unsaturated 2-acyl imidazoles 873, R ¼ alkyl and aryl) with high enantioselectivity under (pybox)-Sc(OTf)3 catalysis to give 2-acylimidazoles 874 (Scheme 214) . It is interesting to note that the enantioselectivity is inversely proportional to the molar percentage of catalyst loading. 2-Acylimidazoles 874 can be converted into a variety of carbonyl derivatives 875, Nuc: OR, NR2, H, Ph) upon activation of the imidazole ring . In the absence of external nucleophiles, the pyrrole ring in 876 cyclizes upon activation to give 877 which serves as a precursor in the synthesis of heliotridane . Sodium pyruvate (carbonyl anion equivalent), in the presence of a thiazolium catalyst, adds to 878 to provide 1,4-diketone 879. This reaction works best with b-aryl substituted 2-acyl imidazoles. 2-Acyl imidazole 879 is activated by MeOTf and converted into esters or amides such as 880 . Cerium(IV)-pybox catalysts promote [3þ2] cycloaddition of nitrones to 873 to give 881 in high ee .

259

260

Imidazoles

Scheme 210

Scheme 211

Imidazoles

Scheme 212

Scheme 213

4.02.7.6 Amino and Related Groups The chemistry of 2-aminoimidazole derivatives in the synthesis of pyrrole-imidazole alkaoids has been reviewed . 4-Amino-5-alkoxycarbonylimidazoles 882 react with isocyanates or, more conveniently, with carbamates in the presence of a hindered potassium base to give 1-substituted xanthines which are further alkylated to 1,3-disubstituted xanthines 883 (Scheme 215) . The chemoand regioselectivities of 2-aminobenzoimidazole adding to unsaturated nitriles are highly dependent on the nature of the substrates. A modest yield of adduct 884 is obtained as a result of exo-(NH2)-b-addition to benzylidenemalononitrile . A 1:1 mixture of regioisomers 886, 887 is obtained in the Boc protection of 885 .

261

262

Imidazoles

Scheme 214

Scheme 215

Imidazoles

Diazonium salts of imidazoles have been discussed in CHEC-II(1996) . Recent examples of Sandmeyer reactions include conversion of amine 888 into iodide 889 and conversion of 890 to 891 (Scheme 216) .

Scheme 216

The reaction of 4-nitroimidazoles 892 with nucleophiles involves initial addition 893 and formation of nitroso 894 that can lead to ring transformations. For example, reaction of 4-amino-1,2,4-triazole and 892 under basic conditions results in the formation of oxadiazole 895 or isourea 896, depending on the substitution pattern of 892. Oxime 897 is isolated in the reaction between phenylacetonitrile and 892 (Scheme 217) .

Scheme 217

In a study of the synthesis of marine 2-aminoimidazole alkaloids, the aminal C–N bond of bicyclic 898 was cleaved regioselectively to form the allylic amine 899. Deuterium exchange results in H-1, H-2, and H-5, but not H-7 exchange, although the C(6)–C(7) double bond underwent isomerization 901. This is atributed to the assistance of the carbamoyl group that formed the oxazoline 900. Hydrolysis of the carbamate group of 899 under basic conditions affords either pyrrole 902 or pyridine 903 (Scheme 218) .

263

264

Imidazoles

Scheme 218

4.02.7.7 Oxygen-Linked Substituents In the bicyclic imidazo[2,1-b]oxazole 904, acid-mediated ether bond cleavage occurs selectively at the oxazole carbon to give either sulfide 905 or iodide 906 . Substitution of an enol phosphate 907 with an iodine function is achieved with NaI in the presence of HI generated in situ (908, Ar ¼ 3,5-dichlorophenyl) (Scheme 219) .

Scheme 219

When a-protons are present in the side-chain of the substituted aminal function of imidazolines such as 909, isomerizations become easy under acidic conditions, leading to rearrangement products 910 through a sequence of dehydration, isomerization, and solvolysis (Scheme 220) .

Imidazoles

Scheme 220

The carbonyl group in 1-methyl-3-trimethylsilylparabanic acid 911 is activated, relative to the nonsilylated parent, to undergo addition of primary amines readily. For example, addition of naamine C 912 affords pyronaamidine 913 in good yield (Scheme 221) .

Scheme 221

4.02.7.8 Sulfur-Linked Substituents In the presence of BF3, imidazolidine-2-thione reacts with 2-phenyloxirane at the nitrogen to give 1,3-bis[(E)-2phenylethen-1-yl]imidazolidine-2-thione (Section 4.02.6.3.3). However, in the presence of SiO2, 1,3-dimethylimidazolidine-2-thione 914 reacts with the oxiranes 915 and 918 to give the 1,3-dimethylimidazolidin-2-one 916 and thiiranes 917 and 919. This S-transfer reaction is highly stereoselective: in the case of (R)-918, the corresponding thiirane 919 is formed with complete inversion at the chiral center (Scheme 222) .

Scheme 222

265

266

Imidazoles

Imidazole-2-thiones 920 reacts with a-chlorosulfanyl chloride 921 (n ¼ 0) or a-chlorodisulfanyl chloride (n ¼ 1) to form di- or trisulfanes 922. Owing to the unfavorable strains introduced by having an sp2 center in a four-membered ring, these chlorosulfanes are stable to purification and characterization by NMR and X-ray analyses (Scheme 223). .

Scheme 223

5-Methyl-2-mercaptobenzimidazole 923 is oxidized with ozone to afford mainly sulfonic acid 924 at low temperature (Table 12, entry 1). The formation of desulfurized product 924 is most likely a result of partial oxidation, followed by intermolecular reduction by 923. At higher temperatures and in the presence of nucleophiles, substitution of the sulfonic acid group takes place . 2-Mercaptoimidazoline reacts similarly under these conditions.

Table 12 Ozonolysis of 923 Entry

Method

Products 924

Yield (%)

1 2 3 4 5 6 7

A (C) A (C) B D, NH3 D, MeNH2 D, Et2NH D, Piperidine

a b c d e f g

86 (77) 11 (15) 67 63 79 71 88

Method A: DCM, 25 C; method B: DCM/MeOH (1:1 v/v), 25 C; method C: DCM/MeOH (1:1 v/v), 0 C; method D: DCM, amine (1.8 equiv/mol), 25 C.

Imidazoline-2-thiones are oxidized with H2O2 (mediated by Na2MoO4-2H2O) to the corresponding sulfonic acid reproducibly, provided the internal temperature is kept at approximately 4 C . Oxidation of 1,3-dihydroimidazole-2-thiones 925 with hydrogen peroxide in an acidic medium affords 1H-imidazole-2-sulfinic acids 926 as the major products and the desulfurized imidazoles 927 as the minor products (Scheme 224). In a neutral medium in ethanol the desulfurized imidazoles 927 are the major products and the ethyl esters of 1H-imidazole-2-sulfinic acids 928a–d are the minor products . Oxidative dethionation of 1-benzylimidazole-2-thiones 929 with hydrogen peroxide affords 930, R ¼ CN, NO2, Br, OMe, H cleanly in HOAc .

Imidazoles

Scheme 224

In the context of natural product synthesis, sulfide 931 was oxidized with Stang’s reagent to a Pummerer intermediate that underwent sequential cyclizations to the tetracyclic product 932 (Scheme 225). The latter was further transformed into the sponge metabolite dibromophakellstatin 933 under oxidative hydrolysis conditions .

Scheme 225

4,5-Diphenyl-2-mercaptoimidazole 934 reacts with ketones, in HOAc and in the presence of small amount of H2SO4 (conc.), to afford the sulfide 935 which, upon treatment with Ac2O, forms 5,6-diphenylimidazo[2,1-b]thiazole 936 (Scheme 226). It has been proposed that disulfide 937 is formed in the ‘acidified’ acetic acid, which then undergoes thiolation on the enol form of the ketone. Overall, this sequence bypasses the preparation of a-haloketones for the synthesis of 935. The reaction has rather general scope as exemplified in the Table shown in Scheme 226 . Like 2-haloimidazoles, direct displacement of 2-sulfanyl or even 2-sulfonyl imidazoles with external nucleophiles is generally a slow process. In contrast, intramolecular ipso-substitution of 2-sulfonylimidazoles 938 (Scheme 227) is an effective reaction for the synthesis of 2,3-dihydroimidazo[2,1-b][1,3]oxazoles 939, R ¼ Ph, 4-ClC6H4; R ¼ Me, Ph) .

267

268

Imidazoles

Scheme 226

Scheme 227

Reduction of imidazole thiones 940 with Na/K in THF leads to carbenes 941 (Scheme 228) . Under similar conditions, imidazoline 943 is formed from 942 . The carbene 944 can be obtained if the reaction is conducted in toluene. The intermediacy of a carbene has been proposed for the reaction of 4,4,5,5tetramethylimidazolidine-2-thione and ()-valine in the presence of C60 fullerene that leads to the formation of an open [5,6] adduct .

Scheme 228

Imidazoles

Displacements of an imidazoline 2-methylthio function by arylamines 946, 948 are generally accomplished by either reacting 1-acyl-2-thioether 945 under acidic conditions giving 947 or displacing the sulfonic acid group 949 which is easily formed under careful oxidation conditions (H2O2, Na2MoO4-H2O, NaCl, 10 to 5 C) 950 (Scheme 229) .

Scheme 229

4.02.7.9 Halogen Atoms Direct displacement reactions of 2-bromoimidazoles with nucleophiles are very difficult. For example, 1-methyl2,4,5-tribromoimidazole fails to react with NaOMe . However, intramolecular ipso substitution reactions such as during the synthesis of 2,3-dihydroimidazo[2,1-b][1,3]oxazoles 952 (Scheme 230) via 951 work well .

Scheme 230

2-Haloimidazolidines are commonly generated in situ for the preparation of heteroatom-substitutions at the 2-position. Recent examples include the synthesis of a potent a-adrenergic antagonist 953 (Scheme 231) and a modified dechloroamination procedure using dimethyl chlorophosphate giving 954 . The reaction between heteroaromatic N-oxides and 2-chloro-4,5-dihydroimidazole 955 results in a formal ureidation of the heteroaryls. This reaction was extended to 2- and 4-picoline N-oxides for the synthesis of 956 and 957, respectively (Scheme 232) . The 2-bromine of nitronyl nitroxide 958 is easily displaced with sodium azolides to give spin-labeled azoles (imidazole, pyrazole, triazole) 959 which are prone to hydrolysis to hydroxamide acid anion 960 . Anions derived from halogenated imidazoles are frequently utilized in the formation of C-heteroatom bonds. Bromolithium exchange of 961 (Scheme 233) followed by azidation 962 and reduction leads to 2-aminoimidazole 963 (PMB ¼ p-methoxybenzyl) . The Mg-imidazolide intermediate from I/Mg exchange of 964, PBB ¼ p-bromobenzyl) reacts with sulfur dioxide for the synthesis of sulfonamide 965 .

269

270

Imidazoles

Scheme 231

Scheme 232

Scheme 233

Imidazoles

Halogenated imidazoles are commonly used in Stille, Heck 966 to 967 (Scheme 234), Sonogashira 968 to 969, and Suzuki reactions with high regioselectivities 970 to 971, 972 .

Scheme 234

Early studies of metal–halogen exchange reactions were discussed in CHEC-II(1996). Since then, a number of new methodologies have emerged . Sequential halogen–magnesium exchange reactions of 2,4,5-tribromoimidazole 973 occur regioselectively to give the di- and mono-bromides 974 and 975 in good yields. Earlier studies seem to suggest that chelation through the protecting group at N-1 led to the observed selectivity (Scheme 235) . However, iodine at the 5-position 976 can be exchanged for MgX and subsequently reacted with electrophiles (including Hþ) to give 977 regardless of the nature of the N-1 protecting groups (MOM, SO2NMe2, SEM, Bn, Me) 978. When the 2-position of the imidazole is nonsubstituted, the nature of the N-1 protecting group and the solvent during the halogen exchange reaction can have noticeable effect on the C-5/C-4 ! C-2 anion isomerization . Selective I–Mg exchange of diiodide 979 followed by Pd-catalyzed phosphonylation resulted in the synthesis of (D)manno- or gluco-tetrahydroimidazopyridine-2-phosphonates 979 to 980 . 2-Substituted 4,5-diiodoimidazoles are converted into the corresponding 4,5-dimagnesioimidazoles upon treatment with i-PrMgCl (2.4 equiv) in THF at 0–5 C. There are no synthetically useful differences in reactivity between the two carbanions. It is found that the dilithioimidazoles are rather difficult to form under lithium exchange conditions .

4.02.7.10 Metals and Metalloid-Linked Substituents Stille reactions of imidazolyl stannanes such as 981 with 2-bromocinnamyl aldehyde occur in the presence of Ag2O as a promoter (Scheme 236) . An in situ generated stannane from 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 982 reacted with a heterocyclic iodide under standard Stille conditions to give 983 . An anomalous Stille reaction of 5-stannylimidazole 984 with 3-iodoindole has been reported to give both the ipso-985 and the cine-986 substituted products .

271

272

Imidazoles

Scheme 235

Scheme 236

Imidazoles

Imidazolyl-zinc reagent 987 added to a chiral ketoester with high diasteroselectivity (>10:1) to give 988 (Scheme 237) .

Scheme 237

4.02.8 Reactivity of Substituents Attached to Ring Heteroatoms 4.02.8.1 Aryl Groups Directed metallation at the ortho position of the N-phenyl imidazoles 989 during lithiation at imidazole C-2 in the presence of excess BuLi and TMEDA results in the formation of a dianion which was captured as the bis diphenylphosphine 990 or 991 . The traditional Pictet–Spengler reaction has been extended to arylamines linked to the N-1 position of substituted imidazoles. Thus, polymer-supported 2-imidazol-1-yl aniline 992 was converted into imidazoquinoxaline 993 under mild conditions (Scheme 238) . The homolog triazabenzoazulene 994 was prepared in a similar way .

Scheme 238

4.02.8.2 Alkyl Groups N-Methylimidazole is efficiently N-demethylated when it is passed through layers of H2O2, sodium salt of 4,6dichloro-2-hydroxy-[1,3,5]triazine, and then basic alumina in a column .

273

274

Imidazoles

Intramolecular cycloaddition of nitrones 996, derived from aldehydes 995, to the N-tethered olefin leads to the formation of two regioisomers, 997 and 998. The product distribution depends on the nature of the substituent (R) (Scheme 239) .

Scheme 239

Aldehydes react with imidazole and TBDMSCl to form a rather stable aminal 999 that can be deprotected with HF in MeCN (Scheme 240) . O-tert-Butyldimethylsilylimidazolyl aminals 1000 react with 2 equiv of organolithium reagents (R9 ¼ Me, n-Bu, Ph, Ar, t-Bu) as if to the parent aldehydes to give the alcohols 1003. The reaction probably proceeds via the 2-lithioimidazole intermediate 1001, which undergoes a ‘retro-Brook’ rearrangement (to 1002) to generate the aldehyde. In fact, with 1 equiv of R9Li only the aldehyde RCHO is isolated. Blocking the 2-position of the imidazole results in complete resistance toward R9Li .

Scheme 240

The CH2 group of o-imidazol-1-yl)acetophenone 1004 is sufficiently activated by the carbonyl and the imidazole group that it readily reacts with aldehydes, aromatic diazonium salts (to form diazo compounds) and acrylonitrile. The reaction of 1004 with phenyl isothiocyanate in the presenceof KOH results in the formation of adduct 1005 that is not isolated but further condensed with phenacyl bromide to afford thienylimidazole 1006 in 87% yield (Scheme 241) . In the presence of a 2-sulfanyl group 1007, the enolate of a-imidazolyl acetophenone 1008 no longer reacts with aldehydes or even alkyl halides except for MeI 1009 . 1-(o-Bromoalkyl) imidazole-4-aldehydes 1010 undergo intramolecular oxidative radical cyclization to give the [1,2-c]fused imidazole 1011 in moderate yields (Scheme 242). This cyclization is highly regiospecific for [1,2-c] (vs. [1,2-a]) formation. When such a mode of cyclization is blocked as in 1010, only reduction of bromide is operative 1012, suggesting that nucleophilic addition of the alkyl radical is the rate-limiting step. However, when imidazole-2aldehyde 1010 is subjected to the reaction, deformylation product 1013 is isolated . This result suggests that pathways involving the formation of a C-2 radical are competing against oxidative cyclizations.

Imidazoles

Scheme 241

Scheme 242

Formation of [1,2-a]-fused imidazoles 1015, 1017 is achieved through having sulfur substituents at the 2-position as, for example, in 1014, 1016 that serve as radical leaving groups (Scheme 243) . Alternatively, xanthate 1018 undergoes regioselective radical cyclization in the presence of a stoichiometric amount of CSA to promote formation of the [1,2-a]-fused product 1019 . 2-Alkyl-1-bromodifluoromethylimidazoles 1020 react with aryl aldehydes in the presence of tetrakis(dimethylamino)ethene as the reducing agent to give 2-alkyl-1-(29-aryl-19,19-difluoro-29-hydroxyethyl)imidazoles 1021 (Scheme 244) . A more efficient generation of a heteroaryl-N-difluoromethyl anion is based on heteroaryl-N-difluoromethyltrimethylsilanes such as 1023, readily prepared from bromide 1022. In the presence of Me4NF, 1023 reacts with aldehydes or ketones (the latter require stoichiometric Me4NF) to give 1024 or 1025 in high yields . (1-Imidazolyl)methyl benzotriazole or 5-phenyltetrazoles 1026 are double-alkylated to give the heteroaminals 1027 which, under basic conditions, undergo elimination to give N-cycloalkenylimidazoles 1028 (Scheme 245) .

275

276

Imidazoles

Scheme 243

Scheme 244

Scheme 245

Imidazoles

4.02.8.3 Alkenyl Groups As a potentially useful protecting group, the vinyl group in N-vinylimidazoles 1029, R ¼ H, SMe, CH(OH)Me, CH2OH, CHO) is readily cleaved with ozone in the presence of Me2S (Scheme 246) . N-Vinylnitroimidazoles are reasonably reactive toward 1,3-dipoles for the construction of potential nucleoside precursors. For example, 4-nitro-1-vinyl imidazole 1030 reacts with THP-OCH2CNO generated in situ to give 1031 in good yield after deprotection .

Scheme 246

Radical addition of xanthate to alkenylimidazoles 1032 in anhydrous acidic medium (to ‘neutralize’ the basicity of the heteroatoms) yields 1033 that can be further functionalized into more complex structures (Scheme 247) .

Scheme 247

Thermolysis of azaene-diyne, 2-ethynyl-1-phenylethynylimidazole, in neat 1,4-cyclohexadiene leads to the formation of cyclopentapyrazine 1034 and the related cyclopropane 1035. In chlorobenzene, the reaction gives rise to imidazo[1,2-a]pyridine 1036. These results contrast with traditional enediyne rearrangements in that other reaction pathways after the Bergman rearrangement are operating in the case of aza-enediynes (Scheme 248) .

Scheme 248

277

278

Imidazoles

Chiral imidazolidinone organocatalysts such as 1037 form iminium intermediates 1038 with enals that participate in a variety of directed enantioselective organic reactions including Diels–Alder, 1,3-dipolar cycloadditions, and Friedel–Crafts alkylations. Conjugate additions such as (hydrido)a-fluorinations/a-chlorinations and intramolecular Michael additions as well as epoxidations, transfer hydrogenations, and organo-cascade reactions of nonsubstituted aldehydes in the presence of 1037 are highly efficient processes (Scheme 249) . (4R,5R)-4,5Diphenylimidazolidine catalyzes enantioselective a-chlorination of ketones .

Scheme 249

4.02.8.4 Acyl and Aroyl Groups Imidazole and benzimidazole esters are quite reactive towards lithium enolates of ketones. Kinetic studies show that the reaction involves primarily monomers of the enolates . This is in contrast to reactions of aryl esters where both monomers and aggregates of the enolates participate in the reaction. Although (thio)carbonylimidazole esters are normally formed between alcohols and 1,19-carbonyldiimidazole or 1,19-(thiocarbonyl)diimidazole 1039, transfer of the imidazole group has been reported in reactions with activated alcohols to give, for example, 1040 (Scheme 250) .

Scheme 250

Di(imidazol-1-yl)methanimine 1041 behaves like cyanogen halides in that both can serve as a nitrile cation equivalents. However, 1041 is a solid and reacts with nucleophiles with high chemoselectivity. Thus, dinucleophiles react with 1041 in refluxing THF to give heterocycles 1042–1046 (Table 13) . Sequential treatment of 1041 or 1047 with two different amines affords guanidines 1049 via the intermediate 1048 (Scheme 251) . Table 13 Dinucleophiles and the products from reactions with 1041

1042, 28–94%

1043, 34%

1044, 61%

1045, 83%

1046, 47%

Imidazoles

Scheme 251

Carbamoylimidazolium salts 1050 are versatile electrophiles that react with amines, alcohols, phenols, or thiols to give the corresponding ureas (Scheme 252) , carbamates or thiocarbamates 1051 . Furthermore, salts 1050 react with carboxylic acids in the presence of amines to afford amides 1052, including Weinreb amides .

Scheme 252

Imidazole carboxylic esters of secondary or tertiary alcohols, such as 1053 and 1054, , form carbonates exclusively with primary alcohols (Scheme 253). Thus, 1054 is a useful reagent for the BOC-protection of primary hydroxyl groups . In some cases, 1054 offers better selectivity than pivaloyl chloride in the protection of carbohydrates . Similarly, 1-(methyldithiocarbonyl)imidazole 1055 and its methyl triflate salt convert alcohols to S-methyldithiocarbonates and amines to S-methyldithiocarbamates or thioureas .

Scheme 253

Deprotection of the N-alloc group of 3-imidazoline 1056 with Pd(PPh3)4 catalyst gives cleanly the desired product 1075 if a basic allyl acceptor is used. In contrast, a mixture of 1057 and 1058 is formed when the acidic allyl acceptor dimedone is used (Scheme 254) .

Scheme 254

279

280

Imidazoles

4.02.8.5 Nitrogen Functions N-Aminoimidazole 1059 reacts with 2-ethoxybenzoyl chloride to give imidazo[5,1-f ][1,2,4]triazinone 1060, which is the precursor to the PDE5 inhibitor vardenafil (Levitra) (Scheme 255) .

Scheme 255

4.02.8.6 Silicon, Phosphorus, and Related Groups Tris- and tetrakis(imidazol-1-yl)silanes are effective dehydrating reagents for the formation of carboxylic acid derivatives via 1-acylimidazole intermediates .

4.02.8.7 Sulfur Groups N-Sulfonyl protecting groups on imidazoles (Scheme 256) are readily cleaved with thiols. For example, the dilithium salt of thioglycolic acid in DMF removes the tosyl group of 1061 to 2-phenylimidazole in 88% yield at rt in 2.5 h . 2-Nitrobenzensulfonamide 1062 reacts with perfluorinated thiol (C8F17C2H4SH) to release imidazole in 76% yield after solid-phase extraction through perfluorinated silica .

Scheme 256

4.02.8.8 Oxygen Groups Like other heterocyclic N-oxides, imidazole 3-oxides 1063 react with Ac2O to give the corresponding imidazolones 1064 and 1065 (Scheme 257). TMSCN transforms 1063 into imidazole 2-carbonitriles 1066, whereas alkyl thiones convert 1063 to 1067 . The 2-aminoimidazoles 1068, formed from the reactions with either isocyanate or isothiocyanate, react further with isocyanates to form ureas but are inert toward thiourea formation. In contrast to nonaromatic imidazole N-oxides (nitrones), oxides 1063 react with DMAD to form butanedioates 1069, rather than the (putative) [3þ2] adduct . Nitronyl nitroxide 1070 is reduced in the presence of thiourea to imino nitroxide 1071, which is further reduced to 2-imidazoline N-oxide 1072 in high yields (Scheme 258) . N-Hydroxyimidazoles are normally converted into the corresponding imidazoles by reductive N–O cleavage with TiCl3 . N–O Cleavage of imidazo[1,2-b]isoxazolidine 1073 can be effected using Raney nickel to afford pyrrolo[1,2-b]imidazolidine 1074 (Scheme 259) . Thermal conversion of 1075 into 1076 has been reported at high temperatures such as are achieved by microwave irradiation .

Imidazoles

Scheme 257

Scheme 258

Scheme 259

4.02.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component 4.02.9.1 Formation of One Bond 4.02.9.1.1

Formation of the 1,2- (or 2,3-) bond

This classification is illustrated in Scheme 260. Formation of the 1,2- (or 2,3-) bond via the activation of an amide or urea group is a versatile method to synthesize imidazoles. Many reagents, such as PPh3-CCl4, PCl5, or acids, etc., have been used for the cyclization process.

281

282

Imidazoles

Scheme 260

Treatment of N-acylated a-aminonitriles 1077 with PPh3 and a carbon tetrahalide affords 2,4-disubstituted 5-halo1H-imidazoles 1078 in good yields. A variety of alkyl and aryl substituents (R1 and R2) are tolerated. A possible mechanism involves the formation of a novel seven-membered ring intermediate and then elimination of triphenylphosphine oxide, as illustrated in Scheme 261 .

Scheme 261

Dipeptides 1079 composed of a C-terminal b-amino a-acid residue undergo cyclization to give imidazolines 1080 in the presence of Ph3PO/Tf2O. The reaction is mediated by bis(triphenyl)oxodiphosphonium trifluoromethansulfonate and includes nucleophilic attack of the tosylamino group on the phosphonium-activated amide carbonyl group. The imidazolines 1080 are obtained in moderate to very good yields, and with excellent enantioselectivity at both chiral centers (Scheme 262) . The method is also utilized to the synthesis of imidazole-containing peptides on solid support . A method to synthesize substituted imidazoles starts from 1,2-aminoalcohols 1081 via a four-step procedure, as demonstrated in Scheme 263. Oxidation of acylated alcohol 1082 leads to a ketone 1083, which is transformed into imine 1084. Activation of the amide bond with dehydrating agent PCl5 leads to intramolecular cyclization, providing

Imidazoles

imidazoles 1085 (Scheme 263) . Similarly, the acylated 1,2-aminoalcohols 1086 are converted into a-amino amides 1087, which undergo cyclization to yield imidazolines 1088 under basic conditions. Oxidation of 1088 with MnO2 in toluene leads to imidazoles 1089 .

Scheme 262

Scheme 263

283

284

Imidazoles

In contrast to the process described in Scheme 261, N-acylated aminonitriles can cyclize to afford imidazoles via three multi-step procedures. The key intermediate is 2-(pentanoyl)amino-3-methylthioprop-2-enoate derivative 1091, which is obtained by the addition of methyl mercaptan to N-acylated a-aminonitrile 1090. Treatment of compound 1091 with PCl5/DMAP at low temperature promotes an intramolecular cyclization, yielding 1,2,4,5-tetrasubstituted imidazole 1092. The cyclization also proceeds in moderate yields by a two-step procedure via the corresponding thioamide intermediate prepared using Lawesson’s reagent. Alternatively, the intramolecular cyclization is achieved in good yields using H2SO4 in DME at ambient temperature (Scheme 264) .

Scheme 264

Activation of amide bonds with an acid (usually at elevated temperatures) to facilitate the 1,2- (or 2,3-) bond formation is a useful method to prepare imidazoles and benzimidazoles (see Section 4.02.9.2(i)). For example, b-ketoester 1093 possessing a diamino acid (diaminobutanoic acid or ornithine) group is activated by AcOH to form bicyclic imidazole 1094 . A library of imidazolines, exemplified in Scheme 265, was prepared from Ugi products under acidic conditions . Urea 1095 undergoes a cyclodehydration process in the presence of Ph3P-CCl4/Et3N to give 2-aminoimidazolones 1096, presumably through a transient carbodiimide that cyclizes spontaneously . Thiourea 1115 is more reactive than urea 1097 and can transform to imidazolone 1098 with the aid of EDC (Scheme 266) . A widely applicable method to synthesize benzimidazoles starts from acylated or thioacylated o-phenylenediamine intermediates (see CHEC-II(1996)). Acids, either Brønsted or Lewis acids, are exclusively used for the amide bond activation. For example, the cyclodehydration of N-acyl-1,2-phenylenediamines (1099, 1101, catalyzed by HOAc or BF3?OEt2) provides benzimidazoles (1100, 1102) in excellent yields . N,N9-Diacyl 1,2phenylenediamines 1103 also cyclize to give benzimidazoles 1104 under acidic condition . Thioamides such as 1105 are routinely activated by HgCl2 or HgO to give 2-aminobenzoimidazoles 1106 . N-(2Aminoaryl)thioureas 1107 undergo CuCl-promoted intramolecular cyclization to give the corresponding 2-(N-substituted amino)benzimidazoles 1108 in good to excellent yields (Scheme 267) . Imines 1110 derived from trifluoromethyl aryl ketones and ortho-phenylenediamines 1109 undergo intramolecular cyclization to afford 2-arylbenzimidazoles 1111. The reaction is carried out under basic conditions and the CF3 group serves as a leaving group (Scheme 268) .

Imidazoles

Scheme 265

Scheme 266

285

286

Imidazoles

Scheme 267

Scheme 268

1,2-Diaminomaleonitrile derivatives 1112 are useful synthons for the synthesis of imidazoles (see CHEC(1984) and CHEC-II(1996)). For example, imidazolone 1115 is obtained from the reaction of 1,2-diaminomaleonitrile with isocyanate 1113 via the intermediate N-[(Z)-2-amino-1,2-dicycanovinylcarbamoyl]-p-toluenesulfonamide 1114 (Scheme 269) .

Imidazoles

Scheme 269

a-Cyano-a-isocyanoalkanoates (1116, R1 ¼ Me, Et, PhCH2, R2 ¼ t-Bu; or R1 ¼ PhCH2, R2 ¼ Et) react with alkoxides to give 4-alkoxy-5-alkyl-1H-imidazoles 1117. When compound 1116 reacts with thiolates, 4H-imidazole-4carboxylates 1118 are the major product. The by-product 1119 is formed via thiolate addition to the isocyanide group (Scheme 270) .

Scheme 270

-Amino esters 1121 and 1123, obtained by 1,4-addition of sarcosine or glycine ethyl ester to conjugated azoalkenes 1120, cyclize to yield 4-methoxycarbonyl-5-methyl-1-ureidoimidazole 1122 and 1-ureido5-methyl-4-imidazoline 1124, respectively, in the presence of copper salts (Scheme 271) . Resin-supported a-bromoacetic acid 1125 undergoes amine displacement, urea formation, and intramolecular cyclization to afford 3-aminohydantoins 1126. A diverse set of 3-aminohydantoins with different substituents at the 1-position was readily prepared (Scheme 272) .

4.02.9.1.2

Formation of the 1,5- (or 3,4-) bond

This classification is illustrated in Scheme 273. As described in CHEC(1984) and CHEC-II(1996), N-substituted amidines, guanidines, ureas, and related structures are used extensively as starting materials for the synthesis of imidazoles or benzimidazoles in this category of imidazole ring formation. The other participating functional group is often either a ketone/aldehyde or an acetal. The cyclization step is usually carried out under acidic conditions . Thus, 1-aryl-2-aminoimidazoles 1128 are obtained from an acid-catalyzed reaction of guanidine acetals 1127 and 2-[(methylamino)methyl]-4,5,6,7-tetrahydro1H-benzimidazole 1130 from an amidine acetal 1129 (Scheme 274) .

287

288

Imidazoles

Scheme 271

Scheme 272

Scheme 273

Alkylation of amidine 1131 with 1-bromo-2-methoxy-2-propene affords regiospecifically N-alkylated product 1132. Treatment of 1132 with pyridinium p-toluenesulfonate in aqueous THF provides imidazole 1133 in good yield. In this reaction, 1-bromo-2-methoxy-2-propene is used as a protected form of a-bromoacetone, which itself leads to poor yields when reacted directly with amidines (Scheme 275) . Reduction of N-(aminocarbonyl)-a-amino esters 1134 and N-(aminothiocarbonyl)-a-amino esters 1135 with DIBALH affords 4-hydroxyimidazolidin-2-ones 1136 and 4-hydroxyimidazolidine-2-thiones 1137, respectively. These substances eliminate a water molecule upon acidic work-up to give imidazol-2-ones 1138 and imidazole-2thiones 1139 (Scheme 276) .

Imidazoles

Scheme 274

Scheme 275

Scheme 276

a-Diazo-b-ketoesters 1140 undergo N–H insertion with primary ureas 1141 in the presence of dirhodium tetraoctanoate to yield a-ureido-b-ketoesters 1142. These ureas 1142 cyclize in the presence of TFA to provide imidazolones 1143 in 72–85% yields. This chemistry is readily translated onto insoluble polymer resins and was utilized to prepare a small array of imidazolones (Scheme 277) . Reaction of diazenes 1144 with 1,3-keto-amides 1145 leads to 2-imidazolin-2-ones 1147 via a two-step procedure. The first step involves a regioselective attack of the active methylene group on the diazene to yield Michael adduct 1146. The adduct 1146 then undergoes an acid-catalyzed cyclodehydration to form imidazolin-2-one 1147 (Scheme 278) .

289

290

Imidazoles

Scheme 277

Scheme 278

A protocol involving the intermolecular cyclization between acetals and ureas has been developed to synthesize imidazolones on solid support. Reaction of polymer-bound glycerol 1148 with bromoacetaldehyde diethyl acetal gives the cyclic acetal bromide 1149. Amination followed by urea formation affords the resin-bound urea acetals 1150. The aldehydes released from the resin upon treatment with TFA immediately cyclize to give 2-imidazolones 1151 in good yields and purity (Scheme 279) .

Scheme 279

Imidazoles

A similar strategy for the preparation of substituted imidazolidin-2-ones in two steps from readily available N-allylamines has been developed. Addition of amines 1152 to isocyanates affords N-allylureas 1153, which are converted to imidazolidin-2-one 1154 with the formation of two bonds and up to two stereocenters when treated with aryl bromides and catalytic amounts of Pd2(dba)3/Xantphos in the presence of NaOt-Bu. Based on the stereochemical and regiochemical outcomes, a mechanism for the transformation has been proposed, as illustrated in Scheme 280 .

Scheme 280

Oxidative C–H amination of N-trichloroethoxysulfonyl-protected ureas (1155, R1 ¼ H, R1 ¼ Et, H2CTCH, Ph; R ¼ Me, R1 ¼ Me, Et, etc.), and guanidines (1157, R ¼ H, R1 ¼ n-Pr, Ph; R ¼ Me, R1 ¼ Me, Et, etc.), to 2-imidazolidinones, 1156, and 2-imino-1,3-imidazolidines, 1158, respectively, has been demonstrated to proceed in high yields for tertiary and benzylic substrates. The success of these reactions is predicated on the choice of the electronwithdrawing 2,2,2-trichloroethoxysulfonyl (Tces) protecting group, the commercial catalyst Rh2(esp)2 [dirhodium bis(,,9,9-tetramethyl-1,3-benzenedipropionate)] (1–2 mol%), and toluene as solvent (Scheme 281) . Transition metal-catalyzed cyclization of (o-bromoaryl)guanidines 1159 generates substituted 2-aminobenzimidazoles 1160. Either copper or palladium complexes have been used, although inexpensive copper salts such as CuI are generally superior to palladium catalysts. Regioselective cyclizations, where R3 ¼ H, are achieved under CuI/1,10phenanthroline conditions. Cyclization of the guanidine occurs preferentially from the less sterically encumbered NH site, and from an NH-aryl rather than NH-alkyl group . This procedure is readily transferable onto the polymer resins . A similar process for 2-substituted benzimidazoles 1162 via the palladium-catalyzed intramolecular N-arylation from (o-bromophenyl)amidine precursors 1161 has also been developed (Scheme 282) .

291

292

Imidazoles

Scheme 281

Scheme 282

Transition metal-catalyzed intramolecular cyclization has also been applied to the formation of imidazoles. Palladium-mediated amino Heck reactions of O-pentafluorobenzoylamidoximes 1163 afford 1-benzyl-4-methylimidazoles 1164 with a range of substituents at the 2-position. This method is particularly suitable for the preparation of imidazoles with a chiral substituent at the 2-position (Scheme 283) . Amidinyl radicals 1166 are readily generated from amidoxime benzoates, for example, 1165, by treatment with a stannane-diazo initiator or with Ni-AcOH and captured by an internal olefin to give the corresponding imidazoline 1167. Interestingly, the use of allyl tri-n-butylstannane in the case of substrate 1168 results in the clean formation of allyl imidazoline 1169. As expected, allylation occurs from the least hindered exo face to give the isomer shown (Scheme 284) (ACCN ¼ 1,19-azobis(cyclohexanecarbonitrile)). Amidines 1170 substituted with electron-rich aromatic rings undergo an oxidative intramolecular cyclization process to give N-substituted benzimidazoles 1172. The reaction proceeds well in MeCN with CAN or electrochemical oxidation and probably involves the cationic intermediate 1171 (Scheme 285) .

Imidazoles

Scheme 283

Scheme 284

Scheme 285

Heating 1-aryl-2-acyl-2-cyanohydrazines 1173 in Ph2O yields 2-aminoacylbenzimidazoles 1174 in poor to excellent yields depending on the nature of the aromatic substituents. A hetero-Cope rearrangement results in the cleavage of N–N bond. Strongly electron-deficient aromatic rings (e.g., structures with R1 ¼ 4-NO2) are poor substrates for this reaction (Scheme 286) .

293

294

Imidazoles

Scheme 286

Enantiopure 1,4-disubstituted 2-imidazolines 1179 can be prepared from chiral b-amino alcohols 1175. The acylated alcohols, N-hydroxyethylamides 1176, are reacted with excess thionyl chloride (or with thionyl chloride followed by phosphorus pentachloride) to yield N-chloroethylimidoyl chlorides 1177. Treatment of 1177 with amines or anilines produces N-chloroamidines 1178, which were converted into imidazolines 1179 upon work-up with aqueous hydroxide (Scheme 287) .

Scheme 287

4.02.9.1.3

Formation of the 4,5-bond

This classification is illustrated in Scheme 288. The synthesis of benzimidazoles via the formation of the 4,5-bond is an uneconomical process because it requires the formation of a benzene ring from a macrocyclic precursor. On the other hand, examples of imidazoline and imidazole formation under this category are known. One reaction, useful to prepare cis-diamines via cis-imidazolines, has been investigated extensively. The process starts with ammonium hydroxide reacting with aromatic aldehydes 1180 to form 2,4-diazapentadienes 1181. Deprotonation of 2,4-diazapentadienes 1181 with a strong base (PhLi) or under thermal conditions results in formation of the transient 2,4diazapentadienyl anion that cyclizes in a disrotatory fashion to furnish cis-imidazolines 1182 (Scheme 289) . This simple, stereocontrolled and economical synthesis of ()-cis-2,4,5-triarylimidazoline can be carried out with diverse forms of NH3, such as silica-supported ammonium hydrogen carbonate, alumina-ammonium acetate, and HMDS in the presence of alumina. Microwave irradiation facilitates the ring-closure process .

Scheme 288

Imidazoles

Scheme 289

Electrocyclization is the key step in a route to 4H-imidazoles 1187 and imidazoles 1188. Thus, activation of N-acylamidines 1183 with trifluoromethanesulfonic anhydride and subsequent condensation with amino compounds 1185 produces 1-amino-2,4-diazapenta-1,3-dienes 1186. Deprotonation of 1186 by the use of strong organic bases yields the corresponding 4H-imidazoles 1187 or imidazoles 1188 after amine elimination through an anionic 1,5electrocyclization reaction. For the cyclization to occur, the amino compound 1185 needs to possess electronwithdrawing substituents such as alkoxycarbonyl or fluorenyl groups (Scheme 290) .

Scheme 290

4.02.9.2 Formation of Two Bonds 4.02.9.2.1

From [4þ1] carbon fragments

4.02.9.2.1(i) Formation of the 1,2- and 1,5-bonds This classification is illustrated in Scheme 291. By definition, imidazole synthesis under this classification requires an amine or its derivatives as one of the starting materials. Enamines, imines, and isonitriles have been used as the other reactants. Thus, reaction of primary amines with methyl 3-bromo-2-isocyanoacrylates 1189 leads to methyl 1,5disubstituted imidazole-4-carboxylates 1190, which can undergo decarboxylation to give 1,5-disubstituted imidazoles 1191 (Scheme 292) .

295

296

Imidazoles

Scheme 291

Scheme 292

Reaction between ethyl 3-N,N-dimethylamino-2-isocyanoacrylate 1192 and a primary amine affords 1-alkyl-4imidazolecarboxylates 1193 in good yields. The process is applicable to unhindered alkylamine substrates (R-NH2), including those containing reactive functionalities such as alcohols and secondary and tertiary amines . Solid-phase bound 3-N,N-dimethylamino-2-isocyanoacrylate 1194 undergoes the same cyclization under microwave conditions (Scheme 293) .

Scheme 293

Heteroarylamines, for example 1195, react with (dimethylamino)propenoate 1196 to yield an imidazolecarboxylate 1199. The imidazole ring is formed via the intermediate diaminoalkenoate 1197, which undergoes an intramolecular Michael addition followed by a retro-aldol-like reaction (Scheme 294) . Similarly, 4-dimethylamino-2-aza-1,3-dienes 1200, serving as g-dielectrophiles, condense with amines or hydrazines neat at 70 C to form N-substituted imidazole-4-carboxylates 1201 in 60–75% yields (Scheme 294) .

Imidazoles

Scheme 294

Cyclization of ketoamides with ammonium salts continues to be the method of choice for preparing structurally diverse imidazoles, which range from monosubstituted to 1,2,4,5-tetrasubstituted (Scheme 295) . For example, N-substituted imidazoles 1203 are obtained from the reaction of N-(2,2-dimethoxyethyl)formamides 1202 with ammonium acetate in good yields . Tetrasubstituted imidazoles 1206 are prepared from ketoamides 1205, which are derived from a-amino alcohols 1204 . Imidazole 1208 was synthesized from chiral a-amino acid-derived ketoamides 1207 without disruption of the chiral center . Notably, the synthesis of 2,4disubstituted imidazoles 1210 was achieved by condensing ketoamides 1209 with ammonium acetate under microwave irradiation . Thiazolium-catalyzed addition of aldehydes 1211 to acyl imines 1212 generates a-ketoamides 1213, which condense with amines in situ to give substituted imidazoles 1214 (Scheme 296) .

297

298

Imidazoles

Scheme 295

Scheme 296

N-Alkyl-N-( -keto)amides 1216 have been prepared using a traceless linker strategy starting from resin-bound benzylamines 1215. The ketoamides 1217 released from the resin react with an ammonium salt to afford 1,2,4trisubstituted imidazoles 1218 in good yields and high purities (Scheme 297) .

Imidazoles

Scheme 297

Replacing the carbonyl group in the ketoamides with a cyano group leads to N-acylated a-aminonitriles (see Section 4.02.9.1(i)). These compounds, such as 1219, react with ammonium acetate at high temperature to give cyclized products, imidazoline 1220 and 1H-imidazol-5(4H)-imine 1221 (Scheme 298) .

Scheme 298

a-Amino acid phenylhydrazides 1222 (R1 ¼ H, Ph, CH2SMe, etc.) react with levulinic acid 1223 providing imidazolidin-4-ones 1224, which undergo a second ring closure to afford the dihydro-1H-pyrrolo[1,2-a]imidazole2,5-diones 1225 (Scheme 299) .

4.02.9.2.1(ii) Formation of the 1,2- and 2,3-bonds This classification is illustrated in Scheme 300. The annelation of o-phenylenediamines with carboxylic acid derivatives is the most common method for the syntheses of benzimidazoles. As discussed in CHEC(1984) and CHEC-II(1996), either Brønsted or Lewis acids can be used to promote the cyclization (e.g., Scheme 301; also see Section 4.02.9.1(i)) . Carboxylic acids and their derivatives, such as acid chlorides, imidates, and phosgene iminium chloride, have been used in these reactions .

299

300

Imidazoles

Scheme 299

Scheme 300

Scheme 301

Aldehydes have been used to condense with o-phenylenediamines, o-nitroanilines, or ethylene diamines to afford benzimidazoles and imidazolines. Either an oxidation or a reduction process may be required during the annelation depending on the oxidation state of the starting material. To prepare imidazolines or benzimidazoles from aldehydes and diamines under anaerobic conditions, the system I2/KI/K2CO3/H2O can be used to oxidize a C–N single bond to a double bond (Scheme 302) . Oxidant K3Fe(CN)6 has also been used to promote similar processes

Scheme 302

Imidazoles

. Reaction of o-phenylenediamine and an aryl aldehyde in the presence of a catalytic amount of scandium triflate Sc(OTf)3 gives 2-(aryl)benzimidazoles in moderate to good yields. In this transformation, oxygen serves as the oxidant (Scheme 302) . o-Nitroanilines are convenient substrates for the synthesis of benzimidazoles since they are readily available from the corresponding o-fluoronitrobenzenes. Various reducing agents are effective in promoting the cyclization of o-nitroanilines with aldehydes. For example, heating a DMSO solution of o-nitroaniline and an aldehyde with aqueous or solid Na2S2O4 provided a series of benzimidazoles (Scheme 303) . Similarly, in situ reduction of o-nitroaniline with SnCl2 followed by cyclization with carboxylic acids under microwave irradiation generated 2-substituted benzimidazoles in high yields (Scheme 303) .

Scheme 303

The chemistry discussed above is readily transferable onto solid-phase. Many procedures are available to prepare structurally diverse benzimidazoles on solid support . Two examples are illustrated in Scheme 304 . Some special methods have been developed to prepare benzimidazoles. For example, N-alkoxy benzimidazoles 1226, 1227 can be prepared in a simple two-step process from 2-fluoro nitroaromatics. The imidazole-forming step involves tandem heterocyclization and O-alkylation with an in situ alkylating agent (Scheme 305) . Photolysis of dinitrobenzenes or nitroanilines in alcoholic solution in the presence of TiO2 leads to 2-methylbenzimidazoles 1228 in excellent yields (Scheme 306) . Reaction of 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-dienecarboxylic esters 1229 with 2-amino- or 2-aminomethylanilines 1230 produces cis-5-(benzimidazol-2-yl)pyrroline-2-acetic acid esters 1231 from a double Michael addition process. Substituents on the nitrogen atoms or in the aromatic ring are tolerated as long as they do not strongly reduce the nucleophilicity of the nitrogen atoms (Scheme 307) . 2-Substituted imidazolines are readily prepared from the condensations of 1,2-diaminoalkenes with aldehydes, carboxylic acids and their derivatives, nitriles, and 1,1-dihaloethenes, etc. Further dehydrogenation with suitable oxidants leads to the corresponding imidazoles. Some examples are illustrated in Schemes 308 and 309. Thus, pyridinium hydrobromide perbromide (PHPB) acts as an oxidant when aldehydes 1232 are used as a starting material , and AlMe3 and P2S5 serve as activating reagents when ester 1233 and nitrile 1234 are used . Nitriles are also activated by a catalytic amount of sulfur under ultrasonic or microwave irradiation to form 2-imidazolines 1235 when coupling with ethylenediamine. The advantages of this system include short reaction times, high yields and the ability to carry out reactions on a large scale . Condensation of arylhydroximoyl chlorides 1236 with ethylenediamine provides an alternative way to prepare 2-arylimidazolines (Scheme 308) . Imidates 1237 undergo cyclization with ethylene-1,2-diamines in alcoholic solution to afford 2-substituted imidazolines 1238 in good yields . Aryl-1,1-dibromoethenes 1239 react with ethylenediamine under mild condition to produce various 2-(arylmethyl)imidazolines 1240. The imidazolines could be further converted into the corresponding imidazoles by Pd-catalyzed dehydrogenation, Swern oxidation or MnO2 treatment (Scheme 309) .

301

302

Imidazoles

Scheme 304

Scheme 305

Scheme 306

Imidazoles

Scheme 307

Scheme 308

Scheme 309

303

304

Imidazoles

Optically active imidazolines are generally obtained from enantiopure 1,2-diamines. For example, chiral ferrocenylimidazolines are prepared from ferrocenyl carboxylic acid 1241 (Scheme 310). Amide 1242 is activated by O-alkylation with Et3OþBF4, generating iminium ether tetrafluoroborate salt 1243. The formation of the imidazoline ring in 1244 is accomplished by condensation of 1243 with the chiral diamine 1245 at room temperature without the need to isolate the intermediate imidate 1243 .

Scheme 310

Reaction of dimethylformamide dimethyl acetal or formamidine with chiral 1,2-diamines provides optically active imidazolines (Scheme 311). In these examples, the 2-position in the imidazolines is unsubstituted.

Scheme 311

Imidazole-2-thione 1249 can be synthesized from sterically hindered diamine 1248, which is derived from the corresponding diazide 1247 by an oxidative addition of azide to the nucleophilic carbon–carbon double bond of 1246 (Scheme 312) . Reaction of succindialdehyde, benzotriazole, and N-phenylethylenediamine provides 1-phenyl-5-(benzotriazol-1yl)hexahydro-1H-pyrrolo[1,2-a]imidazole 1250. Further reaction of compound 1250 with Grignard reagents affords 1-phenyl-5-substituted-hexahydro-1H-pyrrolo[1,2-a]imidazoles 1251 in good to excellent yields (Scheme 313) .

Imidazoles

Scheme 312

Scheme 313

The reaction of diazonium salts with aqueous solutions of 1,2-diaminocyclohexane mixed with formaldehyde affords the 1-[2-aryl-1-diazenyl]-3-({3-[2-aryl-diazenyl]perhydrobenzo[d]imidazol-1-yl}methyl)perhydrobenzo[d]imidazoles 1252 in 23-66% yields (Scheme 314) .

Scheme 314

2-Amino-3-azidoacrylates 1253 undergo aza-Wittig reactions with isocyanates to form 4-substituted 2-aminoimidazoles 1255 (Scheme 315). Presumably, the carbodiimide 1254 is the reactive intermediate that cyclizes to form the imidazole ring .

305

306

Imidazoles

Scheme 315

An unprecedented attack on an azide group by an iminium species, generated in situ under Vilsmeier conditions, furnishes a novel route to construct the imidazole ring. Thus, N-aryl-5-chloro-2-(dimethylamino)imidazole-4-carboxaldehydes 1257 were obtained from the Vilsmeier cyclization of N-aryl-2-azidoacetamides 1256. The possible mechanism for the reaction is illustrated in Scheme 316 .

Scheme 316

4.02.9.2.1(iii) Formation of the 1,5- and 4,5-bonds This classification is illustrated in Scheme 317. Imidazole synthesis under this category is uncommon, as noted in CHEC(1984) and CHEC-II(1996). One example, in which secondary amino-N-carbothioic acid (phenyl-p-tolyliminomethyl)amides 1258 react with dimethyl acetylenedicarboxylate to form 4-aminoimidazoles 1259, has been reported. A reaction mechanism including the formation of a seven-membered cyclic intermediate followed by the extrusion of thioglyoxylic ester has been proposed (Scheme 318) .

Scheme 317

Imidazoles

Scheme 318

4.02.9.2.2

From [3þ2] carbon fragments

4.02.9.2.2(i) Formation of the 1,5- and 2,3-bonds This classification is illustrated in Scheme 319. The Marckwald method has been widely used to assemble functionalized imidazoles (Scheme 319). The original procedure provided a synthetic route to 1-substituted imidazole-2-thione from the reaction of isothiocyanates with aminoacetals or a-aminocarbonyl compounds. For example, substituted 2-mercaptoimidazoles 1261 are obtained by the condensation of isocyanates with aminoacetaldehyde diethyl acetal followed by cyclization of the resulting thioureas 1260 under acidic conditions. The coupling of isothiocyanates with 2-aminocyclopentanone 1262 gives the hydroxyl derivatives 1263, which are converted into the 1-substituted 2-mercapto-1,4,5,6-tetrahydrocyclopent[d]imidazoles 1264 by dehydration with PBr3-pyridine (Scheme 320) . Many modified Marckwald procedures are available to prepare structurally diverse imidazoles; most of them are focused on the preparation of an a-aminoketone or its equivalents. For example, a regiospecific synthesis of trisubstituted imidazoles has been developed. Thus, treatment of BOC-protected a-amino acids 1265 with malonic monoester leads to a-aminoketones. After removal of the BOC protecting group, the resulted a-aminoketone salt 1266 will condense with isothiocyanates to form thioureas 1267. The intermediates 1285 undergo cyclodehydration under acidic conditions, yielding imidazole-2-thiones 1268 in good yields. Both reductive and oxidative desulfonation have been used to convert the imidazole-2-thiones 1268 into imidazoles (1269 or 1270) (Scheme 321) . Another way to form a-aminoketones from a-amino acids is via the Dakin–West reaction, in which amino acids are treated with aliphatic acid anhydrides to give ketone amides. Thus, reaction of ()-phenylalanine with the appropriate aliphatic acid anhydrides followed by acidic hydrolysis afforded keto-amide 1271. Cyclization of 1272 with potassium cyanate gave 5-alkyl-4-benzyl-1,3-dihydroimidazol-2-ones 1273 (Scheme 322) . In situ formation of a-aminoketones has been achieved from the reaction of a-hydroxy- or a-haloketones with amines. 1,3-Dihydroxypropan-2-one has been used as a starting material in the Marckwald synthesis . Also, reaction of 4-chloro-N-methyl-3-oxobutanamide 1274 with amines leads to cyclic (E)-Nmethyl-5-(methylimino)-2,5-dihydrofuran-3-amines 1275, which behave as latent a-aminoketones. Treatment of 1275 with isothiocyanates in refluxing EtOH affords imidazole-2-thiones 1276 (Scheme 323) .

307

308

Imidazoles

Scheme 319

Scheme 320

Scheme 321

Thioamides can serve as surrogates for isothiocyanates in the Marckwald synthesis. For example, reaction of a-amino acetals 1278 with thioamides 1277 in the presence of HgCl2 affords amidine intermediates, which cyclize to form imidazoles under acidic conditions. This method has been applied to synthesize a variety of sugar imidazoles (Scheme 324) .

Imidazoles

Scheme 322

Scheme 323

Condensation of aryl-derived imidate 1279 with a-aminoacetaldehyde dimethyl acetal gives amidine 1280, which cyclizes in the presence of TiCl4 to yield N-aryl imidazoles 1281 (Scheme 325) . A regiospecific synthesis of N-substituted (aminopyridinyl)imidazole 1286 started with ketone 1282 (cf. Section 4.02.9.2(i)). a-Oximination of ketone 1282 with isoamyl nitrite under basic condition provides oxime isomers 1283. Both cis- and trans-oximes 1283 participate in the cyclization process when treated with 1,3,5-trimethyl-1,3,5-triazinane, leading to imidazole N-oxide 1284 that is then reduced with 2,2,4,4-tretamethyl-cyclobutane-1,3-dithione to give 1285 (Scheme 326) (see also Section 4.02.9.3(i)). Amidinylation of a-aminoketones 1287 with cyanamide or activated guanidines such as pyrazole derivative 1288 affords 2-aminoimidazoles 1289. This method has been applied to prepare L-aminohomohistidine, as shown in Scheme 327 . Treatment of a-azido esters 1290 with triphenylphosphine gives E-phosphazides 1291, which subsequently react with isothiocyanates to afford thiohydantoins 1292 after aqueous work-up. The cyclization conditions can also be adapted to hydantoin synthesis when isocyanates are used (Scheme 328) . Reaction of glycine methyl ester with imidate 1293 under optimized conditions affords the rather unstable imidazolinone 1294 in ca. 90% yield (Scheme 329). Treatment of 1294 with POCl3/DMF followed by aqueous work-up gives 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde 1295 in good yield .

309

310

Imidazoles

Scheme 324

Scheme 325

Scheme 326

Imidazoles

Scheme 327

Scheme 328

4.02.9.2.2(ii) Formation of the 1,2- and 4,5-bonds This classification is illustrated in Scheme 330. Imidazole synthesis under this classification consists mainly of two approaches: 1,3-dipolar cycloaddition and one-pot addition–cyclization involving isocyano derivatives. a-Silylimines 1297 derived from N-benzylidenebenzylamine 1296 undergo 1,3-dipolar cycloaddition reactions with trifluoroacetonitrile to give trifluoromethyl-substituted imidazolines 1298. Both benzoyl chloride and benzyl chloroformate can be used to facilitate the formation of the azomethine ylide. The resulting 3-imidazolines are easily cleaved with mild acid hydrolysis to yield the amino-protected trifluoromethyl ketones 1299 . a-Silylimine 1300 behaves similarly to give benzyl 2-methyl-2-phenyl-4-(trifluoromethyl)-2H-imidazole1(5H)-carboxylate 1301 in 57% yield (Scheme 331) .

311

312

Imidazoles

Scheme 329

Scheme 330

Scheme 331

4,4-Dicarboxyimidazolines 1304 are obtained from the Lewis-acid-catalyzed [3þ2] cycloaddition reaction of N-malonylimidates 1302 with imines in good to excellent yields. The cycloaddition proceeds optimally at ambient temperature with a catalytic amount of MgCl2 in CH3CN. The Lewis acid used in the reaction promotes a 1,2-prototropic shift to give a metal-coordinated azomethine ylide 1303 . Similarly, the 1,3-dipolar cycloaddition between N-malonylimidates 1302 and 4-chlorophenyl isocyanate or ethoxycarbonyl isothiocyanate 1305 as dipolarophiles proceeds regioselectively under solvent-free conditions. Scheme 332 illustrates the cycloadduct 1307 obtained via 1306 when ethoxycarbonyl isothiocyanate is used as the reactant .

Imidazoles

Scheme 332

Ruthenium(II)-catalyzed cycloaddition reactions of N-sulfonylimines 1308 with methyl isocyanoacetate 1309 gave trans-2-imidazolines 1310 stereoselectively in 75–90% yields under neutral, mild conditions [R1 ¼ phenyl, substituted phenyl, 2-furyl, trans-PhCHTCH, tert-Bu; R2 ¼ tosyl, PhSO2] (Scheme 333) . In contrast, the same reaction catalyzed by 1 mol% AuCl(c-HexNC) provides 4-methoxycarbonyl-5-alkyl-2-imidazolines 1321 with over 98% cis-selectivity (Scheme 333) .

Scheme 333

Cycloaddition of imines to a mu¨nchnone intermediate 1312 is the key step in preparing imidazoles on solidsupport with linkers directly attached to the synthesized imidazole rings. In this manner, imidazoles 1313 with various aromatic substituents (R1 ¼ Ph, 4-FC6H4; R2 ¼ Ph, 4-FC6H4, 4-MeOC6H4; R3 ¼ 3-pyridyl, 4-pyridyl) are assembled regioselectively from arylglycines, acyl chlorides, and imines (Scheme 334) . Condensation of pre-formed imines with tosylmethyl isocyanide (TosMIC) has been widely used to produce polysubstituted imidazoles . Examples include the preparation of 2-imidazolines and di- and trisubstituted imidazoles (CHEC(1984) and CHEC-II(1996)). The three-component reaction involving the cycloaddition of TosMICs with imines generated in situ is known as the van Leusen three-component reaction (see also Section 4.02.9.3(iv)). The condensation of a-substituted TOSMICs with aldehydes and amines bearing various functional groups has been investigated in detail . Traditional imine-forming reactions employing virtually any aldehyde and amine followed by addition of a substituted TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable

313

314

Imidazoles

Scheme 334

regiochemistry. Thus, an efficient synthesis of alkyne-derived imidazoles 1314 is achieved in a regioselective fashion with good yields . The reaction works quite well with aldehydes bearing O-functional groups in different oxidation states, for example, using pyruvaldehyde as a starting material leads to a free keto group in the product imidazole 1315 , and using glyoxylates leads to an ester group in the product 1316 (Scheme 335) .

Scheme 335

Imidazoles

1,4-Disubstituted imidazoles can also be prepared by a simple variant of the van Leusen procedure. Thus, selecting glyoxylic acid as the aldehyde component leads to 1,4-disubstituted imidazoles 1317 after decarboxylation. Alternatively, using NH4OH as the amine component in conjunction with a variety of aldehydes delivers 4,5disubstituted imidazoles 1318 in moderate to good yields. Employing chiral amines or aldehydes, particularly those derived from a-amino acids, produces imidazoles 1319 with asymmetric centers appended to N-1 or C-5, respectively, with excellent retention of chiral purity (Scheme 336) .

Scheme 336

315

316

Imidazoles

Variants of TosMIC and imines have also been utilized for imidazole synthesis. For example, benzotriazol-1ylmethyl isocyanide (BetMIC), 1320, reacts with aldimines 1321, like TosMIC, to form imidazoles 1322. In this case, the benzotriazolyl group stabilizes the anion formed in the first step and is spontaneously eliminated from the intermediate imidazoline. BetMIC derivatives are found to be unstable in the presence of strong bases such as LDA, n-BuLi, and NaH. The most effective conditions for all of these reactions are found to be potassium tert-butoxide in DMSO or THF (Scheme 337) .

Scheme 337

Reaction of 1,4-benzodiazepinic N-nitrosoamidines 1323, used as synthetic equivalent of imidoyl chlorides, with the monoanion of tosylmethyl isocyanide 1324 affords 3-(4-tosyl)imidazo[1,5-a][1,4]benzodiazepines 1325 (Scheme 338) .

Scheme 338

Base-induced cycloaddition of diethyl isocyanomethylphosphonate 1326 to trifluoroacetimidoyl chlorides 1327 produces 1-substituted diethyl 5-trifluoromethylimidazole-4-phosphonates 1328 with high regioselectivity (Scheme 339) .

Scheme 339

Imidazoles

A Cu2O-catalyzed synthesis of 1,4-disubstituted imidazoles 1331 via cross-cycloaddition between two different isocyanides (i.e., 1329, 1330) has been reported. The reaction is proposed to start with the activation of a C–H bond of the isocyanide by the influence of Cu2O catalyst, as depicted in Scheme 340 .

Scheme 340

4.02.9.2.2(iii) Formation of the 1,5- and 3,4-bonds This classification is illustrated in Scheme 341. In this classification, the N–C–N scaffold is embedded in nitrogencontaining precursors, such as amidines, guanidines, ureas, or thioureas, etc. Reaction of a-halocarbonyl compounds with amidines or guanidines is one of the conventional methods to prepare substituted imidazoles. However, most of amidines and guanidines, especially the alkyl-substituted ones, are strong bases and often cause various side-reactions of the a-halocarbonyl compounds, resulting in lower cyclocondensation yields. Thus, reaction of a-bromoaldehyde 1332 with formamidine provided 5-substituted imidazole 1333 in only a modest 39% yield (Scheme 342) .

Scheme 341

Scheme 342

317

318

Imidazoles

In contrast, condensation of less basic amidines or guanidines such as N-aryl substituted amidines, acyl and carboxy guanidines, with a-halocarbonyl compounds provides substituted imidazoles in good yields. For example, arylbenzamidine 1334 reacts with ethyl 3-bromo-2-oxobutanoate 1335 to yield 1,2-diaryl-1H-imidazole-4-carboxylate 1336 in 70% yield. Subsequent treatment with acid is needed to complete the dehydration step . The process has been used extensively to synthesize 1,2-diaryl substituted imidazoles, for example, 1337 . Similarly, both BOC- and acetyl-protected guanidines have been used to prepare 2-aminoimidazoles, for instance 1338 (Scheme 343) .

Scheme 343

Imidazoles

Another way to avoid the direct condensation of a-halocarbonyl with basic amidines or guanidines is to use latent a-halocarbonyl derivatives. Thus, 2-bromo-3-i-propoxy-2-propenal 1340, acting as a latent a-halocarbonyl compound, reacts with a range of monosubstituted amidines 1339 to provide imidazolecarboxaldehydes (1341, 1342) in moderate yields. The nature of the R1 substituent, whether alkyl or aryl, does not seem to influence the yield of the imidazole product. Employing unsubstituted amidines (R1 ¼ butyl, R2 ¼ H) to synthesize imidazolecarboxaldehydes was unsuccessful. Reaction of 2-bromo-3-methoxy-2-propenenitrile 1343 with monosubstituted amidines 1339 leads to analogous 1,2-disubstituted imidazole-5-nitriles (1344, 1345) with good regioselectivity (Scheme 344) .

Scheme 344

Some naturally occurring carbohydrates, for example, D-fructose (or D-glucose), D-galactose, and L-sorbose, can be condensed with formamidine acetate under microwave irradiation to give imidazoles 1347. Microwave irradiation clearly brings about a sequential double condensation of formamidine followed by acid-catalyzed cyclization of the intermediate linear imidazolyltetritols, for example, 1346 (Scheme 345) .

Scheme 345

319

320

Imidazoles

Imidazolines have been prepared starting from amidines and guanidines. Reaction of amidine 1348 with 2-chloroacrylonitrile gives the imidazoline 1349 in 79% yield, aromatization giving the imidazole 1350 (Scheme 346) .

Scheme 346

Reaction of BOC-guanidine with dihydropyridine 1351 in the presence of bromine provides the bicyclic regioisomers 1352. After removal of the Boc-protecting group, the aminal bond in compound 1353 was regioselectively cleaved in boiling aqueous NaOH solution to yield the 2-aminoimidazole 1354 (Scheme 347) .

Scheme 347

Cyclization of 1-aroyl-3-arylthioureas 1355 with a variety of carbonyl compounds bearing an a-H, in the presence of bromine and triethylamine, provides 1-aroyl-3-aryl-4-substituted imidazole-2-thiones 1356 . The underlying mechanism of this condensation is illustrated in Scheme 348. a-Tosyloxylation of ketones 1357 with [hydroxyl(tosyloxy)iodo]benzene, followed by treatment of amidines 1358 provides a one-pot procedure for the synthesis of 1H-imidazole derivatives 1359 (Scheme 349) . The cycloacylation of benzamidines 1361 with oxalate-derived bisimidoyl chlorides 1360 provides 4H-imidazoles 1362 in good yields. The same products can also be obtained from the displacement of chlorine atoms in compound 1363 with the corresponding anilines in the presence of triethylamine (Scheme 350) .

Imidazoles

Scheme 348

Scheme 349

Scheme 350

321

322

Imidazoles

Primary ureas 1365 are good substrates in rhodium-catalyzed N–H insertion reactions with an array of 2-diazo-1,3keto esters 1364. The products from the insertion reaction cyclize with the aid of acid to yield imidazolones 1366. This chemistry has been translated onto insoluble polymer resins and utilized to prepare a small array of imidazolones (Scheme 351) .

Scheme 351

Imidazolin-2-ones 1368 are obtained from b-ketoesters for example 1367 upon treatment with tert-butyl nosyloxycarbamate and calcium oxide under mild conditions. A possible pathway to explain this unexpected formation of imidazolin-2-ones is shown in Scheme 352 .

Scheme 352

Imidazoles

Reaction of ethyl tosyloxycarbamate 1370 with an electron-rich olefin is the key step in the synthesis of the pyrrole–imidazole alkaloid dibromophakellstatin 1372. The direct annulation of the imidazolinone ring to pyrrolopyrazinone precursor 1371 is achieved by employing an ethoxycarbonylnitrene generated in situ. Samarium diiodide proved to be the best reducing agent for the chemoselective, stepwise deprotection, resulting intetracycle 1372 (Scheme 353) .

Scheme 353

4.02.9.3 Formation of Three or Four Bonds 4.02.9.3.1

Formation of the 1,2-, 2,3-, and 3,4-bonds

Scheme 354 illustrates this classification. Reaction of keto-oximes 1373 (Ar1 ¼ 4-FC6H4, 3-CF3C6H4; Ar2 ¼ 4-pyrimidinyl, 4-pyridyl), ammonium acetate, aldehydes 1374 (R3 ¼ p-tolyl, Et, 4-MeOC6H4, etc.), and glacial acetic acid in a microwave vial yields N-hydroxyimidazoles 1375. Reduction of the N–O bond with TiCl3 upon microwave irradiation affords 2,4,5-trisubstituted imidazoles 1376. Increasing the reaction temperature to 200 C induces a thermal reductive N–O bond cleavage, thus providing the same polysubstituted imidazoles 1378 in good yields in one step (Scheme 355) .

Scheme 354

Scheme 355

323

324

Imidazoles

An aza-Wittig reaction utilizing isocyanates leads to ferrocene-containing imidazolones. Thus, condensation of bferrocenylvinyliminophosphorane 1377 with isocyanates provides the carbodiimide intermediate 1378, which can then be reacted with various amines to give the imidazolones 1379 in good yields (Scheme 356) (see Section 4.02.9.2(i)(b)).

Scheme 356

Treatment of arylglyoxal monohydrates 1380 with tetrasulfur tetranitride 1381 in dioxane at reflux affords 2-aroyl5-arylimidazoles 1382 and 2-aroyl-5-aryloxazoles 1383 in 10–31% and 17–32% yields, respectively (Scheme 357) .

Scheme 357

The N-unsubstituted nonstabilized azomethine ylides generated from the desilylation of N-[(trimethylsilyl)methyl]iminium triflates [1384, R1 ¼ H, R2 ¼ Ph; R1R2 ¼ (CH2)5, (CH2)2O(CH2)2] cycloadd to strongly polarized sulfonylimines 1385 (Ar ¼ Ph, 4-ClC6H4, 4-O2NC6H4) to produce the corresponding 2-imidazolines, for example, 1387, together with the initial cycloadducts 1386 (Scheme 358) .

Scheme 358

Imidazoles

4.02.9.3.2


Scheme 359 illustrates this classification. Bredereck’s formamide cyclization continues to be one of the choices for the synthesis of 4,5-disubstituted or 4(5)-monosubstituted imidazoles . Typically, the reaction proceeds at high temperature with formamides and a-haloketones as the starting materials. For instance, monosubstituted imidazole 1389 is prepared from compound 1388 in 25% yield. 4,5-Disubstituted imidazole 1391 with a hindered side-chain is obtained from 1390 in 48% yield (Scheme 360) .

Scheme 359

Scheme 360

Treatment of a-halo ketones 1392 (X ¼ Br, Cl) with potassium thiocyanate and monosubstituted hydrazines 1393 provides N-aminoimidazoline-2-thiones [1397, R1, R2 ¼ Me, Ph; R1R2 ¼ (CH2)4; R3 ¼ Ph, 4-O2NC6H4, PhCH2, etc.]. The reaction is considered to proceed via the formation of azo-alkenes 1394 and thiocyanic acid 1395. The intermediates, in turn, undergo a [3þ2] cycloaddition reaction to give azomethine imine cycloadducts 1396, which proceed to the final products 1397 (Scheme 361) .

Scheme 361

325

326

Imidazoles

A nonoxidative diamination reaction of a,b-unsaturated ketones 1398 or esters 1401 with N,N-dichloro-ptoluenesulfonamide 1399 (4-MeC6H4SO2NCl2) and MeCN (one of the nitrogen donors) gives polysubstituted imidazolines 1400, 1402. Several transition metal complexes have been utilized to catalyze this transformation. For example, rhodium(II) heptafluorobutyrate dimer is effective to facilitate the reaction at elevated temperatures. The reaction proceeds at 55 C to afford imidazolines in 57–77% yields. A mechanism is proposed in Scheme 362 to explain the resulting regio- and stereoselectivity . The FeCl3-PPh3 complex can also promote the nonoxidative diamination of electron-deficient alkenes. Under this catalytic system, a,b-unsaturated carboxylic esters are better substrates than their ketone counterparts. The reaction proceeds at room temperature without the special protection of inert gases. Modest to good yields (52–84%) and high regio- and stereoselectivity are achieved .

Scheme 362

The direct electrophilic diamination reaction of electron-deficient alkenes can be carried out without the use of any metal catalysts. N,N-Dichloro-p-toluenesulfonamide or the combination of 2-NsNH2/NCS functions as the electrophilic nitrogen source, and alkanenitriles such as MeCN, EtCN, and n-PrCN as the nucleophilic nitrogen source. The reaction proceeds with good regio- and stereoselectivity and modest to good yields (35–84%) . It is proposed that 2-NsNHCl is involved with the nitriles via a [2þ3] cycloaddition mechanism, which is responsible for the excellent regio- and stereoselectivity of the resulting diamination products (Scheme 363) . Electrophilic diamination of nonactivated alkenes (i.e., 1403, 1407) has been achieved with the combination of N-chlorosaccharin 1404/CH3CN. The reaction is believed to proceed via a Ritter-type mechanism involving the attack of the saccharin anion 1411 on an intermediate nitrilium ion 1410, which itself is generated from an alkenederived chloronium ion 1409. The resulting b-chloro sulfonylamidines 1412 can cyclize to yield imidazolines 1414 in situ by treatment with potassium ethoxide solution followed by NaH in DMF. The sequence is compromised by the formation of competing aziridine (i.e., 1406) and allylic chloride byproducts (Scheme 364). Nonetheless, this methodology compliments the diamination reaction with TsNCl2, which has been mainly limited to the reactions of electron-deficient alkenes .

Imidazoles

Scheme 363

4.02.9.3.3

Formation of the 1,2-, 2,3- and 4,5-bonds

This classification is illustrated in Scheme 365. The synthesis of imidazoles under this classification is rare mainly due to the difficulty of C–C bond formation. A palladium-catalyzed coupling of imines 1415, 1417 and acid chloride 1416 to synthesize substituted imidazoles 1418 belongs to this category of ring formation. N-Alkyl and N-aryl imines can be used, as can imines of aryl and even nonenolizable alkyl aldehydes. A plausible reaction mechanism involving 1,3-dipolar cycloaddition with mu¨nchnones is illustrated in Scheme 366 . A similar example to obtain imidazoline carboxylic acids 1422 from a palladium-catalyzed multicomponent condensation reaction employs an imine 1420, an acid chloride 1421 and CO (Scheme 367). The reaction is also believed to proceed through a putative mu¨nchnone intermediate .

4.02.9.3.4


This classification is illustrated in Scheme 368. Imidazole synthesis via the van Leusen three-component reaction, in which an amine, an aldehyde, and TosMIC undergo condensation to give imidazoles, is discussed in Section 9.02.9.1. Like the van Leusen imidazole synthesis, the three-component condensation between an amine, an aldehyde, and an a-acidic isocyanide (i.e., 1423, 1425) provides substituted 2-imidazolines 1424, 1426 in 47–91% yields. The methodology is limited by the reactivity of the isocyanide and by the steric bulk on the imine generated in situ rather than by the presence of additional functional groups on the imine. The isocyanides used in the condensation require an acidic a-proton, such as 2-phenylisocyanoacetate 1423 or 9isocyanofluorene 1425. Reactions with less reactive isocyanides 1427, such as p-nitrobenzyl isocyanide, or less reactive ketones as the oxo-compounds can be promoted by silver(I) acetate (Scheme 369). Ratios refer to anti:syn; only the major diastereomer is depicted. The spiro-2-imidazoline was prepared from 9-isocyanofluorene.

327

328

Imidazoles

Scheme 364

Scheme 365

4.02.9.3.5

Formation of four bonds

This classification is illustrated in Scheme 370. The traditional method of three-component condensation of dicarbonyl compounds (or a-hydroxyketones), amines (including ammonia) and aldehydes are still widely utilized to prepare poly-substituted imidazoles. In a special case where glyoxal and ammonia are the reactants, 2-substituted imidazoles such as 1429, 1430 are the products (Scheme 371) . Synthesis of 2,4,5-trisubstituted imidazoles 1433 is achieved via the reaction of 1,2-diketones 1431 and aldehydes 1432 in the presence of NH4OAc . Reaction of protected benzoins 1434 with ammonium acetate and an aldehyde in the presence of Cu(OAc)2 leads to substituted imidazoles 1435 . Highly substituted imidazole libraries have been prepared on Wang resin via ester or ether linkages in the same three-component condensation process (Scheme 372) .

Imidazoles

Scheme 366

Scheme 367

Scheme 368

329

330

Imidazoles

Scheme 369

Scheme 370

Scheme 371

Imidazoles

Scheme 372

This three-component reaction also proceeds with excellent yields under microwave irradiation with the use of solid-supported reagents. For example, alkyl, aryl, and heteroaryl-substituted imidazoles have been obtained in yields from 80% to 99% with microwave irradiation . A solvent-free, microwave-assisted synthesis of substituted imidazoles 1436 is achieved as a result of the condensation of a 1,2-dicarbonyl compound with an aldehyde and an amine. Acidic alumina impregnated with ammonium acetate serves as the solid support in the reaction . Similarly, the condensation of a-hydroxyketone 1437 with an aldehyde and a primary amine on silica gel or alumina impregnated with ammonium acetate affords tetrasubstituted imidazoles 1438. It is believed that the imidazoline intermediates are oxidized by O2 in situ to give imidazoles (Scheme 373) . The condensation of benzil 1439, benzonitrile derivatives and primary amines on the surface of silica gel under solvent-free and microwave irradiation conditions provides tetrasubstituted imidazoles 1440 in high yields (Scheme 373) .

Scheme 373

331

332

Imidazoles

Reaction of N-Cbz-protected a-amino glyoxals 1441 with R1CHO and NH4OAc in MeOH gives imidazoles 1462. The chirality of the side-chains, originating from a-amino acids or dipeptides, is retained during the cyclization . Alkenyl tricarbonyl esters 1443 undergo a similar reaction with aldehydes and NH4OAc to form imidazole carboxylic esters 1444 . Esters 1445 derived from a-hydroxy acetophenone condense with NH4OAc at elevated temperature to afford 2,4-disubstituted imidazoles 1446 (Scheme 374) .

Scheme 374

3,3,3-Trifluoro-2-oxopropanal 1-(dimethylhydrazone) 1447 is a synthetic equivalent of trifluoropyruvaldehyde. Like its 1,2-dicarbonyl counterpart, compound 1447 participates in the condensation reaction with aldehydes and ammonium acetate to afford 4-trifluoromethylimidazoles 1448 in 42–72% yield . 1,1,1-Trifluoro2,3-alkanediones 1449, also 1,2-dicarbonyl equivalents, condense with aldehydes and aqueous ammonia to yield 4-(trifluoromethyl)imidazoles 1450 . 3-(Dimethylhydrazono)-1,1,1,4,4,4-hexafluoro-2-butanone 1452, obtained from the reaction of trimethylacetaldehyde dimethylhydrazone 1451 with TFAA, reacts in situ with aldehydes in aqueous ammonia solution to afford 4,5-bis(trifluoromethyl)-1H-imidazoles 1453 (Scheme 375) .

4.02.10 Ring Syntheses by Transformations of Another Ring 4.02.10.1 Ring Expansions A wide range of aziridine derivatives undergo Ritter reactions with nitriles in a regio- and stereoselective manner to yield imidazolines. Various Lewis acids are capable of promoting this ring-opening process. For example, BF3?OEt2 catalyzes the reaction of chiral 2-(1-aminoalkyl)-aziridine 1454 with nitriles to provide enantiopure 2,4,5-trisubstituted imidazolines 1455. The neighboring amino group facilitates the ring opening step during the reaction . Similarly, silyl groups can assist the process by stabilizing the positive charge on a carbon through the b-effect of silicon. Thus, 2-tert-butyldiphenylsilylmethyl-substituted aziridines 1456 undergo [3þ2] cycloaddition with nitriles in the presence of BF3.OEt2 to yield imidazolines 1457 (Scheme 376) .

Imidazoles

Scheme 375

Scheme 376

333

334

Imidazoles

N-Tosylaziridines can be transformed to imidazolines without neighboring group assistance. Thus, Lewis acids such as BF3-OEt2 or ZnBr2 catalyze ring opening of phenyl N-tosylaziridine 1458 with CH3CN to yield imidazolines 1459 in good yields . Sc(OTf)3 promotes a similar reaction in the absence of organic solvent to afford the corresponding imidazolines 1460 in good to excellent yields (Scheme 377) .

Scheme 377

Aminomethylaziridines 1461 react with triphosgene and NaH to give 5-alkyl- or 5-aryl-4-chloromethylimidazolidin2-ones 1463 (Scheme 378). The reaction proceeds through the formation of the aziridium ion intermediate 1462 and the addition products are obtained in yields of 71–97% regardless of the stereochemistry .

Scheme 378

Reaction of 2-vinylaziridines 1464 with various heterocumulenes (i.e., 1465, 1467), catalyzed by [Pd(OAc)2] and PPh3 at room temperature, affords five-membered ring products 1466, 1468 in moderate to high yields. The reaction is regioselective and involves a Z3–Z1–Z3 interconversion of a (p-allyl)palladium intermediates (Scheme 379) . This ring transformation also proceeds asymmetrically in the presence of catalyst (Z3-C3H5PdCl)2 and Trost chiral ligands to form cyclic ureas 1469 in 13–95% yields and 52–99% enantiomeric excesses (Scheme 380). Cycloaddition of aziridines 1472 with isocyanates 1470 also proceeds smoothly in the presence of a nickel catalyst. The initial imino-oxazolidine products 1473 can be isolated in good yields. A longer reaction time allows the isomerization of the imino-oxazolidine to the corresponding imidazolidinones 1474. The best results are obtained when the reaction is carried out in the presence of NiI2 (Scheme 380) .

Imidazoles

Scheme 379

Scheme 380

335

336

Imidazoles

4.02.10.2 Transformations of Other Five-Membered Rings 1,3-Dipolar cycloaddition reactions of N-substituted mesoionic oxazolones (or mu¨nchnones) with imines provide a general route for the syntheses of imidazoles and imidazolines . For example, TMSCl promotes the reaction of 2-phenyl-4-methyl-4H-oxazolin-5-one 1475 with imines generated in situ to afford imidazolines 1476 with high diastereoselectivity. Only the trans diastereomers (with respect to R2 and R3) of the imidazolines are observed. A [3þ2] cycloaddition mechanism has been proposed to account for the observed high diastereoselectivity. Typical products are illustrated in Scheme 381 .

Scheme 381

Reaction of aldehyde 1477 with TosMIC and NaCN yields tosyl-substituted oxazoline 1478, which is converted into imidazole 1479 with ammonia at elevated temperature (Scheme 382) (see also van Leusen imidazole synthesis in Section 4.02.9.2(ii)(b)) .

Imidazoles

Scheme 382

A novel ring transformation/desulfurization of substituted 2-methyl-1,2,4-thiadiazolium salts 1481 provides a versatile entry to imidazoles 1482 with a variety of substituents. The starting 1,2,4-thiadiazolium salts 1481 can be prepared from N-(thiocarbonyl)-N9-methylamidines 1480 under mild oxidative conditions. Related salts, 1,2,4dithiazolium triiodides 1483, also react with amines to form imidazoles 1484 . Alternatively, N-(thiocarbonyl)-N9-methylamidines 1485 can be transformed into 1-substituted imidazoles 1487 via S-methylation followed by elimination of methylthiol (Scheme 383) .

Scheme 383

337

338

Imidazoles

Pyrolysis of 1-aroylamino-4,5-diphenyl-1,2,3-triazole 1488 yields 2-aryl-4,5-diphenylimidazole 1489 as the major product (Scheme 384) .

Scheme 384

Cyclic nitrones 1490 (3-imidazoline 3-oxides) react regioselectively with alkyl phenylpropiolates 1491 (or with dimethyl acetylenedicarboxylate) to give the corresponding 2-phenyl-3a,4,5,6-tetrahydroimidazo[1,5-b]isoxazole-3carboxylic acid alkyl esters 1492. Subsequent thermal, base (piperidine, triethylamine, or alkoxide) induced ringopening reactions led to imidazoles 1493 (Scheme 385) .

Scheme 385

(Z)-1-(59-Methyl-19,39,49-thiadiazol-29-yl)-4-arylidene-4,5-dihydro-2-phenylimidazol-5-ones Z-1496 are prepared by the condensation of (Z)-4-arylidene-4,5-dihydro-2-phenyloxazol-5-ones 1494 with 2-amino-5-methyl-1,3,4-thiadiazoles 1495 on basic alumina under microwave irradiation. The E-1496 isomers are also formed as minor products (Scheme 386) .

Scheme 386

N-Monosubstituted 1,2-diaminobenzenes 1497 (R ¼ Me, Ph, PhCH2, and 3,4-Me2C6H3CH2) react with 4,5dichloro-l,2,3-dithiazolium chloride 1498 in dichloromethane at room temperature to give the corresponding imines 1499 which undergo thermolysis to form 2-cyanobenzimidazoles 1500 in fair to good yields (Scheme 387) . Reaction of N,N-dialkyl dichloromethaniminium chlorides 1501 with 2-aminoacetophenones 1502 provides a general route to the formation of 5-aryl substituted 2-(dialkylamino)-1,3-oxazolium salts 1503; these can also be prepared from the corresponding 5-aryl substituted 2-(dialkylamino)-1,3-oxazoles by alkylation with (MeO)2SO2. Treatment of 1503 with NH4OAc gives 1-substituted 4-aryl-2-(dialkylamino)-1H-imidazoles 1504 (Scheme 388) .

Imidazoles

Scheme 387

Scheme 388

Reduction of 4-nitro-5-amino-2,1,3-benzothiadiazole 1505 with Sn/HCl in the presence of a carboxylic acid having a C(1)–C(3) chain yields the corresponding 2,5-dialkylbenzo[1,2-d:3,4-d9]diimidazoles 1506 (Scheme 389) .

Scheme 389

Irradiation of 3-[o-(alkylamino)phenyl]-5-methyl-1,2,4-oxadiazole 1507 leads to concomitant formation of benzimidazoles 1509 and indazoles 1508, presumably arising from a common photolytic species, as shown in Scheme 390 .

Scheme 390

339

340

Imidazoles

A novel singlet oxygen ring cleavage of 4,5-bis(4-fluorophenyl)-,-bis(trifluoromethyl)-1H-pyrrole-2-methanamine 1510 and subsequent acid-catalyzed facile dehydrocyclization gave 4,4-bis(trifluoromethyl)imidazoline 1512 (Scheme 391) .

Scheme 391

3,5-Dichloro-2H-1,4-oxazin-2-one 1513 reacts with a-amino ketones e.g. 1514 to yield bicyclic imidazo-fused intermediates 1516 via an intramolecular cyclization reaction. Reaction of lactones such as 1516 with various nucleophiles generates substituted 1H-imidazoles such as 1517 (Scheme 392) .

Scheme 392

4.02.10.3 Ring Contractions 5-Acylamino-6-hydroxymethyl-3-phenylpyrimidin-4(3H)-one 1518 undergoes a ring contraction process in basic alcoholic solution to afford 2-alkyl-5-hydroxymethyl-4-phenylcarbamoyl-1H-imidazole 1519. 5-Amino-6-benzoylxymethyl-3-phenylpyrimidin-4(3H)-one 1520 is oxidized with CuCl2 in alcohol to give 2-methoxy-5-alkoxymethyl-4-phenylcarbamoyl-1H-imidazole 1521 in 9% yield, accompanied by 5-amino-6-methoxymethyl-3-phenylpyrimidin-4(3H)-one 1522 as the major product (Scheme 393) .

Imidazoles

Scheme 393

Mild alkaline treatment of 5-bromo-29-deoxyuridine 1523 results in a ring contraction of the pyrimidine to form the imidazolinone nucleoside 1524. The a-anomer was isolated after chromatographic purification (Scheme 394) .

Scheme 394

Reaction of 2-aminopyrimidines 1525 with a-bromocarbonyl compounds 1526 affords imidazo[1,2-a]pyrimidinium salts 1528, which undergo a ring-opening process in the presence of hydrazine to yield 2-aminoimidazoles 1529 in good yields (Scheme 395) .

Scheme 395

341

342

Imidazoles

4.02.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available 4.02.11.1 Imidazole and Benzimidazole Oxides and Radicals Imidazole and benzimidazole N-oxides are invariably prepared via ring-closure processes (CHEC(1984) and CHECII(1996)). The synthetic routes for the preparation of 1H-imidazole N-3-oxides (e.g., 1532, 1536) usually involve electrophile–nucleophile (such as 1,2-diimine-a-oximineketone) or nucleophile–electrophile (oxime–formaldimine) synthons. For example, cyclization of 1,2-diimines 1530 with oximes 1531, performed under solvent-free conditions using silica gel and aluminium oxide as supports and catalysts, gives imidazole N-oxides 1532 . Imidazole N-oxides 1536 are obtained as crystalline products in high yields (58–95%) from the reaction of a-(hydroxyimino)ketones 1534 with 1,3,5-trisubstituted hexahydro-1,3,5-triazines 1533 (Scheme 396) .

Scheme 396

A procedure for 1-alkyl(aryl)-1H-4-methylimidazole N-3-oxides 1539 involves the cyclocondensation of a-aminooximes, for example, 1537, and orthoesters 1538. Low yields (6–27%) in the cyclization process are due to the predominant Z-stereoisomer around the oxime moiety in 1537 (Scheme 397) .

Scheme 397

Imidazoline N-oxides or radicals can be produced from the oxidation then reduction of the corresponding N-hydroxy imidazolines. Thus, imidazoline-derived biradicals 1542 and 1543 were prepared from 1,3-di(N-imidazolyl)benzene bis-aldehydes 1540. The 1,3-dihydroxy-4,4,5,5-tetramethyl imidazolidine 1541 was oxidized with NaIO4 to yield 1,3-bis{2-(1-oxyl-3-oxo-4,4,5,5-tetramethylimidazolin-2-yl)imidazol-1-yl}benzene 1542. Reduction of 1542 with NaNO2 in acetic acid affords 1,3-bis{2-(1-oxyl-4,4,5,5-tetramethylimidazolin-2-yl)imidazol-1-yl}benzene 1543 in 85% yield . Oxidation of N,N9-dihydroxyimidazolines 1544 then NaNO2 treatment yields imidazoline oxyl 1545; PbO2 can also be used . Compound 1546 is obtained in a one-pot reaction (Scheme 398) . 2-Substituted 1-oxo-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazoles 1548 have been prepared from N-hydroxy imidazoline 1547, as shown in Scheme 399 .

Imidazoles

Scheme 398

Scheme 399

Treatment of 4H-imidazoles 1549 with dimethyldioxirane resulted in formation of amino-nitrones 1550 regioselectively (Ar ¼ 4-MeC6H4, 4-MeOC6H4, 4-t-BuC6H4, naphthyl). Compounds 1550 are unusually stable due to contributions from anionic as well as cationic delocalized mesomeric structures (Scheme 400) .

Scheme 400

343

344

Imidazoles

Reaction of N-n-butyl-2,6-dinitroaniline 1551 with NaOH in 60% dioxane–water at reflux provided 7-nitro-2-npropylbenzimidazole 3-oxide 1552. Two nitro groups ortho to the amine are needed for this transformation to occur (Scheme 401) .

Scheme 401

4.02.11.2 Nitroimidazoles Formation of nitroimidazoles via ring-closure approaches is rare (see CHEC-II(1996)), and most nitroimidazoles have been prepared from 4(5)-nitroimidazoles and 1,4-dinitroimidazoles . Access to 5-nitroimidazoles bearing one or more tri- or tetrasubstituted ethylenic double bonds at the 2-position via the versatile SRN1 methodology has been reviewed . In addition, N-alkylation of 4(5)-nitroimidazoles , nucleophilic substitution of 4-nitro-haloimidazoles and nucleophilic addition-elimination of 1,4-dinitroimidazoles have been successfully applied to prepare other nitroimidazoles. For example, the reaction of 1,4-dinitroimidazoles 1553, 1556 with amines 1554, 1557 proceeds via nucleophilic addition of the amine to the imidazole 5-position, ring opening, and then ring closure with expulsion of NO2NH2 to yield the N-substituted-4-nitroimidazoles 1555, 1558 (Scheme 402) .

Scheme 402

The synthesis of 1-methyl-2,4,5-trinitroimidazole 1564 illustrates a general approach to 4(5)-nitroimidazole and 1,4-dinitroimidazole (Scheme 403). Thus, imidazole is converted in good yield into 4-nitroimidazole 1577 with the mixed acid comprising 70% nitric acid and concentrated sulfuric acid. Treatment of 4-nitroimidazole with acetyl nitrate (acetic anhydride and fuming nitric acid in acetic acid) at low temperature afforded 1,4-dinitroimidazole 1560. Subsequent thermal rearrangement in refluxing chlorobenzene produces 2,4-dinitroimidazole 1561. The third nitration to 2,4,5-trinitroimidazole 1562 can be performed in mixed acid conditions. The product itself is not stable enough to be isolated; however, its salt, that is, potassium 2,4,5-trinitroimidazole 1563, can be obtained in good yield when treated with K2CO3/KCl solution. The N-methylated derivative 1582 is easily obtained from the 2,4,5trinitroimidazole salt (Scheme 403) .

Imidazoles

Scheme 403

4.02.11.3 Fluoroimidazoles Photochemical Balz–Schiemann reaction of diazonium fluoroborates continues to be the method of choice to prepare fluoro substituted imidazoles. Thus, 4(5)-fluoroimidazole 1565 is prepared from 4(5)-nitroimidazole 1559 in moderate yield by conversion of the nitro group to the diazonium salt followed by irradiation in aqueous tetrafluoroboric acid. Sugar-fluoroimidazole derivatives 1566 and 1567 were prepared using an N-silyl derivative of 1565 (Scheme 404).

Scheme 404

4,5-Difluoroimidazole 1571 has been prepared from 5-fluoroimidazole-4-carboxylic acid ethyl ester 1568. The ester 1586 is converted into the carbonyl azide 1569, which undergoes Curtius rearrangement in tert-butyl alcohol to produce 4-t-butyloxycarbonylamino-5-fluoroimidazole 1570. In situ diazotization of the resulting amine and irradiation produces 4,5-difluoroimidazole 1571 (Scheme 405) .

345

346

Imidazoles

Scheme 405

Photochemical trifluoromethylation of 4-fluoro-5-methylimidazole 1572 provides the trifluoromethyl derivative 1573 in 53% yield. Similarly, 4-fluoro-2-methylimidazole 1574 gives 4-fluoro-2-methyl-5-(trifluoromethyl)imidazole 1575 in 26% yield (Scheme 406) .

Scheme 406

Fluorination of an imidazole side-chain has been reviewed .

4.02.11.4 Selenoimidazoles 1-Mesityl-1,3-dihydroimidazole-2-selone 1576 is prepared in three steps from readily available 1-mesitylimidazole: (1) deprotonation with n-BuLi, (2) treatment with elemental selenium, and (3) addition of HCl (aq). Diselenide 1577 is obtained via the air oxidation of 1576 (Scheme 407) .

Scheme 407

Imidazoles

Reaction of isoselenocyanates 1579 with a-lithiated a,a-disubstituted isocyanides 1578 such as a,a-methylbenzyl isocyanide and diphenylmethyl isocyanide at 78 C for 1 h affords 2-butylseleno-2-imidazoline-5-selones 1580 after trapping with butyl iodide. The yields for these reactions range from 73% to 97% (Scheme 408) .

Scheme 408

4.02.12 Applications and Importance Imidazole analogues, such as histamine and histidine, display many important biological functions, as discussed in CHEC(1984) and CHEC-II(1996). The applications of imidazoles in pharmaceuticals are also well documented, as demonstrated in many drugs such as histamine receptor (H2) antagonist Cimetidine and angiotensin II receptor antagonist Losartan. Figure 40 shows the structures of some marketed imidazole-based drugs. The imidazole-derived structures such as imidazol-2-ylidene 9 and imidazolidin-2-ylidene 10 (see Figure 1) are generally referred to as N-heterocyclic carbenes. They exhibit properties strikingly similar and even superior to those of the electron-rich organophosphanes PR3. Therefore, phosphorus ligands have often been advantageously replaced by N-heterocyclic carbenes as ligands in transition metal catalysis . NHC-containing organometallic catalysts are much more effective than conventional catalysts in a number of reactions. One of the most wellestablished applications of N-heterocyclic carbenes is the second generation of Grubbs’ ruthenium–NHC complex, which catalyzes olefin-metathesis reactions (Figure 41). NHCs have also been shown to be excellent ligands in complexes which catalyze Heck and Suzuki coupling reactions . Chiral NHCs and their transition metal complexes are used as chiral catalysts in asymmetric transformations . Imidazo-2-ylidene and imidazolidin-2-ylidene derived carbenes are also strong bases and have been used as catalysts themselves .

Figure 40

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Imidazoles

Figure 41 Grubbs’ catalyst, second generation.

1,3-Disubstituted imidazolium salts belong to a class of novel solvents known as ionic liquids. Imidazolium-based ionic liquids possess very interesting properties, such as negligible vapor pressure, ability to dissolve organic, inorganic, and polymeric materials and high thermal stability. Thus, ionic liquids have gained popularity as ‘green’ alternatives to volatile organic solvents, to be applied in electrochemical, synthetic, and separation processes .

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1999JOC1331 1999JOC6425 1999JOC7158 1999JOC8084 1999JOM(588)155 1999MRC878 1999OL145 1999OL933 1999OL953 1999PCA4525 1999PCA9336 1999S1613 1999SAA2393 1999SC3025 1999SL1543 1999TA3011 1999T2695 1999T3987 1999T4109 1999T4377

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351

352

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2000TA435 2000T629 2000T2061 2000T4071 2000T5405 2000T6563 2000T10075 2000TA1617 2000TL1165 2000TL1275 2000TL2265 2000TL5031 2000TL5407 2000TL5453 2000TL7503 2000TL8431 2000TL9267 2001AGE3228 2001AGE4229 2001AGE4277 2001AIJ2384 2001BMC613 2001BML1133 2001CC643 2001CC1466 2001CC2274 2001CEJ2007 2001CEJ3122 2001CRV1115 2001CRV1385 2001CRV1421 2001EJO237 2001GC156 2001H(55)243 2001H(55)2109 2001HCA3403 2001JA6404 2001JA7727 2001JA11097 2001JBS417 2001JFC(107)147 2001JHC141 2001JHC773 2001JHC849 2001JHC939 2001JMP911 2001JMT(571)139 2001JMT(574)221 2001JOC1097 2001JOC4687 2001J(P1)1500 2001J(P1)1241 2001J(P1)3054 2001JPC10249 2001JPO770 2001JST(565)107 2001MRC681 2001OL157 2001OL1249 2001OL1319 2001OL3799 2001PCP3569

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Imidazoles

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355

356

Imidazoles

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Imidazoles

2003SC153 2003SC1977 2003SC3193 2003SL102 2003SL780 2003SL1117 2003SL1451 2003SL1533 2003T1657 2003T6027 2003T6759 2003TA951 2003TL1379 2003TL1709 2003TL3667 2003TL4751 2003TL5965 2003TL6397 2003TL6509 2003TL7115 2003TL7485 2003TL8967 2003TL9111 2003TRH19 2003TRH167 2004AGE2674 2004AGE5130 2004AGE5507 2004AGE5896 2004AGE6343 2004AJC113 2004AXB191 2004BMCL1637 2004BML333 2004BML1151 2004BML3521 2004BML3721 2004BML6079 2004CC188 2004CC778 2004CCR2459 2004CED1082 2004CEJ3747 2004CEJ5607 2004CEJ6581 2004CSR619 2004EJO2567 2004EJO2833 2004H(63)87 2004H(63)1613 2004H(63)2769 2004HAC432 2004HCA425 2004HCA719 2004HCA3035 2004JA814 2004JA2807 2004JA4366 2004JA7800 2004JA12776 2004JFC(125)501 2004JHC335 2004JHC701

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357

358

Imidazoles

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2005BML4691 2005BML5136 2005BML5211 2005CC868 2005CC2849 2005CEO514 2005CHE1134 2005CHE1201 2005CJC110 2005CL734 2005CTM987 2005EJO1637 2005GC83 2005GC701 2005H(65)353 2005H(65)1975 2005H(65)2721 2005H(65)2783 2005H(65)2893 2005H(66)263 2005HCA10 2005HCA487 2005HCA707 2005HCA1589 2005HCA2454 2005HCA2705 2005HCA3253 2005JA5675 2005JA8942 2005JA9485 2005JA10070 2005JA12544 2005JA14675 2005JA16366 2005JA16792 2005JA17624 2005JCO317 2005JCO826 2005JCP174501 2005JHC173 2005JHC883 2005JHC899

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Nakamura, N. Aratani, H. Shinokubo, A. Takagi, T. Kawai, T. Matsumoto, Z. Yoon, D. Kim, T. Ahn, D. Kim, A. Muranaka, N. Kobayashi, and A. Osuka, J. Am. Chem. Soc., 2006, 128, 4119. M. Erlacher, K. Lang, B. Wotzel, R. Rieder, R. Micura, and N. Polacek, J. Am. Chem. Soc., 2006, 128, 4453. A. R. Siamaki and B. A. Arndtsen, J. Am. Chem. Soc., 2006, 128, 6050. C. Kanazawa, S. Kamijo, and Y. Yamamoto, J. Am. Chem. Soc., 2006, 128, 10662. V. K. Landry, M. Minoura, K. Pang, D. Buccella, B. V. Kelly, and G. Parkin, J. Am. Chem. Soc., 2006, 128, 12490. J. F. Glister and K. Vaughn, J. Heterocycl. chem., 2006, 43, 217. S. A. Popov, N. V. Chukanov, G. V. Romanenko, T. V. Rybalova, Y. V. Gatilov, and V. A. Reznikov, J. Heterocycl. Chem., 2006, 43, 277. P. Parik, S. Senauerova, V. Liskova, K. Handlir, and M. Ludwig, J. Heterocycl. Chem., 2006, 43, 835. V. Ognyanov, C. Balan, A. Bannon, Y. Bo, C. Dominguez, C. Fotsch, V. Gore, L. Klionsky, V. Ma, Y. Qian, R. Tamir, X. Wang, N. Xi, S. Xu, D. Zhu, N. 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361

362

Imidazoles

2006OL1073 2006OL2249 2006OL2417 2006OL2531 2006OL2779 2006OL3049 2006OL3351 2006OL4083 2006OL4989 2006OL5781 2006PCP2101 2006PCA2269 2006PCA2535

2006PCA7621 2006RCM1071 2006SL227 2006SL965 2006SL1479 2006SL2195 2006T1351 2006T3798 2006T4435 2006T4597 2006T5474 2006T5868 2006T8586 2006T10182 2006T10555 2006TL79 2006TL1509 2006TL2129 2006TL3897 2006TL5033 2006TL5203 2006TL5763 2007T2414

M. Kim, J. V. Mulcahy, C. G. Espino, and J. Du Bois, Org. Lett., 2006, 8, 1073. D. A. Evans and K. R. Fandrick, Org. Lett., 2006, 8, 2249. E. Biron, J. Chatterjee, and H. Kessler, Org. Lett., 2006, 8, 2417. J. A. Fritz, J. S. Nakhla, and J. P. Wolfe, Org. Lett., 2006, 8, 2531. R. Altman and S. Buchwald, Org. Lett., 2006, 8, 2779. A. S. Pelegri, M. R. J. Elsegood, V. McKee, and G. W. Weaver, Org. Lett., 2006, 8, 3049. D. A. Evans, H. J. Song, and K. R. Fandrick, Org. Lett., 2006, 8, 3351. S. Shengule and P. Karuso, Org. Lett., 2006, 8, 4083. Y. Yasui, D. K. Frantz, and J. S. Siegel, Org. Lett., 2006, 8, 4989. D. S. Ermolat’ev’, E. V. Babaev, and E. V. Van der Eyeken, Org. Lett., 2006, 8, 5781. F. Endres and S. Zein El Abedin, Phys. Chem. Chem. Phys., 2006, 8, 2101. P. A. Hunt and I. R. Gould, J. Phys. Chem. A, 2006, 110, 2269. L. Infantes, O. Mo, M. Yanez, M. V. Roux, P. Jimenez, J. Z. Davalos, M. Temprado, M. A. V. Ribeiro da Silva, M. D. M. C. Ribeiro da Silva, L. M. P. F. Amaral, P. Cabildo, R. Claramunt, and J. Elguero, J. Phys. Chem. A, 2006, 110, 2535. A. Akdag, M. L. McKee, and S. D. Worley, J. Phys. Chem. A, 2006, 110, 7621. L. Oresmaa, P. Aulaskari, and P. Vainiotalo, Rapid Commun. Mass Spectrom., 2006, 20, 1071. M. Ishihara and H. Togo, Synlett, 2006, 227. H. Du, Y. He, R. Silvappa, and C. J. Lovely, Synlett, 2006, 965. S. Sayama, Synlett, 2006, 1479. M. Kantam, B. Rao, B. Choudary, and R. Reddy, Synlett, 2006, 2195. N. Coskun, H. Mert, and N. Arikan, Tetrahedron, 2006, 62, 1351. A. Nadipuram and S. Kerwin, Tetrahedron, 2006, 62, 3798. Z. Zhang, J. Mao, D. Zhu, F. Wu, H. Chen, and B. Wan, Tetrahedron, 2006, 62, 4435. S. F. Vasilevsky, S. V. Klyatskaya, O. L. Korovnikova, S. A. Amitina, D. V. Stass, I. A. Grigor’ev, and J. Elguero, Tetrahedron, 2006, 62, 4597. A. Marwaha, P. Singh, and M. P. Mahajan, Tetrahedron, 2006, 62, 5474. A. de la Hoz, A´. Dıáz-Ortiz, M. Mateo, M. Moral, A. Moreno, J. Elguero, C. Foces-Foces, M. Rodrı´guez, and A. SańchezMigalloń, Tetrahedron, 2006, 62, 5868. M. Matschke, C. Kaepplinger, and R. Beckert, Tetrahedron, 2006, 62, 8586. I. Kawasaki, N. Sakaguchi, A. Khadeer, M. Yamashita, and S. Ohta, Tetrahedron, 2006, 62, 10182. P. Krishnamoorthy, S. Rasapalli, H. Du, and C. Lovely, Tetrahedron, 2006, 62, 10555. P. Gogoi and D. Konwar, Tetrahedron Lett., 2006, 47, 79. J. Wu, X. Sun, and H. Xia, Tetrahedron Lett., 2006, 47, 1509. V. Mirkhani, M. Moghadam, S. Tangestaninejad, and H. Kargar, Tetrahedron Lett., 2006, 47, 2129. M. Kantam, G. Venkanna, C. Sridhar, and K. Kumar, Tetrahedron Lett., 2006, 47, 3897. X.-Q. Hao, J.-F. Gong, C.-X. Du, L.-Y. Wu, Y.-J. Wu, and M.-P. Song, Tetrahedron Lett., 2006, 47, 5033. R. Hosseinzadeh, M. Tajbakhsh, and M. Alikarami, Trtrahedron Lett., 2006, 47, 5203. S. Chandrasekhar and P. Karri, Tetrahedron Lett., 2006, 47, 5763. S. Haneda, A. Okui, C. Ueba, and M. Hayashi, Tetradedron, 2007, 63, 2414.

Imidazoles

Biographical Sketch

Dr. Ning Xi received his B.S. (1984) and M.S. (1987) in chemistry from Beijing University, Beijing, and his Ph.D. (1996) in organic chemistry from Rice University, Houston, Texas. After a year stay as a post-doctoral associate at Rice University, he started his drug discovery endeavors at AMRI, Albany, NY in 1997 and continued at Amgen, Thousand Oaks, CA in 1998. He left Amgen in 2007 and co-founded Kintor Pharmaceuticals, Inc. Dr. Xi’s research interests include applications of transition metal-catalyzed reactions, synthesis of bioactive molecules and discovery of drug candidates, especially targeting G-protein coupled receptors and kinases. He has coauthored more than 55 peer-reviewed publications and patents.

Dr. Longbin Liu Received his B.Sc. in Chemistry from NW University in Xi’an, China, in 1983. After a short stint as a teaching assistant in NW Agricultural University, he went to Columbia University in New York City in 1986 where he did his PhD (1991) work on the synthesis of helicenes in Prof. Thomas J. Katz’s group. He then pursued natural product synthesis in the laboratories of Prof. Robert E. Ireland (Virginia) and Prof. Gilbert Stork (Columbia). In 1996, he joined Amgen and is currently a Principal Scientist in the Medicinal Chemistry Department. His current research interests lie in the areas of anti-cancer drug design and heterocyclic chemistry. He has coauthored more than 30 publications and patents.

363

364

Imidazoles

Dr. Qi Huang obtained his B.S. (1986) in medicinal chemistry from Shanghai Medical University and Ph.D. (1998) in medicinal chemistry from University of Wisconsin-Milwaukee, in Prof. James M. Cook’s laboratories. During his Ph.D. work, he discovered a GABAA/BzR subtype selective agonist, which is currently undergoing clinical trials as a selective anxiolytic agent. Dr. Huang has continued his drug discovery efforts at Amgen since 1998 as a research scientist. His current research interests focus on discovering novel anti-cancer drugs. He has coauthored more than 30 publications and patents.

4.03 Isoxazoles D. Giomi and F. M. Cordero Universita` di Firenze, Sesto Fiorentino, Italy F. Machetti Istituto di chimica dei composti organometallici del CNR, Sesto Fiorentino, Italy ª 2008 Elsevier Ltd. All rights reserved. 4.03.1

Introduction

367

4.03.2

Theoretical Methods

368

4.03.2.1 4.03.2.2 4.03.3

Structure

368

Reactivity

369


370

4.03.3.1

X-Ray Diffraction

370

4.03.3.2

NMR Spectroscopy

371

4.03.3.3

Mass Spectrometry

372

4.03.3.4

UV Spectroscopy

373

4.03.3.5

Circular Dichroism Spectroscopy

373

4.03.4


373

4.03.4.1

Stability

373

4.03.4.2

Tautomerism

374

4.03.4.3

Isomerism

374

4.03.4.4

Conformational Aspects

375

4.03.4.5

Chromatographic Behavior

375

Potentiometric Properties

376

4.03.4.6 4.03.5

Reactions of Fully Conjugated Rings

376

4.03.5.1


376

4.03.5.2


377

4.03.5.3


377

4.03.5.4


377

4.03.5.5


378

4.03.5.6

Ring Opening

378

4.03.5.7

Cyclic Transition State Reactions

380

4.03.5.7.1 4.03.5.7.2 4.03.5.7.3 4.03.5.7.4

4.03.6 4.03.6.1

Electrocyclic reactions Diels–Alder reactions Hetero-Diels–Alder reactions 1,3-Dipolar cycloadditions

380 381 381 382

Reactions of Nonconjugated Rings

382

Isomers of Aromatic Compounds Not in Equilibrium with Isoxazoles

4.03.6.1.1 4.03.6.1.2 4.03.6.1.3 4.03.6.1.4

3(2H)-Isoxazolones 4(5H)-Isoxazolones 5(2H)-Isoxazolones (4H)-Isoxazolones

382 382 383 383 384

365

366

Isoxazoles

4.03.6.2

Dihydroisoxazoles

4.03.6.2.1 4.03.6.2.2 4.03.6.2.3

4.03.6.3

Isoxazolidines

4.03.6.3.1 4.03.6.3.2 4.03.6.3.3 4.03.6.3.4 4.03.6.3.5 4.03.6.3.6 4.03.6.3.7

4.03.6.4 4.03.7 4.03.7.1

2,3-Dihydroisoxazoles 2,5-Dihydroisoxazole 4,5-Dihydroisoxazoles

384 388 388

393

Reductive ring opening Oxidation Isoxazolidine ring opening under basic conditions Cycloreversion Reactivity of 5-alkoxyisoxazolidines Reactivity of 5-spirocyclopropane isoxazolidines Reactivity of hexahydroisoxazolo[2,3-b][1,2]oxazines

Isoxazolidinones Reactivity of Substituents Attached to Ring Carbon Atoms Isoxazoles

4.03.7.1.1 4.03.7.1.2 4.03.7.1.3 4.03.7.1.4 4.03.7.1.5

384

393 396 397 398 399 399 402

403 404 404

C-linked substituents N-Linked substituents O-Linked substituents Halogen atoms Metal- and metalloid-linked substituents

404 410 411 411 412

4.03.7.2

Isoxazolines

413

4.03.7.3

Isoxazolidines

416

4.03.7.3.1 4.03.7.3.2 4.03.7.3.3 4.03.7.3.4 4.03.7.3.5

C-linked substituents N-linked substituents O-linked substituents S-linked substituents Metal- and metalloid-linked substituents

4.03.8

Reactions of Substituents Attached to Ring Nitrogen

4.03.9

Ring Syntheses Classified by Number of Ring Atoms Contributed by Each Component

4.03.9.1

4.03.9.2

From atom From atom From atom From atom

fragment: C–C–C–N–O fragment: C–C–C–O–N fragments: C–N–O þ C–C fragments: C–C–C þ N–O

Synthesis of Isoxazolidines

4.03.9.3.1 4.03.9.3.2 4.03.9.3.3 4.03.9.3.4

4.03.9.4

fragment: C–C–C–N–O fragment: C–C–N–O–C fragment: O–C–C–C–N fragment: C–C–C–O–N fragments: C–C–N–O þ C fragments: C–N–O þ C–C fragments: C–C þ N–O þ C

Synthesis of Dihydroisoxazoles

4.03.9.2.1 4.03.9.2.2 4.03.9.2.3 4.03.9.2.4

4.03.9.3

From atom From atom From atom From atom From atom From atom From atom

From atom From atom From atom From atom

fragment: C–C–C–N–O fragment: C–C–C–O–N fragments: C–N–O þ C–C fragments: C–C–C þ N–O

Synthesis of Isoxazolidinones and Isoxazolidinediones

4.03.9.4.1 4.03.9.4.2 4.03.9.4.3

421 422

Synthesis of Isoxazoles

4.03.9.1.1 4.03.9.1.2 4.03.9.1.3 4.03.9.1.4 4.03.9.1.5 4.03.9.1.6 4.03.9.1.7

417 419 420 420 420

Isoxazolidin-3-ones Isoxazolidin-5-ones Isoxazolidinediones

422 423 426 426 427 427 427 436

436 436 437 437 446

447 447 448 449 456

456 456 457 460

Isoxazoles

4.03.10


4.03.11

Syntheses of Particular Classes of Compounds and Critical Comparison of the

4.03.12

461

Various Routes Available

463


466

4.03.12.1

Natural Products

466

4.03.12.2

Biologically Active Compounds

468

4.03.12.3

Chemosensor Compounds

471

4.03.12.4

Liquid Crystals

472

4.03.12.5

Ligands for Asymmetric Synthesis

472

References

473

4.03.1 Introduction Isoxazoles, isoxazolines, and isoxazolidines are five-membered heterocyclic systems with one oxygen atom and one nitrogen atom at adjacent positions. The chemistry of isoxazole is associated with the name of Ludwig Claisen, who recognized in 1888 the cyclic structure of 3-methyl-5-phenylisoxazole, obtained by Ceresole in 1884 from hydroxylamine and benzoylacetone . Claisen suggested for this nucleus the name of ‘monoazole,’ then modified by Hantzsch to ‘isoxazole,’ from the already-known isomeric ring ‘oxazole’ . The parent isoxazole was synthesized by Claisen in 1903 by oximation of propargylaldehyde acetal . Between the three classes of dihydroderivatives, the 2-isoxazolines are by far the most easily prepared and widely studied. The preparation of the first derivative, 3,5-diphenyl-2-isoxazoline from -chloro--phenylpropiophenone and hydroxylamine, was reported in 1895 ; however, the synthesis of saturated compounds was not described until 1918 and isoxazolidine itself was prepared in 1942 . Concerning bicyclic derivatives, the first 1,2-benzisoxazole, 3-phenyl-1,2-benzisoxazole, was synthesized by treatment of o-nitrobenzophenone oxime with alkali in 1892 , and the parent compound was obtained in 1908 . In 1881, 5,6-dimethoxy-2,1-benzisoxazole was the first compound of this class to be prepared , and in 1882 the unsubstituted system was synthesized by reduction of o-nitrobenzaldehyde with tin in acetic or hydrochloric acid . A very significant contribution to the development of isoxazole chemistry came in the period 1930–1946 from Quilico’s studies on synthetic approaches to the ring system from nitrile oxides and unsaturated compounds . However, the study of isoxazolidines began very much more recently being related to the availability of this nucleus and then to the discoveries of cycloadditions of nitrones to olefins and intramolecular cyclizations of unsaturated nitrones . The great interest still nowadays associated with this class of compounds is certainly based on their versatility as synthetic building blocks: their latent functionalities as enaminones, 1,3-dicarbonyl compounds, -amino alcohols, and -hydroxy nitriles have been widely exploited for the synthesis of other heterocycles and complex molecules. Moreover, many derivatives exhibit interesting applications in various fields such as agriculture, industry, and medicine. In particular, the wide spectrum of biological activities characteristic of these systems, including antithrombotic, platelet-activating factor (PAF) antagonist, hypolipidemic, nootropic, immunomodulator, antiviral, antiobesity, and central nervous system (CNS) modulation, may reasonably be ascribed to the easy cleavage of the NO bond with formation of more reactive species. The literature concerning this topic has been presented in different series: Comprehensive Heterocyclic Chemistry , The Chemistry of Heterocyclic Compounds , and Progress in Heterocyclic Chemistry . The following ring systems are discussed in this chapter, and Chemical Abstracts (CA) and common names are given as well as ring position numbering. Monocyclic species follow the normal numbering of the parent compound.

367

368

Isoxazoles

4.03.2 Theoretical Methods Earlier studies were reported in CHEC(1984) on pages 3–4 and in CHEC-II(1996) on pages 224–226.

4.03.2.1 Structure The evaluation of aromaticity is one of the most important aspects in chemistry, but the extent to which reactivity, energetic, magnetic, and geometric criteria are descriptions of a single, unifying property of molecules remains a matter of debate. In this context, a set of energetic, magnetic, and geometric indexes, such as aromatic stabilization energies (ASEs), (magnetic susceptibility exaltations), nucleus-independent chemical shifts (NICSs), and harmonic oscillator model of aromaticity (HOMA), have been determined for isoxazole and many other five-membered p-electron systems, choosing for the computations the highest, reasonable possible levels of theory . Calculated energies and magnetic NICS indexes have also been reported for 2,1-benzisoxazole (anthranil) 1 and its isomers 1,2-benzisoxazole 2 and benzoxazole 3.

The negative values of the calculated NICS indexes (restricted Hartree–Fock RHF)/6-31þG* wavefunctions of the most stable B3LYP/6-311G** geometries), examined as a magnetic criterion for aromaticity, indicate that all species have aromatic character. The NICS values for anthranil are remarkably different evidencing a loss of

Isoxazoles

aromaticity in the six-membered ring and an increase in the aromaticity of the five-membered ring, suggesting that 1 is less benzenoid than its isomers 2 and 3. However, considering the sum of the NICS values for the five- and sixmembered rings, there seem to be similar aromaticities for all the species . Direct computation of the CTOCD-DZ/6-31G** //RHF/6-31G** p-current density, that is, the ‘ring current’, of anthranil 1 and 1,2-benzisoxazole 2 and benzoxazole 3 reveals different patterns of current flow. Isomers 2 and 3 sustain strong benzene-like currents in the six-membered ring and bifurcated flow in the five-membered ring, whereas, in keeping with its lower thermodynamic stability (see Section 4.03.4.1), 1 has only a perimeter circulation without separate monocycle currents. Although the ring current criterion does not offer a sharp distinction between 2 and 3, their difference in thermodynamic stability is identical to that between isoxazole and oxazole, suggesting an aromaticity order 1 < 2 3 . As already reported in CHEC(1984) , isoxazol-5-one can exist in different tautomeric forms. In particular, relative-stability energies (kcal mol1, in brackets) for four forms consisting of three tautomers A, B, and C and a rotamer of 5-hydroxyisoxazole C9 have been computed at the B3LYP/6-31þG(d,p) level. The stability order was found to be C9 < C < B < A.

Ab initio and density functional theory (DFT) methods have been exploited to determine the structures and the interaction energies of 2H-isoxazol-5-one B, and its dimer and trimer structures in the gas phase. For the cyclic trimer, the computed structural parameters resulted in excellent agreement with the X-ray determination of the supramolecular aggregate of 4-(2-methoxybenzyl)-3-phenyl-4H-isoxazol-5-one, involving very strong intermolecular H-bonds of the NH tautomeric form, interpreted in terms of the RAHB (resonance-assisted hydrogen bond) model (see Section 4.03.3.1) .

4.03.2.2 Reactivity The Kemp decarboxylation reaction for benzisoxazole-3-carboxylic acid derivatives leading to salicylonitriles has been investigated using quantum-mechanical/molecular-mechanical (QM/MM) calculations in protic and dipolar aprotic solvents (Equation 1). Aprotic solvents have been shown to accelerate the rates of reaction by 7–8 orders of magnitude over water, suggesting hydrogen bonding as the major factor inhibiting reactivity in protic solvents, through stabilization of the reactant anion. Indeed, in compound 4c (R1 ¼ H, R2 ¼ OH), the inclusion of an internal hydrogen bond effectively inhibits the reaction with near-solvent-independence. Moreover, solute–solvent interaction energies show that poorer solvation of the reactant anion in the aprotic solvents is primarily responsible for the observed rate enhancements . A quantitative structure-reactivity relationship (QSSR) treatment of solvent effects on the decarboxylation of 6-nitrobenzisoxazole-3-carboxylic acid derivative 4d (R1 ¼ NO2, R2 ¼ H) has also been reported .

ð1Þ

The mechanisms by which solvents and catalysts, such as catalytic antibodies and serum albumins, influence the rates of the Kemp elimination, that is, the base-promoted E2 elimination of substituted benzisoxazoles such as 5 (Equation 2), have also been explored theoretically; moreover, the predictions concerning the efficiency of antibody 34E4 as catalyst

369

370

Isoxazoles

and the role of GluH50 as the essential catalytic residue were experimentally confirmed . A DFT study of the Boulton–Katritzky rearrangement of 4-nitrosobenz[c]isoxazole and its anion indicated for these reactions a pseudo-pericyclic character despite the aromaticity of the transition states .

ð2Þ

4.03.3 Experimental Structural Methods Such aspects have been previously reported in CHEC(1984) on pages 4–8 and in CHEC-II(1996) on pages 226–232.

4.03.3.1 X-Ray Diffraction X-Ray diffraction analysis is a common means to determine structure and relative configuration of solid compounds in an unequivocal way. Low-temperature single crystal structure determinations have been carried out on isoxazol-3-ol and 5-methylisoxazol-3-ol, the heterocyclic ring systems used as carboxy group bioisosteres in many neuroactive analogues of 4-aminobutyrric acid (GABA) and glutamic acid. Both compounds form dimers 6 in the solid state with hydrogen bonds between the O(3)–H and N-2. The geometries of the compounds have been optimized by ab initio calculations at the HF/6-31G* level and at the MP2/6-311G* level; the gas-phase calculations are in agreement with the experimental data, especially when correction for the effect of hydrogen bonding is made. According to the observations in the crystal studies, the structural changes in the ring upon substitution in the 5-position are almost negligible. However, the introduction of a methyl group causes a small increase in the calculated dipole moments (from 1.97 to 2.23 D) .

The X-ray structure of 4-(2-methoxybenzyl)-3-phenyl-4H-isoxazol-5-one shows a particular arrangement involving the NH tautomeric form in a supramolecular aggregate 7. The asymmetric unit is made up of three independent molecules held together by strong intermolecular hydrogen bonds N–H OTC in such a way as to form a rigid trimeric unit .

The X-ray analysis allowed comparison of the geometrical features and the intermolecular interaction of the optically pure 5-(2-amino-2-carboxyethyl)-4,5-dihydroisoxazole-3-carboxylic acid 8 with some racemic derivatives .

Isoxazoles

4.03.3.2 NMR Spectroscopy 1

H and 13C nuclear magnetic resonance (NMR) spectra in solution have been used ubiquitously to characterize and determine the structure of compounds containing the isoxazole ring and its derivatives. 19F and 13C NMR techniques were efficiently applied to the study of perfluoroalkylisoxazoles. In particular, concerning 3-phenyl-5-trifluoromethylisoxazole, the 19F NMR spectrum clearly evidenced a single peak at 13.3 ppm for the CF3 group, while the 13C pattern showed, for the substituted isoxazole ring, three signals at 103.5, 159.4, and 162.7 ppm for carbons C-4, C-5, and C-3, respectively. The presence of the CF3 group at position 5 was unambiguously suggested by the C–F coupling leading to a quartet with JC–F ¼ 42.1 Hz for the corresponding C-5 carbon . 15 N NMR spectroscopy has been efficiently applied to structural determination of 5-isoxazolylquinolinone 9. The presence of a 5-substituted isoxazole moiety instead of a 3-substituted one, suggested from homonuclear nuclear Overhauser effect (NOE) experiments, was definitely confirmed through proton-detected 1H–15N gradient heteronuclear multiple bond correlation gHMBC experiment, showing for the isoxazole nitrogen atom only one 3J N-H of ca. 3 Hz and a diagnostic coupling of 15.7 Hz for two bonds J N–H .

The natural abundance 17O NMR chemical shift data for 3,5-diarylisoxazoles and 3,5-diarylisoxazolines in acetonitrile at 75 C have been reported . High molecular weight isoxazolines such as C60-isoxazolines are, in some cases, highly insoluble, preventing their characterization by solution NMR spectra and requiring a solid-state NMR analysis. 13C NMR analysis under cross-polarization/magic angle spinning (CPMAS) conditions of C60-isoxazoline carboxylic acid 10 exhibited the signals of the carboxylic group ( ¼ 168.4 ppm) and the two C(sp3) atoms ( ¼ 75.3 and 108.1 ppm). The peaks of the C(sp2) atoms (CTC and CTN) appeared as broad signals between ¼ 140 and 150 ppm .

Solid-state 13C NMR supported the structure of the triazolidine 12, which is in tautomeric equilibrium with isoxazolidine 11 in solution (see Section 4.03.4.2) (Equation 3) .

371

372

Isoxazoles

ð3Þ

4.03.3.3 Mass Spectrometry Mass spectrometry (MS) has been commonly used for the structure determination of substituted isoxazoles and their derivatives either to validate their molecular weight or to determine their structure. Regioisomeric 4,5-dihydroisoxazoles 13 and 14 were distinguished on the basis of their MS fragmentation pattern: only the 5-phenyl isomer exhibits a peak MHþ-106 in the mass spectrum corresponding to the loss of benzaldehyde .

Electron impact ionization (EI) tandem MS and EI high-resolution MS allowed the elucidation of fragmentation pathways of isoxazolines. 3-Glycosyl-5-aryl-2-isoxazolines were studied in the gas phase under EI conditions. These derivatives showed an interesting fragmentation pattern that was explained through a rearrangement involving opening of the heterocyclic ring. For instance, in compound 15, as it was not possible to lose HCOOH from ion B, a tautomeric equilibrium between B and C was proposed. Ion C arises from O–C-5 bond cleavage of B to afford an oxime that closes to the new ring by reaction with the terminal hydroxymethylene carbon (Scheme 1) .

Scheme 1

High molecular weight isoxazolines such as C60-isoxazolines have been analyzed by the matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) technique. These compounds showed the molecular ion peak [M] and an [M–C60] ion . The nucleoside analogues, 1-(isoxazolidin-5yl)thymine and -uracil, were characterized by fast atom bombardment tandem mass spectrometry (FAB-MS/MS), and their spectra compared to those of dideoxyribose nucleosides and 5-phenyl- and 5-naphthylisoxazolidine .

Isoxazoles

4.03.3.4 UV Spectroscopy In a group of polysubstituted 2,6-dicyanoanilines, the isoxazolyl derivative 16 was one of the species with the most intense fluorescence. Maximum emission wavelengths em ¼ 414, 433, and 440 nm were observed in CH2Cl2, MeOH, and tetrahydrofuran (THF), respectively, while the corresponding fluorescent quantum yields f ¼ 0.08, 0.10, and 0.09 were calculated on the basis of 9,10-diphenylanthracene . Compound 17 shows an intense absorption at 280 nm with a long wavelength shoulder; this characteristic, in conjunction with good solubility and linear structural properties, makes it a good candidate for application as a dye in the construction of artificial photonic antenna systems for the channels of zeolite L .

4.03.3.5 Circular Dichroism Spectroscopy Circular dichroism (CD) experimental data have been used to assign the absolute configuration of isoxazoline amino acids 18 and 19 by a comparison of the experimental and theoretical vibration circular dichroism feature. These absolute configurations were further confirmed using experimental and theoretical values of specific rotation . The relationship between chiroptical properties of several substituted isoxazolidin-5-ones and their molecular structures were investigated by means of CD spectroscopy and X-ray diffraction. The sign of the CD band occurring at ca. 210 or 220 nm was correlated to the absolute configuration of the C-3 carbon of the isoxazolidine ring .

4.03.4 Thermodynamic Aspects These aspects have been reported in CHEC(1984) and CHEC-II(1996) on pages 8–11 and 232–234, respectively.

4.03.4.1 Stability Thermochemical experiments were performed to determine the standard molar enthalpy of formation of anthranil in the gaseous phase. A comparison of this value with that obtained from quantum-chemical calculations for 1,2benzisoxazole showed that anthranil 1 is significantly less stable (H f ¼ 180.8 2.1 kJ mol1) than its isomer 2 (H f ¼ 138.9 3.1 kJ mol1). This difference of about 42 kJ mol1, even if significant, suggests that by thermochemical criteria, if aromatic character is ascribed to 1,2-benzisoxazole, a significant aromatic character must also be associated with anthranil .

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Isoxazoles

4.03.4.2 Tautomerism The tautomeric composition in solution of 4-(arylmethyl)isoxazol-5-one derivatives has been determined on the basis of 1H NMR and infrared (IR) data. The CH form was predominant in chloroform solution, while the NH and OH forms are more common in polar solvents and in the solid state . 5-Hydroxy- and 5-amino-2-isoxazolines show different tautomeric forms in solution. The presence of cyclic hemiacetal or hemiaminal moieties in such molecules allows the easy cleavage of the C-5–O bond to form linear structures. Subsequent intramolecular addition of nucleophiles to the CTN bond gives rise to cyclic structures. Compounds 20 exist, in the crystalline state, as the isoxazoline form A. In solution, a ring–ring tautomeric equilibrium was observed between the isoxazoline form A and the pyrazoline form C. The tautomeric ratio depended on steric factors and on the solvent used. The tautomeric equilibrium was established after several days (Scheme 2) .

Scheme 2

More complex tautomeric equilibria have been observed for compound 21 involving the 1,2,4,5-tetrazin-3-thione C. The equilibrium is strongly shifted toward the isoxazoline form A in solvents such as pyridine, acetone, dimethylsulfoxide (DMSO), and dimethylformamide (DMF), whereas the pyrazoline form D does not exceed 5–10% (Scheme 3) . The presence of the above tautomeric species has been demonstrated by NMR. 5-Hydroxy-3,3,5trimethylisoxazolidine showed a similar behavior . The presence of a CF3 group such as in 22 affects considerably the structure of these compounds, which exist only in the cyclic isoxazoline form .

Scheme 3

4.03.4.3 Isomerism Upon chromatographic purification on silica gel, aldehyde 23 slowly epimerized to the all-trans substituted isoxazolidine 24 via retro-Michael/Michael reactions (Scheme 4) .

Isoxazoles

Scheme 4

Silica gel catalyzed the cis–trans-isomerization of some 4-nitroisoxazolidines through a cycloreversion/cycloaddition process (see also Section 4.03.6.3.4).

4.03.4.4 Conformational Aspects 1

H NMR spectroscopy at various temperatures clarified the dynamic behavior of the oligomethylene chains for [8](3,5)isoxazolophane 25 and [9](3,5)isoxazolophanes 26 and 27, applying the coalescence temperature method. The energy barriers (GC‡) for the bridge flipping (from A and B to C and D, and vice versa) are 18.6 kcal mol1 (TC 100 C) for 25 and 11.5 kcal mol1 (TC 10 C) for 26. Compound 27 (R ¼ Me) does not undergo bridge flipping at temperatures ranging from 25 to 150 C. The energy barriers for the pseudorotation between A and B (C and D) are 11.1–11.2 kcal mol1 (TC 10 C), 9.1 kcal mol1 (TC 70 C), and 8.6 kcal mol1 (TC 80 C) for 25, 26, and 27, respectively (Scheme 5) . The conformational behavior of some N-methyl- and N-phenylsubstituted 4,5-fused isoxazolidines was investigated by 1H NMR at different temperatures .

Scheme 5

4.03.4.5 Chromatographic Behavior Subcritical fluid chromatography using a carbon dioxide/methanol mobile phase has been performed on diastereomeric mixtures of isoxazolines 28–30.

The effect on separation of acid, basic, and neutral additives was studied. For charged analytes, additives that acted as competing ions of the same charge provided dramatically improved efficiency and resolution .

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Isoxazoles

Chiral normal-phase high-performance liquid chromatography (HPLC) allowed efficient ee determination of isoxazolines bearing functionalized chains. Some experimental details are given in Table 1 .

Table 1 Determination of ee by HPLC analysis

C-5

R1

R2

Columna and conditions

Rt (min)

Reference

(S)(R)(S)(R)(S)(R)(S)(R)(S)(R)(S)(R)-

Ar Ar Ar Ar Ar Ar Ph Ph Ph Ph 4-(AcNH)C6H4 4-(AcNH)C6H4

CO2i-Pr CO2i-Pr COSn-Pr COSn-Pr CO2H CO2H OH OH OCOMe OCOMe CONMe2 CONMe2

A A A(B) A(B) A(C) A(C) D D D D E E

7.4 6.7 9.9(24.9) 9.6(23.0) 14.0(23.2) 11.6(25.6) 56.6 41.4 64.9 50.9 16.0 14.0

2001JA11075 2001JA11075 2001JA11075 2001JA11075 2001JA11075 2001JA11075 2005TA1535 2005TA1535 2005TA1535 2005TA1535 2000JA3244 2000JA3244

250 4.6 mm, 10 mm particles. A ¼ Chiracel AS, CO2/[EtOH(1%TFA)] 85:15, 1.0 ml min1, 25 C, 280 nm; B ¼ Chiracel OJ, hexane/EtOH/TFA 60:40:0.25, 0.5 ml min1, 38 C, 280 nm; C ¼ Chiracel OJ, hexane/EtOH/TFA 85:20:0.25, 0.5 ml min1, 38 C, 280 nm; D ¼ Chiralpak AS-H, hexane/PriOH 9:1, 0.5 ml min1, 254 nm; E ¼ Chiralpak AD, hexane/i-PrOH 82:18, 1.5 ml min1, 254 nm. a

Chiral capillary gas chromatography (GC), performed with a -cyclodextrin trifluoroacetyl column, was also used for the determination of ee of isoxazolines . Chiral preparative HPLC has been used to obtain optically pure isoxazolines .

4.03.4.6 Potentiometric Properties An important characteristic of 3-isoxazolols is the relatively high acidity of the 3-hydroxy group, responsible for the use of this heterocyclic unit as a carboxyl group bioisoster in medicinal chemistry. The pKa value of 5.85 of the simplest compound, 3-hydroxyisoxazole, has been determined by 13C NMR titration and compared with the corresponding value of 7.54, obtained for the sulfur analogue 3-hydroxyisothiazole. This difference in acidity is likely to be one of the most important factors determining the different biological behavior observed for these structurally related heterocycles .

4.03.5 Reactions of Fully Conjugated Rings The reactivity of fully conjugated rings was previously discussed on pages 12–36 in CHEC(1984) , while reactions of the rings and/or substituents were covered on pages 234–242 in CHEC-II(1996) . This section is an update of the previous work with particular attention paid to new reagents, processes, and products.

4.03.5.1 Thermal and Photochemical Reactions Thermal isomerization of 4-nitro-3-phenylisoxazole derivatives to the corresponding 4-nitro-2-phenyloxazoles was performed in quite satisfactory yields by heating in xylene at 155 C in the presence of FeCl3–SiO2 . Flash vacuum thermolysis of isoxazolopyrimidinones gave rise to iminopropadienones RNTCTCTCTO, observed in an Ar-matrix .

Isoxazoles

Alkyllithiums or Grignard reagents reacted at room temperature with 3-methylisoxazolo[5,4-b]pyridine and compound 31 was obtained through isoxazole ring opening. By contrast, sodium malonate and sodium borohydride were able to react only under ultraviolet (UV) irradiation, allowing selective trapping of ketenimine or azirine intermediates with formation of enaminopyridone 32 and diastereomeric spiroaziridinopyridones 33, respectively (Scheme 6) .

Scheme 6

4.03.5.2 Electrophilic Attack at Nitrogen 5-Chloro-2-methylisoxazolium triflates 35 were obtained in good yields from the corresponding chloroisoxazoles 34. Treatment of 35a (R1 ¼ Ph, R2 ¼ Me) with the sodium salt of 1,3-dioxo compounds, followed by addition of triethylamine, afforded isoxazolium anhydrobases 36 (Scheme 7) . Reactions of 3-hydroxyisoxazole derivatives with phosgene in toluene gave selectively 2-chlorocarbonyl-3(2H)-isoxazolones, converted in good yields with aniline derivatives into 2-carbamoyl-3(2H)-isoxazolones .

Scheme 7

4.03.5.3 Electrophilic Attack at Carbon A convenient C-4 halogenation of 3,5-diarylisoxazoles was performed with N-halosuccinimides in acetic acid, while the corresponding fluorination has been accomplished using N–F reagent Selectfluor . A new one-pot nitration employing tetramethylammonium nitrate in dichloromethane at room temperature was efficiently applied to 3,5-dimethylisoxazole, leading to the corresponding 4-nitro derivative in high yield and purity . Direct nitration of isoxazoles was also performed with nitric acid/trifluoroacetic anhydride affording mononitro derivatives in average yields of 60% .

4.03.5.4 Nucleophilic Attack at Carbon While 3-bromoisoxazoles were inert to SNAr reactions under thermal conditions, the employment of phosphazene bases under microwave irradiation facilitated the amination process, affording 3-aminoisoxazoles in moderate yields .

377

378

Isoxazoles

4.03.5.5 Nucleophilic Attack at Hydrogen Direct lithiation of 3-(BOC-amino)-5-methylisoxazole and 5-(BOC-amino)-3-methylisoxazole gave dianions that reacted with a variety of electrophiles to afford 4-substituted aminoisoxazoles in good yields (BOC ¼ t-butoxycarbonyl) . A mechanistic investigation of reactions of 3-phenylisoxazole with alkyllithiums has been reported. Alkyllithiums gave 5-H abstraction followed either mainly by ring fragmentation to benzonitrile and ethynolate ion or by formation of alkylated enaminones .

4.03.5.6 Ring Opening Base-induced or reductive cleavage of isoxazole rings followed by silylation of the resulting open-chain products gave rise to bis(siloxy)butadienes in high yields . The interaction of 3,5-disubstituted isoxazoles and isoxazolines with a low-valent titanium isopropoxide reagent, prepared from Ti(OPri)4 and EtMgBr in diethyl ether, led to chemoselective reductive cleavage of the five-membered ring to afford -enaminoketones and -hydroxyketones, respectively . Several enantiomerically pure 9-hydroxy--enaminoketones were synthesized by reductive cleavage of the corresponding isoxazole carbinols obtained in enantiopure form by enzymatic kinetic resolution (KR) of the racemic -hydroxyisoxazoles using lipases . A convenient synthesis of substituted pyran-4-ones from isoxazoles through reaction with Mo(CO)6 has been reported . Reductive cleavage of 3-, 4-, 5-silyl-, and 5-silylmethylisoxazoles 37 gave silyl -enaminones 38, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 39, as well as pyrrole, pyrimidine, and pyridine derivatives (Scheme 8) .

Scheme 8

Hydrogenolysis and subsequent acidic hydrolysis of isoxazolyl-alcohols 40, synthesized via standard procedures, allowed a facile access to 3(2H)-furanones 41, useful intermediates for the synthesis of geiparvarin analogues (Scheme 9) .

Scheme 9

Isoxazoles

Reductive ring opening was exploited for the synthesis of pyrido-condensed heterocycles, containing from five to eight atoms in the fused ring. 4-Substituted isoxazolo[4,5-c]pyridines 42 were easily converted into derivatives 43 with Mo(CO)6 in refluxing methanol (Scheme 10). The same ring-opening/ring-closure strategy was also applied to 4-substituted isoxazolo[5,4-b]pyridine systems .

Scheme 10

Variously substituted isoxazolo[3,4-d]pyridazinones were subjected to reductive cleavage with ammonium formate in ethanol: thus, compound 44 gave the 5-acetyl-4-aminopyridazinone 45, which showed antinociceptive properties . Analogous systems 46 were allowed to react with hydrazine in ethanol leading, through ringopening/ring-closure processes, to 4-amino-5-pyrazolyl derivatives 47 (Scheme 11) .

Scheme 11

3-Methylpyrrolo[3,4-c]isoxazoles 48, prepared from 3-(1-aminoalkyl)isoxazole-4-carboxylic esters (see Section 4.03.9.1.6), after deprotonation and condensation with aromatic aldehydes afforded compounds 49 that were subjected to N–O bond cleavage: the use of Mo(CO)6 gave 3-enoyltetramic acids 50, whereas H2-catalyst allowed further reduction to 3-acyltetramic acids 51 (Scheme 12) . In many synthetic pathways, isoxazoles have been used as latent -ketonitrile functionalities. Reactions of 5-ribofuranosylisoxazole-4-carbaldehyde 52 with 1,2-diaminobenzenes led to Schiff’s bases 53, converted to 3-cyano-1,5-benzodiazepine C-nucleosides 54 through isoxazole ring opening (Scheme 13) . -Ketonitriles can be obtained from 3-bromoisoxazoles by reductive opening with Mo(CO)6 or FeCl2?4H2O. Then, a tandem ring-opening/cyclocondensation of aldehyde-containing 3-bromoisoxazoles allowed the synthesis in satisfactory yields (65–82%) of a series of functionalized 1-benzoxepines, such as 57 from salicylaldehyde derivative 55 through intermediate 56 (Scheme 14) .

379

380

Isoxazoles

Scheme 12

Scheme 13

Scheme 14

Treatment of 5-methylisoxazole with 2 equiv of lithium diisopropylamide (LDA) afforded the dianion of -cyanoacetone, converted to 2-alkylidenetetrahydrofurans and 5-alkylidene-2,5-dihydropyrrol-2-ones by reaction with suitable dihalo derivatives . Some macrocyclic xylene-bridged hosts catalyzed the base-promoted decomposition of 5-nitrobenzisoxazole to 2-cyano-4-nitrophenol with unusually large rate accelerations . 3-Aminobenzisoxazoles gave 2-hydroxybenzamidines by reductive cleavage of the N–O bond. The use of catalytic hydrogenation, as well as Zn/AcOH or NiCl2/NaBH4, allows for chemoselective reduction even in the presence of hydrogenation-sensitive functional groups . Analogous ring opening afforded 2-aminobenzophenones in high yields, by treatment of 3-aryl-2,1-benzisoxazoles with SmI2 .

4.03.5.7 Cyclic Transition State Reactions 4.03.5.7.1

Electrocyclic reactions

Thermal decomposition of dimethyl 2-(5-aryl-3-methylisoxazol-4-yl)-2-oxo-1-diazoethylphosphonates gave naphth[2,1-d]isoxazoles through a tandem Wolff rearrangement/6p-electrocyclization sequence, involving ketene intermediates (Equation 4). The same process was performed on 5-alkenyl or 5-furyl isoxazoles, leading to 1,2benzisoxazoles and benzofuroisoxazoles, respectively .

Isoxazoles

ð4Þ

4.03.5.7.2

Diels–Alder reactions

4-Nitro-3-phenylisoxazole 58 reacted as a dienophile with open-chain and cyclic carbodienes, as well as azadienes, to yield different polynuclear isoxazole systems, such as tricyclic and bicyclic derivatives 59–61 (Scheme 15) .

Scheme 15

4.03.5.7.3

Hetero-Diels–Alder reactions

A few 4-nitroisoxazoles were found to behave as heterocyclic nitroalkene heterodienes with ethyl vinyl ether (EVE) affording spiro tricyclic nitroso acetals through highly diastereoselective pericyclic homodomino processes involving bicyclic nitronates as key intermediates. A [4þ2] hetero-Diels–Alder (HDA) reaction of isoxazoles 62a and 62b with an excess of EVE gave bicyclic nitronates 63a and 63b, converted to diastereomeric 1,6,9-trioxa-5,9a-diazacyclopenta[d]indenes 64a and 64b and 65a and 65b through 1,3-dipolar cycloaddition with the same reagent (Scheme 16) .

Scheme 16

The reaction of isoxazolopyrimidine and cyanoalkenes, in the presence of triethylamine as a catalyst, afforded pyridopyrimidine N-oxides in excellent yields. The reaction likely involves a [4þ2] cycloaddition of the starting isoxazole as azadiene on keteneimine intermediates, derived from cyanoalkenes and NEt3 (Equation 5) .

381

382

Isoxazoles

ð5Þ

4.03.5.7.4

1,3-Dipolar cycloadditions

Upon base treatment with silver carbonate, isoxazolyl-substituted hydrazonoyl chlorides underwent a sequential intra–intermolecular nitrilimine 1,3-dipolar cycloaddition, leading to tetracyclic pyrazolidines (Equation 6) .

ð6Þ

4.03.6 Reactions of Nonconjugated Rings The reactivity of nonconjugated rings was previously discussed in CHEC(1984) and CHECII(1996) . This section is an update of the previous work concerning new reagents, processes, and related products.

4.03.6.1 Isomers of Aromatic Compounds Not in Equilibrium with Isoxazoles 4.03.6.1.1

3(2H)-Isoxazolones

Both enantiomers of 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA) 69, an analogue of the neuroexcitant 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA), were synthesized in 33% overall yield (from pinacolone) and 99% ee. The enantiomerically pure glycine derivative (S)-66 was coupled with 4-bromomethyl-2-methoxymethyl-5-tert-butyl-3(2H)-isoxazolone 67 to give the intermediate (2S,5S)-68, which was hydrolyzed under mild conditions to give enantiopure (S)-69. The use of (R)-66 allowed the synthesis of (R)-69 (Scheme 17) .

Scheme 17

Isoxazoles

4.03.6.1.2

4(5H)-Isoxazolones

A regioselective 1,2-transposition of the carbonyl group has been performed on 3-phenyl-5-bromo-4(5H)-isoxazolone, in the presence of thiourea, leading to 3-phenyl-5(4H)-isoxazolone .

4.03.6.1.3

5(2H)-Isoxazolones

Reactions of 4-aryl-5(2H)-isoxazolones with 1,2-dibromoethane in acetonitrile in the presence of 1 equiv of triethylamine gave 2-bromoalkyl-4-aryl-5(2H)-isoxazolones as major products that were converted to heterocyclic ketene N,O-acetals by treatment with sodium methoxide in boiling methanol . The preparation of quinoline derivatives was achieved by catalytic hydrogenation of 2-(2-formylaryl)-5(2H)-isoxazolones . 4-Nitro-2-methyl-5(2H)-isoxazolone 70 reacted with alkyne and alkene dipolarophiles in MeCN/H2O at room temperature to give cycloadducts 71 and 72 in good yields, probably through a carbamoyl nitrile oxide intermediate generated by loss of CO2 (Scheme 18) . Moreover, reactions of 70 with enolates allowed a convenient synthesis of 3-functionalized (R1 ¼ Me, CH2CO2Et, CO2Et) 4-nitropyrrole-2-carboxylates (R2 ¼ OEt) and 2-acyl-4-nitropyrroles (R2 ¼ Me, Ph) 73. A mechanistic rationale involving nitroenamine intermediates found support in the isolation of compound 74 from the reaction of 70 and acetoacetate (Scheme 18) .

Scheme 18

N-Acylisoxazol-5-ones were converted into the corresponding 2-substituted oxazoles by photolysis or flash vacuum pyrolysis, with CO2 extrusion . Analogous treatments of 2-alkenyl-5(2H)-isoxazolones 76, obtained by Michael addition of propiolate esters to isoxazolones 75, gave pyrroles 77 (Scheme 19) . Moreover, solvolysis of 2-aryl-3-arylamino-5(2H)-isoxazolones in the presence of K2CO3 allowed the synthesis of indoles or imidazopyridines, probably through intramolecular cyclization of intermediate 1,3-dipoles produced from the isoxazolone by loss of CO2 .

Scheme 19

The nucleophilic ring opening of the isoxazolone ring in isoxazolopyrimidine derivatives 78 by optically active amino acid amides led to pyrimidinylmethylamino acid amides 79 with different degrees of stereoselectivity, mostly dependent on the nucleophile used (Scheme 20) .

383

384

Isoxazoles

Scheme 20

4.03.6.1.4

(4H)-Isoxazolones

4-Alkylidene-5(4H)-isoxazolones, obtained by Knoevenagel-type condensation of the 4-unsubstituted species with aldehydes and ketones, have been easily converted to a variety of -branched alkynes. For instance, conjugate addition of an organometallic reagent to compound 80 led to 5(2H)-isoxazolones 81, converted into alkynes 82 through nitrosative cleavage of the heterocyclic ring by treatment with sodium nitrite and ferrous sulfate in aqueous acetic acid (Scheme 21) .

Scheme 21

Hantzsch 1,4-dihydropyridine 84 was exploited for selective reduction of the exocyclic double bond of 4-arylmethylene- and 4-alkylidene-4H-isoxazol-5-ones 83 with high efficiency to give 2H-isoxazol-5-ones 85 (Scheme 22) . 1,3-Dipolar cycloadditions of bromonitrilimine with (Z)-4-arylmethylene-4H-isoxazol-5-ones have been reported .

Scheme 22

4.03.6.2 Dihydroisoxazoles 4.03.6.2.1

2,3-Dihydroisoxazoles

The 4-isoxazoline ring includes an N–O bond connected to a p-system (N–O-vinyl functionality) that shows a low thermochemical stability allowing ring-rearrangement reactions. Aziridines are generally assumed to be involved in

Isoxazoles

the above rearrangements and their further ring opening gives azomethine ylides, the supposed precursors of a variety of other products. However depending on the substituents and the reaction conditions, different pathways can occur. 2,3-Dihydroisoxazoles bearing a butadienyl group at C-4, under thermal activation (short time thermolysis at 280– 320 C), gave in moderate yield the isomeric bicyclic dihydroazepines 88 together with a minor amount of the 1,2annulated pyrroles 89 (Equation 7) .

ð7Þ

The spiroisoxazoline 90 rearranged almost quantitatively at low temperature (10 C) to give the corresponding enamino-ketone 91 (Equation 8) .

ð8Þ

The N–O bond of isoxazoline ring can be also cleaved with Co2(CO)8 in anhydrous acetonitrile at 75 C. In these conditions, the isomeric 2-acylaziridines have been isolated with yields ranging from 39% to 92%. For instance, the optically pure isoxazoline 92 underwent a totally diastereoselective rearrangement to give aziridino ketone 93 as a single isomer (Equation 9) . Quaternization of the nitrogen atom in the 4-isoxazoline system leads to an increased chemical lability of the C-3–N bond also; thus, 3,3-disubstituted 4-isoxazolines 94 were easily converted into enals 95 by treatment with MeI in THF at reflux temperature. When the same reaction was performed in polar solvents such as MeOH, DMF, or MeCN, the formation of minor amounts of ,-unsaturated amides 97 was observed. The amides 97 were obtained as sole products in high yields by heating the preformed isoxazolinium salts 96 in MeOH. This process is believed to proceed through the heterolytic cleavage of the C-3–N bond of 96 assisted by the solvent with formation of an allylic tertiary carbocation intermediate (Scheme 23) .

ð9Þ

Scheme 23

385

386

Isoxazoles

Some stable azomethine ylides were prepared by photochemical excitation of a series of differently annulated 4-isoxazolines. For example, irradiation of a ca. 103 molar solution of 98 in C6H6 with a high-pressure mercury lamp afforded the azomethine ylide 101 in 88% yield after chromatographic purification. The proposed pathway for the transformation is based on photochemically induced N–O bond cleavage in 98 to the diradical 99 followed by bond reorganization to aziridine 100, which then undergoes C–C cleavage to afford the final product 101 (Scheme 24) .

Scheme 24

Stable isoxazolo[3,2-a]isoquinolines, obtained at room temperature by nitrone 1,3-dipolar cycloaddition afforded the corresponding ylides in high yields by heating in refluxing toluene. For example, isoxazoline 102 gave the ylide 103 in 91% yield. Applying the same conditions to a one-pot reaction starting from nitrone and dipolarophile, the same ylide 103 was obtained in 71% yield (Scheme 25) . The rate of the rearrangement of such isoxazolines is strongly affected by the substitution pattern . Similar isoxazolines bearing a primary carbon bonded to the bridgehead carbon atom gave unstable ylides after rearrangement. For example, isoxazoline 104 gave the pyrrole 106 in 79% yield .

Scheme 25

Reduction of stable 2,3-dihydroisoxazoles 107 afforded diastereoselectively substituted -amino ketones and -amino alcohols, depending on the reaction conditions. Treatment of 107 with NaBH4 gave the -amino alcohol 108 with high diastereoselectivity, whereas treatment with zinc powder afforded amino ketones 109 (Scheme 26) .

Scheme 26

Stable chromium and tungsten Fischer dienyl carbenes bearing a 2,3-dihydroisoxazole ring have been treated with isocyanides to give highly functionalized 2,3-dihydro-1,2-benzisoxazoles and indazoles. Treatment of chromium isoxazoline 110 with benzyl isocyanide afforded the tricyclic compound 111 selectively in 82% yield (Equation 10) .

Isoxazoles

ð10Þ

Unstable 4-isoxazolines have also been indicated as intermediates in some reactions . The dihydroimidazolium nitrone 112 reacted with dimethyl acetylenedicarboxylate (DMAD) to give the dione 115. The formation of this bicyclic product can be rationalized by N–O bond cleavage of the primary 1,3-dipolar cycloadduct 113 followed by sigmatropic 1,5-H shift of the bridgehead hydrogen atom and bond reorganization to keteneaminal 114 which cyclises to 115. When propylate was used as dipolarophile, the final cyclization is precluded and keteneaminal was the isolated product (Equation 11) .

ð11Þ

In a similar way, the formation of fused pyrroles 118 and 119 from isoxazolidine 116 has been rationalized on the basis of a rearrangement involving a 1,3-hydrogen shift to give the isoxazoline 117 followed by the usual acylaziridine intermediate rearrangement (Equation 12) .

ð12Þ

4-Isoxazolines are evoked as intermediates in the copper-catalyzed coupling of alkynes and nitrones (Kinugasa reaction). Although not firmly established, a plausible mechanism involves the formation of a 4-isoxazoline 120, derived from the cycloaddition between a nitrone and an in situ-generated copper acetylide. Protonation and subsequent rearrangement via the intermediate oxaziridine 121 provides the final -lactam 122 (Equation 13) . The asymmetric version of the Kinugasa reaction has been reported .

ð13Þ

387

388

Isoxazoles

4.03.6.2.2

2,5-Dihydroisoxazole

The oxidation of 123 with chloranil (tetrachloro-p-benzoquinone) in toluene at reflux temperature yielded the isoxazole 124, whereas treatment of 123 with Ra-Ni and H3BO3 in MeOH/H2O led to the oxime 125 in moderate yield. Attempts at reductive ring opening of 123 failed (Scheme 27) .

Scheme 27

4.03.6.2.3

4,5-Dihydroisoxazoles

The 4,5-dihydroisoxazole ring is usually sufficiently stable to allow the introduction or manipulation of substituents (see Section 4.03.7.2). However ring opening can be smoothly achieved by cleavage of the weak N–O bond and less frequently of the C(5)–O bond using suitable reagents. The use of 4,5-dihydroisixazoles in the synthesis of heterocycles and natural products has been described in detail .

4.03.6.2.3(i) Reaction with ring cleavage N–O bond cleavage can be accomplished by various reagents including hydrogenation over Pd/C or Raney-Ni, treatment with Mo(CO)6, TiCl3, SmI2, LiAlH4, sodium, or by oxidation with ozone. Reagents such as Me4NB(OAc)3H, NaCNBH3, and Zn(BH4)2 are poor performers. The reductive cleavage leads to the formation of various 1,3-bifunctional compounds often in good yields and with complete stereochemical integrity. These methods are often compatible with highly functionalized molecules . In some cases, side-chains are also involved with possible cyclization of the primary reduction product to a new heterocycle. The cyclic sulfate derivative 126 was converted into piperidine 127 through one-pot reduction and cyclization reactions. The process was very efficient, as in the key step the amine attacked the sulfate moiety in a highly stereoand regioselective manner to afford 127 as a single isomer in 82% yield. Anydrous conditions were very important to prevent the competitive hydrolysis of the imine intermediate into ketone. Subsequent sulfate hydrolysis and debenzylation afforded the trihydroxy piperidine 128 (Scheme 28) . The use of enantiopure 126, or similar isoxazolines, allowed the synthesis of enantiomerically pure iminosugar analogues of 1-L-deoxynojirimycin and 1-D-deoxymannojirimycin .

Scheme 28

Suitably protected spiro isoxazoline 129 afforded the amino alcohol 130 with concomitant hydrogenolysis of benzyl ethers and reductive cleavage of the N–O bond by hydrogenation over Pd(OH)2/C (Equation 14) .

Isoxazoles

ð14Þ

Isoxazolines have also been converted into 1,3-amino alcohols by polymethylhydrosiloxane (PMHS)–Pd(OH)2/C. When the reduction was performed in the presence of (BOC)2O, N-BOC protected compounds were directly achieved (BOC ¼ t-butoxycarbonyl). For example, N-BOC--amino alcohols 132 were synthesized from the corresponding isoxazolines 131 in one step and 78–88% yield (Equation 15) .

ð15Þ

An electrocatalytic method for reductive N–O bond cleavage of 3-methoxyisoxazolines in the presence of nickel(0)– bipyridine [Ni(0)bpy] complex has been studied. The nickel complex, generated in situ from Ni(II)bpy, acts as the actual electron source. Under these conditions, isoxazoline 133 afforded a mixture of -hydroxyester 134 and -hydroxynitrile 135 in different ratios, depending on the amount of Ni(II)bpy used, and in high overall yields (Scheme 29) .

Scheme 29

Raney-Ni is a useful reagent to prepare hydroxy ketones . 3,5-Bis(arylmethyl)-2isoxazolines 136 can be smoothly converted into the corresponding hydroxy ketones 137 by a catalytic reduction with Raney-Ni under a hydrogen atmosphere in the presence of water and acetic acid. In the case of compounds 136a and 136b, methanol was successfully used as solvent. However the solubility of the isoxazolines 136c and 136d, having bulky nonpolar naphthyl groups, in methanol was significantly less and manifested itself in long reaction times and poor yields. When methanol was replaced with THF, which dissolved the isoxazolines 136c and 136d, reaction occurred easily, giving the products in high yields (Equation 16) .

ð16Þ

The cleavage of the isoxazoline ring with H2, Raney-Ni, B(OH)3, and MeOH/H2O (5:1) did not yield the expected ketone but the corresponding imine. The resistance of the imine function toward hydrolysis was attributed to steric congestion . Reductive hydrolytic cleavage of isoxazolines 138 with Pd/C as catalyst and boric acid in methanol and water gave the 7-deoxy-8-osulose derivative 139 in 67% yield. These conditions minimized epimerization and competing side reactions involving over-reduction of the putative -hydroxy imine intermediate and retro-aldol fragmentation (Equation 17) .

389

390

Isoxazoles

ð17Þ

The molybdenum-mediated cleavage reactions of a series of disubstituted-4,5-dihydroisoxazoles having aryloxy substituents at C-5 have been studied . Isoxazolines 140 underwent molybdenum-mediated tandem reductive N–O bond cleavage–retro-aldol reactions to provide compounds 141 or 142 as a mixture of stereoisomers (Scheme 30) .

Scheme 30

The Mo(CO)6-mediated reductive ring opening of isoxazolines has been applied to unmask -hydroxy ketones, used as intermediates in the total synthesis of myriaporones . Mo(CO)6 cleaved the N–O bond of polymersupported isoxazolines . The photo-induced ring opening of adamantyl isoxazolines mediated by Mo(CO)6 provided mainly enamino ketones . The isoxazoline syn-143 underwent iodoetheration by iodine monochloride to give THF derivative 144 with good diastereoselectivity (trans:cis ratio ¼ 29:1) (Equation 18) .

ð18Þ

Borane dimethyl sulfide complex cleaved the isoxazoline ring of amino alcohols 145 in good yield diastereoselectively. Chemoselective reduction with LiAlH4 of ester 147 followed by highly diastereoselective reductive cleavage with the borane dimethyl sulfide complex gave the amino alcohols 146 in good yield. One-step reduction/ring cleavage of 147 gave alcohol 146 in low yield (Scheme 31) .

Scheme 31

Isoxazoles

3,5-Disubstituted isoxazolines 148 were reduced by the low-valent titanium isopropoxide reagent. The reaction afforded the corresponding -hydroxyketones 149 in good isolated yields and was tolerant of various functional groups, including alkynyl and sulfide groups (Scheme 32). The reaction probably proceeds via titanium(III)-assisted homolytic cleavage of the N–O bond with the intermediate formation of a titanium(IV) derivative . The use of a high excess of EtMgBr caused low yields .

Scheme 32

Dihydroisoxazoles 150 are stable in concentrated HCl and 50% H2SO4 at a temperature up to 100 C, but by treatment with a base such as sodium methoxide they undergo O–C-5 scission of O–C(5) bond, affording the corresponding oximes 151 in good yields (Equation 19) .

ð19Þ

The products obtained from the reductive cleavage of 5-(bromomethyl)isoxazolines 152 by reaction with magnesium in methanol are temperature dependent (Scheme 33) .

Scheme 33

The substituted isoxazoline 155 was smoothly converted into 156 by treatment with tetrabutylammonium fluoride (TBAF). Subsequent oxidation gave oxazin-3-one 157 (Scheme 34) .

Scheme 34

2-Isoxazolines bearing a proton on C-3 possibly undergo ring cleavage with bases to lead to the formation of the corresponding -hydroxy nitriles . In C60-4,5-dihydroisoxazoles, however, a competitive rearomatization process may consume the product: the oxyanion 159, formed after ring cleavage, can attack the neighboring

391

392

Isoxazoles

cyano group due to the restricted eclipse relationship, and the resulting four-membered imino ether is ready to fragment to give [60]fullerene. The presence of a protic solvent such as methanol prevents the above fragmentation reaction, quenching the intermediate oxyanion. Therefore, treatment of isoxazoline-fused [60]fullerene 158 with NaOMe in the presence of MeOH gave the -hydroxy nitrile derivative 160 in good yield, while using LDA, fullerene itself 161 was obtained (Scheme 35) .

Scheme 35

Bases can also promote the degradation of 4,5-dihydroisoxazoles bearing a labile proton on C-5 or a side-chain (see Section 4.03.7.2). Concentrated H2SO4 or PCl5 have been used to open spiroannulated isoxazolines to give respectively ,-unsaturated oximes or amides . Treatment of a variety of 3-bromo-2-isoxazolines with sodium iodide in the presence of chlorotrimethylsilane gave the corresponding -hydroxy nitriles in good to moderate yields . Hydrogenolysis of dicarboxylic isoxazolines has been achieved with Na/Hg in aqueous ethanol in good yields . Bis-spirocyclopropaneisoxazolines are more stable than their saturated counterparts (see Section 4.03.6.3.6) and rearrange only at higher temperature, and with lower chemoselectivity . 4-Butadienyl-4-isoxazolines underwent thermolysis to afford mainly dihydroazepine derivatives through the formation of an intermediate azomethine ylide .

4.03.6.2.3(ii) Reaction without ring cleavage The addition of diallylzinc to 5-phenylisoxazoline 162 is diastereoselective, giving predominantly the trans-isoxazolidine 163 (Equation 20); comparable reactions with other 5-substituted isoxazolines showed similar diastereoselectivity .

ð20Þ

Isoxazolines 165, prepared by stereoselective 1,3-dipolar cycloaddition of nitrile oxides and enantiopure allylic alcohols, were converted into -amino acids 166 by nucleophilic addition to the CTN bond followed by reductive cleavage of the N–O bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic

Isoxazoles

addition was dictated by the C-5 substituent in either a directed (hydride addition) or a sterically (Grignard reagents addition) controlled manner (Scheme 36) . Starting from more densely functionalized chiral isoxazolines bearing one or two substituents at C-4, the same authors synthesized 3,3- and 2,3,3-amino acids, including cis--prolines .

Scheme 36

Enones 167 derived from disaccharides melibial and gentobial reacted with 2 equiv of hydroxylamine to afford isoxazolines 168 as an inseparable epimeric mixture in 80–83% yield. By treatment with p-toluenesulfonic acid, compounds 168 underwent dehydration to give isoxazole derivatives 169 in high yields (Scheme 37) .

Scheme 37

4.03.6.3 Isoxazolidines Isoxazolidines are useful intermediates in organic synthesis. The synthetic approaches to applications of these heterocycles as building blocks for the preparation of different kinds of compounds have been the subject of several reviews .

4.03.6.3.1

Reductive ring opening

The presence of the labile N–O bond, which can be easily cleaved under mild reducing conditions, accounts for the common use of isoxazolidines as masked 1,3-amino alcohols. The reductive ring opening of an isoxazolidine is mostly performed by hydrogenation in the presence of catalysts such as Pd/C, PtO2, Pd(OH)2, and Raney-Ni, or by Zn/acetic acid, but other reducing agents can be used. For example, Mo(CO)6 in aqueous acetonitrile, nickel chloride–sodium borohydride, or SmI2 was used as selective and mild reagent for N–O bond reduction in the presence of functionalities sensitive to other reducing agents (Scheme 38) . Under hydrogenolytic conditions, the N–O bond cleavage can be followed by a sequence of spontaneous transformations leading to different azaheterocycles, depending on the nature and the position of the substituents on the isoxazolidine ring. For example, hydrogenation in the presence of the Pearlman catalyst converted the bicyclic isoxazolidine 170 into lactam 171 through a cascade reaction sequence involving N–O bond cleavage, chemoselective N-debenzylation, and spontaneous lactamization. The reduction of 170 to the corresponding lactol with diisobutylaluminium hydride (DIBAL-H), followed by hydrogenolysis, directly afforded piperidine 172 via N–O bond cleavage, N-debenzylation, and intramolecular reductive amination . Analogously, hydrogenolysis of the tricyclic isoxazolidine 173 gave an indolizidine (Scheme 39) .

393

394

Isoxazoles

Scheme 38

Scheme 39

Reductive cleavage of the N–O bond of 3-alkoxycarbonyl isoxazolidines and 2,2-dialkylisoxazolidin-2-ium derivatives affords 3-aminodihydrofuran-2(3H)-ones by spontaneous translactonization of the initially formed amino alcohols . This strategy was applied to the synthesis of interesting compounds including substituted butenolides (Scheme 40) and nucleoside analogues.

Scheme 40

Under catalytic hydrogenation conditions, the adducts of nitrones and acrylates, 5-alkoxycarbonyl and 5-aminocarbonyl isoxazolidines, give 3-hydroxypyrrolidin-2-ones by intramolecular N-acylation of the amino group. 3,5-Dicarboxylic

Isoxazoles

isoxazolidines undergo N–O hydrogenolysis followed by 5-exo-trig-cyclization to pyrrolidinones. The competitive formation of the corresponding -lactone by cyclization on the hydroxyl group is usually not observed. For example, 4-hydroxy-D-pyroglutamic acid 175 was prepared from the N-ribose isoxazolidine 174 by a one-pot four-step procedure involving acidic hydrolysis of the sugar moiety, hydrogenolysis of the N–O bond followed by cyclization, and protection of the hydroxyl and amino moieties with t-butyldimethylsilyl and BOC groups (Scheme 41) .

Scheme 41

Bicyclic lactams, such as 2-hydroxypyrrolizidin-3-one 177, were prepared by hydrogenolysis of the corresponding bicyclic isoxazolidines 176 (Scheme 41) . Stereocenters on the isoxazolidine ring were not directly involved in the N–O bond cleavage and cyclization sequence; therefore, their configuration was retained. Similarly, reductive cleavage of the N–O bond was achieved in refluxing aqueous acetonitrile in the presence of Mo(CO)6 or by treatment with Zn/HCl . Hydrogenation of aldehyde 178 over palladium hydroxide followed by MeOH/HCl treatment and acetylation of the amino and hydroxyl moieties afforded glycoside 179 in good overall yield (Scheme 42) . Substituted isoxazolidines bearing a good leaving group on a lateral chain at the - or "-position from the nitrogen atom can undergo intramolecular nucleophilic substitution affording pyrrolidine and piperidine derivatives after reductive cleavage of the N–O bond . Similarly, isoxazolidinium salts prepared by intermolecular N-alkylation undergo N–O hydrogenolysis leading to compound 180 (Scheme 42) .

Scheme 42

395

396

Isoxazoles

4.03.6.3.2

Oxidation

Isoxazolidines can be cleaved by oxidation with generation of nitrones, which can undergo 1,3-dipolar cycloaddition with suitable dipolarophiles to form new isoxazolidine derivatives. Usually, the reaction is performed with m-chloroperbenzoic acid (MCPBA) and is highly regioselective in favor of the less substituted aldonitrone. For example, the enantiopure N-benzyl isoxazolidines 181 gave the C-aryl nitrones 182 by exclusive abstraction of the benzylic proton (Scheme 43). Under the same conditions, N-methyl compounds such as 183 and 184 afforded the more reactive C-unsubstituted nitrones, which spontaneously underwent intramolecular addition of the hydroxy group to the nitrone to give cyclic hydroxylamines (Scheme 43) . Starting from cyclic nitrones, such as 185, the 1,3-dipolar cycloaddition/oxidative cleavage/1,3-dipolar cycloaddition sequence was applied to the stereoselective construction of polysubstituted pyrrolidines (Scheme 44) .

Scheme 43

Scheme 44

Isoxazoles

An example of a ‘third-generation’ cycloadduct 187 was synthesized via alternating 1,3-dipolar cycloaddition and oxidation steps starting from 3,4-dihydro-2H-pyrrole 1-oxide and furan-2(5H)-one (Scheme 44) . Several isoxazolidines such as 188 were prepared by Yb(OTf)3-catalyzed cycloaddition of polymer-supported nitrones and 3-(2-butenoyl)-1,3-oxazolidin-2-one. Oxidative cleavage from the resin with 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ) afforded 2-isoxazoline derivatives in good overall yields (Equation 21) .

ð21Þ

4.03.6.3.3

Isoxazolidine ring opening under basic conditions

3-Alkoxycarbonyl isoxazolidines 189 reacted with an equimolar amount of NaH at room temperature to afford 3-amino-2(5H)-furanones 191 through rearrangement of the isoxazolidine ring. The process is believed to begin with 3-H proton abstraction favored by the presence of the alkoxycarbonyl electron-withdrawing group. Then, the formed enolate evolves via ring opening to the anion 190, which undergoes intramolecular transesterification followed by double-bond migration to the product (Equation 22) . The same process also occurred with weaker bases such as EtONa and TBAF .

ð22Þ

By treatment with NaH, bicyclic furoisoxazolidines 192 failed to give the expected 3-alkyl-substituted 2-aminobutenolides 193, but instead afforded the 3-amino-2(5H)-furanones 195 with conservation of the lactone ring and fragmentation of the isoxazolidine nucleus. In this case, the initially formed anion evolved to 194 with formation of an endocyclic double bond and elimination of formaldehyde (Scheme 45). The two-step process – intramolecular 1,3dipolar cycloaddition and NaH treatment of the furo[3,4-c]isoxazolidine adducts – was applied to the synthesis of enantiopure 3-alkylamino-5-methyl-2(5H)furanones .

Scheme 45

By treatment with NaH, isoxazolidine 196 underwent N–O bond cleavage to afford 198. The process is believed to occur through deprotonation of the carbamate nitrogen followed by proton transfer with simultaneous N–O bond cleavage to imine 197, and subsequent loss of methyl glyoxylate (Equation 23) .

397

398

Isoxazoles

ð23Þ

Mesylation of 3-(ethoxycarbonyl)-5-(2-hydroxyethyl)isoxazolidine 199 was directly followed by intramolecular nucleophilic displacement to salt 200. The bicyclic isoxazolidinium 200 was converted into the piperidone 201 in situ by treatment with 1,4-diazabicyclo[2.2.2]octane (DABCO) in refluxing acetonitrile. This reaction likely involves isoxazolidine 5-H proton abstraction by the base, followed by N–O bond cleavage (Scheme 46) . Under the same conditions, isoxazolidinium salts 202 and 203 afforded the indolizidinone 204 and the quinolizidinones 205, respectively . In these cases, the use of DABCO is critical because other bases such as NEt3, t-BuOK, NaOH, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) failed to give the nonreductive opening of the isoxazolidinium ring (for an alternative synthesis of piperidin-4-one derivatives from isoxazolidines, see Section 4.03.6.3.6(i)). Under reducing conditions, salts 202 and 203 afforded the corresponding hydroxyl derivatives 206 and 207 by N–O hydrogenolysis (Scheme 46).

Scheme 46

4.03.6.3.4

Cycloreversion

Suitably substituted isoxazolidines can undergo a thermally induced cycloreversion to nitrone and alkene. For example, the adducts of nitrones with alkylidene malonates or tolylsulfinylfuran-2(5H)-ones suffer an easy cycloreversion, which determines significant changes in the diastereomeric composition of the cycloaddition mixtures depending on the reaction conditions (kinetic vs. thermodynamic control) . Cycloaddition/cycloreversion processes were also employed to temporarily mask the reactive nitrone functionality . For example, nitrone 208 was protected by cycloaddition with styrene. The isoxazolidine ring remained unaffected during all the reaction steps used to introduce a pendant dipolarophile and obtain the derivative 209. By heating in a sealed tube at 190 C, isoxazolidine 209 underwent cycloreversion restoring the nitrone moiety which was directly trapped by an intramolecular 1,3-dipolar cycloaddition to afford 210 with complete regio- and diastereoselectivity (Scheme 47). Supported dipolarophiles were also used to mask nitrones and tether them to a solid phase. After suitable elaboration, the product was released from the resin through a 1,3-dipolar cycloreversion/intramolecular cycloaddition domino process .

Isoxazoles

Scheme 47

4.03.6.3.5

Reactivity of 5-alkoxyisoxazolidines

The adducts of nitrones with a vinyl ether can undergo ring opening under unusual reaction conditions. For example, the two-step sequence N-alkylation/thermal-induced ring opening was used to convert mono- and bicyclic 5-alkoxyisoxazolidines into -amino esters (Scheme 48) .

Scheme 48

N-Unsubstituted isoxazolidines such as 211 undergo facile decarboxylative peptide couplings with -keto acids (Equation 24) . The use of water as solvent or co-solvent was particularly beneficial for the formation of amides in high yields. The obtained -keto acid esters such as 212 could be saponified to -keto acids, and the -peptide chain extended by reaction with another isoxazolidine.

ð24Þ

4.03.6.3.6

Reactivity of 5-spirocyclopropane isoxazolidines

Isoxazolidines with a highly strained cyclopropane ring spiro-fused at the 5-position show a special reactivity and can be converted into different classes of azaheterocycles depending on the substitution pattern and the reaction conditions .

4.03.6.3.6(i) Thermal rearrangement The thermally induced ring expansion of 5-spirocyclopropane isoxazolidines (Brandi–Guarna reaction) has been studied extensively and proved to be a general method of synthesizing variously substituted tetrahydropyridones, indolizidinones, and quinolizidinones. The process is believed to occur through diradical intermediates and was also studied by mixed restricted/unrestricted DFT (RDFT/UDFT) calculations . Some representative

399

400

Isoxazoles

thermal rearrangements of adducts of acyclic and cyclic nitrones with alkylidenecyclopropanes (Equations 25–28) , bicyclopropylidene (Equations 29 and 30) , and methylenespiropentane (Equation 31) are shown.

ð25Þ

ð26Þ

ð27Þ

ð28Þ

ð29Þ

ð30Þ

ð31Þ

4.03.6.3.6(ii) Two-step metal-mediated rearrangement In an alternative two-step transformation of 5-spirocyclopropane isoxazolidines to tetrahydropyridones, for example, -amino cyclopropanol 214, prepared by chemoselective N–O reduction of isoxazolidine 213, was converted into 215 by treatment with Cu(OAc)2 and LiOAc in the presence of catalytic amounts of Pd(OAc)2. Interestingly, -amino cyclopropanols can also undergo a Pd-catalyzed domino ring-opening/cyclization/oxidation process to afford dihydropyridones such as 216 when the reaction is carried out in the presence of air or O2 (Scheme 49) .

Isoxazoles

Scheme 49

4.03.6.3.6(iii) Acidic thermal rearrangement 5-Spirocyclopropane isoxazolidines can be selectively converted into azetidin-2-one derivatives by heating in the presence of a protic acid such as trifluoroacetic acid (TFA) or p-TsOH. The ring contraction with concomitant extrusion of ethylene appears to be a general process and can be applied to mono- and polycyclic isoxazolidines to form variously substituted monobactam and 3,4- or 1,4-fused azetidinones, respectively (Equations 32–40) . Carbapenames like 217 are unstable under the reaction conditions and undergo -lactam ring opening and acylation of the nitrogen atom to afford -homoprolines (Equation 34).

ð32Þ

ð33Þ

ð34Þ

ð35Þ

ð36Þ

ð37Þ

401

402

Isoxazoles

Analogously, highly strained 3-spirocyclopropane -lactams such as 218–220 were obtained starting from suitable bisspirocyclopropane isoxazolidines (Equations 38–40) . The same compounds were also prepared via a one-pot three-component cascade through in situ formation of the isoxazolidine as well as the nitrone. For example, microwave heating (80 C, 15 min) of a mixture of N-benzylhydroxylamine hydrochloride, ethyl glyoxylate, 1,19-bi(cyclopropylidene) (BCP), and NaOAc in toluene afforded -lactam 218 in 72% yield .

ð38Þ

ð39Þ

ð40Þ

4.03.6.3.7

Reactivity of hexahydroisoxazolo[2,3-b][1,2]oxazines

Generally, nitroso acetals derived from tandem [4þ2]/[3þ2] cycloadditions of nitroalkenes (see Section 4.03.9.3.3(iv)) undergo Raney-nickel-catalyzed hydrogenolysis to afford pyrrolidines, pyrrolizidines, and indolizidines, depending on the substitution pattern . For example, reduction of the tricyclic nitroso acetal 221 caused a double NO bond cleavage, followed by hemiacetal breakdown and reductive amination to afford the fused pyrrolidine 222 with good recovery of the chiral auxiliary (1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol (Scheme 50). The amino alcohol 222 was then transformed into the alkaloid (–)-mesembrine .

Scheme 50

Isoxazoles

In the presence of a suitable functionalization, the pyrrolidine nitrogen can suffer intramolecular acylation or alkylation to afford the pyrrolizidine or indolizidine skeleton common to several natural and unnatural biologically active compounds (Scheme 51) .

Scheme 51

Samarium diiodide selectively cleaves the isoxazolidine N–O bond in nitroso acetals to give 1,2-oxazine derivatives such as 223 and 224 (Scheme 52) .

Scheme 52

4.03.6.4 Isoxazolidinones Isoxazolidin-3-ones undergo ring opening by treatment with amines and hydroxylamines to give 3-(aminooxy)propanamide and 3-(aminooxy)-N-hydroxypropanamide derivatives, respectively. This process was applied to the

403

404

Isoxazoles

synthesis of 3-aminooxy peptides (Equation 41) . Isoxazolidin-5-ones can be easily converted into -amino acids by hydrogenolysis of the NO bond (Equation 42) . The N-benzylated compounds 225 afforded directly the N-unsubstituted amino acids 226 in quantitative yield by hydrogenolysis of the N–O bond and concurrent removal of the benzyl group (Equation 43) . Similar results were obtained by transfer hydrogenolysis with 10% Pd/C and ammonium formate in refluxing methanol . Isoxazolidin-5-ones are reduced to the corresponding isoxazolidin-5-ols by DIBAL-H .

ð41Þ

ð42Þ

ð43Þ

4.03.7 Reactivity of Substituents Attached to Ring Carbon Atoms The reactivity of substituents attached to ring carbon atoms was previously discussed in CHEC(1984) , while reactions of fully conjugated and nonconjugated rings, as well as the reactivity of substituents, were described in CHEC-II(1996) . This section is an update of the previous work concerning the reactivity of substituents attached to ring carbon atoms, with particular attention toward new reagents, processes, and products.

4.03.7.1 Isoxazoles 4.03.7.1.1

C-linked substituents

4.03.7.1.1(i) Alkyl and substituted alkyl groups An optimized procedure for the bromination of the methyl group of 3-aryl-5-methylisoxazole-4-carboxylates allowed access to, almost exclusively, either the monobromo- or gem-dibromomethyl derivatives in excellent yields, operating with N-bromosuccinimide (NBS) under different reaction conditions. The monobromo derivatives were easily transformed into the corresponding 5-formyl-substituted isoxazoles . Transmetallation of 5-lithiomethylisoxazoles with the lower-order cuprate reagent lithium thienylcyanocuprate in THF enabled almost exclusive conjugate addition to ,-unsaturated ketones: for instance, starting from isoxazole 227 and cyclopentenone, ketone 228 was isolated in high yield (Scheme 53). In contrast, the use of samarium tris(hexamethyldisilazide) in diethyl ether gave rise to preferential 1,2-carbonyl addition . Lateral lithiation of ethyl 4-acetyl-5-methylisoxazole-3-carboxylate at the 5-methyl position was smoothly performed when the acetyl moiety was protected with a 5,5-dimethyl-1,3-dioxanyl group. The lithio anion of 229 was quenched with a variety of electrophiles, such as alkyl halides, aldehydes, ketones, isocyanates, trimethylsilyl chloride (TMSCl), Me3SnCl, and MeSSMe, to give 4,5-difunctionalized isoxazole-3-carboxylic acid derivatives 230 as prodrugs for the AMPA glutamate neurotransmitters of the CNS (Scheme 53) . Lateral metallation at the methyl group was performed on ethyl 3-(10-haloanthracen-9-yl)-5-methylisoxazole-4-carboxylates, as well as palladation on the halogenated aromatic moiety .

Isoxazoles

Scheme 53

The Dess–Martin periodinane (DMP) oxidation of -, -, and -hydroxy isoxazoles to the corresponding ketones was easily performed in the presence of the isoxazole ring, as well as other functional groups (Equation 44) .

ð44Þ

3-Bromomethyl-5-methylisoxazole 231 was exploited in reactions with enantiopure benzyloxycarbonyl-protected glycine equivalents 232 for the synthesis of -substituted and ,-disubstituted amino acids 234 through hydrolysis of 233 (Scheme 54) .

Scheme 54

405

406

Isoxazoles

Substituted isoxazolylpyrimidines were synthesized in good yields (80–99%) through a four-component coupling reaction involving 3-methyl-5-trimethylsilylmethylisoxazole, two types of aromatic nitriles, and an acetal, via amidine intermediates. For example, pyrimidine 236 was obtained from 235, benzonitrile, 2-cyanopyrazine, and tetraethyl orthocarbonate, and converted to triazanaphthalene 237 by reductive opening of the isoxazole ring and intramolecular cyclization (Scheme 55) . Isoxazole 235 was also utilized in Peterson reactions with a series of 2-substituted 1-azabicyclo[2.2.2]octan-3-ones in the presence of an organolithium base, leading to (Z)-alkenes as major stereoisomers .

Scheme 55

Isoxazole-supported selenium resins, produced via 1,3-dipolar cycloaddition of nitrile oxides with propargyl selenium resin, were subjected to -alkylation reactions with various electrophiles, leading to 3-aryl-5-E-substituted ethenylisoxazoles in satisfactory yields (62–78%) and purity (90–99%). Compound 238 gave olefin 240, through selenoxide elimination from the -alkylation product 239 (Scheme 56) .

Scheme 56

5-Diethylphosphonomethyl-3-methylisoxazole was alkylated and olefinated by reaction of its anion with alkyl halides and aldehydes . Reactions of 3-methyl-4-nitro-5-styrylisoxazole with bis-enolizable ketones have been investigated. Michael adducts were obtained in good yields with substoichiometric amounts of base while spiroisoxazolines were the major products when the base was employed in large excess .

4.03.7.1.1(ii) Aryl groups A series of iridium-based complexes formed in situ have been used to mediate ortho-exchange of hydrogen with deuterium in model substrates such as 3-phenyl-5-acetylisoxazole . 4,5-Diarylisoxazoles were exploited in the synthesis of phenanthro[9,10-d]isoxazoles. For instance, compound 242 was prepared by

Isoxazoles

intramolecular Stille–Kelly stannylation/biaryl coupling of o,o9-diiodo 4,5-diarylisoxazole 241b (X ¼ I) and by nonphenolic oxidative coupling of the corresponding nonhalogenated substrate 241a (X ¼ H) with phenyliodine(III) bis(trifluoroacetate) (PIFA) (Equation 45) .

ð45Þ

4.03.7.1.1(iii) Aldehydes and Baylis–Hillman adducts The Baylis–Hillman (BH) reaction is one of the most studied carbon–carbon bond-forming reactions of recent years, now considered a standard synthetic methodology, where an aldehyde and an electron-deficient alkene are allowed to react in the presence of a tertiary amine or Lewis acid. This process was extensively studied by Batra and co-workers on isoxazolecarbaldehydes. In particular, 3-arylisoxazolecarbaldehydes 243 undergo extremely fast BH reactions by treatment with a mixture of DABCO and activated alkenes: the reactions went to completion within 10–15 min, leading to adducts 244, suitable for further synthetic elaborations (Equation 46) . On the other hand, the reaction of 243 with cycloalkenones in the presence of TiCl4, as Lewis acid, at lower temperature followed a different reaction pathway, leading to other products in addition to BH adducts .

ð46Þ

5-Isoxazolecarbaldehydes are among the fastest-reacting substrates for BH reactions, and comparative studies on 4-isoxazolecarbaldehydes showed that for these regioisomers a lower reactivity led to poorer yields (10–89%) and longer reaction times (2–7 h). The proposed rationale for this different behavior involves the proton abstraction step in the intermediate I: the proximity of the oxygen atom in the 5-substituted isoxazole derivative perhaps could assist the deprotonation and thus the elimination of the base, with a consequent acceleration of the process (Scheme 57) . This hypothesis was corroborated by the fast and facile BH reactions in substituted 3-isoxazole carbaldehydes, having a proximal nitrogen atom in the corresponding intermediate (product yields: 77–95%, reaction times: 15–30 min) .

Scheme 57

407

408

Isoxazoles

BH reactions of substituted 3-, 4-, and 5-isoxazolecarbaldehydes were even performed on solid phase, in general through immobilization of acrylic acid on the resin. In particular, using solid-phase methods, 3-aryl5-isoxazolecarbaldehydes 243 were exploited as building blocks for the generation of combinatorial libraries through BH reactions, Wittig reactions, nitroaldol condensations, imine and oxime formation, Michael additions, reductive aminations, and alkylation reactions. A sequence of BH reactions/Michael additions of primary amines, followed by cleavage from the solid support, gave substituted amino propionic acid derivatives 245 as diastereomeric mixtures in excellent yields and purity; other synthetic strategies involving reductive amination and alkylation of the NH group led to highly functionalized isoxazoles 246 (Scheme 58) .

Scheme 58

BH adducts coming from 3-, 4-, and 5-isoxazolecarbaldehydes, as well as the corresponding acetates, were subjected to catalytic hydrogenation in the presence of Raney-Ni or Pd–C. Adducts 244 (EWG ¼ CO2Me) and 250 were diastereoselectively converted into enaminones 247 and 251 by the former reagent, while the latter afforded derivatives 248 and 252 through reduction of the double bond and retention of the isoxazole ring . Treatment of esters 244 with NaBH4 even allowed reduction of the ester function, assisted by the secondary hydroxyl group in the -position, with formation of 1,3-diol systems 249 (Scheme 59) . Moreover, operating in aqueous media in the presence of DABCO, the corresponding acetates 253 were easily transformed in excellent yields into azides 254 by treatment with NaN3, while reactions with ,-unsaturated ketones, esters, and nitriles afforded 1,4-pentadienes 255 (Scheme 60) . Acetates 256 were respectively reduced to regioisomers 257 or 258 by treatment with DABCO and NaBH4 or NaBH4 alone (Scheme 60). Further synthetic elaborations of the above BH adducts leading to different heterocyclic systems have also been reported .

4.03.7.1.1(iv) Ketones The reduction of the carbonyl groups in 3-acetylisoxazole derivatives has been carried out by algae and plant cells affording the corresponding (S)-alcohols with high enantioselectivities . In situ generation of CuH ligated by Takasago’s nonracemic ligand, DTBM-SEGPHOS, led to an especially reactive reagent capable of effecting asymmetric hydrosilylation of heteroaromatic ketones under very mild conditions: 3-methyl-5-pentoylisoxazole was reduced to the corresponding (R)-alcohol (68% yield, 83% ee) .

Isoxazoles

Scheme 59

Scheme 60

4.03.7.1.1(v) Carboxylic acids and derivatives 3-Methylisoxazole-5-carboxylic acid was converted into the corresponding 5-carboxamides and 5-(1H-pyrazol-1ylcarbonyl) derivatives in satisfactory yields by treatment with thionyl chloride and amines or pyrazoles . A three-component assembly of isoxazole-5-carboxylic acid chloride, 1,1-dimethylallene, and bispinacolatodiboron, catalyzed by a phosphine-free palladium complex, gave 2-acylallylboronate derivatives regioselectively (Equation 47) . On the other hand, a mild procedure allowed the preparation of ,-unsaturated ketones by simple reaction of 3-aryl-5-methylisoxazole-4-carboxylic acid chlorides with allyl bromide and indium in DMF (Equation 48) .

409

410

Isoxazoles

ð47Þ

ð48Þ

In contrast to 4-nitrobenzonitrile, cyano groups on 3,5-dicyanoisoxazoles 259 were found to be highly reactive to nucleophilic addition of alcohols (or amines) leading to imidates 260 (or amidines); the use of 1,2-diamines, such as ethylendiamine, afforded 3,5-bis(imidazolinyl)isoxazoles 261 (Scheme 61) . The solvent-sensitive decarboxylation of 3-carboxy-1,2-benzisoxazoles was catalyzed by monoclonal antibodies, generated against a 3-phenyl-1,2-benzisoxazole derivative .

Scheme 61

4.03.7.1.2

N-Linked substituents

3-Methyl-5-aminoisoxazole was allowed to react with 4,4,4-trifluoro-3-oxobutanoates in refluxing HOAc to give isoxazolopyridines in satisfactory yields . N-(1-Chloro-2,2,2-trihaloethylidene)-O-methylurethanes 264 underwent cyclization with 3-amino-5-methylisoxazole 262 and 5-amino-3-methylisoxazole 263 to give isoxazolotriazinones 265 and -pyrimidones 266, respectively, through amidine intermediates (Scheme 62) . Compound 262, as well as the 5-t-butyl derivative, reacted with diimidoyl dichlorides 267 in a new and efficient anionic domino process, leading to biologically relevant imidazo[4,5-b]quinoxalines 268 (Scheme 62) . The same 3-aminoisoxazole systems were efficiently transformed into the corresponding salicylaldimines by solvent-free microwave-assisted condensation with salicylaldehyde and were even exploited in the catalytic amination of 5-iodouracil derivatives . Isoxazol-3-yl methylenecyclopropyl amide 269 underwent alkylative ring expansion with aryl aldehydes (and aryl aldimines) in the presence of MgI2, leading to the exclusive formation of hydroxy-alkylated (and amino-alkylated) pyrrol-2-ones 270. The amide nitrogen atom, generally considered non-nucleophilic, was incorporated into the newly formed ring under neutral conditions (Equation 49) .

Isoxazoles

Scheme 62

ð49Þ

4.03.7.1.3

O-Linked substituents

The synthesis of 3-hydroxyisoxazoles (3-isoxazolols), as well as annulated analogues, has been exhaustively reviewed . The regioselective O- versus N-alkylation of 5-carbomethoxy-3-hydroxyisoxazole 271 was studied: 3-O-alkyl products 272 were highly favored with benzyl, benzhydryl, and allyl bromide (91:9), while methylation with diazomethane or methyl iodide gave mixtures of both regioisomers (73:27 and 58:42, respectively). On reduction with DIBAL-H, the esters 272 afforded 3-O-protected carbaldehydes 273, versatile key intermediates in the synthesis of pharmacologically interesting 3-hydroxyisoxazoles (Scheme 63) .

Scheme 63

4.03.7.1.4

Halogen atoms

Palladium-catalyzed coupling reactions of 2-(5-iodoisoxazol-3-yl)pyridine 274 with a variety of organometallic compounds led to derivatives 275–278 through Sonogashira, Suzuki, Negishi, and Stille reactions, respectively (Scheme 64) .

411

412

Isoxazoles

Scheme 64

Even 4-substituted-3-ethoxy-5-methylisoxazoles were easily synthesized (49–98% yields) through analogous Pd-catalyzed processes on 3-ethoxy-4-iodo-5-methylisoxazole and via the corresponding Grignard intermediate formed by an iodine–magnesium-exchange reaction with isopropylmagnesium bromide . Combination of iodine–magnesium exchange and organocuprate oxidation with a new dinitroarene oxidant 280 allowed the conversion of 3,5-dimethyl-4-iodoisoxazole 279 (X ¼ I) into the ‘biaryl-type’ dimer 281 (Scheme 65) . The same dimerization proceeded in only moderate yield (40%) using a palladium-catalyzed system . On the other hand, a tetra-ortho-substituted unsymmetrical biaryl 283 was synthesized via Suzuki cross-coupling of 279 (X ¼ Br) with 2,6-dimethylphenylboronic acid in the presence of the phenanthrene– based ligand 282 (Scheme 65) . Moreover, a two-step sequence involving iodine–lithium exchange and coupling with chlorosilanes and chlorostannanes allowed the preparation of 4-dimethylphenylsilyl- and 4-tributylstannyl-3,5-dimethylisoxazole from 4-iodo derivative 279 (X ¼ I) .

Scheme 65

4.03.7.1.5

Metal- and metalloid-linked substituents

5-Tributylstannylisoxazoles were allowed to react in Pd-catalyzed coupling reactions with 4-bromofuran-2(5H)-ones leading to isoxazole-furanones under very mild conditions . 3,5-Dimethylisoxazol-4-ylboronic acid was exploited in a stereoselective synthesis of isoxazolylmethyleneindolinones by a Pd-catalyzed tandem Heck carbocyclization/Suzuki coupling sequence . The Suzuki cross-coupling reaction of 4-isoxazolyl boronic acids and aryl bromides allowed the synthesis of 3,4-diarylisoxazoles such as the highly potent cyclooxygenase-2 (COX-2)-selective inhibitor 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide (valdecoxib) .

Isoxazoles

4.03.7.2 Isoxazolines Substituents of 4,5-dihydroisoxazole rings have been manipulated with a variety of reagents exploiting the stability of the ring. Chiral isoxazoline 284 was treated with LiB(Et)3H to remove the D-glucose-derived auxiliary R* OH, which was recovered in high yields (Scheme 66) . Both the methyl ester groups of isoxazoline 286 were reduced with sodium borohydride, giving 287 in 89% yield following reaction of the diol with methanesulfonyl chloride. Further reduction of the nitro group and subsequent cyclization by intramolecular nucleophilic substitution of the amino group afforded 288 (Scheme 66) .

Scheme 66

A group of 16 differently substituted isoxazoline diamides 290 was prepared, without isolation of any of the intermediates, through the final amidation of ethyl esters 289 (obtained from a two-step procedure, Schotten– Baumann/1,3-dipolar cycloaddition) with AlCl3 using [bmim][BF4]. The final products were extracted with diethyl ether in 38–51% overall yields, pure by NMR analysis (Scheme 66) . The pyrrole annulation of 291 with different isocyano derivatives afforded the resin-bound products 292, which were released from the resin with 10% TFA leading to 293 (Scheme 67) . The fragmentation of the cyclopropane ring of isoxazoline 294 was achieved with several dehydrating agents, and different amounts of isoxazolines 295–297 (all structurally related to 11(15 ! 1)abeotaxanes) were obtained (Equation 50) . An intriguing group of C60-isoxazolines has been prepared by 1,3-dipolar cycloaddition and subjected to reactivity screening. The acid 299, obtained by acidic hydrolysis from ester 298, reacted with the cubane diol in the presence of dicyclohexycarbodiimide/4-dimethylaminopyridine (DCC/ DMAP) to form the diester 300 and the corresponding monoester 301. Acidic hydrolysis of ester 298 at higher temperature resulted in decarboxylation with isoxazoline ring opening, yielding the fullerenol 302 (Scheme 68) . The anthracenyl group of fullerene-isoxazoline reacted with singlet oxygen to form the 9,10-epidioxide under photooxidation, with no reaction at the heterocycle (Equation 51) .

413

414

Isoxazoles

Scheme 67

ð50Þ

Scheme 68

Isoxazoles

ð51Þ

Reactivity toward nucleophiles of isoxazolines bearing a keto group on a side-chain has been studied. Reactions of isoxazoline 303 with Grignard reagents (vinylmagnesium bromide and allylmagnesium bromide) were successful, despite the presence of the NH, and were completely stereoselective, giving the corresponding alcohols 304 and 305 in good yields. Reductive amination of the same carbonyl group was also completely stereoselective, giving amine 306 in good yield (Scheme 69) .

Scheme 69

In a similar manner, addition of a lithium enolate to a 3-formyl-4,5-dihydroisoxazole afforded the corresponding aldol product in 90% yield . Enzymatic resolution of racemic functionalized isoxazolines is a valuable technique for the preparation of enantiomerically enriched and pure 4,5-dihydroisoxazoles. These enzymatic resolutions exploit a variety of transformations of functional groups resident on the side-chains of the isoxazoline ring. The multipolymer enzymatic resolution of soluble polymer-supported alcohols 307 and 308 was achieved using an immobilized lipase from Candida antarctica (Novozym 435). The (R)-alcohol 309 was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene glycol) (PEG) scaffold (Scheme 70) .

Scheme 70

415

416

Isoxazoles

Isoxazoline 311 was obtained from racemic thioesters 310 in up to 89% yields and >90% ee by means of a dynamic KR catalyzed by lipase PS-30 in the presence of phosphate buffer (pH ¼ 9.2), an amine, and a surfactant (Equation 52) .

ð52Þ

A similar resolution has also been achieved on large scale . The KR of racemic isoxazoline 312 catalyzed by enzymes was studied. The best result was obtained with lipase B from Candida antarctica (CALB), which hydrolyzed the ethyl ester of ()-312 to the corresponding monoacid ()-313. The reaction, which was run in 0.1 M phosphate buffer/acetone at room temperature, spontaneously stopped at 50% conversion to yield monoacid ()-313 and the residual ester (þ)-312 with ees higher than 99% . The C-5 epimer of 312 underwent enantioselective hydrolysis (>99% ee) of the methyl ester linked to C-5 in the presence of the protease proleather (subtilisin Carlsberg), whereas CALB and other lipases were not able to resolve it (Equation 53).

ð53Þ

Lipase-catalysed KR of racemic hydroxylated isoxazoline 314 has been improved using a low-temperature method. Alcohol 314 was prepared on a milligram scale with an ee of 85% (Equation 54) .

ð54Þ

5-Acyl isoxazolines have been resolved by enzymatic carbonyl reduction with Aspergillus niger. The transformation gave an equimolar mixture of diastereomeric 5-dihydroxyethyl isoxazolines. Racemic isoxazoline 315 gave syn- and anti-alcohols 316, both of (R)-configuration, which were separated by repeated chromatography (Equation 55) .

ð55Þ

4.03.7.3 Isoxazolidines Several standard transformations can be performed on lateral chain functional groups without affecting the isoxazolidine ring system. Some selected examples are shown.

Isoxazoles

4.03.7.3.1

C-linked substituents

4.03.7.3.1(i) Functional group interconversions Deprotection of the primary hydroxyl group of isoxazolidine 317, followed by bromination, afforded the corresponding bromo derivative in good yield (Scheme 71) . In some cases, the creation of a good leaving group, such as a mesylate or a bromine atom, at the - or "-position from the isoxazolidine nitrogen atom can be followed by a spontaneous intramolecular nucleophilic substitution with formation of a cyclic isoxazolidinium salt (see also Sections 4.03.6.3.1 and 4.03.6.3).

Scheme 71

4.03.7.3.1(ii) Reductions Isoxazolidines have found numerous applications in synthesis through reductive cleavage of the N–O bond to give 1,3-amino alcohols (see Section 4.03.6.3.1). Nevertheless, scattered examples of reduction of isoxazolidine derivatives without cleavage of the isoxazolidine ring have been reported. Usually these reactions are highly substrate and reagent dependent. For example, ester groups were reduced to aldehydes and alcohols using suitable hydride reagents such as DIBAL-H, NaBH4, LiBH4, and LiAlH4 (Equation 56) .

ð56Þ

The ester group on the isoxazolidine ring of 318 was selectively reduced with NaBH4 in the presence of a sidechain ester function (Equation 57) .

ð57Þ

After deprotection of the methoxymethyl (MOM) ether under acidic conditions, alcohol 319 was deoxygenated through the Barton procedure to obtain the natural alkaloid ()-pyrinodemin A (Scheme 72) .

Scheme 72

417

418

Isoxazoles

Reduction of bromide 320 under phase-transfer catalysis (PTC) conditions provided the 5-methylisoxazolidines 321 and 322 in 86% overall yield. Under the same conditions, the diastereomer 323 remained unchanged. The 5-methyl derivative 324 was obtained along with a substantial amount of pyrrolidine 325 by treatment with sodium cyanoborohydride in boiling DMF (Equations 58 and 59) . Isoxazolidines 320 and 323 underwent a radical-induced rearrangement upon treatment with tributyltin hydride (see Section 4.03.10).

ð58Þ

ð59Þ

Bromide was removed from the aromatic ring in isoxazolidine 326 by a two-step procedure involving conversion to the organolithium derivative followed by hydrolysis and desilylation (Scheme 73).

Scheme 73

4.03.7.3.1(iii) Oxidations The N-substituted isoxazolidine ring is stable under several standard oxidation conditions (for oxidative isoxazolidine ring opening, see Section 4.03.6.3.2). Accordingly, secondary and primary hydroxyl groups on lateral chains can be converted into ketones and aldehydes or carboxylic acid under suitable conditions (Equations 60 and 61) .

ð60Þ

ð61Þ

Oxidative cleavage of the 1,2-dihydroxy- and -hydroxyketone moieties to carbonyl and carboxylic acid groups, respectively, was accomplished with lead tetracetate and periodic acid (Scheme 74) .

Isoxazoles

Scheme 74

Treatment of 2-oxa-3-azabicyclo[2.2.1]hept-5-ene derivatives with RuO4, generated in situ from NaIO4 and RuCl3?H2O, followed by treatment with CH2N2 provided the corresponding dimethyl 3,5-isoxazolidinedicarboxylate by oxidative cleavage of the C–C double bond (Scheme 75) .

Scheme 75

4.03.7.3.2

N-linked substituents

Treatment of cycloserine with Fmoc-Cl or Fmoc-OSu in the presence of pyridine afforded a mixture of endo- and exocyclic N-acylated products (Fmoc ¼ 9-fluorenylmethyloxycarbonyl). Selective protection of the primary amine was achieved on multigram scale and in high yield by in situ formation of the bis-silylated derivative with N,Obis(trimethylsilyl)acetamide (BSA) followed by acylation (Scheme 76) .

Scheme 76

The carbobenzyloxy (Cbz) protecting group was removed in 327 with hydrogenation over Pd/C without affecting the N–O bond. The free amine cyclized in acetonitrile to afford the diketopiperazine 328 in 74% overall yield (Scheme 77) . Radical denitration of nitro-substituted isoxazolidines was accomplished with tributyltin hydride and 2,29-azobisisobutyronitrile (AIBN) in refluxing benzene .

419

420

Isoxazoles

Scheme 77

4.03.7.3.3

O-linked substituents

The reaction of isoxazolidin-5-ols and their methoxy and acetoxy derivatives with allyltrimethylsilane catalyzed by Lewis acids such as TMSOTf and BF3?OEt2 afforded the corresponding 5-allylisoxazolidines in high yields (Equation 62) .

ð62Þ

Similarly, isoxazolidinyl nucleosides were prepared by Lewis acid-catalyzed coupling of isoxazolidin-5-yl acetate derivatives with nucleoside bases (see Section 4.03.11). Some 4-hydroxyisoxazolidines were resolved by lipase-mediated acylation .

4.03.7.3.4

S-linked substituents

Several pentafluorophenyl isoxazolidine-4-sulfonates were converted into the corresponding sulfonamides via amine displacement of the pentafluorophenoxy moiety (Equation 63) .

ð63Þ

Reductive desulfurization of 329 was selectively achieved by treatment with LiAlH4, and no reductive cleavage of the N–O bond was observed (Equation 64) .

ð64Þ

4.03.7.3.5

Metal- and metalloid-linked substituents

4-Hydroxy isoxazolidines were prepared by stereospecific oxidation of the corresponding dioxaborolane by treatment with hydrogen peroxide in THF in the presence of a phosphate buffer (Scheme 78) . A 4-silyl-substituted isoxazolidin-5-one was desilylated by treatment with citric acid . 4-(Phenylselenyl)isoxazolidines underwent reductive deselenylation by treatment with Ph3SnH in the presence of a catalytic amount of AIBN in refluxing benzene .

Isoxazoles

Scheme 78

4.03.8 Reactions of Substituents Attached to Ring Nitrogen A glycosyl chiral auxiliary can be easily removed from cycloadducts of N-glycosylnitrones such as 330 by acidic treatment or with hydroxylamine, to afford N-unsubstituted isoxazolidines . The nitrogen atom of N-substituted and N-unsubstituted isoxazolidines reacts easily with electrophiles such as alkylating and acylating agents. N-Unsubstituted isoxazolidines react with aldehydes in alcohol to give the corresponding aminals. For example, treatment of 331 with formaldehyde in EtOH gave the N-(ethoxymethyl)isoxazolidine, which was directly reduced to the N-methyl derivative 332 (Scheme 79) . Enantiopure tricyclic isoxazolidines were used as chiral auxiliaries in the desymmetrization of meso-anhydrides .

Scheme 79

Catalytic hydrogenation removed the Cbz protection from the nitrogen atom of isoxazolidine 333 without affecting the N–O bond. The nitrogen was then reprotected with 9-fluorenylmethoxycarbonyl chloroformate providing the N-Fmoc-protected isoxazolidine in 75% overall yield (Scheme 80) .

Scheme 80

Fmoc-D-cycloserine (4-aminoisoxazolidine-3-one) and its enantiomer were immobilized on SASRIN resin or 2-chlorotrityl linker resins using Mitsunobu-type reaction or direct tritylation, respectively. The loading of the resulting resins (0.59–0.69 mmol1 g) was determined by spectrophotometry of the in situ-generated piperidine–dibenzofulvene

421

422

Isoxazoles

adduct after Fmoc-group deprotection. The primary amino group of the cycloserine functionalized resins was then reacted with several electrophiles such as carboxylic acids, amino acids, anhydrides, sulfonyl chloride, and activated heterocycle chlorides. Eventually, the serine derivatives were cleaved from the resin with TFA (Scheme 81) . The same methodology was also applied to the parallel solid-phase synthesis (SPS) of libraries of isoxazoline-3-ones.

Scheme 81

Isoxazolidin-3-one 334, prepared by catalytic hydrogenolysis of 3-(benzyloxy)-4,5-dihydroisoxazole, reacted with 1,4-dichloro-2-butyne in refluxing acetone in the presence of K2CO3 to give a 4:1 mixture of the regioisomeric N- and O-alkyl derivatives (Scheme 82) .

Scheme 82

4.03.9 Ring Syntheses Classified by Number of Ring Atoms Contributed by Each Component Ring synthesis was previously discussed in CHEC(1984) and CHEC-II(1996) . This section is an update of the previous work with particular attention toward new reagents, processes, and products. Synthetic approaches have been classified on the basis of the number and arrangement of ring atoms present in each component.

4.03.9.1 Synthesis of Isoxazoles Isoxazoles can be easily prepared from isoxazoline precursors through dehydrogenation or elimination processes. This aspect (see Section 4.03.6.2) is not discussed in detail in this section.

Isoxazoles

4.03.9.1.1

From atom fragment: C–C–C–N–O

This kind of reaction refers to cyclization of synthons containing all five atoms of the isoxazole ring. In some cases, these acyclic species are stable and isolable, but often they are only transient or supposed intermediates coming from C–C–C and N–O fragments. Many synthetic routes involve cyclocondensations of hydroxylamine with 1,3-bielectrophiles. In this context, three-carbon 1,3-difunctionalized units bearing sp or sp2 carbons have been widely exploited. Condensation of silylalkynones with NH2OH?HCl allowed the synthesis of 5-silylisoxazoles . Analogously, using the alkynyl ketone functionality of ynone 335, coming from protected L-aspartic acid, nonproteinogenic heterocyclic substituted -amino acids were synthesized. Reaction with hydroxylamine hydrochloride in EtOH afforded exclusively the 3-substituted isoxazole 336 in 62% yield, while operating in the presence of pyridine a 1:3 mixture of 3- and 5-substituted regioisomers was obtained in 51% yield (Scheme 83) . Starting from ynones 337, electrophilic cyclization allowed an easy access to a variety of 3,5-disubstituted-4-halo- or -4-selenoisoxazoles 339 under mild reaction conditions, by treatment of the O-methyl oximes 338 with ICl, I2, Br2, or PhSeBr (Scheme 83) .

Scheme 83

Various ,-unsaturated ketones were used as versatile synthons in heterocyclizations with hydroxylamine hydrochloride, probably through oxime intermediates, RCOCHTC(Cl)CH2Br (R ¼ alkyl, aryl, furyl), affording 3-substituted 5-bromomethylisoxazoles , and 1-bis(methoxy)-4-bis(methylthio)-3-buten-2-one led to isoxazoles with a masked aldehyde functionality . A regioselective method affording directly 3-phenyl-5-substituted isoxazoles 341, without isolation of isoxazoline intermediates, exploited reactions of NH2OH and -benzotriazolyl-,-unsaturated ketones 340, stereoselectively generated from benzotriazolylacetophenone and aldehydes in the presence of piperidine (Scheme 83) . Treatment of -lithiated benzotriazolylvinyl ethyl ether with acid chlorides followed by cyclocondensation with hydroxylamine hydrochloride gave 4-benzotriazolyl-substituted isoxazoles . A convenient one-pot preparation of 4,5-diarylisoxazoles 343 was performed from enaminones 342 under standard oximation conditions (NH2OH?HCl, MeOH–AcOH, Na2CO3, reflux). The regiochemistry of the final products unequivocally supports a reaction mechanism involving a tandem amine exchange/heterocyclization process (Scheme 84) . This procedure allowed the synthesis of 4,5-bis(o-haloaryl)isoxazoles, which were efficiently converted via intramolecular Stille-type biaryl coupling to phenanthro[9,10-d]isoxazoles in high overall yields (see Section 4.03.7.1.1) . In a similar way, reactions of -alkoxyvinyl trichloromethyl ketones with hydroxylamine in hydrochloric or sulfuric acid gave 5-carboxyisoxazoles, exploiting the reactivity of the trichloromethyl group as a carboxyl group precursor .

423

424

Isoxazoles

Scheme 84

Although the synthesis of 3-isoxazolols from -keto esters and hydroxylamine suffers from the formation of 5-isoxazolones as major products, treatment of acyl chlorides with Meldrum’s acid 344 and subsequent aminolysis gave rise to protected -keto hydroxamic acid derivatives 345 that cyclized to the corresponding 5-substituted-3isoxazolols 346 without formation of any by-product (Scheme 84) . 5-Amino-3-(pyrrol-2-yl)isoxazoles 348 were selectively prepared by treatment of cyano-ethylthio-ethenylpyrroles 347 with hydroxylamine in methanol, probably through replacement of their SEt group with a hydroxylamino moiety. With carbamoyl derivatives 347 (R3 ¼ CONH2), minor amounts of regioisomers 349 were also isolated and their formation was increased (12–48%) operating in the presence of aqueous NaOH (Scheme 84) . Various 3-acyl-lactams 350 were reacted with NH2OH?HCl in boiling EtOH to give 3-substituted 4-aminoalkyl5(2H)-isoxazolones 351 as single regioisomers in satisfactory yields, through oxime intermediates (Scheme 85) . Cyclodehydration of N-substituted salicylhydroxamic acids 352 under Mitsunobu conditions was the key step in the synthesis of N-substituted 1,2-benz-3(2H)-isoxazolones 353 (Scheme 85) .

Scheme 85

Isoxazoles

SPS using the ‘catch and release’ approach allowed the efficient preparation of libraries of substituted isoxazoles. Starting from aniline–cellulose as solid support, N-formylimidazole dimethyl acetal, and different -ketoesters or -ketoamides (X ¼ O, NH, NEt), the one-pot generation of cellulose-bound enaminones 354 was performed in quantitative yields. Following treatment with hydroxylamine hydrochloride, pure isoxazoles 355 were obtained in high yields directly in solution, with recovery of the starting resin (Scheme 86) . Microwave-assisted synthesis was also reported .

Scheme 86

Direct interaction of a nitro substituent with electron-rich and electron-poor side-chains in ortho-substituted nitroaromatic and nitro-heteroaromatic compounds is a well-documented and fruitful source of novel heterocyclization reactions. In this context, efficient solution-phase pyrolytic transformations of 4-nitro-1H-imidazol-5-ylethanoates 356 and 3-nitropyridinyl- and 5-nitropyrimidinyl-ethanoates 358 gave 3,4-fused isoxazoles 357 and 359, plausibly through ketene intermediates (Scheme 87) .

Scheme 87

5-Aminoisoxazoles were obtained from (Z)-3-alkyl-3-nitro-2-phenylpropenenitriles using baker’s yeast . Reductive cyclizations of 2-nitroacylarenes allowed the synthesis of anthranil derivatives. For example, a series of 5-substituted 2,1-benzisoxazoles where prepared by reduction with SnCl2 and subsequent

425

426

Isoxazoles

cyclization of 5-substituted-2-nitrobenzaldehydes . Analogous processes were performed in the presence of 2-bromo-2-nitropropane/Zn in methanolic solution or by controlled cathodic electrolysis reactions. The use of 2-bromo-2-nitropropane and indium in aqueous media solution gave 2,1-benzisoxazoles in excellent yields . Moreover, an efficient Me3SiCl/base-mediated dehydration allowed the synthesis of 3-substituted anthranils from 2-nitrobenzyl derivatives and from reactions of nitroarenes with arylmethylene compounds .

4.03.9.1.2

From atom fragment: C–C–N–O–C

4-Amino-5-acylisoxazole-3-carboxamides 362 were prepared by cyclization of O-(-oxoalkyl)-substituted -hydroxyimino nitriles 361, under basic conditions. A prior treatment of the O-alkylated oximes with LiClO4 increases the purity of the final compounds. The lithium cation is probably responsible for the isomerization of the (Z)-form of oximes 361 into the (E)-form involved in the cyclization (Scheme 88) . Cyclocondensation of malonyl-derived O-acyl hydroxamic acid derivatives 363, in the presence of phosphazene superbase P2But, gave rise to isoxazolone carboxylic esters 364 (Scheme 88) .

Scheme 88

4.03.9.1.3

From atom fragment: O–C–C–C–N

Hypervalent iodine oxidation of o-aminochalcones using PhI(OAc)2–KOH/MeOH led to 3-(-styryl)-2,1-benzisoxazoles in good yields, probably through initial attack of the I(III) reagent on the amino group . Treatment of 2-azido-3-hydroxy-1,4-diones 365 with mesyl chloride in the presence of an excess of base afforded 5-substituted-3-acylisoxazoles 366, probably through vinyl azide and nitrene intermediates (Equation 65) . In a similar way, thermolysis of 3-azido-2-halopropenones gave 4-haloisoxazoles in high yields .

ð65Þ

Isoxazoles

Nitrogen extrusion and electrocyclization of nitrene intermediates are probably involved in the conversion of 2-acyl-1-azido-3-phenalenones and 3-acyl-4-azido pyridine derivatives to the corresponding phenaleno[1,2-c]isoxazol7-ones 367 and isoxazolo[4,3-c]pyridines 368 . Analogous processes allowed the synthesis of isoxazolopyrimidines (see Section 4.03.11) . A DFT study of the concerted cyclization of 3-azidopropenal to isoxazole has been reported .

4.03.9.1.4

From atom fragment: C–C–C–O–N

A one-pot synthesis of 3-amino-1,2-benzisoxazoles was performed through SNAr reaction of ortho-halo- or -nitrosubstituted benzonitriles with acetohydroxamate anion, followed by intramolecular ring closure . An efficient method for the SPS of 3-aminobenzisoxazoles 371 has been developed by application of the Kaiser oxime resin 369 to SNAr reactions with 2-fluorobenzonitriles. The acidic cyclization conditions of intermediate aryl oximes 370 also caused the cleavage from the resin, leading to 371 in satisfactory yields and purity (Scheme 89). A mechanistic rationale involves nucleophilic attack of the nitrogen atom of the oxime or its hydrolysis product (the 2-aminooxybenzonitrile intermediate) on the protonated CN group .

Scheme 89

4.03.9.1.5

From atom fragments: C–C–N–O þ C

Dilithiated 1-tetralone oxime, prepared by treatment of 372 with an excess of LDA, was condensed with a variety of esters, affording, by acid cyclization, substituted 4,5-dihydronaphth[1,2-c]isoxazoles 373 (Scheme 90) . Several 3-(aryl)-2-(3-substituted isoxazol-5-yl)tropanes 375 were synthesized from methyl esters 374 by reaction with the dilithium salt of the appropriate ketone or aldehyde oxime (Scheme 90) . The same procedure was applied to 7-ethoxycarbonyl-2-azabicyclo[2.2.1]heptanes for the synthesis of novel epibatidine analogues, such as 376 . The reaction of -bromoketone oximes with isocyanides and sodium carbonate led to 5-aminoisoxazole derivatives in good yields. Probably, isocyanides are involved in a [4þ1] cycloaddition with nitrosoalkene intermediates .

4.03.9.1.6

From atom fragments: C–N–O þ C–C

Nitrile oxides undergo efficient [3þ2] cycloadditions with alkynes and alkenes to generate isoxazoles and 4,5dihydroisoxazoles, respectively. With unsymmetrical dipolarophiles there exists the possibility of regioisomeric mixtures of products; however, it is generally found that steric effects control the regioselectivity and the more encumbered end of the dipolarophile becomes attached to the oxygen of the nitrile oxide. Thus, terminal alkynes and alkenes afford almost exclusively 3,5-disubstituted isoxazoles and dihydroisoxazoles, respectively (Scheme 91).

427

428

Isoxazoles

Scheme 90

Scheme 91

Cyclodextrins, being cyclic oligosaccharides consisting of -1,4-linked D-(þ)-glucopyranose units, are able to form host–guest or inclusion complexes with a wide variety of hydrophobic species in aqueous solutions. Thus, -cyclodextrin has been used as a molecular scaffold, whereby tethering dipolarophiles to the cyclodextrin and allowing pre-association with aromatic nitrile oxides controls the relative orientations of dipoles and dipolarophiles in the cycloadditions. In this manner, it has been possible to reverse the usual regioselectivity of these 1,3-dipolar cycloadditions. For example, in aqueous solution, 4-t-butylbenzonitrile oxide reacted with a cyclodextrin-tethered terminal alkyne as 6A-deoxy-6A-propynamido--cyclodextrin to give the corresponding 3-(4-t-butyl)phenylisoxazoles 4- and 5-amido-substituted in a 15:1 ratio, respectively. Operating in DMF as solvent, the above ratio became 1:1.5, since DMF usually reduces the thermodynamic stability of the host–guest complexes. Analogous results were observed with cyclodextrin-tethered alkenes leading to isoxazoline derivatives (see Section 4.03.9.2.3) . Methyl 3-( p-nitrobenzoyloxy)acrylate was exploited as a methyl propiolate equivalent with reverse regioselectivity in 1,3-dipolar cycloaddition with nitrile oxides, leading to 3-aryl-4-methoxycarbonylisoxazoles in moderate to good yields . The use of catalysts in 1,3-dipolar cycloaddition of nitrile oxides and alkynes permits significant improvements, especially concerning yields and regioselectivity, that in general are quite low in uncatalyzed processes. In particular, a copper(I) catalyst, generated in situ from Cu(II) salts via reduction with sodium ascorbate or via comproportionation of the Cu(II)/Cu(0) couple, allowed easy access to 3,5-disubstituted isoxazoles 377 as single regioisomers through nonconcerted additions of nitrile oxides, produced from imidoyl chlorides, with terminal alkynes, probably reacting as copper(I) acetylides (Scheme 92). The dramatic acceleration provided by the copper catalyst can be appreciated by comparison of uncatalyzed and copper-catalyzed processes. For example, thermal 1,3-dipolar cycloaddition of 4-methoxybenzonitrile oxide to phenylacetylene resulted, after 8 h at 60 C, in a 4:1 mixture of 3,5- and 3,4-regioisomers, respectively, in 62% combined yield, whereas a single 3,5-regioisomer was obtained in 92% yield after 1 h at room temperature when a Cu(I) catalyst was added. Computational studies support a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles . The above process was exploited in a convenient one-pot three-step procedure, leading to 3,5-disubstituted isoxazoles in satisfactory yields (57–76%) from aldehydes and terminal acetylenes. Aldehydes were first converted to aldoximes, that were transformed without isolation to the corresponding nitrile oxides with chloramine-T trihydrate, which acted as both a halogenating agent and a base. The sequence exhibits wide scope with respect to both

Isoxazoles

components, is tolerant of most functional groups, and performs well in aqueous solvents. For instance, treatment of (E)-cinnamaldehyde with 1-ethynylcyclohexene gave isoxazole 378 with complete regio- and chemoselectivity (Scheme 92) .

Scheme 92

Apart from a few stable species, nitrile oxides exhibit a high tendency toward dimerization to furoxans; for this reason, several methods have been developed for the in situ generation of such dipoles in the presence of the desired acceptor. The most common procedures involve thermal or base-mediated deydrohalogenation of hydroxymoyl halides, oxidation of aldoximes, and dehydration of primary nitroalkanes . A modified Mukaiyama method, employing catalytic triethylamine and 1,4-phenylene diisocyanate instead of phenyl isocyanate, was exploited for generating nitrile oxides from primary nitroalkanes; it resulted in the formation of a diphenyl urea polymer, easily separated by filtration from isoxazole products (the same procedure was also applied to the synthesis of isoxazolines; see Section 4.03.9.2.3) . This method was used to dehydrate methyl nitroacetate, generating the corresponding nitrile oxide in the presence of benzyl propargyl ether to afford isoxazole 379 in 76% yield. Then, conversion into the oxime 380 and reaction of the in situ-generated nitrile oxide with propargyl bromide led to 3,39-diisoxazole 381 which gave rise to the tetraheterocyclic, triisoxazole-containing products 383 by coupling with alcohols 382 (Scheme 93) .

Scheme 93

429

430

Isoxazoles

Nitrile oxides generated in situ by dehydration of primary nitro compounds reacted with pyrrolidine enamines of protected - or -amino--keto esters to afford 5-aminoalkylisoxazole-4-carboxylic esters 384; lactam formation allowed the synthesis of isoxazolo[4,5-c]pyridine-4-one 385 and pyrrolo[3,4-d]isoxazole 386, converted by N–O bond cleavage into 3-acetyl-4hydroxypyridin-2-one and 3-acetyltetramic acid, respectively (Scheme 94) . A complementary strategy, involving 1,3-dipolar cycloaddition of -amino nitrile oxides, formed from -amino acids, to enamines of -ketoesters gave 3-(1-aminoalkyl)isoxazole-4-carboxylic esters 387, converted via pyrrolo[3,4-c]isoxazol-4-ones into 5-substituted-3-acetyltetramic acids 388 (Scheme 94) . Amino esters 387 were coupled at either the C- or N-terminus to produce pseudopeptide segments as peptide mimetics containing a cis-amide bond .

Scheme 94

3-Acetyl- and 3-benzoylisoxazoles 389 (and isoxazolines) have been prepared by one-pot reactions of alkynes (and alkenes) with ammonium cerium(IV) nitrate (CAN(IV)) or ammonium cerium(III) nitrate tetrahydrate (CAN(III))– formic acid, in acetone or acetophenone. These processes probably involve 1,3-dipolar cycloaddition of nitrile oxides produced via nitration of the carbonyl compound by cerium salts. The existence of nitrile oxides as reaction intermediates was proved by the formation of the dimer furoxan 390 when the above reaction was carried out in absence of any dipolarophile (Scheme 95) . An analogous improved procedure has been applied to alkynyl glycosides as dipolarophiles for the preparation of carbohydrate isoxazoles .

Scheme 95

Isoxazoles

1,3-Dipolar cycloaddition was exploited as a versatile and efficient tool for the creation of heterocyclic bridges between different units. In this context, the dimer glycosides 393, containing an isoxazole bridge, were prepared by reaction of the galactopyranosyl nitrile oxide, obtained from the nitromethyl derivative 391, with propargyl glycosides 392, derived from D-glucose or D-galactose (Equation 66). This strategy was also applied to the synthesis of glycoclusters and glycocyclodextrins, revealing an adequate methodology for the construction of synthetic multivalent carbohydrates from complementary functionalized building blocks .

ð66Þ

Analogously, the C-glycosyl alanines 396 featuring an isoxazole ring between the sugar and amino acid residues were prepared by 1,3-dipolar cycloaddition of C-glycosyl nitrile oxides and an ethynyl functionalized amino ester. A DMF solution of C-glycosyl oxime 394 and alkyne 395 (10.0 equiv) was treated sequentially with NBS and NEt3. Chromatographic purification of the reaction mixture furnished the 3,5-disubstituted isoxazole cycloadducts 396 in good yields as the sole regioisomers, alongside small amounts of the corresponding furoxans (Equation 67) .

ð67Þ

3-(N-Methyl-N-methoxycarboxamido)isoxazoles were prepared regioselectively through cycloaddition of Weinreb amide-functionalized nitrile oxides with alkynes . A mild 1,3-dipolar cycloaddition protocol allowed the regioselective preparation of 3-aryl-5-phenylselenomethyl isoxazoles from aryl nitrile oxides and phenyl propargyl selenide . Analogous reactions with phenyl vinyl selenide gave 3-substituted isoxazoles (78–86% yields) through 1,3-dipolar cycloaddition and subsequent oxidation– elimination in a one-pot, two-step transformation . Reactions with stannyl alkynes proceeded regioselectively to afford 4-stannyl isoxazoles in good yields, but no reaction was observed for vinyl or allyl stannanes . An efficient protocol for the regioselective assembly of a range of highly substituted isoxazoles arose from 1,3dipolar cycloaddition of alkynyl boronates 397 with nitrile oxides: isoxazoleboronic esters 398 were isolated in satisfactory yields and with excellent levels of regiocontrol (a single regioisomer was obtained when R2 6¼ H) . 3-Bromo- and 3-chloroisoxazolyl-4-boronates 398 (R1 ¼ Br or Cl) have also been prepared from the corresponding halonitrile oxide, generated in situ from dihaloformaldoxime and KHCO3 in dimethoxyethane at 50 C . The synthetic potential of these intermediates has been explored through a number of crosscoupling reactions; for instance, compounds 398 (R1 ¼ Mes, R2 ¼ Me) participated efficiently in a Suzuki coupling with bromobenzene, affording derivative 399 in excellent yield (Scheme 96). This technique has been applied to the synthesis of trisubstituted isoxazole 4-boronates and disubstituted isoxazoles where the boronic ester moiety can be installed at C-4 or C-5 with high regiocontrol . A DFT study of the mechanism of 1,3-dipolar cycloaddition of benzonitrile oxide toward ethynyl and propynyl boronates has also been reported .

431

432

Isoxazoles

Scheme 96

Alkynyliodonium salts reacted easily with 2,4,6-trimethylbenzonitrile oxide to give the corresponding (isoxazol-4yl)iodonium salts . An efficient preparation of iodoacetylene by reacting iodine with tributyl(ethynyl)tin allowed an easy access to 3-substituted-5-iodoisoxazoles, isolated in 70–90% yields, through 1,3-dipolar cycloaddition with aryl and heteroaryl nitrile oxides generated in situ from the corresponding oxime chlorides . Sequential [3þ2] cycloaddition/silicon-based cross-coupling reactions allowed for the synthesis of 3,4,5-trisubstituted isoxazoles. Regioselective 1,3-dipolar cycloaddition reactions between alkynyldimethylsilyl ethers 400 and ethyl or phenyl nitrile oxides, generated in situ from 1-nitropropane and N-hydroxybenzene carboximidoyl chloride, respectively, gave as predominant products after hydrolysis isoxazol-4-ylsilanols 401, converted into 4-arylisoxazoles 402 by cross-coupling with a variety of aryl iodides (Scheme 97) .

Scheme 97

Completely regioselective additions of benzonitrile oxide to arylsulfinyl-5-alkoxyfuran-2(5H)-ones 403 and 406 gave rise to regioisomeric 4,5-difunctionalized isoxazoles 404 and 407, after spontaneous evolution of the primary adducts through desulfinylation and opening of the lactone ring. Subsequent condensation with hydrazine yielded isoxazolopyridazinones 405 and 408, obtained in 75% overall yield in a one-pot, two-step synthetic sequence (Scheme 98)

Scheme 98

Isoxazoles

. The reactivity of the double bond as dipolarophile is strongly increased by the sulfinyl group, besides influencing the regioselectivity, usually opposite to that exhibited by other dipolarophiles lacking this substituent . Analogous [3þ2] cycloadditions of pyridine-3-nitrile oxide with alkyl 4,4-diethoxy-3-p-tolylsulfinylbut-2-enoates allowed a facile access to 3-pyridin-3-ylisoxazole-5-carboxylates 409, useful starting materials for the synthesis of highly functionalized 3-pyridin-3-ylisoxazoles . An efficient way to construct a library of isoxazoles (and isoxazolines) was developed by solution-phase combinatorial chemistry involving 1,3-dipolar cycloaddition of nitrile oxides, generated from oximes, with alkynes (and alkenes) obtained from arylpiperazines and propargyl (or allyl) bromide. The amine functionality serves as a pharmacophoric group for various receptors and at the same time provides an expeditious means of purification and isolation of the products through precipitation as HCl salts . A soluble polymer-supported synthesis of structurally different isoxazoles (and isoxazolines) was carried out through reaction of a soluble PEGsupported alkyne 410 with nitrile oxides, generated in situ from chlorooximes. Isoxazoles 411 were isolated in good yield and purity after cleavage from the resin (Scheme 99) . SPS of 3-hydroxymethyl isoxazoles 413 was accomplished in acceptable yields and purity through 1,3-dipolar cycloaddition of different alkynes to polystyreneresin-bound nitrile oxide, generated from nitro compound 412 under Mukaiyama conditions. This method is robust enough to be carried out by an automated synthesizer (Scheme 99) . A complementary methodology allowed the regioselective preparation of a library of isoxazoles and isoxazole-containing optically active amino acids (the latter were previously synthesized from alkynes or nitrile oxides obtained from Garner’s aldehyde as a suitable enantiopure starting material ). By anchoring acetylenic compounds 414 on trityl chloride resin and generating the nitrile oxides in situ from suitable carbonyl derivatives, structurally different isoxazoles 415 were obtained in satisfactory yields and purity (Scheme 99) . A convenient route to generate nitrile oxides in situ from nitroalkanes under very mild conditions and microwave irradiation using 4-(4,6-dimethoxy-1,3,5triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and DMAP as catalyst has been developed and also applied to SPS .

Scheme 99

433

434

Isoxazoles

Regioselective 1,3-dipolar cycloaddition of supported vinyl ethers RC(TCH2)O–CH2–polymer gave supported isoxazolines which were released under mild acidic conditions to produce ethyl 5-substituted isoxazole-3-carboxylates. Alternatively, further on-resin functionalization of the R-substituent (R ¼ m-iodophenyl or p-bromophenyl) using Suzuki coupling reactions and release from the support under acidic conditions gave more structurally diverse isoxazoles . Isoxazole-containing alkoxyamines were prepared in excellent yields and purity by cycloaddition of alkyne resins obtained from polymer-supported N-hydroxyphthalimide and nitrile oxides generated from oximes, NBS, and NaHCO3 . Solid-phase regioselective nitrile oxide 1,3-dipolar cycloaddition to an !-alkynyl ester 416 gave isoxazoles 417, converted by reductive -N-alkylation and isocyanate or isothiocyanate -N-acylation into isoxazolohydantoins or isoxazolothiohydantoins 418 in 20–35% and 30–40% overall yields, respectively (Scheme 100) . Analogous nitrile oxide 1,3-dipolar cycloaddition to resin-bound alkynoate esters 419 afforded compounds 420, thus allowing the preparation of an 18-member library of 5-(isoxazol-4-yl)-1,2,4-oxadiazoles 421 (Scheme 100) .

Scheme 100

A base-promoted reaction of C-chloro oximes and cyclic 1,3-diketones gave rise to highly functionalized fused isoxazoles 422, under mild reaction conditions and with notable functional group tolerance . These reactions were also performed with stable 2,6-disubstituted benzonitrile oxides, allowing the synthesis of more sterically encumbered polycyclic isoxazoles in good yields. Mechanistic studies evidenced the necessity for a catalytic amount of base, suggesting a key role for enolate species in the rate-limiting carbon–carbon bond-forming step, either ˚ were via nucleophilic addition to the nitrile oxide or via [2þ3] cycloaddition . Molecular sieves (4 A) exploited as efficient promoters, broadening the scope of this simple approach . Isoxazoles 422 can be directly converted into a variety of polyketide-derived polycyclic structures, including xanthenes, anthracenes, and benzophenones (Scheme 101). Bromine substituents on naphthoquinones effectively activate and orient 1,3-dipolar cycloaddition with nitrile oxides, generated from halo oximes (X ¼ Cl, Br), to afford, regioselectively, tricyclic derivatives 423, as type II polyketide building blocks (Scheme 101) . Analogous reactions of chloro oximes with aminophenyl-,-ynones were exploited to synthesize isoxazolo[4,5-c]quinolines 424 through domino [3þ2] cycloaddition/annulation processes (Scheme 101) . Pyranoisoxazoles 425 have been prepared by intramolecular 1,3-dipolar cycloaddition of nitrile oxides obtained by treatment of nitrooxaheptynes with n-BuLi and Ac2O (Scheme 102) . The coupling of the Ugi multicomponent reaction with the intramolecular N-oxide cyclization (Ugi/INOC) provided access to novel fused isoxazoles 426 in two steps from easily available starting materials in moderate to good overall yields

Isoxazoles

. Intramolecular 1,3-dipolar cycloaddition of nitrile oxides (generated from the corresponding oximes) of 2- and 4-O-propargyl glucose derivatives allowed the synthesis of enantiopure isoxazoles containing THF and oxepane rings in satisfactory yields .

Scheme 101

Scheme 102

An SPS of substituted benzopyranoisoxazoles 427 in high yields and purity has been developed. The procedure exploits very mild conditions for the generation of nitrile oxides from aldoximes on a polymer support followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne to assemble the isoxazoles (Scheme 102) .

435

436

Isoxazoles

4.03.9.1.7

From atom fragments: C–C þ N–O þ C

Four-component coupling of a terminal alkyne, hydroxylamine, carbon monoxide, and an aryl iodide in the presence of a palladium catalyst allowed the regioselective preparation of 3,5-diarylisoxazoles 428. The reaction proceeds at room temperature and an ambient pressure of CO in an aqueous solvent system (Equation 68) .

ð68Þ

4.03.9.2 Synthesis of Dihydroisoxazoles 2,3-Dihydroisoxazoles and 4,5-dihydroisoxazoles can be also obtained from isoxazolidines and isoxazoles .

4.03.9.2.1


4.03.9.2.1(i) Synthesis of 2,3-dihydroisoxazoles This retrosynthetic disconnection was not employed before 1995. First, Stoner et al. reported in 1997 the cyclization of aryl-substituted propargylic N-hydroxy ureas in the presence of Pd(OAc)2 and NEt3 to yield 2,3-dihydroisoxazoles along with small amounts of the corresponding isoxazoles. As shown for the N-hydroxy urea 429, the cyclized product 430 was obtained in only a modest yield (Equation 69) . Later Carreira and co-workers reported the efficient synthesis of a series of 2,3,5-trisubstituted-2,3-dihydroisoxazoles by cyclization of propargylic N-hydroxylamines. Thus N-benzyl hydroxylamine 431 in the presence of catalytic amounts of ZnI2 and DMAP afforded 432 in 91% yield (Equation 70) . More recently, using a slight different functionalized propargylic N-BOC hydroxylamine, Denis and co-workers reported a single example of cyclization using Pd(OAc)2 in the absence of any base (85% yield) .

ð69Þ

ð70Þ

4.03.9.2.1(ii) Synthesis of 4,5-dihydroisoxazoles Dinitronates, activated by O-acylation, gave polyfunctionalized isoxazolines. The plausible mechanism involves attack of one nitronate group on an O-acylated nitronate with consequent intramolecular cyclization. For instance, 433 treated with acetyl chloride at room temperature gave 434 in 96% yield (Equation 71) .

Isoxazoles

ð71Þ

4.03.9.2.2


4.03.9.2.2(i) Synthesis of 2,5-dihydroisoxazoles A series of 4-iodo-2,5-dihydroisoxazoles have been synthesized from O-propargylic hydroxylamines in the presence of iodine. For example, hydroxylamine 435 gave the 3-isoxazoline 436 in 95% yield (Equation 72) .

ð72Þ

4.03.9.2.2(ii) Synthesis of 4,5-dihydroisoxazoles 2-Isoxazolines have been synthesized by an intramolecular rearrangement of O-propargylic hydroxylamines in yields ranging from 60% to 84% . To prevent side reactions, derived from base-catalyzed ring opening, 3-unsubstituted isoxazolines have been prepared starting from free hydroxylamines. For instance, salt 437 treated with base in refluxed methanol gave the isoxazoline 438 in 84% yield (Equation 73). A prior example of this rearrangement but with more severe conditions (18 equiv NaOH, MeOH reflux, 3 h) had been reported .

ð73Þ

4.03.9.2.3


4.03.9.2.3(i) Synthesis of 2,3-dihydroisoxazoles 2,3-Dihydroisoxazoles have been prepared by 1,3-dipolar cycloaddition between nitrones and alkynes. This retrosynthetic disconnection of the ring is the one usually employed for their preparation. This method typically furnishes regioisomeric mixtures of adducts with unsymmetrical alkynes and often, along with the expected cycloadducts, a stable rearrangement product is detected or isolated

437

438

Isoxazoles

(see also Section 4.03.9.2.1). Examples of regioselective 1,3-dipolar cycloaddition have also been reported. For instance, a series of stable chromium and tungsten Fischer dienyl carbenes such as 110 were regioselectively prepared by 1,3-dipolar cycloaddition of alkenylethynyl carbene complexes with nitrones (Equation 74) .

ð74Þ

Complete regioselectivity was found in the organocatalyzed reaction between conjugated alkynoates and nitrones suspended in water, while no reaction was observed in an organic solvent . Enantiopure nitrones have been utilized and the selectivity of their 1,3-dipolar cycloaddition evaluated. A 2:1 diasteromeric mixture of 4-isoxazolines 441 and 442 was obtained from enantiopure nitrone 440 and DMAD . The reaction of the enantiopure endocyclic nitrone 443 with alkynylzinc reagents led to a tandem addition/cyclization process, affording 2,3-dihydroisoxazole derivatives 446 in high yields and with complete diastereoselectivity (Scheme 103) . In fact, although the global outcome of this reaction was that of a 1,3-dipolar cycloaddition, the process followed a two-step pathway involving a propargylic hydroxylamine intermediate 445, similar to that reported by Carreira and co-workers (see Section 4.03.9.2.1).

Scheme 103

The [2.2]paracyclophane 4-isoxazoline 447 and the tricyclic isoxazolines 448 were obtained as single adducts from the corresponding nitrones and DMAD in 61% and 52% yield, respectively . 4-Isoxazolines have also been synthesized from polymer-supported nitrones. Wang polymer-bound cyclic nitrone 449 underwent cycloaddition with monosubstituted alkynes to afford mainly the 5-substituted adducts, which were recovered in 23–54% after cleavage from the resin. Significantly, there was no evidence of thermal rearrangements or decomposition reactions of the isoxazolines .

Isoxazoles

4.03.9.2.3(ii) Synthesis of 4,5-dihydroisoxazoles 1,3-Dipolar cycloaddition of dipoles with alkenes is the most important approach for the synthesis of 4,5-dihydroisoxazoles. Usually the dipole is generated in situ by dehydration of primary nitro compounds or by halogenation– dehydrohalogenation of aldoximes. Since the report of Mukaiyama and Hoshino , phenyl isocyanate has become the most popular dehydrating agent for primary nitroalkanes even if product isolation and purification is often complicated by contamination with 1,3-diphenylurea. To overcome this drawback, Kurth and co-workers have employed 1,4-phenylene diisocyanate. They were able to isolate the cycloadducts from the dehydrating agent side products (urea polymers) by simple filtration (Equation 75) . Basel and Hassner have reported an improved procedure for the generation of nitrile oxides using BOC2O and catalytic DMAP (Equation 76) . The major advantages of this method are the benign nature of side products (CO2 and t-BuOH) along with the low reaction temperature (Equation 77). In addition, this method allowed the generation of unsaturated nitrile oxides used in intramolecular synthesis of isoxazolines .

ð75Þ

ð76Þ

ð77Þ

Other reported procedures used dimethylaminosulfur trifluoride (DAST)/NEt3 , N-(triethylamoniumsulfonyl)carbamate (Burgess salt)/NEt3 , and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM)/DMAP under microwave irradiation . Dihydroisoxazoles were prepared by condensation of primary nitro compounds and alkenes, in the absence of any dehydrating agents, and generally in higher yields compared to previously reported procedures (Equation 77) . Tertiary bases such as DABCO or DMAP promote the dehydration of the nitro compounds as a thermodynamically favored process. Detailed studies on the role of the base in such reactions have been reported . A method which utilizes O-silylated hydroxamic acids as precursors of nitrile oxides has been reported: O-silylated hydroxamic acid 450, treated with Tf2O and triethylamine in the presence of styrene, afforded 451 in 62% yield (Equation 78) . Generation of a nitrile oxide bearing a carbamoyl group under mild conditions is exemplified in the reactions of 4-nitro-3-isoxazolin-5-one 452 with dipolarophiles in MeCN/H2O at room temperature to afford cycloadducts in high yields; it was absolutely inert when heated under reflux in MeCN (Equation 79). The presence of N-methylcarbamoylformonitrile oxide was supported by the isolation of the corresponding furoxane in the absence of dipolarophile .

ð78Þ

439

440

Isoxazoles

ð79Þ

Other reported sources of nitrile oxides utilized in 1,3-dipolar cycloaddition preparations of 4,5-dihydroisoxazoles are nitrolic acid , primary alkyl halides , and acetone/CAN . 2-Isoxazolines have also been synthesized by 1,3-dipolar cycloaddition in supercritical carbon dioxide (scCO2) , ionic liquids such as [bmim][BF4] or [bmim][PF6] , and aqueous media . Kinetic studies have demonstrated that cycloadditions involving electron-rich dipolarophiles are accelerated in water and protic solvents but no special effect was observed with electron-poor dipolarophiles . During the years 1995–2005, combinatorial chemistry has rapidly become an important tool in many fields such as drug discovery, supramolecular chemistry, chiral catalyst development, as well as material science. Combinatorial synthesis has stimulated the development of the synthesis of small organic molecules using polymer-bound substrates. Accordingly, 1,3-dipolar cycloadditions of nitrile oxides have been applied to solid-phase organic synthesis (SPOS), using either polymer-bound olefin or polymer-bound dipole. Combinatorial synthesis of a library of isoxazolines in solution phase has also been reported . The well-known tendency of nitrile oxides to undergo dimerization reactions is reduced under SPOS conditions as the distance between the reactive sites is increased on resin . For example, Wang resin-supported nitrile oxides, generated from resins 453, displayed increased stability and could be isolated or directly trapped with a variety of dipolarophiles. Adducts 455 were recovered by treatment of resin 454 with TFA (Scheme 104) .

Scheme 104

Additional examples of libraries of isoxazolines prepared by 1,3-dipolar cycloaddition of Wang resin or chlorotrityl resin- supported dipolarophiles, generated in the presence of a variety of dipolarophiles, have been reported. The achiral hydantoin- and isoxazoline-substituted bis-spirocyclobutanoids 458 and 459 were produced using SPS (Scheme 105) .

Scheme 105

Isoxazoles

Solid-supported isoxazolines 462 were prepared starting from a sulfinate-functionalized resin 460. Oxidation of the resin-linked cyclobutanols 462, with concomitant cleavage of the sulfone linker, produced isoxazolyl-cyclobutenones 463 in 34–38% overall yield (four steps) (Scheme 106) . A five-step SPS of isoxazolyl-pyrrole-2carboxylates that employs the same traceless sulfone linker strategy was reported .

Scheme 106

Additional examples of supported dipolarophile synthesis of isoxazolines are shown in Table 2.

Table 2 SPOS of isoxazolines using polymer-supported dipolarophile Entry

Dipolarophile

Product

Yield (%) ( purity, %)

Reference

1c

51a (89)

2005JCO726

2c

77a (96)

2005S2143

3b

75

2002JCO652

4b

95

1998TL939

a

Yield of crude product based on the loading on the starting resin. Wang resin. c Selenium resin. b

An alternative to SPS termed ‘fluorous synthesis’ has been reported by Studer and Curran . The separation technique of reverse fluorous solid-phase extraction (r-fspe) was applied to the purification of the fluoroustagged isoxazolines 465. Compounds 465 were synthesized through a two-step sequence consisting of allylation of perfluoroalkyl iodides 464 with an excess of allyl stannane, followed by reaction of the crude allyl perfluoroalkanes with benzonitrile oxide generated in situ from an excess of benzaldehyde oxime under oxidative conditions. At the end, the isoxazolines 465 were easily separated from the complex reaction mixtures by column chromatography on standard silica gel eluting with a mixture of perfluorohexanes (FC-72) and Et2O (Scheme 107). The fluorous liquid

441

442

Isoxazoles

phase selectively eluted the fluorous-tagged fractions from the column while all the ‘nontagged’ compounds were retained on the polar solid phase .

Scheme 107

The approach to product isolation by means of ‘precipiton-functional protecting group’ was applied to the synthesis of some 5-methoxycarbonylisoxazolines. For instance, the soluble isoxazoline 467 was prepared in Et2O. The XZ precipiton auxiliary was then isomerized to the (E)-form to obtain 468 that showed a very low solubility in hexanes, Et2O, and MeOH. All by-products were easily washed away and after methanolysis the isoxazoline 469 was isolated in good yield and high purity (Scheme 108) .

Scheme 108

Nitrile oxide cycloaddition with mono- and trisubstituted alkenes affords almost exclusively 5-mono- and 4,5,5trisubstituted isoxazolines, respectively, the regioselectivity being determined by steric effects. Reverse regioselectivity in nitrile oxide cycloaddition to terminal alkenes has been reported ; for example, 4-tert-butylbenzonitrile oxide was forced to reverse alignment for the cycloaddition by formation of the inclusion complex 470 with -cyclodextrin. Under these conditions, 90% of the 3,4-disubstituted cycloadducts were obtained, whereas in the absence of cyclodextrin the aromatic nitrile oxide afforded only the 5-substituted isoxazoline. When 6A-deoxy-6A-propenamido--cyclodextrin (Z ¼ NH in complex 470) was used as dipolarophile, the cycloadducts were not easily separated from the cyclodextrin, as the amide bond is not readily cleaved. On the other hand, cycloadducts linked with an ester moiety (Z ¼ O in complex 470) were, under basic conditions, readily released from the cyclodextrin through hydrolysis. For example, in aqueous solution, 4-tert-butylbenzonitrile oxide reacted with a cyclodextrin-tethered terminal alkene 471 (X ¼ -cyclodextrin) to give the corresponding 3-(4-tert-butyl)phenylisoxazolines 4- and 5-carboxylate-substituted 472 and 473 in a 20:1 ratio, respectively. Subsequent ester hydrolysis allowed removal of the cyclodextrin moiety recovering the acids 474 and 475 (Scheme 109). As well as reversing the regioselectivity, the cyclodextrin increased the cycloaddition rate . Analogous results were observed with cyclodextrin-tethered alkynes leading to isoxazole derivatives (see Section 4.03.9.1.6). The reaction of nitrile oxides with 1,2-disubstituted alkenes tends to be slower and poorly regioselective. The fundamental and obligatory reference point for any regiochemical result continues to be the study reported by Huisgen on the cycloaddition of nitrile oxides to ,-unsaturated esters . Benzonitrile oxide reacts with methyl cinnamate to afford 5-phenyl and 4-phenyl regioisomers in approximately 80:20 ratio; using N,N-diethylcinnamide as dipolarophile, the ratio was reversed to 23:77. The regioselectivity of 1,3-dipolar cycloaddition of nitrile oxides to crotonic and cinnamic derivatives was strongly influenced by steric factors. This fact was particularly evident in the case of tertiary amides and lactams. Calculated transition state energies agreed with the above experimental results . The regioselectivity was investigated as a function of solvent density performed in scCO2 at different pressures .

Isoxazoles

Scheme 109

1,3-Dipolar cycloaddition reactions of chiral nitrile oxides to achiral dipolarophiles generally result in a low degree of stereoselection due to the linearity of the dipole, the lack of any pre-orientation in the transition state, and the long distance between existing and forming stereogenic centers. Illustrative examples include enantiopure nitroacetate derivatives containing a menthyl residue as precursors of chiral nitrile oxides. Isoxazolines were obtained with low diastereoselectivity (d.r. 50:50) . Moderate diastereoselectivity was obtained in the preparation of isoxazolines 476–478 in a range of diastereomeric ratio from 50:50 to 86:14 (Scheme 110) . A mixture of separable isoxazolines 479 and 480 was produced in 67% yield and a ratio of 60:40. The enantiopure furoisoxazoline 481 was converted into the natural antibiotic L-(þ)-furanomycin 481 and to some analogues of 481 (Scheme 110) .

Scheme 110

Enantiopure isoxazolines were synthesized using both chiral nitrile oxides and chiral dipolarophiles. For example Mg(II)-directed 1,3-dipolar cycloaddition of nitrile oxides with chiral allylic alcohols 482 generated isoxazolines 483 (Scheme 111) . Later, this cycloaddition was applied in a total synthesis of erythronolide A 484 (Scheme 111) . Most of the efforts toward stereocontrolled syntheses of 2-isoxazolines have been based on reactions between chiral dipolarophiles and achiral dipoles. This approach is exemplified by some selected examples in Schemes 112–114 and Equation (80). Enantiopure dipolarophiles such as 485 and 487 , derived from carbohydrates, reacted with nitrile oxides to afford spiro- and bicyclic-isoxazolines 486 and 488, respectively, with high regio- and diastereoselectivity (Scheme 112).

443

444

Isoxazoles

Scheme 111

Scheme 112

The chiral isoxazoline derivatives 490 were prepared in a highly enantioenriched form by 1,3-dipolar cycloaddition of benzonitrile oxide and pivalonitrile oxide with acrylate 489 (Equation 80) .

ð80Þ

Isoxazoles

High diastereomeric ratios were observed in the 1,3-dipolar cycloaddition of various nitrile oxides to the optically active alcohol 491 and the chiral acryloylhydrazides 492 and 493. For example, benzonitrile oxide afforded the isoxazoline 494 in dr ¼ 99:1 . The level of facial selectivity obtained in the same 1,3dipolar cycloaddition with the chiral 3-acryloyl-2-oxazolidinone 493 was very low (d.r. ¼ 43:57), but in the presence of MgBr2 (1 equiv) the reaction proceeded with high diastereoselectivity to give preferentially the isoxazolidine 495 in d.r. ¼ 96:4 .

Scheme 113

The bimetallic tetraene isoxazoline 498 was prepared through a highly diastereoselective intermolecular nitrile oxide–olefin cycloaddition and used as an intermediate in the synthesis of the C-7–C-24 segment of macrolactin A. The addition of the nitrile oxide on the less-hindered face of the s-trans-triene rotomer of 497 was the key to control the absolute configuration of the newly formed stereocenter .

Scheme 114

Chiral metal chelates have been exploited to accomplish enantioselective 1,3-dipolar cycloadditions of nitrile oxides with allylic alcohols and acrylamides. In contrast with the Diels–Alder reaction, it is not easy to accomplish good stereoselectivity using nitrile oxide cycloaddition reactions. The main drawback in controlling the reactions is that the use of Lewis acid usually deactivates the nitrile oxide, stopping the reaction. In addition, the presence of a coordinative amine base necessary for the generation of nitrile oxide decreases the effectiveness of the Lewis acid. This inconvenient effect was overcome utilizing magnesium salts . An enantioselective synthesis of 2-isoxazolines, in which the dipolarophiles are limited to -substituted allylic alcohols, has been described by Ukaji and Inomata . They generated nitrile oxides in situ from hydroxymoyl chlorides in the presence of allylic alcohols, previously treated with diethylzinc and diisopropyl tartrate (DIPT). The use of catalytic (R,R)-DIPT afforded the (R)-2-isoxazolines 500 with high selectivity. The enantioselectivity of the reaction resulted from the formation of a bis-zinc-containing key intermediate 501 (Scheme 115) . An opposite enantiofacial differentiation was obtained using an N-sulfonylated (S,S)-2,3-diaminosuccinate-type chiral auxiliary . A slightly modified procedure was applied to solid-phase cycloaddition using EtMgBr instead of Et2Zn . Examples of highly enantioselective nitrile oxide cycloadditions to electron-deficient alkenes 502 have been reported using substoichiometric amounts (30 mol%) of the chiral Lewis acid derived from MgI2 and 503. The achiral pyrazolidinone template which contains a fluxional nitrogen proved to be effective in the cycloadditions of various aromatic nitrile oxides providing adducts 504 in good yields, and high regioselectivity (99%) and ee (Scheme 116) . A tentative model for the cycloaddition considers a

445

446

Isoxazoles

five- or six-coordinate magnesium bound to the ligand and to the bidentate substrate in an s-cis-conformation (Scheme 116). To avoid potential problems involving coordination of the Lewis acid by amine bases, unstable nitrile oxides were generated by passing the corresponding hydroximinoyl chlorides through an external bed of Amberlyst-21 immediately prior to injection into the reaction mixture. The cycloadditions of aliphatic nitrile oxides also proceeded with good selectivity, although more slowly and in lower yields.

Scheme 115

Scheme 116

An antibody-catalyzed 1,3-dipolar cycloaddition between 4-acetamidobenzonitrile oxide and N,N-dimethylacrylamide has been described for the first time. The most efficient antibody, 29G12, catalyzed the formation of 5-substituted isoxazolines with high regioselectivity which afforded up to 98% ee . Further investigation detailed the substrate specificity and mechanistic parameters .

4.03.9.2.4

From atom fragments: C–C–C þ N–O

Cyclocondensation processes of 1,3-dicarbonyl derivatives or their analogues are widely employed for the synthesis of isoxazoles (see Section 4.03.9.1.1) but are less frequently reported for 4,5-dihydroisoxazoles. Synthesis of 4,5-dihydroisoxazoles. 3-Methyl isoxazolines 506 have been prepared from the ketones 505 by reaction with hydroxylamine hydrochloride and subsequent 5-endo-trig-cyclization, leading to a single isomer (Equation 81) .

ð81Þ

Isoxazoles

Fluorinated 2-isoxazolines have been obtained stereoselectively from 2-(polyfluoroacyl)cycloalkanones and hydroxylamine in the presence of catalytic BF3?OEt2 . Enones 507 derived from disaccharides melibial and gentobial reacted with 2 equiv of hydroxylamine to afford isoxazolines 508 as an inseparable epimeric mixture in 80–83% yield. By treatment with p-toluenesulfonic acid, compounds 508 underwent dehydration to give isoxazole derivatives 509 in high yields (Scheme 117) .

Scheme 117

Oximes with a displaceable group at the -position cyclize in the presence of base. This reaction has been applied to the SPS of isoxazolines using sulfone linker-supported oximes and produced overall yields ranging from 10% to 33% (Scheme 118) .

Scheme 118

Microwave techniques have been applied. Cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones under microwave heating was faster and afforded the product in higher yields than under classical conditions .

4.03.9.3 Synthesis of Isoxazolidines Isoxazolidines can be prepared by addition of nucleophiles to the isoxazoline C–N double bond (see Section 4.03.6.2.3(ii)).

4.03.9.3.1


Isoxazolidines can be prepared by cyclization of homoallylic N-hydroxylamines. In fact, 5-(iodomethyl)isoxazolidines were obtained by iodocyclization of O-silylated N-(but-3-enyl) hydroxylamine derived by allylation of prochiral and chiral nitrones . For example, syn-510 and anti-512 underwent stereospecific iodocyclization to isoxazolidines 3,4-cis-4,5-cis-511 and 3,4-trans-4,5-cis-513, respectively, by treatment with N-iodosuccinimide (NIS) in CHCl3 at 0 C (Scheme 119) . Under the same conditions, aryl-substituted 510 and 513 (R ¼ Ph, 4-MeOC6H4) failed to give the corresponding isoxazolidines. 5-[(Hydroxyamino)methyl]furan-2(5H)-ones, prepared by trimethylsilyl triflate (TMSOTf)-promoted addition of 2-trimethylsilyloxyfuran to nitrones, can undergo cyclization to isoxazolidines. When five-membered cyclic nitrones were used, the formation of the tricyclic isoxazolidine strongly depended on the stereochemistry of the butenolides. For example, after removal of the TMS group, 514 gave the hexahydrofuro[2,3-d]pyrrolo[1,2-b]isoxazol-2(3H)-one 516 by silica gel-induced cyclization. Similarly, the diastereomer 515 gave the desilylated hydroxylamine 517, that, under the same conditions, failed to give the corresponding highly strained cis-syn-cis tricyclic product and was recovered in 12% yield (Scheme 120) .

447

448

Isoxazoles

Scheme 119

Scheme 120

4.03.9.3.2


Optically active isoxazolidines were prepared by endo-cyclization of O-allyl oximes induced by enantiopure selenylating agents (Scheme 121) .

Scheme 121

The O-(2-pyrrolidinylmethyl)hydroxylamine 518 cyclized by treatment with potassium carbonate in acetonitrile to give the cis-fused isoxazolidine 519 (Equation 82) . Under the same conditions, the diastereomeric syn-epoxide failed to cyclize to the thermodynamically disfavored trans-5,5-bicyclic isoxazolidine.

ð82Þ

Isoxazoles

3,5-Diaryl-substituted isoxazolidines were synthesized in a one-pot reaction starting from aryl halides and O-homoallyl hydroxylamines through a diastereoselective cascade reaction catalyzed by Pd(0). The choice of the phosphine ligand was shown to affect the product distribution between the isoxazolidine and the Heck-type product. The best results were obtained when 1 mol% of Pd2(DBA)3/P(o-Tol)3 was used (DBA ¼ dibenzylideneacetone). For example, under these conditions, isoxazolidine 520 was obtained in 79% yield together with a minor amount of the Heck coupling adduct 521 (Equation 83) .

ð83Þ

4.03.9.3.3


4.03.9.3.3(i) Nitrone cycloadditions 1,3-Dipolar cycloaddition between nitrones and substituted alkenes, including both electron-rich and electron-poor dipolarophiles, is the most common method for the synthesis of the isoxazolidine ring system. Depending on the nature of the reactants, the reaction can involve either a LUMO–dipole/HOMO–dipolarophile interaction or a LUMO–dipolarophile/HOMO–dipole or a combination of both modes of interactions (LUMO ¼ lowest unoccupied molecular orbital; HOMO ¼ highest occupied molecular orbital). The regioselectivity and exo/endo-selectivities are a consequence of contributions from electronic and steric factors, further complicated by the possibility of nitrone (E/Z)-isomerism in the case of acyclic nitrones. Diastereoselective nitrone–olefin cycloadditions have been achieved through incorporation of stereogenic elements in both the dipole and dipolarophile. For some examples of 1,3-dipolar cycloaddition of chiral nitrones, see: ; of 1,3-dipolar cycloaddition of chiral dipolarophiles, see: ; of double stereodifferentiation, see: ; and of intramolecular cycloadditions, see: . Many advances have been made in the use of catalysts to influence rate, regioselectivity, stereoselectivity, and enantioselectivity of the cycloaddition but even so, general systems that give predictably high levels of regio- and stereocontrol with a range of nitrones are still lacking. Several reviews covering recent results and developments on nitrone 1,3-dipolar cycloaddition have appeared in the decade 1995–2005 . Several complexes between metal ions such as Sc(III), Ti(III), Co(II), Ni(II), Cu(II), and Zn(II) and different chiral ligands have been studied as catalysts for stereoselective nitrone 1,3-dipolar cycloaddition reactions. Some examples of enantioselective catalytic 1,3-dipolar cycloaddition of acyclic nitrones with electron-deficient alkenes (normal electron-demand reaction) are reported in Schemes 122 and 123 and Equations (84)–(86). Templates such as 1,3oxazolidin-2-one, 1,3-thiazolidine-2-thione, and other cyclic and acyclic amides were introduced in acrylate and crotonate derivatives to obtain bidentate ligands to accomplish rotamer control through Lewis acid-mediated chelation and induce high facial selectivity. In most cases, endo-acylaminocarbonyl cycloadducts were obtained with high enantioselectivity, but also significant levels of exo-selectivity could be achieved by appropriate choice of the chiral Lewis acid and the reaction conditions (Scheme 122) . High levels of regio- and stereoselectivity were also observed in metal-catalyzed 1,3-dipolar cycloaddition of acyclic nitrones with -hydroxy enones. The reaction probably occurs through the formation of reactive 1,4-metal-chelated intermediates. A remarkable diastereo- and enantiocontrol could be obtained through two complementary approaches by using a camphor-derived -hydroxy enone in combination with Cu(OTf)2 or an achiral enone such as 526 in combination with the bis(oxazoline)-Cu(II) catalyst 527. The hydroxylated auxiliary could be easily removed from the final adduct with periodic acid to give the corresponding carboxylic acid (see Section 4.03.7.3.1) (Equation 84) .

449

450

Isoxazoles

Enantioselective cycloadditions of nitrones with alkylidene malonates were catalyzed by the complex of Co(II) with trisoxazoline 528. The cycloaddition was reversible and the diastereoselectivity could be controlled by reaction temperature. For example, N,C-diphenyl nitrone and diethyl 2-benzylidenemalonate reacted at 40 C under kinetic control, affording mainly the cis-adduct 530, but at 0 C the thermodynamically more stable trans-isomer 529 was the major product (Equation 85) .

Isoxazoles

Scheme 122

ð84Þ

ð85Þ

Chiral Lewis acids have been employed as catalysts in the stereoselective 1,3-dipolar cycloaddition of nitrones with dipolarophiles that act as monodentate ligands such as ,-unsaturated aldehydes. Usually, the primary adducts are not isolated, but directly reduced to the corresponding primary alcohols (Scheme 123). For instance, the reaction of several acyclic nitrones and acrolein catalyzed by the chiral bis-Ti(IV) oxide 531 afforded, after reduction with NaBH4, the endo-4-(hydroxymethyl)isoxazolidines with good enantioselectivities (88–97% ee) . High enantioselectivities have been achieved in cycloadditions of cyclic and acyclic nitrones with methacrolein in the presence of the chiral complexes 532 and 533 . The rhodium and iridium cations

451

452

Isoxazoles

[(5-C5Me5)M{(R)-1,2-bis(diphenylphosphino)propane} (H2O)]2þ were found to catalyze the 1,3-dipolar cycloaddition of some acyclic and cyclic nitrones with methacrolein with complete diastereoselectivity and good enantioselectivity. Some intermediates involved in the process were isolated and characterized and a catalytic cycle involving [M]aldehyde, [M]-nitrone, and [M]-adduct species was proposed . The reactions of N-phenyl C-aryl nitrones with the electron-poor -bromoacrolein were effectively catalyzed by Zn(II) complexes such as 534 and afforded isoxazolidine-4-carboxaldehydes, with high diastereo- and enantioselectivity, that were reduced to the corresponding alcohols (Scheme 123) .

Scheme 123

The first enantioselective organocatalytic 1,3-dipolar cycloaddition of acyclic nitrones with acrolein and crotonaldehyde has been reported . In particular, the reversible formation of iminium ions from ,-unsaturated aldehydes and the enantiopure imidazolidinone 535 provided endo-4-formylisoxazolidines in high yields and ees (Equation 86). A polymer-supported version of catalyst 535 was also prepared . The catalytic performance of various chiral pyrrolidinium salts in the cycloaddition of 1-cycloalkene-1-carboxaldehydes was also evaluated .

Isoxazoles

ð86Þ

Catalytic enantioselective versions of the ‘inverse electron demand’ cycloaddition have also been reported. For example, the C-(diisopropylamino)carbonyl N-phenyl nitrone reacted with -substituted allylic alcohols in the presence of diethylzinc, iodine, pyridine N-oxide, and a catalytic amount of enantiopure DIPT to afford 3,5-cisdisubstituted isoxazolidines with high enantioselectivity (Scheme 124) . Enantioselective cycloaddition of nitrones to enol ethers was achieved in the presence of chiral binaphthol–aluminium and chiral copper–bis(oxazoline) catalysts .

Scheme 124

SPS of isoxazolidines through 1,3-dipolar cycloaddition and their transformations have been reviewed . Isoxazolidines were also prepared by nitrone 1,3-dipolar cycloaddition on silica gel in solvent-free conditions under microwave irradiation . Fused polycyclic isoxazolidines were prepared via a multicomponent palladium-catalyzed allene insertion–intramolecular 1,3-dipolar cycloaddition cascade .

4.03.9.3.3(ii) Oxime–olefin cycloadditions Cycloaddition of an oxime with an alkene gives an N-unsubstituted isoxazolidine via tautomerization of the oxime to an N-unsubstituted nitrone. Usually, high reaction temperatures are necessary to induce the thermodynamically unfavorable formation of the nitrone. Pd(II) salts were used to promote the cycloaddition of iminoaldoximes with N-methylmaleimide, which occurred at room temperature through the formation of N-metallonitrones . Treatment of -alkenyl O-silyloximes with BF3?OEt2 smoothly afforded the corresponding N-boranonitrones, which underwent intramolecular cycloaddition at room temperature (Equation 87) .

ð87Þ

Tautomerization of enantiopure -allylamino aldoximes was catalyzed by zinc chloride in refluxing benzene. The in situ-formed nitrones underwent intramolecular 1,3-dipolar cycloaddition to produce condensed bicyclic isoxazolidines .

453

454

Isoxazoles

4.03.9.3.3(iii) Two-step cycloadditions The nucleophilic addition of lithiated allyl phenyl sulfone to nitrones at 0 C afforded 4-(phenylsulfonyl)isoxazolidines as major products. The process probably involves the isomerization of the allylsulfonyl moiety of the initially formed hydroxylamine anion to vinylsulfone which then undergoes intramolecular Michael addition. For example, the chiral nitrone 536 afforded isoxazolidine 537 with high diastereoselectivity (Equation 88) . When the same reaction was carried out in the presence of hexamethylphosphoramide (HMPA) at 80 C, the anti-sulfonyl homoallyl hydroxylamine was obtained.

ð88Þ

4.03.9.3.3(iv) Tandem [4þ2]/[3þ2] cycloadditions of nitroalkenes Nitronates (nitronic esters) undergo 1,3-dipolar cycloaddition to 2-alkoxyisoxazolidines (nitroso acetals), which are useful synthetic intermediates (see Section 4.03.6.3.7) . Extensive studies of the tandem [4þ2]/[3þ2] cycloadditions of nitroalkenes have been made. These comprise an inverse electron demand HDA reaction of a donor dienophile followed by a [3þ2] cycloaddition of the in situ-generated cyclic nitronate with an acceptor dipolarophile (Scheme 125) . Generally, these reactions are performed in the presence of a stoichiometric amount of a Lewis acid. Both cycloaddition steps can be performed in intra- or intermolecular fashion and the process is able to construct four new bonds, up to four new rings, and up to six contiguous stereocenters with high control of the relative and absolute configuration.

Scheme 125

For example, the three-component domino inter-[4þ2]/inter-[3þ2] cycloaddition reaction of the D-galactosederived heterodiene 538 with ethyl vinyl ether and methyl vinyl ketone took place with total chemo-, regio-, facial-, and stereoselectivity to give a single nitrosoacetal 539 in 70% yield (Equation 89) .

ð89Þ

Isoxazoles

The tandem inter-[4þ2]/intra-[3þ2] cycloaddition process involving dienylsilyloxy nitroalkene 540 and chiral vinyl ether 541 in the presence of methylaluminium bis(2,6-diphenylphenoxide) (MAPh) as Lewis acid afforded the single cycloadduct 542 in 66% yield. On a preparative scale, a lower yield (49%) of the purified product was obtained (Scheme 126) . The two-atom linker between the nitronate and the dipolarophile moieties in 540 and the configuration of the chiral auxiliary phenylcyclohexanol could be chosen to obtain the adduct 542 with the relative and absolute configuration at the newly formed stereocenters, as required in the pyrrolizidine alkaloid (þ)-1epiaustraline.

Scheme 126

Analogously, the isomeric ()-7-epiaustraline was prepared through the highly selective two-step inter-[4þ2]/inter[3þ2] cycloaddition process with isolation of the crystalline intermediate nitronate 543 (Scheme 127) .

Scheme 127

Tandem double intramolecular [4þ2]/[3þ2] cycloadditions were performed using nitroalkenes tethered to both the dienophile and the dipolarophile. For example, the [4þ2] cycloaddition of the linear triene 544 was promoted by SnCl4 to afford a 3:2 mixture of 545 and 546 rapidly. The intramolecular [3þ2] cycloaddition was taken to completion by stirring the mixture in toluene at room temperature, and the polycyclic nitroso acetal 546 was then isolated as a single diastereoisomer in 87% overall yield (Scheme 128) .

Scheme 128

Theoretical studies on the mechanism of the domino [4þ2]/[3þ2] cycloadditions of nitroalkenes have been reported .

455

456

Isoxazoles

4.03.9.3.4

From atom fragments: C–C–C þ N–O

Cyclopentadiene efficiently traps highly reactive nitrosocarbonyls (RCONO), affording the HDA adducts which contain an isoxazolidine ring. These bridged bicyclic compounds are useful synthetic intermediates since the double bond can be further functionalized and then, the reductive cleavage of the isoxazolidine N–O bond produces an array of highly functionalized aminols. The nitrosocarbonyls are usually generated in situ by oxidation of hydroxamic acids and nitrile oxides or by photolysis of 1,2,4-oxadiazole-4-oxides. Wang resin-supported nitrosocarbonyls have also been used (Scheme 129) .

Scheme 129

Diastereoselective acylnitroso Diels–Alder reactions were performed using enantiopure hydroxamic acids derived from camphor and -amino acids as chiral auxiliaries (Equation 90) .

ð90Þ

N-alkenyl, N-(adenosine-2-yl), and N-phosphoryl bicyclic isoxazolidines were also obtained by HDA reactions of cyclopentadiene with nitroso alkenes, 2-nitrosoadenosine, P-nitroso phosphine oxides and P-nitroso phosphate, respectively .

4.03.9.4 Synthesis of Isoxazolidinones and Isoxazolidinediones 4.03.9.4.1

Isoxazolidin-3-ones

Diazoketones 547 underwent Wolff rearrangement in the presence of PhCO2Ag and Et3N at 78 C to give 5-substituted isoxazolidin-3-ones 548. The ketene intermediate was trapped by the oxy-amide moiety even in the presence of H2O or MeOH (Scheme 130) .

Scheme 130

Intramolecular halocyclization of butenohydroxamic acids with iodine monochoride, N-bromo- or N-chlorosuccinimide afforded 5-halomethylisoxazolidin-3-ones in high yields (Scheme 131) .

Isoxazoles

Scheme 131

4.03.9.4.2

Isoxazolidin-5-ones

Isoxazolidin-5-ones 549 can be prepared by 1,3-dipolar cycloaddition of nitrones and ketenes or ynolates or, alternatively, by cyclization of 3-(hydroxyamino)propanoates 550 in turn obtained by addition of ketene acetals to nitrones or by Michael addition of hydroxylamine derivatives to ,-unsaturated esters (Scheme 132).

Scheme 132

The anionic inverse electron demand 1,3-dipolar cycloaddition of ynolates with chiral nitrones followed by quenching of the initially generated enolate was applied to the synthesis of 5-isoxazolidinones with high yields and good diastereoselectivity. The primary adducts could also be alkylated to obtain 4,4-disubstituted isoxazolidinones (Scheme 133) .

Scheme 133

457

458

Isoxazoles

Nucleophilic addition of ester enolates to enantiopure nitrones, followed by cyclization of the resulting hydroxylamine, is a general approach to isoxazolidin-5-ones and can be applied to the stereoselective synthesis of these heterocycles . In some cases, the cyclization occurs spontaneously under the reaction conditions. For example, the addition of the sodium enolate of methyl acetate to chiral nitrone 551 gave directly the isoxazolidin-5ones 552 in quantitative yield and high syn-diastereoselectivity (Equation 91) .

ð91Þ

Stereoselective syntheses of 5-isoxazolidinones were also achieved through addition of lithiated chiral oxazolidines to nitrones. In solution, the spiro-fused isoxazolidine 554 was in equilibrium with its open hydroxylamino form 553. Acidic hydrolysis of the chiral auxiliary afforded the highly enantioenriched isoxazolidinone 555 in good yield (Scheme 134) .

Scheme 134

The addition of silyl ketene acetals to nitrones occurs in the presence of a Lewis acid and can afford different products, including open-chain and cyclic adducts in different ratios (depending on the substrate and the Lewis acid employed). The stereoselectivity of the reaction can be controlled by judicious choice of the activating agent. For example, chiral nitrone 551 reacted with 556 in the presence of boron trifluoride etherate to afford the anti-isomer of 552. In the presence of Et2AlCl, a lower syn–anti-selectivity was observed. Finally, the syn-open-chain adduct 557 was obtained as the major product when t-butyldimethylsilyl triflate was used as promoter (Equation 92). The silylated adducts 557 could be converted into the corresponding isoxazolidin-5-ones 552 by sequential desilylation and cyclization . The diastereofacial divergency of the reaction was explained by considering alternative Lewis acid-induced mechanisms, which were also supported by theoretical calculations .

ð92Þ

Isoxazoles

N-Aryl thiourea derivatives were found to behave like Lewis acids to promote the addition of ketene silyl acetals to nitrones and were used in the synthesis of monocyclic and bicyclic isoxazolidinones . The matched double stereoselective reaction between the chiral C-phenyl N-(1-phenylethyl) nitrone and the chiral silyl ketene acetals 558 in acetonitrile/dichloromethane at 20 C under zinc iodide-catalyzed conditions resulted in only the single diastereomer 559 in 98% yield. Exposure of 559 to acid afforded the isoxazolidinone 560 in 74% yield, together with the chiral auxiliary (1R,2S)-2-phenylcyclohexanol (Scheme 135) .

Scheme 135

Conjugate addition of N-substituted hydroxylamines to ,-unsaturated esters affords 3-(hydroxyamino)propanoates, which can be either isolated or cyclized to 5-isoxazolidinones depending on the reaction conditions. A concerted mechanism for the formation of the 3-(hydroxyamino)propanoates was proposed . For example, chiral hydroxylamines 562 were obtained by addition of enantiopure N-(1-phenylethyl)hydroxylamine to acrylate 561. Cyclization of 562 in the presence of a base (lithium hexamethyldisilazide (LiHMDS), THF, 78 C) or a Lewis acid (n-Bu2SnO in refluxing benzene) afforded a mixture of isoxazolidinones 563 and 564 in high yield but with little diastereoselectivity (Scheme 136). Diastereomers 563 and 564 were easily separated and then converted into enantiomerically pure -substituted -amino acids .

Scheme 136

Optically active adducts were obtained in the presence of catalytic amounts of a chiral Lewis acid. For example, the reaction of N-benzylhydroxylamine and pyrrolidinone cinnamate 565 catalysed by Mg(ClO4)2 in the presence of the bisoxazoline ligand 503 gave the isoxazolidinone 566 in 80% yield and 96% ee (Scheme 137) .

Scheme 137

459

460

Isoxazoles

Bulky pyrazolidinones such as the 1-naphthylmethyl substituent in 567 amplified the chiral information from chiral Lewis acid to the reaction center, affording good stereoselectivity at moderate temperature (Scheme 137) . The products of the ene reaction of optically active tiglic amides with 1-nitro-4-nitrosobenzene were converted by silica gel treatment to 4-methyleneisoxazolidin-5-ones in quantitative yield (Scheme 138) .

Scheme 138

Isoxazolo[2,3-a]pyridin-2-one derivatives such as 568 were prepared by intramolecular oximino malonate HDA reactions. These compounds underwent aromatization to substituted pyridines under mild basic conditions (Scheme 139) .

Scheme 139

4.03.9.4.3

Isoxazolidinediones

Cyclocondensation of mono- and disubstituted malonates with hydroxylamine afforded 4-substituted isoxazolidine3,5-diones (Equation 93). Under the same conditions, cyanoacetate derivatives gave 3-amino-4H-isoxazol-5-ones (Equation 94) .

ð93Þ

ð94Þ

Isoxazoles

4.03.10 Ring Syntheses by Transformations of Another Ring A rearrangement of 3-phenyl-2H-azirine-2-carboxaldehyde was rapidly induced by Grubbs’ catalyst at 25 C, producing 3-phenylisoxazole in 90% yield, while very high temperatures (200 C) were required for the uncatalyzed process . Thermolysis in toluene under reflux of 2-benzoyl-2-halo-2H-azirines led to 4-haloisoxazoles in high yields (Equation 95), while the reaction of halogenated cyclopropanes with the nitrosyl cation appears to be a feasible and effective method for preparing 5-chloroisoxazoles (Equation 96) .

ð95Þ

ð96Þ

1,3,4-Oxadiazolylacetones underwent a ring rearrangement with hydroxylamine leading to functionalized isoxazoles . Nucleophilic attack of hydroxylamine at position 6 of 2H-pyran-2-ones afforded stereoselectively, through pyran ring opening and subsequent cyclization, (-isoxazol-4-yl)-,-didehydroamino acids, mainly present as (Z)-isomers (Equation 97) . In a similar way, a short glycal-mediated synthesis of new enantiomerically pure 5-substituted isoxazoles 570a and 570b was accomplished by treatment of enones 569a and 569b, derived from D-galactal and D-glucal, with hydroxylamine and subsequent dehydration of intermediate epimeric isoxazolines (Scheme 140) .

ð97Þ

A ring–ring transformation was observed in the reaction of 2-methylthio-4-nitrothiophene 571 with pyrrolidine and silver nitrate, leading by an initial ring opening to the highly functionalized building block 572: a three-step sequence involving chemoselective replacement of the pyrrolidine group with an aryl residue, reduction of the nitrovinyl moiety, and final cyclization of the resulting oximes accompanied by methanethiol elimination afforded 3-arylmethyl5-(methylthio)isoxazoles 573 in good yields (Scheme 140) . The dianion of ester 574 (see Section 4.03.9.1.6) gave rise to chemo-, regio-, and stereoselective cascade reactions involving base-induced isoxazole–benzisoxazole rearrangement, as well as alkylation by dibromides and SN29 cyclization with THF ring closure (Scheme 136). Compounds 575, obtained as single diastereomers, could be converted by various reducing agents to complex, structurally diverse polycyclic molecules . 3-Substituted isoxazolidin-5-ones bearing a leaving group at the C-29 carbon atom of the side-chain such as 576 underwent isoxazolidinone/isoxazolidine rearrangement by treatment with nucleophiles. The formation of the new isoxazolidine ring occurred with inversion of configuration at the C-29 carbon atom (Scheme 141) . Reduction of methyl [5-(bromomethyl)isoxazolidin-3-yl]acetates 324 with tributyltin hydride in boiling toluene in the presence of AIBN led to opening of the isoxazolidine ring and formation of isoxazolidinones 579. The process is believed to go through the formation of nitroxide radical 577, followed by reduction to hydroxylamine 578 and cyclization to 579 with elimination of methanol (Equation 98) .

461

Scheme 140

Isoxazoles

Scheme 141

ð98Þ

Treatment of the azabicyclo[2.2.1]heptene 580 with MCPBA for 3–5 s generated the oxabicyclo[3.2.1]octene 582 via a rapid Meisenheimer rearrangement of the N-oxide 581. Compound 582 was converted into the thermodynamically more stable isomeric bicyclic isoxazolidine 583 by simple heating (Scheme 142) .

Scheme 142

4.03.11 Syntheses of Particular Classes of Compounds and Critical Comparison of the Various Routes Available Developments of efficient methods for the synthesis of perfluoroalkylated isoxazoles is currently an important subject due to their high potential in agrochemical and pharmaceutical fields. Convenient syntheses of 5-perfluoroalkyl-substituted isoxazoles were achieved through 1,3-dipolar cycloaddition of nitrile oxides and perfluoroalkyl acrylates and by condensation of perfluoroalkyl vinyl iodides with hydroxylamine , in 61–85% and 80–95% yields, respectively. Analogous condensations of 1,3-diketones having a trifluoromethyl group allowed the preparations of 3-trifluoromethylisoxazoles in 73–83% yields . The use of resinbound CF3-containing building blocks has also been reported . Several syntheses of derivatives of nucleotide bases containing the isoxazole, isoxazoline, or isoxazolidine moieties have been reported in the literature. N,O-Nucleosides, that is, modified nucleosides in which the ribose unit is replaced by an isoxazolidine ring, were prepared using nitrones as starting material and following different procedures . An approach involved the 1,3-dipolar cycloaddition of a

463

464

Isoxazoles

C-alkoxycarbonyl nitrone with a vinyl nucleobase followed by reduction with NaBH4. For example, nitrone 584 reacted with vinylthymine with complete regioselectivity and moderate diastereoselectivity. The isolated major trans-disubstituted isoxazolidine 585 was reduced to the corresponding enantiopure 3-hydroxymethyl N–O-nucleoside 586 in 62% yield (Scheme 143).

Scheme 143

Sugar-derived nitrones were used to synthesize derivatives unsubstituted at the nitrogen atom such as 588 and 590 (Schemes 144 and 145 (method A)). Similarly, homo-N,O-nucleosides were prepared using allyl nucleobases as dipolarophiles .

Scheme 144

Scheme 145

Isoxazoles

Isoxazolidinyl nucleosides were also obtained through a less direct approach based on 1,3-dipolar cycloaddition of nitrones with vinyl acetate, followed by coupling of the isoxazolidin-5-yl acetates with silylated nucleobases (Vo¨rbruggen nucleosidation) (Scheme 145, method B) . In the synthesis of 589, the first approach (method A) was more stereoselective whereas method B gave better yields. Alternatively, isoxazolidin-5-yl acetates were obtained by reduction and acetylation of suitable isoxazolidin-5-ones, which, in turn, were prepared by diastereoselective Michael addition of hydroxylamines to unsaturated esters or by nucleophilic addition of enolates to nitrones and subsequent cyclization of the resulting hydroxylamines. For example, the two diastereomeric isoxazolidinones 552 were converted into thymidine analogues 590 (Scheme 146) .

Scheme 146

Bicyclic N,O-iso-homonucleoside analogues such as 591 were synthesized through 1,3-dipolar cycloaddition of an enantiopure 3-hydroxy-1-pyrroline N-oxide and protected allyl alcohol and subsequent introduction of thymine by a Mitsunobu reaction . Furthermore, isoxazole, isoxazoline, and isoxazolidine analogues of C-nucleosides such as 592–594 were synthesized by 1,3-dipolar cycloaddition of nitrile oxides and nitrones derived from uracil-5-carbaldehydes with suitable dipolarophiles .

Nucleoside analogues 595, consisting of isoxazole rings, as modified sugars, and nucleobases (thymine, uracil, and 5-fluorouracil) joined by a methylene linker, have been synthesized from N-propargyl pyrimidines and N-BOC amino aldoximes in the presence of a commercial bleaching agent (containing 4% NaOCl) for the generation of nitrile oxides (Equation 99) .

465

466

Isoxazoles

ð99Þ

3-Alkylisoxazolo[3,4-d]pyrimidine-4,6-diones 597 were synthesized by thermolysis in the presence of polyphosphoric acid of 6-azidouracils 596 with aliphatic carboxylic acids (Equation 100), whereas the use of benzoic acid gave the corresponding oxazole compounds . Analogous derivatives 599 were obtained in satisfactory yields by UV irradiation of N-(5-acyluracil-6-yl)sulfilimines 598 (Equation 101) . In both cases, the mechanistic rationale could involve nitrene intermediates, converted into the final products by electrocyclization processes.

ð100Þ

ð101Þ

4.03.12 Important Compounds and Applications These aspects were previously discussed in CHEC(1984) on pages 127–130 and in CHECII(1996) on page 260. This section is an update of the previous work.

4.03.12.1 Natural Products Both ibotenic acid 600 and muscimol 601 (a structural analogue of -aminobutyric acid, GABA) have been isolated from several fungal species including Amanita muscaria and are active CNS agents of the N-methyl-D-aspartate (NMDA) and GABA receptor systems respectively. Their presence in macromycetes and their biological activities have been recently reviewed . The decarboxylation of 600 to 601, observed in certain circumstances, has been studied in DMSO with 3H2O or D2O .

Isoxazoles

Several natural spiroisoxazolines have been isolated from marine origins including calafianin 602 isolated from the sponge Aplysuina gerardogreeni n. sp. (Aplysinade) , aerothionin 603a, homoaerothionin 603b, caissarin B 603c , fisturalin 3 603d, archerine 604e , and ianthesin C 604f . These isoxazolines were reported to show significant biological activity, with the only exception being 602. A synthesis of calafianin 602 has been described and its structure revised . Optically pure 603a have been synthesized . Alkaloids 604 , including an unprecedented imidazolyl–quinolinone substructure attached to a bromotyrosine-derived spiro-isoxazoline, have been isolated from Oceanapia sp. Compounds 604a and 604b showed inhibitor mycobacteria enzymatic activity . Acivicin 605, isolated from fermentation products of Streptomyces sviceus, is an antitumor agent known to inhibit cell growth and has been used in a Phase II study against astrocytoma .

A family of cis-cyclopent[c]isoxazolidine alkaloids named pyrinodemins was isolated from the marine sponge Amphimedon sp. . These compounds, which show potent cytotoxicity, were synthesized in racemic form by different groups in order to clarify their structures. The asymmetric total synthesis of ()-pyrinodemin A was also accomplished . Both the enantiomers of cycloserine (4-amino-3-isoxazolidinone) act as alanine racemase inhibitors and the mechanism of inactivation has been studied .

467

468

Isoxazoles

4.03.12.2 Biologically Active Compounds The isoxazole, isoxazoline, and isoxazolidine rings are frequently present in biologically active compounds and are used as building blocks in the synthesis of new potential drugs. The first enantioselective, nonenzymatic synthesis of (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (S)-AMPA, a structural analogue of the excitatory neurotransmitter (S)-glutamic acid where the -carboxyl group of L-Glu is replaced by an acidic 3-hydroxyisoxazole moiety, was performed by reaction of 3-isoxazolemethyl bromide 606 with the lithium salt of enantiopure bislactim ether 607 (Scho¨llkopf reagent), chosen for introduction of the chiral -amino acid center. Hydrolysis of the major (2R,5S)-diastereomer 608 gave (S)-AMPA (Scheme 147) .

Scheme 147

The catalytic asymmetric synthesis of the potent AMPA agonist (S)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), in 32% overall yield and good optical purity, has been performed from aldehyde 609 through an asymmetric Strecker reaction catalyzed by Jacobsen’s L,R,R-peptide (Scheme 147) . It was observed that ACPA binds to AMPA receptors in a manner different from that of AMPA itself and that it also binds to kainic acid receptor sites . The synthesis and pharmacological characterization of many agonists at AMPA receptors have been reported. In particular, the tetrazolyl derivative (S)-2-Me-Tet-AMPA has been revealed as the most potent AMPA receptor agonist yet described (Scheme 147) . ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a potent cholinergic channel activator and various synthetic routes have been studied for the preparation of large quantities of this compound, required for its evaluation as a safe and effective treatment for Alzheimer’s disease . The sulfa drug N-[4-sulfamido-N-(5-methyl-3-isoxazolyl)phenyl]maleimide 610, prepared from maleic anhydride and 4-amino-N-(5-methyl-3-isoxazolyl)benzensulfonamide, was polymerized using benzoyl peroxide as a free radical initiator. The polymer showed significant antifungal activity toward both Candida albicans and A. niger .

Isoxazoles

4-Amino-N-(3-methyl-5-isoxazolyl)benzensulfonamide was converted into pyrazole and pyrazolo–triazine and –pyrimidine derivatives 611, having antimicrobial activity .

Condensation of cyclic 1,3-diketo esters with 3- and 5-aminoisoxazole derivatives led to a series of potent antimaximal electroshock analogues such as 612 .

A new series of 1-methylcarbapenems 613–616 containing isoxazole moieties in the C-2 side-chain were synthesized and evaluated for biological activity. In particular, derivatives 614, bearing isoxazole-ethenyl groups on the pyrrolidine ring, and the corresponding carboxylic acid sodium salts 615 showed excellent antibacterial activity as well as high stability to dehydropeptidase-1 (DHP-1) .

469

470

Isoxazoles

3-Isoxazolylvinylcephalosporins 616, containing an isoxazole moiety at C-3 of the cephem nucleus, exhibited a remarkable enhancement in the activity against Gram-positive bacteria including Streptococcus pyogenes and Staphylococcus aureus . 6-(Nitrileoxidomethyl)penam sulfone, prepared in a few steps from commercially available (þ)-6-aminopenicillanic acid by treatment of oxime 617 with NCS and followed by dehydrochlorination with bis(tributyltin)oxide, underwent smooth 1,3-dipolar cycloaddition reactions with various alkynes, and alkenes, to give cycloadducts 618 in moderate to good yields. Some acid derivatives 618 (R ¼ H) showed potent -lactamase inhibitory activity (Scheme 148) .

Scheme 148

The solution-phase synthesis and resolution of new phosphinopeptidic building blocks containing a triple bond and their involvement in 1,3-dipolar cycloaddition with a variety of in situ-prepared nitrile oxides allowed the diastereoselective preparation of a novel class of isoxazole-containing phosphinic peptides 619. Inhibition assays of some of these peptides revealed their behavior as very potent inhibitors of metalloproteases, outmatching previously reported phosphinic peptides in terms of potency .

Isoxazoline derivatives 620 and DMP802 28a are respectively a -glutamyl transpeptidase inhibitor and an antithrombotic agent. 3-Aryl-4,5-dihydroisoxazol-5-ylacetic acid derivatives are important cores of a series of nonpeptide platelet GPII/IIIa antagonists . Among them, roxifiban (DMP754) 621 holds strong promise for the prevention and treatment of a wide variety of thrombolitic diseases .

Isoxazoles

Tests in vitro revealed that amphipathic isoxazolidines 622 upregulate transcription at levels comparable to the natural activation peptide ATF14 . 5-Fluoro-1-isoxazolidin-5-yluracil 623 is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death . Phosphonated N,O-nucleosides 624 show low levels of cytotoxicity and exert, on reverse transcriptase (RT) from two different retroviruses, a specific inhibitory activity comparable with that of azidothymidine (AZT) .

4.03.12.3 Chemosensor Compounds Bicyclic dioxetanes 625, bearing a 3-hydroxy-4-isoxazolylphenyl moiety, underwent base-induced CIEEL (chemically initiated electron exchange luminescence) decay to afford light with high efficiency in an NaOH/H2O system, as well as in a TBAF/MeCN system. In particular, the trifluoromethyl derivative (R ¼ CF3) emitted light (maxCIEEL ¼ 473 nm) in the aqueous system with the highest efficiency (CIEEL ¼ 0.24), which parallels that attained in an aprotic solvent system .

471

472

Isoxazoles

The racemic bicyclic isoxazolidine 626a, bearing a pyrenyl moiety, was shown to be an effective ratiometric fluorescent sensor selective for Ag(I) . The selective complexation of compounds 626a–e and 627 toward Fe(III), Cu(II), and Ru(III) was also analyzed .

4.03.12.4 Liquid Crystals In a search for new isoxazole-based liquid crystalline compounds, a 22-member library of 3,5-diaryl isoxazoles 628 was prepared by parallel synthesis on solid phase (Rink resin) through 1,3-dipolar cycloaddition of supported phenylacetylene units with suitable aryl nitrile oxides generated in situ from hydroxyiminoyl chlorides. Cleavage from the resin under acidic conditions allowed the generation of the cyano moiety .

4.03.12.5 Ligands for Asymmetric Synthesis Isoxazoline rings include two heteroatoms which could serve as Lewis bases. Chiral spiro bis(isoxazoline) ligands, named SPRIXs, bearing a chiral spiro skeleton and two isoxazoline rings, have been reported . Double intramolecular nitrile oxide 1,3-dipolar cycloaddition of 629 generated from the corresponding oximes with sodium hypochlorite afforded racemic SPRIXs, which were resolved by chiral stationary phase chromatography (Equation 102). SPRIX ligands showed a coordinating ability to Cu(II) as chiral ligands. A complex of (þ)(M* ,S* ,R* )-SPRIX and Cu(acac)2 catalyzed the conjugate addition of diisopropylzinc to 2-cyclohexenone to give the Michael adduct in 79% yield with 49% ee (acac ¼ acetylacetonate) . In addition, these ligands showed good affinity for Pd(II) and their Pd-complex promoted either the tandem cyclization of dialkenyl alcohols

Isoxazoles

(Wacker-type cyclization) with good enantioselectivity (up to 97% ee) or the intramolecular aminocarbonylation of alkenyl amines. An illustrative example is given in Equation (103). Amine 630 in the presence of Pd– 631 catalyst and p-benzoquinone in methanol under a carbon monoxide atmosphere afforded 632 in good yield and moderate enantioselectivity . An analogous spiro bis(isoxazole) ligand was also synthesized .

ð102Þ

ð103Þ

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Isoxazoles

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Isoxazoles

2005S3423 2005SC967 2005SL259 2005SL646 2005SL848 2005SL1579 2005SL3139 2005T501 2005T2623 2005T2999 2005T3335 2005T4363 2005T4841 2005T6707 2005T8836 2005T9338 2005TA1403 2005TA1535 2005TA2257 2005TA2821 2005TL173 2005TL657 2005TL1083 2005TL3037 2005TL3789 2005TL4077 2005TL7877 2006CC2798 2006CEJ8571 2006CME539 2006EJO1251 2006EJO3235 2006EJO3016 2006EJO4852 2006H(67)413 2006HCO7 2006JA1452 2006JHC509 2006JME5363 2006JOC894 2006PHC(18)288 2006RCB535 2006S2665 2006SL463 2006SL1125 2006SL1739 2006T90 2006T611 2006T1171 2006T1345 2006T1494 2006T4498 2006T12057 2006TA68 2006TA3075 2006TA3179 2006TL727 2006TL927 2006TL6143 2006TL7179 2007BCF55 2007T3235 2007TL647

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483

484

Isoxazoles

Biographical Sketch

Donatella Giomi obtained her Laurea in chemistry at the University of Firenze in 1984. In 1987, she did research with Prof. León Ghosez at the Catholic University of Louvain (Louvain-LaNeuve, Belgium). She did her Ph.D. in synthetic organic chemistry at the University of Firenze in 1989. She was Ricercatore Universitario at the Organic Chemistry Department, University of Firenze, from 1990 to 2001. Since then, she has been associate professor of organic chemistry at the Faculty of Science, University of Firenze. Her scientific interests include reactivity and synthetic applications of electron-poor nitrogen heterocycles specially related to 1,3-dipolar cycloadditions, Diels–Alder and Hetero-Diels–Alder reactions, and domino processes; nucleophilic aromatic substitutions on cyanopyridazine systems; synthesis of functionalized pyrrole and indole derivatives.

Franca M. Cordero received her Laurea degree in chemistry (in 1988) and her Ph.D. in synthetic organic chemistry in 1992, from the University of Firenze. She was Ricercatore Universitario (researcher), Department of Organic Chemistry, University of Firenze, during 1994–2004. Since 2005, she has been associate professor of organic chemistry at the Faculty of Science, University of Firenze. She joined Prof. Trost’s group at Stanford University (USA) for one year in 1991, and Prof. J. Salau¨n’s group at the University of Paris-Sud (France) for some months in 1997. Her research interests are in development and application of new synthetic methods and strategies for the synthesis of biologically active aza-heterocyclic compounds and peptidomimetics; stereoselective synthesis based on 1,3-dipolar cycloaddition reactions; and chemistry of spirocyclopropane heterocycles.

Isoxazoles

Fabrizio Machetti studied at the University of Firenze where he graduated in chemistry in 1992 in the group of Prof. Antonio Guarna. Subsequently he received his Ph.D. from the same university in 1996 under the co-supervision of Prof. Francesco De Sarlo and Prof. Alberto Brandi working on the synthesis of peptidomimetic compounds. Since 2001, he has been a CNR research scientist focusing on new methodologies for the stereoselective synthesis of heterocyclic compounds and their applications to medicine and biotechnology.

485

4.04 Oxazoles V. Yeh Astellas Research Institute of America, Skokie, IL, USA R. Iyengar Enanta Pharmaceuticals Inc., Watertown, MA, USA ª 2008 Elsevier Ltd. All rights reserved. 4.04.1

Introduction

488

4.04.2

Theoretical Methods

489

4.04.3


489

4.04.3.1

X-Ray Diffraction

489

4.04.3.2

NMR Spectroscopy

490

4.04.3.3

Mass Spectrometry

491

4.04.3.4

UV Spectroscopy

492

4.04.3.5

IR Spectroscopy

492

4.04.4


492

4.04.4.1

Aromaticity

492

4.04.4.2

Basicity

493

4.04.4.3

Tautomerism

493

4.04.5

Reactions of Fully Conjugated Rings

493

4.04.5.1


493

4.04.5.2


494

4.04.5.3


494

4.04.5.4


495

4.04.5.5

Nucleophilic Attack at Hydrogen and Reactions of Metallated Oxazoles

496

4.04.5.6


497

4.04.5.6.1 4.04.5.6.2

4.04.5.7

4.04.6 4.04.6.1

500

Mu¨nchnones Isomu¨nchnones

502 503

Miscellaneous Reactions

505

Reactions of Nonconjugated Rings

505

Oxazolones

4.04.6.1.1 4.04.6.1.2 4.04.6.1.3

4.04.6.2

497 500

Mesoionic Compounds

4.04.5.7.1 4.04.5.7.2

4.04.5.8

Cycloaddition reactions Rearrangement reactions

505

2(3H)-Oxazolones 4(5H)-Oxazolones 5(4H)-Oxazolones

505 505 507

Dihydrooxazoles

4.04.6.2.1 4.04.6.2.2 4.04.6.2.3

509

2,3-Dihydrooxazoles (4-oxazolines) 2,5-Dihydrooxazoles (3-oxazolines) 4,5-Dihydrooxazoles (2-oxazolines)

509 509 510

4.04.6.3

Oxazolidines

510

4.04.6.4

Oxazolidinones

512

4.04.6.5

Oxazolidinediones

512

487

488

Oxazoles

4.04.7


513

4.04.8

Reactions of Substituents Attached to Ring Heteroatoms

516

4.04.9

Ring Syntheses of Conjugated Oxazoles

516

4.04.9.1

One Bond

516

4.04.9.2

Two Bond

519

4.04.9.2.1 4.04.9.2.2

[4þ1] Strategies [3þ2] Strategies

519 520

4.04.9.3

Ring Synthesis of Ring-Fused Oxazoles

523

4.04.10

Ring Synthesis by Transformation of Another Ring

525

4.04.11

Ring Synthesis of Nonconjugated Rings

526

4.04.11.1

Oxazolones

4.04.11.1.1 4.04.11.1.2 4.04.11.1.3

4.04.11.2

2(3H)-Oxazolones 4(5H)-Oxazolones 5(4H)-Oxazolones

Dihydrooxazoles

4.04.11.2.1 4.04.11.2.2 4.04.11.2.3

2,3-Dihydrooxazoles (4-oxazolines) 2,5-Dihydrooxazoles (3-oxazolines) 4,5-Dihydrooxazoles (2-oxazolines)

526 526 527 528

529 529 529 531

4.04.11.3

Oxazolidines

532

4.04.11.4

Oxazolidinones

534

4.04.11.5

Oxazolidinediones

535

4.04.12


536

4.04.12.1

Natural Products

536

4.04.12.2

Medicinal Chemistry

537

4.04.12.3

Polymers

538

4.04.12.4

Ligands for Asymmetric Synthesis

538

References

539

4.04.1 Introduction Oxazoles have played an increasingly important part in heterocycle chemistry research. The first recorded oxazole was synthesized in the 1800s and the chemistry of this heterocycle was expanded during World War II as part of the penicillin effort, which was thought to contain an oxazole core. The parent compound 1 is a stable liquid at room temperature, with a boiling point of 69 C, and was first prepared in 1947 . Oxazoles are weakly basic with a pKa of 0.8, compared with 5.22 for pyridine. Although the parent oxazole is not naturally occurring, a large number of substituted oxazole-containing natural products have been isolated, mostly from marine invertebrates and microorganisms. Many of these natural products are structurally complex and of significant biological interest, and the pursuit of their total synthesis has driven many of the discoveries of novel oxazole chemistry in the decade under review. In addition to their presence in natural products, oxazoles have also found use as azadienes in Diels–Alder reactions, and the corresponding mesoionic derivatives have demonstrated utility in 1,3-dipolar cycloaddition reactions. The chemistry of oxazole published between 1982 and 1995 was reviewed by Hartner in CHEC-II(1996) . A comprehensive compilation of oxazole chemistry can be found in . Annual updates on oxazole natural products can be found in Natural Product Reports, the latest by Jin , and a review focusing on the synthetic aspects of natural product chemistry was written by Yeh . A comprehensive review on synthetic methodologies for preparing oxazoles can be found in Science of Synthesis . As in CHEC(1984) and CHEC-II(1996), oxazole and its derivatives are named and numbered following the conventions of Chemical Abstracts. The general structures are arranged in increasing oxidation state and saturation in Figure 1.

Oxazoles

4

3

4

N

5

3

3a

N

7a

O

O– N+

R N+

2

O 7

1

1

1

2 NH

O

4

–O

O

9 N

O

10 N

O

O

O

12

13

14

15

O

16

6

O

11

NH

O

O

NH

O

5 N

O

O

O NH

NH O O

O

17

R N+

O

N

N

8

NH

3

O

O

7

O

O

N O

O

–O

R N+

O

O

18

19

O

NH

NH O

O

O

20

NH O

O

O

21

O NH O

O

O

22 Figure 1

Oxazoles 1, benzoxazoles 2, oxazolium salts 3, and oxazole N-oxides 4 are fully conjugated compounds (Figure 1). In addition, the two mesoionic structures 1,3-oxazolium-5-olates 5 and (1,3-oxazolium-4-olates) 6, commonly known as mu¨nchnones and isomu¨nchnones, respectively, are also considered to be conjugated rings. There are five systems of hydroxyl-substituted oxazoles and they exist in their oxo forms: the 2(3H)-, 2(5H)-, 4(5H)-, 5(2H)-, 5(4H)oxazolones 7–11. Three forms of dihydrooxazoles are known: 2,3-, 2,5-, and 4,5-dihydrooxazoles respectively 12–14. The fully saturated ring is called oxazoline 15. The monooxo derivatives are 2-oxazolidinone 16, 4-oxazolidinone 17, and 5-oxazolidinone 18. The three variants of oxazolidinediones are 19–21 and the fully oxidized oxazolidinetrione is 22.

4.04.2 Theoretical Methods There have been no significant reports on bond lengths, angles, and charge densities since the last review in CHECII(1996).

4.04.3 Experimental Structural Methods 4.04.3.1 X-Ray Diffraction X-Ray data for many oxazole compounds are documented in the literature. The bond lengths and angles of three derivatives of amino acid-derived oxazoles are shown in Table 1 ; these oxazole units are often found in natural products. X-Ray crystallography has been instrumental in the unambiguous structural elucidation of various natural products. The absolute stereochemistry of a complex marine natural product ulapualide A 26 (Figure 2) was established by X-ray crystallography of the natural product–G actin complex .

489

490

Oxazoles

But

O

H N

O

CO2Me N

But

H N

O

O

CO2Et

CONH2

N

O

S

N

HN

O

O

23

Me N

24

O O

25 Table 1 X-Ray structural data

˚ Bond length (A) O–C(2) C(2)–N N–C(4) C(4)–C(5) C(5)–O C(2)–sub C(4)–sub C(5)–sub Bond angle (deg) O–C(2)–N C(2)–N–C(4) N–C(4)–C(5) C(4)–C(5)–O C(5)–O–C(2) a

23a

24a

25b

1.371 1.297 1.405 1.347 1.375 1.505 1.478

1.354 1.285 1.395 1.335 1.374 1.493 1.460

1.350 1.292 1.379 1.347 1.390 1.491 1.492 1.435

113.8 103.2 111.1 106.2 105.6

113.6 105.1 108.7 108.1 104.6

113.8 105.6 108.8 107.6 104.1

. .

b

Me OHC

Me

Me

Me O

N AcO

Me

O

MeO

O

OMe O

N O

Ulapaulide A

N

OH

26 Confirmed structure

N O O

Me

Figure 2

4.04.3.2 NMR Spectroscopy There is a large body of oxazole 1H and 13C nuclear magnetic resonance (NMR) data in the literature. The order of 1 H NMR deshielding is H-2 > H-3 > H-4. The coupling constant of H-4 and H-5 (J4–5) ranges from 0.75 to 1.5 Hz, and J2–5 and J2–4 are generally small, C-5 > C-4 and has been exploited for ring functionalization. Finally, mesoionic compounds, mu¨nchnones and isomu¨nchnones, are considered fully conjugated rings and their reactivities are discussed in this section.

4.04.5.1 Thermal and Photochemical Reactions Paterno–Bu¨chi reactions of 5-methoxy-2-methyloxazole 36 with aliphatic and aromatic aldehydes has been reported to give [2þ2] cycloadducts 37 with high diasteroselectivities (98:2) and excellent overall yields (85–90%) (Scheme 2) . The resultant oxetanes were then hydrolyzed to yield -acetylamino--hydroxy acid esters 38 with matching diastereomeric ratios and good yields (65–78%). The erythro-configuration of the amino ester products is the result of high exo/endo-selectivity in the cycloaddition step. The exo-preference of the cycloaddition is analogous to the Paterno–Bu¨chi reactions of furans and other heterocyclic dienes. This technology has been further extrapolated to more sterically and electronically demanding 4-alkyl-5-methoxy-2-methyloxazole 39. As in the previous example, products in high yields and diastereoselectivities were also reported in these cases.

H hν

N Me O

36

H

Me

Pr

39

H OMe

hν

OMe H

Me Pr

i

N O

Scheme 2

CO2Me

38

R H+/H2O Pr i OMe

d.r. > 98:2, 83%

R

d.r. > 98:2 R = Ph, 70% R = i-Pr, 78%

O

O

HO AcHN

d.r. > 98:2 R = Ph, 87% R = i-Pr, 86%

H

i

Me O

N O

37

R

R = Ph (a), i-Pr (b)

N

H+/H2O

O

O

OMe

R

HO

R Pr

AcHN

i

CO2Me

d.r. > 93:7, 73%

493

494

Oxazoles

4.04.5.2 Electrophilic Attack at Nitrogen The oxazole nitrogen atom can be alkylated or acylated to give a reactive oxazolium salt that can further serve as a partner in cycloaddition reactions. Thus, N-methylated oxazolium salt 41 of 5-alkenyloxazole 40 has been reported to undergo a facile intramolecular Diels–Alder reaction (Scheme 3) to yield hydroindoleninium salts 42. The onecarbon homologated oxazole 43 similarly gave a decahydroisoquinoline product 44 following borohydride reduction .

Me N O

O

N+

CF3SO3Me CHCl3, rt

H

+ O

+ Me N

N

Me – N+ CF3SO3

O

3

O

3

40

H

i, CF3SO3Me, CHCl3, rt

O

ii, NaBH4 30%

4

Me

42

41 N

H

N OH

43

Me

44

Scheme 3

4.04.5.3 Electrophilic Attack at Carbon Oxazoles can react at the C-4 position with aromatic aldehyde electrophiles under Friedel–Crafts conditions when the C-5 position is substituted with an alkoxy group. This feature has been exploited in a chiral Lewis acid-catalyzed formal [3þ2] cycloaddition of aromatic aldehydes and 2-aryl-5-methoxyoxazoles 45 to generate enantiomerically enriched 2-oxazoline-4-carboxylates 46 (Scheme 4) . These products can serve as masked -hydroxy -amino acids, which are useful synthetic intermediates and have been found in peptide-based natural

O Ph

N H

+

Ar O

M H O

Lewis acid

N

OMe

Ar

45

O +

Ph

N Ar O

OMe

46

Ar = p-MeOC6H4

N

N Al

O

O

But

O

O

Al Me

Me Me

(R )-BINOL-AlMe3

47 Scheme 4

COOMe

Bu

t

But

(R )-[Al complex]

48

But

Ph

Oxazoles

products . The Lewis acid catalysts that have been used for this transformation are chiral, either aluminium or copper, complexes. The (R)- or (S)-2,29-dihydroxy-1,19-binaphthyl (BINOL)–trimethylaluminium catalyst complex 47 afforded cis-2-oxazoline-4-carboxylate 46 with good diastereoselectivity and yields, albeit with modest enantioselectivities. Reactions employing a diaminobinaphthyl-dimethylaluminium chloride catalyst (SalenAl) 48 enabled product formation with very high diastereo- and enantioselectivity in excellent yields (Table 4). Similar reactions have also been described between 2-aryl-5-methoxyoxazoles and ethyl glyoxylate catalyzed by copper(II)-bisoxazoline catalysts to give 2-oxazoline-4-carboxylates in excellent yields and high diastereo- and enantioselectivities .

Table 4 Solvent

Catalyst

Temp. C

Time (h)

Yield

Ratio (c:t)

ee (cis) (%)

MeCN PhCH3

30 mol% (R)-BINOL-AlMe3 47 5 mol% (R)-[Al complex] 20 mol%, AgSbF6 20% LiClO4 48

5 25

72 20

90 99

96:4 95:5

79 99

4.04.5.4 Nucleophilic Attack at Carbon A number of transition metal-mediated cross-coupling reactions like Suzuki, Stille, Negishi, and Sonagashira protocols have been used quite successfully to functionalize oxazole ring systems. Furthermore, coupling protocols have been used in tandem to generate di- and trisubstituted oxazoles. Sequential Stille or Suzuki reactions carried out on 4-bromomethyl-2-chlorooxazole 49 resulted in the generation of 2,4-disubstituted oxazoles 50 in good overall yields (Scheme 5) . Disubstituted oxazoles, especially 2,4-disubstituted, are of synthetic significance as these moieties are frequently found embedded in biologically important natural products. A similar strategy has also been described for the preparation of 2,4,5-trisubstituted oxazoles 51 using sequential Suzuki coupling conditions .

O SnBu3

EtO

+

Cl Br

O

Pd2(dba)3, tri-2-furylphosphine

O

O

N

EtO

49 O

tributyl(vinyl)tin, PdCl2(PPh3)2 dioxane,100 °C, 3 h, 48%

Cl EtOOC

O N EtO

Pd(PPh3)4, PhB(OH)2, aq. K2CO3

O

PhMe, 90 °C, 1 h, 87%

N

Ph

O

50

O

i, NBS, CHCl3, reflux, 2 d, 86%

Ph EtOOC

N

i, NaOH, EtOH, rt, 97%

ii, Suzuki conditions, 93%

Ph

O Ph

Ph EtOOC

Scheme 5

N

Cl N

NMP, 80 °C, 3 h, 85%

ii, KOH, AgNO3, H2O then Br2, CCl4, 75 °C, 79% iii, Suzuki conditions, 89%

Ph

N

51

495

496

Oxazoles

The use of organostannyl oxazoles in Stille reactions has also been reported . 4-Tributylstannyl oxazole 53 can be generated via an organolithium deprotonation of oxazole 52 which underwent a Pd-mediated crosscoupling with a benzyl chloride to give a coupled product in good yield (Scheme 6).

Ph

Ph

sec-BuLi, TMP, THF, –78 °C

O

Ph then Bu3SnCl, 75%

N

Bu3Sn

O Ph

65 °C, 4 h, 95%

N

52

Ph

Pd2(dba)3, Ph3As, CuO

O

Ph

N

53 Cl

Scheme 6

4-Silyl oxazoles 55 have been used as precursors to 4-halooxazoles 56, which can then serve as coupling partners in Pd-catalyzed Sonogashira coupling reactions . The silylated oxazole 55 was prepared in good yield by a Huisgen oxazole synthesis which involved a rhodium-catalyzed reaction between ethyl (triethylsilyl)diazoacetate 54 and benzonitrile (Scheme 7).

O EtO

EtO

PhCN, Rh2(oct)4

SiEt3

Ph

PhH, reflux, 6 h 80%

N2

Et3Si

54

Ph

EtO

N-iodosuccinimide

O

Ph

MeCN, rt 86%

N

N I

55

EtO

H

O

56

O Ph

PdCl2(PPh3)2, CuI Et3N, Et2O, reflux 67%

N Ph

Scheme 7

2-Aminooxazoles 58 have also been obtained from the corresponding 2-chlorooxazoles 57 by displacement with anilines to give products in modest to excellent yields (Equation 3) . R

R Ph

NH2

O Cl N

57

i-PrOH, 80 °C, 8–87%

Ph

O NH

ð3Þ

N

58

4.04.5.5 Nucleophilic Attack at Hydrogen and Reactions of Metallated Oxazoles 2-Substituted oxazoles can typically be prepared by C-2 lithiation followed by quenching with an electrophile. However, this protocol suffers from an accompanying side reaction as the lithiated ring system is in equilibrium with its open-chain form and does not reliably afford the expected C-substituted products.

Oxazoles

R4

R4 N

R

5

Li

O

R

5

N C– + OLi

A number of techniques have been employed to alleviate this issue such as complexation of the electron pair on nitrogen of the heterocycle with a Lewis acid prior to C-H deprotonation, and the use of C-2 silyl-oxazoles which tend to react as a coupling partner via the ring-closed form. Deprotonation of oxazole–borane complex 59 with n-BuLi or s-BuLi generates an organolithium species which reacts with electrophiles, such as an aldehyde, at the C-2 position (Scheme 8) . This oxazole– borane complex can also be generated in situ prior to deprotonation without loss in yields. It should be noted that only one equivalent of the metallating agent is needed, and the deprotonation occurs exclusively at the more acidic C-2 position in preference to C-5 or C-4.

O

BH3–THF, THF

N

rt, 30 min

O

s-BuLi, THF, –78 °C, 30 min

O

OH

then PhCHO 70%

N

Ph

+ N –BH3

59 Scheme 8

Another route to generate 2-substituted oxazoles proceeds via a silylated precursor 60 that was generated by lithiation and subsequent quench with TBSOTf (Equation 4) . The reaction was reported to be selective for C-silylation 60 versus ring-opened O-silyl products 61 when silyl triflates were used to quench the reaction. However, this selectivity was completely reversed when silyl chlorides were employed as the silylating agents. This switch in product formation was directly attributed to the presence of a triflate counteranion instead of chloride and was consistent over a range of silylating agents. Ph

O

i, n-BuLi, THF, 0 °C

N

ii, TBSX, 0 °C to rt

Ph

Ph

O

OTBS

Silylating agent

N+

X = OTf X = Cl

TBS + N

C–

60

60 >99 99% ee

Mes

108 Ru Cl PCy Ph 3

O Ph

N

H2N

OH

O H Ph

109

Oxazoles

In a synthetic study of phorboxazole, oxazolone 110 was converted into triflyloxyoxazole 111, which underwent Stille coupling to give product 112 in good yield (Scheme 27) .

Tf2O, Et3N, THF –78 °C

O

O

6% Pd2(dba)3 CHCl3 12% P(t-Bu)3, LiI, NMP 60 °C

OTf

O

N

OTBS

N

Ph

OTBS

Ph

110

H O

O

111

N

112

Ph H O

Me3Sn

OTBS

Me 60%

OTBS

Me Scheme 27

4.04.6.1.3

5(4H)-Oxazolones

5(4H)-Oxazolones, commonly referred to as azlactones, have enjoyed significant attention due to their synthetic versatility and ease of preparation. The C-3 protons are acidic and the anions of 5(4H)-oxazolones can act as nucleophiles in various addition reactions. Nucleophilic additions to 5(4H)-oxazolones usually occur at C-5 followed by ring opening to give -amino acid synthons. The Trost group has demonstrated the utility of azlactone 113 in asymmetric allylic alkylation reactions. Using a palladium catalyst and gem-diacetate 114, a linear alkylation product 115 was obtained. Product 115 was further elaborated into the natural product sphingofungin F (Scheme 28) . Conversely, under Mo catalysis, the same nucleophile 113 reacted with carbonate 116 to give a branched product 117 with high yield and regio- and enantioselectivity .

O

O NH

HN

PPh2

Ph2P

OAc O

(C3H3PdCl)2, NaH, 0 °C O OAc TBDPSO

O Me

114

OAc

TBDPSO

Me

N Ph

115

d.r. = 11:1, 89% ee

70%

O

OCO2Me

N Ph

O

Me

113

116

O N

Mo(CO)3C7H8, LiHMDS, 65 °C

O

O NH

HN

N

N 92%

Scheme 28

Ph

d.r. = 97:3, 99% ee

117

507

508

Oxazoles

Nucleophilic ring opening of racemic 5(4H)-oxazolones by alcohols catalyzed by chiral DMAP complex 118 occurs under a dynamic kinetic process to give enantiomerically enriched -amino esters 119. The enantioselectivity is critically affected by the solvent and the alcohol nucleophile (Equation 6) . O R3OH

R2

R2

O Me2N

N

CO2R3 NHCOR1

R1

119 N R

M

ð6Þ R R

R R

118 The enantioselective hydrolysis of 5(4H)-oxazolones can also be catalyzed by various lipases, and depending on the source of the lipase, either enantiomer can be obtained. An elegant application of this methodology allowed access to the nonproteinogenic tert-leucine . 5(4H)-Oxazolones undergo Friedel–Crafts reactions with aromatic compounds to give keto intermediates which, under the reaction conditions, cyclodehydrate to give 5-aryl-oxazoles (Equation 7) . R3 R3 O R2

R2

O R1

ð7Þ

O

AlCl3/TfOH ClCH2CH2Cl

N

N R1

R1 = alkyl or Ph R2 = H or alkyl

Unsaturated 5(4H)-oxazolones have an additional exocylic double bond which has been exploited in various reactions. Chiral oxazolone 120 undergoes diastereoselective reaction with diazomethane to give cyclopropane adduct 121, which can be transformed into various cyclopropylamino acids 122 (Scheme 29) . O

O Me Me

CH2N2

O N

O

O

O

Me

O Me

O

O

N

R

OH NH2

Ph

Ph

120

121

122

Scheme 29

An intermolecular Diels–Alder reaction between oxazolone 123 and Danishefsky’s diene gave a cyclohexenone cycloadduct 124, which was elaborated into the natural product epibatidine (Scheme 30) . TMSO i,

N N

Cl

123 Scheme 30

H N

NHCOPh

OMe

N

O

O Ph

Cl

CO2Me

O

ii, HCl, THF iii, DBU, MeOH

N

124

Cl epibatidine

Oxazoles

4.04.6.2 Dihydrooxazoles 4.04.6.2.1

2,3-Dihydrooxazoles (4-oxazolines)

The appearance of 2,3-dihydrooxazoles in the literature is quite infrequent owing to their inherent instability unless they are appropriately substituted. However, substituted 2,3-dihydrooxazoles have been used as reaction partners in various cycloaddition reactions to generate functionalized ring systems. The synthesis of dihydrooxazole 125 is discussed in Section 4.04.11.2.1. This moiety has been used to generate products of [2þ2] 126, and 127, [2þ1] 128, and [4þ2] 129 cycloadditions with a high degree of stereo- and regioselectivity in excellent yields (Scheme 31).

Cl

H O But

Cl

C

O

O

N

H COOMe 78%, R = H

But

N2

EtO

126

COOEt

O O

N COOMe

Cu(II) 59%, R = H

R

128

O But CN NC H CN

CN

O

O O

125

NC CN

O But

N COOMe

94%, R = H

O

93%, R = vinyl

CN

But

N

N

H CN COOMe

H

MeOOC

127

H

O

O

H O

129

Scheme 31

4.04.6.2.2


The reactions of 2,5-dihydrooxazoles are also uncommon. Typically 3-oxazolines have been used as precursors to the corresponding oxazoles. This oxidative transformation can be carried out using a dehydrogenating agent such as chloranil (tetrachloro-1,4-benzoquinone) as demonstrated in the conversion of 130 into oxazole 131 , or via dehydration of a hydroxy-oxazoline substrate 132 under acidic conditions to give oxazole 133 (Scheme 32). This dehydration process is analogous to the acid-catalyzed dehydration of the hydroxy-oxazoline intermediate in the final step of the Robinson–Gabriel synthesis of oxazoles.

Ph N

Ph O

chloranil CH2COOMe

Ph

PhCH3, 110 °C, 40 h 50%

CH2COOMe

Ph

Me

Me O

TFA, DCM, 0 °C Ph OH

Me

132 Scheme 32

O

131

130

N

N

or n-BuLi, THF then MsCl, 0 °C 35–37%

N

O Ph

Me

133

509

510

Oxazoles

4.04.6.2.3


Historically, 4,5-dihydrooxazoles have been widely used as activating groups or chiral auxillaries in asymmetric synthesis. A review by Meyers on the use of chiral 2-oxazolines in asymmetric synthesis has been published . Typically, 2-oxazolines can be modified at the end of their reactive utility to reveal functional groups like carboxylic acids, ketones, aldehydes, or esters. In addition to asymmetric reaction control and substrate functionalization, 2-oxazolines can also serve as versatile masking groups for a number of reactive moieties. For example, the reaction of oxazoline 134 with butyllithium followed by treatment with an electrophile and hydrolysis reveals a chiral ketone 135 bearing an -quaternary center in good yields and moderate enantiomeric excesses (Scheme 33) .

But i, 2 n-BuLi, THF, –78 °C → rt, then BnBr

N Ph

Ph

Me

Bun

ii, 10% oxalic acid, reflux

O

O

Bn

Me

135

134

72%, 73% ee H3O+ But

LiO

LiN Ph

But

O

OLi

Me

LiO

Bun

Me But

N

C

Ph

But

C N Li

Me

Bun Me C N E Ph

E+

Ph

Scheme 33

4.04.6.3 Oxazolidines 1,3-Oxazolidines are prone to ring-opening reactions by attack of nucleophilic species at the activated C-2 position. The activation of 1,3-oxazolidines is typically carried out under catalytic Lewis acid conditions, where the opening of the oxazolidine ring system is presumed to precede trapping with the nucleophilic species. The ring-opening reactions of oxazolidines have also been carried out in the absence of Lewis acid activation and these reactions are thought to proceed via an SN2 process. The products are usually formed in both cases with a high degree of stereoselectivity, which is directed by the substituent stereochemistry on the parent oxazolidine. The ring opening of N-isopropyl-1,3-oxazolidines 136 derived from (R)-phenylglycinol with methyllithium catalyzed by aluminium tris(2,6-diphenylphenoxide) (ATPH) or by attack of methylmagnesium bromide gave diastereomeric products (R,R)-137a or (S,R)-137b with a high degree of selectivity in excellent yields (Scheme 34) . 1,3-Oxazolidine 139 derived from (R)-phenylglycinol has also been used in a one-pot, Lewis acid-catalyzed Mannich reaction with difluoroenoxysilane 138 derived from the corresponding phenylacylsilane to give a -amino ketone 140 in good yield and diastereoselectivity (Scheme 35) . Intramolecular nucleophilic ring-opening reactions of oxazolines are also known. Hydrozirconation of N-allyloxazolidine 141 gave a zirconocene intermediate 142, which reacted with TiCl4 to afford the corresponding 2-substituted pyrrolidine 143 in good yield and diastereoselectivity (Scheme 36) . Fused bicyclic morpholones 145 and 146 have been synthesized in good yields but with modest diastereoselectivity from 1,3-oxazolidines 144 via reaction of the nitrogen of the oxazolidine with a metallocarbene intermediate followed by a benzyl migration (Scheme 37) .

Oxazoles

Ph Pri

Ph Pri

i, ATPH, MeLi, DCM, –50 °C

N

O

N

or ii, MeMgBr

Ph

Ph

Me

(R,R )-137a

136

OH

N

+

Ph

From (R )-phenylglycinol

Ph

Pri

OH

Me

(S,R )-137b

86%, ratios: i, 97:3; ii, 3:97

Pri + N

Ph

– Al(OR)3

O

Ph MeLi

Ph

Ph O

ATPH =

O

Al

Ph

O

Ph Ph

Ph

Scheme 34

H N

Pri

Ph

Ph

OH

O

O Ph

OSiMe3

CF3SiMe3, Bu4N+Ph3SnF2– SiMe3

139

Pri

Ph

F

Ph

DCM, 0 °C, 30 min

HN

O

F

F

BF3 OEt2 F

140 138

63%, d.r. = 79:21

Scheme 35

[Zr]

Ph

Ph

Cp2Zr(H)Cl

N Ph

DCM, 0 °C

O

TiCl4, 15 mol%

N O

Ph

141

Ph

N

OH

Ph

142

143 62%, d.r. = 10:1

Scheme 36

O

O N

Me

O

O

Me

Me N2

Cu0, PhCH3 reflux

O

Me

H O N

O O

Ph

Ph

Me

144

145

+

O

H O N

O O

Ph Me

146

57%, d.r. = 2.8:1 (145:146) Scheme 37

511

512

Oxazoles

4.04.6.4 Oxazolidinones 2-Oxazolidinones continue to attract interest in the field of synthetic organic chemistry due to their versatility as chiral auxiliaries. Most of the chemistry associated with 2-oxazolidinones occur on the nitrogen substituents, such as aldol and alkylation reactions. The nitrogen of 2-oxazolidinone is a useful coupling partner for metal-catalyzed amination reactions of various sp2-hybridized halides. 2-Oxazolidinone can be coupled with chiral allenyl iodide 147 using CuCN as a catalyst in good yields without isomerization of the allenyl stereogenic center (Equation 8) . O HN Ph

O Ph

NHBOC I

O

NHBOC

O

C

C

Cs2CO3, TolH, 50 °C 73%

H

H

147

ð8Þ

N

CuCN (10%), TMEDA (20%) H

H

no isomerization

Vinyl oxazolidinone 148 has been shown to be a good precursor to trans-oxazolines (Scheme 38). Under palladium(0) catalysis, an intermediate p-allyl complex is formed with the loss of CO2. Intramolecular attack by the amide oxygen forms the thermodynamically favored trans-oxazoline 149. This oxazoline was then converted to the natural product balanol .

TBSO

OTBS R

BnO N

O

O

HN dppp

O

N

Pd

Pd2(dba)3CHCl3 O

O

R

148

OBn

149

OH

HN

79% balanol

NH OBn O

Scheme 38

4.04.6.5 Oxazolidinediones -Amino acid-derived 2,5-oxazolidinediones 150 can undergo dynamic kinetic resolution using a modified cinchona alkaloid catalyst to give enantiomerically enriched -amino acid esters 151 (Scheme 39). The C-4 proton of oxazolidinediones is acidic, hence facilitating the rapid base-catalyzed racemization of the starting materials, but once the ring is hydrolytically cleaved the resulting -amino esters are not racemized under the reaction conditions. The process is highly atom economical since both of the enantiomers of the starting material converge to form one enantiomer of the product . The -hydroxy acid-derived 2,4-oxazolidinediones have been successfully utilized as substrates for asymmetric alkylations with a chiral phase-transfer catalyst (Scheme 40). Using 1 mol% of the N-spiro chiral quaternary ammonium bromide catalyst 153, oxazolidinedinone 152 was alkylated in high yield and enantioselectivity and hydrolyzed in situ to give -hydroxy amides 154 .

Oxazoles

R

O

N

Cbz

O

(DHQD)2AQN (0.2 equiv) allyl alcohol Et2O, 4 Å MS, 0 °C

R Cbz

O

Pd(PPh3)4 morpholine, THF

O

NH O

R

O

NH

OH

Cbz

151

150

>95%, >90% ee

R = aromatic or heteroaromatic

DQHD

DHQD

O

DHQD = dihydroquinidyl

O

Scheme 39

O Ph

Ar

N O O

O

(S,S)-153 (1 mol%) RBr (1.2 equiv)

Ph

Ar N O R

25% KOH aq. TBME –20 °C

O dioxane Ph rt

Ar N H

O

152

HO

R

154 >80%, 90–99% ee

Ar = Ph, p-FC6H4, p-MeOC6H4, 2-furyl, 2-thienyl

X

Y

Ar Br–

RBr = ArCH2Br, allylBr, propargylBr

N+

X

Y

Ar

153 Ar = 3,5-(3,5-(CF3)2-C6H3)2-C6H3; X = CF3; Y = H Scheme 40

4.04.7 Reactivity of Substituents Attached to Ring Carbon Atoms Carbon substituents attached to an oxazole ring are activated by the heteroaromatic ring, and possess reactivities like other common benzylic carbons. The protons on the carbon substituents are weakly acidic and can be abstracted by a strong amide base. This reaction can be complicated by competitive abstraction of a ring hydrogen. In their synthesis of marine natural product phorboxazole, Evans and co-workers demonstrated that lithium diethylamide was particularly effective in selective deprotonation of the proton on the 2-methyl-substituted oxazoles 155 (Scheme 41). Kinetically, the deprotonation occurs at both the ring hydrogen and the methyl substituents. However, the use of a nonhindered base, diethylamide, and with diethylamine as additive, led to rapid equilibration between 156 and 157 at low temperature to give the more thermodynamically favored 156, which led to highly selective trapping of electrophiles at the carbon substituent . This methodology was subsequently applied to the successful coupling of two major fragments en route to the total synthesis of phorboxazole (Scheme 42) . The samarium(II)-mediated Barbier reaction has been used as an alternative to the deprotonation chemistry to generate 2-alkyl-metallated oxazoles (Scheme 43). This reaction is very useful for the coupling of 2-iodomethyl oxazoles and aliphatic aldehydes. However, reactions with aromatic aldehydes gave mainly pinacol coupling products .

513

514

Oxazoles

R

R

LiNEt2

N Me

Li

THF, –78 °C

O

R

N Me

O

155

MeOTf

N

156

O

Li

157

R = Ph, CH2OH, alkyls R

R

N

Me

N

+ Me

O

Me

O

>95:5 Scheme 41

OTMS OTES

OTMS

MeO Me

O Me

N Me

O

H

Me

LiNEt2, THF –78 °C

HO

OTPS

N

OTES

Me

O

O

Me

O

MeO

phorboxazole

OTPS Me

80% O O Scheme 42

TBSO

O H

Ph

OTBS

TBSO

CO2Me

O

SmI2, THF, rt

N

+

OH

O

N Ph

I

CO2Me

OTBS 68%

OH O Ph

H

O

N

CO2Me

OMe

Scheme 43

2-Aminomethyl-substituted oxazole 159 has been used as a synthon for the asymmetric synthesis of -amino acids. Condensation of 158 and chiral 2-hydroxypinanone gave chiral imine 160, which can undergo asymmetric alkylation to give products in high diastereoselectivity. This methodology has been demonstrated in the synthesis of a natural pipecolinic acid 161 (Scheme 44). After the alkylation, the chiral auxillary was hydrolytically removed and oxazole ring could be oxidatively cleaved to reveal the carboxylic acid functionality . Oxazole-derived Wittig reagents have been used in several total syntheses of complex natural products. In their total synthesis of marine natural product calyculin C, Ogawa and Armstrong used 163 to join two major fragments. The Wittig reagent was derived from PBu3 displacement of the corresponding oxazole chloride 162. LDA proved to be a suitable base for the coupling step which gave a 99:1 trans:cis ratio of the coupled alkene product 164 (Scheme 45) .

Oxazoles

Me

Ph

O +

Me

Me

N

OH

H2N

BF3 OEt2, TolH Ph

O

Me

Ph

N

2 equiv LDA, THF Ph

O

OH

4 Å MS, reflux

Me

158

N

Br

Me

159

Br

160

O

Me

O

Me

65%

Ph

Ph

Me

N N O

Me

O

OH Me

i, citric acid, THF H2O, rt

Ph

H N

H N

Ph

O

ii, NaHCO3, EtOH

Me

OH

O

Me

Br

CO2H

HO

O

Me

O

N

161 Me

30%, d.r. > 95:5 Scheme 44

OH

Me

O

MeO

O

O

N H

OH

Me2N

Me

Me PBu3, DMF

N

LDA, 0 °C

N

70 °C Cl

162

163

RCHO

P+Bu3Cl–

70% OH

O

MeO Me2N

Me

O

N H

OH

Me

Me

Me Me

Me

OR

Me

RCHO = OHC R1 Me Me O O Me O

Me

Me

Me

OR

OR

Me

Me

OMe

O

O

Me

O Me

Me

CN

N

R1 CN

Me

OR

Me

OMe

164 40% Scheme 45

Similar Wittig reagents can also be generated from 2-substituted bromomethyl oxazole 165 with Et3P, used in this case in the total synthesis of tris-oxazole macrolide mycalolide A. The Wittig ylide was generated in situ using 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) as base, leading, in the presence of aldehyde 166, to product 167 in excellent yield (Scheme 46) .

515

516

Oxazoles

O Br

N

Et3P, DMF, DBU RCHO

O N Me ButO O

N

Me

RCHO = OTBDPS

O

Me

OMe

Me

Me

CHO AcO

O

Me

Me

Me

O

MeO

Me

MeO

O

OMe

TBS

O O

O

166

O AcO

Me

Me

O

165 Me Me

O

N O

O

– Et3P+

N

OMe

O

TBS

N Me

N

HO

O O

OTBDPS

O

OMe

167 93% Scheme 46

4.04.8 Reactions of Substituents Attached to Ring Heteroatoms There are no reports of reactions of substituents attached to the ring heteroatoms of oxazoles. The oxazole nitrogen atom can be alkylated or acylated to give a reactive oxazolium species that facilitate further transformations of the ring. These reactions are summarized in CHEC-II(1996) and further described in Section 4.04.5.2 of this chapter.

4.04.9 Ring Syntheses of Conjugated Oxazoles 4.04.9.1 One Bond New methods for oxazole synthesis have continued to attract interest due to the synthetic study of complex natural products containing oxazole moieties as well as the use of oxazoles in pharmaceutically relevant compounds. Many of these newer methods address the need for oxazole formation in the presence of various sensitive functional groups. One common method of oxazole synthesis is the conversion of a 4,5-dihydrooxazole into the unsaturated oxazole ring using an oxidation reagent. This transformation has traditionally been carried out using a reagent such as nickel peroxide or manganese dioxide, but the yields have often been low or variable. A two-step, one-pot mild and selective synthesis of oxazoles from -hydroxy amides uses either (diethylamino)sulfur trifluoride (Et2NSF3, DAST) or [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxofluor) as dehydrating agent, followed by treatment with BrCCl3 as an oxidation reagent for the dihydrooxazole-to-oxazole conversion. As shown in Equation (9), serine amide 168 can be converted into 2,4substituted oxazole 169 in good overall yields without epimerization of the adjacent stereogenic center . OH

O CbzHN

N H

Deoxofluor –20 °C then BrCCl3, DBU, 0 °C

O CbzHN

CO2Me N

CO2Me Pri

Pri

168

169 59%, >97% ee

ð9Þ

Oxazoles

The cyclodehydration of 2-acylamino ketones to oxazoles, known as the Robinson–Gabriel reaction, is one of the oldest methods for oxazole synthesis. Classical dehydrating reagents such as POCl3, H2SO4, SOCl2, P2O5, polyphosphoric acid, p-toluenesulfonic acid, and trifluoroacetic anhydride (TFAA) have been widely used. Newer reagent combinations such as Ph3P–I2–Et3N, Ph3P–BrCl2CCCl2Br–DBU, and Ph3P(O)–Tf2O have gained broader use in the context of natural product syntheses. In a synthetic study of martefragin A, indole 170 and amide 171 were coupled via a Rh-catalyzed N–H carbene insertion reaction to obtain -keto-ester 172, which was then cyclodehydrated by Ph3P-I2-Et3N to give an oxazole product (Scheme 47) .

BOCHN R

N2 EtO2C O

BOCHN +

Rh2Oct4 CH2Cl2

Me Me

H2N

HN

Ph3P, I2 Et3N, CH2Cl2

O

EtO2C O

O

N Ns

170

171

172

N Ns

NHBOC N EtO2C

R O

N Ns

173 51% 2 steps Scheme 47

A Ph3P(O)–Tf2O-mediated cyclodehydration was utilized in the conversion of -keto-ester 174 to give a key oxazole building block 175, which was used in a total synthesis of marine natural products bistratamide F-I (Scheme 48) .

Pri OH

FmocHN

Pri

i, L-threonine benzyl ester HBTU, Pr2NEt FmocHN

ii, Dess–Martin periodinane

O

O

O

H N

OBn Me

O

174

Pri Ph3PO, Tf2O N

FmocHN O

O Me

175 Scheme 48

OBn

bistratamides

517

518

Oxazoles

Propargylamine amides can readily undergo cycloisomerization to oxazole products using a number of conditions. Conjugated alkynyl amide 176 was converted into oxazole 177 with the aid of silica gel (Equation 10) . O O

silica gel

H N

EtO

EtO

Ph CH2Cl2, rt

O

O

Ph

ð10Þ

N

177

176

90%

Propargylamine amides without electron-withdrawing groups can also cyclize to oxazoles using a Lewis acid such as AuCl3 , or under basic conditions. Treatment of amide 178 with NaHMDS gave 2,5-disubstituted oxazole 179 (Scheme 49) .

R

Et

Me

H N

TrHN

NaHMDS

OBn

N O–

–78 to 70 °C

Me C

Et N

TrHN

C

O

O

179

178

66% Scheme 49

This concept was applied in an efficient synthesis of oxazole-containing natural product muscoride A. The acetylene intermediate 180 was not isolated and the cyclization and desilylation occurred upon basic work-up of the reaction mixture leading to the oxazole (Scheme 50) .

H N

CO2Et

AlMe2

TMS

N Troc

O

0 °C

Cl

H N

N

CO2Et N

N

O

Troc

Troc

CO2Et

O Me

TMS

72%

180 Scheme 50

Like the cycloisomerization of propargylamine amides, allylamine amides such as 181 undergo 5-exo-cyclization in NaOH to give phosphine oxide-substituted oxazoles 182 (Equation 11) . R2

R2 O

NaOH

Cl

NH

Me

P(O)Ph2

181 R2 = alkyl,

rt

N O P(O)Ph2 Et

ð11Þ

182

or vinyl

The 5-endo-cyclization of amino-ketene dithioacetals such as 183 is also a viable method for the synthesis of sulfursubstituted oxazoles 184 (Scheme 51) .

Oxazoles

CN

CN RSH, Et3N

HN Ar

CN Ag2CO3

HN

Cl

SR

Ar

O Cl

N Ar

O

O RS

183

SR

184

Scheme 51

4.04.9.2 Two Bond 4.04.9.2.1

[4þ1] Strategies

Heating -keto-esters 187 with molten ammonium trifluoroacetate at 150 C readily gives oxazoles 188 (Scheme 52). The amino stereogenic center was not epimerized under these conditions. This method allows access to oxazole-5esters, which are not easily obtained using methods presented in the previous section. The -keto-esters 187 were synthesized via nucleophilic displacements on chlorides 186 using N-protected -amino acids 185 . R1 Cbz

OH

N H

Et3N, EtOAc

R2

+

R1

O

O

OEt

O

Cl

185

186

Cbz

65 °C

O O

N H

O

OEt R2

O

187 CF3CO2NH4 150 °C, 5 min

R1 = H, Bn, i -Pr R2 = Me, Ph R1 Cbz

N H

O CO2Et

N R2

188 49% Scheme 52

Reaction of -keto-imide 189 with NaN3 in the presence of methanesulfonic acid gave oxazole 192 (Scheme 53) . The azide anion presumably attacks the -carbonyl group to give 190 followed by loss of N2 and migration to give 191, which is then trapped by the imide carbonyl group.

O

O

N2+

O NaN3, CH3SO3H

Me

N

O

Me

Me Me

190

Me O

N O

N Me

192

O Ph

O

O

N

N

O

O

Me Me

189

Scheme 53

N Me

Ph

Me

Me +

O

O

N

Ph

Me

191

Ph

519

520

Oxazoles

An efficient and practical two-step [4þ1] oxazole synthesis utilizes the condensation of serine methyl ester with ethyl imidate 193 to give an intermediate oxazoline 194. Treatment of 194 under basic conditions brings about elimination of hydrogen chloride to give oxazole 195 in high yield (Scheme 54) .

Cl

Cl

Cl NaOMe Cl

CN

serine methyl ester

OMe

Cl

O

Cl N

NH

193 O

Cl

i-Pr2NEt

194 CO2Me

N

195 CO2Me Scheme 54

A two-step synthesis of 5-substituted-4-cyanooxazoles can be achieved by the condensation of -hydroxy-cyanoenamines 196 with trimethyl orthoformate (Scheme 55). The cyanoenamine intermediates 196 were derived from Lewis acid-catalyzed Passerini reactions between t-butyl isonitrile and aldehydes .

t-BuNC (2 equiv) TMSCl (3 equiv)

O R

H

OTMS

N+ But

N

196

R = alkyl or aryl

CH2Cl2, reflux

NBut

R

Zn(OTf)2 (cat.) CH2Cl2

(MeO)3CH, TsOH (cat)

OH

NBut

R H

O R

N CN

>70% from aldehyde Scheme 55

4.04.9.2.2

[3þ2] Strategies

Tosylmethylisocyanide (TosMIC) reacts with aldehydes via a [3þ2] pathway, under basic conditions, to give 5substituted oxazoles. In one example, the resulting oxazole product was used in the synthesis of a key intermediate for the hepatitis C drug candidate VX-497 (Scheme 56) . K2CO3 is usually the base of choice for this reaction since stronger bases such as KOt-Bu lead to a cyanide product. A polymer-supported TosMIC reagent 196 has been developed in which the isocyanide is attached to a ringopening metathesis polymer (ROMP gel) (Scheme 57). The use of this reagent significantly simplified the purification of the oxazole products .

Oxazoles

N N CHO O2N

O

MeOH, reflux

OMe

O

O

TosMIC, K2CO3

OMe

O2N 96%

N H

NH

O

N H

OMe

VX-497

O O

Scheme 56

O CHO

N

*

Ph

i, 197, t-BuN=C(NMe2)2 X

X ii, filter iii, evaporate 70–80%

SO2

X = various functional groups

NC

197 Scheme 57

Chiral isocyanides such as 198 have also been used for the synthesis of chiral 4,5-disubstituted oxazoles such as 199, which are potentially useful in fluorescence-detected circular dichroism for on-column capillary electrophoresis (Equation 12) .

OMe OMe OMe

ClOC O O

O N

O NC Me

Bn

198

O

OMe

N

Me

P

N N

Me N

O

N

O

ð12Þ

N Bn

199

An iterative Hantzsch reaction was applied for the synthesis of the tris-oxazole fragment of the natural product mycalolide A. The reaction between primary amide 200 and ethyl bromopyruvate in a basic medium followed by dehydration with TFAA gave oxazole 201 (Scheme 58) . The ester was converted into primary amide and the process was repeated twice to give the tris-oxazole. A Rh2(OAc)4-catalyzed cycloaddition between nitrile 202 and dimethyl diazomalonate 203 gave oxazole 204 which was further elaborated into the side-chain of marine macrolide leucascandrolide A (Scheme 59) . Reaction between a -ketoazide and an isothiocyanate gives 2-aminooxazoles. The reaction is initiated by treatment of azide 205 with Ph3P to give an intermediate iminophosphorane 206, which on reaction with an isothiocyanate generates a carbodiimide 207. Cycloisomerization of 207 then leads to the 2-aminooxazole 208 (Scheme 60) .

521

522

Oxazoles

Ph

i, NaHCO3, THF ii, TFAA

O

NH2

Br

+

O Ph

CO2Et

O

200

201

TBDPSO O

83%

N N OHC

CO2Et

N

N

O

O Scheme 58

O

O

MeO

OMe

O

O

O HN

N2

203

HO2C NH

OMe

OMe HN

N

CO2Me

O

OMe

MeO N

CN Rh2(OAc)4 CH2Cl2, reflux

202

O

204 60%

Scheme 59

O AcO

NMe O

Ph3P

N3

O N

Ar

O

PPh3 Ar

206

O

NAr′

207 MeO

N

C

O

N

205

N

NCS

O OAc N

MeO

N H

MeN

O

208 Scheme 60

A one-pot/two-reaction sequential ruthenium- and gold-catalyzed oxazole formation has been reported . The reaction of a propargylic alcohol and a primary amide in the presence of a Ru catalyst facilitates the formation of the intermediate propargyl amide which cyclizes upon treatment with AuCl3 (Scheme 61).

Oxazoles

Cp*

R

H2N

Ar

Cl i, MeS Ru SMe Ru Cl Cp*

+ O

OH

Ar

Ar

N HN

ii, AuCl3

O

Me

R

R

O >59%

Ar = Ph, naphthyl, etc. R = Me, Pr, vinyl, etc. Scheme 61

4.04.9.3 Ring Synthesis of Ring-Fused Oxazoles Benzoxazoles are found in a variety of natural products and routinely find use in pharmaceutical research. They are generally made by condensation of a 2-aminophenol with a carboxylic acid or oxidative cylization of an imine intermediate. A mild copper-catalyzed cyclization of ortho-haloanilides to give benzoxazoles 209 has been reported (Scheme 62) . This route is conceptually different to the aforementioned methods in that the starting material is a 2-haloaniline rather than a 2-aminophenol. The reaction conditions tolerate various functional groups in the amide portion of the molecule. CuI (5%) O

Br

Br NH2

LG

R

Me

H N

R

N H

H N

Me(10%)

O R

O

Cs2CO3, DME, reflux

N

209 R = aryl, alkyl,

Cbz N

60–90%

Scheme 62

Oxazolopyridines are also of interest in the pharmaceutical industry since the pyridine fragment can provide better water solubility or it might offer an additional site of interaction with a target protein through a hydrogen bond with the heteroatom. An efficient route to 2-(aminosubstituted)-oxazolopyridines has been reported. The starting 4-amino-3-hydroxypyridine is derived from directed ortho-lithiation of 4-pivaloylaminopyridine 210 followed by quenching with B(OMe)3 and oxidative workup (Scheme 63) . The amino-alcohol 211 was then reacted with potassium ethyl xanthate or thiophosgene followed by methyl iodide treatment to give sulfide 212, which underwent facile displacement reactions with amine nucleophiles to give 213 in good yields. 2-Alkyl-oxazolopyridines can also be synthesized from amino-pyridinols. The synthetic sequence starts with N-acylation of o-amino-pyridinols such as 214 (Scheme 64) . The resulting amide 215 was then cyclodehydrated with C2Cl6 and PPh3 to give oxazolopyridines 216. Reck and Friedrichsen reported a synthesis of furo[3,4-d]oxazole 218 from diazo derivative 217. Furoxazole 218 can undergo Diels–Alder reaction with dienophiles such as naphthoquinone 219 to give, in this case, the adduct 220 in a modest yield (Scheme 65) . The imidazo[5,1-b]oxazole ring system has been synthesized. Nitroimidazole 221 was alkylated with an -bromo acetophenone to give a mixture of ketones 222 and 223 in a 1:3 ratio. Compound 223 was then cyclized under basic conditions to give the corresponding imidazo[5,1-b]oxazoles 224 (Scheme 66) . A series of piperidines with fused five-membered ring azoles, including a fused oxazole, has been reported. The multistep sequence starts with the reduction of azido alcohol 225 followed by acylation to give amides 226. After oxidation, the amido ketones 227 were cyclodehydrated using the Burgess reagent to give fused oxazoles 228. These compounds were used to generate DPPIV inhibitors such as 229 (Scheme 67) .

523

524

Oxazoles

But HN

O

NH2

i, n-BuLi (2.5 equiv) ii, B(OMe)3; H2O2

OH

iii, 10% HCl

N

HNR1R2 N

SMe

N

O

211

212

76%

90%

R1 N R2

N

85 °C, neat

N

ii, MeI

N

210

i, EtOC(S)SK, EtOH, reflux or CSCl2, rt

O

213 >80% Scheme 63

OH

OH O

NH2 +

HO

N

214

H N

TBTU, NEt3 R

DMF

R

C2Cl6, PPh3, NEt3

O

N

CH2Cl2, rt

215

R = alkyl, aryl

70% O R

N

N

216 40–70% Scheme 64

N

CO2Me

O

N2

Me

Rh2(OAc)4

N Me

ClCH2CH2Cl

O

CHCl3 CO2Me

218

217 OMe O N Me O MeO2C

220 24%

O

reflux

+

O

CO2Me

Scheme 65

O

OMe

39%

O

219

Oxazoles

O

Br N O2N

Ar

N

N O2N

Me

N H

O2N

Br Br

KOH, EtOH, heat

N

Me

Br

t-BuOK

Me

N

THF, 50 °C

O

O

221 Ar O2N

Ar

1 N

O

3

222

Me

N

:

223

Ar

224 48–65% Scheme 66

OH

OH N3

i, Ph3P, H2O, THF ii, RCOCl, Et3N

N

H N

O

Dess–Martin periodinane

R O

N

H N O

N

BOC

BOC

BOC

225

226

227

R

R F

O N

Burgess reagent

NH2 O

THF, heat

N

N

N

R

F

BOC

O

228

229

Scheme 67

4.04.10 Ring Synthesis by Transformation of Another Ring Oxazoles can be formed in a two-step process involving nucleophilic ring opening and rearrangement of N-acylaziridines followed by an oxidation of the initially formed 2,3-dihydrooxazole product . Reactions of Nacylaziridine 230 with sodium iodide gave oxazoline 231, which was then oxidized with nickel peroxide to yield the corresponding oxazole 232 in good overall yield (Scheme 68).

EtO

EtO

OEt NaI, acetone

N

Ph O

230 Scheme 68

NiO2

N

83%

O

Ph

231

EtO

OEt

N

85%

O

Ph

232

OEt

525

526

Oxazoles

N-Acyl-1,2,3-triazoles 234, derived from the reaction of 2-trimethylsilyl-1,2,3-triazoles 233 with acyl chlorides, can also undergo rearrangement to yield oxazoles 237 (Scheme 69) . This rearrangement reaction is reported to be quite sluggish and requires high temperatures and/or long reaction times for efficient conversion. As the reaction progressed, two triazole amide isomers were observed which remained in equilibrium during the course of the reaction. Only the N-1-triazole amide 234 is presumed to progress to product. The reaction proceeds via the heterolysis of the N-1–N-2 bond of the triazole 234 to give zwitterionic product 236, which then undergoes ring closure with the displacement of nitrogen to yield the oxazole product. N

O N N SiMe3 + N

COCl Cl

N

TolH

N N

reflux, 3 d

N N R

O

R 82%

N

Cl

O

233

234

235

237

O– R=

R

Cl

N N2+

236 Scheme 69

Oxazoles 240 have also been prepared by flash vacuum pyrolysis or photolysis of N-acylisoxazol-5-ones 239 (Scheme 70) . The acylisoxazol-5-ones were in turn prepared by the acylation of the corresponding isoxazol-5-ones 238. This method of oxazole production has been reported to give significantly better yields than the rearrangement of the acyltriazole precursors.

O

R H N

O

RCOCl

O

EtO O

Me

DCM, rt

238

O

N

EtO Me

239

FVP 540–600 °C, 0.01 mm

O O

or photolysis 254 nm in CH3CN, silica

O

R

R

O Me

N

CO2Et

240 95% yield from FVP 40% yield from hν

O

N

OEt Me

Scheme 70

4.04.11 Ring Synthesis of Nonconjugated Rings 4.04.11.1 Oxazolones 4.04.11.1.1

2(3H)-Oxazolones

2(3H)-Oxazolone itself can be easily obtained from oxazolidinone through electrochemical reduction as described in CHEC-II(1996). A similar sequence was utilized in the synthesis of indole-substituted 2(3H)-oxazolone 244 (Scheme 71) . Electrochemical oxidation of 2-oxazolidinone in methanol gave a 4-methoxy oxazolidinone 241, which reacted with an organomagnesium indole reagent 242 in the presence of BF3?Et2O, followed by

Oxazoles

(BOC)2O, to give intermediate 243. Final dehydrogenation via C-bromination with N-bromosuccinimide (NBS) yielded oxazolone 244.

H N

i,

OMe

–2e– O

N 242 BrMg BF3 Et2O

NH

O

MeOH O

NH

H N Br NBS, AIBN

O

ii, (BOC)2O

N

O

BOC

N

O

O

O

241

243

244

BOC

Scheme 71

A Rh-catalyzed NH insertion into phenyl carbamate 246 of a carbene generated from diazo compounds 245 gave 247, which, under base treatment, produced oxazolone 248 (Scheme 72) .

O

Rh2Oct4 (2 mol%)

RO

RO

Me N2

O

O

O

Ph

245

O

i-Pr2NEt

Me HN

NH2

Me

O O

O

O

246

247

RO Ph

O HN O

248

Scheme 72

4.04.11.1.2

4(5H)-Oxazolones

A general two-step method has been developed for the synthesis of 5H-5-alkyl-2-phenyloxazol-4-ones 251. This procedure involves the initial condensation of -bromo acid halides 249 with benzamide to form an imide intermediate 250 followed by microwave-mediated cyclization in the presence of NaF to give the corresponding 4(5H)oxazolones 251 (Scheme 73) .

O R

X Br

249 X = Br or Cl R = alkyl

benzamide, pyr DCE, 60 °C

O R Br

O N H

250

Ph

NaF, DMA microwave, 180 °C

O N R

O

Ph

251 44–82%

Scheme 73

Smith et al. adapted Sheehan and Izzo’s synthesis of 2-aryl-4(5H)-oxazolones and developed a general synthesis of 2-alkyl-4(5H)-oxazolones. The reaction between acid halides and AgNCO followed by treatment with ethanol-free diazomethane produced oxazolones 252, which served as precursors to triflyloxyoxazoles 253 (Scheme 74). Triflyloxyoxazole 253 (R ¼ CH2Br) was utilized as a difunctional linchpin for the bidirectional assembly of the natural product phorboxazole .

527

528

Oxazoles

R

Tf2O, Et3N, THF –78 °C

O

O

i, AgNCO,CH2Cl2 X

N

N

R

ii, CH2N2 (ethanol free)

OTf

O

O

R

252

X = Br or Cl R = various alkyl groups, CH2Br

253 48–90%

Scheme 74

En route to a total synthesis of an antibacterial natural product indolmycin which contains an amino-substituted oxazolone, -hydroxy acid 254 was treated with guanidine and KOt-Bu in t-BuOH in the presence of 4 A˚ molecular sieves to produce oxazolone 255 with minimal epimerization of the acidic stereogenic center (Scheme 75) .

Me

Me CO2H N H

H

O 40% aq. MeNH2, 5 °C

i, HCl, EtOH ii, guanidine HCl KOt-Bu, t-BuOH 4 Å sieves

OH

254

O

N H

N NH2

255 67%

Me

N H

O

H

N

O

NHMe

64%, 99% ee indolmycin Scheme 75

4.04.11.1.3

5(4H)-Oxazolones

5(4H)-Oxazolones are generally synthesized by cyclodehydration of N-acyl -amino acids using dehydration reagents such as acetic anhydride or carbodiimides. It has been shown that 5-acyloxyoxazoles 256 rearrange to 4-acyl-5(4H)-oxazolones in the presence of a nucleophilic catalyst. Asymmetric variants of this reaction have been reported by Fu’s group using a chiral DMAP–ferrocene complex 258 , and by Vedejs’ group using a chiral DMAP 257 . This reaction is useful in obtaining chiral -amino acid synthons with a quaternary stereogenic center (Equation 13). H

Me2N

CPh3

O OR3

O R2

O

OAc N

O

O

R3O

257

R2

Me2N

N

O N

259 R1

256

N R

M

R R

R R

258

R1

ð13Þ

Oxazoles

4.04.11.2 Dihydrooxazoles 4.04.11.2.1


There is little chemistry reported on the synthesis of 2,3-dihydrooxazoles as this moiety is inherently unstable except for when it is substituted with electron-withdrawing groups. One reliable method of generation of 4-oxazolines is via the reduction of oxazolinium salts . The oxazolines generated from this method are not stable but undergo ring opening to give azomethine ylides that can serve as cycloaddition partners. There is, however, a report of the synthesis of 4-cyano-substituted 2,3-dihydrooxazoles, for example, 261, by a reaction between 2-alkylidene-3oxo nitriles (e.g., 260) and various nosyloxycarbamates , giving the products in good yields (62–92%) (Scheme 76). This sequence presumably proceeds via the intermediacy of a 2-acyl-2-cyano aziridine/azomethine ylide to generate the heterocycle.

CN

O

Ph

Ph

Ph NsONHCO2Et

CN O

O

N CO2Et

CaO, DCM, rt Et

Et

CN – CN

Ph

N+ CO2Et

O

N CO2Et Et

Et

260

261

Scheme 76

2,3-Dihydrooxazoles such as 263 have also been prepared via an oxidative decarboxylation and elimination of the corresponding oxazolidine-4-carboxylic acid 262 (Scheme 77). The oxazolidine-4-carboxylic acids were in turn derived from L-serine. The thermal oxidative decarboxylation using lead tetraacetate was reported to be higher yielding and more practical than the analogous electrochemical version. Dihydrooxazoles 263 have been extensively used as chiral olefinic components in cycloaddition reactions and these reactions are discussed in Section 4.04.6.2.1.

OAc

CO2H

NH4Br

Pb(OAc)4 O

N CO2Me PhH, reflux 84%

But

O

262

N CO2Me But

1,2-DCE, reflux 73%

O

N CO2Me But

263

Scheme 77

4.04.11.2.2


Traditional methods of generation of 2,5-dihydrooxazoles have involved photochemical or basecatalyzed ring opening of 2H-azirines 264 followed by trapping with aldehydes. In addition to these general routes, ultrasound technology has been used to induce halide displacement on 2-halo-2Hazirines 265 by water, the subsequent autocondensation with its own hydrolysis by-product 266 giving 3-oxazolines 267 (Scheme 78). Another route for the synthesis of 3-oxazolines is via a chlorination/dehydrochlorination sequence of 1,3-oxazolidines, for example, 268 . This net oxidation reaction results in mixtures of 2- and 3-oxazolines (269 and 270, respectively) with the product ratios dependent on the nature of the base used (Equation 14). 3-Oxazolines can also be prepared via a Boyer reaction between aliphatic aldehydes and 2-aryl-2-azidoethanol . As in the earlier example, the 3-oxazoline product 271 was formed along with the generation of isomeric 2-oxazolines. An enantiomerically pure azido alcohol 272 can be used to induce the absolute stereochemistry of the oxazoline product (Scheme 79). The product oxazolines, for example 273, were formed with modest to good ees, albeit in low yields.

529

530

Oxazoles

O

Me N

H

Ph

CH3CHO DABCO 75%

CH2CO2Me

264

N Ph

CO2Et

H

N

H

Ph

N

ultrasound H 2O

Br

265

– N

Me

Ph

Ph

CO2Me

CO2Et

EtO2C

Ph

COPh O– N+

O

OH

CO2Et O

COPh OH CO2Et N

CH2CO2Me

EtO2C

Ph

EtO2C

O

Ph

CO2Et OH

266

COPh O

N 30%

CO2Et OH

Ph

O

267 Scheme 78

Et

Et

Et

i, NaOCl NH

O

N

O

ii, t-BuOK, pentane, 0 °C

+

N

O

Pri

Pri

Pri

268

269

270

ð14Þ

65% total yield, 65:35 ratio

H Ph N3 Ph2CHCHO

+

Ph

N3

BF3 OEt2 OH

DCM, 40 °C 47%

Ph

CHCHPh2 O+

4

O

Ph Ph

O

N

Ph Ph

271 Ph

C8H17CHO

+

N3 S Ph

272

BF3 OEt2 OH

DCM, –23 °C 15%

O *

N C8H17

273 74% ee Scheme 79

N

N2+

2

Ph

Oxazoles

4.04.11.2.3


4,5-Dihydrooxazoles continue to occupy an important place in organic synthesis and medicinal chemistry as they have found use as versatile synthetic intermediates, protecting groups/pro-drugs for carboxylic acids, and chiral auxiliaries in asymmetric synthesis. There are several protocols in the literature for the transformations of functional groups such as acids, esters, nitriles, hydroxyl amides, aldehydes, and alkenes to 2-oxazolines. Newer additions to these methods feature greater ease of synthesis and milder conditions. A weakly acidic zeolite, Ensorb-4, has been used to convert carboxylic acids into 2-oxazolines in 30–90% yields (Equation 15) . N CO2H +

Ensorb-4

HO

NH2

O

ð15Þ

xylene, 140 °C 90%

Alternatively, the condensation of amino alcohols with carboxylic acids has been shown to proceed via a reactive triazine species 274 to generate 2-oxazolines in 71–89% yield (Scheme 80) .

Me

OMe

O N MeO

N

N N

DCM, 0–5 °C

Cl

OMe

OMe

N

MeO

N N

Me Cl – N+

PhCOOH

N

N MeO

O

N

O

Ph

O

274

Me Me NH2

HO

Me Me

N O

78% Scheme 80

4,5-Dihydrooxazoles 275 can be made by the condensation of aryl nitriles with amino alcohols catalyzed by Bi(III) salts or acidic clay in good yields (Bi salts – 70–92%; kaolinitic clay – 56–96%) (Equation 16). The use of Bi salts is only applicable to the formation of 2-aryloxazolines while the latter method works well for both aromatic as well as aliphatic substrates. The conversion of carboxylic esters to 2-oxazolines 276 in good (44–82%) yields with lanthanide chloride as catalyst has also been described (Equation 17). Me Me

N CN

Me +

HO

Cl

Me

kaolinitic clay, reflux, o-DCB, 24 h

NH2

or Bi(TFA)3 or Bi(OTf)3, reflux, 3 h o-DCB = o-dichlorobenzene

O Cl

275

N CO2Me

Me +

HO

Me

0.05 equiv LaCl3, n-BuLi, TolH

NH2

79%

ð16Þ

Me Me O

276

ð17Þ

531

532

Oxazoles

2-Oxazolines can also be prepared via a cyclodehydration reaction of -hydroxy amides using either DAST or Deoxofluor as the dehydrating agent in good yields under mild reaction conditions . A comparison of these two reagents in the context of oxazoline synthesis has been reported . Valinederived -hydroxy amides 277 can be cyclodehydrated using either reagent to give the corresponding 2-oxazoline 278 in excellent (83–92%) yields (Equation 18).

Pri

H N

CbzNH

CO2Me

O

DAST, K2CO3, DCM, –78 °C to rt OMe

O

or Deoxyfluor, DCM, –20 °C to rt

OH

N Pri

O

ð18Þ

CbzNH

278

277

DAST: 92% Deoxofluor: 83%

4.04.11.3 Oxazolidines A common method of generating 1,3-oxazolidines is via condensation of 1,2-amino-alcohols with aldehydes or ketones. These reactions are typically Lewis acid catalyzed and have been reliably and routinely used to generate oxazolidines with high diastereoselectivities. Condensation of ephedrine 279 or pseudoephedrine 280 with ketones has been used to generate oxazolidines 281 in high yields and diastereoselectivities (Equation 19) . 1,3-Oxazolidines 282 can also be generated by Sc(OTf)3-catalyzed reactions between amino alcohols and DMAD in good yields and selectivities (Equation 20). These reactions are thermodynamically driven to yield a single isomer under the reaction conditions.

+ MeHN R1

Me

O

2 Me R R1

Me

Pri

Me N DCE, reflux, 7 d

OH

Ph

15 mol% Sc(OTf)3, 4 Å MS O

ð19Þ

Me Pri

R2 = H;

279: = Ph; ephedrine 280: R1 = H; R2 = Ph; pseudoephedrine

281, from pseudoephedrine 96%, dr > 97:1

Me Me

Ph

MeHN

OH

Ph

MeOOC + COOMe

15 mol% Sc(OTf)3, 4 Å MS

Me

MeCN, reflux, 1 d

MeOOC

N

O COOMe

ð20Þ

282, from ephedrine 89%, single isomer

Synthesis of 1,3-oxazolidines 285 has been described by a palladium-catalyzed cycloaddition of vinylic oxiranes 284 with N-tosyl imines 283 (Scheme 81) . This reaction proceeded with high yields and good regioisomeric selectivity and the palladium catalyst of choice was a 1:2 Pd(dba)2:DPPE complex. A cycloaddition methodology has been exploited in the cation radical-mediated reactions between electron-rich chalcone epoxides 287 and N-aryl imines 286 using tris(4-bromophenyl)aminium hexachloroantimonate (TBPAþ _?SbCl6) as the radical initiator to generate substituted 1,3-oxazolidines 288a and 288b in good yields (Equation 21) .

Oxazoles

N

Ph

Ph

1 mol% Pd(dba)2 2 mol% DPPE

O

O

+

Ts

N

Ts

THF, rt, 2 h

284

283

285 Single regioisomer 97%, 2.7:1 (cis:trans)

Pd(0)

Pd(0) Ph

–O

Pd+

Ts + N – Pd

Ph

N Ts

O

Scheme 81

Ph

N

Ph +

Ph

OMe

O

0.5 mol% TBPA+•

O

O

N Ph

287

286

OMe

O

Ph +

DCM, rt

O

OMe

O

Ph

N Ph

Ph

Ph

288b

288a 65% 12:1 (288a:288b)

ð21Þ Dipolar cycloaddition methodology has also been utilized in a one-pot three-component system to generate oxazolidines 292 . Reactions between sulfonyl azides and vinyl ethers, for example 289, generated aziridine intermediates 290, which then reacted via ring-opened zwitterionic intermediate 291 with aldehydes to generate the oxazolidines in good yields (Scheme 82).

O

O S

CHO N3

+

R1SO2N

OEt DCM, 0 °C, 10 min

R1 R1 = IC2F4OC2F4

–N2 OEt

290

+

R1SO2N

OEt

289

R1SO2N

O

+

O OEt

292a

292b

Major 47%

Minor 15%

– NSO2R1

CHO

EtO

291

Scheme 82

1,3-Oxazolidines 295 and 297 were generated by intramolecular nucleophilic attack on ,-unsaturated ester 293 by an N-hydroperoxymethyl group or by conjugate addition of an N-hydroxymethyl group 296 (Scheme 83) . The former reaction proceeded via an epoxide intermediate 294 generated by initial attack of the peroxy group on the ,-unsaturated system.

533

534

Oxazoles

BOC N

K2CO3

BOC

MeOH at 1.0 M 65%

Bui

OOH

Bui

CO2Me

BOC N

OH O

293

O

N

CO2Me

Bui

CO2Me

HO

295

294 BOC N

K2CO3

OH

Bui

BOC

MeOH, rt 85%

CO2Me

N

O CO2Me

Bui

297

296

>10:1, trans:cis Scheme 83

1,3-Oxazolidines can also be formed via ring-opening reactions of azetidinium salts 298 with amines carried out in dichloromethane as the solvent . In this reaction sequence, the initially generated diamino alcohol afforded by the ring opening of the azetidinium species reacted with solvent in situ to generate the oxazolidine products in modest yields (Equation 22).

Pri

NH2

Pri

OH Bn

N+

Bn BF – 4

O

N Bn

ð22Þ DCM, rt, 2 d 53%

Bn

298

N Bn

299

4.04.11.4 Oxazolidinones A synthesis of 2-oxazolidinones has been reported by a base-mediated reaction between epichlorohydrin and primary amines. This reaction proceeded via an intermediate hydroxy-1,3-oxazinan-2-one 300, which rearranged to the more stable 2-oxazolidinone product under the reaction conditions (Scheme 84) .

O

Ph

NH2 5 equiv

HO

N

Bn

Cl K2CO3 (5 equiv) TEA, MeOH reflux

N Bn

HO O

O

300

O

O 81%

Scheme 84

Overman’s group has reported a highly enantioselective synthesis of N-tosyl-substituted 2-oxazolidinones from linear precursors. The reaction is catalyzed by a structurally unique Pd(II) catalyst COP-OAc 302. At room temperature and with 5 mol% of the catalyst, N-tosylcarbamate 301 cyclized to give 2-oxazolidinone 303 with high yield and ee (Equation 23) .

Oxazoles

NHTs

COP-OAc (5 mol%)

O

O O

OAc

O

NTs

CH2Cl2/CH3NO2 23 °C

301

ð23Þ

303 96%, 91% ee Me

O 2

O Pd N Co

Ph

Ph

Pri

O Ph Ph

COP-OAc

302 Tethered aminohydroxylation is a powerful strategy for the regioselective synthesis of syn-amino alcohols. This concept has been demonstrated by Donohoe’s group, who have found that N-sulfonyloxy carbamates such as the tethered O-mesityl hydroxylamine 304 brought about intermolecular aminohydroxylation. Using catalytic osmium, linear N-sulfonyloxy carbamate underwent aminohydroxylation with concurrent formation of a 2-oxazolidinone 305 (Equation 24). The N-sulfonyloxy group also served as a reoxidant for Os which allowed the process to be catalytic . H N

O

Pr

K2Os(OH)4O2 (4 mol%)

OH Pr

OSO2Mes

PrOH, H2O, rt

O

O

ð24Þ

HN

305

304

O

74%

4.04.11.5 Oxazolidinediones 2,5-Oxazolidinediones are generally readily prepared from amino acids and hydroxy-amides with a carbonate equivalent such as carbonyldiimidazole or diethyl carbonate itself. Isothiocyanates can also be used as starting materials for the synthesis of 2,5-oxazolidinediones (Equation 25) . O2N F3C

O2N

AgCO2CF3, Et3N CH3CN

Me F3C

NCS HO

O

O

OH O

O Me

S

N

F

ð25Þ

S

F

4,5-Oxazolidinediones have been prepared by one-pot condensation of benzyl cyanides, isocyanates, and 2-chloro2-oxoacetate as shown in Scheme 85. The anion derived from BuLi deprotonation of benzyl cyanide attacks the isocyanate to give intermediates 306, which can undergo condensation and cyclization with ethyl oxalyl chloride to give the 4,5-oxazolidinedione products .

535

536

Oxazoles

Ph

Cl

O

O

OEt

NC

CN

Ph

+ Ph

C

N

O

N O

O

NC

Ph

Ph Ph

O–

N–

30–65%, >10:1 E:Z

O

BuLi

Ph

NC

Ph

N–

O

EtO

O

306

O

Scheme 85

4.04.12 Important Compounds and Applications 4.04.12.1 Natural Products Naturally occurring oxazoles were considered rare until the late 1980s when a number of unprecedented oxazolecontaining natural products were isolated from marine organisms. Many of these natural products exhibit potent biological activities, and have been subjects of extensive biological and synthetic studies. Oxazole natural products are reviewed yearly in Natural Product Reports , and a review focusing on the total synthesis of oxazole natural products has also been published . Naturally occurring oxazoles are derived from enzymatic post-translational modifications of peptide-based precursors . The oxygen functionality on the side chain of N-acylated serines (R1 ¼ H) and threonines (R1 ¼ Me) 307 is capable of undergoing heterocyclization onto the preceding carbonyl group to create five-membered saturated heterocycles 308 (Scheme 86). Dehydration followed by two-electron oxidation results in aromatic oxazoles 309.

:B H O O

R1

R1 HO

R1

R1

O

O

O –2H +

R

N H

N O

307 R1 = Me or H

R

2e– N

N O

H

R

308 :B

O

O

R

309 H 2O

Scheme 86

Two examples of oxazole-containing cyclic peptides are YM-216391 and telomestatin (Figure 5). Both natural products are presumably biosynthesized via the pathway described above. YM-216391 is a cytotoxic agent isolated from Streptomyces nobilis , and comprises five consecutive azoles linked via a glycine–valine–isoleucine peptide linker. The structure and absolute stereochemistry were established through a concise total synthesis by Deeley and Pattenden . Telomestatin is a potent telomerase inhibitor isolated from Streptomyces anulatus which is showing promise in cancer chemotherapy . Although no total synthesis of

Oxazoles

telomestatin has yet been reported, an efficient polyoxazole synthesis methodology has been described by Vedejs which could be utilized for the construction of the natural product .

O O Me

NH

O

S N

Me O

Me

H

O

N

O

N

N

Me

NH N

Me

N

O

Me

O

N

N

N

O

N

O

NH

N S

N

N

O

O

O O

YM-216391

telomestatin

Figure 5

Other notable oxazole-containing natural products that have received intense scrutiny include macrolide phorboxazoles and cyclic peptide diazonamide (Figure 6). The structure of diazonamide has been revised from the original assignments as the result of an elegant total synthesis study .

46

MeO

OH

Pri

Br 13

O

Pri

41

N

19

O

11

Me MeO

HO

OH

O O

O

28

O 24

N

HO 32

O

O Me

H N

1

Me

phorboxazole A α -OH phorboxazole B β -OH

HN 1

O

O

N A

O 7

B O E

10

G

NH

26

Cl C NH

18 16

F O

Cl

N

29

D

11

(–)-diazonamide A (revised structure)

Figure 6

4.04.12.2 Medicinal Chemistry Oxazole and its derivatives have been incorporated into a number of medicinally relevant compounds, both as exploratory and advanced drug candidates. Oxazole-containing compounds have found use as tyrosine kinase inhibitors 310 , peroxisome proliferator-activated receptor (PPAR) agonists 311 , prostacyclin mimetics 312 , and COX-2 inhibitors 313 (Figure 7).

537

538

Oxazoles

O F3CO

O

N

Me

HO O

N O

O

O

Me

311

N N NH

310

O

N

N Me O NH2SO2

O O

_

O Na+

F

313

312 Figure 7

4.04.12.3 Polymers Polymers of oxazoles, 4,5-dihydrooxazoles, 2,3-dihydrooxazoles, oxazolidinones, and oxazolidines have been synthesized, studied, and used for some time. This area has been previously summarized in CHEC-II(1996).

4.04.12.4 Ligands for Asymmetric Synthesis Chiral oxazolines (4,5-dihydrooxazoles) occupy a significant place in the area of asymmetric catalysis. Oxazolines are easily synthesized from amino alcohols (Section 4.04.11.2.3), and since a plethora of chiral amino alcohols are readily available, many have been incorporated in the design of oxazoline-based chiral ligands for a variety of asymmetric catalytic reactions. Several of the common motifs are shown in Figure 8. The nitrogen of oxazoline is a good -donor for metal coordination, and the chiral environment is provided by the substituents on the C-4 and C-5 positions of the oxazoline ring. Usually the chiral oxazolines are linked through a rigid tether to form a C2-symmetric bis-oxazolines 314–318. Non-C2-symmetric ligands such as the chiral P,N-oxazolines 319 introduced by Pfaltz are also highly effective in asymmetric transformations. The first bis-oxazoline ligands 314 containing a pyridine backbone (py-box) were introduced by Nishiyama. They were first used in Ru-catalyzed hydrosilation of ketones , but have subsequently found wide application in asymmetric catalysis such as aldol reactions and cyclopropanation of olefins . Bis-oxazolines 315 with a methylene or gem-dimethyl methylene have been used for Diels–Alder and aldol reactions . Amino indanol-derived bis-oxazoline 316 has been used successfully in various asymmetric Michael additions . Dibenzofuran-based bis-oxazoline 317 was first reported by Kanemasa et al. and has been used in nitrone cycloadditions. Chiral binaphthyl-based bis-oxazoline ligands such as 318 contain an additional axial chirality which has been utilized in asymmetric Waker-type cyclizations . Mono-oxazoline ligands 319 have shown their versatility in various Pd-catalyzed reactions . 319 (R ¼ t-Bu) was used in the key Heck cyclization in a total synthesis of Strychnos alkaloid minfiensine .

Oxazoles

R2 R2 O

O

O

O

N N

Me Me O

O N

N

N

R

R

R

R

314

N

N

315

316

R = Ph, t-Bu R2 = H or Me

R = Ph, t-Bu

O N

O

O

O

R

N

O N

N

N

R

PPh2

R

O Ph

Ph

317

318

319

R = Ph, t-Bu

R = Ph, t-Bu

Figure 8

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540

Oxazoles

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Oxazoles

2002S1969 2002TL935 2002TL3985 2003AGE1411 2003AGE4961 2003BML4277 2003CRV3119 2003JA1474 2003JA13368 2003JA15796 2003JOC9899 2003OL89 2003SOS(11)383 2003TA917 2003TL2331 2004BML6113 2004CC2712 2004CHE(B)(60) 2004JA1944 2004JA12776 2004JAN32 2004JOC8810 2004OL597 2004OL3593 2004OL4391 2004S1359 2004SL1963 2004T7591 2004T8937 2004T11995 2004TL3797 2004TL6471 2005BML2253 2005CC797 2005EJO4304 2005JA0186 2005JME1610 2005JOC2859 2005JOC4211 2005JOC5737 2005JOC5840 2005JOC6137 2005OL3081 2005OL3351 2005OL4099 2005OL4145 2005OL4887 2005SL161 2005SL971 2005SL1433 2005SL1707 2005SL2072 2005SL2673 2005SL2747 2005T241 2005T1731 2005T6088 2005T8073 2005TL4077 2005TL5495 2005TL9001 2006AGE3839 2006JA925

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541

542

Oxazoles

2006JA2514 2006JOC1802 2006NPR464 2006TL3953 2006WO032520

T. J. Donohoe, M. J. Chughtai, D. J. Klauber, D. Griffin, and A. D. Campbell, J. Am. Chem. Soc., 2006, 128, 2514. G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71, 1802. Z. Jin, Nat. Prod. Rep., 2006, 23, 464. V. A. Nair, S. M. Mustafa, M. L. Mohler, J. T. Dalton, and D. D. Miller, Tetrahedron Lett., 2006, 47, 3953. T. Hofmeister, U. Reiff, T. Von Hirschheydt, and E. Voss, PCT Int. Appl. WO 06 032520 (2006) (Chem. Abstr., 2006, 144, 350689).

Oxazoles

Biographical Sketch

Vince S. C. Yeh received his B.S. degree (1994) from the University of British Columbia where he participated in undergraduate research under the late Professor L. Weiler. He completed Ph.D. (2001) from the University of Alberta under the guidance of Professor D. L. J. Clive, where he studied the asymmetric syntheses of alkaloids. After postdoctoral research (2003) with Professor B. M. Trost at Stanford University on asymmetric aldol catalysts, he joined Abbott Laboratories as a senior research chemist working in the area of metabolic diseases. His research interests include drug discovery, asymmetric synthesis, and natural products.

Rajesh Iyengar was born in Mumbai (Bombay), India. After receiving his B.Sc. and M.Sc. degrees in chemistry from the University of Bombay, he obtained his Ph.D. in 1998 with Professor Thomas Engler at the University of Kansas. He then undertook a postdoctoral position with Professor Jeffrey Aube´ at the University of Kansas, where he worked on and completed the total synthesis of an Aspidosperma alkaloid, (þ)-aspidospermidine. After a year as a postdoctoral researcher at the Chemical Process Development Group of Bristol-Myers Squibb in Syracuse, NY, he joined Abbott Laboratories in 2001. He is currently an associate research investigator in the metabolic disease area at Abbott Labs. His broad research interests include all facets of organic and medicinal chemistry, total synthesis of natural products, and drug design.

543

4.05 Isothiazoles F. Clerici, M. L. Gelmi, and S. Pellegrino Universita` di Milano, Milan, Italy ª 2008 Elsevier Ltd. All rights reserved. 4.05.1

Introduction

547

4.05.2

Theoretical Methods

547

4.05.2.1 4.05.2.2 4.05.3

Electronic Densities and Bond Orders

547

Energy Levels

550


4.05.3.1

551

Molecular Dimensions

4.05.3.1.1 4.05.3.1.2

4.05.3.2

551

X-Ray diffraction Other techniques

551 554

NMR Spectroscopy

554

4.05.3.2.1 4.05.3.2.2 4.05.3.2.3

Proton NMR spectra Carbon-13 NMR spectra NMR of other nuclei

555 557 557

4.05.3.3

Mass Spectrometry

558

4.05.3.4


561

4.05.3.5

IR and Raman Spectroscopy

561

4.05.3.6

Other Techniques

563

4.05.4


564

4.05.4.1

Melting and Boiling Points

564

4.05.4.2

Solution Properties

564

4.05.4.3

Aromaticity

565

4.05.4.4

Conformations

565

Tautomerism

565

4.05.4.5 4.05.5


567

4.05.5.1

General Survey of Reactivity

567

4.05.5.2


567

4.05.5.3


568

4.05.5.4


569

4.05.5.5

Electrophilic Attack at Sulfur

569

4.05.5.6


569

4.05.5.7

Nucleophilic Attack at Sulfur

573

4.05.5.8

Nucleophilic Attack at Hydrogen Attached to Carbon

574

4.05.5.9

Reactions with Radicals and Carbenes

574

4.05.5.10

Reduction and Electrochemistry

574

4.05.5.11

Cyclic Transition State Reactions with a Second Molecule

574

4.05.6


578

4.05.6.1

Compounds Not in Tautomeric Equilibrium with Aromatic Compounds

578

4.05.6.2

Compounds in Tautomeric Equilibrium with Aromatic Compounds

578

4.05.6.3

Dihydro Compounds

578

4.05.6.3.1

Structural types and general survey of reactivity

545

578

546

Isothiazoles

4.05.6.3.2 4.05.6.3.3 4.05.6.3.4

4.05.6.4

Tetrahydroisothiazoles

4.05.6.4.1 4.05.6.4.2 4.05.6.4.3 4.05.6.4.4

4.05.7

Thermal and photochemical reactions Aromatization Other reactions

578 580 580

582

Structural types and general survey of reactivity Reactions at the ring nitrogen Reaction at the ring sulfur Other reactions

582 583 583 583

Reactivity of Substituents Attached to Ring Carbon

584

4.05.7.1


584

4.05.7.2

Fused Benzene Rings

585

4.05.7.3

Carbon-Linked Substituents

585

4.05.7.4

Nitrogen-Linked Substituents

588

4.05.7.5

Oxygen-Linked Substituents

588

4.05.7.6

Sulfur Substituents

589

4.05.7.7

Halogen Substituents

589

4.05.7.8

Metal Substituents

590

Reaction of Substituents Involving Ring Transformation

590


591

4.05.7.9 4.05.8 4.05.8.1

Ring Nitrogen

591

4.05.8.2

Ring Sulfur

591

Reaction of Substituents Involving Ring Transformations

592

4.05.8.3 4.05.9

Ring Synthesis from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component

4.05.9.1


4.05.9.1.1 4.05.9.1.2 4.05.9.1.3

4.05.9.2


4.05.9.2.1 4.05.9.2.2

4.05.10

Formation of a nitrogen–sulfur bond Formation of a bond adjacent to a heteroatom Formation of a carbon–carbon bond From [4þ1] atom fragments From [3þ2] atom fragments


592 592 592 597 601

606 606 608

609

4.05.10.1

From Four-Membered Heterocycles

609

4.05.10.2

From Other Five-Membered Heterocycles

609

4.05.10.3

From Six-Membered Heterocycles

611

From Fused Heterocyclic Systems

611

4.05.10.4 4.05.11

Comparison of the Various Synthetic Routes Available

612

4.05.11.1

Isothiazol-3-ones

612

4.05.11.2

1,2-Benzisothiazol-3(2H)-ones

613

4.05.11.3

Substituted Isothiazoles and Fused Substituted Isothiazoles

613

4.05.11.4

Sulfonium Salts

613

4.05.11.5

g -Sultams

614

4.05.11.6

2,3-Dihydroisothiazole S,S-Dioxides

614

4.05.11.7

1,2-Benzisothiazole S,S-Dioxides

614

4.05.11.8

Sulfoximines

614

4.05.11.9 4.05.12

Sulfilimines Important Compounds and Applications

614 614

Isothiazoles

4.05.12.1

Chemical Applications

614

4.05.12.2

Industrial and Biological Applications

618

4.05.13

Further Developments

References

620 621

4.05.1 Introduction The importance of isothiazole and of compounds which contain the isothiazole nucleus appears to be growing over the years. New synthetic approaches and unprecedented reactions have been reported and numerous technical and pharmaceutical applications have been discovered. This chapter reports on the new theoretical and analytical aspects, reactivity, synthetic methods and uses, and biological applications of isothiazoles which have been developed in ten years (1996–2006). Occasionally, previous literature sources have been cited whenever judged useful to complete the former reports or to ensure a better understanding of the text. Arguments and information fully developed in CHEC(1984) and CHECII(1996) are not repeated and are simply referred to when necessary. Together with monocyclic compounds, benzisothiazoles (both 1,2 and 2,1) and some heterocondensed compounds have also been considered; fully or partially hydrogenated rings are also discussed. The basic structures of the compounds considered in this chapter are represented by formulas 1–7; structural types that are rare or unusual are not included in this general representation. However, as a general rule, condensed isothiazoles with polycyclic rings or with heterocyclic rings are covered. The patent literature has been considered and fully checked, but not systematically reviewed because it contains a great number of repetitions and matters of general chemical interest are rare. Of all classes of compounds 1, 3–6, and the S-oxidized and the S,S-dioxidized forms are important and widely represented. To avoid misunderstandings which can arise when the numbering of the ring does not indicate the sulfur atom with number 1, in this chapter, these compounds are always referred to as S-oxides and S,S-dioxides, Fully saturated isothiazole derivatives are referred to as isothiazolidines. In the case of S-oxides and S,S-dioxides, the common and widely used names, sultims and sultams, respectively, are used in many instances. The chemistry of isothiazoles has been reviewed in Advances in Heterocyclic Chemistry and a special review was dedicated to isothiazole S,S-dioxides, with particular stress on benzisothiazole S,S-dioxides .

4.05.2 Theoretical Methods 4.05.2.1 Electronic Densities and Bond Orders Earlier calculations of electron densities of isothiazole are reported in CHEC(1984) . Previously calculated net charge densities for isothiazole, its 1-oxide, and its 1,1-dioxide and bond lengths of isothiazole and its 1-oxide are reported in CHEC-II(1996) . Geometries and dipole moments of four isothiazolo[5,4-b]pyridin-3(2H)-ones (sulfide S(II), sulfoxide S(IV), and sulfone S(VI)) were calculated at the semi-empirical (modified neglect of diatomic overlap (MNDO), AM1, PM3, SAM1) and ab initio (Hartree–Fock (HF) and MP2/631G* ) levels of theory. By comparison of the calculated properties with experimental results, MNDO and HF/6-31G* are the best semi-empirical and ab initio methods for S(II) and S(IV) derivatives, while PM3 and MP2/6-31G* are the best semi-empirical and ab initio methods for S(VI). The authors, however, ascribe the good performance of PM3 to an artifact

547

548

Isothiazoles

in the method. The use of AM1 geometries for ab initio single-point calculations also provides reasonable results . Ab initio calculations were performed to calculate the atomic charges and dipole moments of isothiazole and isothiazole 1,1-dioxide at the MP2/6-31G* //HF/6-31G* level; charges were computed by using the Mulliken, natural population analysis (NPA), and CHELPG methods . MM3 force field parameters for sulfurand sulfur–nitrogen-containing heterocycles were developed, thus allowing quite reliable computations of several properties of isothiazoles even at the molecular mechanics (MM) level . Dipole moments of isothiazoles are predicted with good agreement with respect to the experimental data (2.46 D) using MM3 force field and MP2 and MP4 calculations . Geometrical parameters for isothiazole supplied by MP2/6-31G* , B3LYP/6-31G* , and MM3 calculations are reported in Table 1. ˚ and angles (deg) for isothiazole computed at different levels of theory Table 1 Selected distances (A) Method

S(1)–N(2)

N(2)–C(3)

C(3)–C(4)

C(4)–C(5)

C(5)–S(1)

C(5)–S(1)–N(2)

MP2/6-31G* B3LYP/6-31G* MM3

1.665 6 1.680 9 1.651

1.337 8 1.317 4 1.316

1.413 3 1.426 8 1.437

1.379 6 1.369 4 1.378

1.704 4 1.723 3 1.707

96.64 94.93 95.4

The geometries of protonated and deprotonated forms and gas-phase acidities of some biologically active sulfonamides were computed at the CBS-QB3, B3LYP/6-311þG(d,p), and ONIOM(B3LYP/6311þG(d,p):MNDO) levels of theory. Of the NH acids studied, saccharin was characterized by the highest gasphase acidity (1324 kJ mol1) . The twinning phenomenon observed for saccharin as a crystal was explained by a combination of theoretical calculations (MM and AM1) and experimental crystallography, which demonstrated the existence of an additional interfacial hydrogen bond which is a likely driving force for the twinning process, explaining why saccharin twins so readily . Energy and thermochemical parameters of saccharin were calculated at the B3LYP/cc-PVTZ//B3LYP/6-311** and B3LYP/cc-PVQZ//B3LYP/6-311** levels and the theoretical enthalpy of combustion was also reported (3648.5 1.5) . Geometries, charges, and dipole moments of 5-substituted isothiazol-3-ols and S-substituted isothiazol-3-ones were calculated at the HF/631G* and MP2/6-311G** and B3LYP/6-31G* levels . Electronic dipole moments, polarizabilities, polarizability anisotropies, and first- and second-order hyperpolarizabilities of isothiazole were computed at the ab initio, density functional theory (DFT), and semi-empirical (modified symmetrically orthogonalized intermediate neglect of differential overlap, MSINDO), levels . Bond orders (BOs) of several heterocycles were calculated from HF- and MP2-optimized geometries (MP2/6-31G** in the case of thiazoles). Isothiazole BOs were: S(1)–N(2) 1.06; N(2)–C(3) 1.44; C(3)–C(4) 1.24; C(4)–C(5) 1.46. In analogy with imidazoles, pyrazoles, pyrroles, and oxazoles, it can be stated that isothiazoles present one pair of BOs close to unity (1–2 and 5–1 bonds), one intermediate BO (3–4 bond), and the remaining two bonds close to 1.5 . BO calculations were also used to assess aromaticity and are thoroughly discussed in Section 4.05.4.3. Structural and spectral (infrared, IR) changes occurring on conversion of saccharin and thiosaccharin into their anions were studied by experimental IR and theoretical calculations within both the HF and DFT theories . Vibrational studies on ammonium and solid metal saccharinates were performed by combining experimental Fourier transform infrared (FTIR) measurements with theoretical ab initio calculations at the HF/6-31þþG(d,p) and HF/6-31G levels . A rigorous theoretical study of the structure and harmonic frequencies of isothiazole was performed at the MP2, MP4, and CCSD(T) levels using TZVP, QZVP, and cc-pVTZ basis set . Results were compared to experiments and the authors reported that MP2/cc-pVTZ calculations provided the best numerical agreement of the frequencies and relative intensities for isothiazole. Theoretical nuclear magnetic resonance (NMR) and IR calculations were performed for the structural validation of the camphor-condensed isothiazole derivative methanoazuleno[4,5-c]isothiazol-7-one 2,2dioxide (see Section 4.05.7.3, compound 294) . The absolute configuration of the sulfur atom in 3-aminosubstituted isothiazole S-oxides (see Section 4.05.5.5, compound 70), obtained by enantioselective S-oxidation with (þ)- or ()-((8,8-dichlorocamphoryl)sulfonyl)oxaziridine, was assigned on the basis of time-dependent DFT (TDDFT)/B3LYP/aug-cc-pVDZ calculations of the isothiazole S-oxide optical rotatory power []D. The solvent effect was taken into account by the IEF-PCM (polorizable continuum model in its integral equation formulation) for EtOH, MeOH, and CHCl3 and the resulting []D values compared to the experimental. A further confirmation was obtained by a theoretical calculation of the electronic circular dichroism (ECD) spectrum and comparison with the experimental ECD curve. The mechanism of oxidation was also discussed (see Section 4.05.2.2) .

Isothiazoles

QSAR studies. Computer models were investigated in order to study the mechanism and selectivity for human leukocyte elastase (HLE) and PPEase (PPE, porcine pancreatic elastase) inhibition by isothiazolone derivatives. Substitution at the 4-position provides selectivity for HLE. The proposed inhibition mechanism occurs with isothiazolone ring opening (hydrolysis) by Ser-195 . A reaction model for the mechanism of action of -lactams 8 was obtained by ab initio calculations, showing a correlation between the -lactam lowest unoccupied molecular orbital (LUMO) and its activity. Several unconventional -lactams were then compared and the lowest LUMO (higher predicted activity) was obtained for the N–S-fused lactam . Homolytic bond dissociation energies (BDEs) were computed using composite ab initio methods. The authors suggested G3B3 as the most reliable for C–H and N–H BDE. A linear correlation between C–H BDE and bond angle and spin on the Catom involved was found and a quantitative structure–activity relationship (QSAR) model is proposed . BDE values obtained for isothiazole are reported in Table 2.

Table 2 Bond-dissociation energies (kcal mol1) for isothiazole at different theoretical levels Structure

Bond

CBS-Q

G3

G3B3

B3LYP

C(3)–H C(4)–H C(5)–H

112.6 119.1 119.6

112.5 118.9 119.4

111.0 117.3 117.6

108.3 114.6 115.6

A pharmacophore model was derived and used to synthesize new 5-HT7R antagonists. Within those compounds, several isothiazole S,S-dioxides were shown to be active with pKi values between 6 and 7 . Several properties (EFMO, atomic charge and electron density on S-atom, C–S–N angle, dipole moment, molecular volume, molecular weight, solvation energy terms) of some substituted 3-isothiazolones were computed at the MNDO semiempirical level and compared to biological activities with the purpose of deriving a QSAR model. The authors concluded that neither geometries or electronic properties, nor frontier molecular orbital (FMO) energies appear to correlate with the measured biological activity of the isothiazolones considered. On the other hand, a satisfactory relationship was found between the activity and the calculated solvation energy, suggesting that diffusion plays an important role in the mechanism of action . The binding mode of several aza-TSAO derivatives 9 (R1 ¼ H, Me, Et, t-butyloxycarbonyl (BOC); R2 ¼ H, Me; TSAO ¼ [29,59-bis-O-(tert-butyldimethylsilyl)-B-D-ribofuranose]-39-spiro-50-(40-amino-10,20-oxathiole 20,20-dioxide)), which show human immunodeficiency virus reverse transcriptase (HIV RT) inhibitory activity, were investigated by a thorough conformational search at the MM, HF, and DFT levels .

Finally, 116 pesticides (including several isothiazole derivatives) were computationally evaluated in order to derive a QSAR model for avian oral toxicity .

549

550

Isothiazoles

4.05.2.2 Energy Levels Previously calculated electron energy levels of isothiazole are reported in CHEC-II(1996) . Energies of isothiazolo[3,4-c][1,2,3]oxadiazoles 10 (n ¼ 1, m ¼ 0; n ¼ 0, m ¼ 1) were calculated at the B3LYP/6-31G* level and compared to those obtained for the corresponding dinitroso valence tautomers. The energy difference between the most stable furoxan (1-oxide derivative) and the most stable dinitroso valence tautomer was calculated to be þ1.4 kcal mol1 .

Reference orbitals for localized frontier orbitals (LFOs) of some heterocycles were determined by the variational method. A good correlation was found between LFO energy of sp2-type nitrogen in heterocyclic bases and the acidities of conjugate cations. For isothiazole (pKa ¼ 0.51), the LFO value was determined to be 13.818 eV at the HF/6-31G* level . The molecular orbital (MO) energies and atomic coefficients of FMOs of 1-methylisothiazol-3-one and 1-p-tolylisothiazol-3-one were calculated using B3LYP/6-31G(d) optimization. Theoretical calculations showed that the sulfilimines investigated are electron-poor dienophiles that undergo normal electron demand [4þ2] cycloaddition reactions (see Section 4.05.5.11, compounds 164 and 173) and that their LUMOs are almost unpolarized . Electron transmission spectroscopy (ETS) and theoretical (MP2 and B3LYP/6-31G* ) calculations showed that the empty p* -MO of isothiazole is stabilized if compared to thiophene; thus the reactivity of the former heterocycle is predicted to be higher or lower when it acts as electron acceptor or electron donor, respectively. Interestingly, the ET spectrum of isothiazole also displays an additional resonance, ascribed to electron capture into a * -MO with an energy (1.6 eV) intermediate between the two p* -resonances . Theoretical calculations were also performed for assessing solubility as well as to evaluate the relative stability of different tautomers and are discussed in Sections 4.05.4.2 and 4.05.4.5, respectively. Reactivity and reaction models. In the last decade, one of the main innovations in the use of theoretical calculations concerns the investigation of reaction mechanisms. The cyclization mechanism of 2,3-bis(phenylethynyl)-camphorsultam derivatives (see Section 4.05.7.3, compound 288) was investigated by PM3 calculations providing support to experimental NMR measurements . Transition structures for the thermal decomposition of 5azidoisothiazole 11 to 11a were calculated at the MP2/6-31G** level.

The reaction is a concerted but asynchronous process between N2 departure and ring opening on the So surface of the azide. In fact, in the transition structure, the ring remains almost intact . The reactivities of isoxazole, isothiazole, and pyrazole as dienes in Diels–Alder cycloadditions were evaluated qualitatively by AM1 and B3LYP/6-31G* calculations. The reaction is determined to be LUMO heterocycle controlled; however, the classical approach to evaluate reactivity through the FMO gap between reactants provides unreliable results due to the aromaticity of such heterocycles. A better qualitative description is obtained by evaluating the sum of BO deviation within the heterocycles, together with the BO and FMO changes for the transformation of reactants into transition states. Results suggest that these heterocycles could not react as dienes in Diels–Alder cycloadditions, as also confirmed by computed activation barriers (40 kcal mol1, compared to 18.4 kcal mol1 of the experimentally feasible cycloaddition of cyclopropene to furan) . A reaction model for the Diels–Alder cycloaddition between a furan derivative and an isothiazolone 1,1-dioxide (see Section 4.05.5.11, compound 180) was obtained by modeling the reaction transition states at the MP2/6-31G* level. The model explains the experimentally observed regioselectivity . Semi-empirical calculations were conducted to model transition states of the Diels– Alder dimerization of 4-vinylisothiazoline 1-oxides, obtained directly from the addition of vinyltributyltin to the corresponding 4-Br derivative (see Section 4.05.7.3, compound 263), thus explaining the observed diastereoselectivity . PM3 semi-empirical calculations were carried out to cast light on the mechanism of

Isothiazoles

[1,3]-sigmatropic rearrangements causing the O- to N-migration of the allyl group in the pseudosaccharyl ether 12 of naturally occurring myrtenol to give 13 (see Section 4.05.7.5) .

The reactivity of cyclic vinyl sulfilimines in Diels–Alder reactions toward cyclopentadiene and furan was studied at the B3LYP/6-31G* and B3LYP/6-31G* //AM1 levels. The reactions prove to be highest occupied molecular orbital (HOMO) controlled and proceed with high synchronicity. Inclusion of BF3 decreases the activation energies and augments the charge transfer from the diene to the dienophile. The cycloaddition to cyclopentadiene occurs with endo-selectivity, while with furan an inversion from endo to exo can be observed in the gas phase and solvent, respectively (see Section 4.05.5.11, compound 172) . AM1 and ab initio (HF/6-31þþG** ) calculations are performed in order to explain the selectivity of the dehydrohalogenation process of 4,5-halo-3-alkylamino4,5-dihydroisothiazole 1,1-dioxides (see Section 4.05.9.1.1), which affords the 4- and not the 5-halo derivatives . The reaction mechanism (Equation 1) for the nucleophilic reaction between methylthiolate and 4-bromoisothiazole 14 was investigated by HF, MP2, and DFT (B3LYP) calculations using the 6-31þþG** basis set and including the solvent effect by means of single-point PCM and isodensity surface polarized continuum model (IPCM) solvation models. The proposed mechanism consists of a two-step process with a first transition state TS1 leading to the -intermediate I which evolves to product 15 via a [1,5]-sigmatropic hydrogen shift through the transition state TS2 .

ð1Þ A reaction model for the S-oxidation of 3-amino-substituted isothiazoles with (þ)- or ()-((8,8-dichlorocamphoryl)sulfonyl)oxaziridines (see Section 4.05.55, compound 70) was obtained by B3LYP/6-31G(d,p),S(3df) calculations. Transition states’ relative energies are in concordance with the experimental reaction outcome and the analysis of the geometrical parameters allows a description of the reasons governing the observed enantioselectivity .

4.05.3 Experimental Structural Methods 4.05.3.1 Molecular Dimensions 4.05.3.1.1

X-Ray diffraction

A large number of structures of isothiazole derivatives have been determined by X-ray analysis over the years. Bond distances and angles for isothiazoles, 1,2-benzisothiazoles, 2,1-benzisothiazoles, saccharin, and derivatives are reported in CHEC(1984) and CHEC-II(1996) . The important and continuing work in recent years for this class of compounds has produced many publications. The use of X-ray structure determination to aid understanding of reaction mechanisms, by considering bond lengths and angles in relation to chemical reactivity, has been used in both theoretical and experimental contexts. The complete crystal structure analysis of several compounds has been performed because it was expected to yield information concerning the conformation, mutual orientation, and the effects of substituents on receptor affinities. In the decade 1995–2005, due to the growing interest in polycyclic sultams in various asymmetric methodologies and syntheses, X-ray analyses of a number of these compounds were performed.

551

552

Isothiazoles

The norbornane ring system in 16 (X ¼ H) is regular with normal bond lengths and angles comparable to those in related molecules . The bridgehead bond angle is 92.5(2) , typical of norbornane derivatives. The five-membered ring of the sulfonylimine moiety adopts a flattened envelope conformation. The sixmembered ring of the norbornane ring system has a fairly symmetrical boat conformation, with atoms C-3 and C-7 ˚ respectively, from the best plane through atoms C-1, C-2, C-5, and C-6. The displaced by 0.852(3) and 0.845(2) A, two five-membered rings formed by the bridging atom C-4 (C(1)–C(2)–C(3)–C(4)–C(7) and C(3)–C(5)–C(6)–C(7)–C(4)) adopt envelope conformations corresponding to 0.007(2) and 0.015(2), respectively . The angles between the plane of the three-atom bridge C(3)–C(4)–C(7) and each of the four-atom planes of the boat-shaped sixmembered rings (C-1, C-2, C-3, C-7 and C-3, C-5, C-6, C-7) are 56.0(2) and 125.8(2) , respectively. In compound 17, an intermolecular H-bond between the NH and the pseudoequatorial S¼O(2) moiety of a neighboring molecule is evident in contrast to 18a in which a H-bond with the corresponding pseudoaxial S¼O(1) moiety is preferred. The N-atom of 17, and 18b is more pyramidalized than that of 18a (Tables 3 and 4) . The sense of N-pyramidalization has been analyzed for several saccharin-derived sultams and in other compounds .

˚ Table 3 Selected bond lengths (A) Bond

17

18a

18c

18d

S¼O(1) S¼O(2) S–N S–C(8) N–C(1)

1.428 7(15) 1.433 2(13) 1.654 1(14) 1.788 3(19) 1.484(2)

1.426 7(17) 1.429 2(17) 1.641 8(19) 1.799(2) 1.478(3)

1.446 0(16) 1.426 7(17) 1.622 8(18) 1.786 3(199) 1.482(3)

1.436(3) 1.421(2) 1.646(2) 1.770(4) 1.463(4)

Table 4 Selected angles (deg) Angle

17

18a

18b

18c

18d

O(1)¼S¼O(2) C(1)–N–S C(1)–N–R S–N–R

117.79(8) 104.22(10) 115.5(12) 102.2(13)

117.84(11) 104.94(14) 115.7(19) 110.7(19)

109.2(2) 111.6(3) 106.2(2)

115.14(10) 111.91(13) 118.1(19) 108.5(19)

115.84(18) 107.80(19) 116.1(3) 114.7(3)

As an example, a greater N-pyramidalization was observed in compounds 19a and 19b compared to 19c in which the sum of bond angles around nitrogen atom implied an almost planar configuration . X-Ray analyses of many compounds containing the sultam moiety have been performed aiming to ascertain their structure or to aid understanding of their reactions, for example 20 characterized by the S¼O group .

Isothiazoles

The crystal structure of saccharin was published independently by Bart and Okaya . The structure of saccharin features the usual dimeric pattern of solid cyclic imides, with a pair of strong NH OCO hydrogen bonds within the centrosymmetric dimers. Saccharin and its salts and metal complexes have been studied extensively, and synthetic work developed in recent years with metal saccharinates has shown that most can be useful starting materials for the preparation of other complexes and also for the development of interesting new materials. Although no metal complexes of neutral saccharin are known, the corresponding deprotonated saccharin anion acts as a polyfunctional ligand due to the presence of the negatively charged imino nitrogen, carbonyl oxygen, and sulfonyl oxygen atoms. The most common coordination mode of saccharin is ligation through the nitrogen atom, usually observed in the aquabis(saccharinato) complexes of divalent transition metals; coordination via the carbonyl or sulfonyl oxygen is less common . Metal–oxygen coordination is observed in the case of alkali, alkaline earth, and inner transition metals. Furthermore, saccharin can also act as a bidentate or bridging ligand through the N- and O-atoms . A plethora of diffraction structural studies have been devoted to saccharinates. A great number of metal complexes of saccharin have been characterized between 1995 and 2005 and the structural data have been reviewed . The average C–O bond length of saccharinates is notably shorter than the average value between standard double and single C–O bonds, while the average C–N bond length is very close to the average between a C¼Nþ bond and a C–N single bond. As the charge distribution within the saccharinato system (and especially the C(O)NSO2 fragment) influences its geometry and strongly depends on the coordination mode, it is clear that the type of bonding of the deprotonated saccharin should be reflected in its geometry. On going from covalent to ionic saccharinates, the C–N bond shortens while the carbonyl group tends to be lengthened. The values of the C–O distances in the ionic ˚ while the C–N distances are roughly within the saccharinates are in the 1.22–1.26 A˚ range, usually about 1.24 A, ˚ 1.34–1.36 A range. The covalent saccharinates on the other hand show much wider ranges for the C–O and C–N bond lengths. The S–N bonds in covalent saccharinates are usually longer than those in the ionic saccharinates; no saccharinate ions with S–N bonds shorter than 1.59 A˚ or saccharinate ligands with an S–N bond longer than 1.67 A˚ have been found. On going from covalent to ionic saccharinates, the S–O distances are on average larger and the O–S–O angle differs from normal while the C–S–N angle is simultaneously widened . Theoretical calculations are in substantial agreement with experimental data (see Section 4.05.2.1). The first tris(saccharinato) complexes containing copper(II) and zinc(II) are isomorphous with the triclinic space group P-1; the first complex consists of a 2-aminopyridinium (ApyH) cation and a [Cu(sac)3(H2O)2] anion in which the copper(II) ion has trigonal bipyramidal surroundings. The saccharinate ligands exhibit unusual and nonequivalent coordination, behaving as ambidentate ligands: one of them coordinates the metal through the carbonyl oxygen atom, while the other two saccharinate ligands are bonded to the metal via the imino nitrogen atom. The zinc(II) ion in the second complex is tetrahedrally coordinated by three N-donor saccharinate ligands and an aqua ligand. The crystal structure of both complexes are stabilized by intermolecular hydrogen bonds and aromatic p–p-stacking interactions . X-Ray crystallographic analyses have also been performed to study the molecule association in 2,3-dihydro-2-alkyl3-hydroxybenzisothiazole 1,1-dioxides 21 and show that they form hydrogen-bonded dimers in the solid state through S¼O H–O interactions. These dimers comprise bicyclic arrays of 12/14 atoms .

The changes in bond lengths and angles for a series of compounds have been successfully used to explain chemical reactivity by relating ground-state structure as observed by X-ray analysis to supposed transition state structures. Comparison between aryl ethers and pseudosaccharinyl ethers or amines of types 22 and 23 (R1 ¼ H, R2 ¼ Ar; R1 ¼ Alk, R2 ¼ Ar; R1 ¼ H, R2 ¼ Ar) has been performed. In compound 22, the C–O–C unit has been shown to be quite exceptional among aromatic ethers in having one very long C–O bond (a) and one very short C–O bond (b). Effective change in electronegativity has also been confirmed by spectroscopic evidence (see Section 4.05.3.2.1). Also, the marked difference in resistance to hydrogenolytic cleavage of the C–O bond in aromatic or heterocyclic ethers or of the C–N bond in aromatic amines was related to major changes of bond lengths in the case of compounds 22 and 23 (R1 ¼ H, R2 ¼ Ar; R1 ¼ Alk, R2 ¼ Ar; R1 ¼ H, R2 ¼ Ar) .

553

554

Isothiazoles

X-Ray diffraction techniques have been used to support proposed structures for compounds 24–26. The fivemembered 2,3-dihydroisothiazole ring is practically planar. These compounds exhibit a trigonal bipyramidal configuration about the central sulfur atom, with nitrogen and chlorine in 24 or nitrogen and oxygen atoms in 26 in axial positions. In sulfonium perchlorates 25 (Ar ¼ Ph), the axial N–S–O(perchlorate) sequence is far from being linear. The S–N distance in 24 (Ar ¼ Ph) corresponds to a strong S–N covalent bond. The N–S–Cl axial unit in 24 is nonsymmetric and the bond length suggests that S–Cl is strongly polarized .

Bond lengths and angles in the isothiazolopyridine nucleus 27 do not differ significantly from those reported for 1,2-benzisothiazolin-3-one and 7-chloro-1,2-benzisothiazolin-3-one. Spectral analysis of compound 27 suggested the possibility of the occurrence of its tautomeric form 27b, but 27a is the predominant tautomer in solution (Equation 2) . X-Ray analysis has been performed on this compound and the difference electron density map revealed the position of the H-atom as being in the vicinity of the N-atom. Additionally the C–O (b) bond length of 1.249 A˚ is typical for the bond length in a carbonyl group. These two facts indicate explicitly that only tautomeric form 27a exists in the crystalline state. Bond lengths and angles in 27a differ significantly from those observed on derivatives substituted at the nitrogen atom, especially the C–O (b) and N–C (a) distances. The unsubstituted NH isothiazolopyridine ring shows a shorter N–C distance and longer C–O distance, while the N-carbon-substituted derivatives have longer C–N and shorter C–O distances, respectively. This effect is connected with the stronger conjugation between the carbonyl p-system and the lone pair at N for the unsubstituted compounds.

ð2Þ

4.05.3.1.2

Other techniques

Different techniques have been used to determine the molecular geometry of isothiazole derivatives and saccharin salts, such as neutron diffraction, gas-phase electronic diffraction, and microwave spectroscopy, and these were reported in CHEC(1984) and CHEC-II(1996) . Electron paramagnetic resonance (EPR) offers the possibility of measuring accurately and selectively noncovalent intermolecular forces, whose magnitude can give information about the characteristics and character of the bonds. The EPR technique has been used to analyze copper saccharinate and a Cu2þ-doped zinc saccharin complex .


H, 13C, 14N, and 15N NMR chemical shifts and coupling constants for a wide range of isothiazole derivatives, such as 1,2-benzisothiazoles, 1,2-benzisothiazole 1,1-dioxides, and reduced isothiazole 1-oxides and 1,1-dioxides and saccharinrelated compounds are reported in CHEC(1984) and CHEC-II(1996) .

Isothiazoles

In the last decade, the use of different multidimensional sequences of NMR experiments to characterize the detailed structure has become particularly relevant . Recently, theoretical calculations have been used to predict NMR spectra in order to facilitate mechanistic consideration of reaction mechanisms (see Section 4.05.2.1).

4.05.3.2.1

Proton NMR spectra

In order to better explain the spectroscopic features of specific compounds, structural characterization using different 1 H NMR experiments has been performed and there are a vast number of examples in the literature. In particular, 1H NMR can give useful information about tautomerism and conformation (see Sections 4.05.4.4 and 4.05.4.5). The 1H NMR spectrum of triazene 28 shows H-4 and H-7 signals at lower fields, due to the presence of the nitro group in the vicinity, and characterized by a typical splitting pattern: H-4 is split into a doublet with 4J 2 Hz, H-7 into a doublet with 3J 10 Hz, and H-6 into a doublet of doublets with J 2, 10 Hz .

The complete identification of the stereochemistry at the C-6 center of both isomers 29 and 30 could be achieved using nuclear Overhauser effect (NOE) experiments, since each isomer appears to exist mainly in one major conformation in solution. The two substituents on the ring have a trans-relationship in both compounds, and in compound 30 a NOE effect between the Ha, H-3, and H-4 protons, suggesting that a 6S-configuration is not apparent for compound 29, which has the 6R-configuration .

NOE experiments and X-ray analyses have been used to establish the stereochemistry of bicyclic sultams (see Section 4.05.10.1). Both the 1H chemical shifts and NOE data suggest that chloro-4-sulfanes and sulfonium salts 24 and 25 having an o-MeO, o-Cl, or o-Me substituent on the aryl ring assume a skew conformation, whereas the aryl ring in compounds without an ortho-substituent can rotate practically freely about the S–C(19) axis. 1H and 15N NMR examinations of diaryl(acylamino)(chloro)-4-sulfanes 24a–e showed that they exist only in CDCl3 and dimethyl sulfoxide-d6 (DMSO-d6) solvents (Equation 3), whereas in MeOD complete ionic dissociation takes place, leading to the sulfonium chloride (see Table 5) .

ð3Þ

555

556

Isothiazoles

Table 5 Solvent effect on 1H NMR chemical shift of compounds 24 and 25 H(7)

H(69)

Compd.

R1

R2

CDCl3

DMSO-d6

24a 25a 24b 25b 24c 25c 24d 25d 24e 25e

H H MeO MeO Me Me Cl Cl NO2 NO2

H H H H H H H H H H

9.66

9.07

MeOD

CDCl3

DMSO-d6

7.77

7.75

8.50 9.56

8.87

9.71

9.13

9.68

9.21

7.12

7.39

6.39

6.63

6.47

6.70

DMSO-d6

125.0

125.1

121.0

118.8

130.0

126.4

127.8

125.7

104.5 110.2

7.12 6.69

MeOD

109.9

7.04

8.54 8.31

CDCl3

7.55

8.51

8.64

N

7.82

8.35

9.63

MeOD

15

110.2 128.8

7.44

7.80

114.3

101.2

For compounds 31 (R ¼ H, Me), different conformers can be detected by performing 1H NMR experiments. The stability of such conformers can be ascribed to an intramolecular H-bonding interaction between the endocyclic nitrogen and the NH group of the side-chain favored by the formation of a six-membered ring .

1

H NMR spectroscopy has revealed that in the Rh(II)-catalyzed decomposition of diazodiketones in the presence of different sultams, only O-alkylamidates 32 are obtained (see Section 4.05.5.9). The chemical shift for the methine group (OCH), both in 1H and in 13C NMR spectra, is diagnostic .

1

H and 13C NMR spectroscopy has been used to estimate electronegativity of oxygen and nitrogen atoms in substituted benzisothiazole derivatives. The normal electron-donating effect of oxygen in phenols or simple phenolic ethers is changed into a strongly withdrawing effect in heterocyclic ethers 22 (R ¼ Ar) . In the 4-methoxyaniline derivatives 23 (R1 ¼ Ar, R2 ¼ H) and 33 (R ¼ 4-OMe), the protons ortho to the nitrogen are strongly downfield-shifted compared with the corresponding protons in 4-methoxyaniline. This observation indicates an abrupt change in effective electronegativity of the amino nitrogen. Nevertheless, the presence of the second substituent on the amino nitrogen atom in 33 does not increase the electronegativity with respect to 23 .

Isothiazoles

N-Methyl pyrroloisothiazolones 34 (R1 ¼ CO2Me, NO2; R2 ¼ H, Me) show downfield 1H NMR chemical shifts with respect to N-methylated open-chain or cyclic sulfenamides (see Sections 4.05.6.3.4 and 4.05.9.1.1). This behavior can be attributed to a strong deshielding effect caused by a partial positive charge on the N-atom, as depicted in the zwitterionic resonance structure 34a (Equation 4) .

ð4Þ

1

H NMR spectroscopy combined with different techniques (see Section 4.05.3.6) has been used to perform the dynamic characterization of fananserin 35, an anxiolytic drug which can be crystallized as four different polymorphs. The dynamics were monitored by measuring the spin-lattice relaxation and line-shape evolution temperature dependence .

4.05.3.2.2

Carbon-13 NMR spectra

13

C NMR experiments are now routine for the characterization of chemical compounds and there is a vast amount of literature reporting 13C NMR data. 13C NMR combined with 1H NMR spectroscopy has been employed to estimate tautomerism (see Section 4.05.4.5) and electronegativity of oxygen and nitrogen atoms in substituted benzisothiazole derivatives (see Section 4.05.3.2.1). 13 C NMR spectra of organotin derivatives 36–38 and their autoassociated complexes (see Section 4.05.3.2.3) have been recorded and chemical shift shown to be diagnostic of coordination between the tin atom and oxygen of a carbonyl group of adjacent molecules .

4.05.3.2.3

NMR of other nuclei

For high-precision 14N NMR, solvent polarity and hydrogen-bonding effects have been investigated for isothiazoles. An increase in the polarity of the solvent favors the delocalization of the lone pair electrons from the sulfur atoms in the conjugated ring, leading to an increase in electronic charge at the nitrogen atom (Table 6) .

557

558

Isothiazoles

Table 6 Solvent effect on Cyclohexane CCl4 þ77.92

14

Et2O

N NMR chemical shift of isothiazole Benzene Dioxane DMSO Acetone CH2Cl2 CHCl3 EtOH

þ79.62 þ80.02 þ80.63

þ80.97

þ82.01 þ82.11

þ83.98

MeOH H2O

TFE

þ85.27 þ88.02 þ89.87 þ95.84 þ102.62

15

N NMR can be used for the characterization of axial hypervalent S–Cl bond and S O close contact in chloro-4sulfanes and sulfonium salts 24–26 with ortho-substitution in the aromatic ring. The solvent effect has also been investigated: CDCl3 is the most favorable for stabilizing the hypervalent S–Cl bond (see Table 5) . As a nucleus, 33S is far from ideal for NMR observation; thus a high-power and high-field NMR spectrometer is necessary for its study in solution. Isothiazole absorbs at þ53.7 ppm and 3-methylisothiazole at þ51 ppm, while a considerable difference in chemical shift is seen for the 2-methylthiazole isomer (72 ppm) . The 119Sn NMR spectra of compounds 36–38 have been studied. 119Sn NMR chemical shifts are affected by a number of parameters, such as the coordination number of tin and the electronegativity of the groups attached to it. Triorganotin compounds containing electronegative substituents have a strong tendency to autoassociate in the solid state and in concentrated solution. The resulting equilibrium between differently coordinated species makes it possible only to determine an average value for 119Sn chemical shifts. For compounds 36 and 37, values were between 90.0 and 107.0 ppm. Replacement of the phenyl groups by n-butyl substituents in compound 38 causes a downfield shift to 100.6 ppm. 119Sn–13C coupling constants increase distinctly with coordination number .

4.05.3.3 Mass Spectrometry Mass spectrometry (MS) and tandem mass spectrometry (MS/MS) play an important role in the identification of unknown compounds. Different ionization techniques have been used in studying isothiazole derivatives, such as electronic ionization (EI), desorption chemical ionization (DCI), fast atom bombardment (FAB), field desorption (FD), and chemical ionization (CI). Different MS/MS experiments have been described, such as investigation of metastable and collision-induced dissociations to study isothiazoles’ gas-phase ion chemistry. In addition, MS and MS/MS have been used to differentiate isothiazole isomers differing in the position of endocyclic groups or exocyclic substituents . Fragmentations of aromatic isothiazoles and benzisothiazoles are characterized by strong molecular ions and typical pathways are given in CHEC(1984) . Two important primary fragmentation processes are the losses of HCN and CS, both also yielded by metastable decompositions. Some MS data have been published for isothiazolopyridine derivatives. The four 3-methylisothiazolopyridine isomers (39a–d) were characterized and differentiated in the gas phase by a combined MS, MS/MS, and theoretical calculation approach .

Main fragmentations occurring both in the ion source, and in metastable and collision-induced dissociation (CID) experiments involve the losses of a hydrogen atom, HCN, and MeCN. These are competitive processes, whose abundances depend on the position of the nitrogen in the pyridine ring. Stable isotope labeling showed that the loss of HCN occurs from the five-membered ring (Scheme 1). In 1,1-dioxides, loss of SO2 occurs in different fragmentation pathways and McLafferty rearrangement dominates the fragmentation of suitable 3-alkyl derivatives. The fragmentation of N-substituted saccharin derivatives was discussed in CHEC-II(1996) and is dominated by loss of SO2 . 3-(-Phenylvinyl)-1,2-benzoisothiazole S,S-dioxide 40a and its p-methoxy derivative 40b show loss of SO2 followed by that of a hydrogen atom. In this case, a highly stable aromatic fused system may be formed . As an example, fragmentations of 40a are shown in Scheme 2. For 3-dicarbethoxymethylene-benzoisothiazole S,S-dioxide 41, the most abundant fragment ions are produced by decomposition of the side-chain (Scheme 3) .

Isothiazoles

Scheme 1

Scheme 2

Scheme 3

Compound 42 (R ¼ Ph), as a member of annelated alkyl benzisothiazoles, shows the typical loss of SO2 and of a hydrogen atom (Scheme 4) . In view of their importance in enantioselective reactions, many bornane sultams have been synthesized and characterized by MS. Their EI mass spectra show molecular ions with low abundance or are absent. N-Substituted bornane sultams generally show the typical fragmentations of the substituents . 1-Alkyl-7-nitro2,1-benzisothiazole 2,2-dioxides show elimination of an acyl radical from their molecular ions .

559

560

Isothiazoles

Elimination of a formaldehyde molecule is an important fragmentation channel for N-methoxymethyl 43a and N-ethoxymethyl 43b sultams. The process is mediated by an ion neutral complex and it yields a mixture of N- and O-alkylated ions in various ratios . Fragmentations of 43a are shown in Scheme 5.

Scheme 4

Scheme 5

3-Spirocyclopropyl- and 3-spirocyclobutyl-benzo- and -pyridosultams undergo the loss of SO2, with the exception of the 4-NO2 derivatives, for which elimination of CH2O is observed . The high-performance liquid chromatography (HPLC)–MS(MS) technique has been used for monitoring the oxidation of isothiazolium salts with H2O2/acetic acid .

Isothiazoles

4.05.3.4 Ultraviolet Spectroscopy The ultraviolet (UV) spectra of 1,2- and 2,1-benzothiazoles, isothiazolo-3-ones, and saccharin and some of its divalent complexes are described in CHEC(1984) and CHEC-II(1996) . Solvatochromic effects have been studied in the visible absorption of azobenzene dyes 44 containing isothiazole, and heterocyclic derivatives. Selected maxima are shown in Table 7.

Table 7 Solvatochromic effect in compounds 44 Compound

DMSO

Cyclohexane

THF

Toluene

MeOH

CHCl3

R ¼ NHAc R ¼ Me

563.2 568.5

533.8 515.7

547.3 547.1

543.0 537.0

549.0 551.0

549.6 545.1

Correlation analysis has shown that bathochromicity crossover is a function of the relative electronegativity of the substituents in the molecule . Several luminescence studies of lanthanide complexation have been performed. This technique has many advantages over ultraviolet–visible (UV–Vis) measurements. Significantly lower metal ion concentrations are required for measurements, thereby allowing complexation studies to be more accurate and carried out at lower ionic strengths, closer to typical biological concentrations. After excitation at 318 nm, a 614 nm 5D0 ! 7F2 transition is observed for the complex of europium(III) with saccharin in water .

4.05.3.5 IR and Raman Spectroscopy IR and Raman spectra of many isothiazoles and 1,2- and 2,1-benzisothiazoles have been discussed in CHEC(1984) and CHEC-II(1996) . The isomers 45a and 45b have been analyzed by IR spectroscopy. They have absorption bands at 3440, 3200, 1695, 1679, and 1410 cm1 45a and 3390, 3220, 1680, 1630, and 1406 cm1 45b. Several nonplanar deformation vibration bands characteristic of the HC¼CH bond are found at 715 cm1 (cis-form) and 940 cm1 (trans-form) .

Carbonyl stretchings of carbapenem ring systems (see Sections 4.05.6.3.4 and 4.05.9.1.2) are at 1780–1790 and 1800 cm1 for the corresponding S,S-dioxide . The vibrational spectra of solid saccharin and metal saccharinates have been extensively studied and reviewed . The spectrum of free saccharin exhibits a weak band at 3215 cm1 due to the N–H vibration; this band is not present in the spectra of its sodium salt or of saccharinato complexes. The C(3)¼O vibration of isothiazol-3-ones is very sensitive to conjugation and charge density. In saccharin, this band is generally observed as a strong band, at 1725 cm1. Recent low-temperature studies with enhanced resolution have revealed that this band is in fact two bands, whose previous reported value corresponds to the average IR frequency . In the absence of solid-state effects, a single RT C¼O band (1638 cm1) is exhibited by a diluted DMSO solution of saccharin . Earlier work on saccharinates reported, as a regular feature,

561

562

Isothiazoles

C¼O frequencies red-shifted compared with saccharin itself . There are three exceptional compounds with higher C¼O frequencies: Rb and Cs saccharinates M(Hsac)(sac)?H2O and a complex characterized as [VO(OH)(Hsac)(sac)(H2O)2] . These compounds are adducts of molecular saccharin. Saccharinates of Au(III), Zr(IV), and V(IV) have C¼O frequencies at nearly the same wave number of saccharin, suggesting that the complexes have a high covalent character . Saccharinato C¼O frequencies can be used as a qualitative criterion for the evaluation of the degree of covalency of metal–saccharinato bonding . In Table 8 are gathered selected IR data (cm1) for Apy[Cu(N-sac)2(O-sac)(H2O)2] and Apy[Zn(N-sac)2(O-sac)(H2O)2], the first examples of tris(saccharinato) complexes . In S,S-dioxides, the symmetric S¼O stretching vibration is near 1170 cm1 and is very sensitive to substituents, while the asymmetric one is in the range 1300–1350 cm1. The SO2 frequencies of saccharinates are always red-shifted compared to saccharin, except for the saccharin adducts, but there is no straightforward relation with the degree of covalency of the metal–saccharinato bonds .

Table 8 Selected IR data (cm1) for tris(saccharinato) complexes Assignment

Apy[Cu(N-sac)2(O-sac)(H2O)2]

Apy[Zn(N-sac)2(O-sac)(H2O)2]

(OH) (NH) (CH) (CO) (CN) (CC) s(CNS) as(SO2) s(SO2) as(CNS) (CH)

3508, 3445 3352, 3150 3090, 2980 1666, 1630 1605 1556 1292 1246 1153 963 680

3406 3190, 3103 3030, 2950 1674 1628 1589, 1480, 1460 1323 1253 1155 968 679

The partial H/D-substitution technique has provided precise insight into the structure of water in hydrated saccharinates. Correspondences between the numbers of (OD) or (OH) stretchings isotopically isolated in H2O or D2O matrices, respectively, and the structurally nonequivalent OH oscillators have been regularly observed . Unexpectedly, a high (OD) frequency (2531 cm1) was observed in case of D-[Cu(H2O)(py)2(sac)2] . IR spectra of saccharin derivatives 46–48 present the amide-1 and amide-2 bands at high values (1740–1690 and 1715–1690 cm1, respectively) .

Surface-enhanced Raman scattering and IR reflectance spectra of saccharin nitranions adsorbed onto silver metal surfaces have been performed. These studies suggest that the saccharin nitranion is bonded to the silver metal surface through the oxygen atom of carbonyl and the nitrogen atom of the imide ring groups and that the nitranion tilts at the surface . Different theoretical calculations have been developed for studying the structure of isothiazoles, of saccharin, and its complex (see Section 4.05.2.1). The anharmonicity of water stretching vibrations of a series of isomorphus metal(II) saccharinate hexahydrates has been studied using both theoretical and experimental (FTIR) methods. The anharmonicity of OH (OD) vibrations increases with an increase in the hydrogen-bond strength .

Isothiazoles

4.05.3.6 Other Techniques UV photoelectron spectroscopy (PES) of benzosultam shows a first broad band at 8.8 eV, followed by a sharp signal at 9.7 eV, one broad band with two ionizations at 10.95 and 11.25 eV, and a broad intense signal with a maximum at 12.1 eV. The bands at 8.8 and 9.7 eV correspond to the ionization of the electrons of the first two p-orbitals (an orthotoluidine system stabilized by the electron-withdrawing effect of the SO2 group), while the bands at 10.95, 11.25, and 12.1 eV correspond to the 4b1, 4b2, and 6a1 ionizations of the sulfoxide group. The signal appearing at 11.5 eV can be assigned to the third p-ionization of ortho-toluidine (10.63 eV) localized on the nitrogen atom and stabilized by the SO2 group. The spectra of N-alkylbenzosultams are similar to those of the unsubstituted benzosultam . Thermal decomposition of different metal(II) complexes of saccharin were studied in a static air atmosphere and the kinetic parameters determined . Dielectric relaxation, temperature-modulated differential scanning calorimetry (TMDSC), and 1H NMR spectroscopy (see Section 4.05.3.2.1) have been used to perform the dynamic characterization of fananserine 35. The use of these three different techniques gives a coherent set of information and allowed the authors to describe the dynamic properties over a wide range of frequencies and temperatures . Chiroptical properties of isothiazole derivatives have been studied using circular dicroism (CD). Optically active sulfinamide R-(þ)-49a (R ¼ 1-Ad) shows a positive first Cotton effect at 284 nm while S (þ)-49b (R ¼ 2,4,6Me3C6H2) has a negative one at 277 nm .

The CD spectrum of diaryl-spiro-4-sulfane 50a (R ¼ H) (see Section 4.05.6.3.4) shows two bands of opposite sign in the 1La region. A band near 220 nm, inserted between them, is responsible for the low intensity of the shortwavelength band of the couplet. In compound 50b (R ¼ Cl), the negative band showing up at 220 nm is even weaker, which may be a result of the superimposition of the red-shifted negative wing of the couplet and a weaker positive band in between. Using the exciton chirality method for these compounds, it was possible to determine the absolute configuration .

The absolute configuration of the sulfur atom in 3-amino-substituted isothiazole S-oxides (see Section 4.05.5.5) was obtained by theoretical calculation of the ECD spectrum and comparison with the experimental ECD curve (see Section 4.05.2.1) . PES and theoretical studies have provided detailed information on the energies and nature of the filled FMOs in isothiazole. In gas-phase collisions, an isolated molecule can temporarily attach an electron of proper energy and angular momentum into a vacant MO (shape resonance). ETS is one of the most suitable means for detecting the formation of these short-lived anions and elucidating the empty-level electronic structure (see Section 4.05.2.2) .

563

564

Isothiazoles

4.05.4 Thermodynamic Aspects 4.05.4.1 Melting and Boiling Points Isothiazoles and benzisothiazoles are usually liquids or low-melting-point solids; polar substituents increase the melting points because of the possibility of hydrogen bonding and other interactions in the crystalline state. The melting and boiling points for some model isothiazoles are given and discussed in CHEC(1984) and CHEC-II(1996) . Recently, physicochemical data of 1,2-benzisothiazoles have been studied and correlated to antibacterial activity in different QSAR investigations .

4.05.4.2 Solution Properties Isothiazole has a solubility in water of about 3.5% and is miscible with most organic solvents. Benzisothiazoles are soluble in most organic solvents and in strong acids, but insoluble in water. Substituents that can introduce hydrogen bonding, influence the solubility and the pKa of any ionizable groups. Saccharin has a solubility in water of 0.2 g l1 at 20 C, while sodium saccharin has 100 g l1. The solubility of saccharin in acetone and EtOH has been determined both experimentally and using theoretical methods . Saccharin, acting as a weak acid, forms salts with basic active pharmaceutical ingredients and these salts have the desirable property of enhanced water solubility . Lipophilicity is frequently used in QSAR analysis and expressed as the partition coefficient P (or by its decimal logarithm, log P) between a nonaqueous and aqueous phase. Another parameter, which takes into account the equilibrium of an ionizable compound at a stated pH value, is the distribution coefficient (D), which depends on the P of the single species and on the pKa values of the chosen compound. P and D have been evaluated for different N-substituted 1,2-benzisothiazol-3-one derivatives using the partition between n-octanol and water. Selected data are reported in Table 9 .

Table 9 Selected P and D for different N-substituted 1,2-benzisothiazol-3-one derivatives R

log P

log D

pKa

CH2CO2H CH(Me)CO2H CH(Et)CO2H p-C6H4-CO2H p-C6H4-CH2CO2H p-C6H4-CH(Me)CO2H p-C6H4-CH(Et)CO2H p-C6H4-OCH2CO2H p-C6H4-OCH(Me)CO2H p-C6H4-CH(Et)CO2H p-C6H4-CH(CH2)2CO2H p-C6H4-CH(CH2)3CO2H

0.554 0.736 0.772 1.095 1.185 1.630 2.315 0.913 1.471 2.219 1.404 2.322

2.525 2.154 1.735 0.629 0.523 0.092 0.705 1.658 1.070 0.310 0.101 1.255

3.921 4.111 4.494 5.284 5.301 5.286 5.401 4.430 4.460 4.472 5.719 5.972

In 1,2-benzisothiazolin-3-one acid derivatives, the 1,2-benzisothiazolin-3-one nucleus behaves as a weak electronwithdrawing lipophilic substituent on the benzoic acid . Recently, to determine the lipophilicity of 1,2-benzisothiazole derivatives, reversed-phase thin-layer chromatography (TLC) and HPLC were used. In compounds 51 (R ¼ H, Me) and benzisothiazoles 52 (n ¼ 0, 1; R ¼ H, Me) which are highly potent antimicrobial agents, the hydrophobicity chromatographic parameters (log K9) have been compared with log P and theoretical calculations .

Isothiazoles

Solubility and partition coefficients of different sulfonamides, including saccharin, have been calculated using the hybrid ONIOM (B3LYP/6-311þG(d,p): MNDO) method .

4.05.4.3 Aromaticity The concept of aromaticity has been widely discussed in recent years: as it is not a directly measurable quantity, it has no precise quantitative and generally accepted definition. Aromaticity is generally evaluated on the basis of energetic, geometric, and magnetic criteria and, recently, Cyranski et al. have discussed aromaticity as one-dimensional or multidimensional phenomena, also citing isothiazoles . Quantitative definitions have been developed for heteroaromatic systems including isothiazoles. The aromaticity of isothiazoles has been studied using different criteria (Table 10) such as

MO multicenter bond index (Iring) involving the þp electron population (this index is related both to energetic and magnetic criteria) ; the harmonic oscillator model of aromaticity (HOMA) index, which has been used as a quantitative measure of aromaticity of heteroaromatic rings on the basis of crystallographic data from CSD ; absolute hardness, , and aromaticity index, IA ; aromatic stabilization energy (ASE, kcal mol1), and resonance energy (RE, kcal mol1), using six different approaches based on isodesmic reactions ; and exaltation of magnetic susceptibility (), nucleus-independent chemical shifts (NICS and NICS1, ppm), .

Table 10 Selected data for aromaticity Compound

Iring

HOMA

IA

ASE

RE

"p L

L

NICS

NICS1

1 3 4

0.069 6

0.774

7.0 5.75 5.69

91 142 142

16.24

18.91

0.1071

7.13

13.96

11.66

In all cases, isothiazole is clearly a planar aromatic molecule, and its level of aromaticity is similar to that of thiazole and pyrazole, and higher than those of isoxazole and oxazole . The effect of the mutual position of heteroatoms in the ring is also a remarkable feature: isothiazole analogues are more aromatic than thiazoles . The same behavior is predicted also for S,S-dioxide series using the "p Lvalues. Aromaticity increases from thiophene S,S-dioxide through the thiazole and isothiazole 1,1-dioxides and a subset of isomeric thiadazole S,S-dioxides .

4.05.4.4 Conformations General features of the conformations of isothiazole derivatives were discussed in CHEC-II(1996) . Isothiazole and the benzisothiazoles are planar molecules, as are the corresponding S,S-dioxides, saccharin, thiosaccharin, and their salts. 1,2-Benzisothiazoline S,S-dioxide in the crystalline state exists as a 1:1 mixture of two conformers. A great contribution to understanding the stereochemistry and conformations of isothiazole derivatives has come from the use of the X-ray technique (see Section 4.05.3.1.1) and NMR analyses (see Section 4.05.3.2.1). A vast amount of literature concerning QSAR studies and theoretical calculations about conformations has been published in the last decade (see Section 4.05.2.1).

4.05.4.5 Tautomerism General features of tautomerism in isothiazole and benzisothiazole derivatives are discussed in CHEC(1984) and CHECII(1996) and have been reviewed .

565

566

Isothiazoles

Different tautomers can be distinguished by physical methods (see Section 4.05.3.1.1 for X-ray and Section 4.05.3.2.1 for NMR discussions). Annular tautomerism does not occur in isothiazole or benzisothiazole, while ring– chain and side-chain tautomerism often occur depending on the substituent pattern . For compound 53a, the most stable ring–chain tautomer is the benzenensulfonamide 53b (see Section 4.05.9.1.3) . Only the keto tautomeric form 27a exists in the crystalline state (see Section 4.05.3.1.1) .

According to X-ray crystal structure and ab initio calculations for the amino acid thio-ATPA, a potent and selective GluR5 receptor agonist, the 3(2H)-isothiazolone tautomer 54b predominates over 54a in the crystalline form and, most likely, also in weakly acidic aqueous solution . Nevertheless, the presence of the enol tautomer is necessary for O-alkylation with Rh(II) carbenoids to give 32 (see Section 4.05.5.9) . For compound 55, NMR spectra indicate that the N–H tautomer 55b is the predominant one .

Isothiazoloquinoline derivative 56 is an antibacterial compound that interacts with topoisomerase II. The enol form 56b is the major tautomer, as was predicted by optimizing the geometries and calculating the heat of formation (Hf) of both tautomers by means of the semi-empirical molecular orbital AM1 method, both in the gas phase and in aqueous solution (Table 11) .

Table 11 Heats of formation for 56a and 56b tautomers Compound

Hf aq. phase (kcal mol1)

Hf gas phase (kcal mol1)

56a 56b

22.348 24.087

9.937 11.538

Isothiazoles

4.05.5 Reactivity of Fully Conjugated Rings 4.05.5.1 General Survey of Reactivity Many reviews on the general reactivity of isothiazol-3(2H)-ones and on the corresponding 1,2-benzo derivatives have been published in the last decade. Specific topics such as 1,3-dipolar and Diels–Alder cycloadditions on isothiazoles (see Sections 4.05.5.11 and 4.05.7.3) , as well as the phototransformations of 3-, 4-, and 5-substituted isothiazoles (see Section 4.05.5.2) and the syntheses and reactions of lithiated isothiazoles , have been reviewed. Several electrophilic reactions at nitrogen are reported, most aiming to prepare intermediates of biological interest (see Section 4.05.12.2) or enantiopure compounds where substituted isothiazoles are used as chiral auxiliaries (see Section 4.05.12.1). Different methodologies have been described for the arylation of the nitrogen of saccharin (see Section 4.05.5.3). Studies on the chemo- and enantioselective oxidation of the sulfur atom have been performed. Nucleophilic attack on both 5-unsubstituted and halo substituted 3-aminoisothiazoles occurs at C-5 and in some cases together with ring opening or ring transformation. The oxidation of isothiazolium perchlorate derivatives and analogous compounds with hydrogen peroxide has been exhaustively discussed in term of substituent effects. New asymmetric hydrogenation methods for 1,2-benzisothiazoles have been reported. The enzymatic cleavage of both N–SO2 and C–SO2 bonds of saccharin gives salicylamide . Studies on the reactivity of new 4,6-dinitro-1,2-benzisothiazol-3-one toward alkylation, halogenation, and oxidation have been reported .

4.05.5.2 Thermal and Photochemical Reactions The flash vacuum pyrolysis of N-substituted 2,1-benzisothiazolin-3(1H)ones 57 forms iminoketene intermediates which give different products depending on the substituent on the nitrogen atom. The N-acetyl compound gives 3,1-oxazinone 58, the N-methyl derivative a mixture of benzoisothiazole and 2,1-benzothiazole by extrusion of CO, and the N-1-isoquinolinyl derivative (not isolable) a mixture of isoquinoquinazolones 59 (R ¼ H, Cl) . The photochemical reaction of N-propylsaccharin results in the extrusion of SO2 to give a biradical that can be trapped in different ways depending on the solvent. Protic solvents (EtOH) give Npropylbenzamide but 2-aryl-N-propylbenzamides are formed with aromatic solvents. The influence of different aromatic solvents was evaluated in terms of yield and regiochemistry . The photochemical irradiation of 3-, 4-, and 5-substituted isothiazoles has been reinvestigated (see p. 339) with a detailed mechanistic discussion. Results are summarized in Scheme 6 for phenyl derivatives 60. 4- and 5-Phenylisothiazoles 60a and 60b in ether give 2-phenyl-2-cyanoethenethiol 61a and 1-phenyl-2-cyanoethenethiol 61b, respectively, by photocleavage of the N–S bond. They can be trapped by addition of a small amount of triethylamine (TEA) and benzyl bromide, giving the corresponding benzyl thioethers 61c and 61d. When the reaction is performed in MeOH, 4-phenylisothiazole 60a undergoes both photocleavage to cyanosulfide 61a and phototransposition to 4-substituted thiazoles 63a, via the N-2/C-3 interchange pathway (path a, intermediate 62). The addition of TEA during the photochemical process increases the yield of thiazole derivative . Irradiation of 60b gives a mixture of compounds, and both path a and phototransposition via the electrocyclic ringclosure–heteroatom-migration pathway (path b, intermediates 64a–d) were suggested to explain their formation. A different distribution of azole derivatives was observed depending on the polarity of the solvent and the absence or presence of the base. Compound 60c phototransposes instead into 60a and 63c and their distribution is not affected by the reaction conditions .

567

568

Isothiazoles

Scheme 6

4.05.5.3 Electrophilic Attack at Nitrogen Acylation of 57 (R ¼ H) in the absence of a base occurs directly on the nitrogen atom . N-Chloroand N-bromosaccharin can be efficiently prepared using Pb(OAc)4 in MeCN and the appropriate Lewis acid . A convenient preparation of N-bromosaccharin on a multigram scale was reported . A new one-pot protocol for the N-chloromethylation of saccharin and isothiazolidin-3-one S,S-dioxide using a mixture of formaldehyde–sodium hydrogen sulfite adduct and thionyl chloride was given . N-Bromomethylation of saccharin and analogues is performed via N-pivaloylmethyl derivatives then treated with HBr (5%) . 3-Hydroxyisothiazole reacts with benzoylisothiocyanate exclusively at the nitrogen atom . The Mitsunobu reaction was applied to prepare the N-methyl compound 65 (R ¼ Br) using a triphenylphosphine resin, t-butyl diazadicarboxylate, and MeOH . The alkylation at nitrogen of 1,8naphthosultam with 1-chloro-2,3-epoxypropane to give 66 (R ¼ Br) and some transformations of the chain were reported . Different synthetic procedures for the arylation of the nitrogen atom of saccharin have been described proceeding via various mechanisms. Potassium fluoride promotes the N-alkylation of saccharin in ionic liquid 1-butyl-3-imidazolium hexafluorophosphate ((bmim)PF6) . The N-phenyl compound is obtained with o-silylphenyl triflate in the presence of CsF . The C–N bond cross-coupling, catalyzed by cupric acetate and tertiary amines, both using triarylbismuth and arylboronic acid in the presence of an oxidant was performed on saccharin . p-Tolyllead triacetate efficiently arylates the nitrogen of saccharin to give N-tolylsaccharin . Photochemical N-arylation of saccharin was performed with an appropriate aromatic compound and PhI(OAc)2/I2. The substituent effect on radical arylation of aromatic rings was studied . A study on the alkylation and aminomethylation of 2,3,6,11-tetrahydroanthra[2,1-d]isothiazole-3,6,11-trione 67 (R ¼ H; n ¼ 0, 1) (see Section 4.05.9.1.1), performed with different alkylating agents and a mixture of formaldehyde and a secondary amine, respectively, is discussed in terms of N- and O-alkylation . The reaction of alkyl isocyanides, dibenzoylacetylene, and saccharin results in the formation of the N-aminofuryl derivatives 68 .

Isothiazoles

4.05.5.4 Electrophilic Attack at Carbon Perhaloisothiazoles containing both bromine and iodine atoms can be prepared from the readily available 3-hydroxyisothiazole . The addition of bromine, followed by spontaneous HBr elimination, occurs with a different regiochemistry on isothiazole S,S-dioxide 69 (R ¼ H) and 70 (R1 ¼ R2 ¼ H, R3 ¼ Bn, n ¼ 2), and the corresponding 5-bromo derivative 69 (R ¼ Br) and the 4-bromo compound 70 (R2 ¼ Br) are obtained, respectively. For the synthesis of 4-chloro and 4,5-dichloro derivatives 70, see Section 4.05.9.1.1.

4.05.5.5 Electrophilic Attack at Sulfur Studies on the chemoselective and enantioselective oxidation of 3-amino-substituted isothiazoles to the corresponding S-oxides 70 (n ¼ 1) are performed using chiral oxaziridines under microwave irradiation (see Sections 4.05.2.1 and 4.05.2.2). Isothiazolo[5,4-b]pyridin-3(2H)-ones are regioseletively and chemoselectively oxidized with oxone to sulfoxides 71 (n ¼ 1), then transformed into sulfones 71 (n ¼ 2) with NaOCl . The electrochemical behavior of 1,2-benzisothiazol-3-one was studied. The preparation of the corresponding S-oxide is mediated by chloride anions . The oxidation of 72 (R1 ¼ alkyl; R2 ¼ H, NO2; n ¼ 0) (see Section 4.05.9.1.1) with chlorine gives the monoxide and with hydrogen peroxide gives a mixture of S-monoxide and S,S-dioxide depending on the temperature; when R1 ¼ H, the S-oxide is formed exclusively. The use of ammonium persulfate allows the formation of the dioxide. The O-alkyl derivative 73 is oxidized to the dioxide that was not isolated but transformed into 74 .

4.05.5.6 Nucleophilic Attack at Carbon Isothiazolones 75 (R3 ¼ Bn) can be transformed into 3-benzylamino derivatives 70 (R3 ¼ Bn, n ¼ 0), then oxidized to dioxides 70 (n ¼ 2) . The Michael-type addition of various nucleophiles to isothiazoles 69 (R ¼ H, Br)

569

570

Isothiazoles

and 70 (R1 ¼ H, Cl; R2 ¼ H; R3 ¼ Bn; n ¼ 2) is regioselective and occurs at C-5. The addition to 69 (R ¼ H) of mercaptans, alcohols, or trifluoroacetamide gives a mixture of trans- (major isomer) and cis-diastereomers 76 and 77; however, using triethyl phosphite (TEP), a single diastereomer 76 (RX ¼ (EtO)2OP) was obtained. Compound 69 (R ¼ Br) gives the addition/elimination products 78 with mercaptans, amines, and TEP. Derivative 78 (RX ¼ HS) can be alkylated at sulfur using alkyl bromides and a base. The use of an excess of TEP, starting from either 69 (R ¼ Br) or 78 (RX ¼ (EtO)2OP), affords 79. Analogously, compound 70 (R1 ¼ R2 ¼ H, R3 ¼ Bn, n ¼ 2) and 70 (R1 ¼ Cl) react with mercaptans, giving dihydro isothiazole derivatives 80 and compounds 81, respectively.

A different behavior of isothiazoles 69 (R ¼ H, alkyl, Ph, Py, CN) was observed using alkoxides (2 equiv) in alcohol. Addition products like 76 and 77 (X ¼ O) were never isolated but underwent ring opening and SO2 elimination giving a mixture of cis/trans-polyfunctionalized propeneamidines 82 (X ¼ O-alkyl). Similarly, from 69 (R ¼ Br), the 3,3dialkoxypropeneamidines 82 (R ¼ X ¼ O-alkyl) are formed. The reaction of 69 (R ¼ H) with different Grignard reagents affords cis/trans-polyfunctionalized propeneamidines 83 (R ¼ alkyl, alkynyl, aryl) . The reaction of isothiazoles 69 (R ¼ H, MeSO2, MeS, Ph) with sodium azide was also investigated. Sulfamic esters 84, [1,2]thiazete S,S-dioxides 85, benzo[e][1,2]thiazine S,S-dioxides 86, or triazoles 87 were formed depending on the substituent at C-5 and the reaction conditions .

The oxidation of 2-aryl-1,2-isothiazolium perchlorates 88 (R1 ¼ R2 ¼ Me, –(CH2)4–) with hydrogen peroxide has been extensively studied (Scheme 7) and occurs at C-3. The reaction at 25 C gives first the hydroperoxide intermediate 89 transformed into S-oxides rac-cis-90 and rac-trans-90 (not isolable), which are

Isothiazoles

Scheme 7

transformed into sultams 91. The distribution of sultim/sultam compounds depends on the basicity of the aniline. Electron-withdrawing groups (EWGs) located on the aryl ring allow the oxidation process to be halted at the sultim stage; alternatively, electron-donating groups (EDGs) favor the formation of sultams. The oxidation of 88 at 80 C gives directly 3-oxosultams 92, which are also obtained by heating 91 in EtOH. Both sultim and sultam hydroperoxides are reduced with DMSO and sultams also with Na2SO3, affording the corresponding hydroxy compounds 93 and 94 (R4 ¼ H). The oxidation of 88 was also performed with MMPP?6H2O (magnesium monoperoxyphthalate) as the oxidant and with the assistance of ultrasound . 3-Hydroxysultams 94 (R3 ¼ EWG, R4 ¼ H) and the 3-oxosultams 92 (R3 ¼ EDG) were formed directly; without ultrasound, only 94 (R3 ¼ EDG, R4 ¼ H) was obtained. When the reaction was performed in alcohol, the 3-alkoxysultams 94 (R4 ¼ alkyl) were formed . (N-Benzoyl)-isothiazolium-2-imine salts 95 (n ¼ 0, 1) display a similar behavior to 88 toward the oxidation conditions, affording sultim/sultam hydroperoxides. Overoxidation and reduction of the 3-hydroperoxy function were also carried out . The oxidation of isomeric 1-aryl-2,1-isothiazolium perchlorate derivatives 96 (n ¼ 2, 3) gave a different result and, as a result of a Criegee-type rearrangement, alkanoic acid derivatives 97 were formed . The reaction of 88 with anilines affords different products depending on the size of the carbocyclic ring and the electronic effect of the aniline substituent. From 88 (R1 ¼ R2 ¼ –(CH2)3–), the vinamidines 98 (n ¼ 1) were the sole products. From 88 (R1 ¼ R2 ¼ –(CH2)4–), the isomerization products 99 (n ¼ 1) were the main products, in addition to the vinamidines 98 (n ¼ 2) and spiro compounds 100 (n ¼ 1). Finally, the cyclohepta derivatives 88 (R1 ¼ R2 ¼ –(CH2)5–), gave 99 (n ¼ 2) as the main compounds, with only a trace amount of 100 (n ¼ 2). Ring transformation of 4,5-isothiazolium salts 88 (R2 ¼ Me) to the isomeric 3,4-disubstituted compounds 101 can be achieved with substituted anilines; 102 and 103 were detected as by-products .

571

572

Isothiazoles

The transformation of isothiazoloquinolines 104 (R2 ¼ R3 ¼ H) (see Section 4.05.9.1.3) into 105 (replacement of SO2 with CO) can be achieved using TBACN in MeOH; trace amounts of 106 were also detected . Alternatively, using stable carbanions, benzonaphthyridines 107 (Y ¼ EWG) were produced . The known reactivity of nucleophiles toward the carbonyl group of saccharin derivatives has been exploited by different authors and some reactions have been revisited, for example, the reaction of saccharin derivatives 108 (R ¼ CH(R1)CO2Me, R1 ¼ H, Me) with hydrazine. By ring opening, it is the hydrazide 109 that is formed and not the previously proposed carbonyl hydrazone. The reaction of methyl saccharin-2-carboxylate 108 (R ¼ CO2Me) with amino acids yields 110 . A multikilogram synthesis of 111 was carried out in a one-pot reaction from saccharin derivative 108 (R ¼ o-CF3C6H4), MeONa, and methyl bromoacetate .

Saccharin pseudochloride 112 (R ¼ Cl) reacts with 1-diethylamino-1-propyne to give 113. When the corresponding 3-ethoxy derivative 112 (R ¼ OEt) was treated with the same alkyne, a ring-expansion product 114 (R ¼ OEt) was isolated. On the other hand, the analogous thiazepine 114 (R ¼ OSiMe3) is obtained, together with the ketone derived by hydrolysis of the silyl enol ether, by the reaction of saccharin with BuLi/trimethylsilyl chloride (TMCS)

Isothiazoles

and then with the same alkyne. Depending on the solvent, a 1,4- or a 1,2-addition occurs between 115 (see Section 4.05.7.3) and 1-diethylamino-1-propyne to give 116 and 114 (R ¼ CH¼CHAr), respectively .

4.05.5.7 Nucleophilic Attack at Sulfur Salt 117 reacts with the lithium salt of cyclopentadiene derivatives affording 4-aminothialenes 118 . The mechanism of the chlorination of saccharin with phosphorus pentachloride has been investigated: at low temperature and with a short reaction time, the chloride reacts at sulfur, via an O-phosphorus intermediate, to give 2-chlorosulphonylcyanobenzene 119 (X ¼ Cl). By increasing the temperature, 119 gives 112 (R ¼ Cl). Compounds 112 and 119 react with 4-methoxyphenol affording 112 (R ¼ OAr) and 119 (X ¼ OAr), respectively .

Desulfurization of N-2-diaryl-5-(arylimino)-2,5-dihydro-4-nitroisothiazol-3-amines 120 (R1 ¼ Ar1, R2 ¼ Ar2, R ¼ Ar3) with Ph3P results in a ring transformation, via intermediate 121, affording quinoxaline-2-carboxamides 122 and/or nitroquinolines 123, isomeric oxadiazoles 124, and quinoxaline derivative 125, depending on the substitution pattern on the ring . The presence of a nucleophile traps intermediate 121, and compounds 126 (R ¼ R12N, ArS, ArO) are formed. Using benzoic acid leads to benzamide 127, but with thiobenzoic acid, 128 (R1 ¼ R2 ¼ R3 ¼ Ph) is the result . 3

573

574

Isothiazoles

4.05.5.8 Nucleophilic Attack at Hydrogen Attached to Carbon Examples of ring deprotonation are reported in Section 4.05.7.8.

4.05.5.9 Reactions with Radicals and Carbenes Radical arylation reactions of the nitrogen of saccharin are reported in Section 4.05.5.3. Alkylation of 3-oxo derivatives 129 (R3 ¼ H) with diacyl carbenoids 130 occurs at the oxygen atom, giving compounds 131 (see Sections 4.05.2.1 and 4.05.3.2.1). Carbonyl ylides are involved as intermediates, which capture a proton from the NH group to form 131. Using the N-substituted derivative 129 (R1 ¼ R2 ¼ –(CHTCH)2–, R3 ¼ CH2COC(N2)CO2Et), reaction with Rh2OAc4 yields the ylide intermediate 132, in turn trapped with dimethyl acetylenedicarboxylate (DMAD) to give cycloadduct 133 .

4.05.5.10 Reduction and Electrochemistry The tertiary sulfonamide group of 65 (R ¼ H) undergoes Ni(0)-catalyzed reductive cleavage with i-Pr2Mg as -hydride donor with loss of SO2 producing 1-N-methylnaphthylamine. N-Methylsaccharin gave N-methylbenzamide (15%) . Electrochemical reduction of saccharin was performed in DMSO . Reduction of N-protected saccharin with diisobutylaluminium hydride (DIBAL-H) occurs at the carbonyl group affording a hemiaminal . Chiral rhodium complexes were used for asymmetric hydrogenation (HCO2H/TEA) of the CTN bond of benzisothiazoles 112 to give products 134 in high yields and with good enantioselectivity . The same reaction has been carried out with a water-soluble rhodium catalyst . Better enantioselection was obtained using H2 and P-TangPhos complex . The use of H2 and ruthenium–BINAP catalyst under pressure was also reported (BINAP ¼ 2,2-bis(diphenyl-phosphanyl)-1,1binaphthyl) . Reduction of the N–S double bond of 2,3-dialkyl-thioisothiazolium halides 135 with sodium borohydride afforded 136 . An interesting synthetic application for the transformation of the SR2 group in 135 into SR3 group is reported in Section 4.05.9.1.1.

4.05.5.11 Cyclic Transition State Reactions with a Second Molecule The reaction of 5-amino-3-methylisothiazole with pentafluorobenzaldehyde in xylene at reflux (AcOH cat.) yields isothiazolo[5,4-b]quinoline 137 (R ¼ Me, X ¼ F) . Both [4þ2] p- and 1,3-dipolar cycloaddition reactions of several isothiazole derivatives have been reported and reviewed. An example of a Diels–Alder reaction of an ortho-xylylene intermediate containing the isothiazole ring is reported in Section 4.05.7.3 (compound 265). 3-Aminoisothiazole S,S-dioxide 69 (R ¼ H) reacts as a dipolarophile with alkyl and aryl azides giving single regioisomers 138, which can be transformed by heating into the thiadiazabicyclo[3.1.0]hexene derivatives 139. Further transformation of compounds 139 into thiazete dioxides 140, 1,2,6-thiadiazine dioxides 141, and pyrazoles 142 occurs on melting. The process was optimized to afford thiadiazines 141 in useful yields. Pyrimidine 143 was the

Isothiazoles

main product starting from 139 (R ¼ Bn). Mu¨nchnones react with 69 (R ¼ H) affording the single regioisomer 144 but the 5(4H)-oxazolones yield two regioisomers 145 (main product) and 146. Pyrroles 147 (R ¼ Me) are obtained from 144 in a thermal reaction. Basic treatment of 145 gives pyrroles 147 (R ¼ H) .

Compound 69 (R ¼ H) reacts with nitrile oxides affording 148, reduction of which affords a mixture of the (E)- and (Z)-5-(amino-arylmethylene)-isothiazoles 149 which were transformed into 150 by hydrolysis and water elimination . The same regiochemistry was observed in cycloadditions with isothiazoles 70 (R1 ¼ R2 ¼ H; R1 ¼ H, R2 ¼ Br; R3 ¼ Bn, n ¼ 2) which gave cycloadducts 151 or 152, respectively . Isothiazolephosphonate 78 (RX ¼ PO(OEt)2) and nitrile oxides afford dihydroisoxazole derivatives 153 (same regiochemistry). Starting from 153, diethyl phosphate is eliminated with KOH (1 equiv) to give 148, which is transformed into 154 by an excess of base .

Diazomethane reacts with 78 (RX ¼ PO(OEt)2) with an opposite regiochemistry forming pyrazoline 155 and its more stable tautomer 156. Pyrazoles 157 are obtained by treating the mixture of 155/156 with a base .

575

576

Isothiazoles

Comparable cycloaddition products 158 (R ¼ H) and 159 are obtained from 70 (R1 ¼ R2 ¼ H, R3 ¼ Bn, n ¼ 2) with diazoalkanes (R ¼ H, CO2Et, Ph), for example, 70 (R1 ¼ Br, R2 ¼ H, R3 ¼ Bn, n ¼ 2) gives 160; however, 70 (R1 ¼ Cl, R2 ¼ H, R3 ¼ Bn, n ¼ 2) does not react with the above dipoles .

4,5-Dialkyl or -diaryl isothiazol-3(2H)-one S,S-dioxides 129 are claimed to be inert to 1,3-dipolar and Diels–Alder cycloadditions, but compounds 129 (R1 ¼ R2 ¼ Me; R1-R2 ¼ (CH2)4, R3 ¼ H, Me) react with diazomethane affording cycloadducts 161 and the O-methyl derivative 162 (from R3 ¼ H). Cycloadduct 162 can also be obtained from 163 (R3 ¼ Me). More-hindered diazoderivatives give only isothiazole 163 (R3 ¼ CH(CO2Me)2) . Enantiopure (R)-1-p-tolyl-14-isothiazol-3-ones 164 (see Section 4.05.9.1.1) react with diazoethane smoothly, affording a mixture of adducts with almost complete p-facial selectivity and a high exo/endo-selectivity. The anti-approach with respect to the tolyl group and the exo-arrangement of the dipole favor the formation of the anti-165-exoadduct with respect to the anti-165-endo adduct. Diazomethane is less reactive and stereoselective . Treatment of the adducts with LiAlH4 affords the corresponding diastereomers 166 and 1669.

Isothiazol-3(2H)-ones 75 (R2 ¼ H, R3 ¼ Ph) react with nitrile oxides giving isoxazolone derivatives 168 via the cycloadducts 167. An unexpected site selectivity of the carbonyl bond of 5-benzoylisothiazol-3(2H)-one 75 (R1 ¼ PhCO, R2 ¼ H, R3 ¼ Ph) was found with mesitonitrile oxide affording a mixture of 169 and 170 .

Isothiazoles

Diels–Alder reaction of different 5-aminoisothiazole dioxides 69 (R ¼ H) and 70 (R1 ¼ R2 ¼ H) and dienes in different reaction conditions (neat, microwave, ultrasound) afforded cycloadducts 171 and 172 (X ¼ CH2, O; R3 ¼ o-MeOC6H4, H). The exo/endo-selectivity is dependent on the reaction conditions and the type of cyclic diene .

The behavior of compound 164 (R ¼ H) in Diels–Alder reactions with cyclopentadiene , furan, and acyclic dienes was investigated (see Section 4.05.2.2). The reaction, catalyzed by a Lewis acid, works at low temperature, giving 173 (X ¼ CH2, O), and shows almost quantitative endo-selectivity with cyclopentadiene and exo-selectivity with furan. 1-Methoxybutadiene and 1,3-pentadiene reacted efficiently in the presence of a catalyst and pressure (4 kbar) to give the adducts endo-174 (R ¼ OMe, Me) as the major regioisomer. Regioisomer endo-175 (R ¼ Me) was also detected (minor regioisomer). Dane’s diene reacted only under pressure and gave a mixture of two stereomers, endo-176 and exo-176 (opposite regiochemistry with respect to above) . A convergent stereo- and regioselective sequential three-component aza-[4þ2] cycloaddition/allylboration/retrosulfinyl-ene rearrangement between dienes 177 and dienophiles 178 and a series of aldehydes was reported to give cis-2-carboxy-6-hydroxyalkylpiperidines 179 by a regio- and diastereocontrolled reaction . Isothiazolone dioxide 129 (R1 ¼ R2 ¼ H, R3 ¼ t-Bu) reacted with furfuryl alcohol to give a 1:1 mixture of endo/exoadducts 180 (R ¼ OH) (see Section 4.05.2.2) converted to the saccharin derivative 181 with lithium hexamethyldisilazide/trimethylsilyl chloride (LHMDS/TMSCl). With 2-methylfuran, comparable regioisomeric endo/exo-adducts 180 (R ¼ H) (endo major isomer), besides a second regioisomer, were formed .

577

578

Isothiazoles

3-(-Phenylvinyl)-1,2-benzisothiazole S,S-dioxides 115 (Ar ¼ p-MeOC6H4) react in the presence of AlCl3 acting as a dienophile with a second molecule of 115 to give the [4þ2] dimer 182. 3-Methyl- and 3-chloro-1,2-benzisothiazole S,S-dioxides 112 (R ¼ Me, Cl) react with Danishefsky’s diene affording oxopyrido-benzisothiazoles 183 (R ¼ Me) and 184, respectively. The fused pyridone 185 was formed from 3-methyl derivative 112 (R ¼ Me), cinnamoyl chloride, and TEA by the way of a pericyclic reaction of the N-cinnamoyl intermediate .

4.05.6 Reactivity of Nonconjugated Rings 4.05.6.1 Compounds Not in Tautomeric Equilibrium with Aromatic Compounds The general structures of cyclic sulfoximines are reported in CHEC-II(1996) (see p. 348). Very few examples of sulfoximines were reported in the decade under review. The preparation of cyclic sulfilimides 165 and 173 from (R)-1-p-tolyl-14-isothiazol-3-ones 164 and diazoalkanes and cyclic dienes, respectively, have been reported (see Section 4.05.5.11). Furthermore, studies on the alkylation of -sulfonimidoyl carbanions and on their use as chiral ligands in copper reagents were reported (see compounds 227 and 228, Section 4.05.6.3.4).

4.05.6.2 Compounds in Tautomeric Equilibrium with Aromatic Compounds The tautomerism of ketones is discussed in Section 4.05.4.5 and such compounds are considered under the aromatic tautomer.

4.05.6.3 Dihydro Compounds 4.05.6.3.1


The general structures of cyclic sulfoximines were reported in CHEC-II(1996) (see p. 348). Several 1,3-dihydro-2,1-benzoisothiazole and dihydroisothiazolo[4,3-b]pyridine S,S-dioxides characterized by various substitution patterns on C-3 were prepared and extensively used for their ability to generate aza-ortho-xylylenes, then transformed into a variety of new derivatives. Diels–Alder and 1,3-dipolar cycloaddition reactions on 4-isothiazoline S,S-dioxides containing a stereocenter were aimed at preparing chiral auxiliaries; good diastereoselection is observed in general in the above reactions. Different polyfunctionalized 2,3-dihydro-3-ylidene-isothiazole derivatives were prepared and used for their transformation into a new heterocycle or into heterocondensed compounds.

4.05.6.3.2

Thermal and photochemical reactions

The formation of aza-ortho-xylylenes by thermolysis of benzoisothiazolines was covered extensively in CHEC-II(1996) (see p. 348) (Scheme 8). A series of N-alkyl-1,3-dihydroisothiazolo[4,3-b]pyridines 186 (X ¼ N) were prepared and used for the generation, by thermal extrusion of SO2, of intermediate pyrido analogues of aza-ortho-xylylenes 187 (R3 ¼ R4 ¼ H), which enter into [4þ2] p-cycloadditions with N-phenylmaleimide 188 (three fold excess) leading to tetrahydro[1,5]naphthyridines 189 as the main products together with by-products . This reaction has been revisited concerning the structure previously assigned to the diastereomeric by-products 190 and 1909 . They derive from 189 (R3 ¼ H) by Michael addition of a second molecule of 188 and are the main products on prolonging the reaction time. When starting from 186 (R3 ¼ Ph), only the all-ciscompounds 189 are formed. The reaction is unsuccessful when R3 ¼ Me . From 186 (R1 ¼ (CH2)nþ2CH¼CH2, R3 ¼ R4 ¼ H) an intramolecular cycloaddition occurs giving 191 (n ¼ 1, 2) . By heating 186 (R1 ¼ Pr, R3 ¼ R4 ¼ H) in the absence of a diene acceptor, the dimeric azocine 192 is formed. The pyrolysis of 186 (R1 ¼ Me, R3 ¼ R4 ¼ H) in the presence of dimethyl fumarate 193 gives 194 together with the

Isothiazoles

Scheme 8

corresponding azocine 192 (R1 ¼ Me). The thermal reaction of 186 (R3 ¼ Me; R4 ¼ H, Me, SR, SAr) in the absence of a diene acceptor affords 3-amino-2-vinyl pyridines 195, via aza-ortho-xylylene intermediates, which undergo a [1,5]sigmatropic hydrogen shift . A similar behavior was observed for 186 (X ¼ CH, R3 ¼ H, R4 ¼ (CH2)nY (Y ¼ COR, COAr, CN)) . According to the mechanism reported above, spiro compounds 186 (X ¼ CH, N; R3–R4 ¼ (CH2)n) undergo SO2 extrusion to give 196 (from n ¼ 4–6), 197 (from n ¼ 3), and condensed pyrrole derivatives 198 (from n ¼ 2). Compound 199 is formed in an analogous way . Similarly 186 (X ¼ CH, N; R3–R4 ¼ –S(CH2)4–) gives derivatives 200 (n ¼ 2). Interestingly, the homologous 200 (X ¼ N, n ¼ 1) is

579

580

Isothiazoles

directly obtained when 186 (X ¼ N; R3–R4 ¼ H) reacts with 3-bromopropylthiocyanate (see Section 4.05.6.3.4) . The thermal extrusion of SO2 from dichloro compound 186 (X ¼ N, R1 ¼ Me, R3 ¼ R4 ¼ Cl) gives aza-ortho-xylylenes 187 (X ¼ N, R3 ¼ R4 ¼ Cl) which do not enter into [4þ2] p-cycloaddition reaction but add amines, hydroxylamines, or diamines affording amidines 201, diaryl or heteroaryl derivatives 202 (A ¼ N, B ¼ O; A ¼ B ¼ N), respectively . Photoisomerization of sultams 203 gives different results depending on the N-substituent. The reaction of 203 (R3 ¼ H) in MeOH yields the cyclic sulfine hydroxamic acids 204 (R3 ¼ OH). A mixture of anti- (preferred) and syncompounds 204 is formed from 203 (R1 ¼ H; R2 ¼ Me, Ph). Starting from 203 (R3 ¼ CH2OMe, CH2Oi-Pr), the same compound 204 (R3 ¼ CH2OMe) is obtained . Instead, 1,3-2H-benzothiazines 205 (R4 ¼ Ph, EWG) are obtained by photochemical expansion of the sultam ring of 203 (R3 ¼ Bn, CH2EWG). The N-benzyl derivative also gives compound 204 (R3 ¼ OBn), which reverts to the starting material . Photoisomerization of dihydropyrrolo[1,2-b][1,2]benzisothiazole S,S-dioxides 206 (R ¼ EWG) induces rearrangement to 2,3-dihydro[1]benzothieno[3,2-b]pyrrole S,S-dioxides 207 by the way of S–N bond homolysis, formation of a stabilized biradical, and ring closure .

4.05.6.3.3

Aromatization

Since 1995 , no further references to aromatization have been reported.

4.05.6.3.4

Other reactions

Starting from benzosultams and pyridosultams, different functional groups are introduced at position 3. Alkylation of N-methylpyridosultam 186 (R3 ¼ R4 ¼ H) with homologous C2–C6 ,-dihaloalkanes gives the corresponding spiro compounds 186 (X ¼ N, R3–R4 ¼ (CH2)n) . Attempts to functionalize the C-3 position of 186 (X ¼ CH, N) with a thioalkyl or -aryl group providing heterosubstituted aza-ortho-xylylene intermediates 187 (see Section 4.05.6.3.2) is operative in the case of 186 (X ¼ CH; R3 ¼ Me; R4 ¼ H) affording 186 (X ¼ CH; R1 ¼ R3 ¼ Me; R4 ¼ SR, SAr). Indeed, 3-unsubstituted compounds 186 (X ¼ CH, N; R3 ¼ R4 ¼ H) yield anilines 208, suggesting a low stability of heterosubstituted intermediates. When 4-bromobutyl thiocyanate is employed as alkylsulfur donor, spiro compounds 186 (X ¼ CH, N; R3–R4 ¼ –S(CH2)4–) are formed. A different behavior is observed using 3-bromopropyl thiocyanate (see Section 4.05.6.3.2) . 3,3-Dichloro derivatives 186 are generated from 186 (X ¼ CH, N; R3 ¼ R4 ¼ H) and hexachlorohexane under phase-transfer catalysis (PTC) conditions. The treatment of 186 (X ¼ N, R1 ¼ R3 ¼ Me, R4 ¼ H) with NaOH in DMSO gives the autoxidation product 209 (X ¼ N, R1 ¼ R3 ¼ Me) . Arylation of 186 (X ¼ CH, N; R3 ¼ H) with p-fluoronitrobenzene in NaOH yields 3-aryl compounds 186 (R3 ¼ p-O2NC6H4). If the same reaction is performed with potassium carbonate in PTC conditions, benzophenones 209 (X ¼ CH, N; R3 ¼ Ar) are formed directly . The one-pot reaction between 186 (R1 ¼ Me, R3 ¼ R4 ¼ H) and the 3,3-dichloro derivatives 186 yields the corresponding 3-chloro anions which react in situ with nitroarenes giving 3-(nitroaryl)benzosultams 210 (Q ¼ CH, N) .

Convenient procedures for the preparation of substituted camphorsulfonyl oxaziridines have been reported .

Isothiazoles

Optically active diaryl(acylamino)(acyloxy)spiro--4-sulfanes are key intermediates for the interconversion of a sulfoxide stereocenter (see Section 4.05.3.6). As an example, sulfoxide (R)-211 was transformed into spirosulfane (S)-212 using sulfopropionic anhydride. A selective S–O cleavage occurs with tetrafluoroborate affording (R)-213, which is then transformed into sulfoxide (S)-214 with inverted configuration at sulfur .

Ring opening to disulfide 216 (R ¼ NHR1, X ¼ S-216) or sulfonic acid 216 (R ¼ OR1, X ¼ SO3H) occurs in a palladium-catalyzed carbonylation reaction of 215 (see Sections 4.05.9.1.2 and 4.05.3.5) . Raney nickel reduction of (S)-217 (see Section 4.05.9.1.1) gives (S)-N-tosyl-2-methyl-1-phenylpropylamine . Reduction of tricyclic compounds 218 (see Section 4.05.9.1.3) yields 2-aryl-substituted cyclic amines 219 (R ¼ H; n ¼ 1, 2) or N-tosyl-4-phenylbutylamine. Using this route, enantiopure diastereomeric pyrrolidines syn-219 and anti-219 (R ¼ CH2OH, n ¼ 1) were prepared .

The Diels–Alder reaction of sultams 220 (R1 ¼ H, acyl, Bu; R2 ¼ H) and enantiopure sultams 220 (R1 ¼ (S)2-CH(Me)Ph, (S)-2-CH(R3)CO2Me; R2 ¼ H) with different cyclic dienes and 2,3-dimethylbutadiene has been studied . The reaction proceeds at 110 C or in the presence of a Lewis acid. In all conditions, the endo-adduct 221 is the preferred or the exclusive one and increases using the catalyst. Poor diastereofacial selectivity is imparted by the chiral auxiliary. Indeed, from enantiopure compound (S)-220 (R1 ¼ iPr, R2 ¼ Bn), a complete facial stereoselectivity was observed affording endo/exo-cycloadducts 221. Subsequent ringopening metathesis polymerization (ROMP) of the cycloadducts using 1–20 mol% of the Grubbs’ benzylidene catalyst and quenching with ethyl vinyl ether affords oligomeric sulfonamides 222. Various chiral sultams 220 (R2 ¼ H, R1 ¼ chiral group) were used in the 1,3-dipolar cycloaddition reactions with nitrile oxides and chiral nitrones. The reactions are regioselective and a mixture of diastereomeric compounds 223 and 224/2249 were formed, respectively, but a low diastereoselectivity was observed with the first type of dipole. Improved diastereoselectivity with nitrones was attributed to double asymmetric induction . Compounds like 223 and 224 deprotected at nitrogen atom are used as chiral auxiliaries (see Section 4.05.12.1).

581

582

Isothiazoles

A practical preparation of N-(1-alkynyl)-benzosultams and of N-(1-alkynyl)-Oppolzer’s sultam from the NHderivatives and 1-bromo-1-alkynes in the presence of CuI/K3PO4/(CH2NHMe)2 has been reported . Zinc-mediated allylation of 4,5-dihydroisothiazole S,S-dioxides affords 225 (R ¼ H, Me). Oxidative cleavage of the double bond yields acid 226 . Enantiopure 4,5-dihydro-3H-isothiazole 1-oxides 227 (R1 ¼ R2 ¼ H; R1 ¼ H, R2 ¼ alkyl) (see Section 4.05.9.1.3) have been alkylated. Chiral carbanionic ligands, deriving from 227 (R2 ¼ H), in cupric reagents 228 (R1 ¼ H, alkyl) mediate the conjugate addition to unsaturated cyclic ketones, with good diastereoselection .

Pyrroloisothiazoles 229 (n ¼ 0) (see Section 4.05.9.1.1) are reduced with NaBH4 with formation of sodium salt 230 which can be reoxidized to 229 with iodine. Likewise, 229 (n ¼ 0) is obtained by a reduction/oxidation sequence from 229 (n ¼ 1). When starting from 229 (n ¼ 2), the reduction with NaBH4 affords the trans-dihydro derivative 231 (R4 ¼ Ph). From compounds 229 (R3 ¼ H), cis-amido-sulfenato Pt-complexes 232 are prepared by insertion of Pt into the N–S(O) bond . Other ring transformations for similar compounds are reported in Sections 4.05.7.3 and 4.05.10.4. The reaction of 233 (X ¼ OMe; R2 ¼ H, Br; R1 ¼ CO2Me) with methylamine affords 233 (X ¼ NHMe) transformed by heating into 229 (R1 ¼ CO2Me; R2 ¼ H, Br; R3 ¼ Me). Compound 233 (X ¼ OMe, R2 ¼ Br) reacts with hydrogen sulfide and an oxidant giving 4H-1,2-dithiolo[4,3-c]isothiazoles 234 (n ¼ 0). Utilizing the carboxylate groups, several selective functionalizations of both positions 6 and 3 in 234 were performed. An oxido-reduction reaction between 234 and 233 (R1 ¼ CO2Me, R2 ¼ X ¼ S) was performed and 233 was transformed into thiolactone 235 (R5 ¼ SMe, X ¼ S) in the presence of MeI. Treating 231 (R4 ¼ H) with NaOH gave dihydropyrrolone 235 (R5 ¼ H, X ¼ NMe) .

4.05.6.4 Tetrahydroisothiazoles 4.05.6.4.1


For the general structural types of tetrahydroisothiazoles, see CHEC-II(1996) (see p. 351). Apart from some examples of sultams substituted on nitrogen and carbon atoms with alkyl groups, of importance is the equilibrium between S-alkyl-S-acyl sultam and the corresponding isothiazolidinium salt (see Section 4.05.6.4.3), the synthesis and reactivity of thia-1-azabicyclo[3.1.0]hexane S,S-dioxide 243 and its benzo derivative (see Sections 4.05.6.4.4 and 4.05.9.1.2), the preparation of vinylsultams like 252 and 256 (see Section 4.05.6.4.4), and molecules containing the sultam skeleton inserted in a particular structure such as 249 and 257 (see Section 4.05.6.4.4).

Isothiazoles

4.05.6.4.2

Reactions at the ring nitrogen

N-Arylated 1,3-propanesultams 236 (R1 ¼ Ar, R2 ¼ H) are efficiently prepared from a Pd-catalyzed cross-coupling reaction with different aryl bromides in the presence of Xantphos . N-Fluorinated (þ)-camphorsultams 237 (X ¼ H, Cl, OMe; R ¼ F) have been prepared; the corresponding imine 16 and difluoro derivative 238 were formed as by-products. The use of 237 is reported in Section 4.05.12.1 . The syntheses of N-(1-alkynyl)Oppolzer’s sultams are reported in Section 4.05.6.3.4. Many examples of acylated Oppolzer’s sultams are reported in Section 4.05.12.1.

4.05.6.4.3

Reaction at the ring sulfur

Selective reactions on N-substituted isothiazolidinium salts 239/2399 (see Section 4.05.9.1.1) afforded 240 with sodium hydroxide (R ¼ Ph, Ot-Bu), 241 in chloroform, and 242 with sodium borohydride .

4.05.6.4.4

Other reactions

The reaction of nucleophiles with 243 (see Section 4.05.9.1.2) affords products 244 through aziridine ring opening. Starting from 245 (R ¼ H), reaction with a Grignard reagent gave 246 . The rhodiumcatalyzed carbonylation of N-alkylisothiazolidines 247 occurs at the S–N bond and gives tetrahydro-2H-1,3-thiazin2-ones 248 . The conversion of 1-aza-8-thiabicyclo[4.2.1]nona-2,4-diene S,S-dioxide 249 (see Section 4.05.9.1.3) into the strained spirocycle 250 was achieved via photoinduced SO2–N bond cleavage .

A mixture of diastereomers 251 (X ¼ F, R1 ¼ R2 ¼ Ph, R3 ¼ H) was obtained by -fluorination of 251 (X ¼ H, R ¼ dimethoxybenzyl (DMB)) (see Section 4.05.9.1.3). Compound 251 (R1 ¼ Ph, X ¼ R2 ¼ H, R3 ¼ DMB) gave 3

583

584

Isothiazoles

mono- and difluorinated products but in low yields . The condensation of 3,5-di-t-butyl-4hydroxybenzaldehyde and N-substituted -sultams affords an (E/Z)-mixture of aldol-condensation products 252 . The use of the p-quinone methide 253, generated from the corresponding benzaldehyde, leads to a single isomer (E)-252 (R ¼ Et), via a 1,6-Michael addition. The effect of solvent and base on this process was evaluated . A different approach was used to prepare vinylsultams: phosphonates 254 were used in a Wittig–Horner reaction affording 255 (E/Z-mixture) . Lithiated N-methyl sultam adds to an (R)-sulfinyl imine affording 256 in 99% de . Compound 258, an intermediate for the preparation of epicilindricine C, was obtained by reacting the anion of compound 257 (see Section 4.05.9.1.3) with 1-octene oxide, followed by oxidation of the hydroxy group, base-induced -elimination, and Miyaura borylation .

4.05.7 Reactivity of Substituents Attached to Ring Carbon 4.05.7.1 General Survey of Reactivity Few examples of functionalization on the benzene ring of benzisothiazole have been reported (see Section 4.05.7.2). Studies on the reactivity of unsaturated chains in cycloaddition reactions have been reported (see Section 4.05.7.3). The high reactivity of 4-vinylisothiazolin-3-one S-oxides in Diels–Alder cycloadditions, both as diene and dienophile, is illustrated by their tendency to dimerize. 5-Vinylisothiazole S,S-dioxides react at the vinyl function with different 1,3-dipoles. Isothiazolo-3-sulfolenes 265 give an o-quinodimethane which can be trapped with a dienophile. Different isothiazole derivatives substituted with a carbon chain functionalized with heteroatoms have been prepared as ligands for the formation of complexes. 3-Oxocamphorsulfonimide reacts with the anion of alkynes and several studies on the reactivity of the products with electrophiles are reported. Several 4-amino-5-haloisothiazoles have been prepared and used to synthesize isothiazolo[4,5-49,59]pyrazines (see Section 4.05.7.4). Thermal decomposition of 5-azidoisothiazoles yields isothiazoles condensed with a second heterocyclic ring. 3-Allyloxy-1,2-benzisothiazole S,S-dioxides undergo thermal rearrangement forming products of both a sigmatropic [3,3]-shift and of a [1,3]-shift (see Section 4.05.7.5). Only one example of a nucleophilic displacement of the sulfone moiety has been reported (see Section 4.05.7.6).

Isothiazoles

A significant improvement in the use of different cross-coupling protocols from several halo-substituted isothiazoles should be noted (see Section 4.05.7.7). Various reagents and conditions were tested, for example, Stille reactions with stannanes, the Pd(II) cross-coupling reaction with terminal alkenes, the Castro–Stevens Pd-catalyzed reaction with Me4Sn, as well as the Suzuki cross-coupling reaction with arylboronic derivatives. The Sonogashira reaction with alkynes on trihalogenated isothiazoles is selective for C-5. A boronic ester containing the isothiazole ring has also been prepared. Isothiazol-5-yllithium is used to prepare gold and wolframio complexes (see Section 4.05.7.8). A few reactions of substituents involving ring transformation have been reported (see Section 4.05.7.9), including the transformation of 5-alkyl isothiazolium salts into indolines and the nucleophilic ring enlargement of 2-substituted3-isothiazolones to give 1,3-thiazin-4-ones. Finally, the base-catalyzed conversion of 5-alkyl-substituted isothiazolium salts gives 2,3-dihydrothiophene derivatives and the same salts react with a second molecule of a different isothiazolium salts affording 6a4-thia-1,6-diazapentalenes.

4.05.7.2 Fused Benzene Rings The substitution of the chloro atom on the benzene ring with methyl thiolate followed by oxidation gave a series of methylsulfonyl 1,2-benzisothiazole-3-one S,S-dioxides 259 . 4-Thiomethylbenzisothiazolone S,S-dioxide 260 was prepared from the corresponding 4-bromo derivative using 1-(2-hydroxyethyl)-4,6-diphenylpyridine-2-thione (HDPT) as thiolating reagent .

4.05.7.3 Carbon-Linked Substituents The Stille reaction on 4-bromoisothiazolin-3-one S-oxides 261 (R ¼ Et, (S)-2-C(Me)Ph) affords the vinyl intermediates 262 (n ¼ 1), which immediately undergo a Diels–Alder dimerization yielding adducts 263 via an exo-transition state (see Section 4.05.2.2). As a confirmation of the high reactivity of 262 (n ¼ 1) in Diels–Alder reactions, the oxidation of ethenyl derivative 262 (R ¼ Et, n ¼ 0) (see Section 4.05.7.7) affords directly the dimer endo263. By the same reaction in the presence of N-phenylmaleimide, compound endo-264 is formed .

585

586

Isothiazoles

The thermolysis of isothiazolo-3-sulfolenes 265 (see Section 4.05.9.2.1) allows the generation of o-quinodimethane analogues 266 which can be trapped with dienophiles affording 267 or 268 .

5-Vinyl-3-diethylaminoisothiazole S,S-dioxides 269 (R ¼ H, OEt) give a regioselective cycloaddition reaction with nitrile oxides and mu¨nchnones at the exocyclic double bond affording adducts 270 and 271, respectively. Treating 270 (R ¼ H) with TEA leads to an internal oxido-reduction reaction affording 272 (two diastereomers). Heating 271 gives compound 273 via loss of both SO2 and Et2NH. The same behavior was found for compounds 270 which were transformed into pyrazole derivatives 274 . Compound 275 (R1 ¼ Cl, R2 ¼ CONH2, R3 ¼ Bn) was transformed into the 5,6-dihydro-4H-isothiazolo[5,4-b]-1,4-thiazine 276 by a sequence of transposition, oxidation, and intramolecular condensation . The oxidative dehydration with chlorine of the carboxamide group of 275 (R2 ¼ CONH2) giving nitrile 275 (R2 ¼ CN) is assisted by the sulfur atom .

A series of isothiazole-based potential ligands 277 (n ¼ 1, 2), 278, and 279, bearing substituents with additional donor sites at the 5-position of the heterocycle, were prepared and dimeric silver(I) complexes with AgO3SCF3 generated . 3-(-Phenylvinyl)-1,2-benzisothiazole S,S-dioxides 115 (Ar ¼Ph, C6H4-4-OMe) (see Section 4.05.5.6) were synthesized by reaction of 280 or of 3-lithiomethylene-benzisothiazole with the appropriate benzaldehydes. Compounds 115 (Ar ¼ Ph, C6H4-4-OMe) undergo intramolecular Friedel–Crafts alkylation yielding 42 . Racemic 3-carboxysultam 281 (R1 ¼ R3 ¼ R4 ¼ H) is obtained via the cyano derivative 203 (R1 ¼ H, R2 ¼ CN, R3 ¼ MPM). Alkylation at C-3 of N-protected 281 (R1 ¼ H, R3 ¼ MPM (p-methoxyphenylmethyl), R4 ¼ Me) followed by deprotection of functional groups affords 281 (R1 ¼ Bn, H; R3 ¼ R4 ¼ H). The chemical resolution of this acid with brucine was described. The one-pot oxidation/reduction reaction of the chiral diol 203 (R1 ¼ H, R2 ¼ CHOHCH2OH) (see Section 4.05.9.1.2, compound 429) gives alcohol 203 (R1 ¼ H, R2 ¼ CH2OH). Attempts to oxidize this compound to acid 281 (R1 ¼ R3 ¼ R4 ¼ H) failed. The oxidation of N-protected alcohol 203 with RuCl3–NaIO4 afforded the enantiopure acid but in low yield . Selective ozonolysis of 282 yields compound 283, which reacted with diazomethane producing 284 . Michael addition of sulfur nucleophiles to -methylene--sultams 285 (see Section 4.05.9.1.3) gives a diastereomeric mixture of compounds 286 .

Isothiazoles

The reaction of 3-oxocamphorsulfonimide 287 with various deprotonated alkynes has been studied (see Section 4.05.2.2) . The reaction of 288 (R ¼ Ph), obtained from 287 and phenylethynyllithium, with electrophiles leads to the formation of a new ring. The substitution pattern of the ring is dependent on the functionalization of N- and O-atoms . Reaction with Br2 and I2 gives, via intermediates 289 (R1 ¼ R2 ¼ Me), dihalogenated compounds 290 (X ¼ Y ¼ Br, I), and with TiCl4 monohalogenated derivative 290 (X ¼ H, Y ¼ Cl). Intermediate 289 (R1 ¼ R2 ¼ H, X ¼ H) is stable in trifluoroacetic acid (TFA) but undergoes reduction of the sulfonamide to sulfinamide group in other solvents, giving two compounds 291 (X ¼ H, Y ¼ CF3CO2), epimers at sulfur, together with 292 (X ¼ H, Y ¼ CF3CO2). Comparable behavior was observed from 288 (R ¼ H) using Br2 and ICl. A single epimer 291 (X ¼ Cl, Y ¼ H) was obtained with HCl. Reactions with I2 gave a complex mixture containing an epimer of 291 and 290 (X ¼ Y ¼ I) and the derivative 293 (n ¼ 1). Compounds 291 and 290 are not very stable and hydrolyze to 291 and 293 (n ¼ 1), which is reduced to 293 (n ¼ 0). Dialkynyl derivative 288 (R ¼ SiMe3) was prepared in an analogous way and was transformed into 288 (R ¼ H). A Pt-catalyzed cascade reaction promotes the transformation of 288 into 294 (see Section 4.05.2.1) .

587

588

Isothiazoles

4.05.7.4 Nitrogen-Linked Substituents Zeolites efficiently catalyze the reaction of 3-aminobenzisothiazoles and nitriles to give amidines 295 . Starting from 296, the oxidative conversion of the hydrazino group to bromine followed by the transformation of the cyano group into amino afforded compound 297 (X ¼ Br, R ¼ Ph) . The reaction of the amino group of 297 (X ¼ Br, Cl; R ¼ Cl, Me, Ph) with dibromoisocyanuric acid gave dibromoamines 298, photochemical irradiation of which yielded 5-bis-isothiazolo[4,5-49,59]pyrazines 299 (R ¼ Cl, Me, Ph) and N,N9bis-(isothiazol-4-yl)diazines 300 (X ¼ R ¼ Cl; X ¼ Br, R ¼ Ph; X ¼ Br, R ¼ Me) as by-products . Treatment of 298 (X ¼ R ¼ Cl) with Cu/collidine gave 299 in good yield . Thermal decomposition of 5-azidoisothiazoles 301 substituted at C-4 with an electron-withdrawing group yielded bicyclic products 302 (X ¼ O, N–O). The cycloadduct 303 was formed from 301 (R1 ¼ H) and 2-methylbutadiene . N-Aryl-3-amino-4-nitroisothiazol-5(2H)-imines 120 (see Section 4.05.5.7) isomerize spontaneously to 2-(benzothiazol-2-yl)-2-nitroethene-1,1-diamines 304; the substituent effect was discussed . The synthesis of a series of imidazo[4,5-d]isothiazoles has been reinvestigated CHEC-II(1996) (see p. 354) .

4.05.7.5 Oxygen-Linked Substituents 3-Allyloxy-1,2-benzisothiazole S,S-dioxides 305 undergo thermal rearrangement forming products of both a sigmatropic [3,3]-shift 306 and of a [1,3]-shift 307. Compound 306 rearranges to 307, via an ionic transition state . With more rigid allylic systems such as that of myrtenol derivative 12, the [1,3]-rearrangement gives 13 (see Section 4.05.2.2) . The heterocyclic moiety of pseudosaccharyl ethers 22 (R1 ¼ Ar) is a good nucleofuge in Ni-catalyzed cross-coupling reactions with organotin and -zinc reagents and affords aryl ethers . Biohydroxylation of 308 (X ¼ H) was performed using Mortierella alpina, giving 308 (X ¼ OH, 72% de) .

Isothiazoles

4.05.7.6 Sulfur Substituents Several nucleophiles will displace the sulfone group in compound 309 yielding 310 (R ¼ ArO, ArS, NR2) .

4.05.7.7 Halogen Substituents Several 5-heterosubstituted-3-aminoisothiazoles were prepared from the corresponding 5-halo compounds (see Section 4.05.5.6). Cross-coupling reactions have been performed on several halo-substituted isothiazoles using different reagents and conditions. Stille reaction (Bu3SnR, (Ph3P)2PhCH2ClPd) on 5-bromo compound 69 (R ¼ Br) afforded 69 (R ¼ alkenyl, aryl, heteroaryl). As a by-product, the 5-H-substituted compound was formed . N-Substituted 4-bromoisothiazolin-3-ones 261 (n ¼ 0) have been functionalized at C-4 with alkynyl, alkenyl, and aryl stannanes using a Pd(0)-catalyzed Stille reaction . Polyhalogenated isothiazoles under different reaction conditions with several carbon donors, react at position 5. 3-Bromo-4-iodoisothiazole undergoes a base-catalyzed Pd coupling reaction with terminal alkenes giving the corresponding 4-alkenyl derivatives 311 in low to satisfactory yields together with 3,39-dibromo-4,49-isothiazole . The preferred position for cross-coupling of trihalogenated isothiazoles with alkynes is at C-5 in the Sonogashira reaction (CuI, PdCl2(PPh3)2, TEA, MeCN) which affords 312 (X ¼ Br, I). A further alkynylation occurs at C-4 to give 313 only if a 4-iodo atom is present in the starting reagent . Compounds 314 (X ¼ Cl, Br) were prepared from different 3- and 5-dihalogenated-4-cyanoisothiazoles. In this case too, selectivity in favor of C-5 was observed using a Suzuki cross-coupling reaction with arylboronic derivatives. Introduction of a phenoxy group at C-3 can be accomplished under various conditions, depending on the kind of halogen, to give 314 (X ¼ PhO) .

Several functionalized arylboronic derivatives undergo a Suzuki cross-coupling reaction with 5-chloroisothiazolinones affording 129 (R1 ¼ H, R2 ¼ Ar, R3 ¼ t-Bu) . The same ortho-haloaryl-substituted compounds can be prepared using the Heck reaction on isothiazolinones. The reduction of C(4)–C(5) double bond affords the corresponding sultams. Negishi reaction on 3-benzyloxyisothiazole and Suzuki cross-coupling via boronic ester 315 (see Section 4.05.7.8) with electrophiles (ArX or HetX) were unsuccessful. Instead, compounds 316 (R ¼ aryl, heteroaryl) can be prepared in good yields (using the Negishi or Suzuki cross-coupling protocols) and 5-iodo compound 316 (R ¼ I) as electrophile . Using the Castro–Stevens Pd-catalyzed reaction (Me4S/ PdCl2(PPh3)2), 5-iodo-isothiazole 317 (R ¼ I) was alkylated affording 317 (R ¼ Me) . An unusual cleavage of 3,7-dichloro-bis-isothiazolo[4,5-b,49,59-e]pyrazines 299 (R ¼ Cl) (see Section 4.05.7.4) with nucleophiles was reported, the reaction with MeONa giving 318; however, with amines, the diazo compounds 300 (X ¼ Cl; R ¼ BnNH, PhNH, morpholino) and 299 (R ¼ BnNH) were formed in low yields .

589

590

Isothiazoles

4.05.7.8 Metal Substituents 3-Benzyloxyisothiazole 316 (R ¼ H) is regioselectively lithiated at C-5 with LDA and the lithiated species reacts with MeOD and various C-electrophiles . Treatment with I2 or B(Oi-Pr)3/2,2-dimethyl-1,3propanediol affords the iodo compound 316 (R ¼ I) and the boronic ester 315, respectively (see Section 4.05.7.7) . The Grignard reagent of 3-iodoisothiazole reacts with a series of electrophiles . Addition of isothiazol-5-yllithium to gold chloride or to [(CO5)WCl)]NEt4 gives complexes 319 and 320 which can be protonated or alkylated affording the corresponding isothiazolinylidene complexes 321 (R ¼ H, alkyl), 322, and 323. The monogold complex was also prepared.

4.05.7.9 Reaction of Substituents Involving Ring Transformation Thermal reaction of 324 (X ¼ N, CH; R1 ¼ COR, COAr, CN) performed in the presence of diazabicycloundecane gave indolines 325 (X ¼ N, CH), via ortho-xylylenes (see Section 4.05.6.3.2). Starting from 325 (X ¼ N, R1 ¼ COC6H4-p-OMe), compound 326 was also formed . Nucleophilic ring enlargement of 2-substituted-3-isothiazolones 75 (R1 ¼ PhCO, H; R2 ¼ H; R3 ¼ CH(CO2Me)2) to give 1,3-thiazin-4-ones 327 was observed by treatment with TEA .

The base-catalyzed conversion of 5-alkyl-substituted isothiazolium salts 88 (R1 ¼ Me, R2 ¼ Et) to 2,3-dihydrothiophene derivatives 329 occurs in basic conditions via intermediates 328. The distribution of diastereomers 329 is dependent on the base and aryl substituent . Similar behavior was observed in the case of 88 (R1 ¼ R2 ¼ –(CH2)4–) . The condensation of 5-Me-substituted isothiazolium salts 88 with a second molecule of a different isothiazolium salts affords 6a4-thia-1,6-diazapentalenes 330. In this way, macrocyclic ethers 332 were prepared from 331 and their complexation behavior toward sodium(I), silver(I), and mercury(II) studied .

Isothiazoles

4.05.8 Reactivity of Substituents Attached to Ring Heteroatoms 4.05.8.1 Ring Nitrogen Ritter-type reaction of N-chlorosaccharin 108 (R ¼ Cl) with several alkenes in MeCN gives -chlorosulfonylamidines 333, the key intermediates for the preparation of imidazolines 334 through ring opening with MeONa followed by cyclization. Depending on the nature of the alkene, competitive formation of 334, aziridine 335, and the products of allylic chlorination of the alkene are observed . The synthesis of new isothiazolo[3,2-b]1,3,4-oxadiazole S,S-dioxides 337 is achieved from hydroxy compounds 336 in refluxing toluene, via an azomethine imine . The stereocontrolled addition of 3-alkyl-N-alkynylbenzosultams (see Section 4.05.6.3.4) to aldehydes to give 338 is promoted by Ti(i-PrO)4/2i-PrMgCl. Starting from a chiral sultam, a high de was achieved in the formation of the new stereocenter .

4.05.8.2 Ring Sulfur The use of spirosulfane (S)-212 as a key intermediate for the interconversion of a sulfoxide stereocenter is reported in Section 4.05.6.3.4. Stable carbanions react at the sulfur atom of the sulfenyl moiety of N-sulfenyl-1,2-benzisothiazolin3-ones 339 affording compounds 340. Thiols react at the ring sulfur affording ring-opened products 341, and Grignard reagents react at both sulfur atoms giving a mixture of 342 (R1 ¼ OR) and 343. The reaction of Grignard reagents on 344 has been reinvestigated and the structure of the ring-cleavage products 342 (R1 ¼ NHR) confirmed .

591

592

Isothiazoles

4.05.8.3 Reaction of Substituents Involving Ring Transformations The transformation of 2-methyl-1,2-isothiazolium salts 345 with amines into pyrroles 346 (X ¼ CN, CO2NH2) and enamine 347 has been revisited and mechanistic details given . 2-(Benzenesulfonylamino) isothiazolium-2-imines 348 react with hydroperoxide at 0 C, inducing ring enlargement to give 1,2,3-thiadiazines 349. Their oxidation with hydroperoxide at 25 C produces ring contraction to form isothiazol-3(2H)-ones 350 . Optimization in the preparation of oxicams 351 and 352 from saccharin derivatives has been described (see Section 4.05.9.1.1) .

4.05.9 Ring Synthesis from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component 4.05.9.1 Formation of One Bond 4.05.9.1.1

Formation of a nitrogen–sulfur bond

The main and more attractive methods for the construction of the isothiazole ring are based on cyclization of compounds containing an N–C–C–C–S fragment.

Isothiazoles

Oxidative cyclization of dithiooctanediamides via sulfenyl halogenides is a well-known approach to the isothiazole ring . A one-pot procedure giving a high yield of 261 (n ¼ 0) from the thiopropionamide 353 was developed, improving the already-known two-step procedure (see Section 4.05.7.3) . The exploitation of the same procedure starting from 2,29-dithiobis[7-14C]benzoic acid afforded 14C-labeled benzothiazolone 354, which is useful for pharmacokinetic and metabolic studies . 3-Amino-substituted isothiazole dioxides 70 (R1 ¼ R2 ¼ H, n ¼ 2) and their mono- and dihalogeno derivatives 70 (R1 ¼ Cl, R2 ¼ H; R1 ¼ R2 ¼ Cl) can be synthesized taking advantage of chlorination during the cyclization process (see Sections 4.05.2.2 and 4.05.5.4) . Various N-substituted 1,2-benzisothiazolin-3-ones 344 (R1 ¼ H) can be synthesized by reacting N,N9-disubstituted 2,29-dithiobenzamides 355 with O-methylhydroxylamine hydrochloride . Starting from anilides 356 (R1 ¼ H, MeCO; R2 ¼ Ar, Me), the S–N bond formation can be promoted by several reagents such as trifluoromethylsulfenyl chloride or ceric ammonium nitrate (CAN) to give isothiazoles 357 . By applying the same methodology, chiral 3,5-disubstituted isothiazole derivatives 359 of high enantiomeric purity can be obtained by oxidation of chiral 3-amino-2,3-unsaturated thioamides 358 derived from natural -amino acids . The substitution in compounds 135 of the SR2group by new SR3groups can be achieved via 136 (see Section 4.05.5.10), which were transformed into nickel complexes 360 in excellent yields. The reaction of 360 with arenethiols or alkanethiols gives the new isothiazoles 361 through intermediates like 136 oxidized to 135 containing the SR3 groups. Compounds 135 give 361 by deprotection of nitrogen with KI in DMSO. This methodology is particularly useful for preparing 3-(arylthio)substituted isothiazoles 361 (R3 ¼ Ar) .

The reaction of S,N-acetals 136 (R1 ¼ R2 ¼ Me) with acetophenone in the presence of mercury(II) acetate affords 2-methyl-5-phenylisothiazol-3-ones 75 (R1 ¼ Ph, R2 ¼ H, R3 ¼ Me) . 3,3-Diamino-2-nitroacrylthioamides 128 (R1 ¼ Alkyl, Ar; R2 ¼ Alkyl, Ar; R3 ¼ RCO, Ar) (see Section 4.05.5.7) can be cyclized affording 4-nitro-1,2-thiazol-5(2H)imine derivatives 120. The use of diethyl diazodicarboxylate (DEAD) as the dehydrogenation reagent proves to be superior with respect to the previously used reagents affording higher yields, shorter reaction times, and easier isolation of products . Oxidative cyclization of -cyano--thioenaminones 363, prepared from 362, affords a series of 3,5-disubstituted4-isothiazolecarbonitriles 364 (Equation 5). Compared to the previous procedures, this strategy to cyanoisothiazoles is extremely simple and highly flexible .

ð5Þ

The preparation of isothiazolopyrimidine 366 (R ¼ H) is based on the same procedure, and is obtained in good yield (81%) by oxidation of the stable thioaldehyde 365 with Pb(OAc)4 in AcOH . Isothiazole 368 can be obtained by intramolecular cyclization of the thermally labile -cyano-sulfenyl chlorides 367 (R1 ¼ CF3, R2 ¼ Cl). In an analogous way, 367 (R1 ¼ F, R2 ¼ t-Bu) readily reacts with sulfuryl chloride affording isothiazoline 369

593

594

Isothiazoles

. Asymmetric synthesis of -sultam 371 in a multistep procedure takes advantage of the diastereoselective nucleophilic addition of organocerium compounds to the CN bond of 370 . 2,5-Diarylisothiazoles 75 (R1 ¼ Ar1, R2 ¼ H, R3 ¼ Ar2) as novel inhibitors of cytokine-induced cartilage destruction were prepared by exploiting the usual oxidative cyclization with I2 and TEA from 372 . The oxidative chlorination–cyclization process has been developed for the stereoselective synthesis of a variety of 4-amido-isothiazolidinone oxides 373 and 374 (n ¼ 1, 2) through formation of an S–N or C–N bond (see Section 4.05.9.1.2) . The formation of cyclic N-acylaminosulfonium salts 239 (see Section 4.05.6.4.3) was achieved by treating N-protected -aminosulfoxides 240 with 2 equiv of TFA in MeCN at 0 C. The reaction of acyclic N-protected -aminosulfoxides can be successfully extended to the cyclic -aminosulfoxides 375 (R ¼ BOC, Ph2N) affording 376 . (Z)-Sulfinylacrylonitriles 377 (R ¼ H, n-Bu), treated with HBF4 and MeOH, give compounds 164, which were demonstrated to be good chiral dienophiles in asymmetric Diels–Alder reactions (see Section 4.05.5.11) . Efficient formation of isothiazolines 379 (Ar ¼ phenyl, 1-naphthyl, 3-pyridinyl, (3,6-dimethoxypyridazine-4-yl) can be realized through thermolysis of the corresponding aminosulfoxides 378 in high ee . The sulfoxide 380 (R ¼ t-Bu) undergoes thermal elimination of isobutene at quite low temperature and the resulting sulfenic acid 380 (R ¼ OH) is trapped by intramolecular electrophilic addition giving 381. The addition of water to the iminium double bond of 381 followed by ring opening and prototropic shift yields the isothiazolone 382 .

Selective syntheses of nitro-substituted 1,2-benzoisothiazol-3-one S-oxides 72 (n ¼ 1) using gaseous chlorine in wet CH2Cl2 are available from 383 . Application of the same oxidative cyclization pathway allows the preparation of polycyclic systems such as 384 and 67 containing the isothiazole moiety . Mixtures of isomeric compounds 386 (R ¼ H, Cl; R1 ¼ H, Cl) are obtained with N-chlorosuccinimide (NCS) from 385 (R ¼ H, Cl) in different ratios depending on the substitution . From oximes 387, through a known protocol, pyrrolo[2,3-c]isothiazoles 388 were obtained in good yield .

Isothiazoles

Another oxidative cyclization was applied for the synthesis of sinalexin 390 (R ¼ OMe) and brassilexin 390 (R ¼ H) starting from 389 by regioselective formylation under Vilsmeier conditions followed by a work-up with NH3 . Pyrroloisothiazoles 229 (n ¼ 0) are formed by treating enamide 391 with Na2S and then I2 or H2O2. Compound 229 (n ¼ 1) deriving from S-oxidation of 229 (n ¼ 0, R1 ¼ Ph, R2 ¼ COOMe, R3 ¼ H, R4 ¼ Me) can also be obtained by S–N exchange from the corresponding dithiol monoxides (see Section 4.05.10.4) .

A one-step synthesis of isothiazolo[3,4-d]pyrimidine 394 is available by cyclization in toluene at reflux of the sulfilimines 393 deriving from 392 (Equation 6) .

ð6Þ

O-(Mesitylenesulfonyl)hydroxylamine acts as condensing agent on 2-alkylthio-3-acetyl-4-quinolones affording 395 .

Only very mild conditions are required to convert 2,29-dithiobis(benzonitrile) 396 into 3-amino-1,2-benzisothiazoles 397 using secondary amines and CuCl2 as the oxidant .

595

596

Isothiazoles

7-Substituted saccharins 108 (R ¼ Me), which can be transformed into 8-substituted oxicams by a standard ringexpansion methodology (see Section 4.05.8.3), are formed in a one-pot reaction from unsubstituted N-methylbenzensulfonamides . A convenient one-pot synthesis of benzisothiazolones 344 (R1 ¼ H, R2 ¼ NH2, R3 ¼ H) has been developed using a cyclization reaction in which the acyl azide 398 (X ¼ CH) was used as an intermediate. Similarly, 2-mercaptonicotinic acyl azide 398 (X ¼ N) affords the corresponding isothiazolo[5,4-b]pyridin-3(2H)-one .

Flash vacuum pyrolysis of the oxime ethers 399 (R2 ¼ OMe, R3 ¼ Ph) or of the imines 399 (R2 ¼ Ar, R3 ¼ Bn) at 650 C (103 Torr) gives benzo[d]isothiazoles 400 as the major products via the iminyl and thiophenyl radicals .

Treating N-aryl-2-(benzylthio)benzamides 342 with [bis(trifluoroacetoxy)iodo]benzene containing TFA resulted in an interrupted Pummerer-type reaction to give 2-aryl-1,2-benzisothiazol-3(2H)-ones 403 through intermediates 401 and 402, rather than the normal Pummerer-type products (Equation 7) .

ð7Þ

2,3-Dihydro-3-oxo-isothiazolo[5,4-b]pyridines 404 were prepared by cyclization of N-substituted 2-sulfinylnicotinamides in diluted hydrochloric acid–methanol solution at room temperature more readily and in relatively higher yields with respect to the previously known methods . A practical large-scale synthesis of the naphthosultam-based side-chain of an anti-MRSA antibiotic 405 has been achieved taking advantage of a new naphthosultam annelation (MRSA ¼ methicillin-resistant Staphylococcus aureus) . Alkylsulfanylisothiazoles 407 (R ¼ Bn, COPh, Me) were formed using sodium dithiolates 406 as starting components which react with sulfur in the presence of piperidine acetate . Complex 409 is obtained when complex 408 is treated with silica gel .

Isothiazoles

4.05.9.1.2

Formation of a bond adjacent to a heteroatom

The isothiazole ring can be built through formation of either C–S and C–N bonds; however, there are many more examples of methodologies based on C–N bond formation. A large number of examples of syntheses exploiting wellknown methodologies appeared in the literature in the decade 1996–2006, producing a number of new or known isothiazoles opportunely substituted for investigations in different fields . Formation of 411 (R1 ¼ SO2NH2, R2 ¼ H) from 410 (R ¼ SO2Cl) via reaction with NH3 and Michael addition provides a simple and convenient route to 3-methylsulfonamido-1,2-benzoisothiazole 1,1-dioxide, which is otherwise difficult to obtain . The same easy Michael addition, but using cyclohexylamine, produces compound 411 (R1 ¼ COPh, R2 ¼ C6H11) from 410 (R ¼ COPh). With ortho-phenylenediamine, compound 412 is formed .

3-Substituted-1,2-benzoisothiazole S,S-dioxides 112 (R ¼ Me, Et, Ph) and 55b (through the tautomeric compound 55a; see Section 4.05.4.5) were prepared through condensation of polylithiated -ketoesters or -diketones or -ketoamides with lithiated methyl 2-(aminosulfonyl)benzoate. This last can also be reacted with some Grignard or organolithium reagents . Benzoisothiazolo[1,2-b][1,2]isoquinolin-11-one S,S-dioxide 413 derives from the reaction with dilithiated o-toluic acid . In an analogous manner, the reaction of lithiated 2-methylbenzenesulfonamides with N,N-dimethylsulfamoyl chloride afforded 2-substituted-1,2benzisothiazole S,S-dioxide 203 (R1 ¼ R2 ¼ H) as the minor compound together with the major product, the dimer

597

598

Isothiazoles

414 . N-Unsubstituted 1,2-benzisothiazolin-3-ones 344 (R1 ¼ H; R2 ¼ H, Cl, OMe; R3 ¼ H, Cl, OMe) can be prepared in a chlorine-free synthesis by cyclization of 2-sulfenamoylbenzoates 342 (R1 ¼ OR, R2 ¼ NH2) which are prepared by amination of thiosalicylates with hydroxylamine-O-sulfonic acid. N-Substituted sulfenamoylbenzoates, prepared by transamination with different amines, can be cyclized to N-substituted 1,2benzisothiazolin-3-one 344 (R1 ¼ PhCH2, p-MeOC6H4CH2, p-ClC6H4CH2) .

Another application of the well-known cyclization of ortho-substituted benzenesulfonamides consists in the treatment of 415 (R1 ¼ NR2, R2 ¼ Me) with Et3OBF4 followed by aqueous H2SO4 affording good yields of benzisothiazol-3-one 1,1-dioxides 416. Their alkaline hydrolysis afforded 415 (R1 ¼ OH, R2 ¼ R3 ¼ H), which is stable at neutral pH but recyclizes to 416 under even mild acidic conditions (pH < 4) .

The oxidation of 2-methylbenzenesulfonamide is a known method affording saccharin derivatives. Sodium dichromate in sulfuric acid has been proposed as the most efficient oxidation system . The oxidative chlorination–cyclization processes developed for the stereoselective synthesis of 373 and 374 (see Section 4.05.9.1.1) can be applied for the synthesis of other isothiazolidinones through a methodology providing C–N bond formation . Amidation of saturated C–H bonds and aziridination of alkenes catalyzed by metal complexes based on Fe, Mn, Ru, Cu, or Rh are established methodologies for C–N bond formation. The enantioselective version of these methodologies is increasingly used. Intramolecular aziridination of unsaturated sulfonamides 417 and 418 (R ¼ H, Me) catalyzed by metal complexes makes use of dirhodium Br > Cl. 4-Bromo or 4-iodo isothiazoles were prepared from the corresponding 4-cyano derivatives . A highly streoselective asymmetric synthesis of the potent pTyr mimetic (S)-IZD 603 was established in an atom-efficient method. The key transformation is the regioselective and stereoselective addition of hydride to a (R)-sulfinamide heterocycle 604 in high yield and with absolute stereochemical control (>98% de) . Starting from the results obtained on 218 (see Sections 4.05.6.3.4 and 4.05.9.1.3) further investigations concerning the double reduction of Diels–Alder-derived bicyclic sulfonamides 605, 606 were performed (R ¼ i-Bu, Bn; R1 ¼ Ph, H) .

In studies concerning the aymmetric hydrogenation of cyclic N-sulfonylimines (see Section 4.05.5.10) Pd/bisphosphine complexes (Pd(CF3CO2)2/(S)-SegPhos) in TFE as solvent were found to be effective catalysts for the asymmetric hydrogenation of 112 (R ¼ Me, Bu, Bn) to 134. The same conditions were successfully applied for the asymmetric hydrogenation of 422 (see Section 4.05.9.1.2) to give the corresponding chiral sultam 419 (n ¼ 1) . Discussions on the possibility of synthesizing stable isothiazole carbenes have also been recently published . Concerning isothiazole derivatives with potential biological interest, carboxamidine isothiazole derivatives 607 (R1 ¼ cyclohexyl, pyrazolyl, i-Pr, alkylalcohol) have been synthesized as potent ChK2 inhibitors . Benzo[c]isothiazol-3-yl-benzamidines 295 (R ¼ H, Me; R2 ¼ Ar) were prepared as non-acidic anti-inflammatory/ antidegenerative agents . Saccharin derivative 108 (R ¼ CH2CONHArOH) was shown to be a potent analgesic analogue of acetaminophen with no hepatotoxicity .

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M. A. Ciufolini, S. Canesi, M. Ousmer, and N. A. Braun, Tetrahedron, 2006, 62, 5318. L. Xu, H. Shu, Y. Liu, S. Zhang, and M. L. Trudell, Tetrahedron, 2006, 62, 7902. S. Hajra, A. Karmakar, and M. Bhowmick, Tetrahedron: Asymmetry, 2006, 17, 210. N. A. Kulkarni, S.-G. Wang, L.-C. Lee, H. R. Tsai, U. Venkatesham, and K. Chen, Tetrahedron: Asymmetry, 2006, 17, 336. A. Chojnacka, A. M. Piatek, C. Chapuis, and J. Jurczak, Tetrahedron: Asymmetry, 2006, 17, 822. H.-Y. Ku, J. Jung, S.-H. Kim, H. Y. Kim, K. H. Ahn, and S.-G. Kim, Tetrahedron: Asymmetry, 2006, 17, 1111. B. H. Fraser, D. M. Gelman, P. Perlmutter, and F. Vounatsos, Tetrahedron: Asymmetry, 2006, 17, 1152. N. A. Kulkarni and K. Chen, Tetrahedron Lett., 2006, 47, 611. V. Nair, S. M. Nair, S. Devipriya, and D. Sethumadhavan, Tetrahedron Lett., 2006, 47, 1109. H. Firouzabadi, N. Iranpoor, and F. Ebrahimzadeh, Tetrahedron Lett., 2006, 47, 1771. E. Cleator, F. J. Sheen, M. M. Bio, K. M. J. Brands, A. J. Davies, and U.-H. Dolling, Tetrahedron Lett., 2006, 47, 4245. A. Casoni, G. Celentano, F. Clerici, A. Contini, S. Pellegrino, C. Rosini, A. Sala, and S. Tartaglia, Unpublished Result, 2006. H. Cline, K. Guigley, and K. Bullock, US Pat. 2006105657 (2006) (Chem. Abstr., 2006, 144, 490505). Z. Majka, K. Rusin, A. Sawicki, K. Kurowski, K. Matusiewicz, T. Sawinski, D. Sulikowski, and D. Ktudkiewicz, US Pat. 2006160870 (2006) (Chem. Abstr., 2006, 145, 145692). 2006USP2006217390 E.Gunic, T. Appleby, W. Zhong, S. Yan, and H. C. Lai, US Pat. 2006217390 (2006) (Chem. Abstr., 2006, 145, 348567). 2006WO2006001667 D.-J. Choi, S.-Y. Choi, and J.-J. Shin, WO Pat. 2006001667 (2006) (Chem. Abstr., 2006, 144, 93751). 2006WO2006065646 B. S. Brown, R. G. Keddy, and C.-H. Lee, WO Pat. (2006) (Chem. Abstr., 2006, 145, 83316). 2006WO2006073363 J. Bostroem, K. Brickmann, A. Broo, P. Holm, R. Judkins, L. Li, P. Sandberg, M. Swanson, and C. Westerlund, WO Pat. 2006073363 (2006) (Chem. Abstr., 2006, 145, 145685). 2006WO2006074788 P. Wachtler, WO Pat. 2006074788 (2006) (Chem. Abstr., 2006, 145, 118702). 2006WO2006089054 B. J. Bradbury, P. Godwin, W. Qiuping, D. Milind, M. J. Pucci, Y. Song, E. Lucien, J. Wiles, and A. Hashimoto, WO Pat. 2006089054 (2006) (Chem. Abstr., 2006, 145, 271761). 2006WO2006090234 V. J. Sattigeri, V. P. Palle, A. Soni, K. P. Naik, Keshav A. Ray, and S. G. Dastidar, WO Pat. 2006090234 (2006) (Chem. Abstr., 2006, 145, 293032). 2006WO2006091858 H. Hong, E. Goldestein, E. Stauffer, D. Goff, R. Kolluri, I. Darwish, R. Singh, and H. Lu, WO Pat. 2006091858 (2006) (Chem. Abstr., 2006, 145, 293041). 2007AG(E)3118 J. Wolf, W. Boehlmann, M. Findeisen, T. Gelbrich, H. J. Hofmann, and B. Schulze, Angew. Chem., Int. Ed. Engl., 2007, 46, 3118. 2007AG(E)6922 A. DeHope, V. Lavallo, B. Donnadieu, W. W. Schoeller, and G. Bertrand, Angew. Chem., Int. Ed. Engl., 2007, 46, 6922. 2007BMC2206 A. L. Vaccarino, D. Paul, P. K. Mukherjee, E. B. Rodriguez de Turco, V. L. Marcheselli, L. Xu, M. L. Trudell, J. M. Minguez, M. P. Matıá, C. Sunkel, J. Alvarez-Builla, and N. G. Bazan, Bioorg. Med. Chem., 2007, 15, 2206. 2007BML172 G. Larson, S. Yan, H. Chen, F. Rong, Z. Hong, and J. Z. Wu, Bioorg. Med. Chem. Lett., 2007, 17, 172. 2007JOC3199 J. Blanchet, T. Macklin, P. Ang, C. Metallinos, and V. Snieckus, J. Org. Chem., 2007, 72, 31996. 2007JOC3729 Y.-Q. Wang, S.-M. Lu, and Y.-G. Zhou, J. Org. Chem., 2007, 72, 3729. 2007MI1 P. Vicini, M. Incerti, V. Cardile, F. Garufi, S. Ronsisvalle, and A. M. Panico, Chem. Med. Chem., 2007, 2, 113. 2007OBC1381 I. C. Christoforou and P. A. Koutentis, Org. Biom. Chem., 2007, 5, 1381. 2007OL1279 A. P. Combs, B. Glass, L. G. Galya, and M. Li, Org. Lett., 2007, 9, 1279. 2007SC767 W. A. Siddiqui, S. Ahmad, I. U. Khan, H. L. Siddiqui, and G. Weaver, Synth. Commun., 2007, 37, 767. 2007T4733 S. Kelleher, J. Muldoon, H. Mueller-Bunz, and P. Evans, Tetrahedron Lett., 2007, 48, 4733. 2007THC(9)179 F. Clerici, M. L. Gelmi, S. Pellegrino, and D. Pocar, Topics in Heterocycl. Chem., 2007, 9, 179. 2006T5318 2006T7902 2006TA210 2006TA336 2006TA822 2006TA1111 2006TA1152 2006TL611 2006TL1109 2006TL1771 2006TL4245 2006UP1 2006USP2006105657 2006USP2006160870

631

632

Isothiazoles

Biographical Sketch

Francesca Clerici was born in Como, Italy, in 1960. She graduated in pharmacy (1984) and chemistry and pharmaceutical technologies (1994) from the University of Milano. She received her Ph.D. in medicinal chemistry from the same university. After an experience of five years in the Italian pharmaceutical industry, she joined the research group of Prof. Donato Pocar as assistant professor. Since 2003, she has been associate professor of organic chemistry at the University of Milano. Her research interests have been focused on organic synthesis with particular attention on medium-sized S,N-heterocycles, pericyclic reactions, and, in recent years, the synthesis of special heterocycles with biological activity. Since 1992, she has been an active member of Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi Etero- e Carbociclici (Interuniversity Centre on Pericyclic Reactions and Synthesis of Hetero- and Carbocyclic Systems). She has published over 60 papers in international journals.

Maria Luisa Gelmi was born in Leffe, Italy, in 1957. She studied chemistry at the University of Milano, obtaining her degree in organic chemistry with Prof. A. Marchesini in 1981. In 1988, she obtained her Ph.D. in organic chemistry at the University of Milano in the group of Prof. D. Pocar. In 1990, she became assistant professor at the Faculty of Pharmacy at the University of Milano, where she is now a full professor. Since 1992, she has been an active member of Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi Eteroe Carbociclici (Interuniversity Centre on Pericyclic Reactions and Synthesis of Hetero- and Carbocyclic Systems). She has several international and industrial collaborations. Her research fields are the diastereoselective and enantioselective synthesis of nonproteinogenic amino acids, the preparation of peptidomimetics and heterocyclic compounds, and the semisynthesis of natural compounds characterized by biological activity. She is the author of more than 80 publications in international journals and of several patents.

Isothiazoles

Sara Pellegrino was born in Imperia, Italy, in 1978. She studied chemistry and pharmaceutical technologies at the University of Milano, from where she graduated in 2002. She obtained her Ph.D. in medicinal chemistry, also from the University of Milano, in 2005. In 2004, she was a visiting Ph.D. student at the University of Regensburg, Germany. Since 2006, she has been postdoctoral fellow at the University of Milano in the research group of Prof. Maria Luisa Gelmi. Her research interests are in the synthesis of biologically active compounds such as unnatural amino acids, peptidomimetics, and heterocyclic compounds.

633

4.06 Thiazoles B. Chen and W. Heal The University of Sheffield, Sheffield, UK ª 2008 Elsevier Ltd. All rights reserved. 4.06.1

Introduction

638

4.06.2

Theoretical Methods

638

4.06.3


645

4.06.3.1

X-Ray Diffraction

645

4.06.3.2

MW Spectroscopy

649

4.06.3.3

UV Spectroscopy

649

4.06.3.4

Fluorescence Spectroscopy

650

4.06.3.5

IR and Raman Spectroscopy

650

4.06.3.6

NMR Spectroscopy

651

4.06.3.7

Mass Spectrometry

652

4.06.3.8

ESR Spectrometry

653

4.06.4 4.06.4.1


653

Intermolecular Forces

653

4.06.4.1.1 4.06.4.1.2

Melting and boiling points Solubility

653 653

4.06.4.2

Aromaticity and Stability

654

4.06.4.3

Conformations

654

4.06.4.4

Tautomerism

655

4.06.4.4.1 4.06.4.4.2

4.06.5 4.06.5.1

Substituted thiazoles Ring–chain tautomerism

655 656


657


4.06.5.1.1 4.06.5.1.2 4.06.5.1.3 4.06.5.1.4

657

Reactivity of neutral thiazoles Thiazolium ions Thiazolones, thiazolethiones, and thiazolimines N-Oxides, N-imides, and N-ylides of thiazoles

657 657 657 657

4.06.5.2


657

4.06.5.3


658

4.06.5.3.1 4.06.5.3.2 4.06.5.3.3 4.06.5.3.4 4.06.5.3.5 4.06.5.3.6 4.06.5.3.7

4.06.5.4

Introduction Basicity of thiazole Metal ions Alkylation Oxidation Amination Other reactions

658 658 658 659 659 659 659

Electrophilic Reaction at Carbon

4.06.5.4.1 4.06.5.4.2 4.06.5.4.3

660

Reactivity and orientation Nitration Sulfonation

660 660 660

635

636

Thiazoles

4.06.5.4.4 4.06.5.4.5 4.06.5.4.6 4.06.5.4.7

Halogenation The halogen dance reaction Oxidation Other reactions

660 661 662 662

4.06.5.5

Reaction at Sulfur

662

4.06.5.6


662

4.06.5.6.1 4.06.5.6.2

4.06.5.7

Nucleophilic Attack at Hydrogen (Deprotonation)

4.06.5.7.1 4.06.5.7.2 4.06.5.7.3 4.06.5.7.4

4.06.5.8 4.06.6

Oxygen nucleophiles Carbanions

662 662

664

C-Acylation via deprotonation Metallation at a ring carbon atom Hydrogen exchange at ring carbon Other reactions

664 664 665 665

Cyclic TSs with a Second Molecule

666


666

4.06.6.1

Isomers of Aromatic Derivatives

666

4.06.6.2

Dihydro Derivatives

666

4.06.6.2.1 4.06.6.2.2 4.06.6.2.3 4.06.6.2.4 4.06.6.2.5

4.06.6.3

Tetrahydro Derivatives

4.06.6.3.1 4.06.6.3.2 4.06.6.3.3 4.06.6.3.4 4.06.6.3.5 4.06.6.3.6

4.06.7

Tautomerism Aromatization Electrophilic reaction at nitrogen Nucleophilic attack at carbon Other reactions Tautomerism Aromatization Electrophilic reaction at sulfur Electrophilic reaction at nitrogen Ring opening Other reactions

Reactivity of Substituents Attached to Ring Carbons

666 666 667 668 668

668 668 669 669 670 672 672

672

4.06.7.1

General Survey

672

4.06.7.2

Fused Benzenoid Rings

672

4.06.7.3

Alkyl Groups

673

4.06.7.3.1 4.06.7.3.2 4.06.7.3.3

4.06.7.4

Side-chain halogenation Alkylthiazoles C-Alkylthiazolium ions

673 673 673


673

4.06.7.4.1 4.06.7.4.2 4.06.7.4.3 4.06.7.4.4 4.06.7.4.5

4.06.7.5

Aryl groups Carboxylic acids Aldehydes and ketones Vinyl and allyl groups Other substituents

Aminothiazoles

4.06.7.5.1 4.06.7.5.2

Reactions with electrophiles (except nitrous acid) Reactions with nitrous acid: Diazotization

673 674 674 674 675

675 675 676

4.06.7.6

Other N-Linked Substituents

676

4.06.7.7

O-Linked Substituents

676

4.06.7.8

S-Linked Substituents

677

4.06.7.8.1 4.06.7.8.2 4.06.7.8.3

Thiones Alkylthio groups Other substituents

677 677 678

Thiazoles

4.06.7.9

Halogen Atoms

4.06.7.9.1 4.06.7.9.2

4.06.7.10

Metals and Metalloid-Linked Substituents

4.06.7.10.1 4.06.7.10.2 4.06.7.10.3 4.06.7.10.4

4.06.8

Nucleophilic displacement Halogen–lithium exchange Lithium Silicon Tin Other metals


678 678 678

678 678 679 679 679

679

4.06.8.1

Substituents Attached to Ring Nitrogen Atom

679

4.06.8.2

Substituents Attached to Ring Sulfur Atom

679

4.06.9

Ring Synthesis Classified by Number of Ring Atoms in Each Component

4.06.9.1

Synthesis of Thiazoles

4.06.9.1.1 4.06.9.1.2 4.06.9.1.3 4.06.9.1.4 4.06.9.1.5 4.06.9.1.6 4.06.9.1.7 4.06.9.1.8 4.06.9.1.9 4.06.9.1.10

4.06.9.2

Synthesis from C2 þ NCS components Synthesis from C2N þ CS components Synthesis from C2NC þ S components Synthesis from SC2 þ NC components Synthesis from C þ CNCS components Synthesis from NCSC2 components Synthesis from SC þ CNC components Synthesis from C2NCS component Synthesis from SC2NC component Other syntheses

Synthesis of 2-Thiazolines

4.06.9.2.1 4.06.9.2.2 4.06.9.2.3 4.06.9.2.4 4.06.9.2.5 4.06.9.2.6 4.06.9.2.7 4.06.9.2.8

Synthesis Synthesis Synthesis Synthesis Synthesis Synthesis Synthesis Synthesis

from C2 þ NCS components from C2N þ CS components from CN þ SC2 components from C þ SC2N components from CNC2S components from C þ CNCS components from C2NCS component from CSC2N component

679 679 679 681 682 682 683 683 683 683 684 684

685 685 686 687 687 687 688 688 689

4.06.9.3


690

4.06.9.4


690

4.06.9.4.1 4.06.9.4.2 4.06.9.4.3

4.06.9.5

Synthesis of Thiazolidines

4.06.9.5.1 4.06.9.5.2 4.06.9.5.3

4.06.9.6

Synthesis from C2 þ NCS components Synthesis from C2N þ CS components Synthesis from NCSC2 component Synthesis from SC2 þ NC components Synthesis from SC2N þ C components Synthesis from CSC2N component

Synthesis of Benzothiazoles

4.06.9.6.1 4.06.9.6.2 4.06.9.6.3

Jacobson synthesis Ring closure of o-aminothiophenols Other methods

690 691 691

691 691 692 692

692 692 693 694

4.06.9.7

Synthesis of Fused Systems

695

4.06.10

Ring Syntheses by Transformation of Another Ring

696

4.06.10.1

Synthesis from Fully Conjugated Rings

696

4.06.10.2

Synthesis from Di- and Tetrahydro Derivatives

696

4.06.10.3

By Ring Contraction of Other Heterocycles

696

637

638

Thiazoles

4.06.11

Synthesis of Particular Classes of Compounds and Comparison of the Various Routes Available

697

4.06.11.1

Biosynthesis of Thiazole-Containing Natural Products

697

4.06.11.2

Synthesis of Thiazole Peptides

698

4.06.11.3

Synthesis of Thiazole-Containing Natural Products

699

4.06.11.3.1 4.06.11.3.2 4.06.11.3.3 4.06.11.3.4

4.06.12 4.06.12.1

Synthesis of linear peptides Cyclic peptides Macrocyclides Other syntheses

Important Compounds and Synthetic Applications Naturally Occurrence and Their Biological Applications

4.06.12.1.1 4.06.12.1.2 4.06.12.1.3 4.06.12.1.4

Linear peptides Cyclic peptides Macrocyclides and lactones Alkaloids

699 701 703 707

707 707 707 712 724 725

4.06.12.2

Synthetic Thiazole Derivatives and Their Biological Applications

726

4.06.12.3

Synthetic Applications

727

4.06.12.3.1 4.06.12.3.2 4.06.12.3.3 4.06.12.3.4

4.06.12.4

Synthetic equivalence to the formyl group Chiral auxiliaries Thiazolium salts as catalysts Other synthetic applications

Other Applications

4.06.12.4.1 4.06.12.4.2 4.06.12.4.3

Fluorescence PNA probes Synthetic sidephores/fluorophore DNA nucleases

References

727 733 736 740

741 741 742 742

742

4.06.1 Introduction The following structural cores, thiazole 1, benzothiazole 2, thiazolines 3–5, thiazolidine 6, and benzothiazoline 7, as well as their oxo, thioxo, and amino compounds are considered in the corresponding subsections in this chapter.

4.06.2 Theoretical Methods The molecular structure of thiazole has been refined by the joint analysis of data obtained from gas-phase electron diffraction (GED), microwave (MW) spectroscopy, and ab initio molecular orbital (MO) calculations. The combined approach, making use of the structure analysis restrained by ab initio calculations for electron diffraction (SARACEN) method, has led to a very precise structure in which all independent geometric parameters are well defined . The refined bond lengths and angles are listed in Table 1, and these agreed well with experimental data previously obtained (see Section 4.06.3.2 and Section 3.06.02 of CHEC-II(1996)). Ab initio calculation of dipole moments and static dipole polarizabilities were reported for thiazoles and isothiazoles at their MP2/6-31G** geometries and Hartree–Fock (HF) polarizability principle was discussed . Chemical shieldings of the S-nucleus were calculated using the gauge-invariant atomic orbitals (GIAO) method .

Thiazoles

Table 1 Calculated bond lengths and bond angles of thiazole

Bond

˚ Bond length (A)

Bonds

Bond angle (deg)

S(1)–C(2) C(2)–N(3) C(3)–N(4) C(4)–C(5) C(5)–S(1)

1.724 0.001 1 1.310 0.000 2 1.372 0.000 2 1.369 0.001 9 1.714 0.001 3

C(5)–S(1)–C(2) S(1)–C(2)–C(3) S(1)–C(5)–C(4) C(2)–C(3)–C(4) C(3)–C(4)–C(5)

89.41 0.04 115.16 0.06 109.52 0.08 109.97 0.09 115.95 0.11

Ab initio calculations at the RHF/6-31G* and MP2/6-31G* //RHF/6-31G* levels of theory were performed for 2-methyl-4-carboxamido-thiazoles, including rotational profiles for the ring–carboxamide bond, which showed the expected conjugation and hydrogen-bonding effects. A set of newly optimized stretch, bend, and torsional parameters for the AMBER* force field were derived, along with charges from electrostatic potentials using a grid-based method (CHELPG)-fitted partial atomic charges . The static first and second hyperpolarizabilities of thiazole and a number of heteroaromatic ring systems were calculated by the ab initio time-dependent Hartree–Fock (TDHF) method. The computed nonlinear polarizabilities correlate well with frontier orbital energies and hardness parameters . Quantum-chemistry (QC) and molecular mechanics (MM) calculations of 2-thioamide derivatives of thiazole showed that within the thiazole rings, the S(1)–C(2) bond was more affected by the presence of substituents at the 2-position than are the C(2)–N(3) bonds; the C(2)–C(6) bond connecting the thioamide group with the thiazole ring is shortened when both the systems are coplanar, but conjugation is relatively weak and does not enforce such a conformation. The sulfur atoms of the ring (S-1) and the thioamide group (S-7) have a cis-conformation with regard to the C(2)–C(6) bond. Hydrogens at N-8 and sulfur S-7 atoms are in a trans-conformation with regard to the C(6)–N(8) bond. Such arrangements about C(2)–C(6) and C(6)–N(8) are designated as cis–trans-conformation. However, a relatively high energy barrier excluded the possibility of a change of the cis–trans-conformation into the trans–trans by simple rotation around the C(2)–C(6) or C(6)–N(8) bonds. The observed cis–trans-conformation is stabilized by intramolecular H-bonds . Direct comparison of bond lengths of unsubstituted thiazole 1, N,N-dimethylthioamide 8, N,N-dimethylthioamide 9, and N,N-diethylthioamide 10 was carried out using Spartan 2.0 with the HF/3-21G(d) method. The molecules 9 and 10 were chosen because two substituents at N-8 make the formation of an N(8) N(3) hydrogen bond impossible and would enforce twisting of the molecules around the C(2)–C(6) axis. The results are shown in Table 2. The molecule 8, contrary to 9 and 10, can be planar, and an increase of S(1)–C(2)–C(6)–S(7) (1) torsion angles in 9 and 10 causes a small elongation of the C(2)–C(6) bond. The shortening of C(2)–C(6) distances in the planar system is connected with a conjugation between the ring and the thioamide group. A deviation from planarity in the N-methyl compound could be explained as an effect of packing forces in the crystal. The calculated interatomic distances within the thiazole ring are in agreement with the experimental data and confirmed the influence of the thioamide substituent on the geometry of ring. However, in contrast to the MW data , the calculations also showed that in the unsubstituted ring, the S–C bonds are unsymmetrical, and the S(1)–C(2) bond is a little longer than the neighboring S(1)–C(5) bond. Further, it was found that the difference between these bonds in planar N-methylthioamide 8 ( 2 in Table 2) is very similar to that in unsubstitued thiazole, but in nonplanar 9 and 10 the 2 are a little greater. The heat of formation of molecule 8 with various S(1)–C(2)–C(6)–S(7) (1) and S(7)–C(6)–N(8)–C(9) (2) torsion angles and energy barriers was calculated by the semi-empirical PM3 method using the Spartan 2.0 program and by MM calculation using the Biosym Discover program . The results showed that the molecule with a cis–trans-conformation (1 ¼ 0 and 2 ¼ 0 ) possesses the lowest energy. When both the sulfur atoms are in a transconformation (1 ¼ 180 ), a lower heat of formation is observed for 2 within a range of 60–90 . The result also indicated that an oscillation of a molecular fragment around C(6)–N(8) (1 ¼ 0 , 2 up to 100 ) causes only a small

639

640

Thiazoles

˚ Table 2 Bond lengths of thiazoamides 8–10, calculated by the ab initio method 3-21G(d) (A)

Thiazole ring S(1)–C(2) C(2)–N(3) C(3)–N(4) C(4)–C(5) C(5)–S(1) Thioamide group C(2)–C(6) C(6)–C(7) C6)–N(8) N(8)–C(9) 1 ( ) Energy (a.u.) 1 2

Thiazole 1

N-methyl 8

1.728 1.286 1.396 1.343 1.724

1.720 1.292 1.384 1.348 1.715

1.734 1.292 1.383 1.348 1.711

1.734 1.291 1.383 1.347 1.711

1.482 1.637 1.319 1.463

1.486 1.674 1.326 1.482 11.9 1130.18 0.092 0.023

1.491 1.680 1.324 1.485 14.2 1207.81 0.092 0.023

564.48 0.110 0.004

0 1091.35 0.092 0.005

N,N-dimethyl 9

N,N-diethyl 10

1 – difference between N(3)–C(4) and C(2)–N(3) distances; 2 – difference between S(1)–C(2) and C(5)–S(1) distances.

change in the heat of formation. However, the values of rotational barriers, around the C(2)–C(6) and C(6)–N(8) bonds, indicated that a cis–trans-conformation is favorable because of intramolecular hydrogen bonds. Ab initio calculations using time-dependent density functional theory (TDDFT) RI-BLYP/TZVPP predicted that electronic excitations in N-methoxythiazole-2(3H)-thiones and N-methoxypyridine-2(1H)-thiones differ significantly with respect to character and statistical weight of contributing transitions. These effects originate predominantly from contributions of the endocyclic sulfur atom into orbital energies and shapes in thiazole-2(3H)-thiones . These data agree well with the experimental data (Section 4.06.3.1) . A polarizable force field was derived from gas-phase ab initio calculation, and an associated continuum solvation model based on a self-consistent reaction field description. It allows computation and study of energetic and structural features of protein binding to a wide range of ligands in aqueous solvents . A collection of 18 azo dyes of various combinations of five-membered rings including thiazoles has been studied by ab initio quantum-chemical methods within the second-order polarization propagator approximation (SOPPA). It was found that the diazo compounds with two heterocyclic five-membered rings have p–p* excitation energies corresponding to laser wavelengths in the region 450–500 nm whereas one five-membered ring and a phenyl group as diazo components results in wavelengths in the region 400–435 nm . Similarly, the two lowest singlet excitation energies of a further 26 substituted 2-imidazolyl-2-thiazolylazo compounds were calculated using the same method. In many cases, p–p* excitation energies are below 2 eV (corresponding to wavelengths longer than 600 nm), with the longest wavelength being 1049 nm. However, no clear trends were found within the results .

Thiazoles

Global minima for 4-carboxamido-thiazoles were calculated by the ab initio method at the restricted Hartree–Fock (RHF)/6-31G* level of theory and varying the dihedral angle for the ring–carbonyl bonds showed clear discrepancies between energy differences calculated at the MP2/6-31G* //RHF/6-31G* level and those obtained using the parameters present in the currently available version of AMBER* , indicating that revision of the force field was required. Readjustment of the bond stretching and bond angle parameters to take account of the new global minima and development of new torsional parameters for the dihedral angle under study gave much better agreement with the calculated ab initio energies . The torsional angle, bridge bond-length, bond-length alternation, and intramolecular charge transfer from acceptors, such as thiazole and benzothiadiazole, pyrazinoquinoxaline, thiadiazoloquinoxaline, and benzobisthiadiazole, to the donor, fluorene, in alternating donor–acceptor conjugated copolymers were simulated using DFT at the B3LYP level with 6–31G or 6–31G** basis set. The results correlated with the electronic properties, that is, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) level and band gap . The theoretical study suggested that the electronic properties of alternating fluorene–acceptor conjugated copolymers could be tuned by the geometries or acceptor strength . First-principles calculations have been performed to study the electronic band structure and the magnetic properties for thiazole complex, Fe(thiazole)2Cl2. From the total and the partial density of states and the atomic spin magnetic moments, it was found that Fe(thiazole)2Cl2 is a metallic antiferromagnet and has a half-metallic (HM) ferromagnetic metastable state . The equilibrium geometries, one-, two-, and three-photon absorption properties, and the transition nature of a series of Y-shaped molecules which possess an imidazole–thiazole core have been studied theoretically using the parametrization model 3 and Zerner’s intermediate neglect of differential overlap (ZINDO) methods . Geometry optimization and prediction of vibrational and magnetic properties were carried out using ab initio HF and DFT calculations to assist the spectroscopic analysis of the synthetic 2-N-phenylamino-4-(3,3,3-trifluoro-2trifluoromethyl-1-propenyl)thiazole . The mechanism of the addition of 2-silylthiazole to formaldehyde was studied by ab initio calculations at the MP2/ 6-31þG* //6-31G* level . Bond orders were calculated at the HF and second-order, Møller–Plesset (MP2) level for 324 distinct ring bonds in 60 heterocyclic molecules including eight thiazoles . The structure and energy properties of the thiazole/C3O2 1:1 complex have been investigated in solid argon matrices using ab initio HF, MP2, and density functional B3LYP calculations at the 6-31G** level . Ab initio (3-21G* ), frontier molecular orbital (FMO) method at the semi-empirical PM3 level, and molecular hardness calculations were performed in order to explain the high regioselectivities observed in the Diels–Alder reactions of o-quinodimethane and 2- or 3-bromo-5-hydroxynaphthoquinones . The Diels–Alder reactions of various quinodimethanes with ethylene were studied by means of ab initio MO and DFT calculations to show the effect of aromaticity on the reaction path . The suitability of heterocyclic aromatic compounds with two heteroatoms in the ring positions 1 and 3, such as thiazoles as dienes for the Diels–Alder reaction, was investigated by semi-empirical and DFT computational studies . Ab initio (MP2/6-311þG** and MP4(SDTQ)/6-311þG** //MP2/6-311þG** ) and density functional (B3LYP/6-311þG** ) calculations on the ring-closure reactions of conjugated nitrile ylides to the corresponding thiazoles were reported . Ab initio calculation (6-31G* ) of the products of the (Z)-1-chlorodimethylsilyl-1-diethylborylalkenes, prepared by reacting 1-alkynyl(chloro)dimethylsilanes with tetraethyldiborane, and C-lithiated thiazole and 4-methylthiazole revealed that zwitterionic structures which can be regarded as borane adducts of carbenes . Unrestricted Hartree–Fock (UHF), MP2, and DFT at ab initio level and semi-empirical PM3 approaches were developed in order to rationalize the regiochemistry in the radical bromination of 4,5dimethylthiazole with different stoichiometries of N-bromosuccinimide in the presence of 2,29-azobisisobutyronitrile (AIBN), affording regioselectively mono-, tri-, and tetrabromo compounds in good yields . Ab initio MO calculations combined with collision-energy/electron energy resolved two-dimensional (2-D) Penning ionization electron spectroscopy were applied to study electronic structures of thiazole and benzothiazole as well as their anisotropic interactions with a metastable He* (23S) atom. It was found that thiazole and benzothiazole most strongly attract an He* (23S) atom around the region where the nitrogen lone-pair orbital extends. For another heteroatom, sulfur, it is relatively weak, but a certain attractive interaction was found for the directions perpendicular to the molecular plane. Benzothiazole was shown to generally attract an He* (23S) atom in the out-of-plane directions, since the benzene moiety showed a deeper potential than the five-membered ring. Different collision-energy dependences of partial ionization cross sections (CEDPICSs) were clearly observed for different ionic states

641

642

Thiazoles

depending on anisotropic extents of MOs from which an electron is removed. The negative collision energy dependence of the satellite band intensity was well supported by a configuration interaction calculation that assigns these bands to the ionization from p-orbitals accompanying p–p* or n–p* excitations . Quantum-chemical calculations using complete active space self-consistent field (CASSCF) and complete active space with second-order perturbation theory (CASPT2), DFT-based calculations including TDDFT, and resolution of identity approximation coupled cluster method (RI-CC2) were tested with respect to their ability to describe the dissociation process and the vertical excitations for N-(hydroxy)- and N-(methoxy)-thiazole-2(3H)-thiones. The complete active space approach in association with the multistate variant (MS) CASPT2 ansatz gives accurate descriptions of experimental electronic excitation spectra. The same was found for RI-CC2 which in comparison to CASPT2 predicts slightly higher vertical excitation energies (0.1–0.3 eV). The TDDFT results are very dependent on the choice of the functional and the examined state. The BLYP functional in general underestimates the excitation energies systematically while the BHLYP overestimates them. The Becke three-parameter functional (B3LYP) and PBE0 in most cases give excitation energies in the same region as CASPT2. For the thermal and the photolytic bond-dissociation process, only the CASPT2 method provides reasonable results. The near-UV-induced N,O-homolysis of N-(methoxy)thiazole-2(3H)-thione starts from the S2 states and this state is the only state that exhibits significant oscillator strengths, that is, will be populated upon light absorption . Ab initio HF and density functional geometry optimizations at HF/3-21G and B3LYP/6-31G(d) levels were performed on thiazole and oxothiazole derivatives . Excellent correlation between experimental and ab initio acidity constant values (pKa) for nontautomeric molecules 11 and 12 was obtained (Table 3). Changes in base strength arise from steric, inductive, or mesomeric effects caused by different substituents at different positions, which in turn allows for changes in geometries and the perturbation of the electronic configuration of molecules.

Table 3 Comparison of pKa values of thiazole derivatives

X

Y

R

pKa (calc.)

pKa (exp.)

H H CH3 CH3 NO2 H NO2 H NO2

H CH3 H NO2 CH3 Et Et i-Pr i-Pr

H CH3 CH3 CH3 CH3 t-Bu t-Bu t-Bu t-Bu

17.12 4.21 4.66 1.23 2.52 5.78 3.70 6.16 3.86

3.51 3.91 3.98 0.09 2.44 3.48 2.45 3.74 3.60

It was also found that oxo forms were the preferred tautomeric forms for compounds 13–15. An electron-withdrawing group at position 5 (e.g., NO2) seems to increase the stability of the enol form while an electron-donating group at position 4 (e.g., CH3) decreases the KT value (Table 4). OPLS-aa (optimized potential for liquid simulations – all atom) energy minimization was used to optimize the geometry of the cyclic thiazoyl peptide antibiotic thiostrepton and electron density calculation was carried out at the ab initio and semi-empirical AM1 levels (B3LYP/6-31G(d)//AM1) to obtain the partial charge on each atom of the transition state (TS) and the position of the HOMO and LUMO orbitals, which provide an insight into the potential pyrimidalization of the secondary amine and aspects of the mobility of the thiostrepton loop . Conformational properties of thiazole-containing di- and tripeptides have been investigated by ab initio calculations at the HF and DFT level .

Thiazoles

Table 4 Relative stability (RS) values for potentially tautomeric molecules by ab initio method

Process

RSa (kcal mol1)

KTb

2-thiazolone 13; keto-enol 4-methyl-2-thiazolone 14; keto-enol 5-nitro-4-methyl-2-thiazolone 15; keto-enol

12.19 11.81 4511.38

1.06 109 1.07 109 0

a

RS ¼ Ga(enol) Ga(keto); the plus sign indicates the stability of keto form. Calculated using the Ga ¼ 2.303RT log KT, where Ga ¼ Ga(enol) Ga(keto).

b

The importance of the C-59 position for substitution in a novel series of quinazolines substituted at C-4 by thiazole rings has been rationalized by ab initio MO calculations. Results show that a planar conformation, with the sulfur of the thiazole next to the quinazoline N-3, is strongly favored over the other possible planar conformation. Compounds with an acetanilide substituent at C-59 have the greatest cellular activity against a panel of various serine-threonine and tyrosine kinases . Ab initio study of the photochemical isomerization of thiazole derivatives, using 6-31G** basis and Møller–Plesset perturbations (MP2), is in agreement with experimental results and with previous reported data obtained from semiempirical methods and a possible reaction mechanism was discussed . The first hyperpolarizabilities () of the donor–acceptor (D–A) systems containing several 1,3-heteroatom p-bridging units (oxazole, imidazole, and thiazole) have been studied by the ab initio method (HF/6-31G) . The static first and second hyperpolarizabilities of amino- and nitro-substituted chromophores containing thiazole rings have been calculated by the ab initio TDHF method. The computed nonlinear polarizabilities correlate well with frontier orbital energies and hardness parameter () . Composite ab initio CBS-Q, G3, and G3B3 methods were used to calculate C–H and N–H bond-dissociation energies (BDEs) of various five- and six-membered ring aromatic compounds including thiazoles. It was found that all these composite ab initio methods provided very similar BDEs, despite the fact that different geometries and different procedures in the extrapolation to complete incorporation of electron correlation and complete basis set limit were used . Optimized geometries, scaled quantum-mechanics (SQM) force fields, and the corresponding vibrational frequencies, IR absorption intensities, and scale factors were calculated for thiazole and the [2(2)-H], [4-H-2], and [2,5-H2(2)] isotopomers of thiazole using the DFT and B3LYB/6-31G** methods . The route from -iminothioaldehydes to 2,3-dihydrothiazoles has been studied by ab initio MO theory and it was shown that the most energy requiring step is the trans ! cis-isomerization of the methylimino group . Ab initio-optimized geometries and harmonic force fields to predict the frequency, IR intensity, Raman intensity, and depolarization ratio were calculated for benzothiazole at the HF and B3LYP levels of theory using the 6-31G** basis set . The linear polarizability, , the first hyperpolarizability, , and the second hyperpolarizability, , of benzothiazole were studied by the ab initio HF method using 4-31G basis. 13 C NMR chemical shifts in 2-aminobenzothiazole 16, 2-(methylamino)benzothiazole 17, and the reaction product benzamide 18 were calculated using the GIAO, continuous set of gauge transformations (CSGT), and localized-orbital-local-origin (LORG) methods at BLYP DFT level and TZVP basis sets. The results were compared with the empirical ACD method . A GIAO approach using the Gaussian 98 suite of programs at the DFT B3LYP level of calculation over an extended basis set to predict chemical shifts was applied to 15N natural abundance NMR spectra of benzothiazoles . Similarly, the groundstate geometries, electronic structures, and vibrational wave numbers of 2-(2-benzothiazolylthio)-1-(4-bromophenyl)ethanone 19 were studied by DFT-B3LYP, BLYP, and ab initio RHF method with different basis sets .

643

644

Thiazoles

Semi-empirical ZINDO SOS (sum over states) and ab initio quadratic response function (DDRPA) calculations on a series of D–A-substituted p-conjugated chromophores based on styryl benzothiazoles were used to aid in the design of dyes with high nonlinear optical properties . The involvement of skeletal deformations in the ultrafast excited-state proton transfer from 2-(29-hydroxyphenyl)benzothiazole and the identification of the vibrational modes active in the process were studied by a multidimensional ab initio calculation of ground and excited states at the HF/DFT and configuration interaction singles (CIS)/TDDFT levels, rendering the relevant portions of the potential energy surfaces around the minimal energy path connecting the enol and keto configurations . The structural parameters, energies, and vibrational frequencies of 2-methylthiobenzothiazole were obtained by ab initio RHF calculations using the 6-31G** basis set for various conformations. A detailed assignment of most of the observed bands was proposed from the IR dichroism, Raman polarization data, and frequency calculations . HOMO–LUMO interaction of syn-dithiabenzothiazolophane and an anti-bislactone benzothiazolophane was studied . The geometry of various tautomers and isomers of 2-amino-2-thiazoline has been studied using B3LYP/6-311þG(d,p) DFT, MP2/6-311þG(d,p), and CBS-Q model, showing the amino tautomer to be more stable than the imino tautomer. Of the two possible isomers (E and Z) of 2-imino-2-thiazolidine, the (Z)-isomer has the lower energy. The most stable structures are stabilized via intramolecular hydrogen bonds . Ab initio calculation of a chemical shift at the HF/6-31G(d,p)/B3LYP/6-31G(d) level was used for studying the binding mode between Zn2þ and the thiazoline ring of bacitracin A . Different activity of 5-[2-(dimethylamino)ethyl]-9-phenyl-4H-benzo[de]thiazolo[5,4-g]isoquinoline-4,6(5H)dione derivatives as photonucleases may arise from the impact of substituents on the 2-phenyl ring of thiazole on the electron population of the excited triple state according to AM1 semi-empirical calculations . Semi-empirical AM1-SCI calculations have been performed to rationalize the photophysical behavior of two series of compounds: one comprising of 2-(29-hydroxyphenyl)benzoxazole, 2-(29-hydroxyphenyl)benzimidazole (HBI), and 2-(29-hydroxyphenyl)benzothiazole, and the other of 2-(29-hydroxyphenyl)oxazole (HPO), 2-(29-hydroxyphenyl)imidazole (HPI), and 2-(29-hydroxyphenyl)thiazole (HPT). These compounds exhibit intramolecular rotation as well as excited state intramolecular proton transfer (ESIPT). The results suggested that for the first series of compounds two rotational isomers are present in the ground state of HBO and HBI while HBT has a single conformer under similar circumstances. For the other series, existence of rotamers depends very much on the polarity of the environment . Photochemical reactivity between thiazole and nitriles was studied by AM1 calculations on the frontier orbitals of these reactants . 1p ! 1p* Ultraviolet absorption bands and electronic charge transfers in singlet excited states of benzothiazole-2thione were studied using the AM1 approach . Effects of solvents and acid or base concentrations on spectral characteristics of thiazole derivatives were studied using AM1 and DFT . The fluorescence quenching property of 2-(2-phenylethenyl)benzothiazoles can be explained using AM1 calculations . The vibrational frequencies of benzothiazole were analyzed by scaling of the AM1-generated force field . AM1 semi-empirical MO calculations in both gaseous and condensed phases were employed to study excited-state intramolecular proton transfer from 2-(29-hydroxyphenyl) benzothiazole .

Thiazoles

The geometries of various tautomers and isomers of 2-methylamino-2-thiazoline and 2-phenylamino-2-thiazoline have been studied using the B3LYP/6-31þG(d,p) DFT, ONIOM(B3LYP/6-31þG(d,p):HF/3-21G* ), and ONIOM(B3LYP/6-31þG(d,p):AM1) methods. The optimized geometries indicate that these molecules show a distinctly nonplanar configuration of the cyclic moieties . Conformational analysis of famotidine (FAMO) and 2-guanidinylthiazole have been performed using AM1 calculations in order to see the effect of the N-sulfamoyl fragment and the methylthioethyl chain of FAMO on the thiazole ring. The results revealed that the N6H form (the guanidinium cation) was the most stable and might therefore be the best candidate for interacting with the histamine H2-receptor . AM1 was used to calculate electrostatic potential energies of thiazole and derivatives and these parameters were then used for QSAR studies of these compounds against human adenosine A3 receptor . The B3LYP/3-21G* method and semiempirical AM1 and ZINDO methods were employed in the study of the structure and band gap of benzothiazolebased polymers.

4.06.3 Experimental Structural Methods 4.06.3.1 X-Ray Diffraction One additional antibonding p* -resonance from the double-bond nitrogen atom in the thiazole ring was recorded in the X-ray absorption and electron yield spectra compared with pyrrole. The split results from the localized double bond at nitrogen . Crystal structures of two thioamide derivatives of thiazole, N-methylthioamide 8, and N-phenylthioamide 20 thiazoles were determined by X-ray diffraction. The data are shown in Table 5 compared with the unsubstitued compound, determined by MW , and also with the mean values taken from Cambridge Structural Database (CSD) for monosubstituted derivatives .

˚ Table 5 Bond lengths determined by X-ray analysis and compared with MW and CSD data (A)

8A Thiazole ring S(1)–C(2) C(2)–N(3) C(3)–N(4) C(4)–C(5) C(5)–S(1) Thioamide group C(2)–C(6) C(6)–C(7) C(6)–N(8) N(8)–C(9) 1 2 a

1.723 4 1.303 5 1.383 4 1.342 6 1.712 4 1.482 5 1.665 4 1.320 5 1.460 4 0.080 5 0.011 4

8B

1.719 4 1.304 5 1.388 5 1.370 6 1.697 5 1.480 5 1.673 4 1.317 5 1.433 5 0.084 5 0.022 4

20

1.726 3 1.310 5 1.371 5 1.367 5 1.700 4 1.478 5 1.649 4 1.342 5 1.424 5 0.061 5 0.026 4

MW

CSD

1.713 1.304 1.372 1.367 1.713

CSDa 1.720 4 1.296 4 1.377 1 1.322 5 1.706 3

0.068 0

CSDb 1.502 5 1.659 2 1.325 3 1.448 4 0.081 4 0.014 4

Nine hits, R 5%, T ¼ 295 K, thiazole ring with substituent at C-2. Thirty-four hits, R 5%, T ¼ 295 K. 1 – difference between N(3)–C(4) and C(2)–N(3) distances; 2 – difference between S(1)–C(2) and C(5)–S(1) distances; MW – microwave microscopy; CSD – Cambridge Structural Database, Release V5.11; 8A, 8B molecules from independent part of unit cell. b

645

646

Thiazoles

Differences seen between the N(3)–C(4) and C(2)–N(3) distances in 8 are slightly longer than in 20 ( 1 in Table 5). However, the S(1)–C(2) bond lengths in 8 and 20 are similar as in the C(5)–S(1) bond ( 2 in Table 5), but this is in disagreement with the MW results. Layer arrangements in the crystal lattice of these two compounds showed that in 8, the thiazole rings are under the thioamide system and their hydrogen bonds (N(8)–H N(3) and N(3) H–N(8) are between neighboring mole˚ respectively. However, the crystal lattice of compound 20 consists of cules) are of lengths 2.320(46) A˚ and 2.256(47) A, ˚ intermolecular interactions. separated double layers between which exist weak (N(8)–H N(3), 2.631(64) A) Moreover, within the single layer of the N-phenyl compound, the thiazole rings as well as the phenyl rings from the thioamide groups of neighboring molecules form stacks. The X-ray structure of the 4- and 4,5-disubstituted N-methoxythiazole-2(3H)-thiones 21 and 23 and selected N-hydroxy derivatives 22 and 24 were determined and compared with ab initio TDDFT (TD)RI-BLYP/TZVPP predictions . Good agreement was achieved (see Section 4.06.2).

X-Ray analysis of propyl 2-(3-cyano-4-(2-methylpropoxy)phenyl)-4-methylthiazole-5-carboxylate revealed that both the stable and metastable forms are constructed by stacking of the sheet structures . 4-(1-Methyl-1-mesitylcyclobutan-3-yl)-2-aminothiazole , thiazolidin-4-one derivative 2 , 2-aminothiazole 26 and 2-amino-2-thiazoline 27 , 2-amino-4-phenylthiazole , 3-hydroxy-5methyl-4-phenylthiazol-2(3H)-iminium chloride , methyl (2R,4R)-N-ethoxyoxalyl-2-phenylthiazolidine-4-carboxylate , 2-methylthiazole-5-carboxylic acid , 4-(3,3,3-trifluoro-2-trifluoromethyl-1-propenyl)thiazole and 2-phenyl-4-(3,3,3-trifluoro-2-trifluoromethyl-1-propenyl)thiazole , ethyl 4-amino-3-(benzoylamino)-2,3-dihydro-2-iminothiazole-5-carboxylate 28 , proline-thiazole-based cyclic hexa- and octapeptides , 2,29-diamino-4,49-bithiazole , (1S,4S)-camphor 59-fluoro-49hydroxy-49,59-bis(trifluoromethyl)thiazolinyl-29-hydrazone , methyl (2R,4R)-2-(p-methoxybenzoyl)thiazolidine-4-carboxylate, methyl (2R,4R)-2-(p-methoxybenzoyl)-N-(prop-2-ynyloxyacetyl)thiazolidine-4-carboxylate , thiazol-5(4H)-ones, and peptides containing a thiazol-5(4H)-imine moiety , spirocyclic thiazoline 29 , mechercharmycin A , cis,cis-ceratospongamide (cyclo[l-Pro-L-Ile-Meoxazoline-L-Phe-L-Pro-thiazole-L-Phe-]) , thiazole-containing porphycene analogue 30 , thiazole-containing di- and tripeptide mimetics , melithiazole C 31 , 1,1-diphenyl[1,3]thiazolo[4,3-a]phthalazine and 3-(p-bromophenyl)-4-[(E)-styryl]-5-trans-cyano-5-cis-methylthio-2,3,4,5-tetrahydrothiazole , 2-guanidinyl-thiazole , 2-acetylamino-5-(1-acetyl-1-4-dihydropyridin-4-yl)-4-(1methylindol-3-yl)thiazole , spiro-thiazolidine 32 , 2-aminated 5-nitrothiazole rearrangement product 33 , 3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[d]thiazole-2-thione, 3-methyl-2,3,3a,4,5,6,7,7aoctahydrobenzo[d]thiazole-2-thione, and 3,3a,4,5,6,7,8,8a-octahydro-2H-cyclohepta[d]thiazole-2-thione , dichlorodithiabenzazolecobalt(II) monohydrate , thiazole-2(3H)-thiones 34 , (E)-2-[2(1-naphthyl)vinyl]-3-tosyl-2,3-dihydrobenzothiazole , are among the X-ray structures solved and reported.

Thiazoles

X-Ray crystallographic characterization of the complex of potassium and hydrolyzed ascidiacyclamide showed that the potassium ion is bound to the N-atoms of both thiazole rings and the adjacent O-atoms. Two perchlorate anions, located on either side of the plane of the macrocyclic ring, are weakly associated with the potassium cation . Structures of ascidiacyclamide derivatives where an individual amino acid was replaced in the cyclic peptide structure were also elucidated by X-ray diffraction . Aqua(dimethylbithiazole)oxydiacetatonickel(II) trihydrate , a complex of 2-(4-pyridyl)thiazole-4-carboxylic acid with Zn2þ and Agþ ions , thiazole-based iridium(III) complexes , a complex of thiazole-containing antiulcer drug famotidine and cobalt(III) , a ferrocenyl thiazole , 4-diferrocenylthiazole , a copper(II) perchlorate complex of chiral bidentate ligands containing a combination of thiazolyl and pyridyl donor units , dibutyltin(IV) bis(2-thiazolylcarboxylate) , a complex of Pt(II) and 2-(diphenylphosphino)amino-4methylthiazole , diastereoisomeric dinuclear ruthenium complexes of 2,5-di(2-pyridyl)thiazolo[5,4-d]thiazole , Ru(III) complexes with thiazole ligands, thiazolium bis(thiazole)tetrachlororuthenate and thiazolium thiazole (dimethyl sulfoxide, DMSO) tetrachlororuthenate , a hypervalent tin complex with boryl derivatives of 4-methylthiazole 35 , bis(triphenylphosphine) (benzothiazole-2thione) copper(I) iodide , a mercaptobenzothiazole Cr-complex , thiazole-2-dithiocarboxylate methyl ester complexes of chromium, tungsten, and iron carbonyls , platinum(II) and palladium(II) complexes derived from the anion of sulfathiazole , triosmium clusters containing thiazolide ligand 36 , a copper(II) complex containing (Z)-2-(2-aminothiazol-4-yl)-N-(2-hydroxyethyl)-2-(hydroxyimino)acetamide , and dimeric copper(II) complexes of N-substituted thiazole sulfonamides are representative of thiazole-based metal complexes solved by X-ray diffraction.

647

648

Thiazoles

X-Ray crystallography, electrospray mass spectrometry (MS), and NMR spectroscopic analysis of complexes of the potentially tetradentate pyridyl-thiazole ligand 6,69-bis(4-methylthiazol-2-yl)-2,29-bipyridine (L1) with Co(II), Ni(II), Cu(II), Cd(II), Hg(II), Cu(I) and Ag(I) reveal that the complexes [Mn(L1)m]þ z (where n ¼ 1, m ¼ 1, and z ¼ 2, when M ¼ Co(II), Ni(II), Cu(II), Cd(II) and Hg(II); n ¼ 2, m ¼ 2 and z ¼ 2, when M ¼ CuI), retain their solid-state structures in solution. Conversely, the combination of equimolar amounts of AgX (where X ¼ TfO, BF4, or NO3) and L1 (in either nitromethane or acetonitrile) results in the formation of a helicate in solution; in the solid state, an aniontemplating effect gives rise to either mononuclear or dinuclear helicate structures [Agn(L1)n][X]n (where n ¼ 2 when X ¼ TfO; n ¼ 1 when X ¼ BF4 or NO3) . X-Ray diffraction analysis of a Cd(II)Cl2 complex with diaminobithiazole (DABT) showed the complex to be ˚ and 109.970(7) ; R ¼ 0.026. The Cd(II) monoclinic, space group P21/c with a 11.684(2), b 13.625(2), c 14.859(1) A, atom lies in a distorted octahedral environment with two DABT and two Cl ligands in a cis-arrangement. The average internal dihedral angle of 9.3 between the thiazole rings of DABT shows the twisted structure of the ligand in the complex. The Cd(II) atom deviates by ca. 0.570 A˚ from the mean plane of the thiazole ring containing N-4, but the Cd–N(4) bond is the shortest among four Cd–N bonds in the structure. Intramolecular H-bonds between Cl-atoms and amino groups stabilize the cis-configuration of the complex . The crystal structure of an AgNO3 complex with trans-2,29-(1,4-but-2-enediyldithio)-dithiazole showed that it is a 2-D network, in which the Ag(I) atom adopts a distorted tetrahedral geometry with two N- and one S-donors from three distinct ligands and one O-donor from a nitrate anion. The 2-D grid networks are further connected to form an extended 3-D structure through intermolecular C–H O H-bonds. There exist weak Ag–Ag interactions in the complex. The ligand L in the complex adopts two different coordination modes (i.e., N,N-bidentate and N,N,S,Stetradentate modes) and two different conformations obviously are different from the free L, so as to suit the coordination geometry of the metal ion . X-Ray diffraction analysis of complexes between 2-(49-thiazolyl)benzimidazole (tbz) and Na(I), Pb(II), Co(II), Ni(II), Cu(II), and Cd(II) showed that tbz stabilizes bis- and tris-chelated coordination compounds. In solution and in the solid state, the ligand coordinates to the metal ions through the imidazolic and thiazole N-atoms regardless of the nature of the metal ion . X-Ray diffraction and molecular modeling analysis of cobalt(II), zinc(II), and cadmium(II) complexes of the widely used anti-inflammatory drug meloxicam showed that the complexes are isomorphous and isostructural, and the metal chelates with the drug through the nitrogen atom of the thiazole ring and the amide oxygen atom at the equatorial positions . Diacetatobis(2-aminobenzothiazole-kappaN)cobalt(II), [Co(C2H3O2)2(C7H6N2S)2], contains a Co-center with a slightly distorted tetrahedral coordination geometry, involving two acetate ligands and two N-atoms from the thiazole ˚ and Co–N ¼ 2.052 4(18) and 2.056 8(18) A). ˚ The interplanar angle moiety (Co–O ¼ 2.002 5(14) and 1.995 3(16) A, between the two benzothiazole moieties is 77.86(3) . The amine groups, acting as donors, participate in intra- and intermolecular N–H O hydrogen bonds, with N O distances in the range 2.806(2)–2.857(2) A˚ . Powder X-ray and neutron diffraction and Rietveld techniques were used for structural determination of the isostructural polymeric compounds Co(thiazole)2X2 (X ¼ Cl or Br) (space group C2/c, a 17.806(2), b 3.6806(6), ˚ 3, Z ¼ 4; 2, space group C2/c, a 18.079(3), b 3.8138(8), c 15.022(4) A, ˚ ˚ 94.78(1) , V ¼ 967.1(3) A; c 14.807(3) A, 2þ ˚ 92.71(1) , V ¼ 1034.6(4) A; 3, Z ¼ 4). Each linear polymer chain is composed of pseudooctahedral, high-spin Co centers, doubly linked by halide bridges . Similarly, the crystal structure of the 1-D dihalide-bridged polymer dibromobis(thiazole)nickel(II) was determined by powder neutron diffraction . The structure of dichlorodiphenylbis(thiazole)tin(IV) was determined by X-ray diffraction. The crystals are monoclinic (space group P21/c) and consist of discrete trans-SnPhCl2(Tz)2 units with the metal atom coordinated to two C-1 atoms, two phenyl carbons, and the N-atoms of two thiazole rings . The crystal structure determination of the Ga(III) complex of racemized anguibactin (C15H16N4O4S) confirmed that the structure of the complex consists of a dimeric binuclear unit, (C15H14N4O4S?CH3O)2Ga2, which possesses a crystallographic center of symmetry. Each Ga-ion is in distorted octahedral coordination using one of the catechol O-atoms, the thiazoline nitrogen, the hydroxamate (N–O) group, and the imine nitrogen of the imidazole ring. The coordination sphere is completed by two bridging methoxide oxygen atoms. The dimer is further stabilized by a pair of hydrogen bonds between the second benzohydroxy group and the nitroso oxygen of the hydroxamate group . [(2-Amino-5-methylthiazole)(1,4,7-triazaheptane)copper(II)] dinitrate was characterized by X-ray diffraction. There were two crystallographically discernible cations [(amtz)(dien)Cu]2þ and four NO3 ions in the asymmetrical unit of the structure. Dien is tridentate with mean Cu–N ¼ 1.997(5) and 2.021(5) A˚ in the two Cu-ions, respectively. The thiazole ligand is coordinated through its endocyclic N with Cu–N ¼ 2.063(7) and 1.945(6) A˚ in the two ions,

Thiazoles

respectively. The CuN4 unit is approximately square planar and almost perpendicular to the thiazole plane. Both the ˚ contacts . cations make two long (trans-Cu triple bond O ¼ 2.6–2.7 A) X-Ray diffraction of mer-trichlorotris(thiazole-N)ruthenium(III) showed that the crystals are monoclinic, space ˚ 93.14(1) ; Z ¼ 4, dc ¼ 1.978; R ¼ 0.0232, Rw(F2) ¼ 0.055 group P21/n, with a 9.446(1), b 11.486(1), c 14.342(1) A, for 3564 reflections. The structure consists of discrete complex molecules with an octahedral coordination sphere in which the metal center is linked to three chloride ions and to three thiazole ligands through the N-atoms. The Ru–Cl ˚ respectively . and Ru–N bond distances average 2.346 2(6) and 2.085 1(19) A, The thiazole biosynthetic enzyme (THI1), produced using heterologous expression in bacteria, is unexpectedly bound to 2-carboxylate-4-methyl-5--(ethyladenosine 5-diphosphate)thiazole, a potential intermediate of thiazole biosynthesis in eukaryotes. The 3-D structure of this complex was determined by single-wavelength anomalous X-ray diffraction to 1.6 A˚ resolution . The 2.10, 1.93, and 2.65 A˚ crystal structures for the epothilone D-bound, epothilone B-bound, and substrate-free forms of cytochrome P 450epoK are the first crystal structures of an epothilone-binding protein solved. The epothilones are positioned with the macrolide ring roughly perpendicular to the heme plane and I helix, and the thiazole moiety provides key interactions that very likely are critical in determining substrate specificity . An X-ray structure of a benzothiazole ketone derivative (RWJ-56423) complexed with bovine trypsin (1.9 A˚ resolution) showed a hemiketal intermediate formed involving Ser-189, and hydrogen bonds with His-57 and Gln192 . Structures of human thrombin complexed with hirugen and two active site inhibitors, RWJ-50353 (N-methyl-Dtrifluoroacetate phenylalanyl-N-[5-[(aminoiminomethyl)amino]-1-[[(2-benzothiazolyl)carbonyl]butyl]-L-prolinamide hydrate) and RWJ-50215 (N-[4-(aminoiminomethyl)amino]-1-[[2-(thiazol-2-ylcarbonylethyl)piperidin-1-ylcarbonyl]butyl]-5-(dimethylamino)naphthalenesulfonamide trifluoroacetate hydrate), were determined by X-ray crystallography. The refinements converged at R values of 0.158 in the 7.0–2.3 A˚ range for RWJ-50353 and 0.155 in the 7.0–1.8 A˚ range for RWJ-50215. The RWJ-50353 inhibitor consisted of an S-19-binding benzothiazole group linked to the D-Phe-Pro-Arg chloromethyl ketone motif. Interactions with the S(1)–S(3) sites were similar to the D-phenylalanyl-propyl-arginyl chloromethyl ketone structure. In RWJ-50215, an S-19-binding 2-ketothiazole group was added to the thrombin inhibitor-like framework of dansylarginine N-(3-ethyl-1,5-pentanediyl)amine. The benzothiazole and 2-ketothiazole groups interacted with His-57, Try-60A, Trp-60D, and Lys-60F in the cavity. The ring N-atom of the RWJ-50353 benzothiazole moiety formed an H-bond with His-57, and Lys-60F reoriented because of close contacts. The O- and N-atoms of the ketothiazole moiety of RWJ-50215 form H-bond with the NZ atom of Lys-60F .

4.06.3.2 MW Spectroscopy The MW spectrum of the 32S and 34S isotopomers of a thiazole-argon van der Waals complex was measured using molecular beam Fourier transform MW spectrometers . The vibrational frequency of benzothiazole was validated by ab initio calculation of the harmonic force field .

4.06.3.3 UV Spectroscopy In the UV–visible (UV–Vis) spectra of p-aryl/heteroaryl-conjugated coumarin-thiazole systems (Ar ¼ aryl, hetaryl), a main absorption band associated with a dominant pp* -transition was observed in the region of 338–390 nm. The values of max were found to correlate satisfactorily with the O–A characteristics of the p-attached chromophores. Marked changes in the absorption maxima of 37 (Ar ¼ 4-Me2NC6H4) under acidic conditions could be caused by mono- or bis-protonation and modification of the D–A properties of chromophores undergoing protonation. The emission spectra of 37, obtained by exciting the molecules at their main absorption bands, showed emission maxima in the region of 429–537 nm, with relatively high Stokes shifts of 145 and 171 nm being observed for 37 (Ar ¼ 4-Me2NC6H4, 4-O2NC6H4), carrying a pdonor, dimethylaminophenyl, and a p-acceptor, p-nitrophenyl chromophore, respectively .

649

650

Thiazoles

UV–Vis light absorption max for a heterocyclic aromatic polymer poly-p-phenylene-benzo-bisthiazole (PBT) with a fully conjugated rigid-rod backbone is 437 nm. When it was blended with poly-29,29-m-phenylene-59,59-bibenzimidazole (Pbi), the UV absorption band was a superposition of the individual absorptions indicating no intermolecular energy transfer. However, the photoluminescence of the blends excited at 363 nm demonstrated a redshift with increasing PBT content. This was attributed to a template effect of PBT rigid-rod backbone confining coil-like Pbi into an extended chain configuration, leading to improved charge delocalization . UV/Vis spectra of N-methoxy-4-methylthiazole-2(3H)-thione 21, N-methoxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione 23, and selected N-hydroxy derivatives 22 and 24 thereof have been assigned to p–p* -type transitions associated with the thiocarbonyl chromophore as the dominating feature, using the results from ab initio calculations. The p-methoxyphenyl substituent 23 located at position 5 causes a bathochromic shift of 19 nm of the energetically lowest absorption in the spectrum of acid 24 and 15 nm for N-methoxy-substituted heterocycle 21, in comparison to the corresponding bands in 4-methylthiazolethiones 21 and 22 (log " for each compound is included in parentheses) . These are in good agreement with computational results (see Section 4.06.2).

Dialkylaminothiazole dimers act as very strong electron-donating components for azo dyes and show two bands at ¼ 568–737 (" ¼ 24 000–88 000) and 404–475 (" ¼ 9200–52 000) nm in CH2Cl2, respectively . UV spectroscopic methods were used to determine equilibrium constants between cyanine dyes (thiazole orange) and nucleic acid , quantification of DNA , and Ru(II), and Ni(II) complexes containing thiazoles .

4.06.3.4 Fluorescence Spectroscopy The interaction between DNA and the fluorescent dye thiazole orange was studied using absorption and fluorescence spectroscopic techniques. A drastic fluorescence intensity enhancement (up to 103 times) was observed in the presence of DNA . Fluorescence measurement was also used to evaluate the inhibitory potency of 5-(bis(trifluoromethyl)methyl)-2-aminothiazoles . Single-molecule fluorescence spectroscopic techniques have been used to study the sequence dependence of the double-stranded DNA (dsDNA)-binding affinity of TOTO, a thiazole orange dimer that functions as a DNAintercalating fluorophore , nucleosome structure and dynamics using core histones conjugated to a DNA-intercalating dye, thiazole orange , and mRNA transcription using high-affinity peptide nucleic acid (PNA) probes with thiazole orange donor and Alexa-594 acceptor fluorophores .

4.06.3.5 IR and Raman Spectroscopy The Fourier transform infrared (FTIR) study of 2-(2-benzothiazolylthio)-1-(4-bromophenyl)ethanone 19 revealed that the stretching vibration of C–H on the benzene ring appears at 3065 cm1 in FTIR. A peak at 1699 cm1, which is very strong, can be assigned to the stretching vibration of the carbonyl group. The vibrational wave number is slightly shifted down because the carbonyl is conjugated with the phenyl ring. The stretching vibrations of the CTC

Thiazoles

bonds of the benzene ring appear at 1587, 1524, 1397, 1360, and 1306 cm1. The in-plane bending vibrations of the C–H bonds of the phenyl were observed at 1235, 1200, 1174, 1123, and 1071 cm1, while the stretching and bending vibration of the methylene of 19 appears at 2933, 1426 cm1. A very strong band at 997 cm1 can be assigned to the breathing vibration of the benzene ring. The out-of-plane deformations of C–H on the benzene ring appear at 807, 726, and 546 cm1. The very weak bands at 673 and 598 cm1 were assigned to the in-phase deformation of the phenyl. The out-of-phase deformation of phenyl was observed at 493 and 504 cm1 . Other compounds have been characterized by FTIR including 5-bromo-2-hydroxybenzylidene-2-aminobenzothiazole and its complexes with Co(II), Cu(II), and Ni(II) and other metal complexes containing thiazole ligands . The FTIR spectrum and other spectroscopic properties of 2-phenyl-4-(3,3,3trifluoro-2-trifluoromethyl-1-propenyl)thiazole was assigned with the aid of ab initio HF and DFT calculations (see Section 4.06.2). FTIR with reflectance microscopy of thioflavin S and poly(thioflavin S) films formed on a mild steel surface showed that bands in the region of 1400–1620 cm1 are associated with the aromatic carbon–carbon stretching vibrations; in the region 2800–3000 cm1, bands were attributed to the aromatic C–H stretching vibrations; a broad band at 3200 cm1 was attributed to the N–H stretching and the sharp band appearing at around 1050 cm1 was attributed to the vibration of the quinone imine. IR studies confirmed that that the polymer structure retained the aromatic structure of the benzene and thiazole rings with the distinction of a nitrogen quinone vibrational band which is similar to that present in the fully oxidized form of poly(aniline). 2-(2-Benzothiazolylthio)-1-(4-bromophenyl)-ethanone 19 has also been studied by FT-Raman spectroscopy. The stretching vibration of C–H on the benzene ring appears at 3078 and 3060 cm1, and the peak at 1701 cm1 was assigned to the stretching vibration of the carbonyl group. The stretching vibrations of the CTC bonds of the benzene ring appeared at 1587, 1561, 1363, and 1310 cm1. The in-plane bending vibrations of the C–H bonds of the phenyl were observed at 1272, 1238, 1200, 1177, 1124, and 1070 cm1 and the stretching and bending vibration of the methylene appeared at 2914 and 1428 cm1. A medium-intensity band at 998 cm1 was assigned to the breathing vibration of the benzene ring. The out-of-plane deformations of C–H on the benzene ring appeared at 702 cm1. The very weak bands at 675 and 599 cm1 were assigned to the in-phase deformation of the phenyl ring. In the same way, the out-of-phase deformation of the phenyl was observed at 504 cm1. The bands, which are under 400 cm1, arise from torsion or bending vibration of bonds . Surface-enhanced Raman spectra of the two thiazole orange derivatives, TO6 {1-(N,N9-tetramethyl-1,3-propanediaminopropyl)-4-[3-methyl-2,3-dihydro(benzothiazole)-2-methylidene]quinolinium triiodide} and TOTO {1,19(4,4,8,8 - tetramethyl-4,8-diazaundecamethylene)bis-4-[3-methyl-2,3-dihydro(benzothiazole)- 2 -methylidene]quinolinium tetraiodide}, were recorded with Vis (457.9 and 514.5 nm) and near-IR (1064 nm) excitation on silver colloids. The spectra were compared with the corresponding nonenhanced Raman spectra obtained in the near-IR region and the resonance Raman spectra obtained with visible excitation. The qualitative enhancement pattern was explained within the electromagnetic theories. Partial assignment of the vibrational wave numbers was achieved by comparison of observed band positions and intensities in the IR and Raman spectra with wave numbers and intensities from QC calculations. The surface-enhanced Raman spectrum of TOTO on gold colloids was recorded with 1064 nm excitation and compared with the corresponding spectra on silver colloids . Raman spectra of bis-trifluoromethyl 4-hydroxythiazolines and the iodine molecular chargetransfer complexes of thioamide , benzothiazole , 2-methylthiobenzothiazole , and 2-(29-hydroxyphenyl)benzothiazole encapsulated in nanosized zeolites were also recorded. The D shift effects of the transfer H in the resonance Raman spectra were also investigated .

4.06.3.6 NMR Spectroscopy Two-dimensional NMR 1H–13C heteronuclear multiple bond correlation (HMBC) experiments were performed on both 38 and 39 to assign the structure of these two compounds and their regioisomers .

651

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Thiazoles

1

H NMR experiments were conducted on deuterium exchange of 4-aryl-2(3H)-thiazolethiones and phenacylthiothiazoles in DMSO-d6/D2O, CDCl3/CF3COOD, CF3COOD, and CF3COOD/D2O. Deuterium exchange involving hydrogens bound to sp2 carbon atoms was found . Based on various 1-D- and 2-D-NMR studies, including field gradient correlation spectroscopy (FG-COSY), heteronuclear single quantum correlation (HSQC), FG-HMBC, phase-sensitive 13C-decoupled HMBC, and nuclear Overhauser enhancement spectroscopy (NOESY) experiments, the structure of promoinducin, a mycelial extract of Streptomyces sp. SF2741, was established to be a thiopeptide composed of threonine and some unusual amino acids masked at their carboxyl groups by thiazole or methyloxazole rings, sulfomycinamate, and 5-dehydroalanine residues . The 1H NMR spectrum of the phenyl derivatives of thiazole (Tz) tin(IV) complex [SnPh2C12(Tz)2] and a comparison with [SnPh2Cl2] showed very slight shielding of protons at the 2- and 6-positions of the phenyl ring on coordination, less than in the analogous complex with the N-donor ligand bipyrimidine, suggesting the presence of extensive dissociation in solution compared with what was observed in the solid state. The l3C NMR spectra of the phenyl derivatives of thiazole tin(IV) complex [SnPh2C12(Tz)2] and its comparison with the free ligand showed very slight differences between thiazole signals, suggesting that a D–A interaction between SNR2X2 and thiazole exists in solution. Small 2J(Sn–H) values indicated extensive dissociation of the thiazole ligand. The pentacoordinated species [SnR2X2(Tz)] that are initially formed also undergo extensive dissociation, even though the presence of only one set of signals for the Tz ligand in both 1H and 13C NMR spectra shows that the free and coordinated ligands are involved in fast interchange . The structures of the natural products, ceratospongamides from marine red alga (Rhodophyta) Ceratodictyon spongiosum, which each consist of two L-phenylalanine residues, one (L-isoleucine)-methyloxazoline residue, one L-proline residue, and one (L-proline)thiazole residue, were established through extensive NMR experiments, including 1H–13C heteronuclear multiple quantum correlation total correlated spectroscopy (HMQC-TOCSY), and 1 H–15N HMBC . The partial assignment of the 15N NMR resonances of the thiopeptide antibiotic sulfomycin-I produced by Streptomyces viridochromogenes was reported .

4.06.3.7 Mass Spectrometry Electron ionization MS was used to characterize 2-aryl-5-acetylthiazole derivatives in the gas phase. The compounds showed characteristic fragmentation pathways depending on the chemical nature of the substituent at position 2, consisting mainly of the cleavage of both the 1,2- and 3,4-bonds of the thiazole ring. Liquid secondary ion mass spectrometry was applied to study the effects of protonation on the gas-phase unimolecular reactions of this class of compound. Tandem mass spectrometric experiments were carried out on molecular and protonated molecular ions, and also on fragment ions produced in the source, allowing the elucidation of gas-phase decomposition of lowinternal-energy ions . The interaction of thiazole and thiazolidine with a strong (ca. 2 1016 W cm2) femtosecond laser field has been studied at ¼ 790 nm by means of time-of-flight (TOF) MS. The observed relative abundance of the doubly charged intact parent ion in thiazoline is higher than that of thiazole, while the laser-molecular coupling strength is found to be much more efficient for the aromatic thiazole than for the nonaromatic thiazoline. The mass spectrum of thiazoline was attributed to a combination of field ionization with subsequent multiphoton processes. The direct Coulomb explosion within the transient multiply charged parent ions leads to the production of multiply charged atomic ions . Mechanistic pathways for the formation of the fragments encountered in the mass spectrum of compound 40 were proposed. The sequences were validated by linked scans at constant B/E and high-resolution accurate MS .

MS has also been widely used to characterize thiazole-containing odors , flavors , thiazole–metal complexes , natural products , and protein–thiazole complexes .

Thiazoles

4.06.3.8 ESR Spectrometry Electron spin resonance (ESR) spectroscopy was used to characterize the spin adducts, 41a and 41b generated from N-(alkoxy)thiazolethiones 42a and 42b and DMPO by N–O homolysis .

The ESR spectrum of a Cu2þ complex with hydrolyzed ascidiacyclamide suggested that a ligand:metal ratio of 1:1, a single monomeric copper(II) complex, is formed in solution while computer simulation of electron paramagnetic resonance (EPR) spectra indicated a 1:2 ratio . Other ESR studies include 2,29-diamino-4,49-bithiazole and 2,29-bis(acetamido)-4,49-bithiazole copper(II) complexes , patellamide A derivatives, and their copper(II) compounds , endothelial nitric oxide synthase and its reaction with thiazole-containing ligand .

4.06.4 Thermodynamic Aspects 4.06.4.1 Intermolecular Forces 4.06.4.1.1

Melting and boiling points

The polar constituents of the boiling points (Tpol) of thiazole-containing heterocycles were calculated as the difference between the boiling points measured directly and those calculated from gas chromatography (GC) data obtained on a nonpolar column. Depending on the number, nature, and position of heteroatoms and alkyl groups on the rings and the structures of the molecules, the Tpol values vary from 11 to þ82 .

4.06.4.1.2

Solubility

The influence of methanol proportions in solvents, and temperature, on the solubility and the transformation behavior of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid (BPT) was investigated. The transformation behavior was explained by the chemical potential difference between the stable and metastable forms. It was shown that a specific solute–solvent interaction contributes to the preferential nucleation and growth of the stable or metastable forms and influences the transformation behaviors, and the solubility of the solvated crystals is much more influenced by the solvent compositions than the true polymorphs. The solubility ratio of the solvated crystals depends on the solvent composition, whereas the solubility ratio of the true polymorphs is considered to be independent of the solvents. The crystallization behavior was also investigated. The transformation rate after crystallization appeared to depend on the initial concentration of BPT and the addition rate of the antisolvent. The cause of this phenomenon was presumed to be a slight inclusion of the stable form in the metastable form . Certain thiazole-containing water-soluble glycosylated polyamides were synthesized and preliminary anticancer evaluation carried out against three types of cancer cells. Glycosyl moieties were introduced onto the polyamide backbone in order to increase the water solubility of the longer polymers .

653

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Thiazoles

4.06.4.2 Aromaticity and Stability The binding affinity of C-5 thiazole-containing oligodeoxynucleotides (ODNs) for RNA increased with certain methyl substitutions on the thiazole. Depending on the position of the methyl substituent with C-5 thiazole 5-methylthiazole deoxyuridine (dU)- 43 containing ODN exhibited the highest Tm (Tm ¼ þ2.2 C per substitution) because of the ability of the thiazole ring to achieve coplanarity with the uracil base leading to increased base stacking interactions with adjacent base pairs in the canonical double helix to form a more stable complex. However, the benzothiazole-containing ODN 44 exhibited the lowest affinity (Tm ¼ þ1.2 C per substitution) among the thiazole dU-substituted ODNs .

4.06.4.3 Conformations Acetaldehyde reacts with amino thiols, which were synthesized from the corresponding thiosulfonic amines 45 and 46 generated from ephedrine derivatives yielding thiazolidines 47 and 48 each with C-2 isomers in a dynamic equilibrium. The two configurations are interconvertable via a combination of C-2 and N-inversions depending on the configuration of the substituent at C-5 (Scheme 1) .

Scheme 1

Tautomers and conformers (T/Cs) of amthamine (2-amino-5-(2-aminoethyl)-4-methylthiazole) and its derivatives (2-amino-5-(2-aminoethyl)thiazole and 4-methyl-5-(2-aminoethyl)thiazole) in neutral and monocationic states were

Thiazoles

investigated using RHF at 6-31G** //6-31G** level. The results showed that amthamine and its derivative are most stable as trans-conformations. N(3)–H gauche monocations are the most stable structures due to the electrostatic internal interactions. In isodesmic reactions with ammonia, the conformation and proton affinity of amthamine were very similar to those of histamine, which could explain why they both act in a very efficient way when interacting with the histamine H2 receptor . Only one stable form of 2-(2-hydroxyphenyl)benzothiazole (HBT) 49, the normal form in the ground state, exists because of an insignificant energy barrier for the intramolecular rotation, hence the interconversion between the normal and rotameric forms and thus ruling out of the independent existence of the rotamer . This corroborates the observation of dual emission fluorescence bands from HBT. On the other hand, 2-(2-hydroxyphenyl)thiazole (HPT) 50 is similar to those of the corresponding benzo analogues HBT. The rotamer receives stabilization in neither isolated nor solvated conditions. The nonexistence of the rotamer of HPT has been rationalized by a greater single-bond character of the bond joining the phenol and the azole rings, thus allowing for more twisting vibrations whereby the rotamer is unable to obtain any well-defined stability.

The intramolecular proton transfer (IPT) reaction is unfavorable in the ground state from both the thermodynamic as well as kinetic reasons for both compounds. However, both factors favor the ESIPT process in the lowest excited singlet and triplet states. The stereochemistry of stereogenic centers linked to the thiazole C-2 is directly controlled by the rate of carbocation formation during thiazole formation from thioamide and -bromoketones in the Hantzsch reaction . The thiazole-containing cyclic octapeptide patellamides, isolated from the ascidian (sea squirt) Lissoclinum patella, exist in one of two conformations depending on the side-chains present in the molecules, a ‘square’ (type I) conformation or a ‘figure of eight’ (type II) conformation . Solution-state conformations of various natural patellamides and a number of synthetic analogues were reported using direct nuclear Overhauser effect (NOE) and circular dichroism (CD) techniques . The effect of the solvent and desymmetrization of the patellamides on conformational change was demonstrated by molecular dynamics and NOE-restrained molecular dynamics studies . Symmetrical patellamides adopt the open type I conformation in polar solvents, whereas symmetrical patellamides in nonpolar solvents and asymmetrical patellamides in both polar and nonpolar solvents give rise to the folded type II conformation. Similarly, the solution conformations of two cyclic octapeptides cyclo-(D-Thr-D-Val-(Thz)-ILe-)2 and cyclo-(ThrGly(Thz)-ILe-Ser-Gly(Thz)-ILe-) were determined by 1H NMR studies and found to be in type II conformations . Simultaneous detection and determination of the absolute configuration of thiazole-containing amino acids based on Marfey’s method was developed using a sensitive derivatizing agent, 1-fluoro2,4-dinitrophenyl-5-L-leucinamide (L-FDLA), and high-performance liquid chromatography (HPLC) analysis . The conformations of the naturally occurring cyclic octapeptides ascidiacyclamide and patellamide D, which each contain two oxazoline and two thiazole rings, were compared by 1H NMR spectroscopy with the analogues cyclo-(Thr-Val(Thz)-Ile)2 with just two thiazoles, and cyclo-(Thr--Val-Abu-Ile)2, with no five-membered rings. 1H NMR and CD spectroscopic titration studies between these cyclic peptides and calcium perchlorate tetrahydrate showed that the affinity for Ca2þ decreases with increasing number of five-membered ring constraints in the macrocycle . In the complex of trans-2,29-(1,4-but-2-enediyldithio)dithiazole (L) and silver nitrate, there is a symmetric center located at the midpoint of the 1,4-but-2-enediyl group with the two thiazole rings antiparallel to each other .

4.06.4.4 Tautomerism 4.06.4.4.1

Substituted thiazoles

The 2-amino-2-thiazoline tautomer 51a predominates for N,N9-unsubstituted derivatives; thiazolidines with a substituent R1 on the exocyclic nitrogen tend to appear as the 2-iminothiazolidine isomer 52b (R2 ¼ H, Scheme 2)

655

656

Thiazoles

rather than 52a. For 2-substituted 2-iminothiazolidines 52b, (E/Z)-isomerism is possible across the imino double bond. Based on semi-empirical calculations, the (Z)-isomer predominates for 2-(methylimino)thiazolidine, whereas, for 2-(phenylimino)thiazolidine, the (E)-isomer appears to be the most stable, although, in this case, the energy difference between the isomers is rather low. Except for those two derivatives, the subject of (E/Z)-isomerism of 2-substituted 2-iminothiazolidines has not been addressed .

Scheme 2

4.06.4.4.2

Ring–chain tautomerism

The thiazolidine structures in the dihydrothiazolyl hydrazones 53a and 54a were confirmed both by crystallography and in solution by NMR. The stability of the endocyclic N-3 (N-3/N-6 tautomerism) tautomeric forms 53b and 54b, in the gas phase and in water, were confirmed by energy calculations at the MP2/6-31þG(d) level. These tautomeric structures are expected to be the most abundant form (>90%) of the molecule. The anti-E-conformations observed in the crystal structures were retained in solution in agreement with stability predictions (Scheme 3) .

Scheme 3

X-Ray crystallographic studies of polymethoxylated and polyhydroxylated derivatives of 2-amino-4-arylthiazoles bearing a (halogenobenzene)sulfonamide moiety at position 2 revealed the predominance of the 2-imino-2,3-dihydrothiazole form in the amino/imino tautomerism .

Thiazoles

4.06.5 Reactivity of Fully Conjugated Rings 4.06.5.1 General Survey of Reactivity 4.06.5.1.1

Reactivity of neutral thiazoles

Thiazole can be considered to be derived from benzene by replacing a CH group with a nitrogen atom and the CHs at positions 3 and 4 of the resultant pyridine with a sulfur atom. The chemistry of thiazole therefore bears similarities to those of both pyridine and thiophene. Electrophiles react with the lone pair on the ring nitrogen (see Section 4.06.5.3), but not generally with the lone pairs of the ring sulfur atom. Electrophilic attack on carbon occurs preferentially at position 5, then position 4 as shown in Scheme 4 (see Section 4.06.5.4).

Scheme 4

Due to inductive electron withdrawal, nucleophilic attack at position 2 is favored. Deprotonation at this position also occurs in the presence of a strong base, and organometallic reagents so derived react with electrophiles in the usual manner. The reactivity of thiazoles and benzothiazoles toward nucleophiles, electrophiles, and radicals is well explained by data from MO calculations and has been covered thoroughly in CHEC(1984) and CHEC-II(1996).

4.06.5.1.2

Thiazolium ions

A wide range of alkylating reagents can be used to form thiazolium ions by quaternization of the ring nitrogen. These species show an enhanced reactivity toward nucleophiles, particularly at the carbons a or g to the charged heteroatom. Deprotonation at C-2 results in the formation of an ylide, which is stabilized by the adjacent sulfur atom. This feature is of particular significance as the active component of naturally occurring species such as thiamine (see Section 4.06.12.1) and in synthesis (e.g. in the Stetter reaction, see Section 4.06.12.3.2). A thiazolium 2-ylide can be formed by desilylation at C-2, which is a key step in the reaction between 2-trialkylsilylthiazoles and C-electrophiles (Dondoni reaction). Oxidation of variously substituted thiazolium salts with a variety of oxidants gives, for example, dimeric disulfides, thiazolones, thiazolidinones, and thiazolidinediones .

4.06.5.1.3

Thiazolones, thiazolethiones, and thiazolimines

The main feature of these compounds is their tautomerism and resultant ambident electrophilic reactivity. Their reactivity is therefore highly dependent upon the electron distribution within the ring. Electrophilic attack occurs b to either the ring nitrogen or sulfur, whereas nucleophilic attack tends to take place at the a-position, normally C-2. Nucleophiles can also deprotonate the heterocycle, acting as bases.

4.06.5.1.4

N-Oxides, N-imides, and N-ylides of thiazoles

Thiazole N-oxides, N-imides, and N-ylides are formally betaines derived from N-hydroxy-, N-amino-, and N-alkylazolium compounds. Where the cation is involved, reactivity is similar to that of thiazolium ions.

4.06.5.2 Thermal and Photochemical Reactions Ab initio studies on the photochemical isomerization of thiazole derivatives have been reported. The results are in keeping with data from experimental and semi-empirical methods. An alternative mechanism for 2-phenylthiazole photoisomerization has been proposed (Scheme 5) .

657

658

Thiazoles

Scheme 5

Triplet excited 2-phenylthiazole is reported to be a p,p* -triplet with the LSOMO and HSOMO at 29.47 and 26.84 eV, respectively. In this case, the singlet excited state can evolve to give the Dewar thiazole 55, the corresponding excited triplet state being unobtainable. Furthermore, the triplet state cannot be converted into biradical intermediates due to their higher energy (compared to the triplet state), thus preventing the formation of the cyclopropenyl derivatives. Triplet excited 2-acetylthiazole is also reported to be a p,p* -species, showing the LSOMO and the HSOMO at 210.70 and 28.14 eV respectively. Formation of the Dewar isomer is therefore possible as the direct irradiation involves the population of the excited singlet state. Intersystem crossing to the triplet state can occur, and the intersystem crossing quantum yield for this conversion was found to be nearly quantitative. Conversely, the triplet state cannot convert to the Dewar thiazole, but it can give the corresponding biradicals. However, these biradicals are not responsible for the isomerization reactions, being able only to give decomposition products.

4.06.5.3 Electrophilic Attack at Nitrogen 4.06.5.3.1

Introduction

The unshared pair on the ring nitrogen can react with p-acceptors. Although the ring nitrogen of thiazole bears considerable similarity to that of pyridine, it is less basic due to the decreased aromatic stabilization of a positive charge. However, thiazole can delocalize a positive charge more readily than some other 1,3-azoles, such as oxazole, due to the softer nature of sulfur.

4.06.5.3.2

Basicity of thiazole

The basicity of thiazole was well documented . A table of pKa and free enthalpies of dissociation of some representative thiazoles was presented.

4.06.5.3.3

Metal ions

There have been a great many reports of thiazole ligands binding to metal ions through the ring nitrogen and the various approaches to their characterization have been well documented in CHEC(1984) and CHEC-II(1996) . The most common metal for complexation of thiazoles is copper, and thiazole ligands are reported that show selectivity for Cu(II) in the presence of other divalent transition metal ions. Examples of the application of complexes of this type include the synthesis of a novel thiazole-based dipeptide chemosensor for Cu(II) ions in water . Although complexation is predominantly through the ring nitrogen, structures have been reported where a metal ion inserts into the CH bond at C-2 to give bridged structures of the type 56 and 57 (Scheme 6) . Thiazole complexes of diorganotin(IV) dihalides have also been described .

Thiazoles

Scheme 6

4.06.5.3.4

Alkylation

Thiazoles react readily with alkyl halides to form the corresponding thiazolium salts. Many examples exist in the literature and studies of the effect of thiazole ring substituents upon the rate of reaction have been well reviewed . Thiazoles and benzothiazoles substituted with a hydroxy, thio, or amino group can undergo alkylation equally at either the endo- or exocyclic heretoatom. This reactivity has been discussed elsewhere . The thiamin phosphate synthase-catalyzed formation of thiamin phosphate from 4-amino-5-(hydroxymethyl)2-methylpyrimidine pyrophosphate and 4-methyl-5-(1-hydroxyethyl)thiazole phosphate has been studied. A mechanism was proposed, and the substituent effects of the pyrimidine ring upon the TS discussed .

4.06.5.3.5

Oxidation

The formation of N-oxides by peroxy acid oxidation of thiazoles has been reported. Reagents used and typical yields have been discussed elsewhere . N-Oxidation of epothilones A–C with m-chloroperbenzoic acid (MCPBA) has been reported in yields from 20% to 48%, which are typical for this type of transformation. Oxidation was confirmed to have occurred exclusively on the nitrogen atom by X-ray crystallography , controverting an earlier report that treatment of epothilone A with MCPBA resulted in sulfoxide formation .

4.06.5.3.6

Amination

The amination of ester 58 with O-(mesitylenesulfonyl)hydroxylamine 59 proceeded readily, the resultant salt 60 being formed after 30 min and in 84% yield (Scheme 7) .

Scheme 7

4.06.5.3.7

Other reactions

2-Aminobenzothiazoles undergo reaction with formaldehyde and electron-rich alkenes such as cyclopentadiene (Scheme 8) to give a cyclic isothiourea 61 with regio- and stereocontrol .

Scheme 8

659

660

Thiazoles

4.06.5.4 Electrophilic Reaction at Carbon 4.06.5.4.1

Reactivity and orientation

Like pyridine, thiazole has significant p-character, but also like pyridine, the ring nitrogen deactivates the system to electrophilic attack. Furthermore, the acidic conditions involved in many electrophilic substitution reactions means that the reactivity is reduced further by protonation of the ring nitrogen. Activation toward electrophilic substitution is therefore required by the presence of electron-releasing substituents (such as hydroxy or amino groups) on the thiazole ring. The order of reactivity is C-5 > C-4 with substitution at C-2 not occurring at all, which is consistent with the net p-charges calculated for each carbon atom and the electrophilic localization energies of these three ring positions. This means that the heteroatom ring of benzothiazole will not react, whereas the benzene ring will.

4.06.5.4.2

Nitration

The reactivity of thiazole to nitration has been well reviewed . Recently, nitration at C-4 of 2,5dimethylthiazole 62 was accomplished with trifluoroacetic anhydride (TFAA) and fuming nitric acid at 15 C as shown in Scheme 9 to give the product 63 in 67% yield . The nitration of thiazole itself was not studied in this work due to poor solubility under the reaction conditions . See also Section 4.06.7.2.

Scheme 9

4.06.5.4.3

Sulfonation

Typically, forcing conditions are required for the sulfonation of thiazole. The details of sulfonation of 4-substituted 2-aminothiazoles with chlorosulfonic acid have been studied . Mainly 2-aminothiazole-5-sulfonic acids 64 were formed, which upon heating in sulfuric acid rearranged to give the corresponding stable thiazole-2sulfamoylic acids 65 (Scheme 10). Thiazolyl sulfonamides have been prepared by a deprotonation/sulfonylation strategy, involving oxidation of the lithium sulfinate salt by one of two methods: treatment with N-chlorosuccinimide followed by aqueous ammonium hydroxide (for halo- and alkyl-substituted thiazoles) or treatment with hydroxylamine-O-sulfonic acid (for unsubstituted or alkoxythiazoles) to provide the sulfonamides .

Scheme 10

4.06.5.4.4

Halogenation

Direct halogenation of thiazole usually requires harsh conditions, often resulting in mixtures. The Sandmeyer reaction, involving the relevant amino precursors, is selective but laborious and often results in low yields. However, selective metallation, followed by displacement by halide, offers an alternative approach. Thiazole undergoes selective iodination at C-2 with iodine in tetrahydrofuran (THF) after metallation with diisopropylmagnesium chloride . Chlorination of thiazole at C-2 has been reported in 90% yield after activation with lithium and treatment with CCl4. This was followed by selective bromination at C-5 by lithiation and reaction with CBr4 . Other halogenating reagents have been reported for this transformation as alternatives to CCl4 . Also, a 4,5-disubstituted thiazole underwent iodination at C-2 with iodine after lithiation with MeLi . See also Section 4.06.7.2.

Thiazoles

Bromination of a 2,4-disubstituted thiazole at C-5 in good yields has been reported using bromine in acetic acid . Heating 2-(2-pyridyl)-4-methylthiazole or 2-(2-pyridyl)-5-methylthiazole with 2 equiv of bromine in refluxing chloroform/acetonitrile (1:1) for 48 h results in bromination at C-5 or C-4, respectively, in good yields . Bromination of 2-amino- and 2-acetylamino-4-(2-furyl)thiazoles 66 occurs on C-5 when 1 equiv of reagent is used at 10 C in a kinetically controlled reaction (Scheme 11). Bromination of the furan ring occurs at higher temperatures as the result of a secondary, thermodynamic process. This was confirmed experimentally; thus, upon heating for 1 h on a steam bath with 1 mol of hydrobromic acid in glacial acetic acid medium, the 5-bromothiazole 67 underwent 90% conversion to 59-bromofurylthiazole 68, while upon treatment with 2 mol of hydrobromic acid, 5,59-dibromofurylthiazole 69 underwent 70% conversion to the same compound 68 .

Scheme 11

4.06.5.4.5

The halogen dance reaction

An elegant method for the formation of highly functionalized heterocycles, the halogen dance (HD) reaction, involves metallation of a halogenated thiazole followed by transposition of the metal and halogen substituents to form a new organometallic species (Scheme 12). The first example of an HD reaction in a thiazole was reported in the synthesis of natural product WS75624 B . Subsequently, the thiazole HD reaction has been investigated in more detail. A range of electrophiles were used to trap the dance intermediates with yields ranging from 20% to 99% .

Scheme 12

661

662

Thiazoles

4.06.5.4.6

Oxidation

Thiazole is relatively resistant to oxidation. Oxidation reactions at the carbon atoms of thiazole have been reviewed thoroughly in CHEC(1984) and CHEC-II(1996) .

4.06.5.4.7

Other reactions

Deprotonation of benzothiazole with n-butyllithium in the presence of 2-methyl-2-nitrosopropane resulted in the formation of a hydroxylamine 70 as shown in Scheme 13 .

Scheme 13

4.06.5.5 Reaction at Sulfur The sulfur atom of thiazole has been reported to be resistant to oxidation to sulfoxide or sulfone . Desulfurization with Raney-nickel has been reviewed .

4.06.5.6 Nucleophilic Attack at Carbon As predicted by MO calculations, thiazole is most susceptible to nucleophilic attack at C-2, as is the case for benzothiazole also. Position 5 is less reactive and position 4 quite unreactive. Thiazoles bearing electron-withdrawing substituents, or indeed thiazolium salts, display increased reactivity.

4.06.5.6.1

Oxygen nucleophiles

In general, thiazoles and benzothiazoles are resistant to reaction with hydroxide and alkoxide ions. Reactions of thiazoles and thiazolium salts with oxygen nucleophiles have been discussed in detail in CHEC(1984) and CHECII(1996) .

4.06.5.6.2

Carbanions

Generally, organolithium and organomagnesium compounds act as strong bases, abstracting ring protons. The thiazol2-yl acetamides 73 were synthesized from the thiazoles 71, via the diesters 72 according to Dondoni’s procedure (Scheme 14) .

Scheme 14

Thiazoles

2-Chlorobenzothiazole 74 undergoes an iron-catalyzed cross-coupling reaction to give product 75 in the presence of n-C14H29MgBr in 68% yield as shown in Scheme 15. This is an interesting transformation as iron-catalyzed coupling chemistry has received considerably less attention than that of palladium or nickel, for example .

Scheme 15

2,4-Dibromothiazole underwent regioselective substitution at C-2 in a Pd(0)-catalyzed cross-coupling reaction with various organozinc halides in moderate to good yields . En route to the synthesis of hectochlorin, the thiazole subunit was prepared by the use of a Negishi reaction to install the isobutene group of 76 (Scheme 16) .

Scheme 16

The first step in the synthesis of ()-mycothiazole reported by Le Flohic et al. involved the derivatization of 2,5dibromothiazole 77 by prenylmagnesium bromide to form the terminal olefinic compound 78 (Scheme 17) .

Scheme 17

663

664

Thiazoles

4.06.5.7 Nucleophilic Attack at Hydrogen (Deprotonation) Deprotonation of thiazole and benzothiazole (including pKa values) have been discussed thoroughly elsewhere. Metallation and hydrogen exchange were also reviewed . In short, the acidities of thiazole and benzothiazole have been determined as pKa 28.3 and pKa 28.9, respectively, in THF at 60 C. Treatment of both thiazole and benzothiazole with organolithium bases leads to deprotonation at C-2 exclusively.

4.06.5.7.1

C-Acylation via deprotonation

The anion generated by deprotonation of thiazole at C-2 with n-butyllithium reacts with an aldehyde, which, followed by oxidation with MnO2, provides access to the acylated heterocycle as shown in Scheme 18 .

Scheme 18

Silylation of benzothiazole at C-2 was followed by treatment with various aroyl chlorides to form the acylated products in good yields (Scheme 19) .

Scheme 19

4.06.5.7.2


Treatment of thiazole and benzothiazole with a lithium base results in selective deprotonation at C-2. The metallation of thiazole ring carbons has been discussed in great detail in CHEC-II(1996) . A recent example of the lithiation of thiazole at C-2 used a solution of n-butyllithium in hexanes and was carried out in ether at 80 C (Scheme 20) .

Scheme 20

Thiazoles

4.06.5.7.3

Hydrogen exchange at ring carbon

Hydrogen exchange with deuterium has been accomplished using MW irradiation in a mixture of 30% D2O in deuteriomethanol . Dithiazole 79 was irradiated for 600 s resulting at a temperature of 165 C and a pressure of 13 atm. After this treatment, doubly deuteriated dithiazole 80 was formed with >95% deuterium incorporation at both positions (Scheme 21).

Scheme 21

Dithiadiazafulvalenes 81a–c were prepared by triethylamine-catalyzed deprotonation of the thiazolium salts 82a–c in acetonitrile, which resulted in rapid precipitation of the products (Scheme 22) .

Scheme 22

4.06.5.7.4

Other reactions

The kinetics of proton transfer from the C-2a position of 2-(1-methoxybenzyl)thiazolium salts was studied for the 1 p-H and p-NMeþ 3 derivatives by H NMR spectroscopy. The study was carried out by mixing the salts rapidly with sodium hydroxide in a stopped-flow instrument and monitoring the progress of enamine formation and decomposition in the visible region of the spectrum. Under these conditions the thiazolium ring opened, the 1H NMR spectrum of the product being consistent with both cis- and trans-stereochemistry about the newly formed enamine bond (Scheme 23) .

Scheme 23

665

666

Thiazoles

4.06.5.8 Cyclic TSs with a Second Molecule As thiazoles have significant aromatic character, they display poor reactivity in cycloaddition reactions. However, a theoretical study of the Diels–Alder reactions of a thiazole o-quinodimethane 83 with 2- and 3-bromo-5-hydroxynaphthoquinones 84 and 85 has been carried out (Scheme 24) . The findings from the PM3, molecular hardness, and ab initio (3-2 Gp) calculations of this study agree with the experimental results and support the statement that hydrogen bonding plays a crucial role on the regiocontrol of the cycloadditions.

Scheme 24

4.06.6 Reactivity of Nonconjugated Rings 4.06.6.1 Isomers of Aromatic Derivatives Thiazoles bearing hydroxy, thio, or amino groups at C-2, C-4, or C-5 are in tautomeric equilibrium with the corresponding oxo, thioxo, or imino thiazolines. Thiazoles bearing more than one of these groups also display similar prototropic tautomerism, although with some restrictions.

4.06.6.2 Dihydro Derivatives 4.06.6.2.1

Tautomerism

Where substitution results in the formation of an enol, an enethiol, or an enamine, a tautomeric equilibrium exists with the oxo, thioxo, or imino thiazolidines.

4.06.6.2.2

Aromatization

A variety of oxidizing agents have been reported to aromatize thiazolines to thiazoles. For example, 2-[1-(9H-fluoren9-ylmethoxycarbonylamino)-ethyl]-4,5-dihydrothiazole-4-carboxylic acid allyl ester was oxidized to the corresponding thiazole in 91% yield by treatment with activated MnO2 . MnO2 has also been used in conjunction with MW irradiation to oxidize a similar thiazoline to thiazole in 79% yield . Structurally related thiazolidines have also been aromatized to thiazoles using MnO2 . In the case of 2-(2-hydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide, attempts at oxidation with MnO2 resulted in a poor yield. Instead, an alternative procedure using a mixture of CBrCl3 and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) provided the matching thiazole in 87% yield . Other thiazolines have been converted into thiazoles in this way in excellent yields . Aromatization of a thiazoline to a thiazole has also been accomplished by treatment with nickel peroxide in 67% yield . In a synthesis of pateamine A, it was found that the optimum yield could only be obtained from a Hantzsch-type thiazole formation by isolation and purification of the nonaromatic intermediate. This was followed by dehydrogenation by treatment with TFAA, pyridine, and Hu¨nig’s base, giving a 62% yield over the two steps (Scheme 25) .

Thiazoles

Scheme 25

A dehydrogenation reaction on a similar substrate has been reported with TFAA and pyridine, but without Hu¨nig’s base, giving the thiazole in good yield .

4.06.6.2.3

Electrophilic reaction at nitrogen

4.06.6.2.3(i) Alkyl halides Treatment of various 2-methylthiazolines with methyl iodide in nitromethane gave the corresponding N-methylthiazolinium salts in excellent yields . Treatment of thiazolines with various alkyl iodides (at reflux for 48 h) to form the corresponding N-alkylthiazolinium salts has been used in the preparation of ionic liquids . 4.06.6.2.3(ii) Acyl halides Treatment of a 2-methylthiazoline with an acid chloride resulted in the formation of N-acyl--keto cyclic keteneN,S-acetals (Scheme 26) .

Scheme 26

4.06.6.2.3(iii) Other electrophiles Diazabutadione 86 undergoes reaction with ketenes to form benzothiazolopyrimidinones 87 (Scheme 27) .

Scheme 27

Conjugate addition of thiazoline 88 to salt 89 with TFAA in CHCl3 resulted in the highly diastereoselective formation of 90 as shown in Scheme 28 . 2(3H)-Benzothiazolone was acetylated with 2-bromopropionyl chloride in the presence of triethylamine in 37% yield . Interestingly, after N-acylation of 2(3H)-benzothiazolone with a range of acid chlorides in the presence of triethylamine (94–99% yield), heating at 165 C with AlCl3 for 3 h resulted in migration of the acyl group to the 6-position (76–90% yield over two steps) .

667

668

Thiazoles

Scheme 28

4.06.6.2.4

Nucleophilic attack at carbon

4.06.6.2.4(i) Carbanions 2-Thiazolines undergo reaction at C-2 in the presence of Grignard reagents in the expected manner . The reactions of various C-nucleophiles with 3-thiazolines to give the corresponding substituted thiazolidines are also discussed in this review, including organolithium compounds, Grignard reagents, nitronates, and silyl and lithium enol ethers. 4.06.6.2.4(ii) Other nucleophiles Thiazolones undergo ring-opening reactions in the presence of nitrogen nucleophiles. For example, thiazol-5(4H)one 91 underwent direct coupling with a primary amine to give endothiotripeptides 92 in high yields without epimerization as shown in Scheme 29 .

Scheme 29

4.06.6.2.5

Other reactions

Condensation of thiazolidin-5-one 93 with different aromatic aldehydes in ethanol containing catalytic piperidine gave the respective arylidenes 94 (Scheme 30) .

Scheme 30

4.06.6.3 Tetrahydro Derivatives 4.06.6.3.1

Tautomerism

Imino-, oxo-, or thioxo-substituted thiazolidines are in tautomeric equilibrium as discussed in Section 4.06.6.2.1. Many thiazolidines are also found to be in equilibrium with an open-chain form, depending on the substituents (Scheme 31) .

Thiazoles

Scheme 31

4.06.6.3.2

Aromatization

Many examples exist of the aromatization of tetrahydrothiazoles using manganese dioxide. For example, dehydrogenation of 95 was accomplished in 59% yield using activated MnO2 in benzene–pyridine to give the thiazole 96 (Scheme 32) .

Scheme 32

In the example shown in Scheme 33, aromatization of 97 was carried out using NiO2 in preference to MnO2 as this did not result in racemization of the carbon bearing the NHCbz group (Cbz ¼ carbobenzyloxy) .

Scheme 33

An alternative procedure using N-bromosuccinimide in carbon tetrachloride was reported to provide thiazole 98 from thiazolidine 99 in 48% yield (Scheme 34) .

Scheme 34

4.06.6.3.3

Electrophilic reaction at sulfur

Chemoselective oxidation of the ring sulfur of penicillin derivatives 100 and 101 has been reported in the presence of cobalt(III) acetylacetonate and either isobutyraldehyde or propionaldehyde under oxygen to afford the corresponding sulfoxides 102 and 103 in excellent yields as shown in Scheme 35. Overoxidation was not observed and additional functional groups were not affected under these conditions . Conversely, oxidation of 6,6-dibromo-3a-(diphenylphosphate)oxymethyl-2,2-dimethyl penam 104 to the corresponding sulfone 105 was accomplished by treatment with KMnO4 in a mixture of acetic acid–water (62.5:37.5), as is shown in Scheme 36 .

669

670

Thiazoles

Scheme 35

Scheme 36

In a similar study, 4-penam sulfoxides and sulfones were prepared either by controlled oxidation with hydrogen peroxide in acetic acid over 2 days or complete oxidation with KMnO4 . Selective hydrogen peroxide oxidation of 106 was also used to form sulfoxide 107 in 89% yield (Scheme 37) .

Scheme 37

Several hydrogenated thiazolo[2,3-a]isoquinolinone S-oxides (108 and 109) have been prepared from 110 and the performance of MCPBA and H2O2 at both room temperature and in refluxing MeOH and Oxone were discussed; the results are shown in Table 6 .

4.06.6.3.4

Electrophilic reaction at nitrogen

4.06.6.3.4(i) Acyl halides The nitrogen atom of thiazolidines will undergo substitution with acid chlorides in the presence of Na2CO3 . In the preparation of N-acetylthiazolidinethione chiral auxiliaries, deprotonation of the thiazolidine ring nitrogen with n-butyllithium at 78 C was followed by treatment with acetyl chloride to give the product in 90% yield .

Thiazoles

Table 6

Sulfide

Sulfoxide

Cpd.

R

R1

R2

Oxidant

Reaction Time

Yielda (%)

Major

110a

MeO

H

H

110b

MeO

CH3

H

H

H

Me

110d

MeO

H

Me

110e

MeO

Me

Me

0.5 h 6h 2–2.5 h 3h 0.5 h 3d 1.5 h 12 h 3d 3.5 h 0.5 h 3.5 h 2h 0.5 h 3d

91 71 75 71 94 96 97 Decomp. Decomp. 54 90 75 71 Decomp. 58

109a 108a 109a 108a 108b 109b 108b

110c

MCPBA H2O2 (rt) H2O2 (reflux) Oxone MCPBA H2O2 (rt) Oxone MCPBA H2O2 (rt) H2O2 (reflux) MCPBA H2O2 (rt) H2O2 (reflux) MCPBA H2O2 (rt)

a

109c 109d 109d 109d 109e

Crude yield of a and b.

Treatment of 2-phenylthiazolidine-4-carboxylic acid with triethylamine in THF, followed by reaction with benzoyl chloride, provided N-benzoyl-2-phenylthiazolidine-4-carboxylic acid in 76% yield (Scheme 38). However, applying the same conditions to the reaction with p-methoxybenzoyl chloride resulted in a moderate 50% yield. Application of an alternative methodology, without NEt3, provided the N-benzoyl product in only 44% yield, but the N-( p-MeOBz) compound in an improved 75% yield (although in only 50% de) (Scheme 38) .

Scheme 38

4.06.6.3.4(ii) Other electrophiles Thiazolidine has been coupled to a carboxylic acid using 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and DPIEA in dimethyl formamide (DMF) to form the corresponding thiazolidide . The ring nitrogen of thiazolidine has also been t-butoxycarbonyl (BOC)-protected using di-tert-butyl dicarbonate in quantitative yield .

671

672

Thiazoles

4.06.6.3.5

Ring opening

Ring-opening hydrolysis of thiazolidines under acidic or basic conditions gives aldehyde and amino thiol. Peptidyl aldehydes 111 were synthesized in excellent yields from thiazolidine peptides 112 using copper salts (CuO, CuCl2) in acetonitrile/water under the reducing conditions (Scheme 39) .

Scheme 39

4.06.6.3.6

Other reactions

The synthesis and pyrolytic behavior of thiazolidin-2-one 1,1-dioxides have been studied. Extrusion of SO2 leads to the formation of -lactams as shown in Scheme 40 .

Scheme 40

4.06.7 Reactivity of Substituents Attached to Ring Carbons 4.06.7.1 General Survey The reactivity of a thiazole substituent is related to the nature of the ring carbon to which it is attached. Hence, the electron deficiency of C-2 means that alkyl groups in this position are most easily deprotonated, and halogens most readily substituted. In turn, the somewhat electron-rich nature of C-5 and neutral nature of C-4 each influence the behavior of substituents in these positions.

4.06.7.2 Fused Benzenoid Rings Various benzothazolin-2-ones were acylated at the 6-position with a range of acid chlorides and catalytic ZnCl2; yields ranged from 45% to 84% . 5-Hydroxy-2-methylbenzothiazole was selectively nitrated at the 6position in 86% yield with cerium(IV) ammonium nitrate in the presence of NaHCO3 . Upon treatment with NaI and N-chloro-p-toluenesulfonamide sodium salt (chloramine-T), D-luciferin 113 was selectively halogenated at the 7-position (Scheme 41) .

Thiazoles

Scheme 41

7-Methyl-6-nitrobenzothiazole was synthesized in 10% yield by treatment of 6-nitrobenzothiazole with MeMgCl. Treatment of the 7-methyl-6-nitro product with HNO3 for 2.5 h at 120 C gave 7-methyl-4,6-dinitrobenzothiazole in 41% yield. 6-Methylbenzothiazole was selectively nitrated at the 7-position by treatment with HNO3 for 45 min at 45 C to give the product in moderate yield. Carrying out the reaction for 3 h at 120 C resulted in the formation of the 5,7-dinitro-6-methylthiazole in 15% isolated yield. The 5-methylbenzothiazole was nitrated under the same conditions to give a mixture of the 4- and 6-nitro products in 27% and 30% isolated yields, respectively (separated by crystallization and chromatography) .

4.06.7.3 Alkyl Groups 4.06.7.3.1

Side-chain halogenation

Bromination of the methyl group of 2-methyl-5-cyanobenzothiazole and 2-methyl-6-cyanobenzothiazole was accomplished using N-bromosuccinimide and AIBN in CCl4 at reflux . The bromine can then undergo displacement reactions.

4.06.7.3.2

Alkylthiazoles

The deprotonation of alkyl thiazoles was thoroughly reviewed in CHEC-II(1996) . Metallation is achieved using alkyllithium reagents or lithium diisopropylamide, the regioselectivity depending on the nature of the substituents.

4.06.7.3.3

C-Alkylthiazolium ions

Dimethylbenzothiazolium salt 114 underwent reaction at the 2-methyl group in the presence of N-methoxyphenanthridinium hexafluorophosphate 115 to give alkyl-substituted thiazolium 116 as shown in Scheme 42 .

Scheme 42


Aryl groups

Under strongly acidic conditions, 2-phenylthiazole undergoes electrophilic substitution on the benzene ring as the heterocycle is protonated and thus deactivated . The phenyl group of 2-phenylbenzothiazole has been bioconverted to the corresponding cis-1,2-diol in 36% yield by the use of recombinant Escherichia coli cells expressing modified biphenyl dioxygenase genes .

673

674

Thiazoles

4.06.7.4.2

Carboxylic acids

The reactivity of thiazole carboxylic acids was reviewed thoroughly in CHEC(1984) . Thiazole-2-carboxylic acid will undergo standard amide coupling reactions, for example, using 1-ethyl-3-(39-dimethylaminopropyl)carbodiimide (EDCI) and HOBt in DMF . The methyl ester of 6-methoxybenzothiazole-2-carboxylic acid was formed using CH2N2 in THF in 15 min .

4.06.7.4.3

Aldehydes and ketones

The alkylation of various benzothiazolyl and thiazolyl ketones with vinylmagnesium bromide has been studied. Di(benzothiazol-2-yl) ketone gave exclusively the O-alkylated product, whereas 2-acylbenzothiazoles gave solely the corresponding alcohol products. Other ketones gave different ratios of products. To probe this behavior, the reaction of vinyl Grignard and a series of (1,3-benzothiazol-2-yl) para-substituted-phenyl ketones was carried out, and a relative O/C-alkylation ratio, dependent on the nature and on the electronic effect of the substituent on the phenyl ring, was found .

4.06.7.4.4

Vinyl and allyl groups

Thiazole 117 underwent asymmetric dihydroxylation upon treatment with Sharpless AD-mix- in the presence of methanesulfonamide gave the desired ,-dihydroxy thiazole 118 with 91% ee and in 90% yield (Scheme 43) .

Scheme 43

Benzylamine adds to enone 119 to form the ketone 120, which undergoes cyclization in acidic conditions to give the 1-(2-thiazolyl)pentopyranosides 121 and 122 (Scheme 44) .

Scheme 44

Thiazoles

4.06.7.4.5

Other substituents

Halomethyl thiazoles are highly useful synthetic intermediates. Many reactions involve abstraction of an acidic halomethyl proton. For example, the transformation of 2-chloromethyl-4-methylthiazole 123 (among other chloroalkyl thiazoles) into the corresponding epoxide 124 by lithiation with n-butyllithium was followed by reaction with the appropriate ketone (Scheme 45) .

Scheme 45

1-(b-Hydroxyalkyl)benzothiazoles 125 have been prepared in good to excellent yields by the treatment of chloromethyl benzothiazole 126 with various ketones in a samarium-mediated Barbier-type reaction as shown in Scheme 46. The need for 2 equiv of SmI2 suggests initial formation of a radical species, which is followed by reduction to an organosamarium species by the second equivalent of samarium diiodide .

Scheme 46

2-(Aminooxymethyl)-benzothiazole was prepared from 2-bromomethylbenzothiazole using solid-phase chemistry based on the use of a solid-supported N-hydroxyphthalimide reagent using a Mitsunobu reaction followed by methylaminolysis .

4.06.7.5 Aminothiazoles 4.06.7.5.1

Reactions with electrophiles (except nitrous acid)

Aminothiazoles undergo reaction with various electrophiles as discussed at length in CHEC-II(1996) . In general, alkyl halides under weakly basic conditions react with the ring nitrogen, resulting in alkylation. However, under strongly basic conditions, the exocyclic nitrogen is the predominant nucleophile. The following example is illustrative. In the presence of an -bromoketone, aminothiazole 127 reacts to form the 5-phenylimidazo[2,1-b]thiazole 128 via a displacement of the halide by the ring nitrogen (Scheme 47) .

Scheme 47

675

676

Thiazoles

4.06.7.5.2

Reactions with nitrous acid: Diazotization

2-Aminothiazole and 2-aminobenzothiazole readily undergo diazotization upon treatment with nitrous acid/phosphoric acid. The reaction is thought to start with protonation of the ring nitrogen, which is followed by attack by the NOþ ion, the final diazonium salt being in equilibrium with the protonated form. This chemistry has been of particular interest to the dyestuffs industry. For example, the diazotization of various 2-aminobenzothiazoles 130 with phosphoric acid and sodium nitrite, then reaction with N-(2-hydroxyethyl)-1-naphthylamine 129 in hydrochloric and sulfamic acids, followed by basification with NaOH gave compound 131 (Scheme 48) .

Scheme 48

4.06.7.6 Other N-Linked Substituents When the ring nitrogen bears an electrophile, 2-aminothiazoles and 2-aminobenzothiazoles can undergo cyclization to form fused systems. For example, upon heating in glacial acetic acid, salt 132 was found to undergo cyclization to form fused system 133 (Scheme 49) .

Scheme 49

N-Benzyl-2-aminothiazolium salt 134, upon treatment with 1 equiv of PCl3 and 2 equiv of triethylamine, was transformed into the aminodichlorophosphine 135 in 73% yield (Scheme 50) .

Scheme 50

4.06.7.7 O-Linked Substituents Benzothiazolones are formed by demethylation of 2-methoxybenzothiazoles upon treatment with HBr under aqueous conditions . 6-Nitro-2-benzothiazolyl 3,6-di-O-allyl-2,4-di-O-benzyl--D-mannopyranoside 136 has been used as a highly efficient mannosyl donor in the presence of tetrakis(pentafluorophenyl)borate at –78 C in DCM to give the desired -mannosides in high yields .

Thiazoles

4.06.7.8 S-Linked Substituents 4.06.7.8.1

Thiones

Various alkyl Grignard reagents have been shown to attack the thiocarbonyl group of 4,4-dimethyl-2-phenylthiazole5(4H)-thione 137 (where R ¼ Ph, R1 ¼ R2 ¼ Me) to give the products 138 of addition at C-5 . Treatment of similar thiones with 2-azidoketones resulted in the formation of the corresponding 6-oxa-1,9-dithia-3azaspiro[4.4]nona-2,7-dienes 139 in good to excellent yields . Again, when thione 137 (R1 ¼ R2 ¼ Me) was treated with dimethyl diazomalonate in the presence of rhodium acetate dimer in toluene, (4,4-dimethyl-2-phenyl-5(4H)-thiazolylidene) dimethyl ester 140 was formed . Similar thiones form spirocyclic dithiazoles 141 and oxathiolanes 142 upon treatment with aziridines or epoxides , respectively (Scheme 51).

Scheme 51

4.06.7.8.2

Alkylthio groups

Thiazol-2-yl allyl sulfides react with organomagnesium compounds in the presence of CuBr to afford optically active alkenes in good yields and selectivities . Thiazole and benzothiazole allyl sulfides have been shown to react with excess ethyl diazoacetate in the presence of a copper(I) hexafluorophosphate acetonitrile complex to give, via formation of the resultant homoallylic sulfide intermediates, conjugated dienoic esters in good yields . -Ketosulfides of benzothiazole 143 are very prone to deprotonation by weak bases. Treatment

677

678

Thiazoles

of these ‘pronucleophiles’ with ,-unsaturated ketones in an ionic liquid (tetrabutylammonium bromide, TBAB) resulted in the formation of cyclopropanes in moderate to good yields .

4.06.7.8.3

Other substituents

C-2-Alkylsulfonyl benzothiazoles undergo metallation at the -position with various lithium bases, the products of which will then react with electrophiles in the usual manner. Desulfonylation of the products thus formed can be achieved using NaBH3CN to give the desired alkyl species . A sulfone anion has been generated from 2-((2E,4E)-3-methyl-5-(tributylstannyl)penta-2,4-dienylsulfonyl)benzothiazole 144 using sodium hexamethyldisilazide (NaHMDS), which added to (2E,4E)-3-methyl-5-(tributylstannyl)penta-2,4-dienal to form the symmetrical all-E-pentene 145 as shown in Scheme 52 .

Scheme 52

4.06.7.9 Halogen Atoms 4.06.7.9.1

Nucleophilic displacement

Thiazoles bearing halides at C-2 undergo nucleophilic displacement by a variety of nucleophiles such as alkoxides, nitrogen nucleophiles, and other halogens. These transformations have been discussed thoroughly elsewhere . More recent examples include displacement by azide , organometallic cross-coupling , boronic acid cross-coupling , and by alcohols and thiols .

4.06.7.9.2

Halogen–lithium exchange

Only 2-, 4-, and 5-bromo thiazoles will undergo halogen–lithium exchange and this has been accomplished using the common alkyllithium reagents such as n- or t-butyllithium. An example of halogen–lithium exchange at C-4 is the reaction between 2-methyl-4-bromothiazole and n-BuLi . However, exchange at C-2 or C-5 is more common. For example, treatment of 2,4-dibromothiazole with i-PrLi leads to exchange exclusively at C-2 .

4.06.7.10 Metals and Metalloid-Linked Substituents 4.06.7.10.1

Lithium

Organolithium compounds will undergo reaction with various electrophiles in the expected manner. C-2-Lithiated thiazole and benzothiazole have been added to the ketone moiety of artimisinin to form analogues in excellent yields . C-2-Lithiated thiazoles have also been reacted with L-fuconolactone , aldehydes , tributyltin chloride , triisopropylchlorosilane , isocyanates , and esters .

Thiazoles

4.06.7.10.2

Silicon

2-Silylthiazoles and -benzothiazoles react readily with various electrophiles. Recent examples include reactions with esters , ketones , and aldehydes , which are all facilitated by the use of fluoride reagents such as tetrabutylammonium fluoride (TBAF). Other examples, such as addition to acid chlorides and aldehydes , do not require fluoride assistance, the reactions proceeding smoothly without this additive.

4.06.7.10.3

Tin

Thiazoles bearing trialkyltin at either C-2, C-4, or C-5 undergo Stille couplings with vinyl iodides in moderate to excellent yields . 2-Iodo-3-bromothiophene, upon treatment with 2-tributylstannylthiazole, undergoes coupling at C-2 exclusively . Other substrates which react with stannylthiazoles include aryl bromides , a 2-amino-6-toluenesulfonylpurine nucleoside derivative , and 9-benzyl-6-chloro-9H-purine .

4.06.7.10.4

Other metals

Other metals, the attachment of which to thiazoles results in the formation of species of significant synthetic interest, include zinc and magnesium. These reagents react with electrophiles in the expected manner. Examples include the reactions of 2-thiazolylzinc bromide with alkyl and aryl halides , and an alkyl triflate . Grignard reagents have also been formed at the C-4 position of 2-substituted thiazoles, as in the reaction between 2-methyl-4-thiazolylmagnesium bromide and 7-[1-(bromomethyl)ethenyl]-5,5-dimethyl-4,6dioxaspiro-[2.5]octane .

4.06.8 Reactivity of Substituents Attached to Ring Heteroatoms 4.06.8.1 Substituents Attached to Ring Nitrogen Atom Thiazole N-oxides can easily be alkylated on the oxygen. For example, N-(alkoxy)-5-(p-methoxyphenyl)-4methylthiazole-2(3H)-thiones were prepared from N-(hydroxy)-5-( p-methoxyphenyl)-4-methylthiazole-2(3H)-thione tetraethylammonium salt and an appropriate alkyl chloride or tosylate in moderate to good yields . N-Methoxythiazole-2(3H)-thiones were synthesized from the N-hydroxythiazole-2(3H)-thiones by treatment first with a tetraalkylammonium hydroxide in methanol and then methyl para-toluenesulfonate in DMF .

4.06.8.2 Substituents Attached to Ring Sulfur Atom The reactions of substituents attached to the sulfur atom have been reviewed in some detail in CHEC-II(1996) . They are known to undergo silicon Pummerer-type reactions.

4.06.9 Ring Synthesis Classified by Number of Ring Atoms in Each Component 4.06.9.1 Synthesis of Thiazoles The intensity of activity in the field of thiazole and benzothiazole research reflects the importance of these heterocycles in organic and biological chemistry. There has therefore been a large volume of synthesis literature produced since 1995. The following section has been ordered according to the fragments generated by retrosynthetic analysis, which are shown in Scheme 53.

4.06.9.1.1

Synthesis from C2 þ NCS components

4.06.9.1.1(i) Synthesis from -halocarbonyl compounds (the Hantzsch synthesis) By far the most frequently encountered synthesis of thiazoles involves the condensation of an -halocarbonyl compound with an appropriate source of the N–C–S unit, such as a thiourea or a thioamide. Reactions of N-monosubstituted thioureas 146 and -haloacyl halides 147, in the presence of triethylamine, give mesoionic thiazol-3-ium-4-olates 148 (Scheme 54) .

679

680

Thiazoles

Scheme 53

Scheme 54

The reaction of an -haloketone with thiourea gives rise to the 2-aminothiazole. This reaction has been used in a combinatorial approach for the synthesis of libraries of 2-aminothiazoles in excellent yields and purities: first in the solution phase and then on a solid support using Rink amide MBHA, glycyl-Rink amide MBHA, and reductively aminated ArgoGel MB–CHO resins (Scheme 55) .

Scheme 55

Conversely, a-haloketones have been immobilized on resin and reacted with a range of thioamides and thioureas to form 2,4-disubstituted thiazoles in good to excellent yields .

4.06.9.1.1(ii) Other syntheses Leaving groups other than halogens have been used on the C–C fragment. For example, the use of -tosyloxy ketones offers an alternative to the lachrymatory -haloketones. The MW-mediated reaction of several parasubstituted -tosyloxy acetophenones with para-substituted thiobenzamides was accomplished in 88–96% yields with reaction times ranging from 2 to 4 min . Cyclization has also been reported without a leaving

Thiazoles

group in the -position of the ketone, resulting in the formation of both the expected thiazole 149 and the corresponding N-substituted 2-iminothiazole 150, as shown in Scheme 56 .

Scheme 56

In a solid-phase combinatorial approach, resin-bound esters 151 underwent Tebbe-mediated methylenation, followed by bromination with Br2 to give the corresponding dibromides 152. These were reacted in turn with a range of thioamides in a large excess to give the 2,4-disubstituted thiazoles 153 (Scheme 57). The product was easily separated from the remaining thioamide by treatment with 5-(49-chloromethylphenyl)pentylpolystyrene resin (CMPP resin) .

Scheme 57

4.06.9.1.2

Synthesis from C2N þ CS components

2-Aminothiazoles 154 can be synthesized from from a-bromoketimines 155 and ammonium thiocyanate via the thiazolidin-2-imine 156 as shown in Scheme 58 .

Scheme 58

681

682

Thiazoles

4.06.9.1.3

Synthesis from C2NC þ S components

The use of Lawesson’s reagent has been reported in the synthesis of thiazoles 157 (Scheme 59). Where R was isopropyl (Cbz-L-Leu), the thiazole was isolated in 83% yield, whereas in the case of Cbz-D-Trp the yield was 46% .

Scheme 59

A versatile method for the synthesis of 5-aminothiazoles was reported involving a sulfuration step using Lawesson’s or Belleau’s reagent to convert oxygen-containing compound 158, prepared from 159, to the sulfur analogue 160 (Scheme 60). TFAA-mediated cyclization was followed by cleavage of the trifluoromethyl group in 161 under basic conditions to provide amine 162 in moderate to good yields over a range of aromatic and aliphatic R-groups .

Scheme 60

4.06.9.1.4

Synthesis from SC2 þ NC components

(S)-Monodeuteriothiamine 163 was prepared for use in determining the stereochemistry of both the thiaminase I and the bisulfite-catalyzed thiamin-cleavage reactions (Scheme 61) .

Scheme 61

Thiazoles

4.06.9.1.5

Synthesis from C þ CNCS components

Thiazole 165 was formed in moderate yield (54–72%) when equimolar quantities of methyl thioglycolate and thiocarbamoylimidate 164 were heated in methanol under reflux (Scheme 62) .

Scheme 62

4.06.9.1.6

Synthesis from NCSC2 components

2-Aminothiazoles have been prepared from a-halo-b-thiocyanato alkenes 166 and amine hydrochlorides (Scheme 63) .

Scheme 63

4.06.9.1.7

Synthesis from SC þ CNC components

The reaction of methyl isothiocyanate with 2 equiv of lithium diisopropylamide was followed by alkylation with dimethyl sulfate to give 2-methyl-5-N,N-dimethylaminothiazole 167 in 70–80% yield (Scheme 64) .

Scheme 64

4.06.9.1.8

Synthesis from C2NCS component

Thiobenzamide 168 was converted into thiazole 169 in 77% yield by treatment with POCl3 in pyridine (Scheme 65) . Endothiopeptide 170 was converted into thiazole 171 in 95% yield in 10 mol% HCl as shown in Scheme 66 .

683

684

Thiazoles

Scheme 65

Scheme 66

4.06.9.1.9

Synthesis from SC2NC component

Fully protected Cys-Cys dipeptide 172 was transformed into thiazole 173 by treatment with triphenylphosphine oxide and triflic anhydride, the other half of the molecule forming a thiazoline. The product was isolated in moderate yield but excellent enantiopurity (Scheme 67) .

Scheme 67

4.06.9.1.10

Other syntheses

4.06.9.1.10(i) By formal exchange of ring atoms with retention of ring size N-Thioacylisoxazol-5(2H)-ones 174 lose carbon dioxide under photochemical conditions and undergo intramolecular cyclization of the iminocarbene 175 to afford thiazoles 176 in good yields as shown in Scheme 68 .

Scheme 68

Thiazoles

4.06.9.2 Synthesis of 2-Thiazolines 4.06.9.2.1


The polyethylene glycol (PEG)-supported 1,2-diaza-1,3-butadiene 177 was treated with 4 equiv of variously substituted thioamides 178 (Scheme 69). The efficient and mild one-pot syntheses were carried out at room temperature in a solution of dichloromethane (DCM)–methanol (1:5) for 1.0–4.5 h to afford 2-thiazolin-4-ones 179 .

Scheme 69

3-(a-Bromoethyl)quinoxalin-2-ones 180, when reacted with thiourea, form spirothiazoloquinoxalines 181 via intermediate 182 (Scheme 70) .

Scheme 70

3-Aryl-4-formylsydnone 49-phenylthiosemicarbazones 183 were treated with ethyl 2-chloroacetoacetate and 2-bromoacetophenone in buffer systems of sodium acetate and acetic acid, to produce anti-oxidants 2-[(3-arylsydnon-4-ylmethylene)-hydrazono]-4-methyl-3-phenyl-2,3-dihydrothiazole-5-carboxylic acid ethyl esters 184 and 3,4diphenyl-2-[(3-arylsydnon-4-ylmethylene)hydrazono]-2,3-dihydrothiazoles 185 in good yields (Scheme 71) . Thiazolines 186 and 187 were prepared from acetic and benzoic thioamides and bis-trifluoromethyl enone 188. Benzoic thioamide underwent oxidation readily upon treatment with p-toluenesulfonic acid (PTSA) to form the corresponding thiazole 189, whereas methyl variant did not (Scheme 72) .

685

686

Thiazoles

Scheme 71

Scheme 72

4.06.9.2.2


The palladium-catalyzed cyclization of various propargylic amines with CS2 has been reported . In the case of propargylamine 190 (Scheme 73), the corresponding heterocycle 191 was produced in 99% yield. The same yield was obtained when the reaction was carried out in toluene .

Scheme 73

The formation of 1,3-thioxazolidine-2-thione 192 from carbon disulfide and 2-methylaziridine 193 was studied . Equimolar amounts of the CS2 and aziridine were reacted in the presence of a catalyst (5 mol%) in THF at room temperature for 24 h. In the absence of catalyst, no reaction occurred, but the use of LiBr and TBAB resulted in yields of 92% and 94%, respectively (Scheme 74). Reaction of L-cysteine ethyl ester hydrochloride 194 with CS2 in the presence of triethylamine in DCM resulted in the formation of thiazolidine ester 195 in 85% yield (Scheme 75) .

Thiazoles

Scheme 74

Scheme 75

4.06.9.2.3

Synthesis from CN þ SC2 components

Treatment of 2-cyanophenol with cysteine in phosphate buffer (pH ¼ 6.4) and MeOH (1:1) at 50 C for 4 days resulted in the formation of the thiazoline in 85% yield . Several nitriles (RCN, where R ¼ Me, Et, Bn, Ph, and i-Pr) were treated with HCl(g) in EtOH to form the corresponding imino ethers, which were subsequently condensed with (R)-cysteine methyl ester hydrochloride to form the variously substituted 2-thiazolines in 73%, 79%, 83%, 91% and 83% yields, respectively . 6-(2-Thiazolin-2-yl) compounds 196 were obtained by reaction of the corresponding 6-cyano derivatives 197 with stochiometric quantities of 2-aminoethanethiol hydrochloride and triethylamine in ethanol as shown in Scheme 76 .

Scheme 76

Excellent yields were obtained by heating the reaction using MW irradiation over 18 min whereas reaction with conventional heating took 180 min and resulted in lower yields.

4.06.9.2.4

Synthesis from C þ SC2N components

Treatment of an iminotriflate 198, generated by the addition of triflic anhydride to an amide, with an amino thiol resulted in the formation of a thiazoline under quite mild conditions. The proposed mechanism is detailed in Scheme 77 . A convenient method for the synthesis of optically active 2H-2-thiazoline methyl ester 199 from cysteine methyl ester hydrochloride 200 is shown in Scheme 78 . The source of C-2 was the triethyl orthoformate, and the reaction proceeded in quantitative yield.

4.06.9.2.5

Synthesis from CNC2S components

Synthesis of thiazoline 201 was accomplished from fully protected cysteine 202 using Ph3PO (3.0 equiv) and Tf2O (1.5 equiv) to generate an oxophilic Lewis acid catalyst 203 in solution. The reaction gave 201 in 98% yield and >99.5% ee . The proposed mechanism is shown in Scheme 79.

687

688

Thiazoles

Scheme 77

Scheme 78

Scheme 79

4.06.9.2.6

Synthesis from C þ CNCS components

N-Thioacylamidone 204 underwent heteroatom cyclization upon treatment with a trimethylsulfonium ylide to give the thiazoline 205 in 40% yield (Scheme 80) .

Scheme 80

4.06.9.2.7

Synthesis from C2NCS component

One particularly useful synthetic approach to the synthesis of 2-thiazolines 206 makes use of the Burgess reagent. An example shown in Scheme 81 involves the cyclodehydration of N-(hydroxyethyl)thiodipeptides 207 . In a similar manner, D-camphor-10-sulfonic acid (10-CSA) has been used in the synthesis of 2-thiazolines. In the example shown in Scheme 82, endothiopeptide 208 was converted into thiazol-5(4H)-one 209 .

Thiazoles

Scheme 81

Scheme 82

Formation of the 2-thiazoline-containing ()-1-methoxyspirobrassinol 210 was accomplished in 90% yield from 1-methoxybrassinin 211 using dioxane dibromide in dioxane containing 0.5% water over 10 min (Scheme 83) .

Scheme 83

4.06.9.2.8

Synthesis from CSC2N component

Treatment of thiol ester azide 212 with PPh3 in anhydrous THF (under reflux) provided thiazoline 213 in good yield (Scheme 84). In situ generation of a phosphinimine by Staudinger reaction of the azide with PPh3 allowed an intramolecular aza-Wittig reaction to take place with the thioester under the neutral and anhydrous conditions .

Scheme 84

689

690

Thiazoles

4.06.9.3 Synthesis of 3-Thiazolines A synthesis of an enantiomerically and diastereomerically pure 3-thiazoline 214 from 215 has been reported via a modified Asinger reaction. The use of a galactose-derived chiral auxiliary 216 was involved (Scheme 85) .

Scheme 85

Thiocarbamate 217 underwent in situ cyclodehydration to form the corresponding thiazoloquinolones 218 upon treatment with phosphorus pentoxide in AcOH (Scheme 86) .

Scheme 86

4.06.9.4 Synthesis of 4-Thiazolines 4.06.9.4.1


Imino-4-thiazolines have been prepared by condensation of -chloroketones and unsymmetrical thioureas under microwave irradiation. Under these solvent-free conditions, iminothiazolines were obtained directly when reactions were performed on alumina . Solution-phase parallel synthesis of 4-thiazolines 219 was carried out by mixing equimolar amounts of -chloroacetoacetanilides 220 and thioureas 221 in ethanol giving moderate to good yields and in excellent purities (Scheme 87) .

Scheme 87

Thiazoles

4.06.9.4.2


2-Bromo-1-(4-nitrophenyl)ethanone oxime 222 was transformed into 3-hydroxy-4-(4-nitrophenyl)-2(3H)-thiazolethione 223 upon treatment with potassium ethyl xanthate and zinc chloride as shown in Scheme 88 .

Scheme 88

4.06.9.4.3

Synthesis from NCSC2 component

Dithiocarbamoyl derivatives of acetoacetic ester 224 cyclize on standing (and more rapidly upon heating) to give 4-methyl-3-methyl(aryl)-2-thioxy-l,3-thiazolinyl-5-carboxylates 225 in 79–90% yields (Scheme 89) .

Scheme 89

4-Arylthiazol-2(3H)-ones 226 have also been prepared by the treatment of the corresponding -thiocyanatoacetophenones 227 with glacial acetic acid and sulfuric acid and boiling for 10 min (Scheme 90) .

Scheme 90

4.06.9.5 Synthesis of Thiazolidines 4.06.9.5.1

Synthesis from SC2 þ NC components

Reaction of hydrazones 228 and thioglycolic acid 229 in the presence of zinc chloride in dry benzene or dioxane gave the thiazolidinone 230 as shown in Scheme 91 .

Scheme 91

691

692

Thiazoles

4.06.9.5.2

Synthesis from SC2N þ C components

Thiazolidines can be synthesized by the reaction of formaldehyde with an amino thiol. One such example is the reaction of amino thiols 231 with formaldehyde to form the 4-methoxyphenylthiazolidines 232 in moderate to good yields (Scheme 92) .

Scheme 92

4.06.9.5.3

Synthesis from CSC2N component

Thiazolidines 233 were formed in good yields (84–89%) by treating aziridines 234 with catalytic amounts of the Lewis acid TiCl4 in DCM as shown in Scheme 93 .

Scheme 93

4.06.9.6 Synthesis of Benzothiazoles 4.06.9.6.1

Jacobson synthesis

The Jacobson synthesis of benzothiazoles 235 involves oxidative cyclization of an arylthioamide 236 on an unsubstituted ortho-position, using potassium ferricyanide in a basic medium (Scheme 94) . This method has been applied to the synthesis of various benzothiazoles, including analogues of kuanoniamine A .

Scheme 94

Recently, the synthesis of 2-substituted benzothiazoles has been reported via an intramolecular cyclization of arylthioamides 237 by using hypervalent iodine reagents (typically Dess–Martin periodinane, DMP) in CH2Cl2 at ambient temperature. The reaction proceeds via a thiyl radical 238 in high yields (85–95%) to give benzothiazoles 239 and is also amenable to solid-phase synthesis (Scheme 95) .

Scheme 95

Thiazoles

It has been postulated that this radical cyclization and the Jacobson reaction mechanism mentioned above may be linked. Under the Jacobson conditions, the cyclization would appear to depend on the electron density of the aromatic ring, and on the stability of the ions 240a and 240b (Scheme 96). Where R or R1 are H or OMe the reaction proceeds via cation 240b with the replacement of the ortho-hydrogen, in good yields. Where R is more electron withdrawing, the reaction slows down (R ¼ H to Br to NO2, leads to 80%, 45% and 0% yields, respectively, after 24 h) indeed, and where R ¼ NO2 and R1 ¼ OMe the reaction gave only 24% yield after 7 days. Only small amounts of 240c or 240b are formed where the negative charge can be delocalized onto the R-groups, leading to predominance of 240a, which in turn means that greater electron density is required on the ring for cyclization to occur. Conversely, when R is electron-donating, replacement of the ortho hydrogen does not occur. The presence of electron-donating groups para to the thioamide stabilizes cation 240b, rendering it unreactive. The radical species 240c, an intermediate between 240 and 240b, may then be the reacting species and the ortho-OMe is substituted in low yield . Detailed studies of these mechanistic pathways are ongoing.

Scheme 96

4.06.9.6.2

Ring closure of o-aminothiophenols

Benzothiazoles are most commonly prepared by the ring closure of o-aminobenzothiazoles. This methodology has been well reviewed in both CHEC(1984) and CHEC-II(1996) . Typically an o-aminothiophenol is reacted with a suitable electrophile such as an aldehyde, a carboxylic acid, or an ester in a suitable solvent at reflux to provide the desired benzothiazole. Acid chlorides have also been used. The use of esters usually requires harsh conditions, but when the ester is bound to a solid support 241, it has been found that the addition of o-aminothiophenol in the presence of AlMe3 or Et2AlCl as Lewis acid produces the benzothiazole 242 in what has become known as a ‘smart cleavage reaction’ (Scheme 97) . The solid-phase combinatorial synthesis of benzothiazoles 244 from 243 has been used in the investigation of topoisomerase II inhibitiors (Scheme 98) .

693

694

Thiazoles

Scheme 97

Scheme 98

4.06.9.6.3

Other methods

The combinatorial synthesis of 2-arylbenzothiazoles 245 has been explored using a traceless amine linker (Scheme 99) . The advantage of this approach over other reported solid-phase and traceless linker approaches is that the products are cleavable without the need for oxidants other than the presence of air and under neutral conditions. Benzothiazoles 245 were synthesized on solid support, attached via 4-alkoxyaniline linker 246. Group X on formylbenzoic acids 247 was either H, OMe, or Br. The nucleophile used was either n-C4H9OH, n-C9H19SH, or (Me2CHCH2)2NH. The yields are shown in Table 7.

Scheme 99

Thiazoles

Table 7 Yields (%) for solid-phase synthesis of benzothiazoles 245 on solid support R

X ¼ –H

X ¼ –OMe

X ¼ –Br

n-C4H9O– n-C9H19S– (Me2CHCH2)2N–

87 88 47

72 70 33

70 60 31

A novel synthesis of benzothiazoles was reported starting from readily available bis-2-azidophenyl disulfide 248 (Scheme 100). Treatment of 248 with either a disubstituted ketimine and AgNO3 in methanol to give the disubstituted imine 249 (R 6¼ H), or ammonia gas and methanol followed by treatment with an aldehyde in the same pot to give the monosubstituted imine 249 (R ¼ H), was followed by Staudinger reaction with trimethyl phosphine in toluene to give trimethyl phosphazines 250. Subsequent treatment of 250 with various disubstituted ketenes gave the corresponding 2-substituted benzothiazoles 251 in moderate to good yields .

Scheme 100

4.06.9.7 Synthesis of Fused Systems Thiazole esters 252a–c were prepared by Hantzsch condensation with a thioamide in good yield except in the case of 252c, bearing a methyl ester (Scheme 101) .

Scheme 101

695

696

Thiazoles

Iodine and thiourea can be used to form an aminothiazole fused to a cyclopentane ring . In this way, 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamine hydroiodide 253 was prepared by treatment of ketone 254 with iodine and thiourea in either DMF or ethanol with heating (Scheme 102) .

Scheme 102

4.06.10 Ring Syntheses by Transformation of Another Ring 4.06.10.1 Synthesis from Fully Conjugated Rings Thiazoles can be synthesized by a rearrangement of oxazoles, isoxazoles, and isothiazoles; these transformations have been covered in CHEC-II(1996) .

4.06.10.2 Synthesis from Di- and Tetrahydro Derivatives As discussed in Section 4.06.6.2.2, thiazoles can be formed by the aromatization of di- and tetrahydro derivatives.

4.06.10.3 By Ring Contraction of Other Heterocycles 5-Hydroxy-2-imino-6-phenyl[1,3,4]thiadiazinane-5-carboxylic acid methyl ester 255 underwent ring contraction in the presence of NaHCO3, acetic anhydride, or acetone, giving the 2-hydrazino-, the 2-(N9-acetylhydrazino)-, and the 2-(N9-isopropylidinehydrazino)-5-phenylthiazole-4-carboxylic acid methyl esters 256, 257, and 258, respectively (Scheme 103) .

Scheme 103

Thiazoles

4.06.11 Synthesis of Particular Classes of Compounds and Comparison of the Various Routes Available 4.06.11.1 Biosynthesis of Thiazole-Containing Natural Products The thiazole ring is synthesized biochemically by enzymatic post-translational modifications of cysteine-containing peptides. Heterocyclization between cysteine side-chains and neighboring carbonyl groups produces dihydroheteroaromatic thiazolines as initial products followed by a two-electron redox reaction yielding either thiazole or thiazolidine rings (Scheme 104). All three oxidation states are seen in natural products.

Scheme 104

Microcin B17 is a 43-amino-acid, glycine-rich, very poorly soluble peptide that contains four Tzl and four Ozl rings within its backbone, arguably the best characterized of the microcins, and can in many ways be considered the prototype for the group . It was isolated from strains of E. coli and its structure has been determined both chemically and by high-resolution NMR using 15N,13C-isotope-labeled peptides . The structure has subsequently been confirmed by total chemical synthesis of the active molecule . Moreover, Mccb17 shares similarity with a number of well-characterized antitumor agents, such as bleomycin, that also contain such Ozl/Tzl and related heterocyclic structures . With respect to its mode of action, Mccb17 is known to inhibit DNA gyrase, a topoisomerase involved in DNA replication . During the biosynthesis of microcin B17, four cysteine and four serine residues are converted into four thiazoles by the three-subunit microcin 17 synthetase by posttranslational modifications. The thiazole ring is synthesized by cyclization, dehydration, and dehydrogenation in similar fashion. A number of enzymes and proteins have been identified and characterized for the biosynthesis of microcin B17 backbones and subsequent formation of thiazole and oxazole rings . Another example of the biosynthesis of a thiazole ring is in enzymatic biosynthesis of thiamin. Thiamin is a thiazole-containing vitamin whose supply in humans relies on diet. It acts as a coenzyme and plays an important role in carbohydrate and amino acid metabolism . Thiamin deficiency can be fatal. Twelve genes have been identified for the thiamine biosynthesis in prokaryotes such as E. coli, Salmonella typhimurium, and Bacillus subtilis. Of these, six are required for the thiazole biosynthesis which code for key enzymes such as DXP synthase, ThiS, ThiF, ThiI, ThiH/O, ThiG, and Nifs/IscS in these organisms for the assembly of deoxyD-xylulose 5-phosphate, glycine, and a sulfur from cysteine into the thiazole phosphate moiety, which is then coupled to the pyrimidine moiety to form thiamine pyrophosphate (Scheme 105) . Biosynthesis of patellamides A and C was reported to proceed via a microcin-like pathway in Prochloron didemni, the cyanobacterial symbiant of L. patella. Genes responsible for the biosynthesis were identified and their function was validated by heterologous expression of the whole pathway in E. coli .

697

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Thiazoles

Scheme 105

The biosynthetic pathway to cystothiazole A has been investigated by feeding the producing organism, Cystobacter fuscus, with stable-isotope-labeled compounds including [2-13C]acetate, [1,2-13C]acetate, [1-13C]propionate, 13 13 L-[1- C]serine, L-[methyl- C]methionine, and DL-valine-d8 . The polyketide moiety of cystothiazole A was shown to be derived from acetate and propionate, the bisthiazole moiety from L-serine, the O-methyl groups from the S-methyl group of L-methionine, and the isopropyl moiety from L-valine, which should be the metabolic precursor of isobutyryl CoA.

4.06.11.2 Synthesis of Thiazole Peptides Thiazole-containing peptides can be synthesized from dipeptides composed of threonine and cysteine by different cyclodehydration procedures. The methods are compatible with 9-fluorenylmethyloxycarbonyl (Fmoc) peptide synthesis conditions with a range of protecting groups such as N-Fmoc, N-BOC, N-Cbz, and N-allyloxycarbonyl (N-Alloc) . N-Protected dipeptide composed of phenylalanine and O-tritylthreonine was synthesized on Wang resin using standard Fmoc chemistry . After removing the trityl group, the resin-bound dipeptides were subjected to oxidation using the DMP to form -ketoamide derivatives , which were converted into thiazole peptides in situ using Lawesson’s reagent . Alternatively, thiazole peptides can also be synthesized from cysteine-containing dipeptides on Wang resin via thiazoline intermediates prepared by a cyclodehydration–deprotection reaction using bis(triphenyl) oxodiphosphonium trifluoromethanesulfonate (generated from triphenylphosphine oxide (Ph3PO) and triflic anhydride (Tf)2O). Conversions of thiazolines to thiazoles can be achieved by oxidation with BrCCl3 and DBU . Cleavage from the resin with TFA afforded protected thiazole-based dipeptides in good crude purity and moderate yields (Scheme 106). Titanium(IV)-mediated tandem deprotection–cyclodehydration of a protected cysteine N-amide was used in the synthesis of thiazolone- and thiazole-containing heterocycles as building blocks for macrocycle synthesis . Similarly, the directly connected thiazole–oxazole ring system present in microcin B17 was synthesized from aminoacetonitrile hydrochloride . Thiazole units in the thiazole-based cyclic peptides, bistratamides E and J and dendroamide A , were synthesised from dipetides composed of valine and cysteine in a similar manner using activated MnO2 as an oxidizing agent. Bistratamides F–I were synthesized in a similar fashion .

Thiazoles

Scheme 106

4.06.11.3 Synthesis of Thiazole-Containing Natural Products 4.06.11.3.1

Synthesis of linear peptides

Synthesis of barbamide 267 was carried out by a convergent approach . First, treatment of commercially available N-Cbz-L-phenylalanine 259 with an excess of sodium hydride and methyl iodide gave the N-methyl methyl ester which was hydrolyzed to the corresponding acid 260 in 80% yield over the two steps. A modified Hantzsch method was used to form the thiazole ring in which the acid 260 was first converted into an amide via a mixed anhydride . Treatment of the amide with Lawesson’s reagent at room temperature in DCM gave thioamide 261 in 71% yield over the two steps from the acid 260. Reaction of 261 with -chloroacetaldehyde (prepared from the corresponding dimethyl acetal in 1,2-dimethoxyethane (DME) in the presence of potassium hydrogen carbonate) followed by dehydration using TFAA gave (S)-N-Cbz-N-methyldolaphenine 262. Finally, removal of the Cbz protecting group with hydrobromic acid in acetic acid gave an analytically pure sample of the novel secondary amine 263. In parallel, the conversion of (S)-3-(trichloromethyl)butanoic acid 264 to the corresponding acid chloride with thionyl chloride followed by coupling with Meldrum’s acid gave the intermediate 265 (Scheme 107) . Treatment of 263 with 265 gave 266 with the framework of barbamide in 51% yield. Finally, the (E)-enol ether was formed by reaction of -keto amide 266 with sodium hydride and dimethyl sulfate in the presence of hexamethyl phosphoramide (HMPA). A mixture of two products (1:1) was formed in this final stage of the synthesis due to epimerization at C-7 under the basic reaction conditions. These compounds were readily separated by HPLC giving the less polar product barbamide 267. The synthesis of (þ)-curacin A 271 was accomplished by a selective and facile thioacylation of amino alcohol 268 with the benzotriazole thioamide 269 followed by cyclization of 270 using Burgess reagent (Scheme 108) .

699

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Thiazoles

Scheme 107

Scheme 108

Thiazoles

4.06.11.3.2

Cyclic peptides

Thiazole-based cyclic peptides can be efficiently synthesized by a macrolactamization procedure, where peptide chains are assembled prior to the ring formation, or cyclooligomerization reactions of amino-acid-substituted thiazole monomers . In both cases, pentafluorophenyl diphenylphosphinate (FDPP) effects smooth coupling and good overall yields . Cylindrical and conical macrocyclic peptides were obtained by cyclooligomerization of macrocyclic peptides derived from functionalized thiazole amino acids . Similarly, tubular and cage structures were reported to be synthesized from thiazole-containing macrolactams . The total synthesis of raocyclamide A 276 was achieved through cyclization of raocyclamide B 275 with the Burgess reagent (Scheme 109) . The disubstituted thiazole 272 was synthesized from BOCprotected L-isoleucine and L-serine methyl ester by standard peptide coupling to give a dipeptide, which was converted into thiopeptide by Lawesson’s reagent. Subsequent cyclization using Burgess reagent followed by aromatization using BrCCl3 and DBU yielded thiazole 272 . Raocyclamide B 275 was synthesized through the successive condensation of thiazole 272 and with D-Phe-D-Ser-methyl ester to give peptide 273 followed

Scheme 109

701

702

Thiazoles

by reaction with oxazole-amine to give tripeptide 274. Deprotection followed by treatment of the amino acid with Hu¨nig’s base under high-dilution conditions gave raocyclamide B 275, which then produced raocyclamide A 276. This synthesis allowed revision of the previous structure for these natural products whereby L-isoleucine was the stereoisomer involved and not D-isoleucine as previously thought. Full details of the total synthesis of ()-pateamine A 282 and related compounds have been reported (Scheme 110) . The procedure involved the synthesis of the thiazole -lactam synthon 277. After the addition of the enyne side-chain 278, the intermediate 279 was cyclized to 280 followed by reduction to the Z-ene 281. Addition of the side-chain by Stille coupling gave ()-BOC-pateamine A, which was then deprotected to give ()-pateamine A 282.

Scheme 110

Amythiamicin D was the first in the family to be synthesized. The 2,3,6-trisubstituted pyridine core was synthesized from serine-derived 1-alkoxy-2-azadienes and thiazoyl enamide dienophiles ultilizing a biosynthesisinspired hetero-Diels–Alder route under MW irradiation. After successive incorporation of glycine and bis-thiazole fragments, amythismicin D was obtained by macrocyclization . Promothiocin A was initially synthesised by a three-component coupling approach . A Bohlmann– Rahtz pyridine synthesis established the oxazoyl–thiazole–pyridine heterocyclic centerpiece. The thiazole building blocks were obtained by the Hantzsch reaction. Two different strategies for macrocylization were successfully employed, with the dedroalanine side-chain being introduced in the last steps of the synthesis .

Thiazoles

The structure of cyclodidemnamide was rectified by total synthesis using D-valine instead of its L-isomer . The first total synthesis of lyngbyabellin A 293 involved the convergent assembly of four separate fragments: two thiazole fragments 285 and 291, BOC-glycine, and the dichloro -hydroxy acid 286, followed by macrolactamization . The two thiazole fragments were synthesized by entirely different routes. Fragment 285 was prepared from (S)-BOC-isoleucine which with N,O-dimethylhydroxylamine using diethyl phosphorocyanidate (DEPC, (EtO)2P(O)CN) afforded the amide 283. Reduction with lithium aluminium hydride followed by condensation of the resulting aldehyde with cysteine methyl ester and subsequent CMD (chemical manganese) oxidation provided the thiazole fragment 284 in 58% yield without epimerization at the -chiral center of the thiazole ring. After deprotection, 284 was coupled with BOC-glycine to give the fragment 285. The stereoselective synthesis of the dichlorinated -hydroxy acid fragment 287 was achieved from 5,5-dichlorohexanal 286 by the enantioselective aldol reaction developed by Kiyooka et al. . Condensation of 287 with the thiazole fragment 285 gave fragment 288. When the same route, that was used to synthesise fragment 285, was applied to synthesize thiazole 291 from 3,3dimethylacrolein, the reaction yield was very low (17%). So, the thiazole fragment 291 was synthesized from (R)-Fmoc-S-trityl cysteine instead. Methyl esterification followed by deprotection of Fmoc and coupling with 3-methylcrotonic acid yielded compound 289. The titanium(IV)-mediated tandem deprotection–dehydrocyclization of 289 produced the thiazoline which was dehydrogenated with (DBU)/BrCCl3 to give the thiazole 290. Replacement of the methyl ester function with the trimethylsilylethyl (TMSE) group followed by asymmetric dihydroxylation of the thiazole with Sharpless AD-mix- in the presence of methanesulfonamide gave the required ,-dihydroxy thiazole fragment 291 with high enantiomeric excess and yield. The condensation of the two thiazole-containing segments, 288 and 291, was initiated by the removal of the BOC group in the functionalized thiazole 288 followed by coupling with BOC-glycine to produce a depsipeptide intermediate. After cleavage of the allyl ester with Pd(Ph3P)4 in the presence of morpholine, coupling of the resulting carboxylic acid with the ,-dihydroxy thiazole 291 produced the linear precursor 292. Finally, after removal of the TMSE group at the C-terminus by TBAF and then deprotection of the BOC group at the N-terminus with TsOH, the macrolactamization was efficiently achieved using diphenyl phosphorazidate (DPPA, (PhO)2P(O)N3) to provide lyngbyabellin A 293 (Scheme 111). Lyngbyabellin B 302 contains a thiazoline ring which is sensitive under acidic conditions and readily epimerized at -centers attached to the heterocycles under both acidic and basic conditions. Therefore the final formation of the thiazoline ring by Wipf ’s oxazoline and thiazoline interconversion method was employed (Scheme 112) . The linear peptide 298 was synthesized from four key fragments 294–297, each of which was prepared individually prior to the assembly into 298. Macrolactamization yielded the cyclic peptide 299, deprotection with TBAF affording compound 300. This avoided epimerization at the C-terminus. Cyclodehydration of 300 with diethylaminosulfur trifluoride (DAST) yielded the oxazoline 301, which was then treated with H2S followed by cyclodehydration again using DAST to give the corresponding thiazoline product, lyngbyabellin B 302. The first phase of the total synthesis of thiostrepton 303, a highly complex thiopeptide antibiotic, has been described. Retrosynthetic analysis of thiostrepton revealed units 304–308 as potential key building blocks. Concise and stereoselective constructions of all these intermediates have been achieved. The synthesis of the dehydropiperidine core 308 was based on a biosynthetically inspired aza-Diels–Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 305 and the thiazoline–thiazole segment 306 were synthesized by a series of reactions that included asymmetric and other stereoselective processes (Scheme 113) .

4.06.11.3.3

Macrocyclides

The unique structure of epothilones, as well as their potent antitumor activities closely related to that of paclitaxel (Taxol), have evoked a great deal of interest from chemists and biologists (see Section 4.06.12.1.3). A convergent total synthesis of epothilone A has been completed involving diastereoselective aldol condensation to form the C(6)–C(7) bond, macrolactonization and Wadsworth–Emmons reaction of methyl ketone with a phosphonate reagent being key steps . Total synthesis of epothilone A has also been accomplished through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C . In addition, the asymmetric synthesis of two important synthetic precursors of epothilone A, the C(1)–C(6) and C(7)–C(15) fragments, has

703

704

Thiazoles

Scheme 111

Thiazoles

Scheme 112

been achieved from commercially available starting materials . Stereoselective routes to epothilones A and B based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition have been described . These synthetic efforts have led to the development of new reaction methodologies for asymmetric carbon–carbon bond formation. A ring-closing alkyne metathesis (RCM) reaction catalyzed by a molybdenum complex, followed by a Lindlar reduction of the resulting cycloalkyne product, opened an efficient and stereoselective entry into epothilones A and C . A highly diastereoselective addition reaction of a titanium enolate offered an efficient entry to the total synthesis of the epothilone family such as epothilone B . Based on the subsequent Normant reaction, Wadsworth–Emmons reaction, diastereoselective aldol condensation, and macrolactonization, a convergent and stereoselective total synthesis of epothilone B has been achieved . The selective terminal epoxidation of 12,13-desoxyepothilone B (epothilone D 249) to epothilone B, using 2,2-dimethyldioxirane (DMDO), has been investigated . The diastereoselectivity of the epoxidation was highly temperature dependent and the diastereoselectivity increased to >20:1 when the reaction was performed at 78 C.

705

706

Thiazoles

Scheme 113

Thiazoles

A total synthesis of epothilones B and D has been reported in which the trisubstituted 12,13-double bond was introduced stereoselectively using the tin(IV) bromide-promoted reaction between an allylstannane and an aldehyde . A Barton deoxygenation reaction and an aldol condensation were also applied to reach the target epothilones. The epothilones B and D have also been enantiospecifically synthesized from D-glucose . Total synthesis of epothilone, which is 10,11-didehydroepothilone D, has been accomplished by two routes, one utilizing a vinyl boronate cross metathesis followed by a Suzuki macrocyclization and the other using ring-closing metathesis . With the hope of establishing a thorough understanding of epothilone structure–activity relationships (SARs), numerous epothilone analogues, including C-26-(1,3-dioxolanyl)-12,13-desoxyepothilone B , trans-12,13-cyclopropyl epothilone B analogues , [17]- and [18]dehydrodesoxyepothilones B , 9,10-didehydroepothilone D isomers, and 12,13aziridinyl epothilone derivatives have been prepared by total synthesis .

4.06.11.3.4

Other syntheses

One-pot cyclooligomerization of the tetrapeptide derivative H-Ile-Ser-D-Val(Thz)-OH produces a novel series of constrained symmetrical macrocycles cyclo-[-Ile-Ser-D-Val(Thz)-]n, where n ¼ 2–19, containing up to 19 thiazoles in the macrocycle .

4.06.12 Important Compounds and Synthetic Applications 4.06.12.1 Naturally Occurrence and Their Biological Applications 4.06.12.1.1

Linear peptides

Cyanobacteria produce numerous and structurally diverse secondary metabolites having antitumor, antifungal, enzyme-inhibiting activities . 13-Demethylisodysidenin 309 is the main compound isolated from Oscillatoria spongeliae . Lyngbya majuscula is a source of many thiazole peptides: pseudodysidenin 310, nordysidenin 311, and barbamide 267 for example. Pseudodysidenin 310 and nordysidenin 311 have an uncommon trichloromethyl functionality, which was also found in barbamide, 267, which is a mixed polypeptide–polyketide natural product and has molluscicidal activity. It was isolated from a Curacuäo collection of L. majuscula . It is the first marine natural product whose biosynthetic gene cluster was fully sequenced .

Apramides A–G 312–318, are all linear peptides. Apramides A–F 312–317 were obtained from L. majuscula collected at Apra Harbor, Guam, while apramide G 318 was obtained from the same strain, but collected at a different time .

707

708

Thiazoles

A marine sponge Dysidea sp., collected at Bararin Island, Philippines, produced a further eight polychlorinated secondary metabolites, termed dysideaprolines A–F 319–324 and barbaleucamides A 325 and B 326 . Another two polychlorinated metabolites 327 and 328 have been isolated from the sponge Dysidea herbacea sp. 1524 collected from Lizard Island . It is most probable that these compounds are actually derived from a symbiotic cyanobacterium found in close association with the Dysidea sp.

Thiazoles

Dolastin 10 329 and 18 330, originally isolated from the Indian Ocean sea hare Dolabella auricularia, inhibit microtubule assembly and possess potent antineoplastic activity against advanced solid tumors . Symplostatin 1, 331, an analogue of dolastatin 10, was isolated from cyanobacterium Symploca hydnonides and is also solid tumor selective . Its isolation from a bacterium suggests that dolastatintype metabolites from sea hare Dolabella may be of dietary origin.

Lyngbyapeptin A, 332, isolated from cyanobacterium Lyngbaya bouillionii contains a 3-methoxybut-2-enoyl moiety which is rare in natural products . Lyngbyapeptins B 333 and C 334 were isolated from a Palauan collection of apratoxin-producing marine Cyanobacterium lyngbya sp. .

709

710

Thiazoles

Kalkitoxin 335, a novel neurotoxic lipopeptide, was isolated from various Caribbean collections of cyanobacterium L. majuscula and its absolute configuration (3R,7R,8S,10S, 29R) was confirmed by chemical synthesis of kalkitoxin having all possible configurations . Mycothiazole 336 is a polyketide thiazole isolated from the marine sponge Spongia mycofijiensis . Four cytostatic compounds, tubulysins A 337, B 338, D 339, and E 340, have been isolated from the culture broth of strains of myxobacteria Archangium gephyra and Angiococus disciformis . These tubulysins were not active against bacteria and slightly active against fungi, but showing high cytostatic activity against mammalian cell lines with EC50 in the picomolar range. Micromide 341 has been isolated along with apramides from cyanobacterium Symploca sp. collected in Guam.

Thiazoles

Microcyclamide 342, isolated from the cultured cyanobacterium Microcystis aeruginosa, is a cytotoxic cyclic hexapeptide alkaloid containing an imidazole ring system . It showed moderate cytotoxicity against P388 murine leukemia cells.

Lyngbyabellin B 302 (see Section 4.06.11.3.2) is an analogue of the potent microfilament-disrupter lyngbyabellin A 293 (see Section 4.06.11.3.2), isolated as a minor metabolite from the marine cyanobacterium L. majuscula collected at Apra Harbor, Guam . Lyngbyabellin B 302 possesses slightly weaker cytotoxicity than lyngbyabellin A 293. Lyngbyabellin B has also been isolated from cyanobacterium L. majuscula collected near Guam and the Dry Tortugas National Park, Florida . These two lipopeptides are structurally related to dolabellin isolated from sea hare D. auricularia . Lyngbyabellin C 343 was isolated from apratoxinproducing cyanobacterium Lyngbya sp. collected from Palauan site .

Cystothiazoles A–F, 344–349, bisthiazole, and -methoxyacrylate structures are thiazole alkaloids isolated from myxobacterium Cystobacter fusus strain AJ-13278 . Further investigation of a large-scale culture of the strain resulted in the isolation of an additional cystothiazole analogue, cystothiazole G, 350. On the basis of total synthesis, its stereochemistry has now been characterized as 4R,5S,6(E) . By comparison of the spectral data with that of a synthetic sample, the stereochemistry of naturally occurring cystothiazole B 345 has also been identified to be 4R,5S,6(E). Three enantioselective total syntheses of (þ)-cystothiazole A 344 have been described . Bacillamide 351 produced by Bacillus sp. SY-1, a marine bacterium, was shown to be a potent algaecide against dinoflagellate, Cochlodinium polykrikoides, which is responsible for large-scale red tides and mass mortalities of cultured fish and bivalves .

711

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Thiazoles

4.06.12.1.2

Cyclic peptides

The nonribosomal cyclic peptide leucamide A, 352, was isolated from the marine sponge Leucetta microraphis from the Great Barrier Reef of Australia . It was isolated as the principal active component and found to inhibit the growth of three tumor cell lines (stomach carcinoma, liver carcinoma, liver carcinoma with mutated p53). The compound is composed of seven amino acids and amino-acid-derived residues: L-leucine, oxazole, L-alanine, methyloxazole, thiazole, L-valine, and L-proline.

Thiazoles

A characteristic and extremely rare feature of the structure of leucamide A 352 is a mixed 4,2-bis-heterocycle tandem pair formed by the direct connection between the methyloxazole and thiazole residues. Leucamide A 352 closely resembles structures such as tenuecyclamide A 353 and nostocyclamide 354 from Nostoc spp. and dendroamide A 355 from Stigonema dendroideum. The later showed an interesting multidrug-resistance reversing activity .

Nocathiacins I–IV, 356–359, are cyclic thiazolyl peptides with inhibitory activity against Gram-positive bacteria by binding to 23SrRNA of the 50S ribosomal subunit . Originally isolated from Nocardia sp. (ATCC202099) fermentation broth , they are distinguished from other thiazolyl cyclic peptides by an indole ring with an amino sugar attached to the scaffold. The two internal linkers create three additional chiral centers, 10 in all. Nocathiacin IV, 359, can be obtained both enzymatically and chemically from nocathiacin I, 356 . Modifications of nocathiacin IV, 359, by glycolaldehyde followed by tandem reductive amination afforded analogues with improved solubility . Nocathiacins exhibit potent in vitro inhibitory activity against a wide spectrum of Gram-positive bacteria, including multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Enterococcus faecium (MREF), and fully penicillin resistant Streptococcus pneumoniae (PRSP), and also demonstrate excellent in vivo efficacy in a systemic S. aureus infection of mice. A potent cytotoxin with a novel skeleton, apratoxin A, 360, has been obtained from the marine cyanobacterium L. majuscula Harvey ex Gomont from Finger’s Reef, Apra Harbor, Guam . This cyclodepsipeptide of mixed peptidepolyketide biogenesis bears a thiazoline ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. It is remarkably cytotoxic in vitro as well as in vivo; however, the lack of selectivity limits its potential as an antitumor agent. Apratoxin B 361 and C 362 were isolated from Lyngbya sp., originating from Guam and Palau, USA .

713

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Thiazoles

A potent specific telomerase inhibitor designated as telomestatin, 363, was isolated from Streptomyces anulatus 3533SV4 . Although telomerase consists of several components with DNA polymerase or reverse transcriptase activity in addition to its intrinsic telomerase component, telomestatin specifically inhibited telomerase without affecting DNA polymerase and human immunodeficiency virus-reverse transcriptase (HIV-RT).

Thiazoles

Investigations of the sponge Haliclona nigra from Papua New Guinea led to the isolation of two new cyclic hexapeptides, haligramides A 364 and B 365, in addition to the known peptide, waiakeamide 366 . The structures of peptides 364 and 365 were elucidated by extensive NMR analyses and by comparison of their spectral data with those of 366. The identity of 365 was confirmed by its oxidative conversion into 366.

Hectochlorin 367 was isolated from cyanobacterium L. majuscula collected at Hector Bay, Jamaica .

Halipeptins A 368, B 369, and C 370 belong to the depsipeptides family and were isolated from a marine sponge of the Haliclona genus .

715

716

Thiazoles

Obyanamide 371 is a cytotoxic cyclic depsipeptide and was obtained from a variety of marine cyanobacterium Lyngbya confervoides collected at Saipan, Commonwealth of the Northern Mariana Islands .

Six -amino-acid-containing cyclic depsipeptides ulongamides A–F, 372–377, were isolated from apratoxinproducing cyanobacterium Lyngbya sp. NIH 309 from Palau .

Scleritodermin A 378 was iolated from sponge Scleritoderma nodosum Thiele 1900 (Scleritodermidae) .

Thiazoles

Didmolamide A 379 and B 380 were isolated from the ascidian Didemnum molle collected from Madagascar .

Bistratamides C–J, 381–388, are a group of hexapeptides isolated from the ascidian Lissoclinum bistratum collected from Tablas Island in the Philippines .

717

718

Thiazoles

Study of the ascidian L. patella (order Enterogona, family Didemnidae) yielded two new closely related cyclic peptide alkaloids namely lissoclinamide 9 389 and lissoclinamide 10 390 . Their structures were determined by a combination of 2-D NMR, selective 1-D TOCSY, MS, and series-wound electrospray ionization (ESI)-MS (MSn) techniques, and the assignment of absolute stereochemistry was achieved by the hydrolysis of lissoclinamides followed by chiral thin layer chromatography. In the case of lissoclinamide 9, 389, NOE-restrained molecular dynamics studies were also performed confirming the proposed stereochemistry.

A prenylated cyclopeptide trunkamide A 391 produced by ascidians of the genus Lissoclinum, and also its C45 epimer, were isolated .

Gunieamides A 392 and B 393, thiazole-containing depsipeptides, were isolated from a Papua Guinea collection of the marine cyanobacterium L. majuscula .

Thiazoles

The thiostrepton family of peptide antibiotics was first isolated from the culture broth of Streptomyces azureus . Similarily, sulfomycin I was originally isolated from Streptomyces viridchromogenes MCRL-0368 . The bleomycins (BLMs), such as BLM A2, B2, and A5, are a family of antitumor glycopeptide-derived antibiotics isolated from Streptomyces verticillus . GE2270A 394 is an antibiotic produced by Planobispora rosea ATCC 537731. It inhibits Gram-positive bacteria and anaerobes by acting on the protein synthesis elongation factor (EF) . It contains proline, serine, glycine, two thiazolyl amino acids, and a heterocyclic centerpiece of a trisubstituted pyridine, all in a macrocyclic array.

Similar thiopeptides, called the amythiamicins 395–398, were isolated from a strain of Amycolatopsis sp. MI48142F4 . They were originally reported to inhibit the growth of Gram-positive bacteria including MRSA , and, more recently, in common with other thiopeptides, they have been shown to exhibit antimalarial activity against Plasmodium falciparum , the parasite that causes the majority of malarial infections in humans.

719

720

Thiazoles

Promothiocins A and B, 399 and 400, isolated from a Streptomyces sp. SF2741, are potent antibiotics which inhibit protein synthesis in bacteria .

Cyclodidemnamides 401 and 402, isolated from the sea squirt D. molle, having a rare substitution pattern of an alternating sequence of thiazole, oxazoline, thiazoline, and pyrrolidine rings, are weak inhibitors of human colon tumor cell growth .

Thiazoles

Raocyclamides A 276 and B 275 (Section 4.06.11.3.2) were isolated from cyanobacterium Oscillatoria raoi and exhibit moderate cytotoxic activity against sea urchin embryos .

Zelkovamycin, 403, is a new antibiotic isolated from the fermentation broth of Streptomyces sp. K96-0670 .

Further four new cyclic thiazole peptides, patellamide G (404, a novel immunosuppressant), ulithiacyclamides E 405, F 406 and G 407, were isolated from the ascidian L. patella .

721

722

Thiazoles

Micrococcin P1 408 is a structurally complex thiopeptide; its structure has been confirmed .

YM-216391, 409, a potent telomerase inhibitor, was isolated from Streptomyces nobilis . IB-01211, 410, a strong cytotoxic agent, was isolated from a marine organism similar to Thermoactinomyces genus . Both penta-azole containing cyclopeptides and telomestatin were synthesised by macrocyclization of flexible precursors . Another cyclic peptide which contains only two thiazole units called trichamide, 411, was isolated from cyanobacterium, Trichodesmium erythraeum .

Thiazoles

Leinamycin 412 is a unique natural antibiotic product isolated from Streptomyces sp. S-140, which targets DNA. The DNA damage is achieved by the attack of the thiol on the 1,2-dithiolan-3-one 1-oxide heterocycle of the molecule .

A group of cyclic peptide antibiotics named argyrins A–H 413–420, were isolated from myxobacteria Archangium gephyra . Among them, argyrin B is an immunosuppressive agent and a potent inhibitor of T-cell independent antibody formation in both murine and human B-cells.

723

724

Thiazoles

Tallysomycins A and B, first isolated from fermentation broths of Streptoalloteichus hindustanus, are glycopeptidederived antitumor antibiotics structurally related to the bleomycins .

4.06.12.1.3

Macrocyclides and lactones

The epothilones , a class of polyketide macrolides originally isolated from the soil bacterium Sorangium cellulosum, share a common mechanism of action with paclitaxel (Taxol) in promoting microtubule polymerization leading to programmed cell death (apoptosis) . They exert even higher potencies against paclitaxel-resistant human cancer cell lines and display an improved potency against multiple-drug-resistant (MDR) tumor cell lines. A fundamental study of the interactions between epothilones and the paclitaxel-binding site in microtubules has been conducted . Correlations between binding affinity and cytotoxicity were obtained . In addition, epothilones have much higher solubility in water and can be produced in multi-kilogram quantities which make them most promising as anticancer drugs . Epothilones A 421, B 422, E 423, and F 424 contain a C(12)–C(13) epoxide ring while C 425 and D 426 have a double bond instead of the epoxide in the same position.

Initial fermentation using S. cellulosum gave very low yield (20 mg l1), was time consuming (16 h doubling time), and provided a mixture of products. Epothilones A 421 and B 422 were produced in 2:1 ratio while high-therapeuticindex C and D (desepoxyepothilones), 425 and 426, only in trace amounts. This made the production using this organism economically impractical. Molnar et al. isolated four overlapping cosmid clones from a genomic library of an S. cellulosum strain SMP44 and identified the gene cluster coding a polyketide synthetase (PKS), including nonribosomal peptide synthetase (NRPS) module (signature sequences for recognizing cysteine and a cyclization domain) for the formation of thiazole ring from cysteine and a cytochrome P450 epoxidase (epoK) for the conversion of desoxyepothilones to epothilones. The other enzymes introduce structural variations into epothilones. Introduction of the gene cluster into a well-understood and characterized organism, Streptomyces coelicolor CH999, led to the efficient production (a 10-fold faster growth rate) of epothilones A 421 and B 422, which is sufficient for preclinical studies. It was confirmed in radiolabeling studies that epothilones are biologically synthesized from acetate and propionate units as sources of backbone carbons, one cysteine for the thiazole side-chain and a methyl group from methionine as one of the C-4 methyls . Epothilones C 425 and D 426 are the final products produced by the same PKS and they are oxidized by epoK to A and B. The replacement of C(11)–C(12) acyltransferase domain with methylmalonyl-CoA led to specific production of epothilone D 426. The introduction of this PKS into Myxococcus xanthus has resulted in a large-scale production of epothilone D 426 . Epothilones E 423, F 424, and many other natural analogues and fragments have been isolated in minute quantities from S. cellulosum 90/B2 and 90/D13 . Systematic SAR studies of hundreds of epothilones and analogues revealed that the configurations at C-6 and C-8 are vital for the biological activity due to their influences on the overall conformation of the macrocycle through steric and/or stereoelectronic effects ; the epoxide moiety is not essential and a substitution at C-12, particularly a methyl group, enhances the activity as long as the configuration at C-13 agrees with that of the native epothilones perhaps because of the flexibility of C(9)–C(11) trimethylene, allowing them to be accommodated within the binding site. Stereochemistry at C-15 is also very important for the biological activity as C-15 epimers are devoid of any biological activity ; side-chain thiazoles/pyridines with the correct nitrogen location are also important . Using molecular modeling, a common pharmacophore shared by epothilones and known antimitotic drugs, paclitaxel and sarcodictyin, have been identified and validated . Epothilone B 422 is now (2005) in Phase II clinical trials and a few of its analogues, viz. aza-epothilone B (BMS247550) and 12,13deoxyepothilone B, etc., have also entered clinical trials. It is hoped that potent anticancer drugs will emerge from these studies . A recent study on the early enzymes of the epothilone biosynthesis cluster has suggested that combinatorial biosynthesis may be a viable means for producing a variety of epothilone analogues that incorporate diversity into the heterocycle starter unit . Thirty-six natural epothilone variants and six epothilone fragments have been isolated from the culture broth of a 700 l fermentation of S. cellulosum, strains So. ce90/B2 and So. ce90/D13 . Epothilones were also obtained from genetically modified M. xanthus . ()-Pateamine A 282, a thiazole-containing 19-membered bislactone isolated from the marine sponge Mycale sp., is a potent immunosuppressive agent with IC50 of 0.33 nM using interleukin-2 receptor gene assay .

Cytotoxic macrolides, archazolid A 427 and B 428, were identified from the culture broth of both myxobacteria A. gephyra and Cystobacter sp. Archazolids consist of a macrocyclic lactone ring with a thiazole side-chain and are highly potent vacuolar-type ATPase (V-ATPase) inhibitors in vitro and in vivo . Their relative and absolute stereochemistries were determined on the basis of a combination of extensive high-field NMR studies, including J-based configuration analysis, molecular modeling, and chemical methods .

4.06.12.1.4

Alkaloids

Pyridoacridine alkaloids have been isolated from sponges: ascidians, anemones, and a prosobranch. Two thiazolecontaining compounds were obtained, namely kuanoniamine E, 429, and kuanoniamine F, 430 .

725

726

Thiazoles

4.06.12.2 Synthetic Thiazole Derivatives and Their Biological Applications Some 2-[(benzazol-2-yl)thioacetylamino]thiazole derivatives 431 showed antimicrobial activities against E. coli and the fungus Candida albicans . Derivatives of 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]-thio-4H-1,2,4-triazole 432 showed potent antifungal activities against the clinical isolate of C. albicans . Synthesis and biological activities of Schiff bases of thiazole, benzothiazole, and benzo[d]isothiazole were investigated. Two Schiff base compounds containing 2,4-disubstituted thiazoles and cyclobutane rings 433 4-(1-methyl-1-phenylcyclobutan-3-yl)-2-(2-hydroxy-3-methoxybenzylidenehydrazino)thiazole (L1H), 4-(1-methyl-1p-xylylcyclobutan-3-yl)-2-(2-hydroxy-3-methoxybenzylidenehydrazino)thiazole (L2H) and their mononuclear complexes with a 1:2 metal–ligand ratio from acetate salts of Co(II), Cu(II), Ni(II), and Zn(II) in EtOH were synthesized and tested against three yeasts and three bacteria. L2H were active against all microorganisms, while most of its complexes were only active against bacteria, but not fungi. (L2)2Zn exhibited no activity against both bacteria and fungi. L2H and (L1)2Cu were found to be most active against Klebsiella pneumoniae FMC5 .

Thiazole cephalosporin LB 11058, 434, demonstrated a broad antibacterial spectrum and was highly active against Gram-positive bacteria, particularly against multidrug-resistant staphylococci and streptococci .

Thiazoles

Modification of the side-chain thiazole ring of the macrocyclic peptide antibiotics, GE2270, retained the activity while significantly enhancing the aqueous solubility of the parent compound .

4.06.12.3 Synthetic Applications 4.06.12.3.1

Synthetic equivalence to the formyl group

The use of thiazole as a latent formyl group in the assembly of a great variety of densely functionalized and chiral molecular systems has been thoroughly reviewed . The high and varied reactivity of the formyl group has been widely exploited in synthetic endeavors toward complex molecular systems; a drawback of this functionality stems from its incompatibility with various reaction conditions. Consequently, it is convenient, if not necessary, to introduce the formyl group into a substrate in a stable masked form from which it can be liberated at late stage of the synthesis. The thiazolyl-to-formyl equivalence is therefore central to the chemistry involved in synthetic schemes of some complexity. The wide scope of this synthetic strategy relies on two main properties of the thiazole ring: first, its tolerance to a broad range of reaction conditions, thus allowing for the elaboration of the substrate in which it has been introduced, and, second, the easy transformation into a formyl group under almost neutral conditions, thus leaving unaltered stereocenters and acid- and base-sensitive functional groups which may be present in the molecule. An aldehyde can be obtained from a given substrate by three sequential operations: A, introduction of the thiazole ring into a substrate by reaction of a C-2-functionalized thiazole (FGTh) with a suitable functionality of the substrate (coupling); B, transformation of the resulting C-2-substituted thiazole RTh into R1Th by elaboration of the group R (elaboration); C, releasing of the target aldehyde R1CHO from R1Th by cleavage of the thiazole ring (unmasking) (Scheme 114).

Scheme 114

The synthesis of -and -linked thiazolyl C-glycosides began from known L-fuconolactone 436 (Scheme 115), which in turn was prepared by oxidation of 2,3,4-tri-O-benzyl-L-fucose 435. Treatment of 435 in Et2O at 78 C with a solution of 2-lithiothiazole (2-LTT), generated in situ from 2-bromothiazole and n-BuLi, afforded the

Scheme 115

727

728

Thiazoles

thiazolylketose 436 as a single anomer (93%). This compound was acetylated to give the O-acetate 437. The thiazolylketose acetate 438 was treated with two different deoxygenative systems, the trimethylsilyl triflate–triethylsilane mixture (TMSOTf–Et3SiH) or the samarium iodide–ethylene glycol mixture (SmI2–(CH2OH)2). The use of TMSOTf–Et3SiH afforded exclusively the b-L-linked thiazolyl C-fucoside 439 (95%), whereas SmI2–(CH2OH)2 furnished as main product the -linked isomer 440 (93%) . When in other cases the dehydroxylation of the thiazoleketose acetate was unselective resulting in - and -linked thiazolyl C-glycosides 441 and 442 in equal amounts, the replacement of thiazole with benzothiazole as the masked formyl group usually provided very good yield and selectivity. Although Et3SiH–TMSOTf was not as selective as shown in Scheme 115, the -linked benzazolylketose formed can be easily converted to the -isomer to increase the yield of the -isomer. The same isomerization did not occur when thiazole was used . A thiazole-based synthetic methodology for homologating aldehydes and at the same time introducing an -amino group (aminohomologation) was developed . This methodology entailed the coupling of aldonitrones with a 2-metallated thiazole followed by elaboration of the nitrogen-containing functionality of the adducts. When the initial aldehyde was an aldehydo sugar or a protected dialdose, a new entry to amino sugars resulted. The (Z)-N-benzyl nitrone 444 derived from D-glyceraldehyde acetonide 443 was treated with 2-lithiothiazole (2-LTT) generated in situ at low temperature affording the 2-thiazolyl N-benzyl hydroxylamines 445 (syn-adduct) and 446 (anti-adduct) in good overall yield . On the other hand, the addition of diethylaluminium chloride (or titanium tetrachloride) to the nitrone 444 before treatment with 2-LTT gives the same syn- and anti-adducts 445 and 446 (84% overall yield) but in an opposite ratio (3:97). Each individual N-benzyl hydroxylamine 445 and 446 obtained as major product under the above conditions was transformed into the corresponding amine 447 and 449, respectively, by a reductive dehydroxylation reaction using aqueous TiCl3 at room temperature . These reaction conditions were well tolerated both by the thiazole ring and the acid-sensitive acetonide protecting group, whereas the benzyl protected amine was removed. Therefore, the resulting primary amine was protected again as its N-Cbz derivative. Finally, the unmasking of the formyl group by the CuCl2-based method supplied the -amino aldehyde 448 (2-amino-2-deoxy-Dthreose) and the epimer 450 (2-amino-2-deoxy-D-erythrose). The influence of Lewis acids is profound in some cases such as N-benzyl nitrone in the synthesis of destomic acid and lincosamine, but not so profound in other cases such as aldehydo-D-arabinose diacetate (Scheme 116) . 2-LTT was also used to synthesize homoazasugars: 2,5-dideoxy-2,5-imino-D-glucitol, 2,5-dideoxymethyl-3,4-dihydroxypyrrolidine and 2,5-dideoxy-3,4-imino-D-mannitol , -alkoxy -lactam acetaldehyde . Solid-phase thiazole-based homologation using LTT was employed to prepare two different classes of isosteric dipeptides: 2-hydroxy-1,3-propyldiamines 455 and -amino--hydroxy-vinyl sulfones 456 (Scheme 117) . The selected -amino acid, for example, phenylalanine, was anchored by its amine function to a carbamate resin, then transformed into the Weinreb amide 451. This resin-bound substrate upon treatment with a THF solution of 2-LTT afforded the thiazolyl ketone 452. Reduction of this ketone to alcohol and protection by silylation furnished racemic O-silyl ether 453. Finally, application of the mercury-based thiazole-toformyl unmasking protocol to 453 gave the N-terminal BOC-resin-bound O-tert-butyldimethylsilyl-protected -amino--hydroxy aldehyde 454. The transformation of the resin-anchored aldehyde 454 into the hydroxyethylene peptide isosteres 455 (89% purity) and 456 was carried out via Horner–Emmons coupling with a phenylsulfonyl phosphonate and via reductive amination with tryptamine, respectively, followed by the cleavage of the products from the solid support using TFA. The generality of this solid-phase thiazole-based synthesis of functionalized aldehydes was demonstrated using other -amino acids (Val, Lys(Z), Leu, Ile) as starting materials. The use of 2-(trimethylsilyl)thiazole (2-TST) as a reagent in step A (coupling) of the thiazole-aldehyde synthesis allows for the transformation of an aldehydo sugar into a one-carbon-higher homologue in good yield and stereoselectivity. This is equivalent to the addition of the formyl anion to the lower homologue and is reminiscent of the classic Kiliani–Fischer cyanohydrin synthesis. The chain elongation of the triose 458 was brought up to the thiazole nonose 460 via 459 through a series of lower homologues, all exhibiting the anti-configuration in the 1,2-polyol units (Scheme 118). The unmasking protocol C proved to be equally efficient with short and long polyhydroxylated systems . Extension of the scope of the methodology to a full stereocontrol in the addition sequence A in order to obtain either 1,2-anti- or 1,2-syn-diol units was hampered by the inherent anti-selectivity of the addition of 2-TST to ,dialkoxy aldehydes. Control of the selectivity by the use of Lewis acids acting as chelating agents was also foiled by substantial decomposition of 2-TST. This limitation was overcome by conversion of the anti-adduct into the synisomer via an oxidation–reduction sequence . The secondary (R)-alcohol 457 was oxidized to ketone 461 with potassium permanganate partly solubilized with TDA-1 (tris[2-(2-methoxyethoxy)ethyl]amine). It was proved that under these neutral nonaqueous oxidation conditions no appreciable racemization occurred via exchange

Thiazoles

Scheme 116

of the proton at the secondary carbon to the carbonyl. An alternative method of oxidation, which proved to be quite effective in scaled up reactions , was the Albright–Goldman oxidation using acetic anhydride/DMSO. The hydride reduction of the carbonyl of 461 with K-Selectride afforded the (S)-alcohol 462 in very high yield and stereoselectivity. Thus, the overall result of the oxidation–reduction sequence was the inversion of configuration of the -carbon to the thiazole ring. Having the syn-adduct 462 in hand, the synthesis of the protected aldehydo-Dthreose 463 was achieved through the usual steps B and C of the thiazole aldehyde synthesis, that is, elaboration of 462 by protection of the free hydroxyl group and formyl group unmasking. Hence, from the original triose D-glyceraldehyde two tetrose epimers, D-erythrose 459 and D-threose 463, were obtained. Each of them can be further transformed into corresponding nonoses. 2-TST was also employed to synthesize some rare sugar moieties such as fragment G (L-lyxpproanose) of everinomicin 13384-1, L-gulose, L-idose, and the diasaccharide subunit of bleomycin A2

729

730

Thiazoles

Scheme 117

and peptide isosteres . The N,N-diprotected phenylalaninal 465 (Scheme 119) was obtained from L-phenylalanine 464 in good yield. The reaction of 465 with 2-TST provided the expected anti-amino alcohol 466 as a major product. The oxidative removal of the p-methoxybenzyl group with cerium ammonium nitrate (CAN, (NH4)2Ce(NO3)6) and silylation furnished the compound 467, which was transformed into the aldehyde 468 in excellent yield. Other hydroxylated amino acids synthesized using 2-TST include 5-O-carbamoyl polyxamic acid and the natural pseudopeptide antimicrobial agent AI-77-B . The two-carbon chain elongation of aldehydes was performed by use of the thiazole-armed ylide 2-thiazoylmethylene triphenylphosphorane (2-TMP) as a reagent in step A of the thiazole-aldehyde synthesis (Scheme 120) . The coupling of the phosphorus ylide 470 (2-TMP) with the D-galacto-dialdopyranose 469 afforded the alkene 471 (E,Z mixture), which, when subjected to the formyl group unmasking protocol, furnished the two-carbon higher dideoxy homologue 472 in good yield. In a similar way, the coupling of 470 with the nine-carbon atom dialdose 473 obtained from 469 via the iterative one-carbon homologation using 2-TST gave the 2-alkenylthiazole 474, which was subsequently transformed into the dideoxy undecadialdose 475. Scheme 120 illustrates well the sequential use of two thiazole-based reagents (2-TST and 2-TMP) in a reaction sequence leading to a densely functionalized alkyl chain linked to C-5 of a pyranose ring. The three-carbon chain elongation of aldehydo sugars and dialdoses using suitable thiazole-based reagents was also examined. 2-Acetylthiazole (2-ATT) was initially employed in the transformation of aldehydo sugars into higher homologues containing syn- and anti-1,3-diol units . The aldol condensation of the lithium enolate of 2-ATT with 2,3-O-isopropylidene-D-glyceraldehyde 476 (Scheme 121) afforded the anti-adduct 477, a -hydroxy ketone . The elaboration of this product was carried out by reduction of the carbonyl with appropriate metal hydride reducing agents in order to form syn- and anti-1,3-diol systems . Treatment of 477 with tetramethylammonium triacetoxyborohydride (Me4NBH(OAc)3) and acetonization furnished the anti-1,3-dioxane derivative 481, whereas the use of diisobutylaluminium hydride (DIBAL-H) gave the syn-isomer 478, in both cases with excellent diastereoselectivity. Then the application of the thiazole-to-formyl unmasking protocol to 481 and 478 provided the epimeric tetraalkoxy hexanals (3-deoxyaldehydo-hexoses) 482 and 479 in good yield. The same thiazole-based scheme was followed for the three-carbon homologation of 4-O-benzyl-2,3-O-isopropylidene-L-threose (Mukaiyama aldehyde). The sequence was repeated with the aldehyde 479. Finally, the thiazole-to-formyl unmasking gave the polyalkoxy nonanal 480.

Thiazoles

Scheme 118

Scheme 119

731

732

Thiazoles

Scheme 120

Scheme 121

Thiazoles

The ease of oxidation of a formyl group to carboxyl allows exploitation of the thiazole-based methodology for the preparation of natural higher 3-deoxy-2-ulosonic acids and unnatural analogues . The protected aldehydo-D-mannose 481 was employed as starting compound to react with 2-TCMP 482 in order to obtain, via a Wittig–Michael route, the polyalkoxy ketone bearing a -alkoxy group 483 (Scheme 122). The addition of BnONa to the ,-enones 483 led to the diastereomeric ketones 484. The elaboration of 484 via 485 through the usual reaction sequence (hemiketalization, formyl group unmasking) afforded the aldosulose 486, which was then transformed into KDN 487 via oxidation and protecting group removal. The thiazolyl ,-enone was also used to synthesize 4-acetamide-3,4-dideoxy-D-glycero-D-galacto-2-nonulosonic acid 488, a positional isomer of N-acetylneuraminic acid.

Scheme 122

4.06.12.3.2

Chiral auxiliaries

Thiazolidinethiones constitute a class of versatile chiral auxiliaries for asymmetric synthesis. Their easy preparation from readily available -amino alcohols and the high levels of asymmetric induction they provide make them excellent chiral auxiliaries for the preparation of chiral intermediates in the synthesis of natural products. These chiral auxiliaries have been utilized in a wide variety of synthetic transformations such as asymmetric aldol-type acyloin condensation, stereoselective alkylation of different electrophiles (Stetter reaction), and stereoselective differentiation of enantiotopic groups in molecules bearing prochiral centers .

733

734

Thiazoles

Double diastereoselective acetate aldol reactions using the N-acetyl thiazolidinethione-based chiral auxiliaries 489 and 490 and chiral aldehydes were reported (Scheme 123) . Aldehydes in which the chirality is due to the presence of an alkyl group at the -carbon showed the greatest double diastereoselectivity and difference in selectivity of the matched and mismatched reaction pairs. When the chirality was due to - or -oxygenation, little double diastereoselection was observed. The stereoselectivity of the reaction was dictated by the reagent and not the substrate. Similarly, titanium- and (S)-4-isopropyl-N-propanoyl1,3-thiazolidine-2-thione 491-mediated aldol reactions were reported. The reaction of the chiral auxiliary and aldehydes such as (S)-3-benzyloxy-2-methyl-propanal followed by treatment of the resulting diastereomeric mixture with TBDMSOTf/lutidine provided an enantiomerically pure protected aldol 492 in 60% yield over two steps after a simple chromatographic purification (Scheme 124). Next, clean removal of the chiral auxiliary with DIBAL-H produced aldehyde 493 in a single step with excellent yield and stereoselectivity.

Scheme 123

Scheme 124

An optically active (3R,4R,5S)-isomer of eupomatilone-6 498 was prepared via an aldol reaction with thiazolidinethione as a chiral auxiliary as a key step. The titanium enolate of N-propionylthiazolidinethione 495 was reacted with the biarylaldehyde 494 to give 496, the free hydroxyl group of which was protected as a TBS-ether . The reductive removal of the thiazolidinethione auxiliary from 496 with NaBH4 in THF–EtOH gave 497, which subsequently gave (3R,4R,5S)-eupomatilone-6 498 as shown in Scheme 125 . (þ)-Isoretronecanol 503 has been prepared in four steps and 36% overall yield via the diastereoselective addition of the titanium(IV) enolate derived from N-4-chlorobutyryl-1,3-thiazolidine-2-thione 499 to N-BOC-2-methoxypyrrolidine 500, which afforded 2-substituted pyrrolidine 501 in 84% yield (diastereoisomeric ratio ¼ 8:1). This was followed by reductive recovery of the chiral auxiliary and cyclization via 502 (Scheme 126) .

Thiazoles

Scheme 125

Scheme 126

A convergent enantioselective route to brefeldin A (BFA) and 7-epi-BFA was developed. The key C-4/C-5 chiral centers were established by using a thiazolidinone chiral auxiliary-induced intermolecular asymmetric aldolization in the presence of TiCl4 and TMEDA . General enantioselective routes to ,-cis-disubstituted -lactones and ,-cis-disubstituted -lactones using (S)-phenylalanine- or (R)-phenylglycine-derived thiazolidinone as a chiral auxiliary was developed . Other uses include desoxyepothilone F and (þ)-kavain . Enantiomerically pure 1,3-thiazolidine-derived spiro -lactams 505 and 506 were stereoselectively synthesized by means of a Staudinger ketene–imine reaction in the presence of 2-chloro-1-methylpyridinium iodide (Mukaiyama’s reagent) starting from optically active N-BOC-1,3-thiazolidine-2-carboxylic acid derivatives 504 and imines (Scheme 127). The reactions were stereoselective and afforded spiro--lactams with a trans-configuration. The spiro--lactams 505 and 506 were transformed into enantiomerically pure chiral monocyclic -lactams 507 and 508

735

736

Thiazoles

by opening the thiazolidine ring and recovering the chiral auxiliary . A novel, stereoselective synthesis of ,-disubstituted -amino carbonyl compounds was reported via chiral auxiliary-mediated azetine formation .

Scheme 127

The diastereomerically pure thiazolium salt 509 which bears a 2-tert-butylphenyl substituent at the nitrogen atom was converted into a mixture of 510 and its atropisomer 5109 (dr ¼ 75:25) upon treatment with base (Scheme 128). The stereogenic center in the intermediate carbene favors one rotamer 510. Upon reaction with benzaldehyde, it accounts in a similar fashion for the formation of the major enol diastereoisomer 511 over 5119, which, in turn, leads to the major enantiomer 512 rather than 5129 observed in the benzoin condensation catalyzed by 509. The concept of axial chirality was proven to be viable for an efficient chirality transfer. Replacement of the isopropyl group at C-4 by the bulkier 2-phenyl-2-propyl substituent using 8-phenylmenthone is likely thought to increase the ee .

4.06.12.3.3

Thiazolium salts as catalysts

Thiazolium salts as catalysts have attracted considerable attention over the last decade. A strategy utilizing N-heterocyclic carbenes (NHCs) derived from thiazolium salts has been developed for the generation of carbonyl anions from acylsilanes. Synthetically useful 1,4-diketones and N-phosphinoyl--aminoketones have been prepared in good to excellent yields via NHC-catalyzed additions of acylsilanes to the corresponding ,unsaturated systems and N-phosphinoylimines. These organocatalytic reactions are air- and water-tolerant methods to execute robust carbonyl anion addition reactions. Polysubstituted aromatic furans and pyrroles have been efficiently synthesized in a one-pot process using this carbonyl anion methodology .

Thiazoles

Scheme 128

Catalytic multicomponent synthesis of highly substituted pyrroles has been described. A one-pot reaction uses DBU with the commercially available thiazolium salt 513 to produce the necessary nucleophilic zwitterionic catalyst in situ, which promotes a conjugate addition of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4dicarbonyl compounds in situ. Subsequent addition of various amines promotes a Paal–Knorr reaction, affording the desired polysubstituted pyrrole compounds in a one-pot process in moderate to high yields (Scheme 129) . Microwave heating dramatically reduced the reaction time (from 16 h to 30 min), but offered no improvement in yields.

Scheme 129

A proposed reaction mechanism is shown in Scheme 130. It involves the addition of a neutral carbene/zwitterionic species 514 (generated in situ from the exposure of thiazolium salt to DBU) to an acylsilane . This nucleophilic addition initiates a 1,2-silyl group migration (Brook rearrangement)

737

738

Thiazoles

and produces intermediate enol silane 515. The addition of alcohols to the reaction renders the process catalytic in thiazolium salt. The alcohol additive effectively desilylates, thereby generating the ‘Breslow intermediate’ 516 . Due to the attenuated reactivity of the acylsilane, nucleophile 516 undergoes preferential addition to the more-electrophilic ,-unsaturated ketone. The resulting intermediate 517 re-forms the acyl anion carbonyl, which liberates the heterocyclic catalyst and subsequently produces the 1,4-dicarbonyl compound 518. Once the starting ,-unsaturated ketone is consumed, the direct addition of a primary amine, acid, and dehydrating agent (4 A˚ molecular sieves) to the reaction followed by heating generates the desired pyrroles 519 via the standard Paal–Knorr reaction.

Scheme 130

The first MW-assisted intramolecular Stetter reaction was reported for the synthesis of chromanone derivatives using the imidazolium type of room temperature ionic liquids (RTILs) with thiazolium salts and Et3N as catalysts .

Thiazoles

A thiazolium salt-catalyzed intramolecular Stetter reaction is one of the most useful methods for constructing a wide range of compounds. Efficient synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 521 was reported using a one-pot sequential multicatalytic process: a Pd-catalyzed allylic amination–thiazolium salt-catalyzed Stetter reaction cascade (Scheme 131) . The one-pot reaction gave excellent yields by either sequential or simultaneous addition of the catalysts. In the sequential addition protocol (upper scheme), thiazolium salt 520 was directly added to the reaction mixture after the completion of the Pd-catalyzed allylic amination of aldehydes with -acetoxy ,-unsaturated esters, while in the simultaneous addition process (lower scheme), the aldehydes and esters were first dissolved in t-BuOH, and the solution was heated in the presence of both catalysts. In general, nucleophiles with either an electron-donating or electron-withdrawing substituent on the aromatic ring were applicable to this reaction process, affording corresponding products in excellent yields.

Scheme 131

Benzopyrones 524 and benzofuranones 525 were prepared by intramolecular cyclization of 2-alkoxybenzaldehydes 522 catalyzed by thiazolium salt 523 (Scheme 132) .

Scheme 132

Other products prepared by Stetter-type reactions include: chroman-4-ones 527 and 2,3-dihydroquinolin-4-ones 526 with a quaternary carbon using an intramolecular Stetter reaction catalyzed by thiazolium salt ; benzoins ; -amido ketones ; chroman-acetate from an intramolecular Stetter reaction catalyzed by an enantioselective catalyst-functionalized thiazolylalanine in up to 88% yield with 76% ee ; 2,3,5-trisubstituted furans and 1,2,3,5-tetrasubstituted pyrroles ; 1,4-diketones via the solid-supported thiazolium salt-promoted addition of aliphatic, aromatic, and heteroaromatic aldehydes to chalcones ; methyl 2,3-dihydro-3-oxobenzofuran-2-acetate ; -amino ketone synthesis from aldehydes and N-(-dialkylaminoalkyl) benzotriazoles .

739

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Thiazoles

ROMPgel-supported thiazolium salts (ROMPgel ¼ ring opening metathesis polymerization gel) and the effect of pressure on Stetter reactions in the synthesis of hindered aliphatic acyloins and -ketonitriles were also investigated.

4.06.12.3.4

Other synthetic applications

C-Glycosylbenzothiazoles 530, readily prepared by addition of 2-lithiobenzothiazole to sugar lactones 528 to form 529 followed by deoxygenation, were subjected to a one-pot reaction sequence involving N-methylation of the heterocyclic ring with MeOTf, treatment with a Grignard reagent, and finally HgCl2-promoted hydrolysis of the benzothiazoline thus formed. This resulted in the formation of sugar ketones 531 by a uniform route based on the use of benzothiazole as a carbonyl group equivalent (Scheme 133). Treatment of the sugar ketones 531, with various organometallic reagents containing Ph, 2-thiazolyl, TMS-ethynyl, or ethynyl groups, afforded chiral tertiary alcohols .

Scheme 133

As illustrated in Scheme 134, both distereoisomers of thiazolidine 535 prepared from commercially available amino acid derivatives 533 and 534 can serve as -turn mimetics in the secondary structure of peptides and proteins; therefore, they play an important role in many molecular recognition events in biological systems . A similar application can be found with thiazoline lactams .

Scheme 134

Thiazoles

4.06.12.4 Other Applications 4.06.12.4.1

Fluorescence PNA probes

The amount of a specific DNA in a homogenous sample solution can be determined by real-time polymerase chain reaction (PCR) with the aid of fluorescent reporters. Thiazole orange-conjugated short PNAs are often used as ‘lightup probes’ in these assays . A PNA molecule is a chemically modified nucleic acid in which the entire sugar-phosphate backbone is replaced by a polyamide structure. It contains all four natural bases, enabling it to hybridize to complementary oligonucleotide targets. Fluorescence intensity of thiazole orange incorporated in a PNA can increase almost 50-fold upon binding to a complementary nucleic acid, while it is not fluorescent when free in solution. This increase in fluorescence is due to the fact that when bound, the rotation around the bond between the aromatic systems of thiazole orange is restricted. There are two types of PNA probes, one tethered to one end of PNA and the other orthogonally incorporated as a fluorescent base surrogate at a specific position in the PNA chain . Both the quinoline and benzothiazole nitrogen atoms in thiazole orange can be attached through a flexible linker to a PNA probe containing the four common bases: A, C, G, or T. Solid-phase synthesis can be used to prepare these conjugates . Upon double formation, the fluorophores in 536 and 537 can fold back and intercalate between a base pair while as a base surrogate the fluorophores in 538 and 539 are forced to intercalate adjacent to the expected mutation site, which render the fluorophore responsive to mismatch hybridization. The common laserinduced excitation wavelengths are 488 and 510 nm, and emission spectrum is recorded between 505 and 650 nm, depending on the types of probes.

PNA was used for light-up probes because of its good hybridization properties and because the binding of thiazole orange to its linked nucleic acid sequence is minimal, hence useful for monitoring amplification reactions, as reported for real-time PCRs . In addition, they can be used for the identification of specific mRNAs in living cells and in microarray assays .

741

742

Thiazoles

4.06.12.4.2

Synthetic sidephores/fluorophore

Three pyochelin analogues 540–542 containing a thiazole ring have been synthesized from the same Weinreb amide. One of these analogues is HPTT-COOH 542, a molecule released in the course of pyochelin and yersiniabactin biosynthesis . The simplified structures containing thiazoline rings 543 were synthesized as fluorophores for Al(III) detections .

4.06.12.4.3

DNA nucleases

A new family of photonucleases, 5-[2-(dimethylamino)ethyl]-9-phenyl-4H-benzo[de]thiazolo[5,4-g]isoquinoline4,6(5H)-dione derivatives, 544, was synthesized and evaluated. These compounds intercalated into DNA efficiently and damaged DNA photochemically at concentrations as low as 5 mM. Mechanistic studies suggested that a novel naphthalimide-thiazole radical produced via an excited triple state might be involved in the DNA photodamage .

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743

744

Thiazoles

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Thiazoles

2006JME955

2006JME3770 2006JOC4599 2006JOC5715 2006JOC6262 2006JOC8261 2006JOM(691)2237 2006JST(796)86 2006JYR441 2006OBC2313 2006OL2377 2006OL2416 2006OL4637 2006OL4751 2006PCA7097 2006PLE245 2006PLM699 2006SRI325 2006T513 2006TL2361 2006TL4365 2007OL809

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753

754

Thiazoles

Biographical Sketch

Beining Chen graduated from China Pharmaceutical University with a B.Sc., in 1984 and an M.Sc. in 1987, both in medicinal chemistry. She obtained a Ph.D in organic chemistry in 1991 from University of Glasgow under the supervision of Professor Gordon Kirby. After spending three years working for Professor Sir Jack Baldwin at University of Oxford and seven years of employment by Cranfield, she joined Department of Chemistry at University of Sheffield as a lecturer in medicinal chemistry in 2003. The main focus of her research is on the design, synthesis, and screening of biologically active heterocyclic compounds including thiazoles. Over the last three years, she has been intensively involved in the development of therapeutic compounds against acquired variant Creutzfeldt– Jakob disease (vCJD, the human form of mad cow disease), a member of a family of fatal neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs) or prion diseases for which there are no therapeutic drugs currently available. The project was funded by the Department of Health (DoH).

William Heal was born in Norwich, UK, in 1976. He was awarded a B.Sc. with honors in chemistry in 1998 and an M.Sc. in chemical process (research and development) the following year from the University of Liverpool (UK). He stayed on in Liverpool to complete a Ph.D. in 2003, studying the polyleucine-catalyzed asymmetric epoxidation of ,-unsaturated ketones under the supervision of Professor Stan Roberts, funded by the EPSRC and a CASE award from Novartis. He then carried out postdoctoral research in medicinal chemistry at the University of Sheffield (UK), designing and synthesizing small molecule inhibitors of prion disease funded by the Department of Health. He is presently at Imperial College London (UK), carrying out MRC-funded postdoctoral research in the field of chemical proteomics directed toward malaria. His research is carried out at the biology–chemistry interface and he is particularly interested in the design and synthesis of small molecules for use in studying biological systems.

4.07 1,2-Selenazoles J. Młochowski Wrocław University of Technology, Wrocław, Poland ª 2008 Elsevier Ltd. All rights reserved. 4.07.1

Introduction

756

4.07.2

Theoretical Methods

756

4.07.3


757

4.07.3.1

X-Ray Diffraction

757

4.07.3.2

Proton NMR Spectroscopy

758

4.07.3.3

Carbon-13 NMR Spectroscopy

758

4.07.3.4

Selenium-77 NMR Spectroscopy

758

4.07.3.5

Nitrogen-15 NMR Spectroscopy

759

4.07.3.6

Mass Spectrometry

759

4.07.3.7

Infrared Spectroscopy

759

4.07.3.8

Ultraviolet Spectra

759

4.07.3.9

Circular Dichroism Spectra

4.07.4


4.07.5


4.07.5.1 4.07.5.2 4.07.6

760 761 761

Reactivity of Carbon Atoms

761

Reactivity of Heteroatoms

762


763

4.07.6.1

Reactivity of Carbon Atoms

763

4.07.6.2

Reactivity of Heteroatoms

764

4.07.7


767

4.07.8

Reactivity of Substituents Attached to Ring Heteroatom

768

4.07.9


770

4.07.9.1

Isoselenazoles

4.07.9.2

Isoselenazolines and Isoselenazolidines

773

4.07.9.3

Benzisoselenazoles, Benzisoselenazolines, and Benzisoselenazolones

774

4.07.9.4

Heterofused Isoselenazoles and Isoselenazolones

780

4.07.10


781

4.07.11

Synthesis of Particular Classes of Compounds and Critical Comparison of the

4.07.12

771


782


782

4.07.12.1

Oxygen-Transfer Catalysts

782

4.07.12.2

Medicinal Agents

785

4.07.12.2.1 4.07.12.2.2 4.07.12.2.3 4.07.12.2.4 4.07.12.2.5

Antioxidants and anti-inflammatory agents Enzyme inhibitors Antitumor agents Anti-infective agents Cytokine inducers and immunomodulators

References

785 786 786 787 787

787

755

756

1,2-Selenazoles

4.07.1 Introduction 1,2-Selenazole 1, traditionally called isoselenazole, is a five-membered heterocycle containing selenium and nitrogen atoms in the 1- and 2-positions respectively, the numbering system beginning with selenium. The reduced rings are designated isoselenazoline (dihydro) and the isoselenazolidine (tetrahydro). The literature is mainly concerned with three ring systems: isoselenazole 1 and its derivatives, and benzisoselenazoles (1,2-benzoselenazoles) 2 and 3, now known as benzisoselenazol-3(2H)-ones (1,2-benzoselenazol-3(2H)-ones), but previously improperly named 1,2benzisoselenazol-3(2H)-ones. Most of the work on isoselenazoles, particularly on the compounds 3, has been directed toward their syntheses, with some emphasis on their reactions, structural determinations, application as oxygentransfer catalysts, and evaluation of their biological activity.

The unsubstituted isoselenazolidine and isoselazolines remain unknown and only a few representatives of these classes, substituted at the nitrogen and carbon atoms, have been reported. The original review on isoselenazoles in CHEC(1984) was greatly extended in CHECII(1996) , which covered the literature and a number of reviews to 1995. This chapter covers the scientific literature from 1996 to mid-2006, but includes significant earlier references where necessary for discussion. Some reviews on isoselenazoles giving an overview of their syntheses and reactions as well as reviews on the practical applications of organoselenium compounds as reagents, catalysts, intermediates, and pharmaceuticals have been published in this period . It should be mentioned that although it is commonly thought that organoselenium compounds are malodorous and toxic, the isoselenazoles and their benzo-fused analogues have low volatility, are odorless, and probably of low toxicity . For example, 2-phenylbenzisoselenazol-3(2H)-ones 3a (R ¼ Ph), called ebselen, is practically nontoxic (LD50 ¼ 6.8 g kg1 in mice) . In working with various isoselenazoles in the laboratory, no special precautions need to be undertaken, although their direct contact with the skin, eyes, and mouth should be avoided.

4.07.2 Theoretical Methods Although molecular mechanics methods are popular, little has been done on isoselenazoles because the additional parameters required compared with sulfur compounds are not well documented. HYPERCHEM, for example, ˚ to Se (1.14 A), ˚ while the van der Waals radii are the same for S changes the covalent radii on going from S (0.99 A) ˚ The results obtained must therefore be viewed with some caution . and Se (1.97 A). For the 2-methyl- and 2-propanoylbenzisoselenazol-3(2H)-ones 3b and 3c, geometry optimization was performed using the GAUSSIAN-94 suite. The geometry of the isolated molecule was optimized by the complete neglect of differential overlap (CNDO) method, and the resulting structure used as a starting point for further optimization at the Hartree–Fock self-consistent field level. The energy derivatives were computed analytically using Berny’s algorithm. Mulliken population analysis was used to estimate the partial change distribution of the atoms .

1,2-Selenazoles

The energy change involved in the addition of water to 2-methylbenzisoselenazol-3(2H)-one 1-oxide, to give hypervalent dihydroxyselenurane, was estimated to be 13.0 kcal mol1 by molecular orbital (MO) calculations (MP2/ LANDL2DZ). This result shows that seleninamide forms a selenurane more readily than the analogous sulfinamide forms a sulfurane .

4.07.3 Experimental Structural Methods 4.07.3.1 X-Ray Diffraction The results of the X-ray diffraction studies of several isoselenazoles were reported. These were: benzisoselenazole 2 , benzisoselenazol-3(2H)-ones 3a and 3b , 7-nitro- and 7-carbamoylbenzisoselenazol-3(2H)-ones , 2-propanoylbenzisoselenazol-3(2H)-one , 2-alkylthieno[2,3-d]isoselenazol-3(2H)-ones , (1R,19S)-2-[(19-benzyl19-methylcarbamoyl)methyl]benzisoselenazol-3(2H)-one 1-oxide 4 , and camphor-derived isoselenazolidine 5 . Selected X-ray data are presented in Table 1.

Table 1 X-Ray data for isoselenazoles 2

3a

3b

4

˚ Bond length (A) Se(1)–N(2) N(2)–C(3) C(3)–C(3a) C(3a)–C(7a) C(7a)–Se(1) Se(1)–O C(3)–O

1.833 1.292 1.477 1.424 1.845

1.896 1.359 1.465 1.413 1.893

1.880 1.350 1.473 1.392 1.885

1.236

1.246

1.893 1.357 1.502 1.361 1.919 1.643 1.222

Bond angle (deg) C(7a)–Se(1)–N(2) Se(1)–N(2)–C(3) N(2)–C(3)–C(3a) C(3)–C(3a)–C(7a) C(3a)–C(7a)–Se(1) Se(1)–O(out of plane)

91.0 109.6 119.8 110.3 109.2

85.5 116.1 110.8 116.6 110.7

85.7 116.3 110.6 116.2 111.2

84.2 116.4 111.3 114.4 113.5 104.5

757

758

1,2-Selenazoles

The Se–N and Se–C bonds in the isoselenazoles are longer than other ring bonds. The longer bond constricts the N–Se–C bond angle as compared to other ring bond angles. This angle is smaller in the benzisoselenazol-3(2H)-ones than in benzisoselenazole. The nearly planar molecules 3a and 3b form chains with Se O intermolecular distances ˚ The geometries described by bond lengths and angles, as well as conformations for both molecules 3a and of 2.600 A. 3b, are very similar. For the camphor-derived isoselenazoline 5, the bond lengths and angles are normal with Se–N and Se–C distances ˚ respectively, and an N–Se–C angle of 87.1 . The mean value of the Csp3–Csp3 bond lengths in of 1.865 and 1.943 A, ˚ The five-membered ring has an N-envelope conformation and the molecules are the camphor moiety is 1.542 A. ˚ respectively. hydrogen-bonded, forming chains with O O and O–H O separations of 2.769 and 1.840 A,

4.07.3.2 Proton NMR Spectroscopy The 1H nuclear magnetic resonance (NMR) spectrum of unsubstituted isoselenazole 1 has H-3, H-4, and H-5 signals at 9.17, 7.39, and 9.38 ppm, respectively. These can range from 6.89 ppm with an electron-donating group to 10.31 ppm with an adjacent electron-withdrawing group. The coupling constants are J3,4 ¼ 1.6 Hz and J4,5 ¼ 5.2 Hz . For the benzisoselenazole 2, the H-3 signal appears at 9.15 ppm being shifted downfield to 10.10 ppm in the benzisoselenazolinium salt 6 . The H-2 proton of 7-azabenzisoselenazol-3(2H)-one 7a resonates at 9.34 ppm, as for simpler amide protons, while the H-2 signal for selenazoline 8 is shifted upfield to 4.10 ppm .

The 1H NMR spectra of benzisoselenazol-3(2H)-ones 3, their 1-oxides, and isoselenazolones fused to a heteroaromatic ring have the H-4, H-5, H-6, and H-7 signals as double doublets, double triplets, or multiplets in the range 7.10–8.16 ppm. The H-4 and H-7 signals are more downfield as compared to H-5 and H-6 . Proximity to the pyridine nitrogen atom in 7a, and in other 7-azabenzisoselenazol-3(2H)-ones, causes the H-6 proton to appear in the range 8.79–8.80 ppm .

4.07.3.3 Carbon-13 NMR Spectroscopy Aside from use in routine structure determination, only a few publications, following those reported in , concentrated on a more detailed analysis of 13C NMR spectra. The C-3 signal for benzisoselenazole appears at 160.7 ppm . This resonance for benzisoselenazolones 3b and 11b is observed at 166.6 and 168.3 ppm, respectively, while for the isoselenazoles 9 and 10 it moves upfield depending on the substituent present at the 3-position (Table 2). The C-4 (C-3a) signal for the isoselenazoles and benzisoselenazol-3(2H)-one appears in a narrow range, 120.4–130.5 ppm. In contrast, the C-5 (C-7a) signal appears over a broad range, downfield or upfield, in comparison to C-3 when different substituents, a fused benzene ring or an oxygen atom on the vicinal Se-1, are present.

4.07.3.4 Selenium-77 NMR Spectroscopy 77

Se NMR spectroscopy is a useful technique for evaluation of the structure of the organoselenium compounds, including isoselenazoles. The 77Se shift is an essential factor in the determination of the immediate environment of the selenium atom. It moves downfield from diaryl diselenides (ca. 450 ppm) , thus: selenophene 2 (526 ppm) , selenazoline 8 (756 ppm) , isoselenazol-3(2H)-ones 3b, 3d, 12a, 13a (822–925 ppm) , benzisoselenazole 2 (1013 ppm) , to the 1-oxides like 11d (1081–1143 ppm) . Selected data are given in Table 3.

1,2-Selenazoles

Table 2

13

C NMR data for selected isoselenazoles 13

C chemical shift ( ppm)

Compound

Solvent

C-3

C-4(C-3a)

C-5(C-7a)

Reference

CCl4

173.1

119.5

160.2

2002S2220

CCl4

153.1

115.4

161.5

2002S2220

d6-DMSO

166.6

127.6

139.0

1992JST311

d6-DMSO

168.3

130.5

147.2

1992JST311

4.07.3.5 Nitrogen-15 NMR Spectroscopy 15

N signals have been measured for only two isoselenazoles, 2-methylbenzisoselenazol-3(2H)-one 3b and its 1-oxide 11b. The chemical shifts, 280 ppm for 3b, characteristic for amides, and 232 ppm for 11b, are referred to nitromethane. The nitrogen shift for 11b is reduced by about 50 ppm with respect to that for 3b because the oxidation of selenium leads to a reduction of the shielding of the nitrogen atom in the adjacent ring position. The 14N NMR spectra 3b and 11b were also obtained. A simple broad resonance of about 3 kHz width was found in each case with the same chemical shifts as in the corresponding 15N spectra .

4.07.3.6 Mass Spectrometry Authors have reported mass spectra as a tool for confirmation of the molecular structure based on intense molecular ions. Fragmentation of the isoselenazoles and isoselenazolones has not been studied in any more detail than that reported in CHEC(1984) and CHEC-II(1996) .

4.07.3.7 Infrared Spectroscopy Infrared spectroscopy is not very diagnostic for simple isoselenazoles. It is a useful tool to detect the carbonyl group in isoselenazolones where the CO band occurs in a range 1593–1680 cm1, and its oxides where SeO is observed as one or two bands at 800–853 cm1 .

4.07.3.8 Ultraviolet Spectra The ultraviolet (UV) spectra for isoselenazoles, benzisoselenazoles, and benzisoselenazol-3(2H)-ones are similar to their sulfur and tellurium analogues except for a slight bathochromic shift according to the heteroatom in the order

759

760

1,2-Selenazoles

Table 3 Compound

77

Se NMR data for isoselenazoles Solvent

77

CDCl3

756

2000JOC8152

d6-DMSO

888

1992JST311

CDCl3

860

2005JOC868

CDCl3

822

2004EJO3857

CDCl3

925

2000AJC277

CDCl3

1081

2005JOC868

Se chemical shift ( ppm)

Reference

S < Se < Te . The first, long-wavelength band at around 320–358 nm is associated with the electronic transition involving the nonbonded electrons of selenium. This band is observed in the UV spectra of benzisoselenazol-3(2H)-ones but not in their 1-oxides . A summary of the UV spectra of representative isoselenazoles is presented in Table 4.

4.07.3.9 Circular Dichroism Spectra The circular dichroism (CD)/UV spectra of benzisoselenazol-3(2H)-ones 3 of (S)-configuration having a chiral alkylaryl or carboxyalkyl group connected to the nitrogen atom were recorded and discussed in relation to the structure. The spectra are characterized by the presence of four bands in the region down to 200 nm, with a unique solvent-dependent band located between 300 and 350 nm . CD spectra of optically active benzisoselenazol-3(2H)-one 1-oxides were employed for determination of their absolute configuration .

1,2-Selenazoles

Table 4 UV spectral data for isoselenazoles Compound

max (nm) (log ")

Solvent

Reference

256 (3.75)

Isooctane

1984T391

203 (4.15); 228 (4.30); 318 (3.67)

Ethanol

1978JHC865

260 (3.37); 325 (3.30)

Methanol

1986BCJ2179

229 (4.24); 255 (4.02); 321 (3.69)

Methanol

1997MI407-01

201 (4.48); 232 (4.05) 274 (3.42)

Hexane/2-propanol 3:1

2005JOC868

The induced circular dichroism (ICD) spectra of five -cyclodextrin derivatives containing a benzisoselenazol3(2H)-one moiety show two positive Cotton effects at ca. 232–246 and 259–264 nm. This indicates that the benzisoselenazolone moiety lies outside the chiral cavity of -cyclodextrin, and both of the transition moments may be perpendicular to the axis of the -cyclodextrin cavity. In contrast, the ICD spectra of other -cyclodextrin derivatives display one negative Cotton effect at 229 nm and a positive Cotton effect at 248 nm. It can be inferred that the benzisoselenazolone moiety is located inside the chiral cavity of -cyclodextrin .

4.07.4 Thermodynamic Aspects No discussions on the thermodynamical aspects other than those summarized in CHEC(1984) and CHEC-II(1996) were found in the literature in the period under review .

4.07.5 Reactivity of Fully Conjugated Rings 4.07.5.1 Reactivity of Carbon Atoms Many of the known reactions of isoselenazoles and benzisoselenazoles were covered in earlier reviews . Isoselenazoles are stable under normal conditions of storage, but undergo ring opening upon treatment with reducing or nucleophilic agents. The nucleophiles mostly attack the electrophilic selenium and the Se–N bond is cleaved, but with lithium diisopropylamide (LDA) metallation of isoselenazoles 14 takes place at the 5-position. The resulting lithium derivatives 15 can undergo substitution with electrophiles (Scheme 1) .

761

762

1,2-Selenazoles

Scheme 1

The reactivity of the 5-position in fused isoselenazole 16 toward amines was attributed to the importance of the dipolar canonical form 17. The Se–N and Se–C bonds in the adducts 18 are cleaved, the selenium is ejected, and Schiff bases 19 are produced (Scheme 2) .

Scheme 2

Benzisoselenazoles react with nucleophiles by substitution at the 3-position or by cleavage of the ring. 3-Aminobenzisoselenazole was obtained in 36% yield by amination with potassium amide in liquid ammonia . In isoselenazolium salts, the vicinity of the positively charged nitrogen activates the 3-position toward nucleophiles. The conversion of 3-chlorobenzisoselenazolium salts 20 to 3-aminobenzisoselenazoles 21 is an example (Scheme 3) .

Scheme 3

Electrophiles react at the 4-position. Thus, 3,5-dimethylisoselenazole was deuterated with deuteriosulfuric acid at the 4-position while the unsubstituted isoselenazole failed to undergo the H–D exhange . Bromination and nitration of substituted isoselenazoles occurs at the same position but under these reaction conditions the products underwent decomposition. 3-Methyl-5-phenylisoselenazole reacts with a mixture of concentrated nitric and concentrated sulfuric acid to give 3-methyl-4-nitro-5-(4-nitrophenyl)isoselenazole, in 54% yield, accompanied by other nitro derivatives . Bromination and nitration of benzisoselenazole results in substitution in the benzene ring and does not occur at the 3-position; thus nitration afforded an almost equimolar mixture of the 5-nitro- and 7-nitrobenzisoselenazoles in an overall quantitative yield, while bromination led to a mixture of mono-, di-, and tribromo compounds . Thieno[2,3-d]isoselenazole was selectively brominated in the thiophene ring .

4.07.5.2 Reactivity of Heteroatoms Attack by carbanionic nucleophiles on the electrophilic selenium atom leads to an easy ring cleavage. For example, 3,5dimethylisoselenazole 22 (R ¼ Me) treated with phenylmagnesium bromide gave -phenylselenoenone 23 in high yield in contrast to reaction of the 3-methyl derivative 22 (R ¼ H) which resulted in only a low yield of 24. Most probably, in this case, a mixture of (Z)- and (E)-isomers 24 is formed via a reversible alkyne/phenylselenol elimination and the eliminated selenol 25 undergoes oxidation to diphenyl diselenide, thereby no longer being available for the reverse reaction (Scheme 4). The lithium aluminium hydride reduction of 22 (R ¼ H) starts with Se–N bond cleavage, complete reduction and acylation of the intermediate amine, then leading to the amide 26 .

1,2-Selenazoles

Scheme 4

The nitrogen atom is a nucleophilic center readily quaternized by methyl iodide or acid chlorides to give 2-methylbenzisoselenazolium iodide or 2-acylbenzisoselenazolium chlorides, respectively. The quaternary isoselenazolium salts are labile to nucleophiles and can be converted into other heterocyclic ring systems .

4.07.6 Reactivity of Nonconjugated Rings 4.07.6.1 Reactivity of Carbon Atoms No reactions of the carbon atoms in the monocyclic isoselenazolines or isoselenazolidines have been reported and there are only a few reports concerned with the 3-position of benzisoselenazol-3(2H)-ones. Benzisoselenazol-3(2H)ones 3 treated with PCl5 gave 3-chlorobenzisoselenazolinium salts 26 (Scheme 5) . The amide carbonyl group can be converted to the geminal dichloro derivative 27 . Reaction with Lawesson’s reagent , or, better, with P2S5 , yields benzisoselenazol-3(2H)-thiones 28.

Scheme 5

763

764

1,2-Selenazoles

4.07.6.2 Reactivity of Heteroatoms Much work has been devoted to the addition of nucleophilic reagents to electrophilic selenium in benzisoselenazol3(2H)-ones. Oxidation of benzisoselenazol-3(2H)-ones 3 with H2O2 gives the selenoxides 11 (Scheme 6) . These moderately stable cyclic seleninamides lose the oxygen during storage. When ebselen 3a (3, R2 ¼ H, R1 ¼ Ph) was treated with 30% H2O2, used in a large excess, the unstable crystalline compound 29 was produced and immediately fragmented to produce ebselen selenoxide 11 (R1 ¼ Ph, R2 ¼ H), water, and molecular oxygen. More stable hydroperoxyselenurane 30 was obtained when ebselen analogue 31 was oxidized with H2O2 or ButOOH. The hydroperoxyselenuranes are postulated active intermediates involved in the hydroperoxide oxidation of various organic compounds catalyzed by ebselen .

Scheme 6

Optically active benzisoselenazol-3(2H)-one 1-oxides (seleninamides) 32 having various bulky substituents were prepared from the corresponding benzisoselenazol-3(2H)-ones 3 by oxidation with hydrogen peroxide or ozone followed by chromatographic resolution on a chiral column. The pure enantiomer (R)-32 was found to racemize in solution. The recemization proceeds via hypervalent hydrates 33 formed by reaction with water (Scheme 7) .

Scheme 7

1,2-Selenazoles

Oxidation of the benzisoselenazol-3(2H)-ones 34 substituted at N-2 with a chiral group derived from L-phenylalanine generates a new stereogenic center at the selenium. The mixture of diastereoisomers 35a and 35b was recrystallized to give the individual stereoisomers which were resistant to racemization (Scheme 8) .

Scheme 8

The selenium atom in benzisoselenazol-3(2H)-ones and their open-chain analogues (the bis[(2-carbamoyl)phenyl] diselenides) and isoselenazolidines interacts with active oxygen species present in living cells and deactivates them. The mode of biological action of these compounds has been postulated to be similar to that observed for the enzyme glutathione peroxidase (GPx). It results in dehydrogenation of thiols to disulfides while hydroperoxides, peroxynitrite, hydroxyl radical, and superoxide anion are reduced. The postulated mechanism of the enzyme-like action of ebselen and other cyclic selenenamides is presented in Scheme 9 .

Scheme 9

765

766

1,2-Selenazoles

When the concentration of hydroperoxide is high, ebselen 3a is oxidized to selenoxide 11a which reacts with one molecule of the thiol to give selenoxysulfide 36. Intermediate 36 and a second molecule of thiol produce disulfide, while the selenenic acid 37 formed is converted back to ebselen. In biological systems, where the concentration of hydroperoxide is low, ebselen and the thiol give selenosulfide 38 which disproportionates into the disulfide and diselenide 39, subsequently oxidized to selenenic anhydride 40 and finally converted into ebselen. When benzisoselenazol-3(2H)-ones 3 or their 1-oxides are treated with a reducing agent such as hydrazine or triphenylphosphine, the Se–N bond is cleaved to give bis[(2-(carbamoyl)phenyl] diselenides 41 (Scheme 10) . The ring cleavage with thiols leads to the selenosulfides 42 . Less stable selenosulfides spontaneously disproportionate into diselenides 41 and disulfides . Other ring-opening schemes to the 2-(carbamoyl)phenylalkyl or alkenyl selenides 43–45 were also suggested .

Scheme 10

Ring opening by a reducing agent such as Fe/AcOH leads to diselenides, for example, 46 (Scheme 11) , but in the case of 2-ethoxycarbonylbenzisoselenazol-3(2H)-one it was followed by a recyclization resulting in ring expansion to give 1,3-benzoselenazine-2,4-dione 47 .

Scheme 11

1,2-Selenazoles

Several papers have dealt with electrophilic attack at the amide nitrogen of the unsubstituted benzisoselenazol-3(2H)one. Alkylation using KOH and alkyl or allyl halide or halocarboxylic ester gave 2-substituted benzisoselenazol-3(2H)ones and the reaction has synthetic value. 6-[Benzisoselenazol-3(2H)-one]--cyclodextrin, designed as an artificial enzyme, was prepared by reaction of benzisoselenazol-3(2H)-one potassium salt with 6-iodo-cyclodextrin (-CD-6-I) (Scheme 12) .

Scheme 12

The N-acylation and N-sulfonylation of benzisoselenazol-3(2H)-one with carboxylic acid chlorides or sulfonyl chlorides is an efficient method for the synthesis of 2-acyl and 2-sulfonylbenzisoselenazol-3(2H)-ones 48 and 49 . A reaction with formalin resulted in N-hydroxymethylbenzisoselenazol-3(2H)-one 50, while reaction with isocyanates yielded the 2-carbamoylbenzisoselenazol-3(2H)-ones 51 (Scheme 13) .

Scheme 13

4.07.7 Reactivity of Substituents Attached to Ring Carbon Atoms The oxidation of alkyl groups attached to the isoselenazole by heating with SeO2 provides carboxylic acids subsequently converted into the methyl esters by treatment with diazomethane (Scheme 14) .

767

768

1,2-Selenazoles

Scheme 14

A carboxylic group was selectively introduced at the 3-position of isoselenazole by hydrolysis of a trichloromethyl group with aqueous sulfuric acid (Scheme 15) .

Scheme 15

The acylation of the secondary amino group in isoselenazoles 52 with -bromoalkylcarboxylic acid bromides yielded the bromo derivatives 53 subsequently cyclized to the 6,7-dihydro-4H-2-selena-1,4,7-triazaazulene-5,8diones 54 (Scheme 16) .

Scheme 16

Various substituents at the 3-position of benzisoselenazoles were transformed into other functional groups by standard methods (Scheme 17); thus, oxidation of the aldehyde 55 or basic hydrolysis of the amide 56 gave 3-benzisoselenazolecarboxylic acid 57, which was converted into the ester 58 and then by Curtius degradation to 3-aminobenzisoselenazole 60. The amide 56 was dehydrated to the nitrile 59 .

4.07.8 Reactivity of Substituents Attached to Ring Heteroatom The oxygen atom in the ebselen selenoxide 11a can be selectively removed, without ring opening, by treatment with NADPH and thioredoxin reductase (Trx) (Scheme 18) or with benzaldehyde . Reports on the modification of substituents attached to the nitrogen atom are concerned only with benzisoselenazol3(2H)-ones. The 2-(4-carboxyphenyl)benzisoselenazol-3(2H)-one 61 was used as an acylating agent in the synthesis of the -cyclodextrin (-CD) derivatives 62 and 63, thus containing the key ebselen moiety (Scheme 19) . Another -CD derivative containing the benzisoselenazol-3(2H)-one group 65 was synthesized using the ester 64 as an acylating agent (Scheme 20) .

1,2-Selenazoles

Scheme 17

Scheme 18

Scheme 19

769

770

1,2-Selenazoles

Scheme 20

The N-carboxyalkyl chain in the 2-carboxyalkylbenzisoselenazol-3(2H)-ones 66 was elongated by treatment with -amino acid esters followed by hydrolysis, and thus compounds 67, with a dipeptide moiety, were obtained (Scheme 21) .

Scheme 21

The O-alkylation of the 2-(4-hydroxyphenyl)benzisoselenazol-3(2H)-one 68 with 4-(iodobutyl)triphenylphosphonium iodide (IBTP) gave an ebselen analogue with a triphenylphosphonium group, ‘MitoPeroxidase’ 69 (Scheme 22) , and alkylation of the amino group in 2-(2-aminophenyl)benzisoselenazol-3(2H)-one 70 with the chloromethyl group of Merrifield’s resin resulted in the polymer-supported ebselen 71 (Scheme 23) .

Scheme 22

4.07.9 Ring Synthesis Classified by Number of Ring Atoms in Each Component Isoselenazoles and benzisoselenazoles are prepared by ring closure involving the formation of Se–C, N–C, and Se–N bonds. The most common [4þ1] and [3þ1þ1] routes (Scheme 24) are basically the same, which is designated depends on whether the -selenoenone derivative is considered to be the starting material (e.g., Scheme 25) or the addition of selenium (e.g., Scheme 27) is part of the sequence. Only one example of the [3þ2] route has been reported (Scheme 28) but the reaction is of little value for practical synthesis.

1,2-Selenazoles

Scheme 23

Scheme 24

4.07.9.1 Isoselenazoles The most commonly used method for synthesis of isoselenazoles is a [4þ1] route, the addition of ammonia to 3-selenosubstituted enones such as 72 (Scheme 25) .

Scheme 25

A convenient synthesis of 4-methyl- and 4-phenylseleno-1,1,1-trihalo-3-alken-2-ones 74 from the reaction of the corresponding 4-methoxy-1,1,1-trihalo-3-alken-2-ones 73 with methyl- or phenylselenols in the presence of boron trifluoride etherate was reported. The reaction of 74 (R ¼ Me) with bromine followed by ammonia led to 3-trihalomethyl-isoselenazoles in good yields (Scheme 26) .

771

772

1,2-Selenazoles

Scheme 26

The 3- and 5-substituted isoselenazoles 79 were prepared in moderate yields by a one-pot procedure using alkynic aldehydes or ketones 76. Their conversion to the oxime sulfonates 77 with hydroxylamine O-sulfonic acid followed by conjugate addition of potassium selenide in buffered aqueous solution resulted in ring closure. The reaction proceeds via intermediates 77 and 78, and can be classified as a [3þ1þ1] route because three-carbon, mononitrogen, and monoselenium components take part in the ring formation. When the alkynals 76 (R2 ¼ H) were used, the oxime could eliminate hydrogen sulfate to generate the alkynic nitrile allowing a second conjugate addition and thus selenobis(alkenyl)nitriles 80 were obtained as by-products and the isoselenazoles were produced only in low yields (Scheme 27) .

Scheme 27

An unusual 1,3-cycloaddition of benzyne across a CTN–Se grouping in a 1,2,5-selenadiazole leads to the formation of the isoselenazole ring. The benzyne, generated from anthranilic acid, reacts with 3,4-diphenylselenadiazole 81 to afford 3-phenylbenzisoselenazole 82 as confirmed by mass spectrometry and the detection of benzonitrile, but the reaction has no practical synthetic value (Scheme 28) .

Scheme 28

1,2-Selenazoles

The quaternary isoselenazolium perchlorates 86 can be formed, following a [3þ1þ1] route, from 3-chloroprop-2eniminium salts 83, sodium selenocyanate, and an arylamine. The substrate 83 reacts with sodium selenocyanate to give the 3-cyanoselenoprop-2-eniminium salt 84 subsequently converted into 85 by treatment with the arylamine, which cyclizes on heating to isoselenazolium salt 86 (Scheme 29) .

Scheme 29

Another approach for the synthesis of the isoselenazolium salt 88 is based on the formation of one Se–N bond by cyclization of 3-(methylselanyl)prop-2-enamide 87 using phosphorus pentachloride (Scheme 30) . Earlier, in a similar manner, starting from N-alkyl- or N-phenyl-2-(methylselanyl)benzamides, the 3-chlorobenzisoselenazolium chlorides 20 (Scheme 3) were obtained in 80–90% yield .

Scheme 30

4.07.9.2 Isoselenazolines and Isoselenazolidines The parent isoselenazolines and isoselenazolidines remain unknown because the selenamide Se–N bond is susceptible to cleavage followed by disproportionation. Only a few representatives of this class, substituted at the nitrogen and carbon atoms, have been reported. On treatment with sulfuric acid, 3-chloro-2,5-diphenylselenazol-2-ium chloride 88 yields the isoselenazolium sulfate 89. This compound is hydrolyzed with aqueous sodium hydroxide to give 2,5-diphenylisoselenazol-3(2H)one 90 (Scheme 31) .

Scheme 31

773

774

1,2-Selenazoles

Conversion of selenenyl bromides 91 to the selenides 92 followed by ozonization in chloroform or methylene chloride solutions gave unstable selenoxides, which decomposed at 20 C to isoselenazolinones 93. The same compounds 93 were formed directly by treatment of the bromides 91 with triethylamine. They were reasonably stable even at room temperature but were prone to disproportionation. Under acid catalysis, the isoselenazolinone 93 (R ¼ Me) equilibrated with the 1-oxoisoselenazolidin-3-one 94 and diselenide 95 (Scheme 32). The reaction of diselenide 95 with m-chloroperbenzoic acid (MCPBA) or t-butyl hydroperoxide (TBHP), or direct oxidation of the izoselenazolinone 93 (R ¼ Me) gave the same 1-oxide 94 .

Scheme 32

The hydrolytically and thermally stable, crystalline camphor-derived isoselenazolidine 5 was prepared by treatment of the diselenide 96 with bromine and silver triflate (Scheme 33) .

Scheme 33

4.07.9.3 Benzisoselenazoles, Benzisoselenazolines, and Benzisoselenazolones Benzisoselenazoles 2 were prepared, in a similar manner to isoselenazoles, by the addition of bromine followed by ammonia to 2-(methylselanyl)benzaldehydes or 2-(methylselanyl)phenyl ketones 97 . When the aldehyde 97 (R ¼ H) was treated with ethyl carbamate and then with bromine, N-acyl benzisoselenazolinium salt 6 (R ¼ H) was produced. The alternative method for preparation of salt 6 is based on the N-acylation of benzisoselenazoles 2 with ethyl chloroformate (Scheme 34) . The cyclization of the intermediate oxime, formed from 2-cyanoselenobenzophenone 98 and hydroxylamine, leads to 2-phenylbenzisoselenazole N-oxide 99 with concomitant loss of hydrogen cyanide (Scheme 35) .

1,2-Selenazoles

Scheme 34

Scheme 35

For the synthesis of benzisoselenazoline 8, 29-bromophenyl-2-methylpropionitrile 100 was the starting material. It was hydrolyzed to amide and subsequently converted into 2-bromophenylalkylamine. A solution of the amine and KSeCN in DMF was treated with CuI to give 8 in high yield (Scheme 36) .

Scheme 36

Most of the reports on the preparation of benzisoselenazolines are actually concerned with the 3-one derivatives: benzisoselenazol-3(2H)-ones. These compounds were first prepared by Lesser and Weiss in 1924 , but intensive research did not begin in this area until 1984 when their interesting therapeutic properties for a number of disease states, including anti-inflammatory activity, were reported . The earliest and the most versatile approach to preparing benzisoselenazol-3(2H)-one and its derivatives is to react the 2-(chloroseleno)benzoyl chloride 102 with primary amines, used in excess to capture as a base the generated hydrogen chloride. In the meantime, the procedure was modified and optimized. The synthesis starts from anthranilic acid which is first diazotized and the selenium introduced by treatment of the diazonium salt with Li2Se2, obtained from elemental lithium and selenium in an aprotic medium or better with Na2Se2, prepared in advance by the reaction of selenium powder, 100% hydrazine hydrate, and sodium

775

776

1,2-Selenazoles

hydroxide in methanol . The bis[2-(carboxyphenyl)] diselenide 101 thus obtained was treated with thionyl chloride, used in a large excess, to give 2-(chloroseleno)benzoyl chloride 102, the key substrate for the synthesis of different N-substituted benzisoselenazol-3(2H)-ones. This general strategy was employed for the synthesis of a broad spectrum of 2-alkyl and 2-aryl derivatives 3 (Scheme 37) . Among them were 75Se-labeled ebselen, prepared from 75Se , and spin-labeled compounds such as ebselen substituted in meta position of the benzene ring with a trimethyl(pyrrolidynyl) group 103, the compound 104 , and other paramagnetic benzisoselenazol-3(2H)-ones .

Scheme 37

Bulky substituents in the vicinity of the amino group have no substantial influence on the reaction with dichloride 102 and even amines such as t-butylamine, 1-adamantylamine or 2,4,6-trialkylanilines give benzisoselenazol-3(2H)ones 3 in high yields . Bisbenzisoselenazol-3(2H)-ones 105 having both heterocyclic moieties bridged by spacers such as phenylene, bisphenylene, alkylene, oxaalkylene, azaalkylene, and dithiaalkylene groups were obtained from the reaction of 2-(chloroseleno)benzoyl chloride 102 with compounds having two primary amino groups (Scheme 38). The exceptions were 1,2-diaminobenzene and 1,8-diaminonaphthalene where, for steric reasons, only one amino group reacted with dichloride 102. The general tendency to form bis- and not monobenzisoselenazol3(2H)-ones was explained by the fact that selenenylation–acylation of both amino groups in diamines is much faster than the rate of diffusion of the reagents .

Scheme 38

Amino-alcohols and amino-phenols, having a second nucleophilic center (a hydroxy group), react with dichloride 102 preferentially on the amino group, and 2-(hydroxyalkyl)- or 2-(hydroxyaryl)benzisoselenazol-3(2H)-ones 106 are produced (Scheme 39). Similarly, amino thiols give 2-thioalkyl- or 2-thioarylbenzisoselenazol-3(2H)ones 107 since the thiol groups are neither selenenylated nor acylated .

1,2-Selenazoles

Scheme 39

Amino-polyols, such as 1-aminodeoxy-D-sorbitol or D-(þ)-glucosamine, as well as adenine, underwent selenenylation– acylation at the amino groups by dichloride 102 and thus their 2-benzisoselenazol-3(2H)-onyl derivatives 108 and 109 were obtained (Scheme 40). The organoselenium-modified -CDs 110 and 111 were synthesized in a similar way .

Scheme 40

Despite the known ease of synthesis of benzisoselenazol-3(2H)-ones from dichloride 102 and aryl- or alkylamines, it was found that -amino acids react more slowly and the reaction time had to be extended to several days. The reaction representing a general route to 2-(carboxyalkyl)benzisoselenazol-3(2H)-ones 112 (R2 ¼ H) was carried out in anhydrous acetonitrile and the amino acids were used in excess, to act additionally as a base to bind the generated hydrogen chloride. For the synthesis of the alkyl esters 112 (R2 ¼ alkyl), potassium carbonate was used as a base and the reaction proceeded substantially faster. Most of the products from sterically defined substrates were obtained as individual enantiomers . In a similar reaction, 2-(phosphonoalkylamino)benzisoselenazol-3(2H)-ones 113 were obtained by reacting 1-hydrazinoalkylphosphonates with 2-(chloroseleno)benzoyl chloride (Scheme 41) . Some 2-(phosphonoalkyl)benzisoselenazol-3(2H)-ones were synthesized in good yields by the cyclocondensation of dichloride 102 with -aminoalkylphosphonates . Primary carboxamides can be employed for the preparation of 2-acylbenzisoselenazol-3(2H)-ones 114. Because of the low nucleophilicity of the amide nitrogen atom, the reaction requires a relatively long time and although alkylamides 114 are produced in moderate yields, arylamides yielded only minute amounts of the desired products . The 2-propanoylbenzisoselenazol-3(2H)-one 114 (R4 ¼ Et) was also obtained in an alternative way from the urea, which, treated with dichloride, gave the 2-carbamoyl derivative 114 (R4 ¼ CONH2) converted into the

777

778

1,2-Selenazoles

final product by treatment with a mixture of propanoic acid and propanoyl chloride . The 2-sulfonylbenzisoselenazol-3(2H)-ones 115 were obtained in the same manner as 114 using sulfonamides as the substrates (Scheme 41) .

Scheme 41

Benzisoselenazol-3(2H)-ones covalently immobilized on solid supports have been reported . The first 117 was obtained in the reaction of 3-aminopropyltriethoxysilane with dichloride 102 followed by the hydrolysis of the intermediate 116 formed. 4-Aminostyrene, treated with dichloride 102 in the presence of ,9azobisisobutyronitrile (AIBN), gave, in a one-pot reaction, ebselen bound to a polyethylene chain 118. Another polymer-supported benzisoselenazol-3(2H)-one 119 was obtained by reacting dichloride 102 with 1-aminohexylamide gel (Scheme 42).

Scheme 42

1,2-Selenazoles

The expedient method for the synthesis of ebselen reported by Engman and Hallberg utilized a onepot procedure in which benzanilide was ortho-lithiated and treated with selenium powder, followed by cuprous bromidemediated oxidative ring closure. Following this procedure, some 2-substituted benzisoselenazol-3(2H)-ones, among them 77 Se-ebselen (Scheme 42), were obtained . The dilithiospecies 120 can be quenched with dimethyl diselenide or elemental selenium to give selenides 121 or diselenides 122, respectively. Cyclization of selenides 121 or diselenides 122 was accomplished through intermediate selenyl halides, obtained by reaction with bromine or thionyl chloride, treated with a base such as Na2CO3, NaHCO3, Et3N, or pyridine (Scheme 43) . The one-step reaction of dilithiated benzanilide 120 with selenium dichloride gave ebselen in moderate yield . In contrast to N-arylbenzamide lithium salts, their N-alkyl analogues gave benzisoselenazol-3(2H)-ones only in very small quantities.

Scheme 43

Another preparative route to benzisoselenazol-3(2H)-ones is based on intramolecular homolytic substitution with amidyl radicals. Photochemical decomposition of pyridine-2-thionoxycarbonyl imidate esters 124 affords 2-alkylbenzisoselenazol-3(2H)-ones 3. The starting substrates were 2-(benzylseleno)benzamides 123 converted into iminyl chlorides which were not isolated but were reacted immediately with the sodium salt of N-hydroxypyridine-2-thione to afford compound 124 in situ. Subsequent irradiation gave the corresponding benzisoselenazol-3(2H)-ones 3 (Scheme 44) . Presumably, the reaction proceeds via amidyl radicals, which undergo intramolecular homolytic substitution at the selenium atom. Unfortunately, ebselen itself and its t-Bu analogue cannot be prepared by this method. They are available by tert-butyl or benzoyl peroxide-mediated cyclization of 2,29-diselenobis(benzamides) 125

Scheme 44

779

780

1,2-Selenazoles

(Scheme 45) . Since they are readily available by ortho-lithiation of benzanilides or from anthranilic acid via bis[2-(carboxyphenyl)] diselenide , this method represents a convenient procedure for preparation of ebselen and its analogues. When hydrogen peroxide is the oxidant, the cyclization is followed by oxidation of the selenium and benzisoselenazol-3(2H)-one 1-oxides 11 are produced .

Scheme 45

4.07.9.4 Heterofused Isoselenazoles and Isoselenazolones Thienoisoselenazoles and selenoloisoselenazoles were obtained in low to moderate yields from (methylselanyl)thiophene or (methylselanyl)selenophene carbaldehydes by treatment with bromine followed by ammonia . The synthesis of thieno[3,2-d]isoselenazole and selenolo[3,2-d]isoselenazole from the corresponding 2-(methylselanyl)-3-carbaldehydes (Scheme 46) are examples .

Scheme 46

Condensed pyrimidone- and antypyrine[4,3-d]isoselenazoles can be prepared by oxidation of the methyl group in the substrate with selenium dioxide followed by cyclization . Example are syntheses of 1,2selenazolo[4,3-d]pyrimidine-5,7-diones (Scheme 47) .

Scheme 47

The use of selenium monochloride in reaction with 6-amino-1,4-diazepinium perchlorate led to an isoselenazole condensed with a diazepine ring (Scheme 48) . Compounds with a pyridine ring fused to an isoselenazolone moiety were obtained via two alternative routes. The first of them involves lithiation of the anilide 126 derived from nicotinic acid, the resulting dilithium salt subsequently

1,2-Selenazoles

Scheme 48

quenched with dimethyl diselenide to give selenide 127, which, treated with bromine followed by pyridine, yielded 7-azabenzisoselenazol-3(2H)-one 7 . A more versatile method is based on the selenenylation of the 2-chloronicotinic ester 128 to the diselenide 129, subsequently converted into dichloride 130 and then to the final products 7 by treatment with a primary aromatic or aliphatic amine (Scheme 49) .

Scheme 49

The 2-alkylthieno[2,3-d]isoselenazol-3(2H)-ones 13 were obtained by the treatment of 3,39-diselenobis(Nalkylthiophene-2-carboxamides) 131 with benzoyl peroxide in benzene under reflux. The exception was phenyl derivative 131 (R ¼ Ph) which proved too insoluble to react (Scheme 50) .

Scheme 50

4.07.10 Ring Syntheses by Transformations of Another Ring There are no reports on ring synthesis of nonfused isoselenazoles by transformation of another ring although two reactions afford 3-substituted benzisoselenazoles. On treatment first with bromine and then with ammonia, 1-benzoselenophene2,3-dione undergoes ring transformation to afford 3-carbamoylbenzisoselenazole (Scheme 51) .

781

782

1,2-Selenazoles

Scheme 51

The aforementioned cycloaddition of benzyne to 1,2,5-selenadiazole followed by extrusion of selenium, although of no synthetic value, is another example of ring transformation to isoselenazole (Scheme 28).

4.07.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available A variety of strategies have been developed for the synthesis of the isoselenazole ring, and the route selected depends on the substituents required and the availability of starting materials. For the synthesis of fully conjugated rings, the most useful and general method remains the formation of both Se–N and C–N bonds by addition to acrolein or other enones substituted at the 3-position with cyanoseleno or bromoseleno groups. The bromine leaving group can be easily introduced by the bromination of methylseleno or phenylseleno derivatives (see Section 4.07.9.1). Another approach to the synthesis of 3- and 5-substituted isoselenazoles is based on one-pot conversion of alkynic aldehydes or ketones to the oxime sulfonates followed by conjugate addition of potassium selenide, but this is less effective since low yields of the products are obtained particularly when aldehydes are substrates (Scheme 27). Benzisoselenazoles and their heterofused analogues can be obtained in a similar way as isoselenazoles from aromatic or heteroaromatic aldehydes or ketones substituted at the 2-position with a bromoseleno group (Schemes 34 and 46). The formation of quaternary isoselenazolinium salts is based on the formation of the Se–N bond by intramolecular reaction of an azomethine or amide group with a cyanoseleno or selenomethyl group under acidic conditions (Schemes 29 and 30). Elimination of hydrogen bromide from the appropriate open-chain precursors having amide or bromoseleno groups results in cyclization to isoselenazolidines (Schemes 32 and 33). In contrast to isoselenazoles, which have only a limited interest, much synthetic effort has been directed to the preparation of the very important benzisoselenazolone ring system. The most general and useful method is a tandem selenenylation–acylation of the primary amines with 2-(chloroseleno)benzoyl chloride, obtained in a four-step synthesis from anthranilic acid. The substrates are easily available, the procedure is simple, and the products are obtained from satisfactory to excellent yields, depending on the reactivity of the amino group of the substrate. A broad spectrum of 2-substituted benzisoselenazol-3(2H)-ones and their analogues having a pyridine ring instead of a benzene have been obtained in this way (Schemes 37–42 and 49). In situations where the nucleophilicity of the amino group is low, for example in amides or sulfonamides, the N-substituent can be introduced by treatment of the unsubstituted benzisoselenazol-3(2H)-one with acid chlorides in an alkaline medium. Another preparative route, particularly useful for synthesis of ebselen and its analogues substituted in the benzene ring, is based on the lithiation of the benzamides followed by the conversion of dilithium derivatives to the benzisoselenazolones by direct treatment with selenium or via 2-[(carbamoyl)phenyl]methyl selenides or 2-(carbamoyl)phenyl diselenides (Scheme 43). Diselenides are useful substrates for oxidative conversion to benzisoselenazolones, and, depending on the oxidant used, benzisoselenazol-3(2H)-ones or their 1-oxides are produced in high yields (Scheme 45).

4.07.12 Important Compounds and Applications 4.07.12.1 Oxygen-Transfer Catalysts A variety of organic compounds have been oxidized with a mixture of hydrogen peroxide or TBHP and catalytic amounts of selenium(IV) oxide, areneseleninic acids (ArSe(O)OH), or their precursors, the diaryl diselenides (ArSeSeAr). A range of bis(2-carbamoyl)phenyl diselenides 125 and benzisoselenazol-3(2H)-ones 3 also exhibit appreciable catalytic activity. Ebselen 3a (R ¼ Ph) and its open-chain analogue 125 (R ¼ Ph) were found to be the most effective oxygen-transfer agents . The similar catalytic activity of these two compounds is explained by a close relationship between them since the hydroperoxide oxidation of 125 gives 3 followed by 1-oxide and finally by hydroperoxyselenurane (see Scheme 6). Conversely, when 3 is treated with a reducing reagent, the C–N bond is cleaved and diselenides 125 are produced, as shown in Scheme 52.

1,2-Selenazoles

Scheme 52

The first experiments showed that ebselen did not promote the hydrogen peroxide oxidation of thiols such as N-acetylcysteine, butanethiol, and octanethiol , but later it was found that camphor-derived isoselenazol3(2H)-one 5 effectively catalyzed oxidation of phenylmethanethiol to the disulfide . More recently, several reactions were elaborated where ebselen and other benzisoselenazol-3(2H)-ones promoted hydroperoxide oxidation of organic compounds other than thiols. In the typical procedure, ebselen is used at 5 mol% while the stoichiometric oxidant is 30% hydrogen peroxide or 80% TBHP. Sulfides are exclusively oxidized to sulfoxides . Aromatic aldoximes oxidized in methanol gave methyl esters . Nitriles were produced by hydrogen peroxide oxidation of N,N-dimethylhydrazones or from primary benzylamines oxidized with TBHP, while secondary benzylamines gave nitrones 79 . The parent ketones 60 are regenerated from ketazines by oxidation with H2O2 (Scheme 53) .

Scheme 53

The first example of aromatization of a tetrahydropyridine ring by hydroperoxide is the dehydrogenation of 1,2,3,4tetrahydroisoquinoline to the isoquinoline with H2O2 or TBHP in the presence of ebselen . Cyclooctene treated with TBHP and ebselen gave the epoxide accompanied by trace amounts of 3-hydroxycyclooctene resulting from -hydroxylation . Aromatic aldehydes with electron-donating substituents were

783

784

1,2-Selenazoles

oxidized by hydrogen peroxide and ebselen almost exclusively to arenecarboxylic acids; the potentially competitive Baeyer–Villiger reaction to phenol formates was not seen . In contrast, when other catalysts, for example, selenium(IV) oxide, were employed, the acids were accompanied by the phenols, or even phenols were the sole products . The difference between the catalytic action of SeO2 and ebselen was explained by assuming that in the first case the reaction proceeded via peroxyseleninic acid [HOSe(O)OOH], while from ebselen the hydroperoxyselenurane 29 (Scheme 6) is formed and the reaction pathway is different . Although the reactions mentioned above have ionic mechanisms, some others, presented in Scheme 54, proceed via a free-radical mechanism. Oxidation of the benzylic methylene group in alkylarenes to a carbonyl group resulting in the formation of ketones 132 , oxidation of anthracene to anthraquinone as well as oxidative coupling of 2-aminophenol to phenazinone 133 support this assumption. Moreover, it was observed that the results of oxidation of 1,4-dimethoxy-2-methylnaphthalene to menadione 134 and conversion of the azine derived from 2-acetylpyridine to the triazene 135 with TBHP or H2O2 in the presence of ebselen are the same as when cerium(IV) ammonium nitrate (CAN) was the reagent . Since CAN is a well-known one-electron oxidant generating free radical and cation radicals, the ebselen participation in the mechanism involved such intermediates.

Scheme 54

The silica-supported benzisoselenazol-3(2H)-one 117 (Scheme 42) was used as a heterogenous catalyst for hydrogen peroxide oxidation of sulfides to sulfoxides and sulfones, alkylarenes to the ketones and aromatic aldehydes to the arenecarboxylic acids. It exhibited appreciable activity and the results were similar to these when ebselen was a homogenous catalyst. It can be recovered from the reaction mixture simply, and reused .

1,2-Selenazoles

4.07.12.2 Medicinal Agents The biochemistry and pharmacology of selenium-based compounds, among them selena-heterocycles having a selenenamide moiety, such as isoselenazolones, are the subject of intense current interest, especially from the point of view of public health. During the last few years, a tremendous effort has been directed to the synthesis of stable organoselenium compounds, including those with an isoselenazolone ring, which could be used as antioxidants, enzyme modulators, antitumoral, antiviral, and antimicrobial compounds, and cytokine inducers. Their recent pharmacological applications as therapeutic agents in the treatment of several diseases has been revealed in hundreds of papers and discussed in reviews .

4.07.12.2.1

Antioxidants and anti-inflammatory agents

Reactive oxygen species such as hydroxyl radicals, superoxide anion, and peroxynitrite are involved in many cellular processes including the inflammatory response. A prospective anti-inflammatory organoselenium compound is ebselen. It has undergone Phase III clinical trials as a neuroprotective agent and is soon to become the first synthetic organoselenium therapeutic released on the market. Ebselen acts as a GPx mimic by reducing hydroperoxides to water or the corresponding alcohol. The postulated mechanism of the biological action of ebselen is presented in Scheme 9 and discussed in Section 4.07.6.2 . Ebselen does not lose selenium from the molecule during the biotransformation, which probably accounts for its relative lack of toxicity . Ebselen is also able to catalytically reduce hydroperoxides through reaction with the thioreductase (Trx) system. Inflammatory enzymes known as the lipogenases (LOX) and cyclooxygenases (COX), activated by hydroperoxides, are attractive targets for inhibition in the pursuit of anti-inflammatories. The capacity for ebselen to act as an LOX inhibitor is critical to its anti-inflammatory activity. The inhibition of LOX by ebselen may be as a result of its antioxidant activity or through its direct interaction with the enzyme . The protective effects of ebselen against peroxynitriteinduced changes in plasma proteins and lipids were also reported . The GPx-like activity of ebselen can be altered by modifying its structure. It was observed that benzisoselenazol3(2H)-ones substituted at the 7-position with an electronegative group able to exert a nonbonding interaction with selenium showed higher activity than ebselen. The enhancement of the activity of 7-nitrobenzisoselenazol-3(2H)-one 136, and compounds 12a, 12b, and 137 relative to that of ebselen was ascribed to the Se O or Se N interactions. The lower activity of 12c was attributed to its poor solubility .

The efficacy of ebselen is somewhat limited by its low water solubility. In the pursuit of GPx mimics, -CDs with an ebselen moiety tethered to the primary ring were prepared. These compounds have excellent solubility and CD 62 (Scheme 19) displays GPx activity on a par with that of ebselen . Other GPx mimics with an Se–N bond but without the carbonyl group in the five-membered ring have been synthesized and studied for their activity. Although selenazoline 8 exhibited moderate GPx activity, N-substituted derivatives exhibited much lower activity compared with that of the parent compound. Introduction of a methylene group into the heterocycle enhanced the activity, and compound 138, containing a selenenamide moiety in a sixmembered heterocycle, is much more active than 8 . The camphor-derived isoselenazoline 5 also displays appreciable GPx-like activity . The sulfur analog of ebselen and benzoselenazolinones 139, which contain selenium and nitrogen atoms in the heterocycle but do not have any direct Se–N bonds, were devoid of GPx activity under a variety of conditions .

785

786

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4.07.12.2.2

Enzyme inhibitors

Ebselen and some of its derivatives were found to be potent inhibitors of mammalian 15-lipoxygenases (15-LOX) in the absence of thiols; ebselen is the most potent inhibitor among all the 15-LOX inhibitors known so far. Ebselen can selectively block the extracellular actions of 15-LOX. However, its inhibitory potency is drastically decreased in the presence of reduced glutathione (GSH). This may be due to the ability of GSH to react with ebselen via opening of the isoselenazole ring thereby forming a selenyl sulfide, which affects the 15-LOX only at higher concentrations. In the extracellular space, GSH is virtually absent and therefore it may not interfere with LOX inhibition. The selective inhibition of LOX-induced extracellular lipid peroxidation without affecting the intracellular LOX activity may therefore be important for anti-inflammatory activity . The inhibition studies on ebselen show that ebselen alters the geometry of the iron ligand sphere by forming an enzyme–ebselen complex. Therefore, an iron-complexing action other than reaction with free thiol groups is responsible for the inhibition of 15-LOX by ebselen . Ebselen and some other benzisoselenazol-3(2H)-ones, among them carboxyebselen 61 (Scheme 19) and two enantiomeric 2-(2-phenylethyl)benzisoselenazol-3(2H)-ones 3e, were reported to be inhibitors of constitutive endothelial nitric oxide synthase (ecNOS). The observed difference in the activity of the enantiomer (S)-3e, more active than ebselen, and less active (R)-3e was explained by stereospecific interactions between the inhibitor and the enzyme .

4.07.12.2.3

Antitumor agents

Despite very promising research, to date no synthetic organoselenium compounds are in clinical use as anticancer agents. Two prospective heterofused isoselenazoles 140 and 141 were tested against tumor growth in a mouse model. Both of them markedly inhibited the growth of P388 mouse leukemia at a dose of 100 mg/mouse/day without exhibiting any toxicity . The 2-phosphonoalkylbenzisoselenazol-3(2H)-ones 142 exhibited high inhibitory effect against human liver carcinoma BEL-7420 cells and human lung carcinoma PG cells .

1,2-Selenazoles

4.07.12.2.4

Anti-infective agents

The 7-azabenzisoselenazol-3(2H)ones 7 substituted at the 2-position with phenyl or alkyl groups, and the methiodides 143, were found in an antiviral assay in vitro to be strong inhibitors of cytopathic activity of herpes simplex type 1 virus (HSV-1) and encephalomyocarditis virus (EMCV), and more potent than ebselen. The minimal inhibitory concentration (MIC) was in a range 0.4–6.0 mg ml1. The vesicular stomatis virus (VSV) remained resistant toward tested selenium compounds, except active methiodide 144 .

The antibacterial activities of ebselen and several other benzisoselenazol-3(2H)-ones against Gram-positive and Gram-negative bacteria have been reported and it has been postulated that their activity in vitro is due to their reactivity with an essential thiol group . Ebselen and the p-chloro analogue 3 (R ¼ 4-ClC6H4) exhibited strong inhibitory activity against the growth of fungi Saccharomyces cerevisiae and Candida albicans strains . Several benzisoselenazol-3(2H)-ones were tested in vitro against pathogenic bacteria, yeasts, and filamentous fungi. The broadest spectrum of activity against tested microorganisms was observed for 2-methyl-7-azabenzisoselenazol-3(2H)-one 7 (R ¼ Me) having minimum inhibitory dose (MIC) values in the range 2.0–32.0 mg ml1. The biological response for the Gram-positive and Gram-negative bacteria and yeasts C. albicans was substantially stronger than that established for ebselen. The same compound 7 (R ¼ Me) was active against fungi strains Aspergillus niger, Penicillum chrysogenum, and Penicillum citrinum .

4.07.12.2.5

Cytokine inducers and immunomodulators

Cytokines such as interleukins (ILs), interferons (IFNs), and tumor necrosis factors (TNFs) are stimulants which play an important role in mammalian immunological systems. Ebselen, several other benzisoselenazol-3(2H)-ones, and related open-chain bis(2-carbamoyl)phenyl diselenides induce cytokines IL-2, IL-6, TNF-, and IFN- in human blood leucocytes (DBLs). Among the benzisoselenazol-3(2H)-ones, the highest activity was exhibited by ebselen, some 7-azabenzisoselenazol-3(2H)-ones 7 and the compounds 145. The cytotoxicity of most of the compounds tested was low and no correlation was observed between the cytotoxicity and cytokine-inducing activity . Several of these compounds have also been studied for their immunopharmacological activities in mouse, rat cells, and chickens. These studies suggest that the process of cytokine induction by organoselenium compounds is species specific. The drugs that were active in human DBL were found to be inactive in mouse, rat, and bovine cells .

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Biographical Sketch

Jacek Młochowski was born in Warsaw, Poland, in 1937. He studied chemistry at Wrocław University of Technology and completed his Ph.D. thesis on the chemistry of naphthalene and its sulfur analogues derived from coal tar under the supervision of Prof. B. Roga in 1967. In 1975, he completed his habilitation on the synthesis, structure, and reactivity of phenanthrolines. In 1983, he was nominated as a full professor. The main emphasis of his research lies in the development of new synthetic methods; in the last decade, the synthesis of organoselenium compounds as new enzyme mimics, biological response modifiers, and oxygen transfer agents has been his major interest. His work also involves mechanistic studies of the oxidation processes and applications of hydroperoxides in organic synthesis. More recent research topics include selenenylation of carbon and heteroatoms, synthesis of selenium- and nitrogen-containing heterocycles and hydroperoxide oxidation of organic substrates catalyzed by diselenides and selenenamides.

4.08 1,3-Selenazoles M. Koketsu and H. Ishihara Gifu University, Gifu, Japan ª 2008 Elsevier Ltd. All rights reserved. 4.08.1

Introduction

792

4.08.2

Theoretical Methods

792

4.08.3


792

4.08.3.1

X-Ray Diffraction

792

4.08.3.2

NMR Spectroscopy

795

4.08.3.2.1 4.08.3.2.2 4.08.3.2.3

1

H NMR spectroscopy C NMR spectroscopy 77 Se NMR spectroscopy

795 797 800

13

4.08.3.3

Mass Spectrometry

801

4.08.3.4

Infrared Spectroscopy

802

4.08.3.5


802

4.08.4


803

4.08.5


803

4.08.6


804

4.08.7


804

4.08.8

Reactivity of Substituents Attached to Ring Hetero Atoms

806

4.08.9


806

4.08.9.1

1,3-Selenazoles

4.08.9.1.1 4.08.9.1.2 4.08.9.1.3 4.08.9.1.4 4.08.9.1.5

4.08.9.2

806 807 808 809 809

4,5-Dihydro-1,3-selenazoles

4.08.9.2.1 4.08.9.2.2 4.08.9.2.3 4.08.9.2.4

4.08.9.3

806

Synthesis from selenoamides Synthesis from selenoureas Synthesis from selenazadienes Synthesis from isoselenocyanates Miscellaneous

810

Synthesis from selenoamides Synthesis from selenoureas Synthesis from selenoazadienes Miscellaneous

810 810 812 812

1,3-Selenazolidines

4.08.9.3.1 4.08.9.3.2 4.08.9.3.3 4.08.9.3.4

813

Synthesis from selenoureas Synthesis from isoselenocyanate Synthesis from potassium selenocyanate Miscellaneous

813 814 814 814

4.08.9.4

Benzoselenazoles

815

4.08.9.5

Selenazolopyridines

815

4.08.9.6

Selenapenams

816

4.08.10


816

4.08.11


817

791

792

1,3-Selenazoles

4.08.12 4.08.12.1 4.08.12.2 4.08.13

Important Compounds and Applications Dyes Medicinal Agents Further Developments

References

817 817 817 818 819

4.08.1 Introduction Selenazole 1 is a five-membered ring system containing selenium and nitrogen atoms in the 1- and 3-positions, respectively. 1,3-Selenazole chemistry mainly centers on 1,3-selenazole 1, 4,5-dihydro-1,3-selenazole 2, 1,3-selanazolidine 3, benzoselenazole 4, selenazolopyridine 5, selenapenam 6, and selenazoloquinoline 7. Previously, structure 2 was named 1,3-selenazoline, but this was not recommended by the IUPAC council in 1993.

The number of original articles on 1,3-selenazoles in the period of 1938–2005 is 317, with 86 articles in the decade, 1995–2005. In this chapter, recent progress on spectroscopy, reactivity, synthesis, and applications of 1,3-selenazole derivatives during 1995–2005 is discussed. Yearly progress is recorded in a series of reports .

4.08.2 Theoretical Methods Tautomerism of 4,5-dihydro-1,3-selenazoles substituted at positions 2 and 4 by hydroxy and amino groups has been studied using calculations at HF and MP2 levels of theory and nuclear magnetic resonance (NMR) spectroscopy. The relative stabilities of the tautomers of the heterocycles were calculated in the gas phase and in solvents such as CHCl3 and dimethyl sulfoxide (DMSO) utilizing the polarizable continuum model (PCM) method. The ab initio calculations, in agreement with the available experimental data, predict that selenazoles substituted at positions 2 and 4 by a hydroxy and with an amino group exist as the amino form in solution, while 2,4-diamino-1,3-selenazoles occur as mixtures of tautomers (Figure 1).

4.08.3 Experimental Structural Methods 4.08.3.1 X-Ray Diffraction Various crystal structures of selenazoles were reported . The bond angle at selenium in a selenazole ring is less than 90 . The bond angles at selenium of selenazoles 8–12 and 4,5-dihydro-1,3-selenazoles 13–16 are in

1,3-Selenazoles

Figure 1 Tautomers of disubstituted hydroxy/amino selenazoles.

the range 83–85 . Those of selenazolidines 17–23 are around 85–89 . The lengths of the C(2)–N(3) bond in selenazoles, 4,5-dihydro-1,3-selenazoles, and selenazolidines are in the range 1.336 0.04 A˚ which compare with ‘normal’ values of 1.47 A˚ (Table 1). Table 1 X-Ray diffraction measurements of selenazoles and related heterocycles

Compound

Bond angle ( ) C(5)–Se(1)–C(2)

˚ Bond length (A) Se(1)–C(2)

C(2)–N(3)

CCDC no.

Reference

83.95(11) 83.8(3) 84.41(12)

1.899(3) 1.889(5) 1.898(3)

1.330(3) 1.332(6) 1.313(4)

220759 272455 251944

2004S233 2006S31 2005JHC831

83.52(12)

1.899(3)

1.313(3)

251943

2005JHC831

84.6(2)

1.864(5)

1.300(6)

234082

2004CJI63

83.8(2)

1.945(5)

1.318(6)

191471

2003H(60)1211

(Continued)

793

794

1,3-Selenazoles

Table 1 (Continued)

Compound

Bond angle ( ) C(5)–Se(1)–C(2)

Bond length (A˚) Se(1)–C(2)

C(2)–N(3)

CCDC no.

Reference

83.63(11)

1.930(3)

1.326(4)

253133

2005ZN569 2005MI2371

83.24(9)

1.937(2)

1.349(3)

212984

2003H(61)569

83.90(16)

1.881(4)

1.280(5)

183223

2002J(P1)1568

85.47(10)

1.888(2)

1.326(3)

257366

2005BML1361

88.91(13)

1.907(3)

1.401(4)

172023

2002S195

89.4(3)

1.918(6)

1.348(7)

601464

2006CL626

88.2(7)

1.85(2)

1.30(2)

ND*

1997TA3903

(Continued)

1,3-Selenazoles

Table 1 (Continued) Bond angle ( ) C(5)–Se(1)–C(2)

Compound

a

Bond length (A˚) Se(1)–C(2)

C(2)–N(3)

CCDC no.

Reference

85.86(19)

1.983(4)

1.437(5)

164964

2001CC1336

87.87(19) 87.92(18)

1.882(4) 1.865(4)

1.367(5) 1.363(5)

183224

2002J(P1)1568

89.01(12)

1.964(3)

NDa

NDa

2000T5579

No information available.


H,

13

C, and

4.08.3.2.1

77

Se NMR spectra of 1,3-selenazoles were reported in the period 1995–2006.

1

H NMR spectroscopy

1

In H NMR spectra of 1,3-selenazole derivatives, the H-4 and H-5 signals of unsaturated 1,3-selenazoles 8–11, 24–30 are observed in the range of 6.7–8.4, whereas those of saturated 4,5-dihydro-1,3-selenazoles 31–35 and 1,3-selenazolidines 36–40 are in the range of 3.2–4.8 (Table 2). Table 2

1

H NMR data for selenazoles and related heterocycles 1

Compound

H chemical shifts ( ppm)

H-4 (H-2)

H-5

Reference

8.06 9.92 (H-2)

8.01

2005EJO3637

9.86 (H-2)

2003SL1195

(Continued)

795

796

1,3-Selenazoles

Table 2 (Continued) 1

Compound


H-4 (H-2)

H-5

8.75 0.07 (H-2)

7.15

Reference

1997T13667

7.04

2005CL1260

8.06

2002SL1983

8.38 0.23

1999RJO1377

6.74 0.36

2006HAC88

7.74 0.06

2004S233

7.88 0.14

2006S31

7.65 0.12

2005JHC831

7.63 0.03

2005JHC831

4.41 0.21

2001S731 2003HAC106

3.92 0.17

2005CL1260

(Continued)

1,3-Selenazoles


Compound


H-4 (H-2)

H-5

3.39

Reference

1998T2545

3.57

3.24

1998T2545

3.67

3.30 0.03

3.32 0.01

4.78 0.02

2005CL1260

3.71 0.04

2005EJO3128

3.84 0.12

2002S195

3.96 0.02

2006CL626

3.72 0.01

4.08.3.2.2 13

4.26 0.15

2006H(68)1607

4.27 0.05

2002JOC6275

13

C NMR spectroscopy

In the C NMR spectra of most 1,3-selenazole derivatives, the chemical shifts of C-2, C-4, and C-5 are generally observed at lower field in the order C-2, C-4, and C-5. The C-2 signals of 1,3-selenazoles are observed at the lowest field in the range 157–189 (Table 3). 13 C NMR chemical shifts of alkene carbons in 2-acylidene-3-methyl-2,3-dihydrobenzoselenazoles of known geometry were observed in the ranges 90–96 ppm (C-) and 162–167 ppm (C-) indicating appreciable charge polarization in these compounds as in other push–pull olefins (Table 4). The observed shifts were compared with those calculated according to the Pretsch scheme .

797

798

1,3-Selenazoles

Table 3

13

C NMR data for selenazoles and related heterocycles 13

C chemical shifts ( ppm)

Compound

C-2

C-4

C-5

Reference

159.3

143.9

124.6

2005EJO3637

176.7

155.2

119.2

1998T2545

170.1 0.23

142.4 3.21

129.9 0.34

2003S1215

164.0 0.45

149.1 0.46

120.1 0.84

2004S233

178.3 0.83

150.8 2.75

131.4 3.48

2006S31

175.4 2.0

153.0 0.16

115.9 0.36

2005JHC831

171.1 2.2

149.2 3.68

114.9 8.78

2006HAC88

176.5

142.4

36.2

2002S195

164.8

102.9

32.1

1998T2545

160.3

102.9

36.0

1998T2545

182.6 0.4

181.1 1.48

36.8 0.38

2005CL1260

(Continued)

1,3-Selenazoles


C chemical shifts ( ppm)

Compound

C-2

C-4

C-5

Reference

188.0 0.08

141.7 0.19

131.8 0.00

2002MOL320

165.6

138.3

134.8

2001MRC709

167.1

152.2

128.8

2001MRC709

157.1 1.9

147.8 0.10

130.8 0.44

2001MRC709

160.8 0.79

25.5 0.64

49.0 0.35

2005EJO3128

161.2 0.26

39.0 0.10

55.5 0.40

2006CL626

159.6 7.0

65.7 0.80

49.7 0.38

2001MRC739

160.5

68.2

50.5

1997TA3903

2002S195

173.8 1.9

144.6 5.88

33.7 9.05

166.9 2.2

110.4 0.33

135.5 1.37

2002JOC6275

799

800

1,3-Selenazoles

Table 4

13

C NMR data for 2-acylidene-benzoselenazoles

Compound

CTS

CTO

C-

C- (C-2)

C-C-

190.9 (196.5)

93.8 (107.6)

162.0 (144.4)

68.2 (36.8)

184.4 (187.0)

90.6 (107.6)

164.1 (144.4)

73.5 (36.8)

95.3 (93.3)

166.2 (139.7)

70.9 (46.4)

186.5 (188.2)

In CDCl3 solution. Calculated shifts are in parentheses.

4.08.3.2.3

77

Se NMR spectroscopy

77

Se NMR spectral data have been reported frequently. 77Se chemical shifts are expressed in ppm with respect to (CH3)2Se. Though the 77Se chemical shifts of selenazole derivatives are modified by different substituent groups at C-2, C-4, and C-5, a general trend has been recognized. In the case of saturated selenazoles, the 77Se chemical shifts are observed at lower field than those of 4,5-dihydro-1,3-selenazoles and 1,3-selenazolidines. The 77Se chemical shifts of the selenazoles with saturated rings are in the range of 520–765 ppm. In the case of 4,5-dihydro-1,3-selenazoles and 1,3-selenazolidines, they are observed in the ranges of 360–555 and 240–360 ppm, respectively. Selenazoles with more conjugated systems have 77Se chemical shifts at lower field (Table 5).

Table 5 Compound

77

Se NMR data for selenazoles and related heterocycles 77

Se chemical shifts ( ppm)

Reference

764.2 49.2

2003SL1195 2003HAC106

687.6 8.0

2003S1215

655.9

2001S731

528.5 5.5

2004S233

(Continued)

1,3-Selenazoles

Table 5 (Continued) Compound

77

Se chemical shifts ( ppm)

Reference

245.4

2001S731

554.8 1.1

2003H(60)1211

522.3 3.2

2003H(60)1211

506.5 84.9

2001S731 2003HAC106

416.6 2.4

2005CL1260

360.6 3.0

2002S195

357.6 61.1

2002S195

290.4 15.0

2004MOL466 2004OBC2612

240.0 19.2

2002S195

4.08.3.3 Mass Spectrometry The mass spectra of selenazoles 55 are characterized by cleavage of the 1,2- and 3,4-bonds. Following loss of aryl cyanide, Se is extruded to give an ene cation (Figure 2).

801

802

1,3-Selenazoles

Figure 2 Mass spectral fragmentation patterns of 1,3-selenazole.

4.08.3.4 Infrared Spectroscopy No discussions on infrared spectroscopy related to 1,3-selenazoles were found in the literature in the period 1995–2005.

4.08.3.5 Ultraviolet Spectroscopy The UV spectra of selenazole derivatives as solvatochromic dyes were measured. The color is mostly dark red. Absorptions (max) of the 5-(2-thienyl)-1,3-selenazole 56 and the 5-aryl-1,3-selenazole 57 are 462 and 409 nm, respectively. The corresponding selenophenes 58, 59 show absorption at 505 and 445 nm (Figure 3).

Figure 3 Typical UV/Vis absorption maxima of 1,3-selenazoles and selenophenes.

The UV spectra of selenazole, thiazoles, and thiophene derivatives as solvatochromic dyes were compared. Identically substituted compounds of the selenazole and thiazole series absorb at nearly the same wavelength (Figure 4). In contrast, the comparable compounds in the thiophene series absorb at about 40 nm longer wavelength. The spectral shift observed on going from a monomethine dye to an identically substituted trimethine dye has been studied. The shift is ca. 100 nm, nearly the same as going from a trimethine dye to a pentamethine .

Figure 4 Typical UV/Vis absorption maxima of 1,3-selenazoles and 1,3-thiazole methine dyes.

1,3-Selenazoles

4.08.4 Thermodynamic Aspects The photochromic reactions of long-chain derivatives of spirobenzoselenazopyran in monolayers on a water surface have been studied. Long-chain derivatives of spirobenzoselenazopyran and their colored merocyanine forms are shown in Figure 5. The photochromic reaction of MC ! SP in benzene solution proceeds at 0 C under photoirradiation, while in the dark and at 33–35 C the reverse thermal reaction, SP ! MC, proceeds. Introduction of a dimethylamino group gives a slightly fast rate for MC ! SP, whereas the long-chain ester on the chromene ring enhances the rate for the SP ! MC .

Figure 5 Long-chain derivatives of spirobenzoselenazopyran and their colored merocyanine forms together with the abbreviations.

4.08.5 Reactivity of Fully Conjugated Rings 2-Methylbenzoselenazole reacts with alkyl iodides to yield N-alkyl-2-methylbenzoselenazolium iodides 60 in acetonitrile (Equation 1) . 2-Methylbenzoselenazole perchlorate reacts with epichlorohydrin to give N-(3-chloro-2-hydroxypropyl)-2-methylbenzothiazolium perchlorate 61 (Equation 2) .

ð1Þ

ð2Þ

803

804

1,3-Selenazoles

The synthesis of N,N-disubstituted 2-amino-5-arylazo-4-phenyl-1,3-selenazoles 62 has been carried out by addition of 2-amino-4-phenyl-1,3-selenazole to an aryldiazonium salt, for example, an aryldiazonium tetrafluoroborate, in DMSO or in acetic acid (Equation 3) .

ð3Þ

4.08.6 Reactivity of Nonconjugated Rings No discussions on this reaction related to 1,3-selenazoles were found in the literature in the period 1995–2005.

4.08.7 Reactivity of Substituents Attached to Ring Carbon Atoms Alkylation of benzo-3H-1,3-selenazole-2-thione 63 in the presence of base and methyl iodide leads to 2-methylthiobenzo-1,3-selenazole. This could be rearranged to 3-methylbenzo-1,3-selenazole-2-thione using a catalytic amount of iodine at 200–220 C. 3-Methylbenzo-1,3-selenazole-2-thione was converted into 2-alkylthiobenzo-1,3-selenazolium salts in the presence of boron trifluoride diethyl etherate and triethyl orthoformate. These salts treated with sodium hydrogen selenide gave 3-methylbenzo-1,3-selenazole-2-selone 64 (Scheme 1). The reaction of 3-methylbenzo-1,3selenazole-2-thione 63 with 0.5 equiv of 1,2-dibromoethane afforded the S,S9-dialkylated product 16 together with a minor amount of the N,S-dialkylated derivative 65 (Equation 4) . Coupling of 3-methylbenzo-1,3selenazole-2-selone in the presence of triethyl phosphite in refluxing toluene afforded a diselenadiazafulvalene 66. The dicationic salt of benzodiselenadiazafulvalene is formed by treatment of 66 with AgBF4, together with a minor amount of spiroamide 21 which structure was determined by X-ray diffraction (Scheme 2) .

Se S N H

Se

Se

MeI, Et3N

SMe

CH2Cl 2, rt

N

I2 200–220 °C

Me

63 BF3 •Et 2O, HC(OEt) 3

Se

CHCl 3 , reflux

N

SR X Me

NaHSe EtOH, rt

S N

MeI reflux

Se SMe N

R = Me, Et X = I − , BF4−

Se Se N

64

Me

Scheme 1

ð4Þ

1,3-Selenazoles

Scheme 2

2-Methylenedihydrobenzo-3H-1,3-selenazole readily forms a dimer, benzodiselenadiazafulvalene. In order to avoid the formation of the dimer, the methylene compound was generated in situ by deprotection of 2-methylbenzazolium tetrafluoroborate 67 with sodium hydride in the presence of methanesulfonyl azide as a trapping reagent. The reaction gave the ring expanded 3-(sulfonylimino)benzoselenazine 68 via a [3þ2] cycloaddition and loss of nitrogen (Scheme 3) .

Se

Se

CH2

NaH

Me N

THF, 25 °C

Me

Me

BF4

67

O2S Se N

Me

O 2S

Me

Se

Se N

N N

N

MeSO2N3

N

N N

N

Me

1,2-shift of Se −N 2

N

NSO2 Me

Me

Me

68 Scheme 3

5-Selenazolyl fulgides, 2-[5-(4-methyl-2-aryl-1,3-selenazolyl)ethylidene]-3-isopropylidene succinic anhydrides 69, were prepared by reactions of 5-acetyl-1,3-selenazoles with diethyl succinate in alcohol (Scheme 4) . Me Se

Ar

O

COMe + Me

N Me

KOH

Me 3 COK

OEt

Bu t OH

Ar

OEt N

MeCOCl OH

N

Me

OH O Me O

O

Me

O

Se

Me Me

Se

Ar

Me Me Scheme 4

OEt

O Me

EtOH

Me

OH

Se

Ar N

O Me Me O

O

Me

69

805

806

1,3-Selenazoles

4.08.8 Reactivity of Substituents Attached to Ring Hetero Atoms 2-Alkylthio-selenazoles are alkylated on nitrogen using Meerwein salts to produce the corresponding 2-alkylthio-3methyl-1,3-selenazolium salts. The alkylthio group in these salts can be replaced with selenium using NaHSe to afford 3-methyl-1,3-selenazole-2-selenone 70 (Scheme 5) . Se

RS

Me

N CO2 Et

MeO3+ BF4 – CH2Cl2 or MeNO2 reflux

Se

RS BF4– Me

Me

N CO2Et

NaHSe CH3CN/EtOH

Se

Se

Me

N Me

CO2Et

70 Scheme 5

4.08.9 Ring Synthesis Classified by Number of Ring Atoms in Each Component 4.08.9.1 1,3-Selenazoles Syntheses of unsaturated 1,3-selenazole have been achieved mainly by reactions using selenating reagents such as selenoamides, selenoureas, selenazadienes, or isoselenocyanates. There is a review article which gives details .

4.08.9.1.1

Synthesis from selenoamides

Reactions of -bromoketones with primary selenoamides (Equation 5) or selenoformamide (Equation 6) afford 1,3selenazoles .

ð5Þ

ð6Þ

Synthesis of 2-unsubstituted 1,3-selenazoles 24 has been reported by reactions of selenoformamides with -bromoketones. Selenoformamides are prepared by the reaction of formamide with phosphorus selenide using ultrasound. Because of the unstable nature and volatility of 2-unsubstituted 1,3-selenazoles, the yields are relatively low, 6–28%. The cyclizations were achieved in the presence of either pyridine or an acidic ion exchange resin. The absence of base or the use of sodium acetate resulted in formation of considerable amounts of diphenacyl selenides (ArCOCH2)2Se (Scheme 6) .

Scheme 6

1,3-Selenazoles have been prepared by reactions using hypervalent iodine reagents. Condensation of -tosyloxyketones with primary selenoamides affords 1,3-selenazoles in a one-pot process (Equation 7) . Reactions of alkynyl(phenyl)iodonium salts with primary selenoamides give 1,3-selenazoles (Equation 8) .

1,3-Selenazoles

ð7Þ

ð8Þ

N,N-Disubstituted selenoureas react with -bromoesters, amides, nitriles, and bromomethyl aryl ketones to give the corresponding salts. Treatment of the salts with Et3N or NaH gives the corresponding 1,3-selenazoles (Scheme 7) .

Scheme 7

4.08.9.1.2

Synthesis from selenoureas

Condensation of selenourea [H2NC(TSe)NH2] with -haloketones affords 2-amino-1,3-selenazoles (Equation 9). 2-Amino-1,3-selenazole-5-carboxylates are available from the N-acyl-selenoureas by reactions with bromoacetic acid (Equation 10) .

ð9Þ

ð10Þ

A route to 1,3-selenazoles without the use of lachrymatory halo-carbonyl compounds has been developed. 2-Dialkylamino-1,3-selenazoles 30 can be synthesized by the reaction of selenoureas with ketones in the presence of ferric chloride (Equation 11) .

ð11Þ

N,N-Unsubstituted selenoureas reacted with ,-unsaturated ketones at both positions to carbonyl carbon to give two isomeric 2-dialkylamino-1,3-selenazoles 71, 72 in alcohol in the presence of ferric chloride at room temperature (Equation 12). Reactions of a selenourea with methyl vinyl ketone in methanol, n-propanol, i-propanol, and t-butanol also gave corresponding 5-(1-alkoxymethyl)-2-amino-1,3-selenazole derivatives 73 (Equation 13) .

807

808

1,3-Selenazoles

ð12Þ

ð13Þ

4.08.9.1.3

Synthesis from selenazadienes

Condensation of selenazadienes (1.0 equiv) with -haloketones (1.0 equiv) gives 5-acyl-2-amino-1,3-selenazoles 9 under reflux conditions (Equation 14). Reactions of selenazadienes (2.0 equiv) with 1,3-dichloro-2-propanone in the presence of triethylamine (3.6 equiv) gave the corresponding bis(2-amino-5-selenazolyl) ketones 74 at 50 C (Equation 15) .

ð14Þ

ð15Þ

Reactions of selenazadienes with chloroacetyl chloride (2 equiv) then alcohols or amines gave 2-amino-1,3-selenazole-5-carboxylates 8 or 2-amino-1,3-selenazole-5-carboxamides 10, respectively. The reaction is initiated by the nucleophilic displacement by selenium of chloride from the -position of the chloroacetyl chloride, eventually affording the 1,3-selenazole derivatives (Scheme 8) .

Scheme 8

1,3-Selenazoles

Similarly, reactions of selenazadienes with chloroacetonitrile give 2-amino-1,3-selenazole-5-carbonitriles 11 (Scheme 9) .

H Se R

N R1

Se

Et3N

Cl

N(CH3)2 +

N

N

R

reflux, 4 h

N R1

N N

Se

R1

–HNMe2

H

Se R

NMe2 Cl

R N

N

H

N

N R1

NMe2

N

N

11 Scheme 9

4.08.9.1.4

Synthesis from isoselenocyanates

A synthesis of 1,3-selenazoles using isoselenocyanates has been developed. Reactions of allenyl isoselenocyanate with carbon-, nitrogen-, oxygen-, or seleno-containing nucleophiles afford the corresponding 1,3-selenazoles . The allenyl isoselenocyanate reacts distinctly more slowly with the nucleophiles than the unusually reactive allenyl isothiocyanate (Scheme 10) .

EtO2C EtO2C

Se

Me

i, CH2(CO2Et)2, NaH ii, NH4Cl, H2O

C

N

THF, 20 °C, 2 h

HN

Se

NaH, Ph2Se2 THF 75 °C, 1.5 h 40 °C, 5 h 20 °C, 16 h then NH4Cl, H2O

C

Se

PhSe N

SePh

PhNH2 Se

PhNH

MeOH 60 °C, 24 h

Et2O, hexane 60 °C, 17 h

Me

N

Se

MeO

PhOH, Et3N Et2O, hexane 60 °C, 48 h

Me

Se

PhO

Me

N

N

Scheme 10

4.08.9.1.5

Miscellaneous

Synthesis of 1,3-selenazole derivatives has been achieved by reactions of dimethyl N-(ethoxycarbonylmethyl)iminodithiocarbonate with selenothioethanoic acid S-ester . Nucleophilic attack of the carbanion derived from dimethyl N-(ethoxycarbonylmethyl)iminodithiocarbonate at the CTSe group, followed by the elimination of n-butyl thiolate, affords an intermediate which forms the selenazole by intermolecular nucleophilic attack (Scheme 11) .

MeS SMe

Se

Bu OK or LDA

+ EtO2C

N

SMe

SBu

Me

N

THF, –78 °C –SBu–

Se

MeS –

–MeS

Me

N

Se

BuS +

CO2Et Scheme 11

SMe Se

t

Me

CO2Et

Me

N CO2Et

809

810

1,3-Selenazoles

4.08.9.2 4,5-Dihydro-1,3-selenazoles Syntheses of 4,5-dihydro-1,3-selenazole have been achieved mainly by reactions using selenoamides, selenoureas, or selenazadienes.

4.08.9.2.1

Synthesis from selenoamides

4,5-Dihydro-1,3-selenazol-4-one derivatives 31 are prepared by the reaction of primary selenoamides with -haloacyl halides in the presence of pyridine. The cyclization reaction is thought to involve an SN2 substitution reaction. Steric factors at the -position of the carbonyl carbon of -haloacyl halides slow the attack by selenium (Equation 16) .

ð16Þ

Reactions of primary selenoamides with dimethyl acetylenedicarboxylate afford 5-methoxycarbonylmethylene-4,5dihydro-1,3-selenazol-4-ones 75 (Equation 17). Reactions with acetylenedicarboxylic acid in ethanol give 4-ethoxy-4hydroxy-5-carboxymethylene-4,5-dihydro-1,3-selenazoles 76 (Equation 18) .

ð17Þ

ð18Þ

Michael addition of primary selenoamides to ethyl 2-bromo-2-cyclopropylideneacetate and then intramolecular substitution gave 5-spirocyclopropane-annulated 4,5-dihydro-1,3-selenazole-4-carboxylates 77 (Equation 19) .

ð19Þ

Reaction of primary selenoamides with 1,2-diaza-1,3-butadienes affords 4,5-dihydro-1,3-selenazole-5-carboxylates 78. Upon treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), compounds 78 afford methyl 4-methyl-2phenyl-1,3-selenazole-5-carboxylates 79, whereas the same treatment of 80 does not result in any formation of 79, suggesting that the aromatization process involves an anti elimination of the hydrazine moiety (Scheme 12) .

4.08.9.2.2


Reaction of an N,N-unsubstituted selenourea with chloroacetonitrile in aqueous ethanol affords 2-amino-4,5-dihydro1,3-selenazol-4-iminium chlorides 35 via selenocarboimidate hydrochlorides. Reaction in anhydrous solvent gave only the selenocarboimidate hydrochlorides, whilst reaction in aqueous ethanol proceeded through to the cyclization step to give 35 (Scheme 13) .

1,3-Selenazoles

Scheme 12

Scheme 13

Reaction of N,N-unsubstituted selenoureas with a 1,2-diaza-1,3-butadiene affords 2-amino-4,5-dihydro-1,3-selenazol-4ones 81 mainly in the hydrazono form. The reaction proceeds via nucleophilic addition of the selenium atom to the terminal carbon atom of the heterodiene. The subsequent intramolecular nucleophilic attack by the imidic NH at the carboxylate group with the loss of methanol leads to the selenazole ring closure (Scheme 14) .

Scheme 14

Reaction of selenourea with dialkyl acetylenedicarboxylates affords 2-amino-4,5-dihydro-1,3-selenazol-4-ones 82 via 1:1 adducts in acetone solution or in solvent-free conditions. The reaction proceeds stereoselectively to afford the (Z)-stereoisomer (Scheme 15) .

Scheme 15

811

812

1,3-Selenazoles

4.08.9.2.3

Synthesis from selenoazadienes

Hetero Diels–Alder reactions of selenazadienes with dimethyl acetylenedicarboxylate yield 4-selenazolones 13, 53. Interestingly, the reaction does not give the expected Diels–Alder adduct but instead a separable mixture of E/Z isomers of a 4-selenazolone 13, 53 is obtained (Scheme 16) .

Scheme 16

Dimethylsulfoxonium methylide reacts with N-selenoacylamidines to give 4,5-dihydro-1,3-selenazoles 33. The reaction pathway involves the addition of the sulfur ylide to the imine bond of the heterodienes, and then cyclization by a subsequent intramolecular substitution of the dimethylsulfoxonium leaving group (Scheme 17) .

Scheme 17

4.08.9.2.4

Miscellaneous

The reaction of aromatic and aliphatic aldehydes with (Me2Al)2Se in the presence of anthracene gives the [4þ2] cycloadducts 83. Thermally generated selenoaldehydes from 83 react with 5-ethoxyoxazoles to afford 3-selenazolines 84 as a mixture of diastereomers (Scheme 18) .

O R

Se

(Me2Al)2 Se H

R

H

100 °C

Se

R

83 O

Ph

toluene

R

OEt

N

Se

R1

H

160 °C

R1

Se

EtO2C N Ph

84 Scheme 18

R

1,3-Selenazoles

4.08.9.3 1,3-Selenazolidines Syntheses of saturated 1,3-selenazoles have been carried out by reactions using selenating reagents such as selenoureas, potassium selenocyanate, selenium and carbon monoxide or selenocysteine.

4.08.9.3.1


2-Imino-1,3-selenazolidin-4-one derivatives 37 were synthesized by the reaction of N,N9-disubstituted selenoureas with -haloacyl halides in the presence of pyridine in excellent yields (88% – quantitative) (Equation 20). Reaction of an N,N-unsubstituted selenourea gives 2-amino-4,5-dihydro-1,3-selenazolidin-4-one 32 in low yield (29%) (Equation 21) .

ð20Þ

ð21Þ

2-Imino-5-methyl-1,3-selenazolidine derivatives 38 were obtained by the reaction of N-allylselenoureas with hydrogen chloride in excellent yields (81% – quantitative) (Equation 22). The driving force, in this case, is the formation of the more stable carbonium ion. This behavior is in agreement with the cyclization of imidates, amides, and carbonates, which afford five-membered heterocyclic rings exclusively. Treatment of N-allylselenoureas with hydrogen chloride affords preferentially 2-imino-5-methyl-1,3-selenazolidines through 5-endo closure, whereas treatment with iodine gives preferentially 2-amino-5-iodo-4H-5,6-dihydro-1,3-selenazines through a 6-exo closure (Equation 23) .

ð22Þ

ð23Þ

Selenourea alkylated by -bromoesters in the presence of pyridine affords 5-aryl-2-imino-1,3-selenazolidin-4-ones 85, 1H NMR spectra in DMSO-d6, confirming that the compounds are in the imino form (Scheme 19) .

Scheme 19

813

814

1,3-Selenazoles

4.08.9.3.2

Synthesis from isoselenocyanate

One-pot synthesis of 2-imino-5-methylene-1,3-selenazolidines was achieved by reactions of alkyl isoselenocyanates with propargylamines in high yields (Equation 24) .

ð24Þ

4.08.9.3.3

Synthesis from potassium selenocyanate

2-Imino-1,3-selenazolidines have been prepared using potassium selenocyanate; thus, 2-imino-1,3-selenazolidines 86, 87 resulted from reactions of O-methanesulfonyl -amino alcohol hydrochlorides. The products retained the chirality introduced by the amino alcohol fragment (Equations 25 and 26) . + – NH3Cl R

R OMs

+

KSeCN

pyridine H2O 80 °C

Se

HN

R

ð25Þ

HN

86

R

ð26Þ

4.08.9.3.4

Miscellaneous

5-Alkylideneselenazolidin-2-ones 88 have been prepared by reaction of 3-aminoalkynes with selenium and carbon monoxide in the presence of DBU, stereoselectively via cycloaddition of in situ generated carbamoselenoates to the carbon–carbon triple bond (Scheme 20) .

Scheme 20

2-Oxoselenazoline-4(R)-carboxylic acid 89 and 2(R,S)-methylselenazolidine-4(R)-carboxylic acid 90 were prepared from selenocysteine. Selenocysteine is prepared by reduction of selenocystine using sodium borohydride. Reaction of selenocysteine with 1,19-carbonyldiimidazole affords 2-oxoselenazoline-4(R)-carboxylic acid 89 and reaction with acetaldehyde gives 2(R,S)-methylselenazolidine-4(R)-carboxylic acid 90 (Scheme 21) .

Scheme 21

1,3-Selenazoles

1,3-Selenazole derivatives have been prepared from 6-methyl-3-propargylseleno-1,2,4-triazin-5-one via coppercatalyzed, or silica gel and thionyl chloride-catalyzed, cyclization. The reaction affords two kinds of selenazole derivatives 91, 92 in moderate yields. No cyclization takes place in the absence of the catalyst (Equation 27) .

ð27Þ

3,6-Dimethyl-7H-selenazolo[3,2-b][1,2,4]triazin-7-one 93 was prepared in the presence of triethylamine and sodium methoxide (Equation 28). Compound 93 can also be synthesized by reaction of 94 with bromoacetone in the presence of sodium carbonate (Equation 29) .

ð28Þ

ð29Þ

4.08.9.4 Benzoselenazoles 3H-Benzoselenazole-2-thione 63 is obtained by a four-step procedure starting from o-nitroaniline . Reaction of potassium selenocyanate with the diazonium salt yields o-nitrophenyl selenocyanate. Treatment of the o-nitrophenyl selenocyanate with sodium in ethanol affords bis(o-nitrophenyl) diselenide. The in situ reduction of this with sodium hydrosulfide gives an intermediate o-aminobenzeneselenoate, which cyclizes with carbon disulfide in basic medium, work-up giving 3H-benzoselenazole-2-thione 63 (Scheme 22). NO2 NH2

BF3 •Et 2O, But ONO

NO2

CH2Cl2 , –15 °C

N2+

NO2

KSeCN H2O, 0 °C

SeCN

BF – 4

Na EtOH, rt

NO2 Se

O2N

Se NaHS, CS2

S

Se

N H

63 Scheme 22

Various aspects of benzoselenazole chemistry have been reviewed .

4.08.9.5 Selenazolopyridines Selenazolopyridines 96 are obtained by using isoselenocyanates. Heating a solution of aryl isoselenocyanates and 3-amino-2-chloropyridine in 2-propanol under reflux leads to the formation of 2-arylaminoselenazolo[5,4-b]pyridine hydrochlorides 95, the free bases 96 being liberated with aqueous NaOH (Scheme 23).

815

816

1,3-Selenazoles

Cl N C Se Ar

N

+

reflux

H2N

Se HN Ar

N

95

HCl N

Cl Se

Pr i OH Ar

N H

Se HN Ar

N H

Se

NaOH (5–6%) –HCl

Cl

N

HN Ar

N

N H

N

N

96

Scheme 23

4.08.9.6 Selenapenams The antibacterial effect of penicillin was discovered by Alexander Fleming in 1929. The extensive use of -lactam antibiotics such as penicillin has saved thousands of lives but also created major resistance problems in hospitals and in the community worldwide, leading to increased morbidity, mortality, and healthcare costs. The conversion of penicillin into penam has been extensively investigated in order to overcome the drug resistance. Two approaches to selenopenams, selenium analogs of the penam, including a selenazole skeleton, have been reported. Synthesis of selenopenams starts with commercially available 4-acetoxy-2-azetidinone derivatives which are reacted with sodium benzylselenoate, prepared by treatment of dibenzyl diselenide with sodium borohydride, to give 4-(benzylseleno)-2-azetidinones 97. The radical precursor 98 prepared from 97 was irradiated or heated, and the selenopenams 99 were thus obtained (Scheme 24) .

Scheme 24

Another synthesis started from oxazolidinone 96 in reaction with selenoketones. Thermolysis of 100 with selenoketones gave the corresponding racemic selenopenams 23 in moderate yields (25–37%) in one step (Equation 30) .

ð30Þ

4.08.10 Ring Syntheses by Transformations of Another Ring No transformations in this category were reported in the decade 1995–2005.

1,3-Selenazoles

4.08.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available Selenazoles are generally prepared via the [3þ2] route using the Hantzsch method. There are a few reports regarding synthesis of selenazoles by intramolecular cyclization of selenourea derivatives with acid, base, or catalyst (Schemes 7 and 17, Equations 22, 23, and 27–29). Reactions of allenyl isoselenocyanate with nucleophiles give corresponding selenazoles (Scheme 10). The [4þ1] route using selenocysteine affords selenazoles (Scheme 21). Reaction of 3-aminoalkynes with elemental selenium and carbon monoxide gives 4-selenazolidinones (Scheme 20).

4.08.12 Important Compounds and Applications 4.08.12.1 Dyes A benzoselenazole derivative is used as a DNA marker dye in a method for the diagnosis of malaria by stained chromatin and fluorescence (Figure 6). The molecule consists of two parts, the purine portion which is mainly involved in complexation with the DNA and the benzoselenazole part which provides not only the anchoring to the phosphate of the DNA, but also extends the p-electron system which characterizes the molecule in term of electronic properties .

Figure 6 Benzoselenazole derivative as a DNA marker dye.

Some selenazole derivatives have been developed as solvatochromic dyes (Figure 7).

Figure 7 Selenazole derivatives as solvatochromic dyes.

4.08.12.2 Medicinal Agents Some selenazole derivatives have been reported with medicinal properties. Nitric oxide (NO), an important bioregulator and ubiquitous biomessenger in a wide variety of organisms, is produced by oxidation of L-arginine catalyzed by inducing nitric oxide synthase (iNOS). Excessive production of NO has been implicated in the pathogenesis of many diseases involving neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. A potential therapeutic strategy for reducing neuronal cell injury or death in neurogenerative diseases is to identify inhibitors of iNOS induction resulting in decreased NO production. 1,3-Selenazol-4-ones 101, 102 , 2-imino-1,3-selenazolidines 104 , and 2-amino-4,5-dihydro-1,3selenazoles 105 show inhibitory activities against iNOS. Compound 103 also shows an inhibitory effect on mushroom tyrosinase which is the key enzyme in the undesirable browning of fruits, vegetables, and coloring of skin in animals.

817

818

1,3-Selenazoles

Se

p-MeC6H4

R R1

N R R1

O

Se

HN

Et

HN

Se

H2N N

Me

104

105

101 Et Me 102 H Me 103 H H Some antioxidative enzymes/substances, such as superoxide dismutases (SODs), catalase, glutathione peroxidases (GPXs), and certain vitamins (vitamin C and E), act as reactive oxygen species (ROS) scavengers since they quench ROS such as superoxide anion (O2?), hydrogen peroxide (H2O2), and hydroxyl radical (HO?). Ebselen is a fivemembered ring selenium-containing heterocyclic compound showing glutathione peroxidase-like activity. The antioxidative effects of ebselen are also attributed to its selective inhibition of leukocyte infiltration and activation, leading to attenuation of the H2O2 concentration in vitro. Thus, ebselen may be a multifunctional antioxidant and a potential chemopreventive agent in inflammation-associated carcinogenesis. 2-Amino-1,3-selenazoles 106, 107 and 1,3-selenazolidine-4-carboxylic acid derivatives 108–110 have superoxide anion-scavenging activities showing glutathione peroxidase-like activity in vitro .

5-Arylamino- and 6-arylthio-4,7-dioxobenzoselenazoles 111 were synthesized and tested for antifungal activity against Candida and Aspergillus species in vitro. 5-Arylamino-4,7-dioxobenzoselenazoles show, in general, more potent antifungal activity than 6-arylthio-4,7-dioxobenzoselenazoles .

4.08.13 Further Developments Recently, syntheses of 1,3-selenazoles using selenoureas and ability of 1,3-selenazoles as medicinal agents have been reported. N,N-Unsubstituted selenoureas reacted with ,-unsaturated aldehydes or acetylenedicarboxylate to give 2-amino-1,3-selenazoles or 2-amino-4,5-dihydro-1,3-selenazol-4-ones, respectively . Furthermore, reactions of selenoureas with -bromo ketones have been carried out in water as solvent using -cyclodextrin to give 2-amino-1,3-selenazoles . As medicinal agents, 2-(4-methylphenyl)-1,3-selenazol-4-one induced apoptosis in a human ovarian cell line (SKOV3) and a human leukemia cell line (HL-60) . 5-Chloroacetyl-1,3-selenazoles induced activation of mitogen-activated protein (MAP) kinase and Akt in PC12 cells, which resulted in neuronal differentiation and suppression of serum deprivation-induced apoptosis, respectively .

1,3-Selenazoles

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819

820

1,3-Selenazoles

2005BML1361 2005CL1260 2005CPB1439 2005EJO3128 2005EJO3637 2005JHC831 2005MI2371 2005PHC227 2005PS1045 2005PS2439 2005TL233 2005ZN569 2006CL626 2006H(68)1607 2006H(68)2145 2006H(68)2627 2006H(68)2647 2006HAC88 2006JCB807 2006S31 2007BBRC360 2007JHC231 2007JOC1849

S. Ueda, H. Terauchi, K. Suzuki, A. Yano, M. Matsumoto, T. Kubo, H. Minato, Y. Arai, J. Tsuji, and N. Watanabe, Bioorg. Med. Chem. Lett., 2005, 15, 1361. M. Koketsu, H. Tanaka, and H. Ishihara, Chem. Lett., 2005, 34, 1260. A. Sekiguchi, A. Nishina, H. Kimura, R. Fukumoto, K. Kanoh, H. Ishihara, and M. Koketsu, Chem. Pharm. Bull., 2005, 53, 1439. G. L. Sommen, A. Linden, and H. Heimgartner, Eur. J. Org. Chem., 2005, 3128. H. Below, W.-D. Pfeiffer, K. Geisler, M. Lalk, and P. Langer, Eur. J. Org. Chem., 2005, 3637. M. Koketsu, M. Imagawa, T. Mio, and H. Ishihara, J. Heterocycl. Chem., 2005, 42, 831. A. Ramazani, E. Ahmadi, B. Ganjeie, A. R. Kazemizadeh, and A. Morsali, Asian J. Chem., 2005, 17, 2371. Y.-J. Wu, U. Velapanthi, and B. V. Yang, Prog. Heterocycl. Chem., 2005, 17, 227 and Previous Chapters 5.5 in this series. M. Segi, A. Zhou, and M. Honda, Phosphorus, Sulfur Silicon Relat. Elem., 2005, 180, 1045. A. Ramazani, A. Morsali, B. Ganjeie, A. R. Kazemizadeh, and E. Ahmadi, Phosphorus, Sulfur Silicon Relat. Elem., 2005, 180, 2439. S. Ueda, H. Terauchi, K. Suzuki, and N. Watanabe, Tetrahedron Lett., 2005, 46, 233. A. Ramazani, A. Morsali, B. Ganjeie, A. R. Kazemizadeh, E. Ahmadi, R. Kempe, and I. Hertle, Z. Naturforsch, 2005, 60b, 569. M. Koketsu, T. Kiyokuni, T. Sakai, H. Ando, and H. Ishihara, Chem. Lett., 2006, 35, 626. M. Koketsu, T. Sakai, T. Kiyokuni, D. R. Garud, H. Ando, and H. Ishihara, Heterocycles, 2006, 68, 1607. M. Koketsu, K. Kanoh, and H. Ishihara, Heterocycles, 2006, 68, 2145. M. Koketsu, K. Kanoh, and H. Ishihara, Heterocycles, 2006, 68, 2627. M. Koketsu, K. Kanoh, and H. Ishihara, Heterocycles, 2006, 68, 2647. M. Koketsu, K. Kanoh, H. Ando, and H. Ishihara, Heteroatom Chem., 2006, 17, 88. H. J. Ahn, M. Koketsu, E. M. Yang, Y. M. Kim, H. Ishihara, and H. O. Yang, J. Cell. Biochem., 2006, 99, 807. M. Koketsu, M. Kogami, H. Ando, and H. Ishihara, Synthesis, 2006, 31. A. Nishina, A. Sekiguchi, R. Fukumoto, M. Koketsu, and S. Furukawa, Biochem. Biophys. Res. Commun., 2007, 352, 360. M. Koketsu, T. Sasaki, H. Ando, and H. Ishihara, J. Heterocycl. Chem., 2007, 44, 231. M. Narender, M. S. Reddy, V. P. Kumar, V. P. Reddy, Y. V. D. Nageswar, and K. R. Rao, J. Org. Chem., 2007, 72, 1849.

1,3-Selenazoles

Biographical Sketch

Mamoru Koketsu received his Ph.D. in 1995 at the Graduate School of Bioresources, Mie University. In 1997 he moved to his current position at Faculty of Engineering, Gifu University. In 2003 he became an associate professor in the Life Science Research Center, Gifu University. Within this period, he worked in the University of Iowa (Iowa, USA) as a visiting assistant professor (1999–2000).

Hideharu Ishihara graduated from the Faculty of Engineering, Gifu University in 1965, and continued his research as an assistant professor. He received his Ph.D. in 1979 at the Graduate School of Engineering, Tokyo Institute of Technology (Prof. Turuaki Mukaiyama). In 1991 he became a professor in the Faculty of Engineering, Gifu University. Within this period, he was chief of the Instrumental Analysis Center (1997–2001). He is Emeritus Professor, Gifu University.

821

4.09 1,2-Dioxoles and 1,2-Oxathioles R. A. Aitken and L. A. Power University of St. Andrews, St. Andrews, UK ª 2008 Elsevier Ltd. All rights reserved. 4.09.1

Introduction

824

4.09.2

Theoretical Methods

824

4.09.3


824

4.09.3.1

X-Ray Diffraction

824

4.09.3.2

NMR Spectroscopy

825

4.09.3.2.1 4.09.3.2.2

4.09.3.3

Proton NMR Carbon-13 NMR

825 826

Circular Dichroism

826

4.09.4


827

4.09.5

Reactivity of 1,2-Dioxoles and 1,2-Oxathioles

827

4.09.5.1

Introduction

4.09.5.2

Unimolecular Reactions

827

4.09.5.3


827

Cycloaddition Reactions

828

4.09.5.4 4.09.6

827

Reactivity of 1,2-Dioxolanes and 1,2-Oxathiolanes

828

4.09.6.1

Introduction

828

4.09.6.2


828

4.09.6.3


829

4.09.6.4

Nucleophilic Attack at Oxygen

829

4.09.6.5


829

4.09.6.6


830

4.09.7


831

4.09.8


831

4.09.9

Ring Synthesis

831

4.09.9.1

One-Bond Formation between Heteroatoms

831

4.09.9.2

One-Bond Formation Adjacent to a Heteroatom

833

4.09.9.3

One-Bond Formation Remote from Heteroatoms

834

4.09.9.4

Two-Bond Formation from [4þ1] Atom Fragments

834

4.09.9.5


834

4.09.10

Ring Synthesis by Transformation of Other Heterocyclic Rings

836

4.09.10.1

Three-Membered Rings

836

4.09.11

Best Methods of Synthesis

836

4.09.12

Applications

836

4.09.13


837

References

837

823

824

1,2-Dioxoles and 1,2-Oxathioles

4.09.1 Introduction Since the publication of the corresponding chapter in CHEC-II(1996) the few developments in the chemistry of 1,2-dioxoles have involved the fully saturated 1,2-dioxolanes 1 and in one case the 1,2-dioxolan-3ones 2. There have been more advances in the chemistry of 1,2-oxathiole systems including the fully saturated 1,2oxathiolanes 3 and the synthesis of 1,2-oxathiolium salts 4 has been reviewed . The majority of studies, however, have involved S-oxidized species including 5H-1,2-oxathiole 2-oxides 5 and 2,2-dioxides 6, the benzo derivatives 7 and 8, the fully saturated 1,2-oxathiolane 2-oxides 9 and 2,2-dioxides 10, the oxathiolanone dioxides 11, and the 2,1-benzoxathiol-3-one 2,2-dioxides 12. A review of the synthesis and properties of sultines including compounds 9 has appeared . There have also been significant developments in the chemistry of various 4-1,2-oxathiole systems such as the sulfuranes 13 and the derived sulfonium salts 14 as well as spiro sulfuranes containing the structures 15, 16, and 17.

4.09.2 Theoretical Methods There has been little work in this area but the intramolecular Diels–Alder reaction of furan-tethered vinyl sulfinates has been modeled using density functional theoretical methods on compound 18 . Calculations at the B3LYP level using 6-31G and 6-31G-(d) basis sets gave the activation energies and product energies shown for the four possible stereoisomeric products, relative to the starting material.

4.09.3 Experimental Structural Methods 4.09.3.1 X-Ray Diffraction The X-ray structures of the highly hindered 1,2-dioxolane 19 and the fluorinated dioxolanediol 20 as its 1,4-dioxane adduct have both been reported.


˚ indicating partial double bond The structure of the chiral sulfonium salt 21 has an S–O bond length of 1.598(8) A, character with a pyramidal geometry around sulfur . The structure of the enantiomerically-pure benzoxathiole S-oxide 22 has also been determined as has that of the tricyclic oxathiolane oxide 23 . Structure determinations of the chiral oxathiolane S,S-dioxide 24 and the ironcontaining oxathiole S,S-dioxide 25 have also been reported. The spiro sulfuranes 26 and 27 both show significant coordination of the N-acetyl oxygen to the sulfur center . The structures of the chiral spiro sulfuranes 28 both have an essentially trigonal bipyramidal geometry around the sulfur center with the two SO bonds in apical positions as shown . The structures of the spiro sulfuranes 29, 30, and 31 as well as the related salt 32 all exhibit the same pattern .

4.09.3.2 NMR Spectroscopy 4.09.3.2.1

Proton NMR

There has still been no systematic study of the patterns of NMR shifts in systems of this type. A compilation of new data is presented in Table 1.

825

826


Table 1 Proton NMR data for some 1,2-dioxolane and 1,2-oxathiole and oxathiolane derivatives H

4.09.3.2.2

Compound

H-3

H-4

H-5

Reference

6 21 22 24 31 33 34 35 36 37 38 39 40

7.08 4.21, 4.69

6.62

4.54

2.56, 2.79

5.12 5.05 5.45, 5.95 4.78 4.39

1997CC611 1998JOC5265 2005JOC5020 2003EJO3939 1997J(P2)1045 2005TL2757 1998JA4861 1997JOC7021 1997JOC7021 1998JOC5265 2003EJO3939 1998OM5534 1998OM5534

2.85 2.99 5.32 3.94 4.57, 4.69 4.58 3.01, 3.40 3.01, 3.40

4.60

4.34 2.58, 2.80 2.61 2.61

5.45 6.25

Carbon-13 NMR

There has still been no systematic study of the patterns of 13C NMR shifts in most systems of this type. A compilation of new data is presented in Table 2.

4.09.3.3 Circular Dichroism The circular dichroism behavior of the chiral benzoxathiole S-oxide 22 has been measured and used to correlate its absolute configuration with that of the corresponding benzoxaselenole Se-oxide. It gives [] values of 185 at 589 nm and 368 at 435 nm (both c 0.522 in i-PrOH) with a positive Cotton effect of [] ¼ 1.32 104 at 232 nm for the (R) enantiomer .


Table 2 Carbon-13 NMR data for some 1,2-dioxolane and 1,2-oxathiole and oxathiolane derivatives H Compound

C-3

C-4

C-5

Reference

6 21 24 33 34 35 36 37 38 41 42 43 44

137.3

123.9

63.3 173.89 73.8 87.4 51.7

37.6 41.19 59.0 161.1 200.7

61.7 62.7 66.6

41.4 29.7 30.1 43.3 44.3

72.5 105.0 77.4 87.32 90.9 84.0 95.4 100.4 86.0 75.3 74.7 86.7 84.1

1997CC611 1998JOC5265 2003EJO3939 2005TL2757 1998JA4861 1997JOC7021 1997JOC7021 1998JOC5265 2003EJO3939 1998TL991 1998TL991 1998TL991 1998TL991

4.09.4 Thermodynamic Aspects Very little new data in this category have been published but 5H-1,2-oxathiole 2,2-dioxide 6 has been reported to have an mp of 81–83 C .

4.09.5 Reactivity of 1,2-Dioxoles and 1,2-Oxathioles 4.09.5.1 Introduction There has been only limited progress in this area and new developments are confined to reactions of 1,2-oxathiole 2-oxides and 2,2-dioxides , which include thermolysis, reaction with nucleophiles and cycloaddition.

4.09.5.2 Unimolecular Reactions Thermolysis of the benzoxathiole S,S-dioxides 45 provides a convenient method for generation of o-quinone methides for cycloaddition. The reaction was performed in boiling o-dichlorobenzene at 180 C with a variety of substituted maleimides 46 to give the adducts 47 (Equation 1) .

ð1Þ

4.09.5.3 Nucleophilic Attack at Carbon Treatment of the 1,2-oxathiole 2-oxides 48 with Me2CuLi results in nucleophilic displacement of the iron by a methyl group to give 49 (Equation 2) and the corresponding oxathiole S,S-dioxide 50 undergoes a similar reaction to afford 51 while reaction with perchloric acid gives 52 (Equation 3) . Compounds analogous to 48 but with Ph3P(CO)4Mn in place of Cp(CO)2Fe have also been prepared but attempts to remove the metal in these cases failed.

827

828


ð2Þ

ð3Þ

The reactivity of the cyclic sulfonic–carboxylic anhydride 12 toward ring opening with anilines to afford 53 has been examined in detail (Equation 4) .

ð4Þ

4.09.5.4 Cycloaddition Reactions The ready availability of 5H-1,2-oxathiole 2,2-dioxide 6 following publication of an improved synthesis has led to a detailed study of its cycloadditions both with Diels–Alder dienes and 1,3-dipoles. Reaction with dienes gives products such as 54 and 55 while a variety of nitrile oxides give products 56 and nitrones give products 57 .

4.09.6 Reactivity of 1,2-Dioxolanes and 1,2-Oxathiolanes 4.09.6.1 Introduction Apart from photolysis of 1,2-dioxolanes, most studies in this section involve S-oxidized 1,2-oxathiolane derivatives, although the remarkable reactivity of the 1,2-oxathiolane 34 is notable. The reactivity of 1,2-oxathiolane 2-oxides is covered in a review on the properties of sultines .

4.09.6.2 Unimolecular Reactions The triaryl dioxolanes 58 undergo isomerization to give the hydroxy ketones 59, in addition to fragmentation products, when they are photolyzed in acetonitrile (Equation 5) . For Ar1 ¼ 4-MeOC6H4 only, there was also migration of the aryl group to give the isomeric products 60 in 19–27% yield.

ð5Þ


4.09.6.3 Nucleophilic Attack at Carbon The 1,2-oxathiolane 2,2-dioxides such as 54 and 55 formed by Diels–Alder reaction of 6 undergo nucleophilic ring opening with O-, S-, and N-centered nucleophiles at the ring CH2 to give products such as 61–63 from 54 . The initial amine addition product 63 can be cyclized as shown to 64, and by using a chiral amine for this process the resulting diastereomers of 65 have been separated and used to obtain both enantiomers of 66 . Chiral oxathiolane dioxides 67 react with water followed by CH2N2 to give -hydroxysulfonates 68 while similar reaction with a nitrogen nucleophile affords the homotaurine derivatives 69 .

4.09.6.4 Nucleophilic Attack at Oxygen Nucleophilic ring opening involving attack at oxygen occurs upon treatment of bicyclic peroxides such as 70 with either vinyllithium or vinylmagnesium bromide to give 71 in 80–90% yields (Equation 6) .

ð6Þ

4.09.6.5 Nucleophilic Attack at Sulfur Reaction of the camphor-derived sultine 72 with Grignard reagents takes place with inversion of configuration at S to give products 73 and treatment with LiNH2 similarly gives 73 (R ¼ NH2) . The chlorosulfurane 37 is cleanly converted into the corresponding fluorosulfurane by treatment with AgF while both it and the salt 21 are hydrolyzed by aqueous NaHCO3 to give the hydroxysulfoxide 74 . Hydrolysis of spiro sulfuranes 28 under a variety of conditions gave the hydroxysulfoxide acids 75 (Equation 7) .

829

830


ð7Þ

The unusual 1,2-oxathiolane 34 undergoes acid-catalyzed transfer of sulfur to alkenes yielding the corresponding thiiranes (Scheme 1) together with the oxetane 76 and its ring-opened aldehyde isomer 77 . The reaction of 34 with cyclooctyne and TFA initially affords the salt 78, which upon heating is converted into 79 (Equation 8) .

Scheme 1

ð8Þ

4.09.6.6 Miscellaneous Reactions The reaction of 1,2-oxathiolane 2-oxides such as 80 (Scheme 2) with bromine to give various stereoisomers of the products 81 has been examined and for Ar1 ¼ Ar2 ¼ 4-MeOC6H4 reaction of 80 with PCl3 gave 82 . The oxathiolanone dioxides 83 undergo hydrogenolysis to give -oxosulfonic acids isolated as the ammonium salts 84 (Equation 9) .

Scheme 2


ð9Þ

4.09.7 Reactivity of Substituents Attached to Ring Carbon Atoms The 3-hydroperoxy-1,2-dioxolanes 86 are formed by treatment of the corresponding hydroxy compounds 85 with H2O2 and TsOH in MeCN. They were found to be good oxygen transfer agents and readily interact with PhSMe, Et3N, and alkenes to regenerate 85 and give respectively the sulfoxide, the N-oxide, and the epoxides . Hydrogen bonding as shown in structure 86a is said to be important for this reactivity (Scheme 3). Hydrolysis of the 4-amino-1,2-oxathioles 87 under acidic conditions gives the 1,2-oxathiolan-4-one dioxides 83 (Equation 10) .

Scheme 3

ð10Þ

4.09.8 Reactivity of Substituents Attached to Ring Heteroatoms Treatment of the S-chloro sulfurane 37 with AgBF4 resulted in removal of the chlorine atom to afford the sulfonium salt 21 in 96% yield .

4.09.9 Ring Synthesis 4.09.9.1 One-Bond Formation between Heteroatoms The fluorinated 1,2-dioxolanediol 20 was obtained serendipitously as a 1,4-dioxane complex by air oxidation of manganese(II) hexafluoroacetylacetonide dihydrate in the presence of dioxane . A general synthesis of 1,2-oxathiolane 2-oxides 89 involves treatment of 3-mercapto alcohols 88 with sodium periodate (Equation 11) . A convenient synthesis of the camphor-derived 1,2-oxathiolane 2-oxide 72 involves sequential treatment of camphorsulfonyl chloride with Na2SO3, NaBH4, and then HCl to give the sulfinic acid 90 which is then dehydrated to give 72 using MgSO4 (Scheme 4) . When the sulfinamide 91 obtained by reacting 72 with LiNH2 was treated with TFA, it cyclized to give the isomeric sultine 92 . It is interesting to note

831

832


that 92 is isomerized to 72 upon exposure to HCl in CH2Cl2. Chromatography of the products obtained by directed ortho-lithiation of phenylsulfoximines 93 and reaction with an aldehyde electrophile (R2CHO) led to cyclization with loss of the tert-butyl and imino groups to give benzoxathiole oxides 94 (Equation 12) .

ð11Þ

Scheme 4

ð12Þ

Reaction of the hydroxy disulfide 95 with concentrated nitric and sulfuric acids has been used to obtain the oxathiolanyl nitrates 96 and 97 (Equation 13) . A new synthesis of 3-methyl-1,2-oxathiolane 2,2dioxide 99 involved reaction of crotonaldehyde (MeCHTCH–CHO) with SO2 and water followed by catalytic hydrogenation to give the hydroxysulfonic acid 98 which was then dehydratively cyclized to give the product in 52% overall yield (Equation 14) .

ð13Þ

ð14Þ

A variety of spiro sulfurane systems have been formed by dehydrative or oxidative cyclization of bifunctional precursors. Thus, for example, treatment of 100 and 101 with DCC gave sulfuranes 29 and 31, respectively , and reaction of 102 with acetic anhydride and pyridine gave 26 while N,N-dichloro-p-toluenesulfonamide was used to convert 103 and 104 into 27 and 30 and t-BuOCl converts the hydroxy acids 105 into compounds 28 .


4.09.9.2 One-Bond Formation Adjacent to a Heteroatom A variety of suitably functionalized oxetanes undergo cyclization to give 1,2-dioxolanes as illustrated by formation of 107 from ozonolysis of 106 in methanol (Equation 15) and 109 by treatment of 108 with HF (Equation 16) . A new synthesis of 1,2-oxathiolane 2-oxides involves construction of the alcohol-functionalized allylstannanes 110 followed by cyclization with thionyl chloride and triethylamine to give 111 (Equation 17) . The chiral sulfonic acids 112 formed by asymmetric alkylation of chiral arylmethanesulfonates undergo cyclization with TFA to afford oxathiolane dioxides 113 in over 98% ee (Equation 18) and the compounds 24 and 38 mentioned earlier were prepared in this way . A new method of radical cyclization results in conversion of the sulfinates 114 into the benzoxathiole oxides 115 (Equation 19) and monocyclic oxathiolane S-oxides 117 are similarly formed from the bromoalkyl sulfinates 116 (Equation 20) .

ð15Þ

ð16Þ

ð17Þ

ð18Þ

833

834


ð19Þ

ð20Þ

4.09.9.3 One-Bond Formation Remote from Heteroatoms A general synthesis of 4-amino-1,2-oxathiole 2,2-dioxides involves treatment of a cyanohydrin with a sulfonyl chloride to give 118 which can then cyclize with base to afford 119 and this method has also been used to obtain the spiro products 120 . Intramolecular Diels–Alder reaction of the furantethered vinylsulfinate 121 gave compound 23 and the (Z)-isomer behaved similarly . Ring-closing metathesis of allyl vinylsulfonate 122 using the second-generation Grubbs’ catalyst gave 6 in 94% yield .

4.09.9.4 Two-Bond Formation from [4þ1] Atom Fragments A further example of this unusual approach is provided by the reaction of phenylpropargyl alcohol with an aryl Grignard reagent followed by SOCl2 to give the product 123 (Equation 21) .

ð21Þ

4.09.9.5 Two-Bond Formation from [3þ2] Atom Fragments Photolysis of cyclopropanes in the presence of oxygen and catalytic diphenyl dichalcogenide affords the corresponding 1,2-dioxolanes as illustrated by conversion of 124 into 125 (Equation 22) . The highly hindered dioxolane 19 was formed spontaneously from reaction of the hydrocarbon diradical 126 with oxygen in air . Metallated carbonyl oxides, formed in a number of ways, have been added to alkenes to give 1,2dioxolanes. Thus, treatment of ozonides such as 127 with SnCl4 followed by allyltrimethylsilane gave the product 128 in 79% yield (Equation 23) , and in a similar process the silyl peroxyacetals 129 react with SnCl4 and an alkene R3R4CTCH2 to afford products 130 (Equation 24) . The synthesis of 1,2-dioxolan-3-ones 132 from 131 relies upon trapping of the stable cyclopropylmethyl carbocation with H2O2 to give a hydroperoxide which then cyclizes with loss of ethanol (Equation 25), compound 33 for example was prepared in this way .


ð22Þ

ð23Þ

ð24Þ

ð25Þ

The stable 1,2-oxathiolane 34 was formed by cycloaddition of the sulfine thiofluorenone S-oxide 133 to (E)-cyclooctene (Scheme 5) . Iron-substituted 1,2-oxathiolane 2-oxides 39 and 40 were formed in 94% yield by treating the corresponding cyclopropyliron compound 134 with SO2 in MeCN while reaction of propargyliron compounds 135 with SO2 or SO3 gave the compounds 48 and 50, respectively (Scheme 5) .

Scheme 5

835

836


4.09.10 Ring Synthesis by Transformation of Other Heterocyclic Rings 4.09.10.1 Three-Membered Rings The reaction of epoxy sulfonyl chlorides 136 with triethylamine is thought to proceed through intermediate epoxy sulfenes 137 to give the 5H-1,2-oxathiole 2,2-dioxides 138 (Equation 26) . The interaction of phenylmethanesulfonyl chloride with triethylamine, 2,4,6-trimethylpyridine N-oxide, and an alkene probably involves epoxidation of phenylsulfene to give the hitherto unknown oxathiirane S,S-dioxide (-sultone) 139 which then adds to the alkene to afford the products 140 (Scheme 6) .

ð26Þ

Scheme 6

4.09.11 Best Methods of Synthesis The first convenient synthesis of compound 6 involves four steps starting from allyl bromide (Scheme 7) and gives the product in 34% overall yield . This seems more suitable for large-scale synthesis than the method involving metathesis of 122 mentioned in Section 4.09.9.3. The synthesis of compound 72 mentioned in Section 4.09.9.1, which involves four steps from camphorsulfonyl chloride, is also amenable to large-scale synthesis .

Scheme 7

4.09.12 Applications There have been relatively few applications of compounds of this type. The 1,2-dioxolan-3-ones 132 have been tested as anti-malarials but have weak activity . The 4-amino-1,2-oxathiole 2,2-dioxides 119 have been examined as potential reverse transcriptase inhibitors for treatment of HIV-1 but are essentially inactive and the nitrates 96 and 97 have been patented for the treatment of neurological conditions .


4.09.13 Further Developments The stereoselective ring-opening of -sultones 67 by a variety of nucleophiles to give functionalized sulfonates in good de and ee has been reported .

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Kawecki, Tetrahedron: Asymmetry, 1999, 10, 4183. 1999TL6553 P. H. Dussault and X. Liu, Tetrahedron Lett., 1999, 40, 6553. 2000CC189 Y. Morimoto, H. Kurihara, and T. Kinoshita, Chem. Commun., 2000, 189. 2000JOM(598)150 A. L. Hurley, M. E. Welker, and C. S. Day, J. Organomet. Chem., 2000, 598, 150. 2001AXE636 M. H. Dickman, Acta Crystallogr., Sect. E, 2001, 57, 636. 2001CHE649 E. V. Grigor’ev and L. G. Saginova, Chem. Heterocycl. Compd. (Engl. Transl.), 2001, 37, 649 (Chem. Abstr., 2002, 136, 216 798). 2002JA8316 W. Adam, S. G. Bosio, B. Fro¨hling, D. Leusser, and D. Stalke, J. Am. Chem. Soc., 2002, 124, 8316. 2002OL599 W. Adam and B. Fro¨hling, Org. Lett., 2002, 4, 599. 2002SL1727 D. Enders, W. Harnying, and N. Vignola, Synlett, 2002, 1727. 2002SL2019 S. Karsch, P. Schwab, and P. Metz, Synlett, 2002, 2019. 2002SOS(11)31 H. Perst; in ‘Science of Synthesis’, E. Schaumann, Eds.; Georg Thieme Verlag, Stuttgart, 2002, vol. 11, ch. 2, p. 31 (Chem. Abstr., 2003, 138, 401 622). 2003CHE113 E. V. Grigor’ev and L. G. Saginova, Chem. Heterocycl. Compd. (Engl. Transl.), 2003, 39, 113. 2003EJO3939 D. Enders, W. Harnying, and N. Vignola, Eur. J. Org. Chem., 2003, 3939. 2003JHC1071 L. Tian, G.-Y. Xu, Y. Ye, and L.-Z. Liu, J. Heterocycl. Chem., 2003, 40, 1071. 2003S1329 L. Tian, G.-Y. Xu, Y. Ye, and L.-Z. Liu, Synthesis, 2003, 1329. 2003S1856 D. Enders, S. Wallert, and J. Runsink, Synthesis, 2003, 1856. 2003TL395 H. Zhang, W. H. Chan, A. W. M. Lee, and W. Y. Wong, Tetrahedron Lett., 2003, 44, 395. 2004S590 D. Enders, W. Hamying, and G. Raabe, Synthesis, 2004, 590. 2004S2910 D. Enders and W. Harnying, Synthesis, 2004, 2910. 2005BML2057 D. V. Smil, F. E. S. Souza, and A. G. Fallis, Bioorg. Med. Chem. Lett., 2005, 15, 2057. 2005JOC5020 Y. Nakashima, T. Shimizu, K. Hirabayashi, F. Iwazaki, M. Yamasaki, and N. Kamigata, J. Org. Chem., 2005, 70, 5020. 2005OL4333 P. Dai and P. H. Dussault, Org. Lett., 2005, 7, 4333. 2005OL4617 A. Ramirez and K. A. Woerpel, Org. 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837

838


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Biographical Sketch

Alan Aitken was born in the Dumfries and Galloway area of SW Scotland. He studied at the University of Edinburgh where he obtained a B.Sc. in 1979 and his Ph.D. in 1982 under the direction of Dr. I. Gosney and Professor J. I. G. Cadogan. After spending 2 years as a Fulbright Scholar in the laboratories of Prof. A. I. Meyers at Colorado State University he was awarded a Royal Society Warren Research Fellowship and moved in 1984 to the University of St. Andrews where he has been a senior lecturer since 1997. His research interests are in the area of synthetic and mechanistic organic chemistry including asymmetric synthesis, synthetic use of flash vacuum pyrolysis, heterocyclic chemistry, organophosphorus, and organosulfur chemistry.

Lynn Power was born in Co. Wexford, Ireland. She completed a B.Sc. degree at the National University of Ireland, Maynooth in 2004, including a final year research project with Dr. Frances Heaney. She was the recipient of the Kathleen Lonsdale Prize for the best student graduating in chemistry. She then carried out Ph.D. work at the University of St. Andrews in the area of asymmetric synthesis using chiral dioxolanones under the supervision of Dr. Alan Aitken.

839

4.10 1,3-Dioxoles and 1,3-Oxathioles R. A. Aitken and L. A. Power University of St. Andrews, St. Andrews, UK ª 2008 Elsevier Ltd. All rights reserved. 4.10.1

Introduction

842

4.10.2

Theoretical Methods

842

4.10.3


843

4.10.3.1

X-Ray Diffraction

843

4.10.3.2

NMR Spectroscopy

845

4.10.3.2.1 4.10.3.2.2 4.10.3.2.3

4.10.3.3 4.10.4 4.10.4.1 4.10.5

1

H NMR C NMR 17 O NMR and

845 845 846

13

19

F NMR

Mass Spectrometry

847


847

Miscellaneous Physical and Thermodynamic Properties Reactivity of Conjugated Rings, 1,3-Dioxoles, and 1,3-Oxathioles

847 847

4.10.5.1


847

4.10.5.2


848

4.10.5.3

Cycloaddition Reactions

848

4.10.6

Reactivity of 1,3-Dioxolanes and 1,3-Oxathiolanes

848

4.10.6.1


848

4.10.6.2

Electrophilic Attack at Sulfur

849

4.10.6.3


849

4.10.6.4

Nucleophilic Attack at Ring CH

853

4.10.6.5

Radical and Carbene Reactions, Oxidation

855

4.10.6.6 4.10.7


856


857

4.10.7.1

Halogenation of Alkyl Substituents

857

4.10.7.2

Nucleophilic Addition to Alkene Substituents

857

4.10.7.3

Epoxidation, Aziridination, and Cyclopropanation of Alkene Substituents and Other Carbene Reactions

858

4.10.7.4

Cycloaddition with Dienes and 1,3-Dipoles

860

4.10.7.5

Cycloaddition with Dienophiles and Dipolarophiles

861

4.10.7.6

Nucleophilic Addition to Carbonyl Substituents

861

4.10.7.7


862

4.10.8


863

4.10.9

Ring Synthesis

863

4.10.9.1

One-Bond Formation Adjacent to a Heteroatom

863

4.10.9.2


865

4.10.9.3


868

4.10.9.4

Three-Bond Formation

871

841

842


4.10.10

Ring Synthesis by Transformation of Other Heterocyclic Rings

872

4.10.10.1

Three-Membered Rings

872

4.10.10.2

Five-Membered Rings

874

4.10.10.3

Six-Membered Rings

874

4.10.11

Best Methods of Synthesis

875

4.10.12

Applications

876

4.10.12.1

Uses in the Polymer, Food, and Perfumery Industries, and Occurrence in Nature

876

4.10.12.2

Applications Based on Physical and Chiroptical Properties

876

4.10.12.3

Applications as Ligands and Catalysts in Asymmetric Synthesis

877

4.10.12.4

Agrochemical and Pesticidal Applications

880

Medical and Pharmaceutical Applications

881

4.10.12.5 4.10.13


882

References

882

4.10.1 Introduction Since the publication of the corresponding chapter in CHEC-II(1996) , there have been a large number of developments in the chemistry of 1,3-dioxole systems and these have mainly involved 1,3-benzodioxoles 1, 1,3-dioxolanes 2, and the isomeric 1,3-dioxolan-2-ones 3 and 1,3-dioxolan-4-ones 4. There have been specific reviews on the synthesis of 1,3-dioxolium salts 5 and the transformations of the 6,8dioxabicyclo[3.2.1]octane compounds 6 . O

O

O

O

O

O+

O

O

O O

1

O

O

2

3

4

5

Me

O O

6

R Me

There have been fewer developments in the chemistry of 1,3-oxathioles and most of these have involved the saturated 1,3-oxathiolanes 7 although the synthesis of 1,3-oxathiolium salts 8 has been reviewed . O

O+

S

S

7

8

4.10.2 Theoretical Methods A theoretical study of the ‘anomeric effect’ in 1,3-dioxole 9 involving interaction of the oxygen lone pairs with the C–O antibonding orbitals has provided an explanation for the unexpected nonplanarity observed for this compound . A combined theoretical and calorimetric study of the four benzodioxole compounds 10–13 has been used to obtain fundamental thermodynamic data for them . The conformational preferences of trans4,5-disubstituted-1,3-dioxolanes 14 have been analyzed computationally . R

O O

O O

9

R

R

O O

14

10: R = OH 11: R = CH2OH 12: R = CO2H 13: R = CH2CO2H


4.10.3 Experimental Structural Methods 4.10.3.1 X-Ray Diffraction There have been several new X-ray structure determinations of 1,3-benzodioxole systems including compounds 15–17 , 18 , and the fluorinated alcohols 19 and 20 . In addition, structure determinations of the chiral benzodioxoles 21 , 22 , and 23 have been reported. TMS CHO

CHO Br

I

O

I

O

Me

O O

O

O

O

15

17

16 O

F 3C

18 O

OH

F3C F3C

O

O

O

AcHN

OH

OH

O

19

O

But

TMS

O O

O

But Me

CO2Me

21

20 TMS

O

N H

TMS

O

Me

Ph2P

O

Me

Ph2P

O

Me

O

Me

O

But

22

23

1,3-Dioxolane 2 forms inclusion complexes with a variety of inorganic and main group compounds, and structures have been determined for LiBH4?2 , [Liþ Me2NBH3]2?2 , and tetrakis(3,5dimethoxyphenyl)silane?23.3 . A previous diffraction study of compound 24 which assigned the space group as Cc has been found to be in error, and the space group has been reassigned as Fdd2 . Various other X-ray structure determinations of 1,3-dioxolanes have been reported including 25 , the Meisenheimer complex-derived spiro compound 26 , compounds 27 , 28 , 29 , the tricyclic compound 30 , and the sterically hindered poly-yne 31 and the corresponding dioxolanone 32 . O O

CN

O

CN

O2N

Pri

2P

Hexn

S

O Ph

O

O

Me

S

S

O

Me

TMS

29

TMS

O

Br

OHC

28

O

TMS

H

O

TMS S

O

H

27

S

O

MeO2C F3C OHC

CO2Me

Cl Cl

H

O

NO2

NO2

26

25

O

O

O

O

24

Hexn

O

OMe TMS

O

TMS

O

H

O

30 TMS

TMS

31

32

843

844


The X-ray structure of the chiral sulfoxide 33 has allowed correction of a previous incorrect absolute configuration . An area in which a large number of X-ray diffraction studies have been performed is in the quinic acid derivatives 34, 35, and 36–38 which has been examined as precursors of chiral dioxiranes. The 1:1 complex of ()-trans-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyl-1,3-dioxolane (TADDOL) 39 with ethyl 2-pyridyl sulfoxide and the TADDOL-related compounds 40–44 have all had their structures determined. Further simple dioxolanes to have their structures determined include 45 and 46 .

Me

Me O

Me

O

O

Me

O

O

Me

Me

O

O Me

S

Ph

Me

CH2OAc O Me O

CMe2OH O Me O

O

33 Me

Me

O

O O

Me

O

Ph O

Me

O

Me

Me Me

X

O

Me

O

Me

Ph

Ph

38

Me O

O

O O

Me

Me 37

36

Ph

X

Ph Ph

H2NOC

O

Me

H2NOC

O

Me

44

39: X = OH 40: X = Cl 41: X = N3 42: X = NH2 43: X = NHMe

Me

O Me

Ph

O

O

O

Me

35

O

O

O

Me

Me

Me

O

34

Me

O

45

O2N

NO2

F

O

F

O

OMe O2N

NO2

46

X-Ray diffraction studies of the unusual pentacyclic compound 47, isolated as a minor by-product of the cyclization of 2,3-butanedione under acidic conditions, have been reported . A number of X-ray structure determinations on 1,3-dioxolan-4-ones have been reported including those of 48 and 49 . The crystal structures of the 1,3-oxathiolane derivatives 50 and 51 have been reported . The stereoselectivity of the reaction of benzo-1,3-dithiole S-oxide with various electrophiles has been examined, and the X-ray structures of a number of different diastereomeric products including 52–55 have been determined . Finally, X-ray diffraction studies have been reported for substituted benzoxathiole 1,1-dioxides 56 and 57 .

Me

Me O

O Me Me

O O O

O H

OH O

O Me

Ph O

O

Me

O

O

50 O

O H

S OMe

O

52

51 OH

OH

O

O Me Me

O

49

OH

S

O S

H

Me

48

47

Me O

O

But

Me Me S

O

S

H O

53

OMe

H OMe

O

54


OMe

HO

MeO F

O

O

H

S O2

CF3

O O

S

MeO

O HO

S O2

MeO

OMe

56

55

Me

57

4.10.3.2 NMR Spectroscopy 4.10.3.2.1

1

H NMR

There has still been no systematic study of the patterns of nuclear magnetic resonance (NMR) shifts in systems of this type. A compilation of new data is presented in Table 1.

Table 1 Proton NMR data for some 1,3-dioxole and 1,3-oxathiole derivatives Compound

H-2

45 58 59 65

5.20 5.91

H2N

O

Me

H2N

O

Me

H-4/H-5

Other signals

Reference

4.43 3.77

1.39 (2-Me), 7.40/7.47 (NH2) 1.40 (2-Me), 2.82/2.89 (CH2) 1.55 (NH2) (See paper) 3.92 (OMe)

2002RJO104 2002RJO104

4.50

Me(H2C)11HNOC H H Me(H2C)11HNOC

58 O O O

Ph

O O

H

Ph

O Ph

O

O

NPh H Ph

Ph

F F

O

O Me

Ph O NPh

61

Me Me

O

S CO2Me O

O

O

63

O

OH Me

O

H

62

H O NPh

O

O

60

59

NPh Ph

H

Ph

O

H

1996T8275 2002SL996

Me

65

64

The stereochemistry of compounds 60–63 was fully determined by various NMR techniques such as nuclear Overhauser effect (NOE), correlation spectroscopy (COSY), and nuclear Overhauser enhancement spectroscopy (NOESY) . The conformation of the 2,3-butanedione trimer 64 and similar compounds has been examined by NMR at 90 C .

4.10.3.2.2

13

C NMR

There has still been no systematic study of the patterns of NMR shifts in systems of this type. A compilation of new data is presented in Table 2.

845

846


Table 2 Carbon-13 NMR data for some 1,3-dioxole and 1,3-oxathiole derivatives Compound

C-2

C-4/C-5

Other signals

2 45 58 66 67 68 69 70 71 72 73 74 75c 75t 76c 76t 77c 77t 59 65

94.9 111.5

64.4 77.4 80.3 64.5 64.9 64.9 64.9 65.1 65.4 65.1 80.8 80.8 80.2 73.6 78.6 81.0 78.9 81.3

26.2 (Me), 171.3 (CTO) 27.4 (Me), 44.3 (CH2) 25.6 (Me) 19.7 (Me) 27.0 (CH2), 8.0 (Me) 36.0 (C-19), 17.5 (C-29), 14.1(Me) 32.0 (CH), 16.8 (Me) 34.5 (C), 24.3 (Me) 137.9 (i), 126.3 (o), 128.2 (m), 129.0 (p) 32.7, 22.3, 32.7 (ring C) 33.4, 22.3 (ring C), 23.8 (Me), 26.1 (Me) 28.7, 23.8 (ring C) 26.9, 20.6 (ring C) 29.8, 23.7, 30.5 (ring C) 28.8, 24.7, 24.8 (ring C) 27.5, 26.6, 25.1 (ring C) 33.1, 23.2, 27.4 (ring C)

21.8, 161.7

54.2 (OMe), 166.3 (CTO)

108.5 101.6 105.4 104.6 108.4 110.4 103.6 94.3 108.8 95.2 93.7 93.3 94.5 91.8 92.6 96.3 70.3

Reference

H O O

66

4.10.3.2.3

O

Me

O

R

O

R

R

Me

O

67: R = Me 68: R = Et 69: R = Pr 70: R = Pri 71: R = But 72: R = Ph

17

O NMR and

73: R = H 74: R = Me

H O

O n

2001MRC657 2002RJO104 2002RJO104 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 2001MRC657 1996T8275 2002SL996

O H 75c: n = 1 76c: n = 2 77c: n = 3

n

O H 75t: n = 1 76t: n = 2 77t: n = 3

O O

78

19

F NMR

There has only been limited progress in the area of 17O NMR analysis of 1,3-dioxole systems. New data for a range of dioxolanes with two equivalent oxygens are presented in Table 3 . Other authors have reported a value of O 35 for compound 2, and for 78 the signals come at 35.0 for O-1 remote from the methylene group and at 119.0 for the O-3 which is an enol ether .

Table 3 Oxygen-17 NMR data for some 1,2-dioxolane derivatives Compound

O

Compound

O

2 66 67 68 69 70 71 72

34.0 64.1 54.9 50.1 51.9 46.5 40.1 56.1

73 74 75c 75t 76c 76t 77c 77t

63.5 92.4 52.1 50.8 64.8 61.0 67.1 69.1


19

F NMR analysis of compound 65 provided the first such data for a 1,3-oxathiole derivative. Values recorded were F 71.8 (1 F, dd, 2JFF ¼ 243 Hz, 4JHF ¼ 5.8 Hz) and 80.1 (1 F, d, 2JFF ¼ 243 Hz) .

4.10.3.3 Mass Spectrometry A detailed mass spectrometric study of the three dioxolanes 79–81 and the two oxathiolanes 82 and 83 all containing ester groups has been published . O

O

Me CO2Et

O

O

79 O

O

Me CO2Et

S

O

Me

CO2Me

CO2Me

O

80

81

Me CO2Me

S

82

Me

83

4.10.4 Thermodynamic Aspects 4.10.4.1 Miscellaneous Physical and Thermodynamic Properties A thermodynamic study of sesamol 10, piperonyl alcohol 11, piperonylic acid 12, and homopiperonylic acid 13 has been performed using calorimetric techniques as well as theoretical methods . The chiroptical properties and absolute configuration of 84 have also been reported . Interestingly, 85 has been reported to undergo a redox-induced conformational change with the radical cation showing p–p stacking, based on density functional theory (DFT) calculations . The stereochemistry of 86 and related compounds has allowed them to be used as dopants in nematic liquid crystals. This use has been related to absolute configuration and the circular dichroism and twisting ability of these molecules have also been reported . The correction of a previous false optical rotation value has been reported for 87. Previous literature values for this enantiomer were either þ20 or 20, but the value now reported is []D þ19 (c 0.81, CHCl3), following authentic synthesis of the desired enantiomer . O Ph

O

O Me Me O

Me

O

Me

O

NH O

O

85

84

OH

86

O

Me

O

Me

87

4.10.5 Reactivity of Conjugated Rings, 1,3-Dioxoles, and 1,3-Oxathioles 4.10.5.1 Electrophilic Attack at Carbon There has been only one significant new report of reactivity of this type. Deprotonation at C-2 of the substituted benzoxathiole 1,1-dioxide 88 followed by addition of a silyl chloride gave 89. This was then deprotonated again followed by addition of acetaldehyde to furnish the alkene 90 via a Peterson reaction (Scheme 1) .

O S O2

88 Scheme 1

O

LDA R

R

TBDMS-Cl

S O2

89

O

LDA TBDMS

CHMe

R MeCHO

S O2

90

847

848


4.10.5.2 Nucleophilic Attack at Carbon An important report of new reactivity of this type involves the palladium-catalyzed ternary coupling of various aryl bromides, such as p-bromotoluene, and PhSnBu3 with 9 and other simple dioxoles to give dioxolanes 91 (Equation 1) .

Br O R

R

cat. PdCl2[P(o-Tol)3]2 + Bu3SnPh

+

O

80 °C, 24 h, THF

O

Ph

9

ð1Þ

O

91

4.10.5.3 Cycloaddition Reactions There have only been a few new reports of reactivity of this type. The Paterno–Bu¨chi reaction of 92 with substituted pyruvates gives the endo- and exo-products shown (Equation 2) . In a later study, the corresponding cycloadditions of 1,3-dioxol-2-one with a variety of aldehydes and ketones were also examined .

Pri Pri

O

hν

OR2

R1 O

CO2R2

R1

O

Pri O Pri

O

R2O2C +

O

Pri

O (endo-R1)

92 R1 = Me; R2 = Et

O

O

: : :

R1

O

(exo-R1)

80 >98 >98

R1 = But; R2 = Et R1 = But; R2 = Me

Pri

ð2Þ

20 2 2

4.10.6 Reactivity of 1,3-Dioxolanes and 1,3-Oxathiolanes 4.10.6.1 Unimolecular Reactions There have only been a few new reactions reported in this area. One involves a new pyrolysis process that results in ring cleavage and rearrangement of various 1,3-dioxolanes 93a–c to give the corresponding butyrolactones (Equation 3) . The reactions were conducted by flow pyrolysis of the starting materials in benzene solution in a stream of nitrogen at atmospheric pressure and the temperatures required and yields are noted. The 1,3dioxolanes 94 fragmented upon thermolysis with a trace of acid under high vacuum conditions to give the tetraethynylethenes 95 in low yields (Equation 4) . The lactic acid-derived 1,3-dioxolan-4-one 96 can act as a chiral acetyl anion equivalent by diastereoselective Michael addition to give 97 followed by flash vacuum pyrolysis at 550 C to give the chiral keto ester 98 with 86% ee (Scheme 2) .

O O R2

O

R1

FVP

Ph R1

Ph R1 = H;

R2 = H

93a: 93b: R1 = Ph; R2 = H 93c: R1 = Ph; R2 = Ph

700 °C 500 °C 300 °C

R2 19% 27% 56%

O

ð3Þ


R3Si

R3Si

O

R3Si

O

OEt

R3Si

Me

O O

SiR3

R3Si

ð4Þ

cat. CSA –EtOH, – CO2 20–33%

R3Si

SiR3

94

95

Me

LDA

But O

150 °C, vac. (0.1 Torr)

Me

But

EtO2C

Me

CO2Et

96

Me –ButCHO –CO

O

O

O

FVP, 550 °C

O

97

CO2Et Me

98

Scheme 2

4.10.6.2 Electrophilic Attack at Sulfur Only one significant new report of a reaction of this type has appeared. Oxidation of oxathiolane 99 with H2O2 in the presence of a bulky seleninic acid proceeds selectively at sulfur to give the cis-sulfoxide isomer 100 (Equation 5) . O

Me

S

Me NHPh

99

O

H2O2

O

Me

O

S

O Se

Me

NHPh O

OH

ð5Þ

100

Me

4.10.6.3 Nucleophilic Attack at Carbon A wide variety of new reactions of this type have been reported. For the cleavage of 2,2-disubstituted 1,3-dioxolanes to give the corresponding aldehydes and ketones (Equation 6), new methods include the use of PPh3 and CBr4 , CpTiCl3 , and -picolinium chlorochromate . The use of various polymer-supported acid catalysts has been reported including a polymeric dicyanoketene acetal and polyaniline-supported sulfuric acid salt . The use of ceric ammonium nitrate (CAN), which is required only in catalytic amounts and acts as a Lewis acid rather than an oxidizing agent in this transformation , has also been reported . Other suitable reagents are erbium triflate in wet acetonitrile and copper sulfate in the presence of sodium iodide which leads to in situ generation of I2 . O

O

R1

R2

O R1

ð6Þ R2

A number of new reagent systems for the mild cleavage of 2,2-dimethyl-1,3-dioxolanes by hydrolysis to give diols (Equation 7) have been reported including ZnCl2 in aqueous tetrahydrofuran (THF) , a polymersupported dicyanoketene acetal , and CAN in the presence of oxalic acid . Polymersupported ferric chloride can be used as a selective catalyst for the deprotection of acetonides (Equation 8)

849

850


, and 2-phenyl-1,3-dioxolanes are cleaved cleanly to diols by the use of catalytic erbium triflate . A titanium silicate molecular sieve is effective in catalyzing methanolysis of 1,3-dioxolan-2-one to give ethanediol and dimethyl carbonate .

Me

O

Me

O

O

Me

OH

O

Me

OH

ð7Þ

HO HO O

O

ð8Þ RO

RO

O O

O O

Me

Me Me

Me

There have only been a few reports of oxidative cleavage of 1,3-dioxolanes to give the substituted hydroxyethyl esters (Scheme 3). New methods include air oxidation catalyzed by N-hydroxyphthalimide and cobalt acetate , reaction with OXONE in the presence of wet Al2O3 , treatment with 2,29-bipyridinium chlorochromate/m-chloroperbenzoic acid (MCPBA) , and treatment with iodine azide to give the 2-azidoethyl esters 101 .

N3

O R

IN3

O

O

OH

O

R R

O

O

101 Scheme 3

A number of new reports of reductive cleavage of 1,3-dioxolanes to give a variety of alcohols and other reduction products have appeared. Treatment with BH3?Me2S followed by BF3?Et2O allows selective cleavage of acetals derived from 1,2- or 1,3-diols where a neighboring hydroxyl group is present (Equation 9) . The highly stereoselective addition of allyltrimethylsilane to isopropylidene-protected carbohydrates can be achieved in the presence of BF3 (Equation 10) . A similar reaction using TiCl4 also gives the allylated product, and in this case the regioselectivity can be completely changed by altering the order of addition (Scheme 4) .

O

OTBDMS

O

OH

Ph

Me Me

O O

O

HO

Me Me

R O Scheme 4

R

i, BH3•Me2S ii, BF3•Et2O

BnO

OTBDMS

HO

BF3•Et2O

TMS

+

ð9Þ

OH

HO

R

ð10Þ

O

i,

TMS

O R

ii, TiCl4

O

Me Me

R

i, TiCl4 ii,

O

Me Me

TMS

HO


Reductive cleavage of acetals (Equation 11) has been achieved using PhSiH3 in the presence of a rhodium catalyst , i-Bu2AlH in the presence of a catalytic amount of ZrCl4 , and Et3SiH in the presence of EtAlCl2 . The mechanism and stereochemistry of the last reaction has been examined using deuterium-labeled reagents . Reaction of dioxolanes with an organoaluminium compound results in reductive cleavage with alkylation at C-2 , and similar outcomes are observed for reaction with allyltributyltin in the presence of TiCl4 and an excess of Grignard reagent . Further examples of reductive cleavage involving Grignard reagents and aryllithiums in the presence of sparteine have also appeared. R1 R2

R1

O R2

O

ð11Þ

OH

O

When dioxolanes bearing a suitably positioned electron-rich aryl group are treated with TiCl4, they can undergo an oxa Pictet–Spengler rearrangement as illustrated by the conversion of 102 into 103 (Equation 12) . R3

R3 TiCl4 O

MeO

R2

O

R1

OH

MeO

R2

102

O

ð12Þ

R1

103

An interesting observation in the area of spiro 1,3-dioxolane ring cleavage is illustrated by the behavior of compound 104. Upon treatment with Et2N–SiMe3 and MeI it undergoes a normal reaction to give the 2-silyloxyethyl enol ether 105, while in contrast reaction with Et3SiH and MeI gives the unexpected product 106, obviously formed from two molecules of 104 (Scheme 5) .

O Et2N–TMS, MeI

O

OTMS

O

104

105

Et3SiH MeI O

I

O

106 Scheme 5

There has only been one new report of a substitution without cleavage and this involves nucleophilic substitution of the benzotriazolyl group at C-2 of a 1,3-dioxolane by an organozinc reagent giving the substituted product (Equation 13) . The RZnX is produced in situ by reaction of RMgX and ZnCl2 or RBr and zinc. N

RZnX

O R

N O

N O

O

ð13Þ

851

852


A number of new kinetic resolution methods have been reported usually involving enzymes. The first is the use of the porcine pancreatic lipase to effect the resolution of a racemic 1,3-dioxolan-2-one. The (S)-enantiomer remains unchanged while the (R)-enantiomer is selectively hydrolyzed allowing recovery of both products in good yields and ee (Equation 14) . Enzymes have also been used to bring about kinetic resolution of a range of 1,3dioxolan-4-ones by enantioselective alcoholysis . A microbial asymmetric hydrolysis using Pseudomonas diminuta FU0090 is effective in kinetic resolution of 1,3-dioxolan-2-ones with stereogenic centers at both C-4 and C-5 . Somewhat different is the asymmetric Lewis acid-mediated enantioselective ring cleavage of meso-dioxolanes as a route to desymmetrization of meso-1,2-diols . O O

O

O OBn

O

O

OBn

ð14Þ

+ OH

HO

OBn

There have only been a few reports in the area of ring expansion by nucleophilic attack but they include a number of interesting methods. Reaction of the 4-methylene-1,3-dioxolan-2-ones 107 with hydrazine gives the six-membered ring products 108 (Scheme 6), while reaction with ArNHNH2 gives the five-membered ring products 109 and with RNHNH2 both five- and six-membered ring products are formed .

NHAr Me

HO R1 O R2

O

ArNHNH2

N O

O

R1 R2

109

Me

R1

N2H4•H2O

N

R2

O

O

107

NH O

108 Scheme 6

Lewis acid-catalyzed reaction with dichloroketene results in net insertion of the ketene into the ring to form the seven-membered ring products 110 (Equation 15) . Cl O

ZnCl2, Et2O

O

R1 R2

•

O

O

O

R2 R1

Cl

Cl Cl

O

ð15Þ

110 In the area of 1,3-oxathiolane cleavage to give the corresponding ketone (Equation 16) new methods include the use of sodium nitrite in the presence of acetyl chloride resulting in S-nitrosation by in situ-formed acetyl nitrite, followed by hydrolysis , the use of hydrogen peroxide in acetonitrile , vanadium pentoxide and hydrogen peroxide in the presence of ammonium bromide , glyoxylic acid and Amberlyst 15 under solvent-free conditions , and N-bromosuccinimide (NBS) in aqueous acetone which selectively cleaves 1,3-oxathiolanes in the presence of 1,3-dioxolanes . Me

S

Me

Me

O

Me

O

ð16Þ

A new method of 2-imino-1,3-oxathiolane ring opening involves attack by an N-alkoxyamine to give an adamantyl alkoxyurea 111 with elimination of thiirane (Equation 17) .


O O R1O

+ N

S

NHR2

N H

N

OR1

ð17Þ

R2

111 Ring expansion of 1,3-oxathiolanes to give six-membered ring products has been achieved in a number of ways. One useful method involves reaction of a styryloxathiolane and a styrene derivative in the presence of TiCl4 followed by KOH to give a 3,4-dihydro-2H-thiin (Equation 18) in a process involving [4þ2] cycloaddition of an in situgenerated ,-unsaturated thioketone . O

Me

i, TiCl4

R2

ii, KOH

Ar R2

S

+

Ph

S

Me

Ar R1

R1

ð18Þ

Ph

1,3-Oxathiolan-5-ones have been used to introduce a mercaptoacetic acid unit indirectly into amino acid esters (Equation 19) and also into a variety of ring-fused nitrogen heterocycles . R2 H2N

O CO2R1

HS

Pri

+

R2

O

O

ð19Þ N H

S

CO2R1

It has been shown that it is possible to exchange one halogen for another at the 4-position of a 1,3-oxathiolan-5-one (Equation 20), as chlorine is efficiently replaced by fluorine using HF in the presence of triethylamine and zinc bromide . O Cl Cl

O R S

O

Et3N, HF

O R

F

ZnBr2

ð20Þ

S

F

Kinetic resolution of one 1,3-oxathiolan-5-one has been reported, using a method similar to that used for the 1,3dioxolan-4-ones described above .

4.10.6.4 Nucleophilic Attack at Ring CH There have been only a limited number of developments in this area, the majority of which involve the use of lithium diisopropylamide (LDA) with chiral 1,3-dioxolan-4-ones to deprotonate the C-5 position and allow reaction with a suitable electrophile (Equation 21). Electrophiles used to alkylate the enolate include iodomethane , ethyl crotonate , ,-unsaturated ketones , various substituted nitrostyrenes , substituted nitroaryl fluorides and acylsilanes . R2 O

O O

R1 But

LDA +

E

R2 E O

O

R1

O

But

ð21Þ

The anion formed by deprotonation of 112 at C-2 with butyllithium undergoes spontaneous fragmentation to give the benzoate anion together with (E)-thiacycloheptene 113. The former reacts with a second molecule of 112 to give 115, while the latter reacts with butyllithium to give 114 (Scheme 7) . Alkyllithium compounds have been used to induce a new anionic ring contraction proceeding by a complex mechanism involving carbenes and illustrated by reaction of a furan-fused 1,3-dioxolane to form the oxetane product (Equation 22) .

853

854


O Ph

BuLi

S

Ph –

O

O S

112

O–

+ Ph

S

O

O

113

112

BuLi

O Ph

Bu

Ph

O

S

114

O

S

115 Scheme 7

O R1

O O

R3Li

H

R3

R1

O

OH

ð22Þ

R2 R2 OH

Two equivalents of LiHMDS (HMDS ¼ hexamethyldisilazide) have been used to deprotonate a 1,3-dioxolan-4one derived from malic acid having an acetic acid group at C-5; alkylation and acid work-up then gave the substituted dioxolanone (Equation 23) . i, LiN(TMS)2 (2 equiv) THF, –78 °C

But O O

O H

O

O

ii, RX iii, 1.5 M HCl

OH

But

O

O

ð23Þ

O OH

R

There have been a number of reports of ring halogenation, the majority of which concentrate on fluorination. There was only one report of chlorination which involved the use of tetraethylammonium trichloride in an unusual mode of reaction as chlorination might be expected to occur on R rather than at the 2-position (Equation 24) . O

O

R

H

Et4N+(Cl3)–

O

O

R

CI

ð24Þ

Anodic fluorination using Et4NF?4HF has been examined in detail and is found to give different results depending on the solvent used (Equation 25): in 1,2-dimethoxyethane (DME) the product obtained was mainly 116, but in CH2Cl2 it was mainly 117 . Monofluorination of 1,3-dioxolane at C-2 and 1,3-dioxolan-2one at C-4 can be achieved by the same method . O O O

–2e–

SAr (F–,

from electrolyte)

O O O

116

SAr F

+

O O O

F

ð25Þ

117

Further fluorination of 4-fluoro-1,3-dioxolan-2-one has been achieved using F2 or F2/N2 to give the 4,4-difluoro1,3-dioxolan-2-one in 5% yield, trans-4,5-difluoro-1,3-dioxolan-2-one in 59% yield, and cis-4,5-difluoro-1,3-dioxolan2-one in 11% yield . Deprotonation of 1,3-benzoxathiole S-oxide with LDA followed by stereoselective alkylation with a variety of electrophiles has been studied , and this is the way in which compounds 52–55 were obtained.


Selective anodic monofluoriation of 1,3-oxathiolan-4-ones at the 5-position has been achieved using Et4NF?4HF .

4.10.6.5 Radical and Carbene Reactions, Oxidation The majority of radical reactions reported have involved radical formation at the C-2 position of 1,3-dioxolanes. Reaction of 1,3-dioxolan-2-yls with substituted alkenes has been achieved by a number of different methods. Generation of 1,3dioxolan-2-yl and its conjugate addition to various substituted butenolides has been achieved both using tetra-nbutylammonium peroxydisulfate as a radical initiator and under photochemical conditions in the presence of a catalytic amount of benzophenone . For reaction with a difluoromethacrylate, either dibenzoyl peroxide or 2,29-azobisisobutyronitrile (AIBN) was used , while intramolecular cyclization was achieved using tributyltin chloride initiated by AIBN . Radical addition of dioxolan-2-yls to ,-unsaturated esters catalyzed by N-hydroxyphthalimide and Co(OAc)2 can be followed by trapping of the resulting radical by O2 to give -hydroxy--dioxolanyl esters . Conjugate addition of 1,3-dioxolanes to ,-unsaturated ketones has been reported under photochemical conditions in the presence of benzophenone to give monoprotected 1,4-diones , and addition to activated alkynes can be achieved similarly . Radical addition of 2-dimethylamino-4-chloromethyl-1,3-dioxolane to 1-hexene has been achieved under photochemical conditions with the radical formation occurring at C-2. A small amount of the radical dimer was also obtained . A Barbier-type allylation in water has also been reported involving reaction of a 1,3-dioxolane with allyl bromide in the presence of -cyclodextrin, zinc, and ammonium chloride (Equation 26) . O

β -CD, H2O

Br

+

R

OH

ð26Þ Zn, NH4Cl

O

R

Mercury photosensitization has been used to synthesize 1,3-dioxolane dimers by dehydrodimerization. For 1,3dioxolane itself or analogues with substitution at C-2 or C-2 and C-4, radical formation occurs at the C-2 position, whereas when substitution is at the C-4 position radical formation occurs at the 4-position. In most cases, a small amount of product from ring opening was also reported . For 2,2-dimethyl-1,3-dioxolane, radical formation occurs at the 4-position, and one common way to achieve this is the use of dimethylzinc in air. Addition of various alkenes and related groups can then be performed, such as addition to tosyl imines , and addition to perfluorinated alkenes and alkenyl ethers . Reductive cleavage of 2,29-bis(4,5-dialkyl-1,3-dioxolanes) to give the corresponding diols has been achieved using BH2Cl (Equation 27) . R

O

O

O

O

R

BH2Cl

R

OH

HO

R

ð27Þ R

R

R

O

O

R

There have only been a limited number of new reports of carbene reactions. Reaction of 2,2-dimethyl-4-phenyl1,3-dioxolane with dichlorocarbene under phase-transfer conditions proceeds by carbene insertion into the C-4–H bond to give 2,2-dimethyl-4-dichloromethyl-4-phenyl-1,3-dioxolane . Intramolecuar rearrangements involving carbenes or ylides have also been reported such as that of the diazo-containing ketal 118, which, in the presence of copper(II) bis(hexafluoroacetylacetonate) catalyst, generated the ylide 119 which then rearranged to give the bicyclic product 120 as a single diastereomer (Scheme 8) . R O

R

R

O

Cu(hfacac)2

N2

R OMe

Me O

118 Scheme 8

CO2Me – O + O O Me

O

119

O O O

MeO R

Me O

R

120

855

856


Ring enlargement of 1,3-dioxolanes by reaction with methyl diazoacetate in the presence of BF3?Et2O to give the corresponding 1,4-dioxanes has been described (Equation 28) . O

R1

O

R2

+

R1 R2

O

BF3•Et2O N2CHCO2Me

ð28Þ

CO2Me

O

Only a few new reports of ring oxidations have appeared. One method uses dimethyldioxirane or methyl(trifluoromethyl)dioxirane to convert 2,2-dimethyl-1,3-dioxolanes into 2-hydroxyketones under mild conditions (Equation 29) . Ozonolysis of 1,3-dioxolanes has also been examined, and the primary reaction product of 2-alkyl1,3-dioxolanes with ozone was identified as the 2-alkyl-1,3-dioxolan-2-ol . Me

O

Me

O

Me

O

R

O

Me

O

ð29Þ Me

OH

The only reports involving 1,3-oxathiolanes in this area are of ring expansion using diazo compounds to give 1,4oxathianes. Reaction with ethyl diazo(triethylsilyl)acetate in the presence of a copper(II) catalyst gave a 1,4-oxathiane by rearrangement of the initially formed S-ylide (Equation 30) . A similar process also takes place with methyl 3,3,3-trifluoro-2-diazopropionate . Reaction of 2-styryl-1,3-oxothiolane with methyl diazoacetate in the presence of a rhodium catalyst can give either a 1,4-oxathiane by a [1,2] C–C shift or the isomeric oxathiocane 121 by a [2,3] C–C shift . O

+

Ph

EtO2C

S

EtO2C Et3Si

SiEt3

MeO2C

O

Ph

Cu(acac)2

N2

ð30Þ S

S O

Ph

121

4.10.6.6 Miscellaneous Reactions An unusual reaction is reported involving treatment of the aminotrichloromethylbenzodioxole 122 with PCl5 to give the phosphoroimine 123, supposedly via the intermediates 124 and 125 (Scheme 9) . Treatment of the azetidinyl 1,3-dioxolane 126 with Et2AlCl causes it to undergo a rearrangement to give 127 (Equation 31) . The palladium-catalyzed reaction of 4-alkynyl-4,5,5-trialkyl-1,3-dioxolan-2-ones with electron-deficient alkenes proceeds with loss of CO2 to give 2-alkenyl-2,5-dihydrofurans via tandem C–C and C–O bond formation . Cl

O

NH2

Cl

O

CCl3

PCl5

Cl Cl

122

Cl CCl3

123

CCl3

Cl

O

Cl

O

124 Scheme 9

O Cl Cl P O N

N PCl3 CCl3

Cl

O

Cl

O P Cl Cl Cl

N

125


Ph

Ph

H

AlEt2Cl

N

N O O

MeO

O

ð31Þ

H O

MeO

126

127

4.10.7 Reactivity of Substituents Attached to Ring Carbon Atoms 4.10.7.1 Halogenation of Alkyl Substituents Only a limited number of new reports have appeared in this area. A number of new TADDOL derivatives can be formed by their treatment with either 1 or 2 equiv of SOCl2. By this method it is possible to introduce one or two chlorine atoms, which can then be replaced by various nucleophiles . Conversion of 2-(2-hydroxyethyl)2-methyl-1,3-dioxolane into the corresponding 2-(2-bromoethyl) compound can be achieved in 75% yield using Ph3PBr2 . Monobromination of a methyl group on 2-methyl-1,3-dioxolane or 2,2-methyl-1,3-dioxolane is possible using bromine in the presence of a crown ether in benzene . Selective fluorination of various S-containing 1,3-dioxolane derivatives by Et3N?3HF is reported to give monofluorinated products 128 with up to 80% de (Equation 32) . F PhS

O

R1

O

R2

Et3N•3HF

PhS

O

R1

O

R2

ð32Þ

128

4.10.7.2 Nucleophilic Addition to Alkene Substituents The majority of new reactions in this area involves the use of metal catalysts; however, two reactions have been reported without their use. Nucleophilic addition of secondary amines to a chiral dioxolanylacrylate can be achieved under solvent-free conditions with microwave irradiation to give 129 with up to 76% de . Syn- or antiselective Michael additions of -sulfonyl carbanions to give 130 or its diastereomer have likewise been reported (Equation 33). In the absence of any complexing agent, mainly the anti-product was observed, but the addition of hexamethylphosphoramide (HMPA) to the reaction mixture caused the syn-product to dominate . Stereoselective addition of trialkylstannyllithium gave only the syn stannylated product 131 whereas use of the stannylcuprate or zincate gave the opposite selectivity . Diastereoselective conjugate addition to chiral 1-dioxolanyl-2-nitroalkenes can be achieved using various organometallic compounds with yields and selectivities depending on the nature of the organometallic compound and the solvent . Similarly, stereoselective conjugate addition of functionalized alcohols to dioxolanylnitroalkenes gave modest to high selectivity in the presence of a metal catalyst at low temperatures . Me

Me Me

Me O

O O

O CO2R

CO2R Nu 129: Nu = NR1R2 130: Nu = CH(R)SO2Ph 131: Nu = SnR3

ð33Þ

Further chiral dioxolane-directed conjugate additions include that of a vinyl Grignard reagent in the presence of copper cyanide which proceeded to give 62% de at the new center and addition of organolithium and

857

858


organocopper reagents as nucleophiles in Equation 33 . The reaction of a phenylcopper reagent in the presence of BF3?Et2O with various dienic acetals such as 132 was reported to occur by overall anti-SN29 and syn-SN20 processes. The regioselectivity depends on the geometry of the diene and the substitution pattern of the dienic system (Equation 34) . O O Ph

Et

i, PhCu, BF3 –30 °C, Et2O

Ph

Ph Et

O H

ii, Ac2O, DMAP 70%

132

Ph

AcO 100% ee SN2″ product

O

Et Ph H

Ph

AcO Ph 100% ee SN2′ product

Ph

ð34Þ

Another interesting reaction reported involved the ultrasound-promoted diastereoselective addition of an alkyl iodide to 1,3-dioxolan-4-ylacrylates and 5-methylene-1,3-dioxolan-4-ones in the presence of zinc and copper iodide in aqueous conditions. Moderate to good de was observed for these reactions .

4.10.7.3 Epoxidation, Aziridination, and Cyclopropanation of Alkene Substituents and Other Carbene Reactions A new epoxidation method has been reported involving the use of a polyleucine catalyst in the epoxidation of 133. The use of the immobilized D- or L-polyleucine can overcome the inherent substrate-directed diastereoselectivity in the reaction . Me O

Me O COPh

133 A new aziridination method has been reported involving the use of ethyl (4-nitrobenzenesulfonyloxy)carbamate, NsONHCO2Et, in the presence of calcium oxide. Reactions with 134 or 135 give between 20% and 30% de while 136 gives 60% de (Scheme 10) .

R

R O

O

R NsONHCO2Et, CaO

R

O

O

or N3CO2Et, hν NCO2Et R = Me (20% de) R = Ph (60% de)

134: R = Me 136: R = Ph

Me O

Me NsONHCO2Et, CaO

O

Me O

Me O COR NCO2Et

COR

135 30% de Scheme 10

There have been a number of new developments in cyclopropanation chemistry of chiral dioxolane-containing alkenes and two reports involve the use of the Simmons–Smith reaction (CH2I2, Zn/Cu) under ultrasonic conditions


to give the products 137 and 138 in moderate to good de . Another simple method for cyclopropane formation involved a thermal reaction of diazomethane to the appropriate alkene followed by photolysis to give products such as 139 in 87% yield . R1

O

O O

R1

Me

R1

O

O

R2 Me

n

Me

Me

Me

NHBOC

O O

R2

CO2Me

O

138

R3

139

137 Various sulfur and phosphorus ylides are effective in bringing about cyclopropanation of 1,3-dioxolan-4-ylacrylates in excellent de and the mode of attack (Re or Si face) and the reaction selectivity were also examined . One sulfur ylide that can be used is ethyl (dimethylsulfuranylidene)acetate, which adds to 135 to give the ethoxycarbonylcyclopropane in over 90% d.s. . In another study, the stereoselectivity of cyclopropanation of dioxolanylnitroalkenes using Ph2STCMe2, Ph2STCH2, and phase-transfer generated dibromocarbene were compared . The use of dimethyl diazomalonate (MDM) in the presence of copper acetylacetonate has been studied with interesting results. Reaction with 140 gave only one product as expected (Equation 35); however, reaction with 141 gave the desired product 142 plus two additional side products 143 and 144. These arise from C–O insertion and [2,3] sigmatropic rearrangment via carbene–oxygen ylides (Equation 36) . Another method of cyclopropanation is illustrated by reaction of the lithium salt of isopropyl phenyl sulfone with 145 to give 146 in 67% yield and 90% de (Equation 37). The lithium salt of 2-nitropropane gave the same product in 53% yield but only 28% de and the reaction outcome is also solvent and conditions dependent .

O

MDM [Cu(acac)2]

O

O

O CO2Me

PhH, heat

ð35Þ

CO2Me n

n

140: n = 0,1

R

MDM [Cu(acac)2]

O O

MeO2C CO2Me O R

O R

O

MeO2C

141: R = Me or Ph

+

CO2Me

Me

O

Me

O

H CO Me 2

145

R

O

143

ð36Þ

O

144 Me

Me

Li

Me

SO2Ph

Me

O

ii, DMSO, 80 °C 67%

Me

O

i,

O

+

142

CO2Me

CO2Me

MeO2C

Me CO2Me

ð37Þ

H CO Me 2

146 90% de

Reaction of a 1,3-dioxolane-containing diazo compound proceeds by insertion into the C-5–H or C-4–O bonds to give isomeric products in the presence of Rh(OAc)4 or Cu(hfacac)2 (Equation 38) .

Me Me

O O

CH=N2

Me Me O

O

O O

+

Me

O

Me

O

O

ð38Þ

859

860


A report of improved chemoselectivity in intramolecular alkylidenecarbene C–H insertion has appeared. Once generated, the carbene can insert into C-4–H to give 147, the expected product, or insert into a C–H of the terminal OMe to give 148, which was in fact the main product (Scheme 11) .

Me

Me

O

O

i, (Ph)3P=CHCl ii, KHMDS

Me

Me

O

O

or TMSCH=N2, MeLi

OMe

OMe

O C-4–H insertion Me

Me

O

O

OMe insertion

Me

Me

O

O

O MeO

148

147

Scheme 11

4.10.7.4 Cycloaddition with Dienes and 1,3-Dipoles There have been a few reports of new [4þ2] cycloaddition reactions including reaction of the 2-alkylidene-1,3benzoxathiole dioxides 149, formed as shown in Section 4.10.5.1, with diene 150 to give products 151 (Equation 39), and this is how compound 57 was prepared . The chiral 4,5-diaryl-2-methylene-1,3-dioxolanes 152 have been reacted both with formylcyclohexenones 153 (Equation 40) and 2-acetylaminomethylene-1,3-diones 154 (Equation 41) to give the corresponding hetero-Diels–Alder adducts . MeO O

OMe

O CHR1

R2 S O2

+

R2

MeO

O S O2

OTMS

149: R1 = Me, CF3

151

150 O

O O

O

Ar

O

Ar

O

+

O

Me Me

Me MeH

O

O

O

Ar

O

Ar

R

Me O

+ NHAc

154

O

152

ð40Þ

Ar

Me

R

Ar

O

152

153 O

ð39Þ R1

AcNH

Ar

O

ð41Þ

Ar

There have also been a few reports of 1,3-dipolar cycloaddition to dioxolane-containing dipolarophiles. The regioselectivity of nitrile oxide addition to give products 155 and 156 has been examined, in some cases using ultrasound , and the stereochemistry of mesitonitrile oxide addition to compounds


135 has been examined . Reaction of C,N-diphenylnitrone with 4-phenyl-2-methylene-1,3-dioxolane gave all four possible products 60–63 whose structures were assigned by NMR methods . R2 O N

O

R2

O

O

R1

R1

155

156

Me

Me

N O

O

O–

O O

R

Me Me

Me O

O H

157

Me

N+

O

158

4.10.7.5 Cycloaddition with Dienophiles and Dipolarophiles There have been only a few reports of reactions of this type including cycloaddition of dienes 157 with the powerful dienophile 4-phenyl-1,2,4-triazoline-3,5-dione and stereoselective cycloaddition of the chiral nitrone 158 with a variety of dipolarophiles . A rare example of intramolecular hetero-Diels–Alder reaction involving a 4-methylene-1,3-oxathiolan-5-one S-oxide is provided by the cycloaddition reaction of 159 to give 160 (Equation 42) . Me

O

Me

O

Me

Me

O

O

ð42Þ O

S

O

O

O

S

R1 R2

R1 R2

159

160

4.10.7.6 Nucleophilic Addition to Carbonyl Substituents There have been a number of new reports of reactions of this type including several involving addition to the aldehyde function of 161. Reaction with diphenyltrimethylsilylphosphine gave 162 while reaction with phenylbis (trimethylsilyl)phosphine gave 163 (Scheme 12) .

H Me Me

OH CO2H

O

H2N

164

oxynitrilase H Me Me

O O

165

Me

CN

H Ph2P–TMS

O

Me

O

Me

O

161 NC OH Me

OH

O

Me

L-threonine aldolase

NH2

O

CO2H

CHO

OTMS PPh2

162 PhP(TMS)2

Me

H Me Me

O

OTMS P Ph

OTMS H O O

O

Me Me

163

Scheme 12

Enzyme-catalyzed reactions in this area include reaction with glycine catalyzed by L-threonine aldolase to afford 164 and the use of almond oxynitrilase to catalyze the formation of cyanohydrin 165 by reaction of 161 with acetone cyanohydrin .

861

862


Cyclocondensation reactions of benzodioxole diester 166 with ethylenediamine and hydrazine to give spiro heterocycles have been reported . For spiro 1,3-oxothiolane species such as 167–169, a study of the influence of the S and O atoms on the facial selectivity of nucleophilic addition to the carbonyl group has been undertaken. Under normal conditions, the addition to CTO takes place anti to S and syn to O. However, the use of a chelating reagent such as NaBH4 or i-Pr2AlH for a hydride reduction reversed this facial preference .

O

O

O

O CO2Et

O

O

O

O

S S

S

CO2Et

167

166

168 169

4.10.7.7 Miscellaneous Reactions Other developments include a report on the preparation by elimination of HI (Equation 43) and applications of cyclic enol carbonates , migration of Br or I accompanying lithiation of systems such as 170 (Scheme 13) , and a detailed study of reactions of 4-lithiated 2,2-difluoro-1,3-benzodioxole with a wide variety of electrophiles . There has been an interesting report of what is said to be the first ortho-lithiation of an iodobenzene then using dimethylformamide (DMF) as the electrophile (Equation 44) . Desymmetrization of the chiral -sulfinyl acetals 171 was shown to be kinetically controlled with the C–O bond syn to the sulfinyl oxygen being cleaved exclusively (Equation 45) . R1

R1

O

LiHMDS

O R2 R3

O

O

R2

I

O O

F

O O

Li

O

F F

F F

O

Br

O

E+

O

Br

F F

E

Li

Br

Br

Br

Br

LDA

F

ð43Þ

O R3

Br

Br

O

170 Scheme 13

CHO

Li I

O

LDA

I

O

O

I

DMF

O

O

ð44Þ

O

16

O

S

O O LDA (3 equiv)

O

171

THF –78 °C

OH

S

O

ð45Þ


A number of reports on enzymatic resolution or similar reactions have appeared including the use of Candida antarctica B to resolve 1,3-dioxolan-4-ones and either Rhizopus sp. lipase , lipase AK , or pig liver esterase (PLE) with hydrated MPEG resin to catalyze reaction of 4-hydroxymethyl-1,3-dioxolanes with vinyl butyrate or propionate resulting in preferential acylation of one enantiomer. Amidohydrolase has been used to catalyze hydrolysis of racemic methyl 2,2-dimethyl-1,3-dioxolane-4carboxylate leaving the (S)-ester unchanged . A reinvestigation of the Birch reduction of benzodioxole and simple derivatives has shown that, contrary to early reports by Birch, treatment with sodium in liquid ammonia with added methanol gives the 4,7-dihydrobenzodioxole in quantitative yields and subsequent addition of KNH2 and ammonia gives the 3a,4-dihydrobenzodioxole . Electrochemical anodic oxidation of 2,2-dialkyl-1,3-benzodioxoles leads to cyclotrimerization via the 5,6-positions to form triphenylene tris(dioxoles) in good yields . Treatment of the hydrazones of aromatic aldehydes with 2-trichloromethyl-1,3-dioxolane followed by acid hydrolysis of the intermediates 172 provides a useful route to the corresponding -chlorocinnamaldehydes (Scheme 14) .

Ar

N

NH2

O +

CuCl H2NCH2CH2NH2

O HCl Ar

Cl3C

DMSO

O

CHO

Ar

O Cl

Cl

172 Scheme 14

4.10.8 Reactivity of Substituents Attached to Ring Heteroatoms No significant new reports have appeared in this area.

4.10.9 Ring Synthesis 4.10.9.1 One-Bond Formation Adjacent to a Heteroatom Oxidative cyclization of benzyl and other 2-hydroxyethyl ethers to afford dioxolanes (Equation 46) can be achieved using N-iodosuccinimide in nitromethane for R ¼ Ph or photochemical reaction with iodine and polymer-supported iodobenzene diacetate in acetonitrile . In a related process, RuCl2(Ph3P)2 catalyzes the isomerization of allyl 2-hydroxyethyl ether to form 2-ethyl-1,3-dioxolane . HO

O

[–2H]

ð46Þ

R R

O

O

A variety of methods involving metallated 2-hydroxyethyl vinyl ethers have also appeared where cyclization gives a 2-metallomethyl-1,3-dioxolane, which can then be trapped by a suitable electrophile (Equation 47). Examples include use of Grignard reagents or diisobutylaluminium hydride (DIBAL-H) to give intermediates 173 with M ¼ MgBr, R2Al or (RO)3Ti , which are then trapped with aldehydes to give 174 (E ¼ CH(OH)R). In the last case, the process can be rendered asymmetric by using titanium 1,19-bi-2-naphthol (BINOL) or TADDOL derivatives. Under Heck-type conditions, the intermediate 173 with M ¼ (L)nPd reacts with aryl bromides to give 174 (E ¼ Ar) . M–O O

O M

O

173

E+

O E

O

ð47Þ

174

A new oxidative cyclization of propargylic acetates to 1,3-dioxolanes has been achieved using a palladium(II) catalyst with carbon monoxide in methanol (Equation 48) .

863

864


2 R1 R

Pd(II) CO, MeOH

O R3

R3

O

MeO

O

R1 R2

H O

ð48Þ CO2Me

Rhodium-catalyzed intramolecular reaction of diazo ketones like 175 leads mainly to carbenoid insertion into the -C–H bond but a minor product is the 1,3-dioxolane (Equation 49) . O

O Rh2(O2CR)4

N2 R1

R1

CH2Cl2, rt

O

O

O

R2

R2 Major product

175

O

R1

+

R2

ð49Þ

Minor product

Spiro benzodioxole-cyclohexadienones have been prepared from 4-(2-hydroxyphenoxy)anilines by oxidation using 5 equiv of manganese dioxide (Equation 50) . OH

NH2

O

R2

MnO2 (XS)

O O O R1

R1

ð50Þ

R2

Fluoride-induced deprotection in the unusual substrate 176 was accompanied by O–O cleavage in the dioxetane ring to give benzodioxole 177 (Equation 51) .

O O TBDMSO

O

HO O

TBAF

O Ph

HO

Ph

176

ð51Þ

177

The difluorinated 1,3-oxathiolan-5-one 65 was synthesized from an ,-difluorosulfoxide by a Pummerer rearrangement followed by ring closure (Equation 52) . Treatment of a 2-hydroxyalkyl thiocyanate, readily obtained by epoxide ring-opening, with a hindered alcohol such as isoborneol or adamantanol in the presence of H2SO4 gives a 2-imino-1,3-oxathiolane (Equation 53) . The -halo--aldehydophosphonate 178 was converted with thiocyanate into 179, and this readily cyclized with heat or base treatment to afford the 2-imino1,3-oxathiole 180 (Scheme 15) . F MeO2C

S O

F

i, TFAA

CO2Me

O

O MeO2C S

ii, cat. TsOH

F

ð52Þ

F

65

OH R1

NR2

R2OH O

SCN H2SO4 AcOH

R1

S

ð53Þ


O PriO P PriO

H

SCN–

CHO

O PriO P PriO

Cl/Br

178

O PriO P PriO

heat or base

H CHO

S

SCN

O NH

180

179 Scheme 15

4.10.9.2 Two-Bond Formation from [4þ1] Atom Fragments A large number of new reports of reactions of this type have appeared, the majority of which involve reaction between a 1,2-diol or equivalent and an aldehyde, ketone, or other component that supplies C-2 of the resulting dioxole ring. Synthesis of aromatic fused dioxoles will be considered first before dioxolanes and dioxolanones. Several new catalysts have been introduced for the condensation reaction of catechol with aldehydes and ketones to form 1,3-benzodioxoles (Equation 54) including montmorillonite and super-acid sulfated zirconia . Catechols can also be transformed into benzodioxoles by reaction with dimethyl acetylenedicarboxylate (DMAD) and 10 mol% of 1,4-diazabicyclo[2.2.2]octane (DABCO) (Equation 55) and by reaction with 1-methoxycyclopentene in cyclopentanone to give the product in 54% yield (Equation 56) . Ring-fused ortho-quinones such as anthraquinone can be converted into the corresponding dioxoles in one step either by cathodic reduction in dichloromethane or by reaction with a nitroalkane anion (Scheme 16) . OH

O

+ OH

R1

OH

DMAD

R2

O

O

R1

O

R2

CO2Me

R

R 0.1DABCO

OH OMe

OMe

OH +

O

+

ð56Þ O

OH CO2H

O

R1

O

R2

ð55Þ

CO2Me

O

O

OMe

ð54Þ

OMe

NO2 – R2 R1

O

+2e– (cathode)

O

O

CH2Cl2

O

Scheme 16

For the formation of 1,3-dioxolanes from a 1,2-diol and a carbonyl compound (Equation 57), a wide variety of new catalysts and other methods have been reported including the use of triethyl orthoformate and 1% Me2SþBr Br , catalytic TMS-OTf and 1 equiv of i-PrO-TMS , polymer-supported Ph3P/I2 , polyaniline-supported sulfuric acid salt , zeolite HSZ-360 , K-10 montmorillonite , and an Al/Fe pillared montmorillonite . Microwave irradiation has been found to be effective for this process either in conjunction with a Dean and Stark trap , silica-supported NaHSO4 , or CdI2 in the absence of solvent . The combination of

865

866


microwave irradiation with anhydrous CuSO4 on SiO2 in the absence of solvent is selective for aldehydes over ketones . OH

O +

OH

R1

R2

O

R1

O

R2

ð57Þ

Particular dioxolanes of interest made by this method include the perfume ingredient ‘apple ester ’ 181 formed using silicotungstic acid, H8[Si(W2O7)6] , compound 182 formed using catalytic tartaric acid in ethyl acetate , the glyoxylic ester-derived dioxolanes 183 formed using H2SO4 , and dioxolanes 184 which may act as a ‘fluorous protecting group’ for carbonyl compounds . Me O

O

O

CO2Et

Me

O

O

R3

Me Me

R1O2C

Me

181

O

R2

OH

182

O OMe

O

RF

RF

183

RF = C6F13 or C8F17

184

Dioxolanes have been formed from 1,2-diols in several more unusual ways (Scheme 17), including reaction with SOCl2 or POCl3 in dimethyl sulfoxide (DMSO) (where the CH2 apparently comes from DMSO) , reaction with 1,2-bis(phenylsulfonyl)ethene to give the sulfonylmethyl product , reaction with an aromatic thioketone and silver trifluoroacetate , reaction with -phenylthiodihydropyran to give a spiro product 185 , reaction with butynone proceeding by bis(hydroalkoxylation) , and reaction with appropriate quinone derivatives to give spiro products 186 .

R

O O

R

SOCl2 or POCl3

186 O R

R O

O

H

R

O

R

O

O

R

PhO2S

OH

H

O

R

Me O

SPh

R

O

R

O

SO2Ph

Ag+ CF3CO2–

S Ar

O

R SO2Ph

OH

R O

DMSO

Ar

R

O R

O

Ar

O

Ar

185 Scheme 17

Formation of 1,3-dioxol-2-ones 187 can be achieved by treatment of -hydroxy ketones with a suitable carbonyl source such as phosgene or N,N9-carbonyldiimidazole or triphosgene, Cl3C–O–C(TO)–O–CCl3 (Equation 58). In an unusual process, transfer hydrogenation of -sulfonyloxyketone 188 with a chiral rhodium catalyst and formic acid as hydrogen source afforded the 1,3-dioxolan-2-one 189 with 94% ee (Equation 59) .


HO

R1

O

R2

O

+ X

O

R1

O

R2

O X

ð58Þ

187 O O

Ru(II)(L*)n OTs

Ph

HCO2H

188

O

O

ð59Þ

Ph

189

Several new methods for the conversion of -hydroxy acids into the corresponding 1,3-dioxolan-4-ones by reaction with aldehydes or ketones (Equation 60) have appeared and examples of effective reagents include Sc(OTf)3 in the presence of BINOL to give a chiral product , 5 mol% I2 in THF , either Sc(OTf)3 or Sc(NTf2)3 and anhydrous CuSO4 under solvent-free microwave conditions . Conversion of tartaric acid into bis(dioxolanones) 190 involved treatment with an aldehyde and LiClO4 in Et2O . As an alternative to the method of Equation 60, reaction of aromatic thioketones with -hydroxy acids in the presence of AgNO3 and Et3N also gives dioxolanones and a preparation of compound 191 in this way from Micheler’s ketone and mandelic acid has been patented . R2

HO

O

HO

R1

+

O R3

O

R

H

O O

R2

O

O

R3

O

R1

O

O

O

Ph

ð60Þ

Me2N O

O

H

R

O

190

Me2N

191 The reaction of 2-mercaptoethanol with aldehydes and ketones to form 1,3-oxathiolanes (Equation 61) has been much investigated and effective new reagent and catalyst systems include LiBF4 in MeCN , i-Pr3Si– OTf in dioxane , In(OTf)3 , Sc(OTf)3 , Yb(OTf)3 in an ionic liquid , Me2SþBr Br , Bu4Nþ Br 3 , and 30 mol% NBS in CH2Cl2 . SH

O

S

R1

O

R2

ð61Þ

+ R1

OH

R2

Various solid-supported catalysts have also been effective including K-10 montmorillonite , silicasupported HClO4 , TaCl5 on SiO2 , aminopropyl hydrochloride-functionalized silica , and a fluorinated cation exchange resin containing sulfonic acid groups . Reaction of -mercapto acids with hexafluoroacetone gives the oxathiolanones 192 (Equation 62) which provide a useful protected form of the acid and also allow introduction of a mercapto acid unit into peptides . HO

F3C O F 3C

O

+ HS

R

F3C F 3C

O

O

S

R

192

ð62Þ

867

868


Isocyanides react with 2-phthalimidosulfanylphenols to give 2-imino-1,3-benzoxathioles (Equation 63) , and water-soluble 4-imino-1,3-oxathiolane derivatives have been formed by reaction with diiodomethane followed by a silver or lead salt (Equation 64) . A convenient route to oxathiolanes from 2-hydroxyalkyl tert-butyl sulfides and aldehydes has appeared (Equation 65) . O

OH

O

R2N C:

NR2

R1

R1

N

S

ð63Þ

S O

+ NH N H

+ NH

i, CH2I2 ii, AgNO3 or Pb(II)

OH S– NAr

NAr ButCHO, BF3•Et2O

S

PhSMe, CH2Cl2

O

OH

MeO2C

ð64Þ

S

N H Me

Me SBut

O

But MeO2C

ð65Þ

4.10.9.3 Two-Bond Formation from [3þ2] Atom Fragments The iodonium salt 193 derived from methyl acetoacetate behaves as an -ketocarbene equivalent and adds to methyl ketones to give the dioxoles 194. Similar addition to CTS occurs for thioketones to give 195 and with CS2 to give the oxathiole-2-thione 196 (Scheme 18) . The corresponding diazo compound 197 reacts with succinimide and a rhodium catalyst to give the spiro dioxole 198 . S MeO2C Me

S O

Ar

Ar Ar

Ar

MeO2C Me

195: Ar = 4-MeOC6H4

Me

+ IPh

O

MeO2C

R

Me

O

193 O S

Me

O

Me

196

H N

O

O

N2

MeO2C

S

Me R

194: R = Me, Et

CS2 MeO2C

O

MeO2C

O

Me

O

Rh(II) cat.

O

H N

O

198

197

Scheme 18

Further studies on -diazo ketones with a second more remote carbonyl group have appeared and formation of a carbonyl ylide and its addition to an added aldehyde yields bicyclic dioxolanes 199 (Scheme 19) . A rearrangement is clearly involved in the more complex reaction of a silyl diazo ester to give a dioxolan-4-one (Equation 66) .

Me

O R

N2

O

Rh(II) cat.

Me

O Me + R – O

ArCHO

O

O

O

R Ar

199 Scheme 19


O R13Si

OCH2Ph

+ R3

N2

PhH2C

Rh(II) cat.

O

R13Si

R2

O

O

O

R3

R2

ð66Þ

Further studies on the HCl-induced oligomerization of butanedione have allowed the isolation of compound 200, as well as 47, both in very low yield . Alcohols with an adjacent leaving group react with CO2 under conditions of electrochemical reductive activation to give the corresponding dioxolanones (Equation 67) . Treatment with silver carbonate in acetone results in conversion of -bromo glycosidic amides into the corresponding spiro 4-imino-1,3-dioxolanes (Equation 68) . Condensation of a hydroxyacetophenone carbonate with an aldehyde under basic conditions gives the trans-dioxolan-2-ones 201 (Equation 69) . Me

O

Me

OH O

OH

O

Me

O Me

200

CO2, e–

OH

O

ð67Þ

O O

OTs

OAc

OAc

Ag2CO3 acetone

O

AcO AcO AcO

CONH2

AcO AcO

Br

NH

O

ð68Þ AcO

O Me

O O

Ar1 O

OMe

+

O

NMe

Mg(ClO4)2 bipyridyl

O

Me Ar2

Ar1

Ar2CHO

O

O

O

ð69Þ

O

201 A TiCl4-induced tandem aldol–cyclization reaction takes place between the dihydropyran 202 and carbonyl compounds such as isatins to give bicyclic spiro dioxolanes 203 (Equation 70) . Conversion of propargyl alcohols 204 into 4-alkylidene-1,3-dioxolan-2-ones 205 (Equation 71) can be achieved either, for R3 ¼ H, with CO2 and CuCl in an ionic liquid or, for R3 ¼ CF3, with Na2CO3 and a palladium(II) catalyst in DMF . A highly unusual palladium-catalyzed domino reaction featuring elimination and reincorporation of CO2 is involved in the reaction of propargylic carbonates 206 with substituted phenols to give dioxolanone products 207 (Equation 72) . Dimerization of phthalimidoalkyloxiranes occurs under the influence of BF3?Et2O to give dioxolanes (Equation 73) . Me O Me

Me

O O

202

TiCl4 +

O O

O N R

COMe O N R

203

ð70Þ

869

870


R3 R3CH

O O

ð71Þ

R2 O R1

R2 OH R1

205

204

O OH

O

OMe

HO

O

O

Pd cat.

+

ð72Þ

O

R

R

O

206

207 O

O

O

N

(CH2)n

O

n = 2, 3

O

O

BF3•Et2O

(CH2)n

N

(CH2)n

O

ð73Þ

N

O

O

A new and unexpected route to oxathiolanes involving interaction of a thione, dimethyl fumarate, and phenyl azide is illustrated by the overall reaction of 208 going to 209 (Scheme 20), although the mechanism is complex with seven steps including loss of N2 and MeOH . The same thione 208 also underwent a Rh(II)catalyzed reaction with dimethyl diazomalonate to give 210 and 211 . CO2Me

MeO2C

Me Me

Me Me PhN3

S

CHCO2Me

O

NPh

O

S

O

Me Me

Me Me

208

209

MeO2C N2 MeO2C Rh(II)

Me Me

Me Me

CO2Me

S

S +

O O

O O Me Me

OMe

Me Me

210

CO2Me O

211

Scheme 20

In a related study, the spiro thiadiazoline 212, formed by reaction of 208 with CH2N2, reacts with methyl pyruvate or its trifluoro analogue to give oxathiolane products 213 resulting from thiocarbonyl ylide cycloaddition (Equation 74) . Reaction of fluorobenzoquinone with chloromethanesulfinic acid affords the benzoxathiole S,S-dioxide 214 (Equation 75) . Me Me

Me Me O

S O N Me Me

212

N

+

S O

R3C

CO2Me

R = H, F

–N2

O Me Me

213

CO2Me CR3

ð74Þ


F

O

Cl

+

i, HCl ii, NaOH

F

O

51%

HO

S O2

HO2S

O

214

ð75Þ

4.10.9.4 Three-Bond Formation Various new methods have been reported in which a carbene or equivalent reacts with 2 equiv of an aldehyde or other carbonyl compound to form a 1,3-dioxolane. A simple example is provided by reaction of dimethylalloxan 215 with isonitriles to afford products 216 (Equation 76) . A more general process is that shown in Equation 77, which has been reported for Rh(II)-catalyzed reaction of ethyl diazoacetate (R1 ¼ CO2Et, R2 ¼ H) and methyl diazotrifluoropropionate (R1 ¼ CO2Me, R2 ¼ CF3) . More recent variations include treatment of the carbene with two carbonyl compounds of different reactivity to give products such as 217 and 218 . The similar product 27 was formed by treatment of 1-heptanal and ethyl propiolate with Et3N at 78 C . O O NMe + RN=C:

MeN

2

Me O O N

MeN

NMe O

O

O NR

ArCHO

:

Ar

R2

O

O+ –

R1

O

Ar

ArCHO

R1

R2

O

R2

ð77Þ

Ar

O

MeO

ð76Þ

216

215

R1

O

O

O

O

Me N

O

Ph

O

Me

CO2Me

CO2Me CO2Me

C6H11n

O

C6H11n

27

But NO2

217

CHCO2Me

O But

O O2N

O

218

Other approaches to the key carbonyl ylide intermediates are also effective and SmI2 treatment of an -iodo silyl ether in the presence of an aldehyde also gives the dioxolane product (Equation 78) . Similarly, desilylation of 219 gave an intermediate that added to carbonyl compounds to give dioxolanes and to thioketones to give oxathiolanes (Scheme 21) . R OSiEt3 2

Ph

I

+ RCHO

SmI2

O Ph

O

ð78Þ Ph

Mechanistic studies have led to a proposed pathway for formation of the oxathiolanone 220 in low yield by electrochemical reduction in the presence of H2S (Equation 79) . No reasonable mechanism has yet been suggested for the formation of oxathiolane 221 (Equation 80) .

871

872


O

R1 O

O

R1 O

R2

+

Ar

O

O

–

CsF Ar

Ar

R2

TMS

R1 R2

O+

Ar

Cl

219

R1

R1 R2

S

S R2

Ar

R1 S

R2

+

Ar

O

O

Scheme 21

O Ph

e–, H2S

Br

Ph

graphite cathode

Br

O

O

Ph

Ph Ph

S

Ph

ð79Þ

220 Me Me

Me Me

+ N

O

HO SH

N

CN

S NC

221

S

Me Me

ð80Þ

CHCN

4.10.10 Ring Synthesis by Transformation of Other Heterocyclic Rings 4.10.10.1 Three-Membered Rings The reaction of epoxides with carbonyl compounds, particularly acetone, to afford 1,3-dioxolanes (Equation 81) continues to be of major interest and a large number of new reagent and catalyst systems for this reaction have been described including Cu(OTf)2 , TiCl3OTf , TiCl4 at 78 C which is particularly good for chiral epoxides , LiBF4 , BF3?Et2O , Bi(III) salts such as BiCl3, Bi(OTf)3, and Bi(CF3CO2)3 , RuCl3 , MeReO3 , potassium dodecatungstocobaltate, K5CoW12O40?3H2O , tin(IV) tetraphenylporphyrin salts , and photolysis in the presence of a quaternary pyridinium salt .

O R1

R1

O + R2

R3

O O

R2 R3

ð81Þ

An intramolecular example is provided by the zirconocene-catalyzed cyclization of epoxy esters 222 to give bicyclic products 223 (Equation 82) . When the closely similar fluorinated epoxy esters 224 are formed in situ, polymerization occurs to give poly(dioxolanes) (Scheme 22) . Tetrabutylammonium cyanide catalyzes the isomerization of 225 to afford benzodioxoles 226 (Equation 83) .

O R

Cp2ZrCl2 AgClO4

Me O

222

O

O R

Me O O

223

ð82Þ


O RF

OH

+

O

Bu4P+Br–

Br

O

RF

O

O

O

n O RF

O

224 Scheme 22

O

O

Bu4N CN

R

R

ð83Þ

O O

225

226

The other reaction of epoxides that has been of very great interest is the industrially important carboxylation to form 1,3-dioxolan-2-ones (Equation 84), and a large number of new catalysts and reaction conditions have been reported. Some of the more important of these are ZnBr2 and pyridine , mixed indium, lead, and alkali metal halides , Nb2O5 and NbCl5 , MgO in DMF , magnesium-containing heterogeneous smectite materials , CoCl2 in DMF , (CO)5ReBr and supercritical CO2 , mixed manganese and alkali metal halides , the zincsubstituted polyoxometalate Na12[WZn3(H2O)2(ZnW9O34)2]?48H2O together with a Lewis base such as 4-dimethylaminopyridine (DMAP) , (Ph3P)2NiCl2 together with Ph3P, Zn, and Bu4Nþ Br , the quaternary stibonium salt Ph4Sbþ Br , and various quaternary ammonium salts . O

CO2

R1

O

ð84Þ

O

R1

O

Various metal azamacrocycles are effective catalysts including aluminium phthalocyanines , copper and manganese phthalocyanines, porphyrins, and salens , salen complexes of cobalt , chromium , and aluminium , a cobalt porphyrin , and aluminium, chromium, and iron(III) 8hydroxyquinolinates . Solid-supported catalysts have also been reported including the I– form of an ion exchange resin , poly(ethyleneglycol) KI complex , quaternary ammonium saltterminated poly (ethyleneglycol)s , polymer-supported gold nanoparticles , and a silica-supported quaternary phosphonium salt . Ionic liquids have been used and electrocatalysis of the reaction as well as the use of supercritical CO2 in ionic liquids have been examined. Finally, in this section, the reactions shown in Equation 84 can be carried out substituting DMF and O2 for CO2 if a BiBr3 catalyst is used . The chlorinated dioxolanones 227 are readily prepared by treatment of epoxy alcohols with phosgene (Equation 85) . R COCl2, Et3N

O HO

R

O O

Cl

ð85Þ

O

227: R = H, Ph The corresponding reaction of epoxides with thiocarbonyl compounds to furnish 1,3-oxathiolanes (Equation 86) has also been examined in some detail although it is limited by the availability of stable thiocarbonyl compounds. Specific examples of compounds prepared in this way are 50 and 51 prepared from butadiene monoepoxide , 228 prepared from cyclohexene oxide , and 229 prepared from a thiazolinethione .

873

874


R1

S

O

O

+

R1

R2

R3

S

Me Me S

R2

ð86Þ

R3

R2 R3 S

N O Me Me

O

S

R1

228

229

A new approach to oxathiolanones involves direct reaction of an epoxide, sulfur, and CO under pressure with catalytic NaH in THF (Scheme 23) . As shown, the method is stereoselective.

O

O

R

O

CO, S, cat. NaH

O

O

R

THF

R

R

CO, S, cat. NaH

S

O

S

THF

R

R

R

R

Scheme 23

4.10.10.2 Five-Membered Rings Reaction of either 1,3-oxathiolanes or 1,3-dithiolanes with ethanediol and NBS leads to an exchange reaction to afford the corresponding 1,3-dioxolanes (Scheme 24) .

R1

O

R2

S

OH

HO NBS

R1

O

R2

O

OH

HO NBS

R1

S

R2

S

Scheme 24

4.10.10.3 Six-Membered Rings Interaction of 1,3,5-trioxane with CO over zeolite HZSM-5 results in elimination of formaldehyde to give 1,3dioxolan-4-one (Equation 87) . Acid-catalyzed rearrangement of functionalized 1,3-dioxanes 230, formed by peracid addition to 1,3-dioxins, results in loss of carboxylic acid and formation of 1,3-dioxolane-4aldehydes (Scheme 25) . An unusual base-induced rearrangement of the tartratederived chiral 1,3-dioxane 231 gave the 1,3-dioxolane 232 (Equation 88) . 1,4-Oxathiins react with singlet oxygen to give isomeric oxathiolane S-oxides via a novel rearrangement (Equation 89) . O

O O

CO, HZSM-5 O

–CH2O

ð87Þ

O O


Me

OCOAr

MCPBA O

Me CHO

Me OH

O

O

cat. H+ O

O

R1 R2

2 R1 R

R1 R2

O

– ArCO2H

230 Scheme 25

Me OMe Me

Me O

O MeO

O OMe

MeO

LDA CO2R

Me

CO2R

231

O

ð88Þ

CO2R

232

1O

S

2

S O

O

S

O

+

R1

O

R2

R1

CO2R

O

O

R2

O

ð89Þ

R2 R1

4.10.11 Best Methods of Synthesis Most of the heterocycles covered in this chapter are either best made by relatively standard methods that were adequately covered in CHEC-II(1996) or else are so unusual that only one preparative route is known. However, some new reliable procedures for a few key compounds can be mentioned here. An improved method for preparation of 1,3-dioxol-2-one (vinylene carbonate) 233 involving dehydrochlorination with Et3N in dioxolanone as solvent has been patented (Equation 90) . A simple cost-effective one-pot synthesis of cyclopentadienylidenedioxolane 234 involves treatment of a metal cyclopentadienide with 2-chloroethyl chloroformate followed by base (Scheme 26) . A reliable procedure has been published for largescale synthesis of TADDOLs 235, which have many applications as described in Sections 4.10.12.2 and 4.10.12.3 (Equation 91) .

Cl

O O O

Et3N

O

O

O

O O

ð90Þ

233

O

O Cl

O

Cl

H O

– M+ O

Scheme 26

base

O

Cl O

234

875

876


Ar Ar Me Me

O

CO2Et

O

CO2Et

ArMgBr

Me Me

O

OH

O

OH

ð91Þ

Ar Ar

235

4.10.12 Applications 4.10.12.1 Uses in the Polymer, Food, and Perfumery Industries, and Occurrence in Nature Dioxolane compounds that have formed the basis of polymers include 236 and 237 and the perfluorinated compounds 238 and 239 . A range of 1,3-oxathiolanes, such as 240 and 241, have been evaluated as flavor ingredients . New dioxolane perfume ingredients examined include 181 , 242 , and 243 . The toxic component of a poisonous mushroom has been identified as the diacid 244 .

O

R3

O

O

O

O O

2 R1 R

O

O

O

F F

F

O

F

S

F

O

F2 C

O F

237

F

F

F2C

2 R1 R

236

F

O

F

F

238

F F

F

239

240 Ph

O S O

241

Me

CO2Me

O TMS

Me Me Me

EtO2C

O O

Me

O

CO2H

O

CO2H Ph

242

243

244

4.10.12.2 Applications Based on Physical and Chiroptical Properties A range of bis(dioxolanes) such as 245 have been patented as components of liquid crystal displays . The photochromic dioxolone 246 has been prepared and studied . Triarylbismuth compounds such as 247 have been used as contrast agents for X-ray imaging , while benzodioxole- and benzoxathiole-containing triarylmethyl radicals such as 248 have been used as image-enhancing agents in magnetic resonance imaging (MRI) . The dioxolane-containing amino acid 249, synthesized enzymatically, is a chiral gelator of organic solvents and compounds such as 250 have been examined as positively charged lipids . Simple dioxolanones have proved useful as electrolyte solvents and examples include 251 , fluorinated dioxolanones such as 252 which have been used in electrolysis , and compounds such as 253 that have been used in battery electrolytes .


BuO2C

O

O

CO2Bu

BuO2C

O

O

CO2Bu

O O

245

Me Me Me O

Me

S

S S

O

Me Me S Me

H

O

S Me

Me

S

OH

250

O

CO2Et

O

CO2Et

F3C

O

O

Me

Me Me

O

CF3

O O

O

248

Bi

X–

O

NH2

249

S

Me Me

C15H31n

3

247

+ N Me2

O

CO2H

O

Me Me

SO2

N H

O

OH

Me

O

Me Me

S

Me Me

O

246

S

• O

O

O

251

252

253

The so-called TADDOLs of general structure 235 have found many applications and, as a result, the synthesis of new derivatives has been of interest. Derivatives synthesized include 40–44 , mono- and di-unsaturated TADDOL esters , TADDOL–crown ether hybrids , and unsymmetrical derivatives 254 . A new Weinreb amide-based route to compounds 255 has appeared . R1 R2 Me Me

O

OH

O

OH Ar

Me Me

O

OH

O

OH 2 R1 R

Ar

254

255

A major application has been resolution of racemic compounds by means of crystalline TADDOL inclusion complexes, and new examples include resolution of butenolides and pyrazolines using 235, of 2-methylpiperidine and 2,2-disubstituted cyclic ketones using 256, of 2-benzylcyclohexanone and 4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane using 257, of various compounds using 258 , and of oxaziridines using either 235 or 258 . The bis(TADDOL) compounds 259 have also been useful for resolution and enantioselective molecular recognition studies . The TADDOLs have also been used to direct asymmetric reactions and examples include a Diels–Alder reaction in an inclusion complex with 256 , the [2þ2] photochemical dimerization of coumarin in an inclusion complex with 235 (Ar ¼ Ph) under high vacuum , and intramolecular [2þ2] cycloaddition in inclusion complexes with either 256 or 257 . The other major application of TADDOLs as ligands and catalysts for asymmetric synthesis is described in Section 4.10.12.3. Ar Ar O O

OH OH Ar Ar

256

Ar Ar O

OH OH

O Ar

Ar

257

Ar Ar

Ar Ar

Ar Ar

O

OH

HO

O

O

OH

O

OH

HO

O

O

OH

Ar Ar

258

Ar Ar

Ar Ar

259

4.10.12.3 Applications as Ligands and Catalysts in Asymmetric Synthesis Catalytic asymmetric epoxidation of alkenes has been achieved by means of dioxiranes formed in situ from OXONE and dioxolane-containing cyclic ketones such as 34, 35 , and 260 derived from

877

878


quinic acid and the tetrahydropyranone analogue 261 . Salts of structure 262 have been used as asymmetric phase-transfer catalysts for alkylation and Michael addition of a protected glycine equivalent . Compound 58 has been examined as a ligand in rhodium-catalyzed hydrogenation and the carbohydrate-derived phosphite 263 has been used for hydrosilylation of acetophenone . The dioxolane bis(oxazolines) 264 are effective as ligands in copper-catalyzed cyclopropanation and aziridination , and the oxazolidinone 265 derived from D-mannitol has been used for Evans-type chemistry . New bidentate ligands evaluated include 266 and 267 , and 268 is effective in palladium-catalyzed Suzuki cross-coupling . Chiral cyclopentadienes such as 269 have been prepared and evaluated as ligands . Me Me

Me Me

O O

Me Me

O

O

O But

O

O O

O

O

O

260

261

Me Me

Me Me

O

+

O

NMe(CH2Ar)2

O

NMe(CH2Ar)2 2 X–

O

+

P

O

O 3

262 O

O

R

R N

N

O

Me

O

O

O

O

O

Me Me

Me Me

263 O

O

N O Ph2P

R

Me Me

R

265

264

Me Me

NH

O

O

O

266

Me Me O

O

O

O Me

N

PPh2

Me

O

O

Me O

O

Me Me

P(c-C6H11)2

267

268

269

The dioxolanylphenyl groups play an important part in the effectiveness of binaphthol-derived phosphite 270 . An improved process for manufacture of the diphosphine oxide 271 has been described , and the fluorinated diphosphine analogues 272 have been reported . Other dioxolane-containing ligands include 273 , the triphosphines 274 , and the borane adducts 275 which are effective in rhodium-catalyzed hydrogenation of CTC bonds . CO2Me O OP(OAr)2 OP(OAr)2 CO2Me

O

P(O)Ph2

O

P(O)Ph2

O

270: Ar = 271

O O


Me Me

R F

O

F

O

PPh2

F

O

PPh2

F

O

O

P(Fc)2

O

P(Fc)2 CO2Me

273: Fc = 2-ferrocenyl O

PPh2

(CH2)n O Ph2P

PPh2

Me

R

272: R = H, SiEt3

Me Me

O

PPh2•BH3 PPh2•BH3

O

CO2Me

274: n = 2–6

275

There have been a large number of reports of the use of TADDOLs in asymmetric synthesis, both on their own and, more commonly, in conjunction with transition metal catalysis, and this area has been reviewed . The dichlorotitanium compound 276 catalyzes asymmetric Diels–Alder cycloaddition , 1,3-dipolar cycloaddition of nitrones , silyl enol ether addition to nitroalkenes , and osmium-mediated diimination of a double bond . The corresponding diisopropoxy compound 277 catalyzes asymmetric Simmons–Smith cyclopropanation of allylic alcohols . The allyl compound 278 effects enantioselective allylation of aldehydes , while the cyclohexadienyl analogue 279 also adds to aldehydes to give 1,3-cyclohexadienyl alcohols 280 (Equation 92) . The bis(TADDOL) titanium 281 catalyzes asymmetric iodocarbocyclization of alkene-containing dialkyl malonates , while the cerium compound 282 reacts with aldehydes to give secondary alcohols with up to 70% ee . Zirconium TADDOL compounds formed in situ catalyze both asymmetric cyanohydrin formation from aldehydes and Meerwein–Ponndorf–Verley reduction . Copper(I) thiol–TADDOL complexes are effective in catalyzing conjugate addition of Grignard reagents to enones . TADDOL itself in the absence of any metal brings about addition of enamines to nitrosobenzene giving -hydroxylamino ketones and also promotes Michael addition of diethyl malonate to a nickel-complexed enone . Ph Ph O

O

Me Me

H Cp

OH

RCHO

R

Ti O

ð92Þ

O Ph Ph

280

279

Ph Ph Me Me

O

Ph Ph

O

R1 Ti

O

2 O R

Ph Ph

276: R1 = R2 = Cl 277: R1 = R2 = OPri 278: R1 = Cp; R2 = allyl

Me Me

O O

O O Ti O O Ph Ph

Ph Ph

Ph Ph

Ph

281

O O Ph

Me Me

Me Me

O Ce R O

O O Ph

Ph

282

The ligand 283 is effective in palladium-catalyzed coupling of aryl chlorides with aryl Grignard reagents, silanes, and boronic acids to give biaryls , while the phosphites 284 catalyze conjugate addition of Et2Zn to enones . The TADDOL–phosphite oxazolines 285 are effective for palladium-catalyzed allylic substitution and iridium-catalyzed alkene hydrogenation as well as rhodium-catalyzed hydrosilylation of ketones .

879

880


O

O

Me Me

O

Me Me

P O

Ph Ph

Ph

Ph Ph

H

O

O

O

O

P O

Ph Ph

Ph

O

O

O

Me Me

Ar

P O O

O

284

283

Me Me O

Ph Ph

Ph

R

N

285

Finally, in this section, various studies on solid-supported TADDOL compounds have appeared, including polymer-supported TADDOL titanium catalysts , immobilization of TADDOL monomers on polyethylene fibers , and use of polymer-bound or silica-supported TADDOLs to catalyze addition of Et2Zn to benzaldehyde.

4.10.12.4 Agrochemical and Pesticidal Applications Compound 286 is claimed to activate wheat seeds toward germination and protect plantlets from water stress , while compounds 287 are potential pyrethroid synergists . Carboxylic acidcontaining dioxolanes such as 288 and 289 have been used for controlled release of volatile aldehydes for control of insect pests . New herbicidal dioxolanones are exemplified by 290 , while a range of antifungal agents containing a key central dioxolane unit are illustrated by the examples 291 , 292 , 293 , and 294 .

O

Pri

O

O

O

N

N MeO

O

HO2C

O

HO2C C9H19

O C9H19

CO2H

O

288

289

O

O

OH Me N

Cl Cl

Me

Cl

291 N

O

Cl

O

O

Me

O

O

N

O

O

F

290

HO2C

287 X = OCOR, NR2

O

N

X

O

286

N

Prn

O

N N

O

O

Ph

O

N

N

N

N

N

Cl

F Cl

Cl

292

293 N

N

OMe

O

O

N

N O

Me

O

O

O

N

N

294

N

N

N

Et

OR Me


4.10.12.5 Medical and Pharmaceutical Applications The dioxolane-containing bicyclic amino acid derivatives 295 have been examined for use in peptidomimetics , and work in this area has been reviewed . The basic concept has been extended to the isomeric system 296 , the larger ring analogue 297 , and the tricyclic compounds 298 . Studies have continued on the antimuscarinic activity of compounds such as 299 . New examples of medicinally useful benzodioxoles include cannabinoid receptor antagonists such as 300 to tackle obesity , the adrenergic agent 301 , the 3-adrenoceptor agonists 302 , and the tumor necrosis factor -inhibitor 303 . The nucleoside analogues 304 have been examined as antiviral agents and monoamine oxidase inhibitory and psychostimulant properties are claimed for 305 . The piperazinyl-dioxolane 306 has antitussive activity . Dioxolane 307 has been evaluated as a heme oxygenase inhibitor , and the new dioxolane-containing furocoumarin dimer paradisin C 308 has been isolated from grapefruit juice and is found to inhibit cytochrome P450 enzymes .

R2

R2

O

O O

R1N

CO2H

R1N O

HN

HO2C

295

BnO

O

O

O N O O

O

296

297

298

R1

HO O

Ph

I–

O

+ NMe3

Ph

O

Ph

O

O S O2

R2

299 O O

301 O

O

HO

305

O

N

303

307

PhN

Me S

O

Et

O

Et

N

306 Me Me

O O

Cl

H

304

O O

O N R

O

N O

HO2C

N

NH

O

302

O O

R

O

CO2R3

NHAc

O

OMe

CO2R2

O

N

N

300

R1

N

CO2Me

CO2Me

O O

O

NH2 O

O

OH

O

Me

O

308 Me

Me OH

The simple dioxolanone 309 has been prepared and has antidiabetic activity , and the dioxolone structure 310 has been used as a pro-drug for pharmaceutically active amines R22NH to which it is degraded in vivo . Dioxolanone-containing compounds such as 311 have squalene synthetase and cholesterol synthetase inhibitory activity and can be used to treat hypercholesterolemia .

881

882


Me

O Me Me

O

O

O

O

OH MeO2S

Pri R1

O O

HO O

O

NR22

S O O

Pri

N H

O

F

O

N N

311 S

HO

O

O

O

O

310

O

O

309

Me NH2

313

312

The oxathiolane nucleoside analogue 312 has antiviral activity , benzoxathiole S,S-dioxides such as 57 which are analogues of griseofulvin have been tested as antifungal agents , and benzoxathiolones such as 313 containing a hindered phenol function are effective antiviral agents against meningoencephalitis and herpes simplex virus .

4.10.13 Further Developments The range of electrophiles used in studies of the deprotonation and alkylation of chiral 1,3-dioxolan-4-ones at the 5-position has been further extended to include butenolide , 2-benzylidene-1,3-diketones , o-nitrobenzyl bromides which after subsequent reduction and cyclization afford dihydroquinolinones , and sugar-derived chiral N-sulfinyl imines . Use of 1,3-dioxolan-4-on-5-yl phosphonates in the Wadsworth–Emmons reaction with substituted benzaldehydes to give 5-benzylidene-1,3-dioxolan-4ones has been reported . New results on the radical addition of 2,2-dimethyl-1,3-dioxolan-4-yl to chiral N-toluenesulfinyl imines have appeared . The cycloaddition behavior of 5-alkylidene-1,3-dioxolan-4ones has been extended to include [2þ2] cycloaddition with dichloroketene generated from trichloroacetyl chloride and zinc. Diastereomeric mixtures of cyclobutanone-spiro-dioxolanones are obtained . Further results on the Pd-catalyzed cyclization of 2-hydroxyethyl vinyl ether in the presence of an aryl halide (Equation 47) to give isomeric 1,3-dioxolanes have appeared and further work on the method of Equation (48) has been described . An efficient new route to 2-substituted 1,3-dioxolanes is provided by reaction of non-enolizable aldehydes and ketones with 2-chloroethanol and KOBut at low temperature . Further studies on metal-induced cyclization of allylic and propargylic carbonates leading to 1,3-dioxolan-2-ones (cf. Equation 72) have been reported . Pinacol reduction of acrolein followed by treatment with diethyl carbonate has been used to obtain cis- and trans-4,5-divinyl-1,3-dioxolan-2-one and the stereoselective nucleophilic ring-opening of these has been examined . Reaction of diaryl epoxides with acetone in the presence of Amberlyst 15 affords the corresponding 2,2-dimethyl-1,3dioxolanes with excellent yield and retention of stereochemical integrity . Further catalysts for the reaction of epoxides with CO2 to give dioxolanones (Equation 84) include a rhenium complex covalently anchored to an ionic liquid component , the system (Bu2N)3CBr/ZnBr2 , and natural -amino acids . In one case Pd-catalyzed epoxide carboxylation was accompanied by addition of a phenol across an adjacent triple bond . Wolff rearrangement of the carbene derived from 2-diazirino Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione-5-spiro-39-diazirine) by photolysis in methanol leads efficiently to 2,2-dimethyl1,3-dioxolan-4-one-5-carboxylic acid . Finally, an improved synthesis of a number of simple chiral 1,3-dioxolan-4-ones such as 96 from the corresponding -hydroxy acids has been described .

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2005S2491 2005S2946 2005SC675 2005SC1441 2005SC3127 2005SL854 2005SL923 2005SL2195 2005T43 2005T2849 2005T12131 2005TA635 2005TA3394 2005TA3848 2005TL1837 2005TL2341 2005TL3687 2005TL3815 2005TL7813 2005WO40156 2006ARK(vii)292 2006CC1419 2006CC1664 2006CC4300 2006EJO765 2006EJO3007 2006H(68)1329 2006H(68)1861 2006JA3931 2006JMO(250)30 2006JOC6785 2006OL515 2006OL3745 2006OL5729 2006RJO1213 2006S2159 2006S2286 2006S2497 2006S3122 2006S3915 2006SL215 2006SL305 2006SL331 2006T829 2006T931 2006T2545 2006T3610 2006T4153 2006T5464 2006T5803 2006T8069 2006T9174 2006T11218 2006TL8369 2006TL1271 2006TL2133 2006TL2643 2007ARK(viii)58 2007CC2175 2007S108 2007S118 2007SL255 2007SL575 2007SL638

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Biographical Sketch

Alan Aitken was born in the Dumfries and Galloway area of SW Scotland. He studied at the University of Edinburgh where he obtained a B.Sc. in 1979 and Ph.D. in 1982 under the direction of Dr I. Gosney and Professor J. I. G. Cadogan. After spending two years as a Fulbright Scholar in the laboratories of Professor A. I. Meyers at Colorado State University, he was awarded a Royal Society Warren Research Fellowship and moved in 1984 to the University of St. Andrews, where he has been a senior lecturer since 1997. His research interests are in the area of synthetic and mechanistic organic chemistry including asymmetric synthesis, synthetic use of flash vacuum pyrolysis, heterocyclic chemistry, organophosphorus and organosulfur chemistry.

Lynn Power was born in Co. Wexford, Ireland. She completed a B.Sc. degree at the National University of Ireland, Maynooth, in 2004, including a final-year research project with Dr. Frances Heaney. She was the recipient of the Kathleen Lonsdale prize for the best student graduating in chemistry. She then carried out Ph.D. work at the University of St. Andrews in the area of asymmetric synthesis using chiral dioxolanones under the supervision of Dr. Alan Aitken.

891

4.11 1,2-Dithioles ˇ R. Markovic´ and A. Rasovi c´ University of Belgrade, Belgrade, Serbia ª 2008 Elsevier Ltd. All rights reserved. 4.11.1

Introduction

894

4.11.2

Theoretical Methods

895

4.11.3


895

4.11.3.1

X-Ray Methods

895

4.11.3.2

NMR Spectroscopy

895

4.11.3.3

Electron Scanning Chemical Analysis and PE Spectroscopy

899

4.11.3.3.1

4.11.3.4

1,2-Dithiolanes

899

UV and Visible Spectroscopy

899

4.11.4


900

4.11.5


900

4.11.5.1

Reactions of 1,2-Dithiolium Salts

900

4.11.5.2


902

4.11.5.3

Reactions with Electrophiles

905

Reactivity of Ring Substituents

905

Reactivity of S-Substituents

905

4.11.6 4.11.6.1

4.11.6.1.1 4.11.6.1.2 4.11.6.1.3 4.11.6.1.4 4.11.6.1.5 4.11.6.1.6

Thio and thiol substituents Reactions with dipolarophiles Atropisomeric 1,2-dithiole-3-thiones Reactions involving organometallic compounds Oxidation and reduction Thermal reactions

907 907 909 911 913 913

4.11.7

Reactivity of Nonconjugated Rings: 1,2-Dithiolanes

914

4.11.8

Synthesis

917

4.11.8.1

Direct Synthesis by Formation of One Bond

917

4.11.8.2

Direct Synthesis by Formation of Two Bonds

920

4.11.8.3

Direct Synthesis by Formation of Three Bonds

924

4.11.8.4

Direct Synthesis by Formation of Two Bonds

927

4.11.8.5

Direct Synthesis by Formation of Three Bonds

928

4.11.9

Ring Synthesis from Acyclic Compounds

929

4.11.9.1

From 3-Oxoesters

929

4.11.10

Syntheses of Particular Classes of Compounds

930

4.11.10.1

1,2-Dithiolanes and Other Saturated Derivatives

4.11.10.2

Synthesis of Potentially Biologically Active Compounds Containing 1,2-Dithiolanes

935

4.11.10.3

1,2-Dithiolium Salts

937

Synthesis of LA and Derivatives

938

4.11.10.4 4.11.11 4.11.11.1

Important Compounds and Applications LA and Derivatives: Synthesis, Natural Occurrence, and Biological Applications

893

930

941 941

894

1,2-Dithioles

4.11.11.2

Natural Occurrence and Biological Applications

944

4.11.11.3

SAMs

946

References

950

4.11.1 Introduction In accordance with the format of the two preceding reviews in CHEC(1984) and CHEC-II(1996) covering the chemistry of 1,2-dithioles, 1,2-dithiolanes, and related compounds, this chapter follows basically the same concept. Thus, the review aims to describe (1) the various reactivity aspects of these compounds; (2) strategies to obtain them, not only by previously developed synthetic pathways but also via application of new routes; and (3) their diverse applications. Much effort has been directed to structural and spectroscopic characterization of particular compounds, containing the basic 1,2-dithiole 1 or 1,2dithiolane core 2, which possess projected physicochemical properties. There are several reasons for interest in these compounds. First, some are isolated natural compounds from medicinal plants, and second they are expected to possess some degree of activity. Because of the interesting biological features of the naturally occurring compounds, such as lipoic acid 3 (LA, 1,2dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric acid, or thioctic acid), which is a strong natural oxidant, and dihydrolipoic acid (DHLA, 6,8-dimercaptooctanoic acid, or 6,8-thioctic acid), in reduced form, they were utilized as precursors for the synthesis of a variety of bioactive derivatives. A large number of biologically useful compounds have LA, basic 1,2-dithiole, or 1,2-dithiolane fragments in their structure, which is also the case, for example, with potential cancer chemopreventive agent oltipraz 4, or natural antibiotic leinamycin 5.

With respect to reactivity and synthetic aspects, various specific transition metal-mediated syntheses of new 1,2dithioles and reactions, thereof, have been reported. Novel metal complexes have been isolated in a number of cases and they provide insight into new chemistry of 1,2-dithioles. The attention of several research groups was attracted in the late 1990s toward synthetic methodologies for selfassembled monolayers (SAMs) containing LA as a binding species to the solid surface. In the context of extensive and diverse research on a variety of compounds with integral 1,2-dithiole and 1,2-dithiolane fragments, several reviews with emphasis on synthetic aspects or various specific advances were published.

1,2-Dithioles

4.11.2 Theoretical Methods The molecular and electronic structures of cyclic disulfide cation radicals of 1,2-dithietane 6 and 1,2-dithiete 7, and radical cations of 1,2-dithiolane 2 (2A–C represent stable conformations determined in terms of the symmetry restriction of Cs, C2, and C2v), with emphasis on the nature of a two-center three-electron (2c-3e) sulfur–sulfur bond have been examined by ab initio molecular orbital (MO) calculations . Unrestricted Hartree–Fock (UHF)/ MIDI-4(d) computations showed that this bond in organodisulfide radical cation 2þ? is shorter in comparison to 1,2dithiolane 2 and possesses partial p-bond character (structure A), as previously implied by electron spin resonance (ESR) spectroscopy , which correlates best with the Cs form as the most favorable conformation of the cation radical 2þ?. Contrary to the repulsive S–S interaction in the parent 1,2-dithiolane arising from the lone pairs of electrons, the hemi-p-bond formed by one-electron oxidation should stabilize the five-membered ring of 2þ?, or, for example, a similar cation radical of LA 3 which is involved in diverse biochemical reactions.

Density functional theory (DFT) and post-Hartree–Fock MP2 in conjunction with the B3LYP employing the 6-31G(d) basis set were used to predict structure and correlate assignments of the fundamental vibrational modes of 3H-1,2-dithiole-3-one 1a and 3H-1,2-dithiole-3-thione 1b with experimental data . These sulfur-rich heterocycles, characterized by a long and weak S–S bond, are represented in accordance to the simple p-MO theory by resonance contributor 8, involving a cationic 6p-1,2-dithiolylium part and an anionic thiolate or olate part, and the exocyclic CTS bond is more delocalized than the CTO bond. However, computational evidence suggests structures with localized bonds and relatively low ‘aromatic’ delocalization, which is also supported by the low values of the dipole moments, that is, 3.54 D for 1a and 4.12 D for 1b.

4.11.3 Experimental Structural Methods 4.11.3.1 X-Ray Methods As illustrated in Table 1, roughly according to chronological order, single crystal X-ray diffraction has been used for the structural characterization of a large number of 1,2-dithiole derivatives. For some compounds not listed in the Table, the single crystal X-ray diffraction analyses are mentioned within the text.

4.11.3.2 NMR Spectroscopy The general synthetic methodology for the preparation of a series of 4–12-membered ring heterocycles bearing different numbers of Si-, Sn-, S-, Se-, or Te-atoms, including selected heterocycles with mixed combinations of these elements (S–Si, Se–Sn, etc.), was recently reported 2006JA14949>. Specifically, regarding the 1,2-dithiolane core, 1,5-dithiocane 44a, when submitted to NOPF6 oxidation at 78 C, is transformed via transannular bond formation to a yellow dication 45a (Scheme 1), as supported by nuclear magnetic resonance (NMR) spectral data (Table 2).

895

896

1,2-Dithioles

Table 1 Structures of selected 1,2-dithioles and 1,2-dithiolanes determined by single crystal X-ray diffraction

1998JOC2189

1997JFC(81)103

1998CC453

1998EJM1577

1998JCX689

1998JOC2189

1999CC29

1999CC73

1999CC1891

1999J(P1)223

1999JOC5010

(Continued)

1,2-Dithioles

Table 1 (Continued)

2001JMC2293

2001JOC5766

2001SL1129

2002BML147

2003CCC1243

2003H(60)1083

2003T10255

2004OL2623

2004PS985

(Continued)

897

898

1,2-Dithioles

Table 1 (Continued)

2004TL7671

2005PES104

2005TL4711

2006RJO124

2006JOC808

2007CRT84

Scheme 1

Table 2

1

H and 13C NMR data (ppm) for dication derived from 1,5-dithiocane 1

1

H NMR (CD3CN) 2.20–2.70 (m, 4H); 2.90–3.60 (m, 8H)

13

C NMR (CD3CN) 35.0; 53.0

1,2-Dithioles

It is thought that intermediate 45a, upon quenching with 2-propanethiol, undergoes fragmentation and subsequent nucleophile-initiated cleavage to give 1,2-dithiolane 2a, although in an unspecified yield. Similarly, the related 1,2diselenolane 2b and 1,2-ditellurolane 2c were synthesized.

4.11.3.3 Electron Scanning Chemical Analysis and PE Spectroscopy 4.11.3.3.1

1,2-Dithiolanes

The static and dynamic characteristics of a helical hexapeptide 47 derivatized as an amide at the N-terminus with racemic LA and subsequently chemisorbed on a gold surface has been studied by scanning tunneling microscopy under ultrahigh vacuum conditions . The surface structure of the self-assembled peptide monolayer (SAM) comprises the nanometric domains of parallel oriented ‘stripe-type structures’ which are 7 nm wide and 0.4 nm high, and a prevailing ‘hole-type’ phase at high local peptide concentration.

4.11.3.4 UV and Visible Spectroscopy In order to gain further insight into the antioxidant functions of LA (a vitamin-like coenzyme) and DHLA (as its reduced form) , which apparently maintain major antioxidants (vitamins C and E, glutathione, etc.) in their biologically active state, the photochemistry of the LA/DHLA couple has been studied by laser flash photolysis and continuous irradiation experiments (Scheme 2) . As outlined in Scheme 2, the anions of LA and DHLA in aqueous solution are photoionized by 266 nm irradiation, giving rise to the radical cation LASS? þ, which is a strong oxidizing agent, and the radical anion LASS?. In turn, LASS?, formed by intramolecular cyclization of the mercaptothiyl radical LASSH?, acts as a reducing species which can be subsequently transformed into LASS and DHLA via second-order decay. The formation of the LASSH? radical species is the result of the photoionization of DHLA and deprotonation of the DHLA radical cation. The same one-electron redox process involving LA and DHLA can take place in photochemical or radical reactions in vivo. In addition to photoionization under ultraviolet (UV) irradiation, another feature of LASS is its fast reaction rates with triplet states of some photosensitizers, for example, acetone, thymine, uracil, riboflavin, flavin adenine dinucleotide (FAD), and vitamin K3.

Scheme 2

899

900

1,2-Dithioles

4.11.4 Thermodynamic Aspects The pKa values of a series of functionalized 1,2-dithiole-5-carboxylic acids 48 and 49 in the pKa range 1.1–1.3 and those of 1,2-dithiole-4-carboxylic acids 50 and 51 in the range 1.9–3.2, determined by ultraviolet–visible (UV–Vis) spectrophotometry at room temperature (Table 3), indicate that they are relatively strong acids . In addition, the pKa values of the 5-(hydroxyphenyl)dithiolethiones 52a and 52b and conjugate acids of the 5-(aminophenyl)dithiolethiones 52c and 52d indicate that these acids are stronger in comparison to phenol (pKa ¼ 10.0) and the anilinium ion (pKa ¼ 4.6), respectively. These values are in accord with the values obtained for the derivatives 53–55 . The results are interpreted in terms of solvation effects, thermodynamic ionization parameters, and electronic effects of the 3-thioxo-1,2-dithiol-4-yl- and -5-yl groups and 3-oxo analogues, implying the influence of a withdrawing inductive effect of the 1,2-dithiole nucleus, strong stabilization through contributions of the dithiolylium sulfide polar forms, and the possibility for conjugation between the dithiole ring and appropriate substituents, that is, the carboxylic group or aryl group.

Table 3 Acidity of selected 1,2-dithiole-5-carboxylic acids and 1,2-dithiole-4-carboxylic acids 44–47, dithiolethiones 48 and 50, and dithiolones 49 and 51

48a: X ¼ S pKa ¼ 1.08 48b: X ¼ O pKa ¼ 1.08

49: X ¼ S pKa ¼ 1.26

50a: X ¼ S pKa ¼ 2.77 50b: X ¼ O pKa ¼ 3.22

51a: X ¼ S; R ¼ Me pKa ¼ 1.93 51b: X ¼ O: R ¼ Me pKa ¼ 2.69

52a: Y ¼ p-NH3þ pKa ¼ 2.31 52b: Y ¼ m-NH3þ pKa ¼ 3.25 52c: Y ¼ p-OH pKa ¼ 7.86 52d: Y ¼ m-OH pKa ¼ 8.96

53a: Y ¼ p-OH pKa ¼ 8.27 53b: Y ¼ m-OH pKa ¼ 8.91

54a: Y ¼ p-NH3þ pKa ¼ 3.95 54b: Y ¼ m-NH3þ pKa ¼ 3.95 54c: Y ¼ p-OH pKa ¼ 9.28 54d: Y ¼ m-OH pKa ¼ 9.58

55a: Y ¼ p-NH3þ pKa ¼ 2.31 55b: Y ¼ p-OH pKa ¼ 9.39

4.11.5 Reactivity of Fully Conjugated Rings 4.11.5.1 Reactions of 1,2-Dithiolium Salts In an investigation regarding the design of new photosensitizers and electron-transport materials, promising results based on fluorene push–pull compounds, depicted by general structure 56 (Scheme 3) of the D(TCH–CHT)A type with an incorporated 1,2-dithiole moiety, were reported . The physical properties of compounds 58, such as nonlinear optical effects and photoconductivity, are dictated by the presence of the electron-acceptor nitrofluorene moiety and electron-donor ability of the 1,2-dithiole fragment. Typically air- and moisture-stable push–pull 1,2-dithiole-fluorene derivatives 58 were prepared in good yields (40–88%) from dithiolium salt 57, obtained by treating the 1,2-dithiole 56 with dimethyl sulfate, and 2,7-dinitro-4-R1,R2-fluorenes 59 in dimethylformamide (DMF). They are highmelting, intensely colored compounds (orange-red to black), and characterized by low solubility in organic solvents. However, they are soluble in concentrated sulfuric acid, giving rise to a colorless solution of the corresponding salt.

1,2-Dithioles

Scheme 3

Strong intramolecular charge transfer (ICT) from the donor part to the acceptor fluorene ring of compounds 58a and 58b, stabilized by the contribution of zwitterionic resonance structure 60, results in the presence of two longwavelength absorption bands in the range of 470–485 and 560–575 nm. In comparison to the position of these bands in push–pull 1,3-dithiole-fluorenes 61a and 61b, a redshift of both ICT bands in the case of 1,2-dithiole-fluorenes 58a and 58b was observed (Table 4), which expands the possibilities of utilizing 1,2-dithioles for the design of optoelectronic devices.

Table 4 max (nm) of two ICT bands in 1,2-dithiole-fluorenes 58a and 58b and 1,3-dithiole-fluorenes 61a and 61b in dioxane and acetone at room temperature Compound 1

Dioxane 2

61a (R ¼ H; R ¼ CN) 61b (R1 ¼ NO2; R2 ¼ H) 58a (R1 ¼ H; R2 ¼ CN) 58b (R1 ¼ NO2; R2 ¼ H)

418.2 419.6 470.0 480.0

Acetone 514.9 525.3 565.0 572.2

419.3 420.3 480.0 485.0

520.1 530.3 564.9 573.1

Based on standard procedure, a sequence of reactions on a series of 5-aryl-1,2-dithiole-3-thiones 62 led, via 5-aryl-3methylthio-1,2-dithiolium iodides 63, , 2-alkyl-5-arylisothiazole-3-thiones 64 and 2-alkyl-3-alkylthio-5-arylisothiazolium iodides 65, to synthetically useful thioaroylketene S,N-acetals 66 (Scheme 4) which were employed as precursors in an efficient synthesis of 3-alkylamino-5-arylthiophenes 67 having various substituents X at C-2 .

901

902

1,2-Dithioles

Scheme 4

According to a modified literature method , the 4-aryl-1,2-dithiolium iodides 68 have been transformed with chiral diamines, such as (R,R)-()-1,2-diaminocyclohexane 69 (Scheme 5), into tetradentate dithioaldehydes 70 in good yields . Further cyclization of 70 by excess diamine led to the chiral macrocyclic tetraaza ligands 71 in modest yields. Subsequently, the iron(II) and iron(II)-porphyrin complexes of the macrocyclic ligand 71 (Ar ¼ Ph), whose structure was confirmed by a diffraction analysis, were prepared. The design of the chiral tetraaza ligands has resulted in their utility in asymmetric cyclopropanation of styrene via the catalytic activity of the corresponding iron(II) complexes. Similar transition metal chelating ligands of type 70 were also obtained from the perchlorate salt of 3-aryl-1,2-dithiolium 72 and selected chiral and nonchiral diamines.

Scheme 5

4.11.5.2 Nucleophilic Attack at Sulfur A simple synthesis of symetrically functionalized dithiosalicylides 77a–d from the 3H-1,2-benzodithiol-3-ones 75 and triphenylphosphine was described (Scheme 6) . As indicated, the preparation of precursors 75 was based on a known transformation of the substituted anthranilic acid derivatives 73 to the thiosalicylic acid derivatives . Upon treatment with thioacetic acid in sulfuric acid, cyclization afforded products 75 in 38–64% yield. Dimerization of a benzothietan-2-one 78a or ketene 78b , arising presumably from initially formed intermediate 76, was proposed to account for the product formation. As revealed

1,2-Dithioles

by an X-ray analysis, the dithiosalicylide 77d exists, like the parent compound 77a , in a boat conformation wherein the aromatic rings create a well-defined ‘v-shaped pocket’, with dihedral angles between the rings of 65 and 56.6 , respectively. Furthermore, molecules of both compounds form, through p–p interactions, selfincluded dimers that subsequently result into supramolecular layered arrays.

Scheme 6

A recent study on the reactivity of the parent benzo-1,2-dithiolan-3-one 1-oxide 79a (R1 ¼ R2 ¼ H) and o- and p-substituted derivatives 79b–g with n-propyl thiol in acetone/water mixture (7/3) was prompted (Table 5) by the observation that the DNA-cleaving activity and antitumor activity of leinamycin 5 depends, in part , on initial thiol attack on its 1,3-dioxo-1,2-dithiolane functionality. Experimental results have proved that the presence of chlorine as an electron acceptor in the para-position relative to the sulfinyl sulfur S-1 of precursor 79e and orthosubstituents with lone electron pairs in the case of precursors 79b and 79d are responsible for increased product formation of polysulfanes 80 and 81. A rationale in terms of substituent effects, operating through-space and throughbond of the intermediates a and b, respectively, was suggested. In other words, the reaction is favored by orthosubstituents with lone pair electrons next to the dithiolanone-oxide (S-1) reaction center or a decrease of the electron density at the para-position. In a study related to the biological chemistry of 1,2-dithiolan-3-one 1-oxide 79 and the antitumor antibiotic leinamycin 5, it has been shown that primary amines 85a, 85b, and 85e and substituted anilines 85c and 85d (Scheme 7), but not those containing electron-withdrawing groups, are good nucleophiles for conversion of 79 into 1,2-benzisothiazolin-3(2H)-ones 87a–e under mild experimental conditions . It was postulated that the reaction proceeds by nucleophilic attack of nitrogen on the carbonyl group of heterocycle 79. Subsequent extrusion of sulfur yields a relatively unstable 2-(carbamoyl)benzenesulfenic acid 86, and dehydrative cylization leads to the observed product 87. With the intention of comparing the biological activity of numerous 2-substituted 1,2-benzisothiazol-3(2H)-ones 88b and their sulfur analogues 88a , with that of the pyridine series and their derivatives, isothiazolo[5,4-b]pyridin-3(2H)-ones 90b and isothiazolo[5,4-b]pyridin-3(2H)-thiones 90a, the

903

904

1,2-Dithioles

Table 5 Formation of aromatic and aliphatic polysulfane products

Compd.

Substituent a

Products 80 þ 81

Products 82–84

Yield b(%)

79a 79b 79c 79d 79e 79f 79g

H o-Cl o-Me o-OMe p-Cl p-Me p-OMe

18 63 9 51 53 5 15

16 29 2 26 26 2 12

34 83 11 77 79 7 27

a

The other substituent in 79a–g is hydrogen. Relative yields were determined by 1H NMR.

b

Scheme 7

N-substituted 2-sulfanylnicotinamides 91b and carbothiamides 91a, as well as N-substituted-N-[3H-[1,2]dithiolo[3,4-b]pyridine-3-ylidene]amines 92 were synthesized by conventional methods , starting from the pyridine-fused 1,2-dithioles 89a,b. These compounds are easily interconverted by mercury acetate (CTS ! CTO) or Lawesson’s reagent (LR) (CTO ! CTS). All compounds were tested for their antimicrobial activity against several Gram-positive and Gram-negative bacteria and fungi.

1,2-Dithioles

4.11.5.3 Reactions with Electrophiles As outlined in Scheme 8, a synthesis of 1,6a4-dithia-6-azapentalenes 94a–d from dithioles 93a–d and isonitriles is an example of utilization of the HCl formed in a catalytic amount from phosphoryl chloride and moisture in the air. The liberated acid and isonitrile produce the reactive electrophilic species 97 that reacts with the dithiole giving rise to the intermediate, cycloaddition product 96, which then leads to final product via release of HCl. An alternative mechanism was also considered, implying that the -addition reaction of the isonitrile to the dithiolylium halide 95, obtained by protonation of 1,2-dithiole 93, gives rise to the intermediate salt and then to the final product .

Scheme 8

4.11.6 Reactivity of Ring Substituents 4.11.6.1 Reactivity of S-Substituents It was shown that thiacyl thioketenes are intermediates for the reductive dimerization of 5-alkylthio-1,2-dithiole-3-thiones with P(OMe)3 in refluxing benzene, giving rise to 2,4-bis(2-thioxoethylidene)1,3-dithietanes, known as thioxodesaurins. Later, the intramolecular variant was applied successfully ,

905

906

1,2-Dithioles

an outline of which is given in Scheme 9. Thus, a macrocyclization process using P(OMe)3 and bridged bis(5methylthio-1,2-dithiole-3-thione)s, 100a and 100b, formed by alkylation of 4-mercapto-5-methylthio-1,2-dithiole-3thione 98 with 1,8-dibromo-3,6-dioxaoctane 99a or 1,11-dibromo-3,6,9-trioxaundecane 99b, was carried out. In addition to unknown polymeric material, the macrocyclic (Z)-thioxodesaurin 101 was stereoselectively synthesized from 100a, whereas (E)-thioxodesaurin 102 and (E)-1,3-dithiafulvene 103, whose structure was determined by X-ray analysis, were obtained from 100b.

Scheme 9

Based on similar chemistry, an improved procedure for the synthesis of the ,-isomer of 1,3-dithiolo[4,5-d]-1,2dithiole-2,5-dithione 105 from the disodium salt of 1,2-dithiole 104 and thiophosgene was reported (Scheme 10) .

Scheme 10

The almost-planar ,-isomer 105, with lowest symmetry and whose crystal structure was determined, is one of the four possible isomers (compounds 107–109 being the rest) of carbon sulfides of the formula C4S6.

1,2-Dithioles

Like thioamides and thiazolidinethiones , the reaction of 105 with iodine in carbon disulfide as a solvent led to the formation of the thermally rather stable adduct 106, in which, as determined by X-ray crystallography, the coordination of the (C)(S)CTS thiocarbonyl group to I2 takes place. A stable polymorphic adduct was previously obtained on crystallization of ,-C4S6-I2 from acetonitrile . Possessing the SCCCS fragment, this binary compound could presumably be a source for the generation of carbon subsulfide, C3S2, under the conditions of flash vacuum thermolysis.

4.11.6.1.1

Thio and thiol substituents

A number of known condensation reactions of the fluorine-containing 1,2-dithiole-3-thiones 110 with hydrazines and hydroxylamine in the presence of sodium acetate to 3-imino derivatives 111 takes place directly in ethanol under reflux . Similarly, the authors reported an alternative preparation of the same products 111, and push–pull-type 3-ylideno derivatives 113, employing ethyl cyanoacetate, via intermediate 1,2-dithiolium salts 112. These salts, derived from equimolar quantities of the corresponding thiones 110 and sulfuryl chloride or chlorine, cannot be formed from the oxygen analogues, that is, 1,2-dithiol-3-ones.

4.11.6.1.2

Reactions with dipolarophiles

The following part describes the efforts by several research groups to apply the classical [3þ2] cycloaddition reaction to give new and structurally diverse 1,3-dithioles from various 1,2-dithioles, acting as masked 1,3-dipoles, and electron-deficient alkynes, such as dimethyl acetylenedicarboxylate (DMAD). For example, in the presence of 1 equiv of DMAD, the cycloaddition with 4,5-dichloro-1,2-dithiole-3-one 114 gave, in almost quantitative yield, the cycloaddition product 115 (Scheme 11) . Its stability, as confirmed by X-ray crystallography, is explained in terms of an attractive intramolecular interaction between the ˚ . As two sulfur atoms positioned at a distance smaller than the sum of van der Waals radii (3.68 A) ˚ shown, the distance between the thiocarbonyl sulfur atom and a ring sulfur atom, being 2.91 A, is roughly 0.9 A˚ longer ˚ However, by addition of 3 equiv of the appropriate alkyne to the 1,2than a covalent sulfur–sulfur bond (2.01 A). dithiole 114 at room temperature in xylene as a solvent, then followed by reflux, completely different types of product, that is, thienothiopyrans 116 and 117, were formed by a new molecular rearrangement, accompanied by a loss of chlorine. In a small number of examples , 1,2-dithioles without halogen at C-4, such as 118, have been converted with diacetylacetylene into the resulting thials 119, which can be isolated, and then via a known dimerization–desulfurization process to functionalized trienic tetrathiafulvalenes 120 with four electron-withdrawing acetyl groups.

907

908

1,2-Dithioles

Scheme 11

The [3þ2] cycloaddition reactions of equimolar quantities of DMAD and 4,4-dimethyl-4,5-dihydro-1,2dithiolo[3,4-c]quinoline-1-thiones 121 led at room temperature after prolonged reaction time (20–30 h) to the 1,3dithioles 122 in good yields (72–86%) . In the presence of excess DMAD (2/1 molar ratio of DMAD/ thione 121), or upon a treatment of the resulting 1,3-dithioles 122 with an additional equivalent of DMAD, the products of multiple additions afforded the bright yellow spiro-type 1,3-dithioles 123.

In an analogous series of reactions utilizing polycyclic bis-1,2-dithiole-3-thiones 124 or 125 and DMAD, depicted in Scheme 12, the type of major product, bis-spiro-1,3-dithiolethiopyranepyrrole 126a from 124, and bis-spiro-1,3dithiolethiopyrane-1,4-thiazine 127 and bisdithiafulvenyl-1,4-thiazine 128 from 125, depends on the control of the reaction conditions .

1,2-Dithioles

Scheme 12

Typically, the first approach based on use of bis[1,2]dithiolo[1,4]thiazine dithiones and 2.5 equiv of DMAD, preferably in the presence of a catalytic amount of scandium triflate, was employed to effect, for example, the formation of the 1:2 adduct 128a. In situations where a low or an exceedingly high excess of dipolarophile is used (5 and 60 equiv, respectively), the initial 1,3-dipolar cycloaddition adduct, as shown for 124 and 125a, undergoes in situ an additional hetero-Diels–Alder reaction to provide two 1:4 adducts, 126a and 127a. Application of the cycloadditions for the synthesis of the constitutionally similar compounds afforded, specifically in the case of dibenzoylacetylene (DBA) (12 equiv) as a dipolorophile and precursor 125, the corresponding 1,4 adduct 129. 1H NMR dynamic experiments based on the presence of the diastereotopic methylene group in the N-ethyl group indicated that 129 exists as two diastereomeric species, asymmetrically and symmetrically folded conformers with a rotational barrier of approximately 11 kcal mol1.

4.11.6.1.3

Atropisomeric 1,2-dithiole-3-thiones

As an extension of this chemistry, the [3þ2] cycloaddition reaction of new atropisomeric 4-dialkylamino-5-chloro-1,2dithiole-3-thiones 130 and DMAD or its diethyl analogue has been utilized to give thioacid chlorides 131 (Scheme 13) . These have been converted into thioamides 132 with 2 equiv of pyrrolidine (or morpholine) by substitution of the 5-chloro substituent and phthalimide ring opening. Similar reactivity toward 1 or 2 equiv of pyrrolidine was noted for 130, which was obtained according to the general method described.

909

910

1,2-Dithioles

A dynamic 1H and 13C NMR study revealed the atropisomerism of compound 130 (R ¼ Pri) which exists at room temperature as a pair of two, nonplanar, axially chiral enantiomers due to the steric interaction between the isopropyl and 1,2-dithiole groups.

Scheme 13

A multitude of diverse transformations of conjugated 1,2-dithioles have been reported in the decade under review. These include the cycloaddition of mono(ferrocenecarbonyl)acetylenes 134a–c and bisdithiolothiazine ketothione 135 (1 equiv) catalyzed by scandium triflate (50 mol%) in dichloromethane that gave at room temperature the 1:1 cycloadducts (Z þ E), viz. monoferrocenecarbonyl-1,3-dithiol-2-ylidene[1,2]dithiolo[1,4]thiazines 136a–c, in good yields (Scheme 14) . A cycloaddition reaction under similar conditions with a symmetric acetylene, bearing two ferrocene groups, such as the 1,4-bisferrocenylbut-2-yn-1,4-dione with ketothione 135 was also acomplished in high yield (97%) to give bis-ferrocenecarbonyl-1,3-dithiol-2-ylidene[1,2]dithiolo[1,4]thiazine 137, thus avoiding the formation of geometric isomers.

Scheme 14

1,2-Dithioles

4.11.6.1.4

Reactions involving organometallic compounds

Studies have shown that a variety of conjugated thiones, such as 3H-1,2-dithiole-3thiones 138 , can be reactive toward organometallic reagents (Scheme 15). Thus, 1,2-dithioles 138 containing the thiocarbonyl group (X ¼ S) react with Fischer carbene complexes 139 via insertion of the carbene moiety into the S–S bond, giving rise to new chromium complexes 140 in moderate yields (34–55%). However, under similar conditions, the 1,2-dithiole 138 (X ¼ O) is unreactive toward 139, suggesting that the 1,2-dithiole-1,3-dithiin ring expansion 138 ! 140 starts by the nucleophilic attack of the thiocarbonyl group to an electrophilic carbenic carbon of the carbene complex 139. Attempts to promote a demetallation reaction of 140a with methanol resulted in the formation of a 1,3-dithiin dithio-orthoester (78%), whereas the chromium complexes 140b and 140c decomposed.

Scheme 15

The use of naphtho[1,8-cd]-1,2-dithiole 142 and a complex titanocene dicarbonyl , or iridium–1,5cyclooctadiene p-complex has been demonstrated as a synthetic approach to new titanocene 1,8dithiolato-naphthalene 143 and bimetallic iridium(II) 1,8-dithiolato-naphthalene 144 in good yields (Scheme 16). In order to study the steric effects, the fully characterized thiolato complexes with Cp2Ti group and the modified naphthalene moiety were also obtained via oxidative addition reactions of 1,2-dithiole ligands 145, 147, and 148. Oxidative additions of similar S–S-bridged ligands, including the 1,2-dithiole 1-oxide-type ligand 146, to the Ir(I)–1,5cyclooctadiene dimer were also carried out.

911

912

1,2-Dithioles

Scheme 16

Regarding the synthesis of tetrathiafulvalenes (TTFs), the preparation of a series of substituted naphtho-1,3dithiole-2-thiones 150 in good yields (50–78%), from 3,4,7,8-tetrachloronaphtho[1,8-cd;5,4-c9d9]bis(1,2-dithiole) 149, and an excess of sodium trithiocarbonate and alkyl halide were reported (Scheme 17) . The monosubstitution products 151 were formed when equimolar quantities of derivatives 149 and sodium trithiocarbonate were used. Upon desulfurization with mercury(II) acetate, the bis- and monosubstituted 1,3-dithiol-3-thiones 150 and 151, respectively, yielded the corresponding 1,3-dithiol-2-ones, whereby dechalogenation of 150 (R ¼ i-C5H11) with triethyl phosphite gave rise to the TTF 152.

Scheme 17

1,2-Dithioles

4.11.6.1.5

Oxidation and reduction

The stepwise reduction of 4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-3H-1,2-dithiole-3-thione 153 with 2 mol equiv of sodium sulfide, acting both as the reducing and nucleophilic reagent, has found use in a synthesis of the sodium salt of trithiapentalene 154 (Scheme 18), which was converted upon acidification into 3,4-difluoro-2-mercapto1,6,6a4-trithiapentalene 155 in moderate yield .

Scheme 18

However, the outcome of the reduction depends on the quantity of Na2S used. In particular, the ring-transformed product, viz. 3,5-difluoro-4-mercaptothiopyran-2-thione 157, was obtained directly from the trithiapentalene derivative 155 by reduction with another molar equivalent of Na2S, or from the precursor 153 in the presence of 3 equiv.

4.11.6.1.6

Thermal reactions

The formation of the transient thioformyl thioketene 159 and thiacyl thioketene 160 has also been confirmed in flash vacuum pyrolysis (FVP) of 1,2-dithiole-3-thiones 1b and 158, in the temperature range 800–1000 C, respectively (Scheme 19) . A hitherto-unknown transformation of the intermediates 159 and 160, as the most carbon rich carbon sulfides, into linearly shaped carbon subsulfide C3S2 (1,2-propadiene-1,3-dithione) was obtained and identified in an argon matrix at 10 K.

Scheme 19

913

914

1,2-Dithioles

This is the only sulfur-containing heterocumulene CnS2 (n > 1) that is sufficiently stable to be isolated for a short time at room temperature. FVP of a series of the analogous 1,2-dithiol-3-ones 161 at 800–1030 C resulted in a principal fragmentation to OCS and thioketenes 163 (Scheme 20), as confirmed by a combination of Ar matrix isolation, Fourier transform infrared (FTIR) spectroscopy, and collisional activation mass spectrometry (MS) . In addition to competing thermal decomposition, leading to the corresponding alkyne 164, CO, and sulfur, the thioketenes 163 presumably arise from a Wolff-type rearrangement of carbene or diradical intermediates 162. The thermal- and electron ionization-induced fragmentation of 1,2-dithiole-3,6-dithione derivative 165a and oxygen counterpart 165b indicated the presence of C3S2, S2, and CS2 (from 165a), and C3S2, C3SO, S2, and CS2CSO (from 165b) as the most dominant compounds . The dithiolodithioledione 165b and thioxodithiolodithione 165c are also precursors of the radical cations 166.

Scheme 20

4.11.7 Reactivity of Nonconjugated Rings: 1,2-Dithiolanes An effective way of producing a thioacetal-based linker for solid-phase synthesis, using racemic -lipoic acid 3, has been described . The methyl ester of commercially available racemic -lipoic acid 3 can be conveniently used, after reduction to the ester of DHLA, as a linker for the immobilization of ketones on a solid support (Scheme 21). The preformed thioacetal-based linker 167 was immobilized with aminomethyl polystyrene resin, diisopropylcarbodiimide, and N-hydroxybenzotriazole in DMF at room temperature, giving rise to resin 168. Subsequently, the solid-phase syntheses of 4-acetylbiphenyls 169 and 4-alkoxyacetophenones 170 via Suzuki and Mitsunobu reactions, using [bis(trifluoroacetoxy)iodo]benzene as the cleavage reagent (2.5 equiv, CH2Cl2/EtOH/ H2O 4.5/4.5/1; 30 min, rt), were carried out in 28–59% overall yield. In another variation, thioctic acid together with N-hydroxysuccinimide has been used for the synthesis of a photocleavable cross-linker, i.e., succinic acid succinimidyl ester 5-thioyloxy-2-nitrobenzyl ester 171 (SSTN), possessing the o-nitrobenzyl ester moiety as a core . An interesting feature of SSTN, as in other photolabile linkers based on the o-nitrobenzyl group , is a fast and clean photofragmentation upon irradiation to nitrosobenzaldehyde 172 and succinic acid monosuccinimidyl ester 173 (Scheme 22). The presence of the dithiolane fragment and N-hydroxysuccinimidyl group allow the specific application of this photocleavable crosslinker to covalently anchor proteins (avidin or antibodies) to a gold-coated substrate. The fact that immobilized proteins can be subsequently released under UV irradiation without degradation is in principle significant in terms of controlled protein delivery on the nanometer scale.

1,2-Dithioles

Scheme 21

Scheme 22

Desulfurization of a number of thiols and disulfides, including the lipoic acid amide 174 under visible light irradiation, has received attention because of mild reaction conditions and the possibility to apply the same method in peptide chemistry (Scheme 23) . Accordingly, thioctic amide 174, that is, 5-(1,2-dithiolan-3-yl)pentanamide, was photochemically desulfurized in 36 h in a one-pot reaction, giving 1-octanamide 175 in good yield.

Scheme 23

An enzyme-catalyzed enantioselective esterification of racemic LA 3 with n-alcohols containing one to eight carbon atoms in hexane as a solvent, using Candida rugosa lipase , has been described (Scheme 24). The best selectivity at 30% conversion was obtained with n-hexanol, yielding the (S)-ester 176 with 72% ee, along with (R)lipoic acid (20% ee); this decreased with n-octanol (58% ee for an ester and 24% for acid) and there was a drastic drop

915

916

1,2-Dithioles

in enantioselectivity with n-butanol and n-propanol, whereas the process is unsatisfactory with ethanol and methanol. The topography of the enzyme was proposed based on the best fit of the nucleophile attacking the acyl enzyme intermediate, formed in a rate-determining step.

Scheme 24

In a related investigation, the native lipase of C. rugosa has also been used successfully for enantioselective and regiospecific transformation of butyl 2,4-dithioacetyl butyrate 177 to (R)-2,4-dithioacetyl butyric acid (R)-178 and butyl (S)-2-thio-4-thioacetyl butyrate (S)-178 with high enantiomeric purity (>98% ee) (Scheme 25) , which were subsequently utilized for the preparation of (R)- and (S)-lipoic acids 3, respectively.

Scheme 25

The reactivity of 4,49-dialkyl-substituted 1,2-dithiolanes 179a–d, which are not susceptible to polymerization, with lithiated furans 180 and 182, benzofuran 183, dihydrofuran 184, and dihydropyran 185 were examined . In the presence of a small molar excess of the lithiated compound 180, dithiolane ring opening takes place, affording products 181a–d (Scheme 26). A mixture of products and much lower yields of the structurally similar ring-opened products were isolated in the case of lithiated benzofuran, while in the case of lithiated dihydrofuran and dihydropyran 184 and 185, the spiro-1,3-dithianes 186 and 187 were formed in high yields from initially formed compounds during the acidic work-up.

Scheme 26

1,2-Dithioles

4.11.8 Synthesis The following section describes developments in procedures to synthesize 1,2-dithioles and 1,2-dithiolanes, including the corresponding salts . For syntheses before 1995, see CHEC(1984) and CHEC-II(1996) . Different approaches are presented based mostly on new methods toward the ring construction on one hand, and, in a limited number of cases, transformations of the preformed ring skeleton. In order to maintain uniformity between the present and previous updates, the retrosynthetic classifications are depicted in Scheme 27.

Scheme 27

4.11.8.1 Direct Synthesis by Formation of One Bond Direct synthesis from SC3S unit is discussed here (Figure 1).

Figure 1 Formation of a sulfur-to-sulfur bond.

The functionalized 1,2-dithioles-3-ylidene thioamides 191 were formed in high yields in a one-pot procedure by ring-opening-closing reactions of (Z)-2-alkylidene-4-oxothiazolidines 188 with LR (Scheme 28). From the retrosynthetic point of view, the method can be traced to an S–S bond formation, involving the SC3S skeleton (Figure 1) present in the cis-configured –S–CTC–CTS moiety of an intermediate 190 obtained by an O/S exchange in an initial stage (188 ! 189) of the reaction. The overall transformation reveals the importance of the directional nonbonded 1,5-type S O interaction in 4-oxothiazolidine precursors 188.

Scheme 28

917

918

1,2-Dithioles

An X-ray crystal structure characterization of ethyl (Z)-(5-ethoxycarbonylmethyl-4-oxothiazolidin-2-ylidene)ethanoate 188c gave the evidence, in combination with a nuclear Overhauser effect (NOE) experiment, for the (Z)-configuration ˚ which is less than the sum of the van der Waals radii (3.22 A). ˚ Due to and short 1,5-O S nonbonded distance (2.87 A), the 1,5-type S S close contact, the concomitant 4-thioxothiazolidine ring-opening–1,2-dithiole- ring-closing (190 ! 191) induces this specific transformation to final products. In the 1H NMR spectrum, the C-4 proton of dithioles 191a–c absorbs at very low field, viz. 8.37–8.42 ppm, which indicates the aromatic nature of the dithiole ring. In addition, the 13C shifts for C-3, C-4, and C-5 point to highly delocalized derivatives 191, which imply a significant aromatic contribution from the 10p-electron 3,3a4,4-trithia-1-azapentalene structures 191A or 191B. With respect to an analogous effect of the through-space bonding S S interaction on reactivity, it was reported that photochemical reaction of a series of naphtho[1,8-ef ][1,4]dithiepins 192, using a 500 W high-pressure mercury lamp at room temperature, yielded quantitatively the 1,2-dithiole 142 and the corresponding alkenes 193 (Table 6) . The S S distance in 192 (R ¼ Ph; R1 ¼ H), as determined by X-ray analysis, is 3.132 A˚ versus 3.70 A˚ for the sum of the van der Waals radii. The proposed photodecomposition occurs via an excited singlet state as a one-photon process. Ab initio calculations on compound 192 (R ¼ R1 ¼ H), indicated a decrease of the S S distance ˚ which presumably favors the reaction. for the optimized S1 state by 0.5 A, Table 6 Preparation of naphtho[1,8-cd]-1,2-dithiole 142 and diethyl 2-alkylidenemalonates 193 by irradiation of naphtho[1,8-ef][1,4]dithiepins 192

Precursor 192

Yield (%)

Yield (%)

R

R1

142a

193a

Ph p-Tol PhCHTCH 2-Furyl Ph Ph

H H H H Me PhCH2

100 97 99 98 99 98

92 91 91 96 96 97

a

Isolated yields.

As an extension of the synthetic strategy for the synthesis of naphtho[1,8-cd]-1,2-dithiole 142, based upon a through-space interaction between the two sulfur atoms (which activates naphtho[1,8-cd]-1,3-dithiinylidene 1-oxides 194 toward photoirradiation), it was demonstrated that the corresponding ketenes 195, as important intermediates, are formed along with the expected 1,2-dithiole 142 (Scheme 29) (70–95%).

Scheme 29

1,2-Dithioles

The generation of ketenes was confirmed, as illustrated in Scheme 29, by trapping experiments with methanol or benzylamine, producing the methyl ester or amide 196. Upon photolysis of precursor 194 (R ¼ Ph; R1 ¼ H), the formation of phenyl ketene, which was monitored by IR spectroscopy, was indicated by the appearance of the CTCTO band at 2120 cm1. The even more efficient generation of ketenes was also achieved by photolysis of the selenium analogues of compounds 194. In an investigation designed specifically as a route to compounds which might serve as sulfur-monoxide-transfer reagents, the trisulfide 2-oxide 198 was prepared in modest yield . Reduction of naphtho[1,8-cd]-1,2dithiole 142 (Scheme 30) was followed by reaction with SOCl2. The 1,2-dithiole 142 was synthesized in 31% yield from 1-bromonaphthalene 197 via a sequence of reactions, involving the lithium–halogen exchange, directed deprotonation, and trapping of the 1,8-dilithionaphthalene with elemental sulfur.

Scheme 30

The important structural properties of reagent 198, such as a nonplanarity of the trithiane ring and transannular interactions between the two sulfur atoms at the 1,8-positions of the naphthalene, were elucidated by X-ray crystal analysis. As might be expected, the trisulfide 2-oxide 198 does transfer sulfur monoxide in the presence of an excess of dienes 199a–d, forming cyclic unsaturated sulfoxides 200a–d in very good yields with almost quantitative recovery of naphtho[1,8-cd]-1,2-dithiole 142 (Table 7).

Table 7 Preparation of sulfoxides 200 from dienes 199 and trisulfide 2-oxide 198

R1

R2

Time (h)

200/yield (%)

Me H Ph H

Me H Ph CH2CH2CHTCMe2

14 6 6.5 6

100 74 65 93

Following a lead discovered by Furukawa and co-workers that dealkylation of monooxides of 2,29-bis(alkylthio)biphenyls 201 to thiasulfonium salts 203 (R ¼ ethyl, isopropyl, benzyl, etc.) occurs readily upon treatment with triflic anhydride via dithia dications 202 , again owing to through-space S S interaction, it was found that alkyl 2-(methylthiomethyl)phenyl sulfoxides 204 also undergo the same reaction (Scheme 31) . Contrary to the highly unstable dications 205, serving as a new source of carbocations R upon monodealkylation, the resulting thiasulfonium salts 206 can be isolated and spectroscopically identified. An experiment with the chiral phenethyl sulfoxide 204 at 40 C showed that nearly completely racemized N-phenylethyl acetamide was obtained, suggesting that the dealkylation from dithia dication proceeds through an SN1 mechanism.

919

920

1,2-Dithioles

Scheme 31

The examples above emphasize the synthetic significance of transannular interactions on reactivity of selected compounds giving rise to 1,2-dithiole-type products, implying the presence of an SC3S unit, either present in another heterocyclic moiety or generated during the reaction. The latter is the case regarding the thermolysis of dipropyl polysulfides 210, affording, in the gas phase at 350 C, 1,2-dithiole-3-thione 1b (Scheme 32) as a major product in 44% yield, in addition to the corresponding thiol, sulfide, and disulfide, with concomitant generation of hydrogen sulfide, propene, and hydrogen as gaseous products . It was hypothesized that thermolysis proceeds via a propyltrisulfanyl radical (CH3CH2CH2S3?) which undergoes subsequent intramolecular cyclization to 1,2dithiole-3-thione.

Scheme 32

4.11.8.2 Direct Synthesis by Formation of Two Bonds Direct synthesis from [3þ2] units is discussed here (Figure 2).

Figure 2 Formation of two carbon-to-sulfur bonds.

1,2-Dithioles

A new synthetic method based on the transformation of N-(2-chloroethyl)diisopropylamine, N,N-diisopropylethylamine (Hu¨nig’s base), or diisopropyl sulfide with disulfur dichloride in the presence of 1,4-diazabicylo[2.2.2]octane (DABCO) has been found to provide, under various conditions, a wide range of possibilities for the synthesis of 1,2dithiolo[3,4-b][1,4]thiazine-3-thione 11 , 4-ethyl-bis[1,2]dithiolo[3,4-b;k9,39,49-e]thiazine-3,5-dione 14a , bis[1,2]dithiolo[1,4]thiazine imines 211 , bis[1,2]dithiolopyrroles 124 and 15a,b , and disulfides 212 and 213 containing one or two 1,2-dithiole-3-thione rings .

The proposed reaction mechanism, exemplifying in particular the formation of the products 14a and 124 (or 15a,b) from Hu¨nig’s base and disulfur dichloride (Scheme 33), includes an array of the basic steps, (1)–(4). (1) An initial oxidation reaction between Hu¨nig’s base and disulfur dichloride, or reactive complex 214 formed with DABCO, leading to the iminium ion 215 is well known as well as subsequent deprotonation giving enamine 216. (2) The subsequent sequence 216 ! 217 for the formation of the 3-chlorodithiolium salt 218 incorporates both the enamine 216 and an excess of S2Cl2 (or 214), allowing the possibility for ring closure. (3) The repetition of the whole transformation, occurring on the remaining isopropyl group in the dithiolium salt 218, affords the bis-dithiolium salt 220, which cyclizes by further reaction with S2Cl2 to 3,5-dichloro-bis-dithiolium salt 221 as the key intermediate for the synthesis of bis[1,2]dithiolo[1,4]thiazines 14 and bis[1,2]dithiolopyrroles 124 or 15. (4) Thus, while the reaction of 221 with sulfur nucleophiles, formed in the reaction mixture, yields the thiazine 14a (X ¼ S), the corresponding 3,5-dione 14b (X ¼ O) and 3-oxo-5-thione 14c (X ¼ S; another X ¼ O) are isolated in the presence of formic acid as oxygen nucleophile. Similarly, the 1,4-thiazines 14, which are stable in low boiling solvents (dichloroethane, tetrahydrofuran (THF)), can be selectively transformed into the bis(1,2-dithiolo)pyrroles 124 or 15 by sulfur extrusion in refluxing xylene or chlorobenzene. With respect to the order of formation of the heterocyclic rings in products 14 and 124 (or 15), the isolation of N,N-bis(dithiolyl)ethylamines 222a and 222b and 4-(ethylamino)-1,2-dithiole-3-thione 223 in very low yields indicates that the final bridging sulfur atom of the thiazine ring is incorporated after the formation of the dithiole rings. Alternatively, bis(dithiolo)pyrroles, such as 124, containing different substituents at nitrogen have been obtained in two steps from N-substituted 2,5-dimethylpyrroles 224 and S2Cl2–DABCO complex 225 (Scheme 34). The corresponding pentathiepins 226, products of the first step, react efficiently and readily with the same complex providing the final products 124. A one-pot reaction of reactants 224 with an excess of S2Cl2 and DABCO also gave rise to 124 but in very low yields. An example of the use of disulfide-bridged dinuclear tetracationic Ru(III) complex 227, [{Ru(P(OCH3)3)2(MeCN)3}2(m-S2)](CF3SO3)4, has been described for C–S bond formation in reaction with allyl

921

922

1,2-Dithioles

Scheme 33

Scheme 34

1,2-Dithioles

halides, which results in a new Ru(III) complex 228, possessing a 1,2-dithiole ring (Scheme 35) . Related CS bond-formation reactions with the high-valent electron-deficient Ru-complex 227 acting as a Lewis acid are possible with terminal alkenes , alkynes, and dienes.

Scheme 35

With respect to the mechanistic pathway, as depicted in Scheme 36, after coordination of the allylic halide to Rucomplex 227, giving rise to Ru-complex 229, the C–S bond formation occurs via activation of the allylic C–H bond and subesquent C–H cleavage (step 229 ! 230). The rotation of the organic moiety around the C–S bond (step 231 ! 232) precedes HX elimination, which is the final step leading to Ru-complex 228.

Scheme 36

When terminal alkenes such as 1-pentene, allyl ethyl ether, allyl phenyl ether, 1,4-hexadiene, and 3-methyl-1butene were used, reactions with the same disulfide-bridged Ru(III) dinuclear complex 227 gave the corresponding metal complexes 233a–e, having the C3S2 1,2-dithiolane ring (Scheme 37). Mechanistic aspects of this interesting

Scheme 37

923

924

1,2-Dithioles

transformation also involve, as in the case of allyl halides as organic precursors, the activation of the allylic C–H bond as initial key step, and then the formation of the C–S and S–H bonds, leading to an intermediate I9a–e. The 1,2dithiolane ring of the final Ru-complexes 233a–e, which have been, with the exception of 233b, characterized by X-ray analyses, is formed by the anti-Markovnikov addition of the S–H bond of the corresponding intermediate I9. The [3þ2] cycloaddition reactions of new cyclopentedienyl iron dicarbonyl 1-2-alkynyl complexes 236 with disulfur monoxide produce metal-substituted 1,2-dithiolene-1-oxides 239, which after demetallation yield the dithiolene oxides 241 (Scheme 38) . The cyclopentadienyl iron dicarbonyl (Fp) anion, obtained by stirring a solution of dicyclopentadienyl dicarbonyl iron 235 in THF over sodium amalgam (5 h), reacted with propargyl tosylates 234, affording the iron complexes 236. The authors utilized 4,5-diphenyl-3,6-dihydro-1,2-dithiin-1-oxide 237, which, via electrocyclic ring opening induced by iron complexes 236, acting as a nucleophile served as a source of disulfur monoxide . It has been proposed that the intermediate 238 is formed initially, prior to cyclization to the products 239. The best yield of dithiolene oxide 241 was obtained with R ¼ 4-CF3C6H4 (95%). However, with R being 1-cyclohexenyl and 4-MeC(O)C6H4, the yields were much lower (19% and 24%, respectively).

Scheme 38

A slight variation of the [3þ2] cycloaddition approach has also been employed for the diastereoselective synthesis of the corresponding anti- and syn-iron-substituted 1,2-dithiolane 1-oxides 243 from 237, as a source of electrophilic disulfur monoxide, and 1-allyl iron complex 242 (Scheme 39). The method was also tested with cyclopentadienyl iron dicarbonyl crotonyl complex 244 when four diastereomers 245–248 were generated in modest yields (35%) .

4.11.8.3 Direct Synthesis by Formation of Three Bonds Direct synthesis from C2, CS, and S units (Figure 3) is discussed here. Two-component reactions, involving dilithiated ethyl thioglycolate and 1,2-diimidoyl-1,2-dichloroethanes 250, gave rise, under the conditions specified in Scheme 40, to 4-imino-1,2-dithioles 251 in relatively modest yields (23–30%). Depending on the experimental conditions, instead of 251, 2,5H-pyrrol-5-ones, 4H-thiopyrans, and 6H-1,3-oxazines can be prepared .

1,2-Dithioles

Scheme 39

Figure 3 Formation of a carbon-to-sulfur bond, a carbon-to-carbon bond, and a sulfur-to-sulfur bond.

Scheme 40

The proposed reaction pathway to 251 (Scheme 41) starts by nucleophilic attack of the dianion of the ethyl thioglycolate I on 1,2-diimidoyl-1,2-dichloroethane 250, affording an intermediate II. Two possible routes, A and B, have been hypothesized for the formation of intermediate IV, which by proton migration leads to reactive species V. The cyclization step with simultaneous elimination of lithiated ethyl acetate, followed by protonation, complete the reaction cycle to give product 251. A general cyclization reaction of lithium acetylides with sulfur and carbon disulfide was reported ; it can be utilized for a one-pot synthesis of 1,3-dithiole-2-thiones 253. The sequential addition of n-BuLi, sulfur, and CS2, precisely in this order, is crucial for the successful synthesis. A similar procedure for efficient preparation of the isomeric 4-mercapto-1,2-dithiole-3-thiones 254a–c under mild conditions in THF solution based on deprotonation of terminal alkynes 252, followed by addition of the same reagents, however, in the opposite order, that is, CS2 and then sulfur, has been described (Scheme 42) . Acidic quenching of a resulting intermediate anion I0 in the presence of sulfur afforded compounds 254a–c, whereas a treatment of the same intermediate I0 with sulfur and methyl iodide provided 4-methylthio-1,2-dithioles 255 in yields of 38–50%. Upon crystallization of compound 254a (R ¼ Ph) from THF/ethanol, the corresponding disulfide 38, characterized also by X-ray analysis (Table 1), was isolated as a result of spontaneous oxidation during the crystallization.

925

926

1,2-Dithioles

Scheme 41

Scheme 42

1,2-Dithioles

A one-pot transformation of ketones 256 into 3H-1,2-dithiole-3-thiones 258 in good yields via intermediate dianions of 3-oxodithioic acids 257 (Scheme 43) is an extension of the methods based on the combination of the C2, CS, and S units . Treatment of the corresponding ketone with CS2 and 2 equiv of KH in THF in the presence of a dipolar aprotic co-solvent, such as N,N9-dimethylpropyleneurea (DMPU) or hexamethylphosphoramide (HMPA), results in high conversion to the dianion 257. The former is then subjected to hexamethyldilathiane (HMDT) and hexachloroethane as an oxidizing agent, giving rise via a series of intermediates to dithiolethiones 258a–e.

Scheme 43

4.11.8.4 Direct Synthesis by Formation of Two Bonds Direct synthesis from SC3 and S unit (Figure 4) is discussed here.

Figure 4 Formation of a sulfur-to-carbon bond and sulfur-to-sulfur bond.

This method is exemplified by a three-component reaction in which ketene dithioacetals 259 react with magnesium bromide and sulfur to give fluorinated 3H-1,2-dithiole-3-thiones 260 (Scheme 44) . The same transformation was achieved in excellent yield using, for example, elemental sulfur and the crotonic derivative 261a obtained from the corresponding perfluoroketene diethylthioacetal 259a and MgBr2.

927

928

1,2-Dithioles

Scheme 44

4.11.8.5 Direct Synthesis by Formation of Three Bonds Direct synthesis from 2SC units and C unit (Figure 5) is discussed here.

Figure 5 Formation of two carbon-to-carbon bonds and a sulfur-to-sulfur bond.

1,2-Dithiolo-condensed benzothiopyran-4-ones 263 can be synthesized in good yields by the reaction of o-bromacetophenone 262 (1 equiv), potassium ethyl xanthate (3.5 equiv), and an aromatic or heteroaromatic aldehyde (1 equiv) (Scheme 45) .

Scheme 45

By combining the advantages of known ortho-selective nucleophilic substitution of 2-haloanilines with potassium (or sodium) ethyl xanthate, followed by facile intramolecular cyclization step, a possible reaction pathway implies the formation of 2-thioxothio-chromen-4-one anionic intermediate Ia from o-bromoacetophenone and the xanthate. This intermediate can thereafter be transformed into the final products with yet another key intermediate, viz. thioaldehyde, obtained apparently in situ from an appropriate aldehyde and potassium ethyl xanthate.

1,2-Dithioles

4.11.9 Ring Synthesis from Acyclic Compounds 4.11.9.1 From 3-Oxoesters A series of 3H-1,2-dithiole-3-thiones 258 were prepared by thionation of various 3-oxoesters 264 with either (1) the reagent combination of P4S10, hexamethyldisiloxane (HMDO), and sulfur or (2) LR (Scheme 46) . For all precursors, thionation by the P4S10/HMDO/S8 system gave higher yields than those obtained with LR (Table 8).

Scheme 46

Table 8 Comparative yields of 3H-1,2-dithiole-3-thiones 258 from 3-oxoesters 264a and 264f–i using P4S10/HMDO reagent or LR Yield (%) Run

Product

Reagent

Solvent

Time (h)

HPLC

Isolated

1 2 3 4 5 6 7 8 9 10

258a 258a 258f 258f 258g 258g 258h 258h 258i 258i

P4S10/HMDO LR P4S10/HMDO LR P4S10/HMDO LR P4S10/HMDO LR P4S10/HMDO LR

Xylene PhMe Xylene PhMe Xylene Xylene Xylene Xylene Xylene PhMe

1 3 1 5 8 4 2 8 1 10

83 80 98 84 93 79 86 80 98 73

70 80 83

86

Similar synthesis of 5-alkyl- or 5-arylthio-3H-1,2-dithiole-3-thiones 267 from dithiomalonic esters 265 containing phenyl, benzyl, or primary, secondary, and tertiary alkylthio group at the C-5 position was accomplished with (1) P4S10/S8 in boiling xylene in the presence of 2-mercaptobenzothiazole/ZnO as catalyst, or (2) with LR as sulfurizing reagent (Scheme 47) .

Scheme 47

929

930

1,2-Dithioles

Conversion of the 1,2-dithiole-3-thiones 267 into corresponding 5-alkyl- or 5-arylthio-3H-1,2-dithiol-3-ones in low to moderate yields (18–70%) was acomplished with mercury acetate in glacial acetic acid . The yields are not high due to the complexity of the remaining residue. In a separate study on the synthesis of 5-phenyl-1,2-dithiole 258a, molybdenum dithiopropiolato complexes 268 were treated with trimethylamine-N-oxide (TMNO) to give oxo complexes 269a–c, whose thermolysis under mild experimental conditions resulted in the formation of the final product (Scheme 48). The direct preparation of this compound, achieved by reacting 268a–c with TMNO in acetonitrile, presumably via in situ-formed oxo complexes 269a–c, also affords 258a in yields of 80%, 33%, and 44%, respectively.

Scheme 48

4.11.10 Syntheses of Particular Classes of Compounds 4.11.10.1 1,2-Dithiolanes and Other Saturated Derivatives An efficient approach to the synthesis of 1,2-dithiolan-3-one 1-oxide, which is the bioactive moiety of macrolactamtype antiobiotic leinamycin 5, involves the sequence of reactions shown in Scheme 49 .

Scheme 49

1,2-Dithioles

The (E)-,-unsaturated thioester 271, obtained from 3-phenylpropanal 270 by a Wittig reaction, was transformed upon treatment with hydrogen sulfide in dioxane in the presence of triethylamine into the mercaptothiolic acid 272. Without isolation, this product was oxidized with potassium hexacyanoferrate(III) to the dithiolanone 273, which gave rise to the S-oxide 274 with dimethyldioxirane in another oxidation step. Extension of this chemistry has been successfully applied to leinamycin antibiotic analogues by incorporation of the 1,2-dithiola-3-one-S-oxide moiety into aldehydes such as aldehydo-D-arabinose 270b; open-chain aldehyde 270c possessing a triple bond, and the uridine derivative 270d. Regarding the synthetically and biologically exceptionally important oxidation of thiols to disulfides, several methods have been described for the preparation of 1,2-dithiolane 2 from 1,3-propanethiol (Scheme 50). The first, being based on an interesting variation of the well-established use of iodine as an oxidizing reagent, was described in an investigation related to the preparation of -glycosyl iodides and vicinal iodohydrins . Other methods, which will be briefly discussed, utilize benzyltriphenylphosphonium peroxodisulfate I under nonaqueous conditions , potassium permanganate adsorbed on copper sulfate pentahydrate , or catalytic Re sulfoxide system II as a oxidizing reagent in the reactions of various thiols, including 1,3-propanethiol. In the first redox process (Equation 1), instead of focusing on the iodine itself, the formation of the by-product, that is, HI, is scrutinized because an efficient thiol oxidation depends on HI removal by a base, or its dissolution in a biphasic reaction mixture. Thus, in a reaction monitored by 1H NMR, 1,3-propanethiol (1 mmol) was quantitatively oxidized to dithiolane 2 with iodine (0.5 mmol) in the presence of 2-methyl-2-butene (1 mmol), which was completely converted into 2-iodo-2-methylbutane by HI formed in situ. In this case, as well as with thioacetic acid, the same alkene was completely converted by HI to 2-iodo-2-methylbutane, while in an absence of the butene derivative the corresponding disulfides were not detected. Two further examples demonstrate the use of different oxidation reagents, viz. benzyltriphenylphosphonium peroxodisulfate I (Equation 2) and KMnO4/CuSO4?5H2O (Equation 3), for the oxidation of diverse thiols, including the oxidation of 1,3-propanethiol, where much lower efficiency was observed. The oxidation of 275 in the presence of a catalytic amount of Re(DMSO) as reactive species, formed from catalytic precursor II and DMSO (Equation 4), is of interest due to the oxygen atom transfer to initially formed 1,2-dithiolane 2 giving rise to 1,2-dithiolane S-oxide 276 in high yield (DMSO ¼ dimethyl sulfoxide).

Scheme 50

931

932

1,2-Dithioles

This is in accordance with the oxidation of LA under mild experimental conditions to the corresponding oxo derivatives 277 and 278 in high yield (90%).

Though intramolecular oxidation of 1,3-dithiols initiated by a variety of oxidizing reagents is the most common method for the preparation of 1,2-dithiolanes, free radical cyclization of 2,2-diethyl-1,3-propanedithiol 279 and 3-tertbutylthio analogue 282 to 1,2-dithiolane 281 (Scheme 51) proceeds in the presence of a catalytic amount of 2,29azobisisobutyronitrile (5 mol%) . It has been shown, utilizing a limited number of precursors, that the cyclization is restricted only to processes involving the formation of intermediates such as 280 and 283, which subsequently transform to 281 and corresponding tertiary leaving radicals.

Scheme 51

In a study related to the conformational properties of the cyclohexane-fused six-membered heterocycles, new bicyclic dithiolanes, 285-trans (Scheme 52) and 285-cis (not shown), were prepared along the reaction pathway, as precursors used further for the syntheses of 2-methyl substituted and unsubstituted trans-fused 4a,5,6,7,8,8a-hexahydro-2H,4H1,3-benzodithiines, exemplified by structure 288-trans (R ¼ R1 ¼ H) . Thus, ditosylation of cis-2hydroxymethyl cyclohexanol 284, and subsequent reaction with sodium sulfide and sulfur, provided a mixture of new bicyclic products 285 and 286, albeit in very low yields, with configurational inversion at C-1. These were reduced by LiAlH4 to provide trans-2-mercaptomethyl cyclohexanethiol 287-trans. Upon acetalization or transacetalization, the desired 288-trans derivative was obtained. The same methodology with the precursor 284-trans was extended to the preparation of the cis-fused bicyclic compounds 285–288.

Scheme 52

1,2-Dithioles

Another method for the formation of dithiolane derivatives, exploiting the potential of organometallic reagents but limited to two examples, is the nucleophilic ring opening of aziridines 289 and 295 (Scheme 53) with benzyltriethylammonium tetrathiomolybdate 290 .

Scheme 53

In the case of the precursor 289, the role of the reagent 290, acting also as a sulfur-transfer reagent, is believed to be the generation of an intermediate 293 via nucleophilic attack on the aziridine from the less-hindered side. The intermediate 293 undergoes a thiaza Payne-type rearrangement , affording the major trans-thiirane 291, whereas a competitive intramolecular cyclization (step 293 ! 294), followed by disulfide formation, presumably due to the through-space interaction between the nonbonded sulfur atoms, gives rise to minor product 292. In a onepot reaction of the cis-aziridino epoxide 295, the anancomeric dithiolane 296 was obtained in high yield, as a result of the ring opening of aziridine and epoxide rings. The oxidative dimerization of ,!-dithiols carried out by a large number of oxidizing reagents is a well-known and widely used method for the synthesis of cyclic disulfides. An alternative one-step conversion of the acyclic bisthiocyanates 297 using TBAF in dry THF at room temperature to form cyclic disulfides in moderate yields, including a limited number of 1,2-dithiolanes 298 (Scheme 54), has been developed . The available mechanistic information indicates that the process, induced by so-far-unreported nucleophilic attack by fluoride, tolerates ester and ketal groups, while silyl ethers are cleaved.

Scheme 54

933

934

1,2-Dithioles

An unusual rearrangement of silylated 1,2-dithiins 299 has been used in the preparation of bicyclic compounds 300 containing a 1,2-dithiolane fragment .

Presumably this reaction proceeds via an allylic carbocation intermediate 301 formed by Lewis acid-initiated C–S cleavage, then ring closure to a new carbocation 302 stabilized by the silyl group. As illustrated in Scheme 55, the subsequent steps, leading to final product 300, involve disulfide bond formation, double-bond shift, and hydride migration.

Scheme 55

In contrast to the preparations of 1,2-dithiolane derivatives described in this section, the sulfurization of -dithiolactone 303 (Scheme 56) with 2 equiv of elemental sulfur provides a single example of formation of a 1,2-dithiolane3-thione derivative 305 . An ionic intermediate 304 has been invoked to explain a ring enlargement via simultaneous departure of pyridine and migration of sulfur.

Scheme 56

It has been found that a cycloaddition of compound 305 with DMAD affords exclusively spirane 307, which includes a 1,3-dithiole ring (Scheme 57). The expected [3þ2] cycloaddition as a first phase giving rise to an intermediate 306, followed by a ring closure, rationalizes the reaction outcome. In comparison to 305, a broad range of 1,2-dithiole-3-thiones can be efficiently converted into corresponding 2-(2-thioxoalkylidene)-1,3-dithioles, as exemplified by the reaction of 308 with DMAD. Depending on the reaction conditions and structural properties of the initially formed cycloadduct, such as 309, further transformations are possible.

1,2-Dithioles

Scheme 57

A convenient three-component coupling reaction of Meldrum’s acid, acrolein, and thioacetic acid was described for the synthesis of 2-(1,2-dithiolan-3-yl)acetic acid 315 (Scheme 58). As shown, diacetylthiolated propyl Meldrum’s acid 311 was refluxed in methanol affording ester acid dithioacetate 312, which without purification was transformed upon acid-catalyzed methanolysis into diester 313. The subsequent oxidation step led to ester 314 which afforded the final acid 315 by a hydrolysis–decarboxylation sequence.

Scheme 58

4.11.10.2 Synthesis of Potentially Biologically Active Compounds Containing 1,2-Dithiolanes Another significant development regarding the exploration of biological functions and specific chemical reactivity of 1,2-dithiolanes is directed toward the synthesis of biologically active oligosaccharides and peptide derivatives that contain this five-membered cyclic disulfide. Thus, one potential photooxidant and immunomodulator 318 , an analogue of the tumorassociated T-antigen, Gal1,3GalNAc, was synthesized from 317, bearing a thiocyanate group at C-6 and a triflate leaving group (steps i and ii, Scheme 59). In turn, compound 317 was obtained by a standard procedure from compound 316. An ability of 4,6-epidithio-modified T-antigen analogue 318 to bind via hydrogen bonding and hydrophobic interaction to natural receptors, such as the carbohydrate binding sites in specific legume lectin from peanut, was tested, and found to be 30 times weaker than that of T-antigen.

935

936

1,2-Dithioles

Scheme 59

The first peptides with an incorporated 4-amino-1,2-dithiolane-4-carboxylic acid residue (Adt), represented by structures 319 , 320 , and 321 , were synthesized in order to restrict their conformational mobility and stabilize defined secondary structures, thus making them chemically more stable and biochemically active.

The biological activity of the chemotactic 1,2-dithiolane-containing tripeptide 320, an analogue of the N-formyl-Lmethionyl-L-leucyl-L-phenylalanine methyl ester, For-Met-LePhe-OMe (fMLF-OMe), in which Adt residue replaces L-leucine, was tested on human neutrophils. The structure of the linear achiral N-protected dipeptide methylamide BOC-Adt-Adt-NHMe 321 , containing two Adt residues, was confirmed by a crystal structure analysis (BOC ¼ t-butoxycarbonyl. Just as in the case of known carba analogue BOC-Ac5c-Ac5c-NHMe , where Ac5c stands for 1-aminocyclopentane-1-carboxylic acid, compound 321 adopts a type III -turn conformation not only in the crystal state, but in chloroform solution as well, as established by 1H NMR and NOE data. The Adt moiety is an integral structural part of a natural product isolated from the New Zealand ascidian Pycnoclavella kottae. The example in Scheme 60 provides a nice illustration of the efficient synthesis of a 1,2-dithiolane analogue of leucine, of interest in medicinal chemistry due to the biological activity of the heterocyclic ring. Thus, the stereocontrolled synthesis of N- and C-protected derivative of (S)-amino-3-(1,2-dithiolan-4-yl)propionic acid 326 and its reduced 1,2-dithiolic form from tert-butyl (S)-N-tert-butoxycarbonylpyroglutamate 322 as a precursor were reported .

1,2-Dithioles

Scheme 60

4.11.10.3 1,2-Dithiolium Salts The preparation of 1,2-dithiolium perchlorate 330 was described from the dithiazinium perchlorate 329 (Scheme 61), derived by the reaction of 1-benzoyl-2-phenylacetylene 327 with 1,5-diphenyl-2,4-dithiobiuret 328 in glacial acetic acid in the presence of an equimolar amount of perchloric acid .

Scheme 61

The sterically crowded benzodithiolium salt 333 has been prepared, and its structure determined by single crystal X-ray diffraction (Scheme 62) . Due to the repulsive interactions between the isopropyl substituents at the C-2 and C-6 positions of the aryl group and the ortho-hydrogen of the benzodithiolium group, the planes of these two groups in the solid state are almost orthogonal.

937

938

1,2-Dithioles

Scheme 62

The one-electron reduction of the salt 333 with sodium in THF forms the stable dithiolyl radical 334 with a 7pelectron system that is not susceptible to dimerization. However, the radical 334, which is a green solid, whose structure was determined by MS and electron paramagnetic resonance (EPR) spectroscopy, undergoes reversible oxidation in the presence of NOBF4.

4.11.10.4 Synthesis of LA and Derivatives Several enantioselective syntheses of the precursors leading to the naturally occurring (R)-(þ)-lipoic acid, or (S)enantiomer, have been reported in the 10 years since 1995 . The key step in the synthesis described in Scheme 63 is the catalytic asymmetric allylstannation of the methoxycarbonyl- and n-propoxycarbonyl-5-substituted aldehydes 335 with allyltributylstannane 336 to chiral 6-hydroxy-8-nonenoate 337, which can be converted into the target compound according to a known procedure (Scheme 63) . The chirality at the C-6 position is induced by the BINOL/Ti(Oi-Pr)4 catalyst , and the best reaction conditions regarding enantiomeric purity and yield are given in the table as a part of Scheme 63.

Scheme 63

1,2-Dithioles

The following examples utilize Sharpless asymmetric dihydroxylation and Rucatalyzed asymmetric hydrogenation as the key steps in the reaction sequence affording (R)-lipoic acid (Schemes 64 and 65). The ,-unsaturated ester 338 was obtained according to a known procedure from cis-2butene-1,4-diol. Transformation to the hydroxy lactone 339 from 338 was acomplished using the AD-mix- for Sharpless asymmetric dihydroxylation and in situ cyclization.

Scheme 64

Scheme 65

The synthesis of the same precursor 340 from olefinic ester 341 and 344 from 343 (Scheme 65) take advantage of the previously mentioned Sharpless asymmetric dihydroxylation and Ru-catalyzed asymmetric hydrogenation. A synthetic strategy based on Jacobsen’s hydrolytic kinetic resolution of readily available racemic epoxide 345 offers the possibility to produce in a good yield enantiomerically enriched (R,R)- and (S,S)-epoxides 345 as chiral building blocks for the preparation of (R)-lipoic acid and (S)-lipoic acid (Scheme 66) . A useful synthesis of racemic methyl lipoate from the key intermediate 348, prepared via a six-step reaction sequence, starts from tricarbonyl(diene)iron complex 350 (Scheme 67) . The main goal of this practical method, based on the use of the optically active iron complex 350, was a possible stereoselective synthesis of LA and other structural analogues. A preparatively useful synthesis of (R)-lipoic acid involves Baeyer–Villiger monooxygenase-catalyzed biotransformation of 2-(2-acetoxyethyl)cyclohexanone 351 to the key precursor, that is, chiral lactone 352 (Scheme 68) . The enzyme-catalyzed lactone 352 was then converted by a standard reaction procedure into the desired acid on enantioselective esterification of racemic lipoic acid, using C. rugosa lipase.

939

940

1,2-Dithioles

Scheme 66

Scheme 67

Scheme 68

1,2-Dithioles

4.11.11 Important Compounds and Applications 4.11.11.1 LA and Derivatives: Synthesis, Natural Occurrence, and Biological Applications Interest in LA as a component in various compounds was stimulated by its diverse biological activity on the one hand, and the possibility of controlling pharmacological properties, such as selectivity, solubility, stability, or cellular penetration. A variety of synthetic or naturally occurring compounds contain an -lipoic acid moiety, mainly in the form of an amide. The first instance, exemplified by the synthesis of a new amphiphilic antioxidant PBNLP 353 from LA as the hydrophobic part and -phenyl-N-tert-butyl nitrone (PBN) as a free radical spin-trap, involves -aminobutyric acid (GABA) as a spacer .

The hydrophilic lactobionamide moiety connected to the para-position of PBN increases the water solubility. In vitro biological experiments, which showed an increased protection of erythrocytes against exogenous free radicals exhibited by 353 in comparison to PBN and lipoic acid, were analyzed in the context of the favorable amphiphilic nature, that is, the bioavailability of this antioxidant. Similarly, the coupling of LA to arylthiophene imidamide derivative 355, via a carboxamide linker, led to lipoic acid analogue 354, acting as a metabolic antioxidant and a nitric oxide synthase (NOS) inhibitor as well .

Within the context of pathophysiological properties of nitric oxide (NO), significant experimental evidence has been presented regarding the catalytic role of two cellular dithiols, viz. thioredoxin (Trxn), the protein implicated in cell growth DNA synthesis, etc., and DHLA, the reduced form of LA . These dithiols catalyze the denitrosation of S-nitrosoglutathione, S-nitrosocaspase, S-nitrosoalbumin, and S-nitrosometallothionenin to their reduced state, occurring with simultaneous formation of nitroxyl (HNO), which is the one-electron reduction product of NO. It is known that a cooperative effect between LA and other natural antioxidants, such as tocopherol (vitamin E) or ascorbic acid, affords the possibility to reduce the formation of reactive oxygen species (ROS), associated with various pathological disorders. Thus triamine spacer as backbone was used to attach Trolox, a water-soluble analogue of vitamin E, and LA, to obtain new analogues 356 which were tested as inhibitors of the microsomal lipid peroxidation. Attachment of LA to the chroman moiety, as in compound 357, is a useful extension of this study .

941

942

1,2-Dithioles

The preparation of a series of dipeptide-derived -keto-amide compounds, including among others derivatives 358 and 359, with an incorporated lipoyl residue, has been described . These substrates, tested in an animal model, exhibit the potential to be effective for treatment of a specific form of muscular dystrophy, known as Duchenne muscular dystrophy. While the type of substituents in 358 and 359 and related compounds is of interest regarding the biological activity, the presence of a nonpolar lipophilic lipoyl group is an important advantage in comparison to other lipophilic moieties due to the increase of the permeability into the muscle cell.

Ester and amide derivatives of lipoic acid (i.e., 360 and 361) are capable of increasing the rate of glucose transport in myotubes in culture in the absence or presence of insulin . Due to the improved lipid solubility, these compounds surpass the potency of LA, which is used as an auxiliary drug for the treatment of diabetes, by a few orders of magnitude.

Potent antioxidant analogs of LA, exemplified by structures 362 and 363 , containing the N-alkylsubstituted morpholine ring and thioamide or thiocarbamate moiety, respectively, have also been developed and pharmacologically tested. In comparison to the structurally related amide or carbamate linker analogues, compounds 362 and 363 are more promising antioxidants.

1,2-Dithioles

A synthesis of chemically modified insulin 364 containing LA covalently bonded to the "-amino group of LysB29 of insulin has been described . Its potency regarding glucose-lowering activity was similar to that of native insulin, but the compound loses efficacy more slowly.

In a specific biochemical investigation regarding the reduction of the lipoyl group in the presence of lipoamide dehydrogenase of the glycine decarboxylase multienzyme system and tris(2-carboxyethyl)phosphine as a disulfide reducing reagent , several water-soluble lipoates were synthesized, and one of them 365 possesses a protected N -benzyloxycarbonyl lysine.

In an effort to obtain LA derivatives with improved antidiabetic activity , a class of hybrid LA derivatives was prepared, including 366 and water-soluble analogue 367, containing 1,3-thiazolidine-2,4-dione moiety covalently bonded via C-5 to an amide linker.

A series of compounds, such as 368 and 369, containing a 1,2-dithiolane moiety as an integral structural part, were evaluated in terms of their multiple biological properties, including their ability to inhibit intracellular oxidative stress .

943

944

1,2-Dithioles

4.11.11.2 Natural Occurrence and Biological Applications The isolation of kottamide E 370, an alkaloid, containing a dibromo-indole enamide, oxalic acid diamide, and 4-amino-1,2-dithiolane-4-carboxamide fragment (Adt), from the New Zealand ascidian P. kottae, and its characterization have been described . This is the first time that the presence of the Adt residue, which is a conformationally rigid analogue of cysteine, has been observed in a natural product. Structurally related kottamides A–D, possessing the 2,2,5-trisubstituted imidazolone ring instead of the 4,49-disubstituted-1,2-dithiolane ring, had been isolated previously as major components from this New Zealand ascidian of the genus Pycnoclavella.

Experimental and theoretical studies have shown that intramolecular nonbonded S X (X ¼ O or S) interactions in a large number of organosulfur compounds, including natural antitumor antibiotic leinamycin 5, are important in controlling their structural properties and chemical reactivity . Density functional theoretical and semiempirical calculations on compound 5 and benzodithiolanone oxide 372 as a member of the model systems 371–374 confirm the stabilizing effect of interactions of that type, which amounts to approximately 6 kcal mol1 in the case of 5.

1,2-Dithioles

The 3H-1,2-benzodithiolan-3-one 377 (Scheme 70) having the reactive alkene side-chain with the role of the C(6)TC(7) double bond in leinamycin 5 (Scheme 69) has been synthesized, as a highly simplified structural analogue of antitumor antibiotic leinamycin 5 . Reaction of 5 with thiols, as shown, affords, via several intermediates, involving 375, an episulfonium ion 376, which subsequently participates in DNA alkylation processes.

Scheme 69

The authors suggested a mechanistic rationale to account for the fact that 377 as a small molecule mimics key elements of thiol-initiated DNA alkylation by leinamycin according to the mechanism depicted in Scheme 70.

Scheme 70

The formation of cyclic compound 381, formed in 50% by reaction of 377 with thiol (1 equiv) in a 1/1 mixture of acetonitrile and sodium phosphate buffer, was explained as a result of attachment by water on the episulfonium ion 380, which is structurally related to the intermediate 376. Oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione) (Scheme 71) is probably one of the most widely cited compounds and belongs to a series of 1,2-dithiole-3-thiones with cancer chemopreventive properties . It has been suggested that its biochemical action is the result of the induction of the ‘phase 2’ enzymes which are involved in carcinogen detoxification. In order to gain additional insights into the molecular mechanism of this biological process , the synthesis and characterization of two compounds, 382 and 383, from oltipraz was undertaken. All three compounds in reaction with the biological thiol glutathione (GSH) yield the same metabolite 384 in almost quantitative yield, as indirectly confirmed, which after methylation gives product 385. It has been indicated that among others the parent 1,2-dithiole-3-thione 1b, in addition to cyclopentano analogue 386 and 5-tert-butyl-substituted 1,2-dithiole-3-thione 387, shows promising chemoprotective activity.

945

946

1,2-Dithioles

Scheme 71

4.11.11.3 SAMs Within the field of SAMs , numerous investigations have been reported in the 10 years since 1995 on the use of LA as one of the most reactive organosulfur compounds that form SAMs on gold surfaces. It is believed that the formation of SAMs by chemisorption of molecules of LA, or other disulfides, occurs via an oxidative addition mechanism of the S–S bond to the gold surface, giving rise to a gold thiolate species according to the following equation. þ

RS SR þ Auon ! RS– Au Auon Due to the pendant carboxylic group, SAMs of lipoic acid have been used in a large number of surface modifications, providing access to new structure systems with potential applications in biotechnology and molecular electronics, etc. A compilation of modified structures employed for the SAMs containing the LA moiety and bound to the Ausurface is presented in this section. An example of this is the structural modification of a self-assembled monolayer of LA on gold polycrystalline gold wire electrode with 1,8-diamino-3,6-dioxaoctane as a spacer and thiocholine which resulted in the formation of the functionalized monolayer 389 .

The presence of a choline group led to the possibility of attaching b-galactosidase from Escherichia coli connected to choline-binding domain of (acetylmuramoyl)-L-alanine amidase from Streptococcus pneumoniae. With respect to the

1,2-Dithioles

development of synthetically prepared models with biological functions, it is relevant that the stability, the hydrolase activity, and the affinity for choline of the specifically immobilized enzyme in 389 were preserved. As a continuation of these studies, a mixed monolayer modified with the epoxy-boronic acid and epoxy groups as indicated by structures of 390 and 391 was prepared .

In another example, mono-6-amino-permethyl-b-cyclodextrin (TMCD), that is, the cyclic oligosaccharide with seven -1,4-connected D-(þ)-glucopyranose units belonging to a well-known class of water-soluble cyclodextrins, was coupled to lipoic acid in the presence of 1-(3-dimethylamino)ethyl carbodiimide to afford b-cyclodextrin–lipoic acid adduct 392 (TMCDLA) via formation of an amide bond . Due to the chemisorption properties of the lipoic acid moiety of (TMCDLA), an interaction with colloidal gold surfaces was demonstrated. However, regardless of the inherent hydrophobic, torus-shaped cavity of TMCD, which also predisposes the cavity of TMCDLA to serve as a host for guest molecules, the meso-tetrakis(4-sulfonatophenyl)porphyrin as an external strong guest did not interact with TMCDLA, most likely because of the self-inclusion of the LA residue.

In order to improve synthesis of TMCDLA, the self-assembly of monolayers on a gold electrode based on a protected cyclodextrin–LA derivative, viz. mono-6-lipoyl-amido-2,3,6-O-peracetyl-b-cyclodextrin, has also been performed involving the deacetylation step on the electrode surface after monolayer formation . Applying the same methodology, immobilization of the -cyclodextrin–LA derivative, mono-6-deoxy-lipoyl-amidoper-2,3,6-O-acetyl--cyclodextrin on the solid surface was employed for the preparation of cyclodextrin-modified gold electrodes. The synthesis of LA–pyrenemethylamine conjugate 393 and its self-assembled organic monolayer formed on a gold surface, based as in previous examples on the anchoring ability of the cyclic disulfide moiety of LA, has been carried out for the purpose of the potential design of electrochemical immunosensors of monoclonal antibody–benzo[a]pyrene interaction.

947

948

1,2-Dithioles

In other work , synthetic methods were given for SAMs, exemplified by structures 394–396 , 397, and 398 (Scheme 70) , which have been developed for studies of their cation-recognition properties.

Monolayer characterization of the structurally similar ester derivatives 394 and 395 and the crown ether 396 on a gold surface by reflection absorption IR spectroscopy was based on the presence of methylene C–H stretching vibrations bands at nearly identical positions at 2925 cm1 for 394 and 395 and 2924 cm1 for 396. The characteristic C–O stretching modes of the ether moiety at 1129, 1126, and 1138 cm1 were observed for the monolayers of compounds 394, 395, and 396, respectively. In addition, a strong absorption in the region of 1740–1721 cm1 was assigned to the C–O stretching of the carbonyl group. A group of p-electron donors of dithia-crown TTF derivatives 400 and 401 with two and one hydroxy groups, respectively, were synthesized by reduction of the crown ether TTF diesters 399 (Scheme 72) with NaBH4 and LiCl. Coupled with thioctic acid, the major diols 400 and monoalcohols 401 (isolated in trace quantities) gave high yields of dithia-crown-annelated TTF disulfides 397 and 398, respectively. They were also employed as the binding motif for stable SAMs on gold, contaning a crown ether ring as a terminal group capable for detecting alkali metal ions at the solution interface . Due to the presence of an immobilized oligo(ethyleneglycol) fragment in 394 and 395 and a crown ether moiety in 396–398, these SAMs have been evaluated by cyclic voltammetry for their alkali cation-recognition properties with a potential to be utilized as thin-film ion sensors. In addition to the SAMs of bis-LA ester derivatives of oligoethylene glycols and crown ether-annelated TTFs , SAMs stable of two conformational isomers of p-tert-butylcalix[4]crown-6 derivatives 402b and 403b were obtained on gold electrodes. Those derivatives were prepared from the corresponding bis-alcohols 402a and 403a and lipoic acid. While the conformer 402b exhibits a high affinity to Csþ-ion, the spatial restriction of the stereochemically different cone-shaped isomer 403b prevents the recognition of this metal cation. The same group reported the preparation and 1H NMR and UV–Vis spectroscopy testing regarding the recognition of the monovalent anions OAc, Cl, Br, NO3, HSO4, and H2PO4 by the hydrogen-bond-forming tripodal anion receptor, that is, thioctic ester derivative of cyclotriveratrylene . The comparative results of the NMR titration of compound 404 with the monovalent anions in DMSO-d6 showed that the position of one broad signal centered at 7.86 ppm, assigned to NH protons, changes appreciably only upon addition of acetate salt. Thus, a significant downfield shift of the NH peak and its splitting into two peaks at 7.98 and 8.01 ppm due to the existence of two nonequivalent NH protons was attributed to the strong binding of the host 5 with OAc via hydrogen bonding. In addition, the selective acetate anion recognition of the resulting SAMs on a gold surface in aqueous solution was investigated by impedance spectroscopy.

1,2-Dithioles

Scheme 72

949

950

1,2-Dithioles

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1,2-Dithioles

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Biographical Sketch

ˇ stanj, Slovenia, is a Professor in Organic Chemistry at the Rade Marković, born in 1946 in Soˇ Faculty of Chemistry, University of Belgrade, Serbia. He obtained his undergraduate degree in 1970 at the same University and Ph.D. from the University of California, Santa Barbara in 1981. After postdoctoral research at UCSB and the Institute of Chemistry, University of Zurich he has been working at the Faculty of Chemistry, University of Belgrade. His field of research focuses on a variety of studies in physicochemical and synthetic chemistry of heterocycles, particularly that of thiazolidines, 1,2-dithioles and thiazines.

Aleksandar Raˇsović was born in 1967 in Podgorica, Montenegro. He obtained his B.Sc. in 1996 and M.Sc. in 2002 at Faculty of Chemistry, Belgrade University, Serbia. From 2003 Aleksandar Raˇsović has been employed at Institute of Chemistry, Technology and Metalurgy, Centre for Chemistry, Belgrade. Currently he is pursuing his PhD studies at the Faculty of Chemistry, University of Belgrade under the guidance of Professor Rade Marković, investigating the role of intramolecular non-bonded S O interactions on regioselective synthesis of 1,3-thiazines by sequential 4-oxothiazolidine to 1,2-dithiole to 1,3-thiazine transformations.

4.12 1,3-Dithioles P. Bałczewski ´ Poland Centre of Molecular and Macromolecular Studies PAS Ło´dz, W. Kudelska Jan Długosz University (JDU), Cze¸stochowa, Poland A. Bodzioch ´ Poland Centre of Molecular and Macromolecular Studies PAS Ło´dz, ª 2008 Elsevier Ltd. All rights reserved. 4.12.1

Introduction

956

4.12.2

Theoretical Methods

957

4.12.3


959

4.12.3.1

Absorption Spectroscopy

959

4.12.3.2

1

963

4.12.3.3

Mass Spectrometry

4.12.3.4

Cyclic Voltammetry

967

4.12.3.5

X-Ray Crystallography

971

4.12.4


972

4.12.5


972

4.12.5.1

H and

13

C NMR

965

Reactivity of 1,3-Dithiolium Ions; Mesoionic 1,3-Dithiol-4-ones, -4-thiones; 1,3-Dithiol2-ones, -2-thiones

4.12.5.1.1 4.12.5.1.2 4.12.5.1.3 4.12.5.1.4 4.12.5.1.5

4.12.6

974

Thermal and photochemical reactions Electrophilic attack at carbon Nucleophilic attack at carbon Intermolecular cyclic transition state reactions Enzymatic reactions


974 974 975 982 983

983

4.12.6.1

Reactivity of 1,3-Dithioles

983

4.12.6.2

Reactivity of 1,3-Dithiolanes

990

4.12.6.2.1 4.12.6.2.2 4.12.6.2.3 4.12.6.2.4 4.12.6.2.5 4.12.6.2.6

4.12.7

Cleavage reactions Reactions with electrophiles Reactions with nucleophiles Miscellaneous reactions Oxidation at sulfur atoms Radical reactions

990 997 999 1000 1000 1002


1002

4.12.7.1

Substituents Attached to Mesoionic 1,3-Dithiol-4-ones, -4-thiones, -4-selenones

1002

4.12.7.2

Substituents Attached to 1,3-Dithiole

1003

4.12.7.3

Substituents Attached to 1,3-Dithiolanes

1012

4.12.8


4.12.9


1014 1014

4.12.9.1

1,3-Dithiolium Ions

1014

4.12.9.2

Mesoionic 1,3-Dithiole-4-thiones

1015

4.12.9.3

1,3-Dithioles

1015

4.12.9.4

1,3-Dithiolanes

1020

955

956

1,3-Dithioles

4.12.10 4.12.10.1 4.12.10.2 4.12.11

Ring Syntheses by Transformation of Another Ring

1027

1,3-Dithioles

1027

1,3-Dithiolanes

1030

Synthesis of Particular Class of Compounds – TTFs and Critical Comparison of the Various Routes Available

4.12.11.1

TTFs by C–C Coupling of 1,3-Dithiol-2-ones, -2-thiones, or -2-selenones

4.12.11.2

TTFs by C–C Coupling of 1,3-Dithiolium Salts and 2-N-, 2-S-, 2-P-Substituted 1,3-

1032 1033

Dithioles

1035

4.12.11.3

TTFs from Other TTF Structures

1038

4.12.11.4

Miscellaneous Methods and Compounds

1048

4.12.11.5

p-Extended TTFs (p-exTTFs)

1050

4.12.12


1068

4.12.13


1073

References

1074

4.12.1 Introduction This chapter deals with the synthesis, reactivity, and characterization of five-membered heterocycles containing two ring sulfur atoms (1,3-dithiole derivatives) and is a review of the literature in the period 1995–2006. Previous reviews covered the literature till 1982 (CHEC(1984)) and 1995 (CHEC-II(1996)) . Among 1,3-dithiole compounds, 1,3-dithiolylium ions 1, mesoionic 1,3-dithiol-4-ones 2, mesoionic 1,3dithiole-4-thiones 3, 1,3-dithioles 4, 1,3-dithiolanes 5, and the tetrathiafulvalene (TTF) system 6 as a special class of compounds are discussed. p-Extended tetrathiafulvalenes (p-exTTFs) containing more than one conjugated multiple bond between two 1,3-dithiole moieties are also discussed, in conjunction with 6.

The 1,3-dithiolylium (also named 1,3-dithiolium) ions 1, which can be formally derived from 1,3-ditholes 4 by abstraction of a hydride anion, possess a 6p-electron aromatic system and can be represented by canonical structures 1a–1e.

The mesoionic compounds 2 (also named 1,3-dithiolylium-4-olates or 1,3-dithiolium-4-olates) and 3 (also named 1,3-dithiolylium-4-thiolates or 1,3-dithiolium-4-thiolates) are described by canonical structures 2,3a–e, of which those with an oxyanion or a thioxyanion 2a and 2b, are presumably most representative.

1,3-Dithioles

Based on theoretical studies (semi-empirical modified neglect of diatomic overlap (MNDO)/PM3 and AM1) and chemical evidence on mesoionic 2-N-cycloalkylamino-5-alkyl-1,3-dithiolium-4-thiolates and other compounds, Oliveira et al. formulated a definition of mesoionic compounds which is the following: ‘‘Mesoionic compounds are planar five-membered heterocyclic betaines with at least one side-chain whose a-atom is also in the ring plane and with dipole moments of the order of 5 D. Electrons are delocalized over two regions separated by what is essentially a single bond. One region, which includes the a-atom of the side-chain, is associated with the HOMO and negative p charge whereas the other is associated with the LUMO and positive p charge’’ . Furthermore, they found that delocalization regions of positive and negative charges with bond orders between 1 and 2 were separated by single bonds which led to the possibility of introduction of a new notation of structures of mesoionic compounds. Consequently, these compounds should not be considered as formally aromatic (Bird aromaticity indexes of the order of 50 are substantially less then values for benzene (100), pyridine (86), or thiophene (66)).

4.12.2 Theoretical Methods In the previous reviewing periods (CHEC(1984), CHEC-II(1996)) theoretical methods were applied in order to understand certain chemical and physical properties of 1,3-dithiole compounds, especially 1,3-dithiolylium ions, 1,3dithiol-2-one and 1,3-dithiole-2-thione. Since 1995, theoretical methods have been applied, mainly to a particular class of compounds, TTFs, which as electron donors easily form charge-transfer (CT) complexes. These complexes show a wide variety of electronic behaviors leading to semiconductor, metal-like, or superconductor properties. Thus, ab initio quantum-mechanical calculations including Hartree–Fock (HF), second-order Møller–Plesset (MP2) perturbation theory, and density functional theory (DFT) for TTF-based donors (X) of organic superconductors showed that ionic donors (Xþ) were planar but neutral donors (X) deformed to a distorted boat conformation . The first-order ab initio calculations of one-dimensional (1-D) band structures of mixed-stack TTF–benzoquinone derivatives revealed that the dispersion differed qualitatively from existing model calculations . Further studies on electron momentum density of TTF–TCNQ (tetracyanoquinodimethane), by measuring Compton scattering, showed a significant anisotropy of the measured profiles. The directional anisotropies were compared with those derived by two different theoretical approaches. The first, simple molecular orbital (MO) approximation showed that electronic wave functions of TTF and TCNQ in the crystal are not very different from those in isolated molecules. The second ab initio pseudopotential band-structure approach revealed a better agreement due to the more accurate description of crystallinity . As a continuation of this subject, to gain a deeper understanding of the oxidation and reduction processes, the molecular geometries of both neutral and charged molecules (radical cation, radical anion, and dianion) of functionalized 1,3-dithiol-2-ylidene anthracene units bearing both electron-donor and electron-acceptor substituents were optimized at the ab initio 6-31G* HF level showing a good agreement with the X-ray data . Similar types of TTFs and acyclic 1,3-dithiol-2-ylidene compounds of donor–p-acceptor and donor–p-donor properties, varying the central p-electron unit (one, two, or four conjugated double bonds) and possessing dicyanomethylene or N-cyanoimine groups as acceptors, were also assessed with the DFT approach . Also, electronic spectra of TTF and its radical cation TTFþ within the framework of time-dependent density functional theory (TDDFT) using a conventional hybrid functional were studied . In a continued investigation on extended p-donors, in which two dithiole rings are separated by conjugated naphthacene or pentacene spacers, theoretical calculations at the semi-empirical ab initio and DFT levels predicted the appearance of a low-energy CT absorption band in the ultraviolet–visible (UV–Vis) spectra for the neutral compounds with fused polyacenic acceptors . The semi-empirical PM3 method was validated by a good agreement, with X-ray data revealing a distorted geometry from planarity, with the naphthalene spacer forming an angle of 35 with the TTF rings . In turn, semi-empirical calculations supported the electrochemical studies performed under different conditions (solvent, temperature, scan rate, working electrode) and revealed that conjugated ferrocene–p-exTTF multicomponent donor–p-donor molecular hybrids essentially retained the redox characteristics of both ferrocene and p-exTTF components . Theoretical calculations at both semi-empirical and ab initio levels were performed on other donor–p-acceptor systems prepared by Knoevenagel condensation of formyl-containing p-exTTFs with active methylene compounds. The PM3 method provided an even better description of molecular structure of p-exTTFs than ab initio HF/6-31G* calculations .

957

958

1,3-Dithioles

The molecular geometry of the first covalently linked donor–acceptor (D–A) system formed by the moderate acceptor C60-fullerene and a highly conjugated TTF derivative with the p-quinodimethane structure, calculated with the semi-empirical PM3 method, revealed a geometry highly distorted from planarity for the donor fragment and a most stable conformation in which both 1,3-dithiole rings were far away from the C60 surface . The electronic and atomic structure of three hypothetical cycloproducts of buckminsterfullerenedithio-TTF (C60DT-TTF) formed by the 1,2-, 1,4-, and 2,3-cycloadditions of a cyclohexatrienyl unit of C60 to TTF were calculated at the level of semi-empirical HF MO theory (PM3, AM1, MNDO), showing that the 1,2-regioisomer was the most stable (by 0.507 and 0.681 eV in relation to 1,4- and 2,3-C60DT-TTF, respectively). The net charge of the acceptor C60 fragment was negative while the donor DT-TTF was positive . Because of the complexity of some conjugated TTF derivatives, electron charge density distribution was calculated applying combined semi-empirical and ab initio methods . The structures and vibrational spectra of TTF and 1,3-dithiole-2-thione derivatives were examined with DFT B3LYP and ab initio MP2 calculations focusing on the C–S bond . Based on combined statistical and ab initio study (MP2), it was shown that S S intermolecular interactions in the TTF molecular crystals were attractive and anisotropic. Their strength was similar to that reported for C–H S hydrogen bonds and contributed significantly to the cohesive energy of the TTF-based crystals . The geometry and interaction energy of fullerene C60 with CS2 and TTF were further calculated using HF and DFT methods with various base sets, among which the HF/6-31G gave reasonable predictions for these weakly interacting complexes . Ab initio calculations, revealed and analyzed an unknown mechanism that plays an important role in ‘neutral to ionic’ transitions under temperature or pressure variations as well as in the cooperative relaxations accompanying photoexcitations in the TTF–chloranil and related mixed stack organic compounds . A charge close to þ0.5 on superconducting and semiconducting CT salts of the type [bis(ethylenedithio)TTF]4[AIMIII(C2O4)3]?PhCN (AI ¼ H3O, NH4, K; MIII ¼ Cr, Fe, Co, Al) was calculated from CTC and C–S bond distances for two crystallographically independent molecules . Static hyperpolarizabilities and geometry of TTF-derived chromophores were calculated to evaluate second-order nonlinear optical (NLO) properties using the finite field (FF) approach included in MOPAC 6.0 and the coupled perturbed CP-HF scheme included in Gaussian 94w (both for hyperpolarizabilities), semi-empirical calculations (AM1 or PM3 Hamiltonians for geometry and hyperpolarizibilities), and ab initio calculations (3-21G* basis set for geometry, 6-31G* basis set for hyperpolarizability). The FF-PM3 gave a more accurate prediction of the static second-order NLO response than FF-AM1 or CP-HF/6-31G* calculations . In other cases, the latter gave a better quantitative agreement with the experimental values than PM3 calculations . A possible influence of different chemical parameters on nonlinear susceptibility of the TTF derivatives was also investigated, using ab initio calculations and force field MMþ for final geometries . The optical spectra, polarized along the [bis(ethylenedithio)–TTF]2[bis(dithiosquarate)platinate] stack, were well reproduced by a semi-empirical model which took into account the coupling of bis(ethylenedithio)–TTF (BEDT–TTF) molecular vibrations with the CT electrons . Futher ab initio study on structures and electronic phases of BEDT–TTF clusters and salts showed in the ground state various phases: antiferromagnetic, charge ordering, and paramagnetic controlled by long-range Coulombic interactions (2-D extended Hubbard model with HF approximation) . The TDDFT approach was applied to study the UV–Vis spectra of TTF derivatives for the first time and the NLO properties of TTF-derived radical cations. This method provided low excitation energies with high accuracy compared to semi-empirical (complete neglect of differential overlap/spectroscopic (CNDO/S), Zerner’s intermediate neglect of differential overlap (ZINDO)) and ab initio methods (configuration interaction singles (CIS) or time-dependent Hartree–Fock (TDHF)) but was poorer at higher energies . The point molecule approximation, where each molecule was replaced by a point charge at its center of mass, turned out to be inadequate to calculate the electrostatic energies in both ground and excited states of the TTF-p-chloranil complex . The electrostatic potential, calculated in the region of the CT cation–anion of 1-D organic metal bis(thiodimethylene)–TTF TCNQ, was shown to be topologically similar to most hydrogen bonds revealing a typical saddle point between the donor and acceptor atoms . Ab initio STO 6-31G calculations were used to correlate cyclic voltammetry and UV data for the selected 1,3-dithiole and TTF compounds (STO ¼ Slater-type orbital) . Trihalide anions (I3, I–I–Br, Br–I–Br, Br–I–Cl, etc.) were identified in BEDT–TTF salts by Raman spectroscopy and confirmed by a good agreement with ab initio-calculated bond lengths and vibrational frequencies .

1,3-Dithioles

Theoretical methods have also been applied to other classes of 1,3-dithioles. Ab initio molecular dynamics geometry optimization of a C60–2-thiono-1,3-dithiole cycloadduct took into account the superposition of all possible molecular conformations with weighting factor and multiple interactions . Semi-empirical quantum-chemical calculations (PM3) were used to elucidate the role of counterions in five complex anions (M ¼ Ni, Pd, Cu, Cd, Hg) formed from 4,5-dimercapto-1,3-dithiole-2-thione and combined with a hemicyanine dye . Qualitative MO theory (extended Hu¨ckel molecular orbital ((EHMO) method) was employed for a rationalization of the electron density distributed over the three centers S–I–I in diiodine adducts of 4,5-ethylenedithio-1,3-dithiole2-thione . Another group of compounds treated with theoretical methods was associated with the 1,3-dithiol-2-ylidene moiety. Thus, semi-empirical MO calculations of 2-(4-dicyanomethylenecyclohexa-2,5-dienylidene)-4,5-ethylenedithio-1,3-dithiole and its extended quinonoid analogues indicated a moderately strong intramolecular chargetransfer (ICT) transition in the ground state . Based on quantum-chemical calculations, it was shown that molecules with multidirectional CT (MDCT) transitions possessed significantly higher hyperpolarizability than their unidirectional CT (UDCT) analogs and that calculated NLO properties revealed no red shifts of CT transitions on going from UDCT to MDCT molecules possessing the same length of the D–A moiety . Ab initio calculations at the HF/6-311þG** //HF/6-311G** level showed that the driving force of the base-induced rearrangement of 1,4-dithiins to 1,3-dithiol-2-ylidene derivatives was a greater thermodynamic stability and weaker acidity of the latter . Several donor–p -acceptor chromophores with 1,3dithiol-2-ylidenes (for instance, phenylenevinylene, thienylenevinylene) were synthesized and ab initio-calculated at the RHF/6-31G(d)//RHF/6-31G(d) level (RHF ¼ restricted Hartree–Fock), in particular showing that the highest occupied molecular orbital (HOMO) was located mostly in the 1,3-dithiolium ring while the lowest unoccupied molecular orbital (LUMO) mostly at the cyanomethylene fragment . Molecules containing a 1,3,4,6tetrathiapentalene (TTP) moiety, i.e. 2,5-bis(1,3-dithiol-2-ylidene)-TTP and TTP-2,5-dione were also calculated with a modified internal valence force field at the ab initio level . Bis(1,3-dithiole)-poly(mono-, tri-, penta-, and hepta-)methine dyes, which constitute a new series of unusually stable 1,3-dithiole compounds possessing a strong near-infrared (NIR) optical transition and a very good transparency in the visible region, were calculated by both ab initio and semi-empirical methods (AM1, PM3) .

4.12.3 Experimental Structural Methods 4.12.3.1 Absorption Spectroscopy In this section, some selected results concerning Raman, IR, and UV–Vis investigations are discussed. Raman spectroscopy is an effective method for investigation of CT. This phenomenon is accompaned by frequency shifts and a redistribution of band intensities that can give information about the degree of CT and charge distribution in molecules. Raman spectroscopy possesses a high diagnostic value in the evaluation of strength of interactions between donors and acceptors. Thus, the reaction of 1,3-dithiole-2-thione 7 as a donor with diiodine as an acceptor, being investigated at different temperatures, provided evidence for formation of the 1:1 adduct (Table 1) .

Table 1 Selected IR (KBr) and Raman peaks (cm1) for 7 and its adducts with I2 and IBr (CTC)

(CTS)

(CS)3

Compound

IR

Raman

IR

Raman

IR

Raman

7 7?I2 7?IBr

1477

1479 1461 1461

1062, 1042, 1015, 996 1065, 1029 1056, 1015, 1005, 998, 978, 945

1052, 1036 1016

524 534

424 532 538

959

960

1,3-Dithioles

Rich frequencies and relative intensities of the IR and Raman active vibrations in the range of 116–3106 and 176– 3072 cm1, respectively, were recorded for 2,5-bis(1,3-dithiol-2-ylidene)-1,3,4,6-tetrathiapentalene 8 (BDT–TTP), which turned out to be the most basic molecule in the TTP family .

Electronic absorption spectra (Table 2) were also used for analysis of the electron-donor–acceptor systems represented by compounds 9–14 and displayed a broad low-energy ICT band in the visible region (500–700 nm); the energy (h ICT 1.7–2.5 eV) and intensity (" 5000–50 000 M1cm1) depended on the nature of both 1,3dithiole electron donor and dicyanomethylene or 9-fluorenyl acceptor moieties and on the structure of the linker unit .

Table 2 Electronic absorption spectroscopic data and ICT energies (h ICT) derived from the longest wavelength absorbances Compound

Solvent: max (nm) (" (M1cm1))

h ICT (eV)

9 10 11 12 13 14

DCM: 500 (31 600), 324 (17 800) DCM: 474 (38 000), 356 (32 400) Acetone: 510 (19 000), 430 (29 500) DCM: 547 (46 500), 339 (10 500), 293 (14 500) DCM: 564 (28 000), 380 (16 000), 275 (12 900) DCM: 550 (23 800), 415 (23 200), 272 (14 200)

2.48 2.67 2.4 2.27 2.21 2.29

A comparative study on spectroscopic properties of [2-pyrrolidino-1,3-dithiolium-4-yl]phenolates 15 based on UV–Vis spectroscopy demonstrated the internal CT character of the long-wavelength absorption bands. These compounds also exhibited a small negative solvatochromic effect .

1,3-Dithioles

UV–Vis spectra were also applied for analysis of the TTF derivatives 16–19, and their radical cations and dications. Thus, the UV–Vis spectrum of TTF 16, recorded in nonpolar solvents, showed four absorption bands above 300 nm, a very weak (" ¼ 270) absorption at 450 nm (2.76 eV), a weak absorption (" ¼ 1900) at 368 nm (3.37 eV), and two intense bands (" ¼ 21 500 and 13 000) at 317 and 303 nm (3.91 and 4.09 eV), respectively. The UV–Vis spectra of the TTFþ? radical cation, recorded in different solvents, displayed some common features: (1) the lowest energy absorption observed at ca. 580 nm (2.14 eV), (2) the most intense band located at ca. 435 nm (2.85 eV) and two weak bands at 2.52 and 3.08 eV, which were visible depending on the experimental conditions . BEDT–TTFþ? 18 and BEDO–TTFþ? 19 radical cations (BEDO ¼ bis(ethylenedioxy)tetrathiafulvalene) gave an absorption band at ca. 1.2–1.3 eV in sharp contrast to other TTF derivatives, the radical cations of which displayed spectra analogous to that of the unsubstituted TTF radical cation . It was earlier found that the UV– Vis spectrum of the TTF2þ? radical dication shows intense absorptions at 3.15 and 4.54 eV .

The steady-state UV–Vis spectra of functionalized 1,3-dithiol-2-ylidene anthracene donor units 20–22 contained solvatochromic bands arising from ICT between the 1,3-dithiole donor and the keto, dicyanomethylene, and cyanoimine acceptor groups. Time-resolved spectroscopic studies indicated that at least two excited states may be formed on photolysis and that the lifetime of 170–400 ps strongly depended on the solvent polarity .

When the neutral extended TTF 23 with an anthracene core as a spacer was subjected to flash photolysis (in CHCl3), the transient radical cation 23þ? was generated. This radical cation was characterized by Raman spectroscopy. In the degassed solution, 23þ? disproportionated to give the dication 232þ, which in turn was characterized by spectroelectronical techniques. Photolysis of 23 in aerated solution gave as photodegradation product the ketone 20 .

961

962

1,3-Dithioles

Polarized Raman spectra of crystals of 24 (4,9-bis(1,3-benzodithiol-2-ylidene)-4,9-dihydronaphth[2-c][1,2,5]triazole (BDNT)) and its derivatives BDNT?PF6, BDNT?(PF6)2, and BDNT(ClO4)2?CH2Cl2, recorded in the region of 1300–1700 cm1, were used to monitor a charge transfer from BDNT molecules to PF6 and ClO4 acceptors .

A comparison of electronic spectra of the pyrrolo–TTF derivatives 25 containing a quinone acceptor system with macrocyclic D–A systems with the compound 26 based on the 4,49-bipyridinium dication showed that both compounds contained in their structures moderate acceptors and the same strong TTF donors. Direct p-overlap between donor and acceptor was evidenced by a strong band (" ¼ 403) in the rigid structure of 26 . In contrast, the UV–Vis spectrum of 25 did not exhibit CT bands between 500 and 820 nm .

Analysis of C–S and CTS vibrations in the STCS2 fragment of important 4,5-disulfenylated 1,3-dithiole-2-thione derivatives 27 was performed using IR and Raman spectroscopy .

1,3-Dithioles

4.12.3.2

1

H and 13C NMR

1

H Nuclear magnetic resonance (NMR) and UV–Vis spectroscopies were applied to studies on complexation between various TTF donors, among others, TTF 16 and the p-electron-accepting tetracationic cyclophane 28 (CBPQT4þ). The results obtained were of fundamental importance in designing interlocked molecular systems like molecular switches in which CBPQT4þ and TTF units were incorporated . 1H NMR investigations of similar systems are referred to at the end of this subsection.

The characterization and recognition of regioisomeric 1,3-dithiolanes 29 and 30 were possible mainly on the basis of diagnostic values of 1H and 13C NMR chemical shifts of the CH2 group at positions 2 and 5 (Table 3) .

Table 3 Diagnostic 1H and 13C NMR chemical shifts of 29 and 30 R12

R22

Compound

(1H)

(13C)

H2

(Me2CH)2

29 30

3.63 (2-H2) 3.72 (5-H2)

30.3 (C-2) 49.0 (C-5)

Me, H

29 30

3.57 (2-H) 4.55 (5-H)

35.9 (C-2) 52.8 (C-5)

H2

29 30

3.34 (2-H2) 3.38 (2-H2)

25.5 (C-2) 49.7 (C-5)

29 30

3.26 (2-H2) 3.69 (5-H2)

25.4(C-2) 49.6 (C-5)

H2

963

964

1,3-Dithioles

In a series of phosphoryl-substituted 1,3-dithiolanes 31 and 32, the 13C NMR signal due to CH2 appeared at 32.4– 31.8 ppm and exhibited a characteristic differentiated coupling with the P-atom (3J(C,P) ¼ ca. 5.6 Hz for 31 and ca. 10.6 Hz for 32) .

Two-dimensional NMR spectroscopy ((double quantum filtering (DQF), correlation spectroscopy (COSY), heteronuclear multiple quantum correlation (HMQC), heteronuclear multiple bond correlation (HMBC)) as well as liquid secondary ionization mass spectrometry (LSI MS) and UV–Vis spectroscopies were used to establish crown structures of TTFs 33 (n ¼ 1–3). In the case of the macrocycle 33 (n ¼ 1), two protons of each methylene group of the SCH2CH2O fragments were not identical and gave an AA9BB9 system. This observation was in accordance with the expected low conformational mobility of the polyether bridge in (E)-33 (n ¼ 1) as compared with (Z)-33 (n ¼ 1). The macrocycle (E)-33 (n ¼ 2) behaved similarly to (E)-33 (n ¼ 1), whereas the protons under discussion were equivalent in (E)-33 (n ¼ 3) .

Analysis of the 13C NMR chemical shifts of monopyrrolo-TTFs 34–36 (Table 4) showed that the tosyl group caused a shift of most of the 13C NMR resonances in all three heterocyclic rings. A significant change in the chemical shift of the fulvene CaTC bond indicated a pronounced extension of the p-surface in these systems. Similar changes were observed in 1H NMR chemical shifts (from H ¼ 7.40 for R ¼ Ts to 6.78–6.81 for R ¼ H, Me) .

Table 4

13

C NMR chemical shifts for N-substituted monopyrrolo-TTFs 34–36 (75 MHz, DMSO, 25 C)

R

Fulvene CaTC

Fulvene CTCb

Dithiole TCc–CT

Pyrrole Cd

Ts H Me

112.52 107.27 107.24

117.73 121.95 121.34

126.14 117.16 116.77

112.84 110.88 114.66

1,3-Dithioles

The ability of electron-rich macromolecules 37 to act as donors to the electron-acceptor Paraquat 38 was investigated by means of 1H NMR and UV–Vis spectroscopies. A 1:1 mixture of 37 and 38 exhibited a broad CT band centered at 601 nm in addition to significant changes in the H-a and H-b chemical shifts in the Paraquat unit 38 .

4.12.3.3 Mass Spectrometry In CHEC(1984) and CHEC-II(1996), investigations involving mass spectrometry (MS) were not presented. Selected applications of this technique for solving structural problems concerning 1,3-dithiole derivatives are presented below. Tandem MS was applied to characterization and differentiation of the connectivity of the C2S3?þ radical cation (m/z ¼ 120) generated by dissociative electron ionization (EI) of the 1,3,4,6-tetrapentalene-2,5-dione 39. The structural assignment of the radical cation C2S?þ as the C-sulfide ethenedithione, SCCS2?þ 40, was based on the results of ion–molecule reactions of C2S3?þ with nitric oxide, acetonitrile, and methyl isocyanide. The collisional activation spectra of these ion–molecule reaction products recorded on a new type of hybrid tandem mass spectrometer of sectors–quadrupole–sectors configuration allowed the confirmation of the ascribed structure 40 (Scheme 1) .

Scheme 1

Some general features of mass spectra of 1,3-dithiolanes of types 29, 30, and 51 were elucidated based on adamantyland tetraphenyl-substituted dithiolanes as examples (Schemes 2 and 3) . A comparison of the mass spectra of various regioisomeric 1,3-dithiolanes 29 and 30 allowed the reconstruction of supposed fragmentation pathways. Thus, the dissociative EI of the adamantyl-substituted dithiolane 30 generated the

965

966

1,3-Dithioles

radical cation species 41 (Scheme 2). Four possible fragmentation pathways of 41 were found: (a) and (b) providing acyclic radical cations 43 and 44, respectively, and (c) and (d) leading to cyclic three-membered radical cations 47 and 49, respectively. The main peak in the MS spectrum of the adamantyl-substituted dithiolane 30 (m/z ¼ 226) is consistent with the radical cation 49, generated according to the pathway (d) from 45 via 48; 49 transforms into the 9-fluorenyl cation 50 .

Scheme 2

Scheme 3

1,3-Dithioles

The major fragmentation pathway of the radical cation 51þ?generated from the corresponding C2v-symmetrical dithiolane 51 was 1,3-cycloreversion, which led to the generation of two fragments, radical cations 52 and 53 (Scheme 3). The radical cation 54 is present in MS spectra of nearly all dithiolanes of type 51. The radical cation 54 lost the fragments SH or C6H5 to form 50 or 55, respectively . Laser desorption/ionization (LDI) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MSs have become useful tools for the characterization of various conducting polymers. For instance, analysis of poly[2,5-di(thien-2-ylidene)–1,3,4,6-tetrathiapentalene] 56 (DT–TTP) showed ions above m/z ¼ 500 corresponding to oligomers of DT–TTP with up to five monomer units .

The ability of MS to mimic some catalyzed intramolecular reactions was applied to study cyclization reactions of dithiocarbamate derivatives of polyhalopyridines in a mass spectrometer. It was found that cyclization of polychloropyridines containing N,N-dialkyl dithiocarbamates and alkyl xanthate groups at positions 2 or 4 in the pyridine ring underwent intramolecular substitution reactions leading to identical 1,3-dithiol-2-one products formed in solution and in the gas phase (EI). The presence of electron-withdrawing groups para to the leaving groups favored these reactions. In particular, chlorine was a better leaving group than fluorine under EI conditions .

4.12.3.4 Cyclic Voltammetry Cyclic voltammetry (CV) is a specific type of voltammetry, that is, an electrochemical potentiodynamic measurement that allows study of redox properties of compounds and interfacial structures. The cyclic voltammogram of 57 showed a reversible oxidation wave, which was deconvoluted into two peaks corresponding to a one-electron process for each. Cyclic voltammograms of 58 and 59 showed three one-electron reversible oxidation waves corresponding to the successive generation of the radical cation for each TTF unit. Two other reversible waves at higher positive potentials were related to the formation of the dication on each TTF, the second wave being attributed to both equivalent TTF moieties .

Electrochemical properties of p-extended 1,3-dithioles 60–62, containing an anthraquinone core, were studied by CV in solution. All derivatives showed the typical quasi-reversible two-electron oxidation wave of the core at a potential which varied slightly depending on the substituents attached to the dithiole ring. The CV of 62 showed two two-electron oxidation waves corresponding to the sequential formation of cations 622þ and 624þ, providing evidence for significant intramolecular interaction .

967

968

1,3-Dithioles

Various electrochemical investigations revealed that a molecular hybrid consisting of 63, ferrocene (Fe), and an p-exTTF of type (donor 1–p-donor 2) essentially retained the redox characterization of the constituents, showing initial oxidation from neutral to dicationic (Fe–p-exTTF ! Fe–p-exTTF2þ) and finally to tricationic (Fe–pexTTF2þ ! Feþ–p-exTTF2þ) states in two distinct steps. Pronounced intramolecular electronic interactions between the two different electron-donating moieties were observed by CV, Osteryoung square wave voltammetry (OSWV), and UV–Vis in both the ground and charged states .

Depending on the nature of aryl groups (R ¼ p-O2NC6H4, p-NCC6H4, C6H5, p-MeOC6H4, p-Me2NC6H4, o-O2NC6H4) and solvent, two single-electron reversible transfers or one two-electron reversible process were observed for vinylogous 64 and 65 .

The dendralenes 66 and 67 displayed reversible single-electron waves, leading to the sequential formation of the cation radical and dication species. The third oxidation process for 66 and 67 occurred at a considerably higher potential, which was consistent with values for an isolated (nonconjugated) 1,3-dithiol-2-ylidene system. This last oxidation was assigned to the orthogonal 1,3-dithiole ring of 66 and 67 .

1,3-Dithioles

The redox properties in solution of vinylogous 68–71 analyzed by CV revealed a reversible one-electron oxidation wave, attributed to the formation of the radical cation of the 1,3-dithiol-2-ylidene moiety and an irreversible one-electron reduction to form the radical anion located on the dicyanomethylene or N-cyanoimine groups .

The electrochemical properties of the first highly conjugated vinylogous 72 covalently attached to C60-fullerene and determined by CV in solution revealed the electroactive character of both donor and acceptor moieties. Thus, the p-extended donor fragment showed a two-electron single wave due to formation of a stable dicationic species in contrast to the behavior of TTF itself and its derivatives, which formed stable radical cations .

The CV investigations of 1,5- and 2,6-bis(1,4-dithiafulven-6-yl)naphthalenes 73 and 74 revealed that donors 73 underwent a slower electrooxidation process than donors 74, which possessed the same substitution scheme. All donors showed an irreversible oxidation peak on the first scan, which decreased upon successive scans, with formation of a new reversible wave at a lower potential value, which was attributed to generation of dimeric or oligomeric TTFs. This electrochemical behavior suggested an ECE mechanism. In an attempt to characterize the intermediate radical cationic species involved in the electrochemical dimerization of dithiafulvene derivatives 73 and 74 into the corresponding vinylogous TTF, the electrochemical oxidation of these models was monitored by electron paramagnetic resonance (EPR) spectroscopy. These spectrochemical experiments confirmed the formation of dimeric species from the dithiafulvene derivatives 73 and 74 supporting the ECE process. Reaction of donors 73 and 74 (R1 ¼ Me) with strong electron-acceptor molecules such as 75, 76 (2,3-dichloro-5,6-dicyano-1,4-benzoquinone DDQ), or 77 (TCNQ) resulted in the chemical oxidation of the donors and a subsequent oligomerization process to afford solid CT complexes containing the vinylogous TTF species as the cation radical .

969

970

1,3-Dithioles

Examples of solution oxidation potentials obtained from cyclic voltammograms of TTF 16 and pyrrolo-annelated TTFs 78–80 are summarized in Table 5. The cyclic voltammograms of all compounds revealed two pairs of reversible redox waves, indicating a good stability of the corresponding radical cation (D?þ) and dication (D2þ) species. The N-tosylated pyrrolo-TTFs revealed the highest oxidation potential in both bis(pyrrolo)-TTF series and monopyrrolo-TTF series, whereas the N-alkylated pyrrolo-TTFs showed the lowest oxidation potential, due to the relative inductive effects exhibited by tosyl and alkyl groups, respectively .

Table 5 Oxidation potentials E11/2 and E21/2 of pyrrolo-TTF derivatives Compound

E1/21 (V)

E1/22 (V)

Ep (V)

16 78 (R ¼ H) 78 (R ¼ Ts) 78 (R ¼ Me) 79 (R ¼ Me) 79 (R ¼ n-Bu) 79 (R ¼ CH2CH2CN) 80 (R ¼ Me, n-Bu)

0.34 0.38 0.55 0.36 0.60 0.59 0.66 0.44

0.73 0.72 0.96 0.70 0.87 0.86 0.95 0.75

0.39 0.34 0.41 0.34 0.27 0.27 0.29 0.31

The substituted TTF derivatives 81 containing peripheral selenium atoms showed two one-electron reversible waves. They revealed good electron-donor abilities which made these compounds suitable for application in the synthesis of CT complexes and radical cation salts .

1,3-Dithioles

4.12.3.5 X-Ray Crystallography X-Ray investigations were reported in both CHEC(1984) and CHEC-II(1996) and have continued and are discussed here. Halogen adducts of 1,3-dithiole derivatives 82 and 83 were characterized by X-ray crystallographic studies. The adducts feature an array of intramolecular and intermolecular close contacts involving chalcogen–chalcogen, chalcogen–halogen, and halogen–halogen interactions. In addition, the ester and acid moieties are involved in hydrogen bonding .

X-Ray diffraction analysis of a single crystal of 84 (2,5-bis(dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA–TTP)) showed that the three tetrathioethylene units are situated almost in a common plane, while the two trimethylene end groups are far out of that plane in opposite directions and the dihedral angle around the intramolecular sulfur-to-sulfur axis in each dithiole ring is 53.6 .

X-Ray crystallographic analysis revealed that extended TTFs 85 with anthracene cores as spacers adopt nonplanar butterfly or saddle-like conformations in the neutral state. The central ring of the anthracene unit has a boat conformation with folding of the two dithiafulvenyl arms. Such a conformation allows a reduction in steric hindrance between the sulfur atoms of the 1,3-dithiole rings and the hydrogen atoms in the peri-positions of the anthracene unit . Several such compounds were obtained by modifications of both 1,3-dithiole and anthracene moieties and were described as ‘molecular saddles’ . All donor compounds 85 could be directly oxidized to the corresponding dications and this was accompanied by a marked structural change. The X-ray analysis was conducted on a crystal of the dicationic salt 852þ(ClO4)2 obtained during the electrolysis of 85 in the presence of tetrabutylammonium perchlorate. In the structure of 852þ(ClO4)2, the dication possesses crystallographic Ci symmetry and the anthracene moiety is almost planar. The 1,3-dithiolium rings are also planar and connected to the spacer by single bonds. The dihedral angles between the anthracene and the dithiolium planes are 77 , which confirmed that the two positive charges located within the dithiole rings are not connected across the spacer .

The molecular structure of the neutral aryl-substituted TTFs 86 and 87, determined by X-ray analyses, revealed a severely distorted structure with a nonplanar geometry due to a steric hindrance. Dicationic salts of TTFs 86 and 87, obtained as single crystals by electrochemical oxidation or reaction with various metallic salts, adopted a new conformation with a planar extended TTF core, whereas phenyl groups were located in the perpendicular plane . Owing to steric interactions of the phenyl groups, the crystal structures of vinylogous TTFs were unusual. The cation radical salt 86?PF6 has a 2-D columnar structure in which donor molecules bridged two others to avoid steric interactions . In the crystal of

971

972

1,3-Dithioles

87?Au(CN)2, anions were sandwiched between the donor molecules . Other derivatives of type 86 and 87 containing hydroxyphenyl groups afforded cation radical salts with unusual crystal structures involving hydrogen bonding between the OH group and the counteranions .

The only significant difference in the length of the formally double C-3–C-4 bond of the monopyrrolo-TTFs 79 and 88 (1.348 A˚ for 79 and 1.30 A˚ for 88) indicated a more extended p-electron system in the former compound .

X-Ray analyses of neutral compounds 81 showed that these molecules did not form stacks. The molecule 81 (RR ¼ (CHTCH)2) was almost planar with the exception of the acetoxyphenyl group, while other molecules (RR ¼ (CH2)3 and RR ¼ (CH2)2) were significantly bent and adopted boat conformations . Many X-ray analyses were carried out for other TTF systems .

4.12.4 Thermodynamic Aspects In this section, selected data concerning thermodynamic aspects of 1,3-dithiole derivatives are described. Calculations of dipole moment by two methods involving the improved additivity model and the empirical PM3 method gave complementary information concerning suitable conformations and the relative strength of conjugation effects. Thus, the calculated g value (2.8 D) of the completely optimized molecule 89 is close to the experimental value exp (2.79 D) .

Many 1,3-dithiole derivatives, including TTF systems, are solids possessing distinct melting points. Some representative data are shown in Table 6. In particular, values of melting points determined for 4,5-disubstituted-1,3dithiolanes 29 turned out to be double those for 2,5-disubstituted derivatives 30 (Table 7).

4.12.5 Reactivity of Fully Conjugated Rings In this section, 1,3-dithiolium ions, mesoionic 1,3-dithiol-4-ones, and 4-thiones are discussed. Reactivity of 1,3dithiol-2-ones (XTO) and 2-thiones (XTO) is also reported here on the grounds that ionic canonical structures 94b–e make the 1,3-dithiole ring ‘fully conjugated’.

1,3-Dithioles

Table 6 Melting points of selected 1,3-dithiole and TTF derivatives m.p. ( C)

Compound

Reference

119–119.5

1997S407

196–197

2004TL5103

>300

2001JOC8872

163–164

1997JFC(82)175

150

2000CEJ1955

Table 7 Melting points of selected 1,3-dithiolane derivatives R12

R22

Compound

m.p. ( C)

Reference

H2

29 30

203–205 126–128

1999T11475

H2

29 30

106–107 51–52

2005EJO1519

For 2-vinylidene-1,3-dithioles and their p-extended analogues, analogous ionic structures can also be formally drawn; however, no reactions at C-2 in such systems were reported in the reviewed period. The synthesis and reactivity of 1,3-dithiole derivatives with fully conjugated rings were the subject of three reviews .

973

974

1,3-Dithioles

4.12.5.1 Reactivity of 1,3-Dithiolium Ions; Mesoionic 1,3-Dithiol-4-ones, -4-thiones; 1,3-Dithiol-2-ones, -2-thiones 4.12.5.1.1

Thermal and photochemical reactions

Photochemical irradiation of thien-3-yl-substituted 1,3-dithiol-2-ones 95 and 96 led to formation of thieno[3,4-c]dithiins 97 and 98 via a unique ring cleavage followed by loss of carbon monoxide and a subsequent structural rearrangment (Scheme 4). Similar treatment of symmetrical 4,5-di(thien-2-yl)-1,3-dithiol-2-one 101 gave the product 102. Treatment of 97 and 98 with NaBH4 led to a reductive cleavage of the S–S bond and cyclization to hemithioacetals 99 and 100, respectively .

Scheme 4

4.12.5.1.2

Electrophilic attack at carbon

These reactions involve lithiation of 1,3-dithiole-2-thione 103 with lithium diisopropylamide (LDA) followed by reactions of the resulting carbanions with various electrophiles. Thus, the direct lithiation and subsequent bromination of 1,3-dithiole-2-thione 103 allowed a selective preparation of mono- and dibrominated derivatives in 80% yields. For instance, the reaction of 103 with LDA (1 equiv), followed by treatment with 1,2-dibromotetrachloroethane, produced monobrominated derivative 104, whereas the reaction of 103 with excess of LDA (3 equiv) led to the isolation of dibrominated derivative 105 (Scheme 5) . Earlier attempts at bromination of 103 using, for example, p-toluenesulfonyl bromide or 1,2-dibromotetrachlorethane yielded mixtures of mono- and dibrominated derivatives in low yields (25–30%).

Scheme 5

An efficient route to the diol 107 involved the reaction of the lithiated 1,3-dithiole-2-thione 103 with 2-thiophenecarboxaldehyde 106. Further oxidation of 107 with permanganate followed by the reaction of the resulting diketone with P2S5 gave the polythiophene 108 (Scheme 6) . Another reaction of the lithiated 1,3-dithiole-2-thione 103 with aryl carboxaldehydes, followed by acidic quenching of the resulting oxyanions, afforded bisalcohol products 109. In the presence of perchloric acid, a 1,4-aryl shift was observed to furnish new formylated derivatives 112 and 113. Phenyl and 2-methoxyphenyl diols gave dihydrofurans 110 and 111, respectively (Scheme 7) .

1,3-Dithioles

Scheme 6

Scheme 7

4.12.5.1.3

Nucleophilic attack at carbon

4.12.5.1.3(i) With C-nucleophiles In this section, reactions of 1,3-dithiolium cations and their precursors with carbanions (generated mostly from the corresponding C–H acids using various bases such as LDA, n-BuLi, t-BuOK, EtONa, pyridine) are discussed. The 1,3-dithiolium cation 114 containing the piperidine moiety as a potential leaving group reacted with the carbanions generated from acetonitrile, ethyl acetate, or acetone by means of LDA, to afford the corresponding adducts 116. These compounds underwent direct transformation into functionalized vinylogous 1,3-dithioles (also called dithiafulvenes or ketene dithioacetals) 117 using acidic silica gel (Scheme 8) .

Scheme 8

The final stage of the synthesis of thiophene-functionalized fluorenes 121 involved the condensation of lithio derivatives of compounds 120 with the 1,3-dithiolium salt 119, prepared almost quantitatively from 118 by S-methylation (Scheme 9) .

975

976

1,3-Dithioles

Scheme 9

The nitro-substituted fluorenes 125 and 126 containing 1,3-dithiole units were synthesized by condensation of carbanions derived from fluorenes 122 with the dithiolium salts 123 or aldehydes 124. Selected examples of final products are shown in Scheme 10 .

Scheme 10

1,3-Dithioles

Treatment of 1,3-dithiolium cations 123 with malononitrile, in the presence of pyridine (py) to generate the corresponding carbanion, gave (1,3-dithiol-2-ylidene)dicyanomethanes 127 (Equation 1) .

ð1Þ

Carbanions 128, generated from the corresponding Fischer carbene complexes with n-butyllithium, reacted with 2-methylthio-1,3-dithiolium salts 123 to give heterocyclic organometallic carbenes 129. Reactions of allylic carbanions 130 afforded a mixture of mono- and diheterocyclic condensation products 131 and 132, respectively (Scheme 11) .

Scheme 11

The reaction of 1,3-dithiolium cation 133 with the anion of 1,3-indanedione afforded the 1,3-dithio-2-ylidene derivative 134. Subsequent reaction of the latter with 1 or 2 equiv of the carbanion derived from 135 allowed the introduction of two further 1,3-dithiole units to give 136 and 137, respectively (Scheme 12) . The reaction of the 1,3-dithiolium cation 138 with 2,6-di-tert-butylphenol gave the dithiafulvene 139 in 23% yield (Equation 2) .

977

978

1,3-Dithioles

Scheme 12

ð2Þ

The 1,3-dithiole derivative 141 was prepared in the reaction of 2-methylthio-1,3-dithiolium salt 140 with phenylmalononitrile. Similarily, the reaction of 140 with the corresponding 1,3-dimethyl-5-phenylbarbituric acid or 1,3-diethyl5-phenylthiobarbituric acid gave quinonoid derivatives 142 and 143, respectively (Equations 3 and 4) .

ð3Þ

ð4Þ

The condensation of 2-methylthio-1,3-dithiolium salts 144 (2 equiv) with the thienoquinoxaline derivative 145 in the presence of potassium tert-butoxide as a base gave p-extended dihydrothienoquinoxaline–TTF derivatives 146 (Equation 5) .

1,3-Dithioles

ð5Þ

Merocyanines containing a proaromatic donor unit (1,3-dithiol-2-ylidene moiety) and a proaromatic acceptor (1,3diethylthiobarbituric acid) 150–152 were obtained in reactions of 147 with dithiolium salt 138 or aldehydes 149 and 150, respectively (Scheme 13) .

Scheme 13

The benzo-1,3-dithiole derivative 153, a precursor of a 1,3-dithiolium cation, was used to synthesize substituted 155 and 3,4-disubstituted-pyrrole-2,5-dicarbaldehydes 156 (Scheme 14) . Thus, in the aromatic electrophilic substitution reaction of pyrrole with 153, the symmetrical 2,5-disubstituted pyrrole 154 was obtained, from which, following functionalization of positions 3 and/or 4, then the final removal of benzo-1,3-dithiole moieties under hydrolytic conditions using the HgO–HBF4–DMSO, the corresponding 155 and 156 were formed, respectively (DMSO ¼ dimethyl sulfoxide).

Scheme 14

The same procedure was employed for the synthesis of 2,5-diformyl sulfolenepyrrole 159. Thus, starting from pyrrole 157 and 1,3-benzedithiole 153, the bis-adduct 158 was formed in a high (95%) yield, hydrolysis with HgO– HBF4–DMSO then giving the desired product 159 (Scheme 15) .

979

980

1,3-Dithioles

Scheme 15

4.12.5.1.3(ii) With N-nucleophiles The 1,3-dithiol-2-ylidene derivatives 162 containing an azine spacer were prepared via reaction of 2-methylthio-1,3dithiolium salts 138 or 160 with a hydrazone 161 in the presence of pyridine (MeOH, 0 C to rt) (Equation 6) .

ð6Þ

4.12.5.1.3(iii) With O-nucleophiles The reaction of 1,3-dithiolium ion 163 with 2-deoxynucleosides 164 gave nucleoside derivatives 165 modified by a benzo-1,3-dithiol-2-yl group (Equation 7) .

ð7Þ

4.12.5.1.3(iv) With S-nucleophiles The reaction of substituted 4-(2-hydroxyaryl)-2-(N,N-dialkylamino)-1,3-dithiolium salts 166 (NR2 ¼ pyrrolidine, piperidine, morpholine) with sodium sulfide in EtOH at room temperature afforded the corresponding 1,3dithiole-2-thiones 167, whereas reaction in boiling EtOH led to formation of 2-hydroxyacetophenones 168 (Scheme 16) .

4.12.5.1.3(v) Reduction Reduction of 2-iminium-1,3-dithioles 169 with NaBH4 and further deamination using HPF6 gave 2-dimethylamino1,3-dithioles 170 and the 1,3-dithiolium salts 171, in turn (Scheme 17) . Reduction of the iminium salt 172 with NaBH4 led to formation of the 4-methyl-1,3-dithiole derivative 173, which upon treatment with Ac2O, HPF6, and then NaI afforded 174, then reacted with triethyl phosphite to form the phosphonate 175 (Scheme 18) .

1,3-Dithioles

Scheme 16

Scheme 17

Scheme 18

981

982

1,3-Dithioles

4.12.5.1.4

Intermolecular cyclic transition state reactions

Aryl trifluoromethyl alkynes 177 underwent 1,3-dipolar cycloaddition with 1,3-dithiolium-4-olates 176 to yield 2,3,5triaryl-4-trifluoromethylthiophenes 178 and 179 with good regioselectivity and fair chemical yields (Equation 8) .

ð8Þ

When a similar mesoionic compound 180 was used in the cycloaddition reaction with 1,2,3-triphenyl-1H-phosphirene 181, the cycloadduct 182 was obtained. Irradiation of the latter afforded exclusively the thiophene 183 (Scheme 19) .

Scheme 19

Compound 180 reacted with dimethylamino- and acetoxymethylene compounds 184 to give the cyclopentathiapyran derivative 186. When fulvene 185 was used, the bridged dithiepinone 187 was isolated (Scheme 20) .

Scheme 20

1,3-Dithioles

The reaction of benzyne with 1,3-benzodithiole-2-thione 188 in 1,2-dichloroethane gave the bicyclic sulfonium chloride 190 by trapping of the intermediate 189 (Scheme 21) .

Scheme 21

4.12.5.1.5

Enzymatic reactions

Enzymatic reactions constitute a new and developing area in organic synthesis and for the first time they have been successfully applied to 1,3-dithiole derivatives. Thus, enzymatic C–S bond cleavage and oxidative dimerization of the 1,3-dithiole-2-thione 191, by employing Pseudomonas chlororaphis ATCC 9447, resulted in formation of the tetrathiocin derivatives 193 and 194. Formation of the bis(methylthio)-substituted thiophene 192 was observed when fermenting cells of Emericella unguis ATCC 10032 were applied to the same substrate 191 (Scheme 22) . The cleavage of the C–S bond in 191 occurred most probably through a hetero- (O, S, or N) nucleophilic attack by the enzymes used.

Scheme 22

4.12.6 Reactivity of Nonconjugated Rings In this section, the reactions of 1,3-dithioles and 1,3-dithiolanes, in which at least one ring atom is involved in any chemical transformation or undergoes a change of hybridization (cycloaddition reactions), are described.

4.12.6.1 Reactivity of 1,3-Dithioles Reaction of 195 with titanium tetrachloride afforded the benzo-1,4-dithiin 196 in low yield (Equation 9) .

983

984

1,3-Dithioles

ð9Þ

1,3-Benzodithioles 197 (dienophiles) were employed in aza-Diels–Alder reactions with N-arylimines 198 as a versatile approach to tetrahydroquinolines 199. Subsequent transformations of the latter under reductive and oxidative conditions provided an access to 2,3-disubstituted tetrahydroquinolines 200, inaccessible through the conventional [4þ2] cycloaddition strategy, and also to 2,3-dihydro-4-quinolones 201 and 4-quinolones 202 (Scheme 23) .

Scheme 23

The method of Liebeskind was adapted for the coupling of 6-iodopterins 203 with the stannylated 1,3-dithiol-2-one 204 in the presence of copper thiophene-2-carboxylate to produce pteridine derivatives 205 and 206 containing the 1,3-dithiol-2-one unit (Equation 10) .

1,3-Dithioles

ð10Þ

The 1,3-dithiole-2-thione 207 possessing vicinal bis(bromomethyl) groups was a precursor of the diene 208 by a reductive elimination using iodide (Equation 11) .

ð11Þ

The [4þ2] cycloaddition reaction of both 2-oxo- 209, 2-thiono- 208, and 2-seleno-4,5-bis(methylene)-1,3-dithiole 210 to C60-fullerene produced the cycloadducts 211–213 constituting interesting synthetic substrates (Scheme 24) . Cleavage of the 1,3-dithiol-2-one 211 was achieved by treatment with sodium methoxide to give the disodium dithiolate 214, which was further trapped with thiophosgene or iodomethane to afford fullerene derivatives 212 and 215, respectively (Scheme 25) .

Scheme 24

The Diels–Alder cycloaddition reaction between the transient diene 208 and p-quinonic dienophiles such as p-benzoquinone or 1,4-naphthoquinone, followed by further aromatization with DDQ, afforded cycloadducts 216 and 217, which were used for the preparation of TTF derivatives (Scheme 26) .

985

986

1,3-Dithioles

Scheme 25

Scheme 26

Application of 2-phosphorus-substituted 1,3-dithiole 2-carbanions is an example of functionalization at C-2 via reactive intermediates. Thus, the aroyl cyanides 220 were applied in reactions with 1,3-dithiole Wittig reagents 218 and Horner–Wittig reagent 219 to afford alkenes 221 possessing a nitrile group (Equation 12) . These two phosphorus reagents were also used in reaction with 1,2-dialdehydes as described in Section 4.12.7.3 .

ð12Þ

Lehnert’s reagent was used in the synthesis of the extended 1,3-dithiole 224 from the aldehyde 223, which in turn was obtained in the Wittig reaction involving the phosphonium salt 218 and hexa-2,4-dienal 222 (Scheme 27) .

Scheme 27

1,3-Dithioles

Conjugated yne-2-ynylidene 1,3-dithioles 228 were synthesized via Wittig reactions of phosphonium salts 225 with 3-phenyl-substituted propargyl aldehydes 227 (R1 ¼ H, R2 ¼ Ph). Diaryl-substituted derivatives 228 were prepared in Horner–Wittig reactions of phosphonates 226 with ketones 225 (R1 ¼ R2 ¼ Ph or p-O2NC6H4) (Equation 13) .

ð13Þ

The Wittig reaction of the ylide obtained from the phosphonium salt 229 upon treatment with n-BuLi with the aldehyde 230 gave the functionalized 2,5-diphenyl-1,3,4-oxadiazole 231 (Equation 14) .

ð14Þ

The Horner–Wittig reaction of the carbanion generated from the phosphonate 232 with 2,5-diformylthiophene 233 afforded 1,3-dithiole derivatives 234 (Equation 15) .

ð15Þ

The p-extended 1,3-dithiole 237 containing a cycloproparene moiety was synthesized in the Horner–Wittig reaction involving the phosphonate carbanion derived from 235 and the benzoyl-substituted cycloproparene 236 (Equation 16) .

987

988

1,3-Dithioles

ð16Þ

The Wittig olefination of 238 with formaldehyde afforded unsubstituted 2-methylidene benzo-1,3-dithiole 239 (Equation 17) .

ð17Þ

It was found that carbanions 241 derived from mono- or unsubstituted diethyl 1,3-dithiol-2-yl phosphonates 240 existed in an equilibrium with open forms 242 which could dimerize to dianions 243 followed by protonation to give 244 as a cis/trans-mixture (Scheme 28). This reaction sequence was responsible for the low-yield synthesis of unsymmetrically substituted TTFs .

Scheme 28

Other examples of functionalization at C-2 via phosphorus ylides and phosphonate carbanions are described in Section 4.12.11. Utilization of 2-non-phosphorus-containing carbanions was also exemplified. Thus, 2-silicon-substituted 1,3-benzodithioles were synthesized via deprotonation of benzo-1,3-dithiole 245 with n-BuLi and subsequent treatment of the resulting anion with trimethylsilyl chloride (TMSCl) to give 2-(trimethylsilyl)-benzo-1,3-dithiole 246 (Scheme 29). The second silyl group was introduced by further deprotonation of 246 (n-BuLi) followed by the reaction with an additional equivalent of TMSCl. Tin-substituted benzo-1,3-dithioles were synthesized in a similar way but the deprotonation of the monostannyl derivative was carried out with LDA (Scheme 29) .

1,3-Dithioles

Scheme 29

The alkylation of 2-methoxy-substituted 1,3-dithiole derivatives 248 with organometallic reagents such as R3Al or RMgX (X ¼ Cl or Br)/TiCl4 converted the OMe into an R-group and produced 4,5-(alkylmethylenedithio)-1,3dithiole-2-chalcogenones 249 (Equation 18) .

ð18Þ

2-Benzylidene-4,5-dicyano-1,3-dithiole 250 reacted with LiO-n-Bu to afford the linear polymer 251 (Equation 19). Related polymers could be obtained from 250 using either lactose as a reducing sugar or sucrose as a nonreducing sugar .

ð19Þ

The reaction of 1,3-dithiol-2-one 253, obtained from the 1,3-dithiole-2-thione 252, with MeMgBr followed by trapping of the corresponding dimagnesium salt with Cl2Sn-n-Bu2 produced organotin thiolates 254. Transmetallation of the latter with n-BuLi followed by treatment with methyl dichloroacetate gave esters 255 (Scheme 30) .

Scheme 30

Reduction of the 29-deoxynucleosides 165 bearing a 39-(benzo-1,3-dithiol-2-yloxy) group with tributyltin hydride in the presence of 2,29-azobisisobutyronitrile (AIBN) followed by methylation with methyl iodide afforded deoxynucleosides 256 in high yields (Equation 20) .

ð20Þ

989

990

1,3-Dithioles

Only a few examples of functionalization of the ring sulfur atoms were reported in the reviewed period. The chloroperoxidase (CPO)-catalyzed asymmetric synthesis of cyclic sulfoxides was applied to 1,3-benzodithiole producing the corresponding sulfoxide in low chemical yield (24%) and very low ee (3%) . Oxidation of 2-methylbenzo-1,3-dithiole using selected strains of Pseudomonas putida yielded chiral sulfoxide isomers as a mixture of cis (257; >98% ee, [1S,2R], 40% yield) and trans (258; >98% ee, [1S,2S], 5% yield) products .

Deprotonation of the benzo-1,3-dithiole dioxide 259 with n-BuLi or sodium hexamethyldisilazide (NaHMDS) and subsequent reaction of the resulting carbanion with pivaldehyde gave a mixture of products 260 and 261 (Equation 21) .

ð21Þ

Oxidation of the 39-O-benzodithiol-2-yl derivative of thymidine 262 with m-chloroperbenzoic acid (MCPBA) gave the monosulfoxide 263, bis-sulfoxide 264, or bis-sulfonyl derivative 265 (Scheme 31) .

Scheme 31

4.12.6.2 Reactivity of 1,3-Dithiolanes 4.12.6.2.1

Cleavage reactions

1,3-Dithiolanes, also named five-membered 1,3-dithioacetals or S,S-acetals, find wide applications in organic synthesis, particularly in protection of carbonyl functions and their reductive conversion to hydrocarbons or olefins. Due to the stability of 1,3-dithiolanes toward various reagents and reaction conditions, they have attained an important position in this area despite the fact that dedithioacetalization to the corresponding carbonyl compounds is sometimes not an easy process. There are three general strategies that can be used for deprotection of 1,3-dithiolanes involving

1,3-Dithioles

(1) proton and metal coordination (i.e., Hg2þ, Ce4þ, Tiþ, Tl3þ) to sulfur atoms; (2) quaternization (i.e., alkylation, halogenation); and (3) oxidation (chemical, photolytic, or electrolytic) processes in the first stage of such transformations. Since each of these methods has specific applications and some limitations, in recent years milder, less expensive, and more efficient procedures have been developed for deprotection of 1,3-dithioacetals. One of these utilizes the cheap and stable oxidant – zinc dichromate trihydrate (ZnCr2O7?3H2O) – for clean and rapid deprotection of various types of aromatic 1,3-dithiolanes 266, with electron-releasing or electron-withdrawing groups, to give the corresponding aldehydes and ketones in 85–90% yields (Equation 22) .

ð22Þ

A combination of solid silica chloride (silica gel treated with thionyl chloride) and KMnO4 provides another oxidizing system for the mild and highly selective cleavage of 1,3-dithioacetals to aromatic and aliphatic carbonyl compounds, used in dry CH3CN at room temperature, in 81–92% yields. KMnO4 was ineffective in the absence of sillica chloride. The reaction mechanism assumed an attack of nucleophilic sulfur atom of 1,3-dithioacetals 266 onto a chlorine atom of silica chloride and formation of sulfonium chloride intermediates 268 which underwent (1) immediate carbon–sulfur cleavage to highly reactive resonance-stabilized carbocationic species and (2) oxidation of the latter with KMnO4 to form the corresponding carbonyl compounds 267 (Scheme 32) .

Scheme 32

Other methods for efficient conversion of 1,3-dithiolanes to the corresponding carbonyl compounds employed selenium dioxide , periodic acid , 2,3-dichloro-5,6-dicyano-p-benzoquinone , nitrogen oxides , ferric nitrate/silica gel , iron(III) nitrate , zirconium sulfophenyl phosphonate , p-toluenesulfonic acid (PTSA) , silver salt–iodine , trifluoroacetic acid–H2O , cerium(III) chloride–NaI , iron(III) chloride , zinc bromide , organic ammonium tribromides , alkylative methods using methyl iodide , t-butyl hydroperoxide (TBHP) , natural kaolinite , benzyltriphenylphosphonium peroxymonosulfate , o-iodoxybenzoic acid , N-bromosuccinimide (NBS), N-chlorosuccinimide, 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one and trichlorocyanuric acid (TCCA) , 2,4,6-trichloro-1,3,5-triazine , trichloroisocyanuric acid/silica gel , ammonium persulfate on wet montmorillonite K-10 clay , NaNO2 , and 1-benzenesulfinyl piperidine (BSP) with triflic anhydride . The ambiphilic carbon–sulfur bond in 1,3-dithiolanes can be utilized for the synthesis of a new C–C bond in SN2-type reactions with organometallic compounds. Thus, nickel-catalyzed reaction of propargylic 1,3-dithiolane 269 with Grignard reagents led to formation of 271 via the allene-1,3-dication synthon 270 (Scheme 33) . The reaction proceeded in excellent yields (90–95%) when methyl or silylmethyl Grignard reagents were employed. Aryl and primary alkyl Grignard reagents gave the corresponding products in moderate yields (55–57%).

991

992

1,3-Dithioles

Scheme 33

Aliphatic 1,3-dithiolanes in the absence of auxiliary chelating groups did not react with Grignard reagents, even in the presence of the typical nickel triarylphosphine catalyst. The increase in nucleophilicity of the nickel catalyst by incorporation of a trialkylphosphine ligand enhanced the reactivity of the catalytic center toward the oxidative addition across the C–S bond . Treatment of aliphatic 1,3-dithiolane 272 with Grignard reagents gave alkenes of type 273 (Equation 23).

ð23Þ

2-Aryl-substituted 1,3-dithiolanes were useful substrates for the preparation of vinylsilanes. Treatment of 2-phenyl-substituted 1,3-dithiolanes 274 with Me2(i-PrO)SiCH2MgCl in the presence of a Ni-catalyst afforded the vinylsilane 275 in 85% yield. Subsequent reduction of the Si–O bond with LiAlH4 led to the formation of 276 in 75% yield (Scheme 34) .

Scheme 34

Allylic 1,3-dithiolanes 277 derived from alkenals were transformed into silyl-substituted conjugated dienes 278 (Equation 24) .

ð24Þ

On the other hand, allylic 1,3-dithiolanes 279 derived from alkenones could be converted into alkenes 280, geminally substituted by two methyl groups at the allylic position, as a result of attack by the Grignard reagent at C-2 of the 1,3-dithiolane (Equation 25) .

ð25Þ

1,3-Dithioles

On the other hand, a regioselective attack of n-Bu2CuLi on the sulfur atom in 1,3-dithiolane 279 afforded the corresponding vinyl sulfides 281 as (E/Z)-mixtures upon reaction with organic halides, in good yields (Equation 26) .

ð26Þ

Gilman reagents behaved in a different way toward propargylic 1,3-dithiolanes 269 than Grignard reagents and gave organocopper thioethers 282 and 283, being in an equlibrium, as a result of the C–S bond cleavage. Soft alkyl halides reacted with the intermediate 283, providing propargylic thioethers 285 (entries 3,4) in a selective carbon– carbon bond formation. Transmetallation of the organocopper intermediate 282 with ZnBr2 in the presence of palladium catalysts and subsequent reaction with electrophiles gave the corresponding allenes 284 (entries 1 and 2, Scheme 35) .

Scheme 35

Alkyllithium reagents also yielded the corresponding alkylated sulfur-stabilized allenyl anions. Thus, treatment of 286 with n-BuLi gave the lithio derivative 287 which was reacted with the aldehyde 288. Upon acidification with trifluoroacetic acid (TFA), the furan-containing diester 289 was obtained in 67% yield (Scheme 36) . In another reaction of this type, propargylic 1,3-dithiolane 290 reacted with n-BuLi, then with ethyl bromoacetate, to give the corresponding enyne 291, as an example of new carbon–carbon double-bond formation (Scheme 37) . Selective introduction of a fluorine atom into organic compounds is important due to the unique biological and physical properties of fluorinated compounds. One useful method for C–F bond formation is desulfurative fluorination realized by a cleavage of C–S bonds of dithioacetals. Thus, 1,3-ditholane derivatives undergo a facile reaction

993

994

1,3-Dithioles

Scheme 36

Scheme 37

with nitrosonium tetrafluoroborate in the presence of pyridinium poly(hydrogen fluoride) (PPHF). NOþBF4/PPHF is a suitable system for substrates with two aromatic substituents containing even strongly donating groups (MeO or 3 Me). Under the same reaction conditions, dialkyl dithioacetals underwent an oxidative cleavage to the corresponding ketones . Another system, NBS/PPHF, used for the fluorodesulfuration of 1,3-dithiolanes, afforded a mixture of products containing brominated aromatic rings . The proposed mechanism for the desulfurative fluorination of 1,3-dithiolane 292 derivatives using NOþBF4/PPHF is presented in Scheme 38.

Scheme 38

The diaryl 1,3-dithiolanes 294 could also be converted into the corresponding gem-difluoro compounds 295 by passing fluorine through a stirred solution of the 1,3-dithiolane and iodine in dry acetonitrile at room temperature (Equation 27). The presence of electron-withdrawing substituents in the aromatic ring inhibited the fluorination process while electron-donating groups encouraged the reaction .

ð27Þ

1,3-Dithioles

gem-Difluoro compounds were also prepared from 1,3-dithiolanes in good (68–80%) yields on treatment with hexafluoropropene–diethylamine and N-iodosuccinimide (HFP–DA/NIS) or 1,3-dibromo-5,5-dimethylhydantoin (HFP–DA/DBH) or HF/pyridine and an oxidant such as difluoroglutamic acid . It was earlier discussed that 1,3-dithiolanes underwent an interesting desulfurdimerization reaction leading to dimeric olefins on treatment of metal carbonyls, such as W(CO)6 or Mo(CO)6 . In the case of the monomeric 296, this reaction performed with W(CO)6 in refluxing chlorobenzene for 48–60 h afforded the corresponding oligophenylenevinylenes (OPVs) 297 in 67–81% yields (Equation 28) ’’.

ð28Þ

2-Methylidene-1,3-dithiolanes 298 reacted with dimsylsodium to afford the respective vinyl dithioesters 301 in good yields (82–92%; Scheme 39). The reagent deprotonates 298 at C-4 giving an intermediate carbanion 299, which subsequently undergoes fragmentation of the 1,3-dithiolane ring to give thioenolates 300 and then dithioesters 301 after protonation .

Scheme 39

Treatment of substituted 1,3-dithiolanes 302 with dimsylsodium led to the formation of thiopyranone derivative 304 in 75% yield via the intermediate thioenolate 303 (Scheme 40) .

Scheme 40

Reaction of the 1,3-dithiolanes 305 with binucleophiles such as hydrazine hydrate or ethanolamine afforded pyrazoles 306 and isoxazoles 307, respectively (Scheme 41) . The pyrimidine 309 was obtained in the reaction of the 1,3-dithiolane 308 with N,N-dimethylguanidine sulfate (Equation 29) .

995

996

1,3-Dithioles

Scheme 41

ð29Þ

Reaction of benzaldehyde with the vinylidene 1,3-dithiolane 310 in the presence of a stoichiometric amount of 311 afforded the disubstituted 1,3-dithiolane 312 in 88% yield, from which, upon radical desulfurization, b-hydroxyester 313 was formed in 82% yield (Scheme 42) .

Scheme 42

Ring expansions using spiro 2,2-disubstituted-1,3-dithiolanes 314 turned out to be useful route for the construction of larger rings bearing sulfur atoms like 1,4-dithiins 315 (Equation 30).

ð30Þ

For this purpose, the following reagents were employed: TiCl4 , NBS , 1,4,6trichloro-1,3-5,-triazine , MoCl5 , WCl6 , and SiO2Cl/DMSO . 1,4-Dithiins 317 were also obtained from 1,3-dithiolanes 316 prepared from aryl methyl ketones (Equation 31). These reactions were carried out in the presence of N-chloro-, N-bromo-, N-iodo-, N-cyano-, N-azido-, and N-thiocyanatosuccinimides in good to excellent yields .

1,3-Dithioles

ð31Þ

Treatment of the 1,3-dithiolane 318 with TPP/DEAD/HN3 provided a mixture of 1,4-dithianes 319, 320, and 1,4dithiin 321 in moderate yields (52–71%; TPP ¼ tetraphenylporphyrin; DEAD ¼ diethyl azodicarboxylate; Equation 32) .

ð32Þ

A 1,2-sulfur atom migration, carried out using the MsCl/DMAP reagent system, produced the alkylidenedithianes 323 in yields of 59–87% (DMAP ¼ 4-dimethylaminopyridine; Equation (33)) .

ð33Þ

Rhodium(II)-catalyzed decomposition of diazoketones 324 bearing the 1,3-dithiolane moiety, in the presence of benzaldehyde and ClTi(Oi-Pr)3, afforded a mixture of the ring-enlarged enone 325 in 22% yield and the ringtransformed thiophenone 326 in 55% yield (Equation 34) .

ð34Þ

4.12.6.2.2

Reactions with electrophiles

Monosubstituted at C-2, 1,3-dithiolanes are easily deprotonated to give the corresponding carbanions which can easily react with various electrophiles. Thus, treatment of the 1,3-dithiolane 327 with LDA followed by

997

998

1,3-Dithioles

reaction with ethyl .

6-iodohexanoate

afforded

2,2-disubstituted-1,3-dithiolane

328

(Equation

35)

ð35Þ

Alkylated 1,3-dithiolane derivatives 331 with formyl or ester groups at C-2 could be prepared starting from the unprotected aldehyde 329 or ester 330 (no yields given) (Equation 36) .

ð36Þ

An interesting transformation was observed in the case of the 1,3-dithiolane derivative 332, which after deprotonation with LDA smoothly produced the thiolothionophthalic anhydride 335. The proposed mechanism assumed a loss of ethene and intermolecular attack of the resulting intermediate dithiocarboxylate 334 onto the ester function. Further heating of 335 afforded the 3,39-bithiophthalide 336 in 83% yield (Scheme 43) .

Scheme 43

The Michael addition of ethyl 1,3-dithiolane-2-carboxylate 330 to methyl vinyl ketone (MVK) followed by in situ aldol condensation afforded the spiro 1,3-dithiolane 337 (Equation 37) .

ð37Þ

The reaction of cis- and trans-4,5-dimethyl-2-trimethylsilyl-1,3-dithiolanes 338 and 339 with benzaldehyde in the presence of TBAF or CsF afforded adducts 340 and 341 in yields of 57% and 54%, respectively (Equations 38 and 39) .

1,3-Dithioles

ð38Þ

ð39Þ

4.12.6.2.3

Reactions with nucleophiles

1,3-Dithiolanes with a carbon–carbon double bond or carbon–heteroatom double bond at C-2 are good Michael acceptors. As an example, cyclocondensation reactions of the compound 342 with chloracetyl chloride and mercaptoacetic acid gave the corresponding azetidinone 343 and 4-thiazolidinone 344, respectively (Scheme 44) .

Scheme 44

A selective reduction of the double bond in 345 was achieved under acidic or neutral conditions (zinc in acetic acid or magnesium in methanol or ethanol), in 42–52% yields (Equation 40) .

ð40Þ

999

1000 1,3-Dithioles The 2-phosphoryl-substituted 1,3-dithiolanes 348 were synthesized from 2-chloro-substituted 1,3-dithiolane 347 (Equation 41) .

ð41Þ

4.12.6.2.4

Miscellaneous reactions

1,3-Dithiolan-2-ones 352 were prepared in the reaction of 1,3-dithiolane-2-thiones 349 with epoxides 350 in the presence of HBF4?Et2O in 65–95% yields. The reaction, performed in anhydrous CH2Cl2 or chlorobenzene, produced 352 via the spiro intermediate 351 in 65–95% yields (Scheme 45) .

Scheme 45

The 1,3-dithiolane 354 underwent dehydrohalogenation under solvent-free conditions using microwave irradiation (power 75 W, 70 C, 5 min) to give 2-methylidene-1,3-dithiolane 355 (Equation 42) .

ð42Þ

4.12.6.2.5

Oxidation at sulfur atoms

Several oxidation reactions of sulfur atoms in 1,3-dithiole derivatives were reported in the reviewed period; however, no further attempts to functionalize the oxygen atoms in the products obtained were made (see Section 4.12.8). Optically active 1,3-dithiolane monooxides serve as chiral masked acyl groups. Although, numerous methods have been reported for oxidation of racemic 2-substituted-1,3-dithiolanes, asymmetric syntheses were not known. Highly enantioselective sulfoxidation was observed using the di--oxo Ti(salen)/UHP (salen ¼ N,N9-bis(salicylaldehydo)ethylenediamine; UHP ¼ urea hydrogen peroxide) catalyst complex in methanol (Equation 43). In oxidations of 1,3-dithiolane derivatives, enantioselectivity increased with the size of the 2-substituent .

ð43Þ

1,3-Dithioles

One of the most stereoselective oxidizing reagents for this type of substrate is a system comprising a d0 transition metal and alkyl hydroperoxide (Equation 44). Thus, a Ti(Oi-Pr)4-promoted process afforded a mixture of diastereomers 358 and 359 in 78% yield and high stereoselectivity (trans/cis ¼ 94:6) .

ð44Þ

2-Acyl-1,3-dithiolanes 360 were enantioselectively oxidized at 20 C to monosulfoxides 361 using the Sharpless epoxidation procedure either directly (path i) or via corresponding silyl enol ethers (path ii) (Equation 45) .

ð45Þ

Dioxygenase enzymes, produced by P. putida and present in the soil, also biocatalyze 1,3-dithiolane oxidation, generally with a high degree of regio- and stereoselectivity . High enantioselectivity was also achieved by growing cultures of Acinetobacter calcoaceticus , cyclohexanone monooxygenase (from Acinetobacter) , or CPO (from Caldariomyces fumago) . 1,3-Dithiolane 1,3-dioxide 363, prepared in 84% yield by oxidation of 1,3-dithiolane 362 with MCPBA , was smoothly converted to the dimethylamino derivative 364 in 100% yield. Hoffman elimination using methyl iodide and Hu¨nig’s base at room temperature gave 365 in 86% yield (Scheme 46).

Scheme 46

The 1,3-dithiolane 1,3-dioxide 365 was also investigated in the Diels–Alder reaction with a range of simple dienes (cyclopentadiene, 1-methoxybutadiene, 1-methoxy-3-trimethylsilyloxybutadiene, furan) and 1,3-dipolar cycloadditions with N-tert-butyl-C-phenyl nitrone or 3-oxidopyridinium betaines . 2-Ethenyl-1,3-dithiolane 1,1-dioxides 367 were prepared by oxidation of the 2-ethenyl-1,3-dithiolane 366 using the catalytic OsO4/Me3NO system (Equation 46) .

ð46Þ

1001

1002 1,3-Dithioles 4.12.6.2.6

Radical reactions

Radical cyclization reactions have become a powerful tool for the construction of carbocyclic and heterocyclic frameworks. Irradiation of 368 in the presence of benzophenone (BP) for 20 min provided the spiro 1,3-dithiolane 370 in 63% yield along with the substrate (14%) via the radical intermediate 369 (Scheme 47). The reaction carried out in the presence of acetone or acetophenone, instead of BP, resulted only in isomerization of the olefin geometry .

Scheme 47

4.12.7 Reactivity of Substituents Attached to Ring Carbon Atoms In this section, the reactivity of carbon- and heteroatom-containing substituents attached directly or indirectly to the heterocyclic ring of 1,3-dithiole derivatives is discussed. Here, chemical manipulations on these systems exclude ring carbon and sulfur atoms, which are the subject of Section 4.12.6. Special 1,3-dithioles called p-extended TTFs, containing two or more 1,3-dithiole moieties linked together via TC–(CTC)n–CT or similar conjugated spacers, are discussed with typical TTFs in Section 4.12.11, although formally they constitute an example of functionalization of the 1,3-dithiole by 2p-extended substituents, terminated by another 1,3-dithiole moiety.

4.12.7.1 Substituents Attached to Mesoionic 1,3-Dithiol-4-ones, -4-thiones, -4-selenones The 5-alkyl-2-dimethylamino-1,3-dithiolium-4-thiolate mesoions 371 underwent chlorination with sulfuryl chloride to form the corresponding sulfenyl chlorides 372 which reacted in situ with a number of electron-rich aromatic compounds to produce arylthio-substituted 1,3-dithiolium salts 373 (Scheme 48) .

Scheme 48

1,3-Dithioles

4.12.7.2 Substituents Attached to 1,3-Dithiole The chemistry of the 1,3-dithiole-2,4,5-trithione oligomer system 374 derived from monomers 375 and 376 (Scheme 49) has been the subject of a review . This system easily depolymerized (heat or UV irradiation at 253 nm) and was effective in Diels–Alder-type cycloadditions. Reactions with unsaturated compounds constituted an efficient method for synthesis of functionalized 1,3-dithiole-2-thiones containing substituted 1,4dithiin rings and are examples of reactivity of thione or sulfenyl substituents (structures 374–376) attached to the 1,3dithiole ring carbon atom.

Scheme 49

Application of 374 in reaction with the aldehyde 377 allowed the preparation of the thione 378. Deprotection of the acetal function with formic acid then produced the dialdehyde 379, which was employed in the reaction with phosphorus reagents 380 or 381 to form 382 (Scheme 50) .

Scheme 50

The phosphonate carbanion derived from 383 reacted with diformylmethylideno-1,3-dithiole 384 to give the corresponding Horner–Wittig olefin-containing chloroalkenic moieties, which under mild basic conditions suffered loss of HCl and gave the bisacetylene derivative 385 (Equation 47) .

ð47Þ

1003

1004 1,3-Dithioles Starting from 374 and commercially available trans-3-hexene, the thione 386 was obtained as a mixture, cis/ trans ¼ 85:15 (Equation 48) .

ð48Þ

The 1,3-dithiole-2-thione derivative 389 was formed in the reaction of 374 with phenyl vinyl sulfoxide 387 via the intermediate 388. The compound 389 was then used for the preparation of 1,4,5,8-tetrathianaphthalene (TTN) 390 (Scheme 51) .

Scheme 51

Similarly, the Diels–Alder-type reaction of 374 with reactive dienophiles such as styrene and trans-stilbene produced phenyl-substituted thiones 391 and 392, respectively, by thermal reactions and/or photoreaction (Scheme 52) .

Scheme 52

The Diels–Alder cycloaddition of 374 to the electron-deficient alkene 393 yielded the diketone 394 (Equation 49) .

ð49Þ

1,3-Dithioles

Other cycloaddition reactions involving 374 show further possibilities of introducing various functional groups onto bicyclic thiones. Schemes 53–55 below show some newer examples of this reaction. Compounds 396 containing methylenehydroxyl group were prepared from 395 (Scheme 53) . Similarly, the reaction of 374 with allyl cyanide 397 furnished the cyanomethyl-containing thione 398 (Scheme 53) .

Scheme 53

The trithione 374 was also widely used in reactions with unsaturated heterocycles 399–401 to give 402 , 403 , and 404 , respectively (Scheme 54).

Scheme 54

Finally, the reaction of 374 with cyclic unsaturated substrates such as 1,3-cyclohexadiene, 1,4-dihydronaphthalene 1,4-dioxide, or acenaphthalene resulted in formation of cycloadducts 405, 407, and 409, respectively. These compounds could be subsequently aromatized by the use of DDQ in the case of 405 and 409 or polyphosphoric acid (PPA) in the case of 407 to generate 1,3-dithiole-2-thiones 406, 408, and 410 (Scheme 55) . The compound 410 was further treated with potassium tert-butoxide to give the dithiolate intermediate 411, which underwent dialkylation leading to 412 (Scheme 56) .

1005

1006 1,3-Dithioles

Scheme 55

Scheme 56

An alternative for the use of 374 in functionalization reactions of 1,3-dithiole-2-thiones involves using the tetraethylammonium salt of the zinc complex 413. Its versatility was demonstrated in the synthesis of heterocycles such as the bicyclic 416 and the tricyclic 417 via the dialkylation reaction of 413 with dibromides 414 and 415, respectively (Scheme 57) .

Scheme 57

The reaction of tetra-n-butylammonium salt of the zinc complex 418 with electrophilic reagents such as methyl iodide, 3-bromopropionitrile, or benzyl chloride in the presence of pyridine hydrochloride as well as 3-chloromethylpyridine hydrochloride and 4-chloromethylpyridine hydrochloride led to formation of the difficultly accessible thiones 419 and 420 (Scheme 58) .

1,3-Dithioles

Scheme 58

The reaction of the zinc complex 413 with the chiral bromo ether 421 led to the formation of the bisfunctionalized 1,3-dithiole derivative 422 (Equation 50) .

ð50Þ

Oxidation with iodine in EtOH of the selenium-containing zincate salt 423 afforded the oligomeric derivative 424, which was depolymerized with PBu3 to give the reactive 1,2-diselenone 425. The latter was trapped with dimethyl acetylenedicarboxylate (DMAD) to afford the 1,4-diselenine 426, which was subsequently converted into the 1,4diselenine-2,3-dithiolate 427 with sodium methoxide (Scheme 59) .

Scheme 59

Reaction of 1,8-diketones 430 containing the 1,3-dithiole-2-thione moiety with Lawesson’s reagent or phosphorus pentasulfide led to formation of either unsaturated 1,4-dithiin or thiophene rings 431 or 432, respectively, as outlined in Scheme 60. The starting 1,8-diketones were obtained by alkylation of the sodium dithiolate 429 with -haloketones 428. The 1,8-diketone ring closure found further important applications in syntheses of fused 1,4-dithiins and thiophene derivatives .

1007

1008 1,3-Dithioles

Scheme 60

The reaction of 4,5-bis(benzoylthio)-1,3-dithiole-2-thione 434 (R ¼ Ph) or 1,3,4,6-tetrathiapentalen-2-one-5-thione 435 with excess of alkoxide base followed by dialkylation of the resulting dithiolate 433 1,3-dithiole-2-thione-4,5dithiolate (DMIT) with 1,2-dichloroethylene or 4,5-dibromo-1,2-dibromomethylbenzene 436 afforded TTN 390 or the 1,3-dithiole-2-thione derivative 437, respectively (Scheme 61) . Diacylation gave the acylated products 438 (Scheme 61) .

Scheme 61

The nitrosation of a series of 2-alkenyl-substituted 1,3-dithioles 438 was carried out with the known procedure based on the use of isoamyl nitrate. The nitroso derivatives 439 obtained are stabilized by resonance and intramolecular oxygen–sulfur interactions (Scheme 62) . þ A reaction between the carbanion 128 (M ¼ W, M9 ¼ Et3NH) and the heterocyclic iminium salt 440 (Y ¼ NþMe2) afforded the vinylogous carbene 442. The use of the aldehyde 441 (Y ¼ O) in the presence of TMSCl gave a better yield of 443 (Equation 51) . Functionalization of the aldehyde function in 444 was carried out using Lehnert’s reagent (TiCl4, pyridine, and malonitrile) to afford dicyanomethylene-terminated 1,3-dithiole 445 (Equation 52) . The condensation of aldehydes 446 with arylmalonitriles (Ac2O, pyridine, 80 C) afforded new derivatives 447 and 448 containing a quinoid spacer and strong electron-acceptor groups (Scheme 63) . Peterson olefination using the a-silyl anion 449 with ketones 450 or 451 provided p-extended 1,3-dithioles 452 and 453 in 13% and 6% yields, respectively (Scheme 64) .

1,3-Dithioles

Scheme 62

ð51Þ

ð52Þ

Scheme 63

1009

1010 1,3-Dithioles

Scheme 64

4,5-Bis(hydroxymethyl)-1,3-dithiole-2-thione 454 could be easily transformed into the dibromide 207 with phosphorus tribromide . The reaction of the latter with tosylamide afforded the dihydropyrrole derivative 456, which was dehydrogenated with DDQ to produce 457. Treatment of 207 with n-butylamine in the presence of cesium carbonate led to N-n-butyldihydropyrrole 455 (Scheme 65) .

Scheme 65

The Arbuzov reaction of the dibromo derivative 207 with trimethyl phosphite gave the bisphosphonate 458 (Equation 53) .

ð53Þ

The acid-catalyzed rearrangement of the symmetrical 1,3-dithiole derivative 459 afforded a variety of products 460–463, depending on the choice of solvent and acid catalyst (Equation 54) .

1,3-Dithioles

ð54Þ

The electrophilic chlorination of the 1,3-dithiole derivative 464 with 1 or 2 equiv SO2Cl2 afforded the corresponding monochloro 465 or 1,2-dichloro derivatives 466, respectively (Scheme 66). With Selectfluor, [1-(chloromethyl)4-fluoro-1,4-diazoniabicyclo[2.3.3]octane bis(tetrafluoroborate)] or XeF6 fluorination of 464 was also achieved .

Scheme 66

The reaction of acetylenes 467 with TCNQ afforded compounds 468 in 45–85% yields (Equation 55) .

ð55Þ

The Knoevenagel reaction of 234 with malononitrile (EtOH, piperidine) afforded the dicyanovinylthiophene derivatives 469 (Equation 56) .

1011

1012 1,3-Dithioles

ð56Þ

The bromination of 239 with NBS gave the dibromide 470, which was used in Pd-catalyzed Sonogashira couplings to yield 471 (Scheme 67) .

Scheme 67

4.12.7.3 Substituents Attached to 1,3-Dithiolanes The iododecarboxylation reaction of the 1,3-dithiolane 472 allowed a synthesis of the iodo derivative 474 by conversion of carboxylic to iodo group. This transformation was easily carried out under mild conditions with iodine as halogenating agent and a saturated aqueous solution of NaHCO3 at room temperature. Although its mechanism involved formation of the ring carbocationic intermediate 473, this manipulation did not directly involve the 1,3dithiolane ring (Scheme 68) .

Scheme 68

Functionalization of the b-position in the 1,3-dithiolane derivatives 475 was achieved via lithiation with LDA or lithium 2,2,6,6-tetramethylpiperidide (LTMP). The resulting b-lithio derivatives were trapped with various electrophiles to form the corresponding b-functionalized 1,3-dithiolanes 476 in 55–96% yields (Equation 57) .

1,3-Dithioles

ð57Þ

The Diels–Alder reaction of the spiro 1,3-dithiolane 477 with typical dienophiles proceeded smoothly in acetonitrile to afford the corresponding adducts 478–482 in 75–93% yields .

Another modification of a cyclopentene moiety was achieved by the cycloaddition reaction of the 1,3-dithiolane derivative 483 with singlet oxygen 1O2 to form the endoperoxide 484, which upon treatment with either triethylamine, triphenylphosphine, or bromine gave the corresponding hydroxy ketone 485, a mixture of the epoxide 486 and the enone 487, or a mixture of isomeric adducts 488 and 489, respectively (Scheme 69) .

Scheme 69

1013

1014 1,3-Dithioles A selective reduction of the carboethoxy group in the 1,3-dithiolane 490 with NaBH4 in ethanol or in a mixture of ether/MeOH provided the alcohol 491 in quantitative yield (Equation 58). A selective reduction of the ester group to formyl was also possible .

ð58Þ

The 2-thiophosphoryl-substituted 1,3-dithiolanes 492 and the selenophosphoryl analogue 493 were synthesized from 2-phosphoryl-substituted 1,3-dithiolane 347 (Scheme 70) .

Scheme 70

Reactivity of groups not directly bound to C-2 has also been described .

4.12.8 Reactivity of Substituents Attached to Ring Heteroatoms In the reviewed period of 1995–2007, no synthetic work on the reactivity of substituents attached to ring heteroatoms was published. Oxidation at ring sulfur atoms is reviewed in Section 4.12.6.2.5. Cleavage reactions with formation of the intermediate sulfonium species (dedithioacetalization process) and reactions with organometallic reagents occurring at ring sulfur atoms of 1,3-dithiolanes are described in Section 4.12.6.2.1.

4.12.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component In the reviewed period, most work was connected with synthesis of 1,3-dithioles and 1,3-dithiolanes. Only a few contributions on the synthesis of 1,3-dithiolium ions, mesoionic 1,3-dithiol-4-one and -4-thione derivatives were reported during this time.

4.12.9.1 1,3-Dithiolium Ions 1,3-Dithioliumyl-diphenylphosphine tungsten complexes 495 were synthesized by protonation of the (dithioalkylcarbonyl)diphenylphosphinotungsten complexes 494 with HBF4 (Equation 59) .

ð59Þ

1,3-Dithioles

A new approach to the synthesis of 1,3-dithiolium salts 498 involved a cyclization of the corresponding dithiocarbamates 497, obtained from 496 in 78–83% yield, with a superacid mixture of P2O5–CH3SO2OH (Scheme 71) . The same reaction sequence was used for the quantitative preparation of 5-ethyl-2-(N,N-dialkylamino)-1,3-dithiolium salts 499, using a mixture of concentrated H2SO4 and glacial acetic acid .

Scheme 71

4.12.9.2 Mesoionic 1,3-Dithiole-4-thiones The mesoionic 2-N-cycloalkylamino-5-alkyl-1,3-dithiolium-4-thiolates 504 were prepared from 1,3-dithiocarbamoyl acid 503 in a retro-1,3-dipolar cycloaddition reaction. The acids were obtained by S-alkylation of triethylammonium 1,3-dithiocarbamates 501, easily synthesized from secondary cyclic amines 500 and CS2, with bromo acids 502 (Scheme 72) .

Scheme 72

4.12.9.3 1,3-Dithioles The benzene hexathiol 505 was used in a Zn(OTf)2-catalyzed condensation with p-tolylaldehyde to produce a mixture of isomeric tris(1,3-dithiole)-substituted benzenes 506 (aaa) and 507 (aab) (Equation 60) .

1015

1016 1,3-Dithioles

ð60Þ

The NaH-catalyzed reaction of benzene-1,2-dithiol with (Z)-1,2-bis-(phenylsulfonyl)ethylene 508 provided the 2-phenylsulfonylmethyl-substituted benzo-1,3-dithiole 509 in high yield (Equation 61) .

ð61Þ

The 1,3-dithiol-2-ones 511 were conveniently prepared in a one-step reaction involving diisopropyl xanthogen disulfide 510 and terminal alkyl and aryl alkynes in the presence of radical initiators (Scheme 73) . This synthetic strategy was also applied to the preparation of the quinoxaline derivatives 512 .

Scheme 73

The 4,5-di(thien-3-yl)-1,3-dithiol-2-one 517 was prepared from the thiophene-3-carboxaldehyde 513 which was first converted into the benzoin derivative 514. Subsequent Appel’s reaction of the latter with PPh3 and carbon tetrachloride afforded the chloride 515, which underwent reaction with potassium ethyl xanthate to form 516, from which the 1,3-dithiol-2-one derivative 517 was obtained in overall 50% yield from 514 upon treatment with HBr/ AcOH (Scheme 74). The unsymmetrical 522 was prepared by transformation of the carboxylic acid 518 to the corresponding acid chloride which took part in a Friedel–Crafts reaction with thiophene in the presence of AlCl3 to

1,3-Dithioles

give the ketone 519. Bromination of the latter with CuBr2 produced the bromide 520, which was next converted into 521 by reaction with potassium ethyl xanthate. The final cyclization with HBr/AcOH gave 522 in 36% overall yield from 519 (Scheme 75) .

Scheme 74

Scheme 75

The reaction of O-methyl S-prop-2-ynyl dithiocarbonates 523 with alkenes 524 led to 1,3-dithiol-2-one derivatives 525 (Equation 62) .

ð62Þ

1,2-Bis-triisopropylsilanylsulfanyl alkenes 527, generated from bis-triisopropylsilyl disulfide 526 and alkynes, reacted with soft and hard electrophiles such as thioacyl chlorides and chlorothioloformates. Thus, the reaction of 527 with thiophosgene as well as phenyl chlorothionoformate resulted in the formation of 1,3-dithiol-2-thiones 528, whereas the reaction with phenyl chlorothioloformate gave 1,3-dithiol-2-ones 529 (Scheme 76) .

1017

1018 1,3-Dithioles

Scheme 76

A series of 2-(alkylimino)- and 2-(arylimino)-1,3-dithioles 532 (azadithiafulvenes, DTFs) were synthesized by the [4þ1] cycloaddition reaction of a-thioxothioamides 530 with isocyanides 531. This method, depicted in Equation (63), found applications in syntheses of mono-, bis-, and tris-(1,3-dithiole) derivatives .

ð63Þ

S-Propargyl dithiocarbonates (xanthates) 533 bearing a variety of substituents were convenient precursors of 1,3dithiole-2-ylidene derivatives 534 by reaction with active methylene compounds involving a [3,3]-sigmatropic rearrangement (Equation 64) . In all cases except dibenzoylmethane, a mixture of regioisomers was obtained, with double bond exo or endo.

ð64Þ

1,3-Dithioles

The reaction of the dipotassium salt 535 with short-chain (one to three carbon atoms) alkyl halides led to formation of bis-alkylated products 537 in 42–60% yields, while the comparable reaction with long-chain (4–10 carbon atom) or sterically hindered (i-propyl) alkyl halides gave a mixture of 1,3-dithioles 536 (7–31%) along with 537 (3–24%) (Equation 65) . The formation of 536 was a result of domino reactions involving conjugate addition of monoalkylated 535 to diprotonated 535 followed by loss of hydrogen sulfide and elimination of the nitro group.

ð65Þ

Treatment of 1,1-diphenyl 2,2-difluoroethene 539 with disodium benzene-1,2-dithiolate produced the benzo-1,3dithiole derivative 540 (Equation 66) .

ð66Þ

In another version of this reaction, fluorine atoms were replaced by chlorine atoms. Thus, the 1,3-dithiole 542 was prepared in the reaction of the pentachlorobutadiene 541 with benzene-1,2-dithiol 538 according to the general scheme, previously referred to in CHEC-II(1996), involving an exchange of the vinyl chlorine atom by the thiolate sulfur (Equation 67) .

ð67Þ

The dithioketal 544 which can be formally regarded as a 1,3-dithiole derivative was obtained by reaction of benzene-1,2-dithiol 538 with ketone 543 (Equation 68) .

ð68Þ

The phase-transfer-catalyzed (PTC) reaction of 1,2-dicyanoethene-1,2-dithiolate with 3,3-dichloroprop-2-enal gave the 1,3-dithiole derivative 545 in 77% yield (Equation 69) .

ð69Þ

Similarly, both bromine atoms in fluorenylidene dibromomethane 547 were replaced by the 1,2-dithiolates 546 to give fluorenylidene persulfenylbenzodithiafulvenes 548 (Equation 70) .

1019

1020 1,3-Dithioles

ð70Þ

The fluorine containing p-exTTF 550 was obtained in the 1,3-dipolar cycloaddition of DMAD to dithiocarboxylic moiety of the dithiocrotonate 549 and subsequent reaction of the resulting intermediate ylide with the starting 549 as a Michael acceptor in an addition–elimination process followed by ethyl bromide elimination. Formation of the second 1,3-dithiole moiety in 550 was connected with the consecutive cycloaddition followed by ethyl bromide elimination (Equation 71) .

ð71Þ

On the other hand, the reaction of saturated ethyl and n-propyl perfluorodithiopentanoates with DMAD gave exclusively 2-perfluoroylidene-1,3-dithioles 551 (Equation 72) .

ð72Þ

The 2-cyanoacrylamide derivative 552, a building block for the synthesis of polyfused heterocyclic systems containing the 1,3-dithiole moiety, was obtained in the reaction of either ethyl cyanoacetate or cyanoacetamide with CS2 and ammonia and further reacted with tetrabromo-1,4-benzoquinone to give the corresponding 1,3-dithiole 553 (Scheme 77) .

Scheme 77

4.12.9.4 1,3-Dithiolanes Among a variety of methods reported for construction of 1,3-dithiolanes, the most important play a role in conversions involving carbonyl compounds. For this reason, this group of compounds is also named five-membered 1,3-dithioacetals or S,S-acetals. 1,3-Dithiolanes can be easily prepared by condensation of carbonyl compounds with 1,2-ethanedithiol in

1,3-Dithioles

the presence of Bro¨nsted or Lewis acid catalysts. Numerous methods employing such catalysts like HCl, PTSA, SO2, AlCl3, SiCl4, TiCl4, FeCl3/SiO2, SOCl2/silica gel, Mg(OTf)2, Zn(OTf)2, BF3–OEt2, Nafion-H, or Amberlyst-15 have been reported. As reported in CHEC(1984) and CHEC-II(1996), many of these methods required reflux temperatures, long reaction times, anhydrous conditions, and stoichiometric amounts of catalysts. Other limitations associated with some of these methods included poor selectivities, failure to react with aromatic and aliphatic ketones, formation of secondary products such as hemithioacetals or vinyl sulfides from enolizable carbonyl compounds, and low yields. Therefore, there is still a need to develop simple and efficient methods for synthesis of 1,3-dithiolanes. One of the effective reagents for highly chemoselective dithioacetalization of carbonyl compounds is ceric ammonium nitrate (CAN) in chloroform. When a mixture of benzaldehyde and acetophenone was allowed to react with 1,2ethanedithiol and a catalytic amount of CAN, the 1,3-dithiolane derived from the aldehyde was obtained in 84% yield while the ketone was recovered unchanged. It is noteworthy that aromatic ketones, -lactones, and acylic ketones did not react at all under these conditions and even at elevated temperatures for longer reaction times . Perfect chemoselectivity (100% of dithioacetals) was also achieved with kaolinitic clays as catalysts for protection of various aldehydes (aliphatic, aromatic, heteroaromatic, a,b-unsaturated) with 1,2-ethanedithiol . Various carbonyl compounds were efficiently converted into the corresponding 1,3-dithiolanes using triethyl orthoformate as a water scavenger and (bromodimethyl)sulfonium bromide as an efficient catalyst under solventfree conditions . This protocol can be applied for the chemoselective protection of aldehydes in the presence of ketones on a large scale (Equation 73).

ð73Þ

The ionic liquid based on the 1-n-butyl-3-methylimidazolium cation was also used as an efficient catalytic medium for the chemoselective dithioacetalization of carbonyl compounds. This reaction proceeded with both activated and weakly activated aromatic aldehydes in almost quantitative yields in short reaction times. In addition, an acidsensitive substrate such as furfural also gave the corresponding 1,3-dithiolane without a formation of any side products (Table 8). Moreover, aromatic ketones did not produce dithioketals under the same reaction conditions (room temperature, 10–20 min) or even after a prolonged reaction time . Table 8 Dithioacetalization of aldehydes in the ionic liquid [bmim]Br Aldehyde

Product

Time (min)

Yield (%)

20

85

13

92

10

90

15

81

1021

1022 1,3-Dithioles Treatment of a mixture of a carbonyl compound and 1,2-ethanedithiol in dry dichloromethane at room temperature with anhydrous zirconium(IV) chloride dispersed on silica gel gave excellent yields (96–99%) of the respective 1,3dithiolanes. The high reactivity of this reagent was also observed in the case of less reactive aromatic ketones at room temperature and a,b-unsaturated aldehydes such as cinnamaldehyde 556 (Equation 74) .

ð74Þ

Other catalytic procedures for the synthesis of 1,3-dithiolanes from various acyclic carbonyl compounds used clay , LiBF4 , LiBr , acid ion exchange , Mg(ClO4)2 450 nm) (Scheme 150). Electrochemical switching function also accompanied the photochromism in what was the first example of photochromism in a TTF compound .

1071

1072 1,3-Dithioles

Scheme 150

During 1995–2005, interest in TTF chemistry has arisen in a variety of new fields by taking advantage of its solidstate and solution properties. New TTF derivatives continue to be extensively studied as p-electron donors for the preparation of ICT complexes and radical ion salts, which possess notably high electrical conductivity in the solid state. Several TTF–spacer–A diads (A ¼ electron-acceptor moiety) containing acceptor groups such as C60 982 , quinones 25 , pyrdinium 983 , or bipyridinium cations 26 have been studied as a function of the steric and electronic properties of the donor and acceptor moieties and the spacer unit.

1,3-Dithioles

Dendrimers with up to 96 redox-active TTF moieties on the periphery, which allow the generation of polycationic species bearing up to 192 positive charges on the surface, were incorporated into electrodes. These dendrimermodified electrodes find application in electrochemical sensing of metal cations (i.e., Ba2þ), thanks to the grafting of crown ether/TTF units on the periphery of dendrimers < 2001AGE224>. Push-pull systems of general structures D–p-A containing TTF units 984 were actively studied as NLO-phores . An increase in the NLO properties of these materials was observed when using strong electron acceptors attached to the TTF moiety.

Different types of TTF-containing metallic radical cation salts with paramagnetic anions were prepared to study the possibility of new physical phenomena resulting from mutual interaction between delocalized conduction electrons and localized magnetic moments . Paramagnetic and chiral anions [Fe(C5O5)3]3 were combined with the organic donor BEDT–TTF to yield the first chirality-induced -phase and paramagnetic metal . Much attention was devoted to bis(1,3-dithiole-2-thiono-4,5-dithiolate) complexes with metals, especially with nickel, [Ni(dmit)2] 985. After preparation of the first example of a superconductor in this series, that is, TTF[Ni(dmit)2], research interest has broadened to molecules possessing electrical, magnetic, and optical properties within the same compound and to processing of molecular-based materials as thin films and nanowires. Among others, investigations toward switchable spin crossover molecular conductors and metallic thin films of 985 and ferromagnetism in [MnCp* ]2[Ni(dmit)2] complexes were undertaken.

4.12.13 Further Developments A number of publications of substantial significance have appeared in literature since the preparation of this chapter up to October 2007. These concerned mostly 1,3-dithiolanes, 1,3-dithioles and TTF systems. No new investigations were reported on 1,3-dithiolylium ions, mesoionic 1,3-dithiol-4-ones and mesoionic 1,3-dithiole-4-thiones. Bis(1,3-dithiole-2-chalcogenones) in which the 1,3-dithiole fragments were linked through bridging groups were used to synthesize bridged TTFs . Scanning tunneling microscopy was used to study the first stages of growth of 2-[9-(1,3-dithiol-2-ylidene)anthracen-10(9H)-ylidene]-1,3-dithiole, as an electron donor, on a Au(III) substrate, to assist a precise control of the nanometer-scale morphology in donor–acceptor systems utilized in organic solar cells . Syntheses, structures and electrochemical properties of new platinum(II) 1,3-dithiole complexes were also studied . The thermal behavior of bis(tetrabutylammonium)bis(4,5dithiolato-1,3-dithiole-2-thione)copper was investigated by means of thermogravimetric analysis (TGA) and differential thermal analysis (DTA) measurements in air . Propargylic 1,3-dithiolanes underwent AuCl-catalyzed transformation to 2,3-dihydro-1,4-dithiofluorenes containing a 1,4-dithiin moiety . Another example of one-pot ring expansion of 1,3-dithiolanes to 1,4-dithiins was demonstrated by Patel et al. using 1,19-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) as a promoter of the 1,3-dithiolane formation and as a reagent in the ring expansion step . A highly efficient BF3?OEt2 catalyzed C–C coupling reaction between -EWG-containing ketene 1,3-dithiolanes and various dibenzylic alcohols was also described . 1,2-Ethanodithiol underwent double conjugated Michael addition to a conjugated terminal acetylenic ketone in the presence of 1-methyl-3-butylimidazolium hydroxide [bmIm]OH ionic liquid acting as a solvent and a reagent to produce the corresponding -keto 1,3-dithiolane .

1073

1074 1,3-Dithioles A new p-extended TTF ligand featuring a furanoquinonoid spacer and pyridyl functional groups showed unprecedented electrochemical sensing behavior and excellent coordinating properties toward selected divalent metal ions. Solid-state structures of this ligand and its NiCl2 complex were also described . Synthesis of bis(ethylenedithio)tetrathiafulvalene (BEDT-TTF) derivatives functionalized with two, four, or eight hydroxyl groups involving the cycloaddition of 1,3-dithiole-2,4,5-trithione with alkenes was reported and the first synthesis of a single diastereomer of tetrakis(hydroxymethyl)BEDT-TTF was also achieved . A dithiophene-tetrathiafulvalene (DT-TTF) and a linear benzene-fused bis(tetrathiafulvalene) were shown to be promising organic semiconductors for organic transistors while (tetrathiafulvalene)(tetracyanoquinodimethane) [(TTF)(TCNQ)] was shown to be an excellent electrode material for bottom-contact transistors . Synthesis of concave truxene derived of tetrathiafulvalene-type donors as supramolecular partners for convex fullerenes, to be used in the manufacture of fullerene-based self-assembled optoelectronic devices, was described. This synthesis was realized via the Horner–Wittig reaction of truxene and 2-dimethoxyphosphoryl-1,3-dithioles . IR and Raman spectral studies of other fullerene-tetrathiafulvalene based systems were performed . Generation of polyoxyethyl-vinylogous tetrathiafulvalene electroactive films in the electropolymerization reaction of substituted dithiafulvenes was described . The synthesis, crystal structure and electrochemical properties of a silver(I) coordination derivative of 2,3-dimethylthio-6-pyridyl tetrathiafulvalene and ruthenium(II) polypyridine complexes {(bpy ¼ 2,29-bipyridine; dppz ¼ 49,59-bis(propylthio)tetrathiafulvenyl[i]dipyr[Ru(bpy)3-n(TTF-dppz)n](PF6)2, ido[3,2-a:29,39-c]phenazine)} were also investigated. The electronic absorption, fluorescence emission, photoinduced intramolecular charge transfer, and electrochemical behavior of another phenazine derived tetrathiafulvalene (TTF)-fused dipyrido[3,2-a:29,39-c]phenazine (dppz) compound were studied . An interesting synthesis and radical coupling of pyridine-bridged extended tetrathiafulvalene (TTF)-type donors and push–pull analogues were performed by Priego et al. .Other investigations on TTFs included: crystallographic studies of p-radical cationic salts of tetrathiafulvalene derivatives with pyromellitate forming twodimensional sheets , photomodulation of the electron-donating ability of new heterocyclic tetrathiafulvalenes with an azobenzene moiety , intramolecular electron transfer within the substituted tetrathiafulvalene-quinone dyads facilitated by metal ions and photomodulation in the presence of spiropyran . Classification of macrocyclic compounds containing tetrathiafulvalene moieties, synthetic methods, the latest advances in research on electrochemical properties and applications to molecular recognition and development trends in research on such macrocyclic compounds were outlined and reviewed .

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1088 1,3-Dithioles

2007IC866 2007JA6839 2007JCC2319 2007JMC736 2007JOC6247 2007JOC139 2007JOC1192 2007MI349 2007MI677 2007MI1220 2007MI1504 2007MI2602 2007MI193509 2007OBC1201 2007OBC3172 2007OL3753 2007RJOC135 2007S1621 2007T776 2007T1007

Y. Ji, R. Zhang, Y.-J. Li, Y.-Z. Li, J.-L. Zuo, and X.-Z. You, Inorg. Chem., 2007, 46, 866. H. Wu, D. Zhang, L. Su, K. Ohkubo, C. Zhang, S. Yin, L. Mao, Z. Shuai, S. Fukuzumi, and D. Zhu, J. Am. Chem. Soc., 2007, 129, 6839. Y. Liu, Q.-Y. Zhu, J. Dai, Y. Zhang, G.-Q. Bian, and W. Lu, J. Coord. Chem., 2007, 60, 2319. X. Gao, W. Wu, Y. Liu, S. Jiao, W. Qiu, G. Yu, L. Wang, and D. Zhu, J. Mater. Chem., 2007, 736. G. Wen, D. Zhang, Y. Huang, R. Zhao, L. Zhu, Z. Shuai, and D. Zhu, J. Org. Chem., 2007, 72, 6247. Q. Zhang, S. Sun, J. Hu, Q. Liu, and J. Tou, J. Org. Chem., 2007, 72, 139. L. Peng, X. Zhang, S. Zhang, and J. Wang, J. Org. Chem., 2007, 72, 1192. X. Q. Wang, D. Xu, Q. Ren, G. H. Zhang, X. B. Sun, X. Q. Hou, W. F. Guo, and H. Lu¨, Cryst. Res. Technol, 2007, 42, 349. J. Massuea, J. Ghilanea, N. Belleca, D. Lorcy, and P. Hapiot, Electrochem. Commun., 2007, 9, 677. L. Hong-Qi, S. Yan-Xib, P. Jia-Jianc, and Q. Hua-Yuc, Chinese J. Org. Chem., 2007, 27, 1220. C. Goze, C. Leiggener, S.-X. Liu, L. Sanguinet, E. Levillain, A. Hauser, and S. Decurtins, Chem. Phys. Chem., 2007, 8, 1504. ´ cija, G. Fernndez, J. M. Gallego, L. Snchez, N. Martıń, and R. Miranda, Nano Lett., 2007, 7, 2602. R. Otero, D. E K. Shibata, H. Wada, K. Ishikawa, and H. Takezoe, Appl. Phys. Lett., 2007, 90, 193509. E. M. Priego, L. Sańchez, M. A. Herranz, N. Martıń, R. Viruela, and E. Ortı´, Org. Biomol. Chem., 2007, 5, 1201. R. J. Brown, A. C. Brooks, J.-P. Griffiths, B. Vital, P. Day, and J. D. Wallis, Org. Biomol. Chem., 2007, 5, 3172. S. Dolder, S.-X. Liu, F. Le Derf, M. Salle´, A. Neels, and S. Decurtins, Org. Lett., 2007, 9, 3753. G. I. Abashev, A. Bushueva, K. Lebedev, and E. Shklyaeva, Russ. J. Org. Chem., 2007, 43, 135. N. Crivillers, N. S. Oxtoby, M. Mas-Torrent, J. Veciana, and C. Rovira, Synthesis, 2007, 1621. B. C. Ranu, S. Banerjee, and R. Jana, Tetrahedron, 2007, 48, 776. S. Murru, V. Kavala, C. B. Singh, and B. K. Patel, Tetrahedron, 2007, 48, 1007.

1,3-Dithioles

Biographical Sketch

Piotr Bałczewski was born in Ło´d´z (Poland); he studied chemistry at the Technical University of Ło´d´z and partly at the Center of Molecular and Macromolecular Studies (CM&MS), Polish Academy of Sciences (PAS), Ło´d´z, where he obtained a B.Sc., M.Sc. (Eng.) in 1979 and his Ph.D. in 1985, both with Professor M. Mikołajczyk. In the meantime (1979–82), he made further part-time studies at the Institute of Organic Chemistry, PAS, Warsaw. After spending 1989–91 at the laboratories of Professor J. A. Joule, University of Manchester, UK, where he worked on total syntheses of alkaloids produced by sea sponges, he returned to CM&MS, Ło´d´z, where he made his habilitation in 1997. Subsequently, he received a position of a docent (1999) and in 2001 took up his present duties as a Head of Laboratory of Metallo- & Metalloidoorganic Chemistry, CM&MS, PAS. Since 2002, he has also been a professor at Jan Długosz University of Cze¸stochowa, Poland. He has visited chemical departments of University of Milan, University of Rome (1986), Zentral Institut fu¨r Organische Chemie, Berlin (1986, 1987), University of Manchester (1989–91), University of Barcelona (1991), National Research Center, Cairo (1995), Ben Gurion University of the Negev, Beer-Sheva, and Hebrew University, Jerusalem (1997), Laboratoire de Chimie de Coordination du CNRS, Toulouse (2007). His scientific interests include synthetic and mechanistic aspects of heteroatom (mainly phosphorus and sulfur) chemistry and its applications to total syntheses of biologically active compounds (cyclopentanoids, alkaloids, anti-HCV lignans), organometallic chemistry, free radical, carbene, and carbanion aspects of heteroatom chemistry, and syntheses of heteroatom-modified polyaromatics for thin-layer devices of molecular electronics.

Wiesława Kudelska was born in Poland (1951); she studied pharmacy at the Medical University of Ło´d´z, Poland (1969–74), where she also carried out her Ph.D. work (1974–82). She joined Professor G. Descotes’ group at the Claude-Bernard University of Lyon, France (1985). In 1988, she spent one year in USA working as a postdoctoral research fellow with Professor J. Loz at Harvard University, Laboratory for Carbohydrate Chemistry. From 1974 to 2004, she was employed at the Medical University of Ło´d´z, Faculty of Pharmacy. Since 2004, she is a professor at the Jan Długosz University of Cze¸stochowa, Poland. Her scientific interests are centered on carbohydrate chemistry.

1089

1090 1,3-Dithioles

Agnieszka Bodzioch was born in Kielce (Poland); she studied chemistry at the University of Ło´d´z, ´ Since then, she has where she obtained an M.Sc. in 2005 under direction of Professor G. Mloston. been employed at the Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, working with Professor P. Bałczewski on synthesis of polyheteroaromatics for thin-layer devices of molecular electronics and on total synthesis of novel anti-HCV lignans.

4.13 Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium M. B. Nielsen University of Copenhagen, Copenhagen, Denmark ª 2008 Elsevier Ltd. All rights reserved. 4.13.1

Introduction

1092

4.13.2

Theoretical Methods

1092

4.13.3


1094

4.13.3.1

X-Ray Diffraction

4.13.3.2

Mass Spectrometry

1096

4.13.3.3

Ultraviolet–Visible Spectroscopy

1096

Nuclear Magnetic Resonance Spectroscopy

1097

4.13.3.4 4.13.4 4.13.4.1

1094


1097

Electrochemistry and Conductivity

1097


1099

4.13.5.1

Electrophilic Attack at Heteroatoms

1099

4.13.5.2

Reductive Ring-Opening Reactions

1099

4.13.5

4.13.6


1100

4.13.6.1

Thermolysis

1100

4.13.6.2

Ring-Opening Reactions

1100

Other Reactions at Ring Heteroatoms

1105

4.13.6.3 4.13.7


1106

4.13.8


1106

4.13.9


1106

4.13.9.1

One-Component Syntheses

1106

4.13.9.2

[1þ4] Two-Component Syntheses

1111

4.13.9.3


1113

4.13.9.4

Multicomponent Syntheses

1113

4.13.10


1114

4.13.11


1114

4.13.12


1114

4.13.13


1115

References

1115

1091

1092 Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium

4.13.1 Introduction Five-membered monocyclic rings containing one selenium or one tellurium atom and another adjacent heteroatom (oxygen, sulfur, selenium, tellurium, or nitrogen) comprise different ring systems, including saturated and partially saturated examples, summarized in Figure 1. 1,2-Selenazoles and derivatives thereof are covered in Chapter 4.07 and are therefore not part of the present chapter. Even so, a few references are given when judged valuable.

Figure 1

Of the parent systems, 1,2-diselenolane , 1,2-ditellurole , 1,2-selenazole , and 1,2-ditellurolylium are known. Thus, both 1,2-azaselenolane and -tellurolane as well as both 1,2-oxaselenolane and -tellurolane remain unknown. Yet, many derivatives of these molecules have appeared in the literature in recent years, in particular benzo-annelated derivatives and 3-oxo-substituted heterocycles. Some compounds, particularly benzoselenazoles (e.g., 2-phenyl-1,2-benzisoselenazol-3(2H)-one with the trivial name epselen), have attracted considerable interest for their biological activities. The exploitation of peridichalcogen-bridged polyacenes as candidates for organic conductors was described in CHEC-II(1996) and it continues to be an area of intense research as reflected in Section 4.13.4.1. Other compound classes, covered briefly in CHEC-II(1996), that stand out in this chapter are selenurane and tellurane dication salts, both in respect to synthesis, reactivity, and structural characterization. A review on the synthesis and properties of dichalcogena dications and trichalcogena hypervalent dications has been published .

4.13.2 Theoretical Methods Single point ab initio calculations were performed at the RHF/3-21G(* ) level on the dicationic tellurane 1 . Atomic charges were evaluated by the natural population analysis. Various electronic properties are summarized in Table 1. The total 5d-orbital population of Te is small, and the d orbitals are not primarily involved in the Te–Se bonds. The Mulliken valency values can be rationalized in terms of the two resonance structures shown in Equation (1). A total positive charge of þ2.639 is located exclusively on the three chalcogen atoms and is larger than þ2 owing to the polarization of the Te–C and Se–C bonds.

Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium

Table 1 Electronic properties of dication 1 Quantity

Atom or bond

Value

Atomic chargea

Te Se(1) Se(2) Te–Se(1) Te–Se(2) Te Se(1) Se(2) Te

þ1.422 þ0.602 þ0.615 0.556 0.587 3.08 2.59 2.61 0.033

Bond orderb Valencyb

5d occupancya a

Natural population analysis. Mulliken values.

b

ð1Þ

Calculations (natural population analysis) on the dication 2 revealed that the charge on the central Se atom is þ1.020 and the charges of the apical Se atoms are þ0.701 . Charge distributions were also calculated for O–Se–O and Se–Se–O derivatives . Calculations on hybrid dichalcogena dications (S–Se, S–Te, Se–Te) were also reported .

An ab initio molecular orbital calculation was made on the tetratelluronaphthalene 3 . The highest occupied molecular orbital (HOMO) was found to have anti-bonding character in the Te–Te bond.

1093


4.13.3 Experimental Structural Methods 4.13.3.1 X-Ray Diffraction The crystal structures of naphtho[1,8-cd]-1,2-diselenole 4 and naphtho[1,8-cd]-1,2-ditellurole 5 were reported ˚ respectively, while . The Se–Se and Te–Te bond lengths are 2.3639(5) and 2.727(3)–2.7348(3) A, ˚ the same bonds in PhSe–SePh and PhTe–TePh are 2.29 and 2.712(2) A , respectively. The structure of the tetraselenoanthracene 6 has also been reported .

A radical cation salt of tetraselenotetracene 7 with the anion [Fe(NO)(CN)5]2 was prepared and the crystal structure reported, which revealed the composition (7)3[Fe(NO)(CN)5] . Charge-transfer salts of 7 and nickel(IV) bis((3)-1,2-dicarbollide) were also investigated by X-ray crystallography . The X-ray crystal structure of phenanthro[1,10-cd:8,9-c9d9]bis-1,2-diselenole 8 has been reported .

X-Ray crystal structure analyses of neutral 3,4-dimethylanthra[1,9-cd:4,10-c9d9]bis-1,2-ditellurole 9 and its cation radical salts with several anions have been performed . Crystal structures of 3?(SCN)0.88, 3?(ClO4)0.88, 3?(AsF6)0.7, 3?Ag(CN)2, and 3?Au(CN)2 were reported .

X-Ray crystal structure determinations on Te-centered hypervalent dications 1 and 10 (counter ions BF4or CF3SO3) revealed that the hypervalent Te is at the center of a distorted trigonal bipyramid with apical sulfono or selenonio ligands connected via transannular bonds . X-ray crystallographic analysis of 2?2CF3SO3 showed that 2 adopts a distorted boat–boat form fixed by the three-center transannular bond between the three selenium atoms . The dication in 11?2CF3SO3, with two unsymmetrical apical oxy- and seleno-ligands, also adopts a twin-boat form according to X-ray crystallographic analysis .


The X-ray crystal structure of 1-iodo-2-p-tolyl-1-tellura-2-azaindene 12 was reported . The structure of chlorophenylselenurane 13 shows a slightly distorted trigonal bipyramidal geometry around the central selenium atom .

The molecular structure of the selenenate 14 shows the presence of intermolecular nonbonding Se O(formyl) interactions . The structures of 15 and 16 were also reported .

X-Ray crystallographic analysis of compound 17 revealed a distorted pseudo-trigonal-bipyramidal structure at the selenium atom . The oxygen and nitrogen atoms occupy two apical positions, whereas the two carbons as well as the lone pair occupy three equatorial positions. X-Ray crystallographic analysis of the 1,2,5-oxaselenazolidine 18 revealed that the selenium atom has a slightly distorted pseudo-trigonal-bipyrimidal structure with two oxygens at the apical positions . Its oxaselenazolidine ring exists in almost envelope form, where the nitrogen atom is located at the tip above the least-squares plane defined by the other four atoms.

X-Ray crystallographic analysis of the dioxaselenanonane 19 revealed that the O–Se–O bond angle is 172.99 , while the C–Se–C bond angle is only 102.95 . A racemic mixture of selenurane oxide 20 was separated into its two enantiomers, and the X-ray crystal structure was solved for the R configuration . The structure of one enantiomer of the spiroselenurane 21 was also reported . X-Ray crystal structures of the spirotellurane 22 and peroxide 23 have been reported.

X-Ray crystal structures of the 1,2-diselenolylium and 1,2-ditellurolylium salts 24?Cl and 25?Cl were reported .

1095


Finally, it is briefly noted that the 1,2-selenazole derivatives 26–31 have been investigated by X-ray crystallography .

4.13.3.2 Mass Spectrometry Mass spectra have been used extensively for structure elucidations and for characterization of many of the compounds dealt with in this chapter. As the mass spectrometry data have not been the subject of systematic discussion, no details are given here.

4.13.3.3 Ultraviolet–Visible Spectroscopy In this section, only papers dealing with a more systematic discussion of UV–Vis spectra are mentioned. A comparison of the chromophoric properties of tetraselenoanthracenes and tetraselenophenanthrenes 8 and 32–35 is presented in Table 2 .


Table 2 Absorption maxima in chloroform max (nm (log ")) 32 33 8 34 35

294 (4.27), 345 290 (4.38), 423 289 (3.90), 333 331 (4.05), 394 336 (4.35), 410

(3.61), 432 (3.62), 554 (4.03) (3.57), 500 (3.98), 532 (4.11) (4.18), 401 (4.14) (3.97) (4.15)

Circular dichroism spectra were obtained of optically active seleninate esters 36 .

4.13.3.4 Nuclear Magnetic Resonance Spectroscopy Nuclear magnetic resonance (NMR) spectra have been used extensively for structure elucidations and for characterization of many of the compounds dealt with in this chapter. In this section, only papers dealing with a more systematic discussion of NMR spectra are mentioned. The 77Se NMR spectrum of the selenurane 2?2PF6 showed two resonances at 535 and 830 ppm, and 77Se satellites in the proton-decoupled 77Se NMR gave a value of 200 Hz for the 1JSe–Se coupling constant . The conformation is fixed as a boat form by transannular bonds between the three selenium atoms. Variable-temperature NMR studies on hybrid dichalcogena dications 37 (S–Se, S–Te, Se–Te) revealed that the stability among the chalcogenides followed Te >> Se > S .

4.13.4 Thermodynamic Aspects 4.13.4.1 Electrochemistry and Conductivity A comparison of half-wave oxidation potentials of tetraselenonaphthalenes, tetraselenoanthracenes, and tetraselenophenanthrenes is presented in Table 3 . It transpires that the phenanthrenes are significantly poorer electron donors. Methyl substitution in the anthracene series lowers both the first and the second oxidation potentials. Charge transfer complexes between the naphthalenes and tetracyanoquinodimethane (TCNQ) were studied . The 1:1 complex with 6 is highly conductive with a conductivity of 14.4 S cm1, whereas the 1:1 complex with 39 is nearly insulating (8.9 109 S cm1) and the 1:0.77 complex with 40 is semiconductive (2.4 103 S cm1).

1097


Table 3 Half-wave oxidation potentials obtained by cyclic voltammetry (vs. Ag/AgCl in benzonitrile)

6 8 34 35 38 39 40 41 42

E1=2 (1) (V )

E1=2 (2) (V )

0.48 0.64 0.58 0.58 0.51 0.49 0.45 0.35 0.47

0.93 1.02 0.98 0.90 0.92 0.92 0.98 0.71 0.78

Magnetoresistance and diffuse X-ray experiments in conjunction with single-electron band structure calculations were performed in order to elucidate the nature of the ground state of tetraselenotetracene 7 . The conductivity of the salt (7)3[Fe(NO)(CN)5] along the stack direction was determined to 5–7 S cm1, at room temperaIII ? ture . The electrical conductivity of the charge-transfer salt (7)?þ 2 [{closo-(3)-1,2-C2B9H11}2Ni ] , was 1 found to be 17.3 S cm . The charge-transfer complex of the tetraselenophenanthrene 8 with TCNQ (1:1) showed an electrical conductivity of 55.5 S cm1 . The salts formed between 8 and TCNQF4 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) showed conductivities of 8.0 S cm1 (2:1 complex) and 7.0 102 S cm1 (1:1 complex), respectively . The conductivity of the 1:1 complex between 35 and DDQ was found to be 2.0 101 S cm1 . Electrocrystallizations of 8 and 35 were also performed with different counteranions and the conductivities are listed in Table 4 together with conductivities obtained for salts

Table 4 Conductivities (293K) of salts of 3, 8, 9, and 35 293K (S cm1) Anion

ClO4 BF4 ReO4 PF6 AsF6 SbF6 Br I3 SCN CuI2 NO3 Ag(CN)2 Au(CN)2 Cu(SCN)2 N(CN)2 Mo6O192

3

9 1

7.6 10 9.9

1.3 101 3.0 101 6.0 102 5.9 102

7.60 102 7.20 102 8.40 102 .

Treatment of the spirotelluranes 82 and 83 with tris(diethylamino)phosphine resulted in ring opening and generation of the telluride 84 (Equation 10).

ð10Þ

Compounds 85a–c were treated with bromine, which resulted in rupture of the O–Te bond with the formation of carbonyl compounds 86a–c (Equation 11). For R ¼ Me, bromination of the methyl group occurred to give a mixture of products 87 .

ð11Þ


Treatment of compound 85a with 2 mol equiv of bromine in refluxing acetic acid gave rise to the benzaldehyde derivative 88 (Equation 12) .

ð12Þ

The exchange of chloride between chlorooxachalcogenuranes 89 and chalcogenides 90 to provide 91 and 92 was studied (Equation 13) .

ð13Þ

The salts 93?ClO4 were treated with organometallic reagents according to Equation (14) . Reactions at room temperature gave only benzyl alcohols 94, and reactions under reflux in tetrahydrofuran (THF) afforded benzophenone derivatives 95 and benzyl ethers 96 in addition to 94. Reactions with phenyllithium or methyllithium at room temperature gave the reduction product 94 only, and the reaction with methyllithium at 10 C gave the ligand coupling product 96 in 8% yield.

ð14Þ

Treatment of 93 (R1 ¼ Ph, R2 ¼ H) with sodium hydride gave the benzophenone derivative 95 (R1 ¼ Ph) (Equation 15) .

ð15Þ

Reactions of 97?ClO4 with organolithiums gave complex mixtures of products 98–100 (Equation 16) . Reactions with phenylmagnesium bromide afforded a ring-opened product 98, a benzo[c]furan derivative 99a, and dihydrodibenzoselenepinol 100. Reaction at room temperature provided the furan derivative in greater yield than that at lower temperature. When phenylmagnesium iodide was used instead of the bromide, the product 100 was obtained in 56% yield. Methylmagnesium iodide similarly gave this product in high yield (71%).

ð16Þ

1103

1104 Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium Reactions of either 101 or 97?BF4 with triethylamine gave 5,10-epoxydihydrodibenzoselenepine 102 in 18% and 68% yield, respectively (Equation 17) .

ð17Þ

Treatment of selenurane oxide 20 with 2 equiv of triphenylphosphine caused ring opening to the symmetrical hydroxyalkyl selenide 103 (Scheme 4) .

Scheme 4

Reacting the cyclic seleninate ester 15 with an excess (three fold) of pentanethiol gave the selenenyl sulfide 104 (Equation 18) . Treating 105 with benzyl thiol provided the selenenyl sulfide 106 via the intermediates depicted in Scheme 5 .

ð18Þ

Scheme 5

Reaction of optically active seleninate ester (R)-()-107 with methylmagnesium bromide gave the selenoxide (R)-(þ)-108 (Equation 19) .

ð19Þ


Treating 19 with 2 mol equiv of benzylthiol generated the selenide 109 quantitatively (Equation 20) .

ð20Þ

1,19-Spiro(3H-2,1-benzoxatellurole)-3,3-dione 82 was converted into 1,19-spiro(3H-2,1-benzoxatellurole)-3,3thione 83 by Lawesson’s reagent, while 83 was converted into 82 by treatment with aqueous sodium hydroxide .

4.13.6.3 Other Reactions at Ring Heteroatoms The dications 110a and 110b lost the isopropyl group at temperatures above 20 C, which gave cations 111a and 111b (Equation 21) .

ð21Þ

Selenuranes 112 were converted into oxaselenolium salts 93?ClO4 upon treatment with silver perchlorate (Equation 22) . Similarly, compounds 113 were converted into oxaselenolium salts 114 (Equation 23) .

ð22Þ

ð23Þ

A racemic mixture of the selenurane oxide 20 was prepared by oxidation of the parent selenurane 21 with metachloroperbenzoic acid . The parent selenurane 21 can be regenerated by treatment with HCl . The thiotelluroxide 65 underwent selective S-methylation with 1 equiv of methyl triflate to provide the corresponding ring closed Nþ–Te–SMe triflate salt . Reaction between the palladium pincer complex 115 and trimethylstannylphenylselenide 116 is assumed to result in formation of a phenyl selenide-coordinated complex 117 (Equation 24) .

ð24Þ

1105

1106 Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium Oxidation of the spirodioxytellurane 118 with hydrogen peroxide gave the peroxide 23 (Equation 25) .

ð25Þ

4.13.7 Reactivity of Substituents Attached to Ring Carbon Atoms There are no examples to report here.

4.13.8 Reactivity of Substituents Attached to Ring Heteroatoms There are no examples to report here.

4.13.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component Ring syntheses from acyclic compounds can be classified in three groups according to the number of building blocks required in the reaction: (1)‘one-component synthesis’, in which the starting molecule is cyclized by joining two heteroatoms or by joining one heteroatom and one carbon atom; (2) [1þ4] ‘two-component synthesis’, in which a oneatom unit is joined with a four-atom unit; (iii) [2þ3] ‘two-component synthesis’, in which a two-atom unit is joined with a three-atom unit.

4.13.9.1 One-Component Syntheses A review on the synthesis of dichalcogena dications and trichalcogena hypervalent dications has been published . Oxidation of the cyclic selenides 61 and 119 by sulfuric acid or nitronium hexafluorophosphate has provided selenurane salts 2 and 62 (Equation 26) .

ð26Þ

Reaction of the selenoxide 120 with triflic anhydride gave the selenurane dication 11 (Equation 27) . In a similar way, 2 was prepared as well as a derivative with two outer oxygens and one central selenium .

ð27Þ

Compound 61 was oxidized by the action of the sulfuranyl dication 121 to the diselena dication 2 .


Reactions of 122 (or the corresponding Te-oxide) and 123 with nitronium tetrafluoroborate or trifluoromethanesulfonic anhydride provided dications 1 and 10 . Synthesis of the dicationic telluranes 124 and 125 proceeded in a similar way .

Treatment of compounds 126 and 127 with triflic anhydride gave dications of general formula 37 (S–Se, S–Te, and Se–Te) as investigated by NMR analysis (Scheme 6) . The tellurathia dications (X ¼ Te, Y ¼ S, R ¼ Et or R ¼ i-Pr) were stable enough to be isolated. Dealkylation was investigated by variable-temperature NMR studies. The salt of 128e (X ¼ Te, Y ¼ Se; i.e., 111b) was isolated preparatively by treatment of 126 (X ¼ Te, Y ¼ Se, R ¼ i-Pr) with 1 equiv of trifluoromethanesulfonic anhydride in anhydrous acetonitrile at 40 to 20 C.

Scheme 6

Treatment of the thiotelluroxide 66 with thionyl chloride gave the chloro-substituted ammoniotellurane 65 . Compounds 129 and 130 were oxidized by meta-chloroperbenzoic acid to the monoselenoxides 131 and 132 that rearranged quite rapidly to the products 133 and 134 (Scheme 7) .

Scheme 7

1107

1108 Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium Tellurides 135 were treated with a phenacyl halide, diethyl bromomalonate, or diethyl dibromomalonate to afford a selection of 2-alkyl/aryl-2-halo-1,2-oxatellurolanes 136 (Equation 28) .

ð28Þ

The spiro compounds 19 and 118 were prepared by treating the selenide 109 and telluride 137, respectively, with excess tert-butyl hydroperoxide (or hydrogen peroxide) (Equation 29) . The spiro compound 16 was prepared in a similar way .

ð29Þ

The first unsubstituted monocyclic seleninate ester 105 was prepared from allyl 3-hydroxypropyl selenide 138 (Equation 30) by a series of oxidation and [2,3]-sigmatropic rearrangement steps . Synthesis of the cyclic seleninate ester 15 was accomplished by reacting 139 with tert-butyl hydroperoxide or by treating 140 with an excess of hydrogen peroxide (Scheme 8) . Compound 142 was prepared in a similar way from 141 (Equation 31) .

ð30Þ

Scheme 8

ð31Þ

Treating 143 with hydrogen peroxide gave the tellurium analog 144 (Equation 32) . Yet, the Teanalog of compound 139 could not be converted into 144. Oxidation of the ditelluride 145 afforded the 1,2oxatellurolane oxide 146 (Equation 33) .

ð32Þ


ð33Þ

The selenate ester 14 was prepared from the diselenide 147 by treatment with thionyl chloride, bromine, or iodine under ambient conditions (Equation 34) .

ð34Þ

Tetracoordinate 3-phenyl-1,2-oxaselenetanes 50 were prepared from 148 by treatment with triethylamine (2 equiv) and bromine (1 equiv) (Equation 35) .

ð35Þ

Oxidation of the -aminoalkylselenide 149 with meta-chloroperbenzoic acid gave a mixture of two diastereoisomers of tetracoordinate 1,2-selenazetidines (17 and 150) in yields of 40% and 8%, respectively, after chromatographic work-up (Equation 36) . Treating instead 151 with meta-chloroperbenzoic acid gave the 1,24,5oxaselenazolidine 18 (Equation 37) .

ð36Þ

ð37Þ

Dehydrohalogenation of benzyl alcohol derivatives 152 with AgF or Al2O3 and Et3N gave benzo-fused halooxatelluranes 153 (Equation 38) .

1109


ð38Þ

Treating compounds 154 and 155 with silver perchlorate in acetone gave 156a and 156b (Equation 39) .

ð39Þ

Oxidation of 157 in the presence of base gave benzisotellurazole derivative 158 (Equation 40) .

ð40Þ

The telluride 159 was employed for debromination of vic-dibromides to give alkenes and the bromide salt 74?Br (X ¼ Br) .

Compound 160 was chlorinated with N-chlorosuccinimide to give the oxaselenole derivative 161 (Equation 41). Similarly, compounds 162 were converted to oxaselenole derivatives 112 (Equation 42) .

ð41Þ

ð42Þ


In a similar way, compounds 163 and 164 were converted into chloroselenuranes 101 and 113 (R ¼ Ph) .

Treatment of the selenides 165 with tert-butyl hypochlorite in a dichloromethane solution followed by reaction with triethylamine yielded the enantiomerically pure spiroselenuranes 166 (Equation 43) .

ð43Þ

Treating tellurides 167a,b with tert-butyl hypochlorite gave enantiomerically pure chlorotelluranes 168a and 168b (Scheme 9) . Subsequent hydrolysis of (Z)-isomers under basic conditions gave the spirotelluranes 22 and 169b.

Scheme 9

4.13.9.2 [1þ4] Two-Component Syntheses Treatment of 170 with thioacetamide gave 2,1-benzothiaselenophenone 171 (Equation 44). Reaction with amine nucleophiles instead provided a large selection of 1,2-benzisoselenazol-3(2H)-one derivatives .

ð44Þ

1111

1112 Five-membered Rings with Two Adjacent Heteroatoms with at least One Selenium or Tellurium The isotellurazole 172 was prepared by treating either 2-bromotellurenyl-1-cyclohexenal 173a or 2-methyldibromotellurocyclohexenal 173b with ammonia in benzene (Scheme 10) . Other isotellurazoles were prepared in a similar way .

Scheme 10

Treatment of compound 174 with lithium ditelluride gave the heterocycle 175 in low yield (Equation 45) . Analogous 1,2-selenazoles (derivatives of epselen) were prepared in a similar way by treatment with lithium diselenide (but in high yields) .

ð45Þ

Treatment of compound 176 with sodium diselenide unexpectedly gave the diazo compound 177 (Equation 46) .

ð46Þ

Seleninate esters 36a and 36b were prepared from bromobenzyl alcohol derivatives 178 via selenides 179 (Scheme 11) . Seleninate ester 36c was prepared from 2-(chloroseleno)benzoyl chloride 170 . Compounds 36b and 36c were successfully subjected to optical resolution on a preparative scale,

Scheme 11


while racemization of 36a occurred during the time it took to elute from a column. The nonsubstituted seleninate ester 36a racemized most rapidly among the three seleninate esters, in 2-propanol. Studies indicated that a small amount of water remaining in the solvents may cause the racemization of the esters and two possible mechanisms were suggested. A racemic mixture of the spiroselenurane 21 was prepared in one step from diethylselenite 180 and the Grignard reagent derived from 2-bromocumyl alcohol 181 (Equation 47) . Chiral HLPC gave enantiomerically pure fractions. Other derivatives were prepared in a similar way .

ð47Þ

4.13.9.3 [2þ3] Two-Component Syntheses Phenanthro[1,10-cd:8,9-c9d9]bis-1,2-diselenole 8 and its methyl and methylthio derivatives 34 and 35 were synthesized from 1,8,9,19-tetrachlorophenanthrenes 182a–c and sodium diselenide (Equation 48) . Compounds 6 and 39 were synthesized in a similar way by heating 183a and 183b with sodium diselenide (Equation 49) . Cl

Cl

R = H: Na2Se2, DMF 140 °C, 48 h

Se

Se

R

R = Me/SMe: Na2Se2, CuCl2 HMPA 160 °C/155 °C 48 h

R

R

Cl

Cl

R

182a: R = H 182b: R = Me 182c: R = SMe Cl

8: R = H (20%) 34: R = Me (14%) 35: R = SMe (31%) Se

R Cl

183a: R = H 183b: R = Me

Se

ð48Þ

Cl Me

Cl

Se

Se Me

Na2Se2 DMF, reflux 22 h

ð49Þ

R Se

Se

39: R = H (52%) 6: R = Me (41%)

4.13.9.4 Multicomponent Syntheses The dichalcogenolylium salts 24?Cl and 25?Cl were prepared by heating tetrachlorocyclopropene 184 with SeCl4 and TeCl4, respectively, in dichloromethane under solvothermal conditions (Equation 50) .

ð50Þ

1113


4.13.10 Ring Syntheses by Transformations of Another Ring Photoirradiation of naphtho[1,8-de]-1,3-diseleninylidene 1-oxides 185 in the presence of benzylamine afforded naphtho[1,8-cd]-1,2-diselenole 4 after liberation of ketenes (Equation 51) .

ð51Þ

Treatment of 1,19-spirobi(3H-2,1-benzoxatellurole)-3,39-dione 82 with Lawesson’s reagent gave 1,19-spirobis(3H2,1-benzothiatellurole)-3,39-dione 83 .

4.13.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available In particular, several synthetic procedures for oxaselenolanes, oxatellurolanes, spiroselenuranes, spirotelluranes, seleninate and teleninate esters have been developed in the past decade, that is, heterocycles that contain either Se–O or Te–O in the five-membered ring. Moreover, several new tetraselenonaphthalenes and tetraselenophenanthrenes have been prepared from tetrachloroanthracene and tetrachlorophenanthrene precursors.

4.13.12 Important Compounds and Applications Peridi- or tetrachalcogen-bridged polyacenes are mainly targeted for the purpose of preparing electrically conducting materials. The lipoic analog, 1,2-diselenolane-3-pentanoic acid 186, protects human low density lipoprotein against oxidative modification mediated by copper ions . Moreover, this compound has been investigated for its ability to inhibit the activity of the mammalian pyruvate dehydrogenase complex (PDC) .

The cyclic seleninate ester 105 exhibited remarkable glutathione peroxidase-like catalytic activity in a model system where tert-butyl hydroperoxide was reduced with benzyl thiol to afford dibenzyl disulfide and tert-butyl alcohol . The selenenate 14 exhibited excellent glutathione peroxidase-like catalytic activity . Compounds 15 and 16 were also investigated . Both the seleninate ester and the spirocyclic compound were found to be more efficient catalysts than epselen. For other studies on Se–O and Te–O heterocycles, see . Palladium pincer complex 115-catalyzed selenylation of propargyl, allyl, benzyl, and benzoyl halides could be achieved under mild reaction conditions employing trimethylstannylphenylselenide 116 as selenylating agent .


4.13.13 Further Developments Synthesis, structure, and chemical transformations of 1,2-ditellurolane have been reported . Generation of 1,2-diselenolane has been reported .

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Biographical Sketch

Mogens Brøndsted Nielsen was born in 1972 in Gren˚a, Denmark. He received his Ph.D. degree in 1999 from the University of Southern Denmark in Odense under the supervision of Professor Jan Becher. During his Ph.D. studies, he spent one year in the group of Professor J. Fraser Stoddart at the University of California in Los Angeles (UCLA). After postdoctoral work with Professor François Diederich at ETH in Zu¨rich from 2000 to 2002, he returned to the University of Southern Denmark as assistant professor. In 2004, he moved to a position as associate professor at the University of Copenhagen. His research topics cover heterocyclic chemistry (mainly tetrathiafulvalene), acetylenic scaffolding, conjugated biochromophores, as well as macrocyclic and supramolecular chemistry – targeting new redox-active molecules, photoswitches, and devices for molecular electronics. He has been awarded the 2004 Knud Lind Larsen prize for his contributions to synthetic and supramolecular chemistry.

1117

4.14 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium M. B. Nielsen University of Copenhagen, Copenhagen, Denmark ª 2008 Elsevier Ltd. All rights reserved. 4.14.1

Introduction

1120

4.14.2

Theoretical Methods

1120

4.14.3


1121

4.14.3.1

X-Ray Diffraction

1121

4.14.3.2

Mass Spectrometry

1124

4.14.3.3

Ultraviolet–Visible Spectroscopy

1124

4.14.3.3.1

4.14.4 4.14.4.1 4.14.5

Nuclear magnetic resonance spectroscopy


1125

1126

Electrochemistry and Conductivity

1126


1129

4.14.5.1

Thermal Rearrangement

1130

4.14.5.2

Photochemical Reactions

1130

4.14.5.3


1130

4.14.5.4

Nucleophilic or Electrophilic Attack at Carbon

1131

4.14.5.4.1 4.14.5.4.2 4.14.5.4.3

4.14.5.5

Transchalcogenation of heteroatom at carbon-2 Coupling reactions at carbon-2 Other substitution and addition reactions at carbon-2

Nucleophilic Attack at Hydrogen (Deprotonation)

1131 1131 1133

1133

4.14.6


1134

4.14.7


1137

4.14.7.1 4.14.7.2

Reactions of Substituents Attached to Carbon-2

1137

Reactions of Substituents Attached to Ring Carbon-4 and Carbon-5

1141

4.14.8


4.14.9


1143 1143

4.14.9.1

One-Component Syntheses

1143

4.14.9.2


1144

4.14.9.3


1146

4.14.9.4

Multicomponent Syntheses

1147

4.14.10


1149

4.14.11


1150

4.14.12


1150

4.14.13


1151

References

1151

1119

1120 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium

4.14.1 Introduction The various types of parent five-membered monocyclic rings containing two nonadjacent heteroatoms and at least one selenium or tellurium atom are shown in Figure 1. 1,3-Selenazoles are covered in Chapter 4.08 and hence are not included, except for a few examples, in the current chapter.

Figure 1

The construction of conducting salts of tetrachalcogenafulvalenes is an ongoing area and many new modifications of the donors have been made since CHEC-II(1996). A whole issue of Chemical Reviews was dedicated to molecular conductors, and the following articles from this issue deal to a large or small extent with the synthesis and conducting properties of selenium- or tellurium-containing fulvalenes (and other heterocycles): . Moreover, the synthesis, reactions, and selected physicochemical properties of 1,3- and 1,2-tetrachalcogenafulvalenes has been reviewed . The synthesis and characterization of donor–acceptor chromophores for materials applications has also attracted strong interest during the decade 1996–2006.

4.14.2 Theoretical Methods The structures of compounds 1 and 2 as well as their radical cations were geometry-optimized at the PM3 level. The spin density distribution in the radical cations was shown to be delocalized over the entire molecules. For 2?þ this result is in agreement with ESR measurements, while in contrast, electron spin resonance (ESR) measurements showed the spin population to be higher on the sulfur atoms in 1?þ.

Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium

The highest occupied molecular orbital (HOMO) energy of the cis- and trans-isomers of dibenzodioxadiselenafulvalene 3 were calculated at the B3LYP/6-311þG(2d,p) level .

4.14.3 Experimental Structural Methods 4.14.3.1 X-Ray Diffraction The X-ray crystal structure of the salt 4?I was reported . The CTS bond length is 1.668(14) A˚ and hence slightly longer than a normal CTS bond.

The X-ray crystal structure of the nitroso compound 5 was reported . Short intramolecular ˚ respectively, were observed. Se???O–N and Se???OHC distances of 2.513(8) and 2.733(8) A,

The crystal structure of 6 contains two crystallographically independent molecules (A and B) . The tetraselenafulvalene skeleton adopts a boat conformation in both molecules, and the folding angles are 20.4 and 20.6 for molecule A and 14.1 and 21.9 for molecule B. The packing motif is controlled by Se???Se and strong I???Se interactions. The structure of compound 7 was also reported . Short intermolecular contacts exist between the iodine and nitrogen atoms, while a similar shortening of the intermolecular distance was not observed between the chlorine and nitrogen atoms.

X-Ray crystal structures of (8)2?FeCl4 and (8)2?GaCl4 salts were reported . The structures of the neutral compounds 9 and 10, as well as the salts of 9 and 11 with AsF6 were reported . The crystalline form of 9 contains two independent molecules, of which one is almost planar, while the other has a bent shape. Compound 10 adopts a bent shape. Crystal structures of salts 12?I3 and 12?GaCl4 have also been reported .

1121


X-Ray crystal structures of the metallocene diselenolate chelates 13–15 were reported .

X-Ray crystal structure of cis-3 and trans-3 revealed almost planar skeletons for both compounds . Compounds 16 and 17 were also subjected to X-ray crystallographic analysis Both molecules possess a crystallographic inversion center and adopt small chair-like distortions, the dithiole/diselenole rings folding by 7.8 (16) and 7.0 (17) along the S(Se)???S(Se) vectors. Molecules in the crystals are arranged in planar layers with interplanar separations of ca. 3.68 (16) and 3.64 A˚ (17).

The crystal structure of the complex between triselenatellurafulvalene 18 and tetracyanoquinodimethane (TCNQ) was reported . The crystal structure is dominated by homogeneous stacks of segregated donors and acceptors. Moreover, the complex between compound 19 and TCNQ was investigated . Donor columns with short Se–Se, Te–Te, and Se–Te contacts as well as acceptor columns were observed. However, the relative position of the donor and acceptor columns is entirely different from that of 18?TCNQ. Along the a-axis direction, each donor or acceptor is related to the lateral ones by a translational operation, resulting in belt-like arrays of donor and acceptor molecules. Between the donor neighbors, there are two side-by-side Se–Te ˚ and between the adjacent donor and acceptor, a short Te–N contact (3.04 A) ˚ was observed. A similar contacts (4.11 A), packing mode has been observed for the complex between tetratellurafulvalene 20 and TCNQ, where side-by-side Te–Te interactions between the donor columns play an essential role in suppressing the metal-to-insulator transition .


X-Ray crystallographic analysis shows that compound 21 has a slightly bent structure and forms a face-to-face dimer with a center of symmetry arranged orthogonally to the neighbouring dimers . The structure of the salt (21)2?AuI2 was also reported . The donor here is completely planar and uniformly stacked along the a-axis. The structures of 22 and 23 were also reported . The central C6Se8 moiety of 23 is essentially planar, and the alkyl substituents stand perpendicular to this plane.

According to X-ray crystallographic analysis, the central anthracene-9,10-diylidene ring of 24 adopts a boat conformation . The bending is larger than in the related sulfur analog, which is explained by the increased steric repulsion between the larger selenium atoms and the hydrogen atoms at positions C-1 and C-8 of the anthracene. The structure of 2-phenylimino-1,3-diselenole 25 was reported . The compound crystallizes in the form of two independent molecules. The heteroring of each molecule adopts a strongly flattened envelope. The phenyl ring plane is turned relative to the heteroring plane by 67 and 50 , respectively, in the two molecules.

The structure of the 4-alkylidene-1,3-oxaselenolane 26 was reported as well as that of the oxaselenolane 5-fluorocytosine nucleoside analog 27 .

X-Ray crystal structure analyses of the complexes 28 and 29 were reported.

As 1,3-selenazoles are outside the scope of this chapter, it is only mentioned that X-ray crystallographic analyses of compounds 30–36 have been performed .

1123


4.14.3.2 Mass Spectrometry Mass spectra have been used extensively for structure elucidations and for characterization of many of the compounds dealt with in this chapter. Mass spectrometry data that have not been systematically discussed are not dealt with here. The mass spectra of 2-phenylimino-1,3-diselenole 25, 4-methyl-2-phenylimino-1,3-diselenole 37, and 2-phenylimino-1,3-thiaselenole 38 are characterized by abundant molecular ion peaks . Scheme 1 shows the fragmentation pathways of the molecular ion derived from 25. The intensities of the fragment ion peaks suggest that two pathways of fragmentation are most probable: loss of PhNC or PhNCSe. The contribution of the third pathway (loss of C2H2) is insignificant and not observed at all for compound 37. The presence of two different heteroatoms in the five-membered ring of 38 gives rise to two fragmentation pathways involving expulsion of either PhNCSe or PhNCS from the molecular ion.

Scheme 1

4.14.3.3 Ultraviolet–Visible Spectroscopy In this section, only papers dealing with a more systematic discussion of UV–Vis spectra are mentioned. The three dendralenes 1, 2, and 39 show their longest-wavelength absorption maxima at max 407, 404, and 409 nm, respectively, in dichloromethane .


The location of a low-energy intramolecular charge transfer absorption for the donor–p-acceptor molecules 24 and 40–44 is collected in Table 1 . The lowest energy absorptions are observed with compound 24 and 44, for which the anthracene unit achieves aromaticity when charge transfer occurs.

Table 1 Longest-wavelength electronic absorption maxima in CH2Cl2 Compound

24

40a

40b

41a

41b

42

43

44

max(nm)

556

338

356

437

482

427

458

552

4.14.3.3.1

Nuclear magnetic resonance spectroscopy

Nuclear magnetic resonance (NMR) spectra have been used extensively for structure elucidations and for characterization of many of the compounds dealt with in this chapter. In this section, only papers dealing with a more systematic discussion of NMR spectra are mentioned. Complexes of 2-methyl(phenyl)benzo-1,3-tellurazoles 45 and 2-methyl(phenyl)benzo-1,3-selenazoles 46 (Scheme 2) with tungsten pentacarbonyl and boron trifluoride were studied by heteronuclear NMR spectroscopy (1H, 13C, 77Se, and 125 Te) . The NMR spectra of 45 (R ¼ Ph) and its complex with W(CO)5 in which the coordination occurs via the Te atom (49; R ¼ Ph: 28) showed that complex formation results in an upfield shift of the 125Te signal: Te ¼ 842.4 ppm in free ligand, Te ¼ 654.9 ppm in the complex. In contrast, in the spectrum of the complex of 2phenylbenzo-1,3-tellurazole with BF3, N is complexed as shown in 47 and the 125Te signal is shifted downfield, Te ¼ 914.2 ppm. Thus, the direction of the 125Te shift can be used for estimating the coordination mode. The 77Se NMR spectrum of 2-methylbenzo-1,3-selenazole and W(CO)5 showed the presence of two signals at Se ¼ 646.34 and 677.13 pm, which were assigned to the free ligand and the N-coordinated complex, respectively. A downfield shift of the

1125

1126 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium 77

Se signal in the NMR spectrum of 2-methylbenzo-1,3-selenazole complex with BF3 relative to the free ligand also suggested N-coordination of BF3. Comparable coordination was also suggested for R ¼ Ph.

Scheme 2

The coupling constant between the two adjacent protons in N-cyanoimine derivative 42 was determined to be 4 Hz, which indicates an s-cis conformation . Such a conformation is presumably favored owing to a close N???Se interaction.

4.14.4 Thermodynamic Aspects 4.14.4.1 Electrochemistry and Conductivity The electrochemistry of Se-containing dendralenes 1, 2, and 39 is collected in Table 2 . Table 2 Oxidation potentials of [3]dendralenes in CH2Cl2; potentials vs. SCE Compound

E1(V)

E2(V)

E3(V)

1 2 39

0.308 0.551 0.43

0.523 0.780

1.175 1.646

The electrochemistry of Te-containing dendralenes 50–52 is collected in Table 3 . The first oxidation for 51 occurs at a lower potential than for the corresponding diselenole analog 2.


Table 3 Cyclic voltammetry data in CH2Cl2; potentials vs. SCE Compd.

Pa1 (V )

Pa2 (V )

Pa3 (V )

Pc4 (V )

Pc5 (V )

Pc6 (V )

Pc7 (V )

50 51 52

0.228 0.464 0.287

0.409 0.633 0.483

1.104 1.53 1.112

1.733a 1.199 1.309a

0.856 0.495 1.757a

0.094 0.314 1.729

0.165

a

Anodic peaks Pa4 and Pa5.

The redox properties of the vinylogous systems 16 and 17 were studied by cyclic voltammetry . They both display two reversible, one-electron oxidations; thus, 16 is oxidized at 0.36 and 0.50 V vs. Ag/AgCl in acetonitrile, while 17 is oxidized at 0.29 and 0.44 V vs. Ag/AgCl. The redox properties of the selenium derivatives 9–12 and 53–56 were investigated in comparison to the parent sulfur compound 2,5-bis[4,5-bis(methylthio)-1,3-dithiol-2-ylidene]-1,3,4,6-tetrathiapentalene 57 (Table 4) . Charge-transfer salts were also investigated . The 12?I3 salt was found to be an insulator. The 12?GaCl4 salt showed a conductivity of 280 S cm1 at room temperature and exhibited metallic conduction down to about 60 K. The conductivity is 6 S cm1 for 9?(AsF6)0.32 and 11 S cm1 for 11?(AsF6)0.35 .

Table 4 Redox potentials vs. Ag/AgCl in benzonitrile Compound

E11=2 (V )

E21=2 (V )

E31=2 (V )

E4ox (V )

9 10 11 12 53 54 55 56 57

0.45 0.46 0.48 0.40 0.46 0.45 0.53 0.42 0.48

0.69 0.70 0.73 0.63 0.68 0.69 0.74 0.65 0.67

0.91 0.92 0.95 0.86 0.93 0.93 0.93 0.90 0.89

1.12a 1.16a 1.17a

a

1.21a 1.14a 1.16a 1.18a 1.01a

Irreversible.

The electrochemistry of several halogenated tetraselenafulvalenes has been studied (including 6 and 58–60) . For example, compound 6 is oxidized at 0.29 and 0.52 V vs. Fcþ/Fc in benzonitrile . The brominated compounds 58 and 59 are oxidized at 0.73, 0.96 V and 0.73, 0.99 V vs. Ag/AgCl in benzonitrile, respectively . In comparison, the parent tetraselenafulvalene 61 is oxidized at significantly lower potentials, namely 0.48 and 0.80 V vs. Ag/AgCl in benzonitrile. Thus, owing to the electron-withdrawing nature of halogen substituents, the donor properties are decreased upon

1127

1128 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium halogenation. Electrocrystallization of compounds 58 and 59 gave radical cation salts 58?PF6 and (59)2?ClO4 with room-temperature conductivities of 0.16 and 400 S cm1, respectively .

The electrical conductivity of the (8)2GaCl4 salt was determined to be 12 S cm1 at room temperature . It showed a current-induced metallic state. The redox properties of donor–p-acceptor molecules 24 and 40–44 are collected in Table 5 . The compounds display a reversible one-electron oxidation wave, which corresponds to the formation of the radical cation of the 1,3-diselenole donor moiety, and an irreversible one-electron reduction wave forming the radical anion located on the dicyanomethylene or N-cyanoimine group. The derivatives 24 and 44 are both easier to oxidize and reduce than the other compounds, which is explained by the gain of aromaticity of the spacer unit. The second one-electron reduction of these compounds is ascribed to reduction of the anthracene unit. Table 5 Cyclic voltammetry data in dry MeCN; potentials vs. Ag/AgCl Compound

24

40a

40b

41a

41b

42

43

44

E1,ox1=2(mV) Ered (mV)

þ966 920, 1300

þ2180 1240

þ1790 1690

þ1580 1050

þ1110 1070

þ1690 1140

þ1595 1180

þ920 1010, 1520

Cyclic voltammetry of 21 showed two reversible redox waves at 0.52 and 0.75 V vs. Ag/AgCl in benzonitrile . The salt (21)2?AuI2 exhibited a very high conductivity of 2000 S cm1 at room temperature . The extended compounds 62 and 63 showed four pairs of single-electron redox waves; the first three redox processes are reversible, while the last is irreversible . The first oxidation potential of 62 is more positive by 0.05 V than that of the all-sulfur analog, which indicates that the donor ability becomes weaker by exchange of sulfur atoms with selenium. This positive shift is almost the same as that experienced by 64 relative to its corresponding all-sulfur analog (þ0.06 V), which suggests that the positive charge in the radical cation of 62 lies mainly on the vinylogous diselenadithiafulvalene moiety. A 1:1 charge-transfer complex between 62 and TCNQ showed a conductivity of 20 S cm1 at room temperature. The conductivity of radical cation salts of 62 with various anions exhibited conductivities of 101–102 S cm1 at room temperature.

The cyclic voltammogram of compound 19 (cis/trans-isomeric mixture) showed two one-electron oxidation waves at þ0.43 and 0.73 V vs. Ag/AgCl . The dimethyl derivative 65 has slightly lower oxidation potentials at þ0.41 and þ0.71 V vs. Ag/AgCl. Compound 19 formed crystalline 1:1 charge-transfer complexes with TCNQ and TCNQF2 that exhibited high room-temperature conductivities of 1400 and 900 S cm1, respectively . Compound 65 also formed a conductive 1:1 complex with TCNQ exhibiting a conductivity of 37 S cm1. Variable temperature measurements on 19?TCNQ demonstrate that the conductivity steadily increases to 2.5 times this value as the temperature drops to 4 K, and there is no metal–insulator transition as seen for the tetratellurafulvalene complex with TCNQ. Thus, the two tellurium atoms of 19 serve to enhance intermolecular interactions enough, not only to induce the high conduction of its charge-transfer complexes, but also to suppress the


Peierls transition . The triselenatellurafulvalene 18 was oxidized at 0.45 and 0.75 V vs. Ag/AgCl in benzonitrile and is accordingly a slightly better donor than tetraselenafulvalene 61 . It formed a charge-transfer complex with TCNQ showing a room temperature conductivity of 2000 S cm1, while that of the complex formed between 61 and TCNQ has a conductivity of 800 S cm1.

The 1:1 charge transfer complex between the tetratellurafulvalene 66 and the electron acceptor 11,11,12,12tetracyano-2,6-anthraquinodimethane 67 showed a conductivity of 11.5 S cm1 .

Cyclic voltammetry of dibenzodioxadiselenafulvalenes cis-3 and trans-3 revealed reversible first oxidations (halfwave potential of 0.17 V vs. Fc/Fcþ in acetonitrile) but irreversible second oxidations . Cyclic voltammetry of diselenadiazafulvalenes 68 and 69 revealed first and second oxidation potentials of 0.07 V, þ0.09 V and 0.18 V, þ0.36 V, respectively, versus saturated calomel electrode (SCE) in CH2Cl2 . The second oxidation is more difficult for 69, which can be explained by the presence of the bridge between the two heterocyclic rings which hinders conformational modification upon oxidation.

Comparison of the electrochemical behavior of the diselenadiazafulvalenes 70a,70b, and azino-diselenadiazafulvalene 71 shows that insertion of an azino spacer between the selenazole cores considerably decreases the electrondonating ability since Epa1 for 71 is 550 mV higher than for 70a and 70b .

4.14.5 Reactivity of Fully Conjugated Rings The reactivity of fully conjugated rings is briefly summarized in Figure 2. The following sections will clarify these reaction types.

1129


Figure 2 Summary of reactivity of fully conjugated rings.

4.14.5.1 Thermal Rearrangement Although benzoselenazoles are covered in Chapter 4.08, one example of thermal rearrangement is given here. Thus, 2-(methylthio)benzoselenazole 72 underwent thermal rearrangement to provide compound 73 in the presence of a catalytic amount of iodine (Equation 1) .

ð1Þ

4.14.5.2 Photochemical Reactions For long-chain derivatives of spirobenzoselenazopyran, such as 74, photochromic reactions (between 74 and 75) in monolayers on a water surface were investigated (Equation 2) .

ð2Þ

4.14.5.3 Electrophilic Attack at Nitrogen In CHEC-II(1996), protonation of the nitrogen of 1,3-benzotellurazole with hydrochloric acid was described as was alkylation with trifluoromethane sulfonate. 2-Methyl-5,6(15-crown-5)benzo-1,3-tellurazole 76 was methylated with methyl iodide to provide the salt 77?I (Equation 3) . Benzo-1,3-selenazoles were alkylated in a similar way . Methylation of 1,3-selenazoles using Meerwein’s reagent was also reported .

ð3Þ

Benzotelluroazoles 45 were exploited as ligands for soft and hard Lewis acids . Complexation at Te with the soft Lewis acid W(CO)5 was observed in the crystal structure of 28, whereas an equilibrium between N- and


Se-coordination existed in (CD3)2CO and C6D6 solutions according to Scheme 2. Reactions with BF3, SnCl4, and ZnCl2 gave complexes in which the coordination bonds are located at the hard nitrogen atom. Treatment of 2-methylbenzotelluroazole 45 (R ¼ Me) with triiron dodecacarbonyl gave instead both a direct coordination compound 29 and a cluster compound 78 as the result of a ring-opening reaction (Equation 4) .

ð4Þ

4.14.5.4 Nucleophilic or Electrophilic Attack at Carbon 4.14.5.4.1

Transchalcogenation of heteroatom at carbon-2

Transchalcogenation of the thione 79 to the ketone 80 was accomplished with mercury(II) acetate (Equation 5) .

ð5Þ

Transchalcogenation reactions of the thiones 81 and 82 with mercury(II) acetate gave the carbonyl compounds 83 and 84, respectively .

The hexafluorophosphate salt of 2-(1-piperidinium)-2[13C]-4,5-dimethyl-1,3-diselenole 85 was treated with H2Se to give the 13C-labeled 4,5-dimethyl-1,3-diselenole-2-selone 86 (Equation 6) . Similarly, N-methylN-phenyl-1,3-diselenole-2-iminium iodides and N-phenyl-1,3-diselenole-2-iminium perchlorates were converted into 1,3-diselenole-2-selones by the action of hydrogen selenide .

ð6Þ

4.14.5.4.2

Coupling reactions at carbon-2

Refluxing of the ketone 80 with triethyl phosphite in toluene gave the tetraselenafulvalene 87 without de-iodination (Equation 7) . In contrast, de-iodination occurred in similar coupling reactions of the dithiole analog . Coupling of 4,5-diodo-1,3-diselenole-2-selone gave 87 but in only 14% yield . It should be noted that C-2 of one heterocycle reacts as the electrophile, while C-2 of the other heterocycle (the ylide formed by attack of phosphite at the heteroatom at C-2) reacts as the nucleophile in these coupling reactions.

1131


ð7Þ

Phosphite-mediated synthesis is a frequently used method for obtaining tetrachalcogenafulvalenes as described already in CHEC-II(1996). During the past 10 years, many more compounds have been made by this method, such as 6, 7, 9–11, 19, 22, 23, 53–56, 58–60, 65, and 88–101 .

The diselenadiazafulvenes 68–70 were also obtained by phosphite-mediated coupling of corresponding 1,3selenazole-2-selone precursors . Treatment of the 1,3-diselenonium cations 102a,b?CF3SO3 with malononitrile, using pyridine as base, gave compounds 40a and 40b, which contain the dicyanomethylene acceptor group (Equation 8) . In the same report, the syntheses of 24, 43, 44, 103, and 104 are described .

ð8Þ


4.14.5.4.3

Other substitution and addition reactions at carbon-2

The cation salt 105?BF4 was treated with either triphenylphosphine or tributylphosphine to give the salts 106?BF4 and 107?BF4 (Equation 9) . The latter decomposed rapidly and could not be isolated but was employed immediately after preparation for further reactions.

ð9Þ

The triflate salt of 102a was reduced with sodium cyanoborohydride to give the dithiole 108 (Equation 10) .

ð10Þ

The phosphorus ylide 109 (Wittig reagent) was treated with a variety of aldehydes to provide a selection of 2-ylidene-1,3-diselones 110 along with a significant amount of the dihydro compound 111 (Equation 11) . Compound 103 was obtained in this manner from terephthaldehyde . MeO2C

Se PPh3

MeO2C

Se

109

R′CHO

MeO2C

Se

MeO2C

H +

0.5–2 h R′ = 2-F3CC6H4 R′ = 2-pyridyl R′ = 2,4-(O2N)2C6H3 R′ = C(O)Me R′ = CHO

MeO2C

Se

R′

MeO2C

Se H Se H

110

111

21–36%

16–42%

ð11Þ

4.14.5.5 Nucleophilic Attack at Hydrogen (Deprotonation) Iodinated 1,3-diselenole-2-thione 79 was prepared by slow addition of lithium diisopropylamide (LDA) to a mixture of 1,3-diselenole-2-thione 112 and perfluorobutyl iodide (PFBI) according to Equation (12) . The monoiodide is an alternative starting material for the iodination.

ð12Þ

Dilithiation of compound 112 with LDA at 78 C followed by treatment with 1,2-bis(selenocyanato)ethane provided compound 113 in 20% yield and the expected thione 81 but in only 3% yield . In order to avoid ring transformation, the reaction protocol was changed. Thus, first a rather dilute tetrahydrofuran solution of 112 and 1,2-bis(selenocyanato)ethane was prepared and then LDA was added at 78 C. This sequence gave 81 in 21% yield and recovered starting material in 43% yield. The methylenediseleno derivative 82 was prepared in a similar way in a yield of 34% . The cyclization could in this case be carried out at higher

1133

1134 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium concentration as intramolecular cyclization competes effectively with intermolecular polymerization when forming a five-membered ring. Other similar reactions were reported .

As described in CHEC-II(1996), 1,3-diselenole-2-selone-4,5-diselenolate can be prepared efficiently from the parent 1,3-diselenole-2-selone via lithiation and selenium insertion at C-4 and C-5 . Dilithiation of 114 followed by treatment with selenium gave 1,3-diselenole-2-selone-4,5-diselenolate, isolated as its zinc complex 115 after addition of tetrabutylammonium bromide and zinc chloride (Scheme 3) . i, LDA, THF –90 °C, 1 h

Se

–Se

Se Se

Se Se

114

ii, Se –90 °C –30 °C, 1.5 h –30 °C, 1 h

–Se

82%

Se

Se

Se

Se

Bu4NBr, ZnCl2/MeOH 1h

Se

Se

Se

Se

Se

Zn Se

Se

Bu4N

2

115 Scheme 3

The lithiation of tetraselenafulvalene 61 followed by reaction with electrophiles was also described in CHEC-II. Further reports have appeared since then. Thus, treatment with 2 equiv of LDA followed by reaction with methyl 3-thiocyanatopropionate gave selectively the product 22 (Equation 13) . Treating 61 with an excess of LDA and methyl 3-thiocyanatopropionate gave the protected tetrathiolate 116 .

ð13Þ

4.14.6 Reactivity of Nonconjugated Rings The dithiole 108 was treated with tetrafluoroboric acid followed by triphenylphosphine to give the phosphonium salt 117 (Scheme 4) . Treatment with triethylamine gave the phosphorus ylide 109 .


Scheme 4

The sulfonium salt 118?Cl was subjected to alkaline hydrolysis, which gave the eight-membered ring sulfoxide 119 (Equation 14) .

ð14Þ

The 1,3-benzodiselenole 120 was treated with LDA and subsequently alkylated with methyl iodide to afford compound 121 (Equation 15) .

ð15Þ

Alternatively, treating 1,3-benzodiselenole 120 with butyllithium followed by methanolysis gave the corresponding 2-alkylseleno-1-butylseleno benzenes . 1,3-Benzoditellurole 122 was metallated with lithium dicyclohexylamide at 80 C and the lithiated product 123 was then treated with methyl iodide to produce the methylated product 124 or with carbon dioxide to produce the carboxylic acid 125 (Scheme 5) .

Scheme 5

The lactone 126 was reduced with diisobutylaluminium hydride followed by in situ acetylation to give the acetylated oxaselenolane derivative 127 (Scheme 6) . This compound acted as a precursor for pyrimidine oxaselenolane nucleosides 128.

1135


Scheme 6

Compounds 129 and 130 were converted into diselenides 131 and 132, respectively, according to Equation (16) .

ð16Þ

When the mesylate 133 was treated with a large excess of sodium methoxide, thin-layer chromatography (TLC) indicated a gradual conversion of the initially formed epoxide 134. A Payne rearrangement with intermediates depicted in Scheme 7 is assumed and after acetylation of intermediate 135, the final product 136 was obtained .

Scheme 7

Ethylene triselenocarbonate 137 underwent a cycloaddition reaction with dimethyl acetylenedicarboxylate to give the 1,3-diselenole-2-selone 138 (Equation 17) .

ð17Þ


4.14.7 Reactivity of Substituents Attached to Ring Carbon Atoms 4.14.7.1 Reactions of Substituents Attached to Carbon-2 The triflate salt of compound 102a was prepared by treating the 1,3-diselenole-2-selone 138 with methyl triflate (Equation 18) . The cation 102b was prepared similarly .

ð18Þ

2-Phenylimino-1,3-diselenole 25 was methylated with methyl iodide to give the salt 139?I (Equation 19) . Compound 37 was N-methylated in a similar way. Protonation of the imine nitrogen was accomplished with perchloric acid .

ð19Þ

Vilsmeier–Haack diformylation of 2-methylene-1,3-diselenole 140 gave 2-diformylmethylene-1,3-diselenole 141 (Equation 20) that served as a precursor for the dendralene-type vinylogs of tetrathiafulvalene 1, 2, 39, 142, and 143 by condensation with suitable dithiolium phosphonium salts or phosphonates in the presence of base .

ð20Þ

A Wittig reaction between the aldehyde 144 and the phosphorus ylide obtained from 107 gave compound 16, that is, a vinylog of tetramethyltetraselenafulvalene (Equation 21) . A similar synthesis of the CO2Me-substituted analog was described in CHEC-II(1996); decarboxylation of this compound gave the parent ethylene-extended tetraselenafulvalene 64. Alternatively, treating aldehyde 144 with a dithiole reagent provided 16 .

ð21Þ

1137

1138 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium The aldehyde 144 and its CO2Me-substituted analog 145 were also employed for the synthesis of the donor– acceptor compounds 41a, 41b, and 42 (Scheme 8) . Thus, treating 144 and 145 with Lehnert’s reagent (titanium tetrachloride, malononitrile, and pyridine) in refluxing dichloromethane gave 41a and 41b. Almost quantitative conversion of 145 into the N-cyanoimine derivative 42 was accomplished using bis(trimethylsilyl)carbodiimide (BTC) and titanium tetrachloride in refluxing dichloromethane .

Scheme 8

Treatment of the phosphonate 146 with LDA in the presence of the aldehyde 145 gave compound 147 in 48% yield (Scheme 9) . Subjecting 147 to a phosphite-mediated coupling with the thione 148 gave compound 63 .

Scheme 9

Vilsmeier–Haack formylation of the unstable ditellurole 149 gave the dialdehyde 150 according to Equation (22) .

ð22Þ


The dialdehyde 150 was condensed with malononitrile to give the donor–acceptor compound 151 . Condensation with different phosphoranes and phosphonates gave the dendralene-type vinylogs of tetrathiafulvalene 50–52 and the donor–acceptor compound 152 .

Treating benzo-1,3-oxaselenole-2-selone 153 with triphenylphosphine gave a cis/trans-isomeric mixture of dibenzodioxadiselenafulvalene, that is, cis/trans-3 (Equation 23) .

ð23Þ

Phosphite-mediated coupling of carbonyl compounds 154 and 155 with the 1,3-dithiole-2-thione 156 gave compounds 157 and 158 (Equation 24) .

ð24Þ

The hemicyanine 159 was prepared from the salt 77?I according to Equation (25) . Moreover, the series of cyanine, merocyanine, and squarylium dyes 160–165 was prepared.

O

O

O

Te Me

O O

N+

O

Me

O

PhNHCH=Ph Ac2O, reflux

I–

CH CH

O O

O

Te CH

O O

O

N Ph

ð25Þ I–

159

S O

N+ Me

77

O

Ac

Te

N

CH S

N Me

160

O

CH2CO2H

O O

CH

O O

Me

Te

O

O

CH

N Me

161

Me O

1139


O

O O

O NH

Te CH CH

O O

N

O

O

Te

O

N+

CH

O

O NH

O

Me

O

Me

NMe2

CH n

I–

163a: n = 1 163b: n = 2

162 O–

O

O

Te

X

N+

O

O

N O

Me

O

R O–

O

Te

O

N+ Me

Te

O

N

O

O

CH

CH

O O

164a: X = S; R = Et 164b: X = Se; R = Me

CH

CH

O

O

O Me

O

165 1,3-Diselenole-2-ylidene derivatives 145, 166, and 167 served as precursors for nitroso compounds 5, 168, and 169 upon treatment with isoamyl nitrite according to Equation (26) .

ð26Þ

Benzoyl deprotection of the oxaselenolane nucleosides 128 was accomplished by either methylamine in methanol or by NaOMe, MeOH, and HS(CH2)OH under reflux . Deacetylation of the 1,6-episeleno sugar 129 was accomplished by sodium methoxide at 0 C to provide compound 170 (Equation 27) .

ð27Þ

The mesylate 133 was treated with sodium methoxide at 0 C to give the epoxide 171 (Equation 28; see also Scheme 7) . This epoxide was subjected to further reactions .

ð28Þ


4.14.7.2 Reactions of Substituents Attached to Ring Carbon-4 and Carbon-5 Equations (27) and (28) provide examples in this category. The zinc complex 115 was alkylated with methyl 3-bromopropionate to give compound 172 (Equation 29) . Se

Se

Se

Se

Se

Zn Se

Br(CH2)2CO2Me Se

Se

Se

Se

Bu4N

R

Se

R

Se

Se 2

MeCN, reflux, 1 h 82%

ð29Þ

172: R = CH2CH2CO2Me

115

Treating the protected tetrathiolate 116 with 2 equiv of cesium hydroxide followed by an excess of methyl iodide gave a cis/trans-mixture of 101 (Equation 30) .

ð30Þ

The cyanoethyl groups of compound 98 were removed with sodium methoxide, and the resulting dithiolate was subsequently converted into compound 173 according to Equation (31) .

ð31Þ

In a similar manner, compound 99 was treated with sodium methoxide base to give the dithiolate that was subsequently converted into compound 174 according to Equation (32) . This compound was subjected to phosphite-mediated coupling with 4,5-bis(methylthio)-1,3-dithiole-2-thione to provide the extended donor 12. Treating 100 with cesium hydroxide followed by chloroiodomethane gave compound 175. This compound was treated with sodium iodide to cause halogen exchange and spontaneous transalkylation to the product 21 via an intermediate sulfonium salt 176?I (Scheme 10) .

MeS

S

Se

SR

MeS

S

Se

SR

i, NaOMe, acetone, MeOH, 40 min ii, ZnCl2, Bu4NBr, MeOH

MeS

S

Se

S

MeS

S

Se

S

O

99: R = CH2CH2CO2Me

iii, triphosgene, –80 °C 47%

rt

ð32Þ

174

Scheme 10

Treating the monothiolate generated in situ from 100 (by treatment with base) with bromochloroalkanes gave the products 177–179 that underwent a ring-closing reaction to 180–182 promoted by sodium iodide (Equation 33) . The optimum solvent for obtaining 180 was 2-pentanone (reflux, 1.5 h), while DMF (90 C, 15 h)

1141

1142 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium was most effective for making 181. For the preparation of 182, the intermediate halogen exchanged product (i.e., the iodide) was isolated (solvent: 2-butanone, reflux, 20 h). Then this iodide was treated with sodium iodide in refluxing DMF for 1.5 h to finally provide 182. Starting from dichlorides 183–185, compounds 186–188 were similarly obtained . The compounds 186 and 187 were also obtained by treating the tetrathiolate generated from 116 with diiodomethane and 1,2-dibromoethane, respectively . Similarly compounds 180 and 181 were obtained from alkylation of the dithiolate generated from 22 .

ð33Þ

The [NBu4]2[W(C3Se5)3] salt (C3Se52 ¼ 1,3-diselenole-2-selone-4,5-diselenonate) was prepared by the reaction of Na2[C3Se5] with WCl6 in ethanol, followed by addition of tetrabutylammonium bromide . Decarboxylation of 4,5-dicarboxy-1,3-diselenole-2-thione 189 upon treatment with iodomethane in nitromethane gave the salt 190?I (Scheme 11) . Subsequent refluxing with pyridine in benzene gave 1,3diselenole-2-thione 112.

Scheme 11

Compound 63 was decarboxylated with an excess of lithium bromide in hexamethylphosphoramide (HMPA) according to Equation (34) .

ð34Þ

Treatment of the trimethylsilyl-substituted compounds 191a–c with Bu4NF in the presence of C2Cl6, C2F4Br2, or CF3(CF2)5I, respectively, gave the dihalogenated compounds 192a–c (Equation 35) .

ð35Þ


Desilylation of compound 96 was accomplished with potassium fluoride in water/tetrahydrofuran to afford the unsubstituted compound 18 in a yield of 86% . Metallocene diselenolate chelates 13–15 were prepared by treating 4,5-diselenolates with metallocenedichlorides . Hydrolysis of compound 193 gave the alcohol 194 (Equation 36), while hydrolysis of compound 195 gave the aldehyde 196 (Equation 37) .

ð36Þ

ð37Þ

4.14.8 Reactivity of Substituents Attached to Ring Heteroatoms There are no examples to report here.

4.14.9 Ring Syntheses from Acyclic Compounds Classified by Number of Ring Atoms Contributed by Each Component Ring syntheses from acyclic compounds can be classified into three groups according to the number of building blocks required in the reaction: (i)‘one-component synthesis’, in which the starting molecule is cyclized by joining two heteroatoms or by joining one heteroatom and one carbon atom; (ii) [1þ4] ‘two-component synthesis’, in which a one-atom unit is joined with a four-atom unit; (iii) [2þ3] ‘two-component synthesis’, in which a two-atom unit is joined with a three-atom unit.

4.14.9.1 One-Component Syntheses The hexafluorophosphate salt of 2-(1-piperidinium)-2[13C]-4,5-dimethyl-1,3-diselenole 85 was prepared by adding the 13C-labeled diselenocarbamate 197 to cold concentrated sulfuric acid, and after stirring for 1 h pouring the mixture onto crushed ice containing 60% aqueous HPF6 solution (Equation 38) .

ð38Þ

Compound 198 underwent cyclization to give 1,3-oxaselenolanes 199 within 5 min in the presence of a catalytic amount of trifluoroacetic acid (Equation 39) . Compound 200 was made in a similar way . The similar cyclization of the -hydroxyethyl vinyl selenide 201 had previously been reported to give the 1,3-oxaselenolane 202, but in only 2% yield (Equation 40)

ð39Þ

1143


ð40Þ

4.14.9.2 [1þ4] Two-Component Syntheses N-Lithioethynyl-2-lithiopyrrole, generated by dilithiation of N-ethynylpyrrole 203 with 2 equiv of butyllithium, was treated with either selenium or tellurium followed by addition of a mixture of t-butyl alcohol and hexamethylphosphoric triamide to give the bicyclic compounds 204 and 205 (Scheme 12) .

Scheme 12

Unsymmetrical dihydrotetrachalcogenafulvalenes were synthesized via Me3Al-promoted reactions of organotin compounds with esters . Thus, reaction between 206a–c and 207 gave compounds 208a–c (Equation 41). Compounds 209–214 were obtained in a similar manner. Transmetallation of compound 215 with 2 equiv of butyllithium followed by treatment with methyl dichloroacetate gave the ester 216 (Equation 42) that was employed for the synthesis of compound 210 .

ð41Þ


ð42Þ

The diselenol 217 reacted with aldehydes or ketones to give 1,3-benzodiselenoles 218 (Equation 43) .

ð43Þ

A cyclization reaction between the ditellurolate 219 and dichloromethylbenzene 220 gave 2-phenylbenzo-1,3ditellurole 221 according to Equation (44) .

ð44Þ

Refluxing a mixture of the telluride 222, acetic anhydride, and hypophosphorus acid in tetrahydrofuran gave 2,4,6trimethylbenzotellurazole 223 (Equation 45) .

ð45Þ

Treating the bromo tosylate 224 and bromo mesylate 225 with sodium hydrogen selenide gave the 1,6-episeleno sugars 129 and 133, respectively (Equation 46) .

ð46Þ

1145


4.14.9.3 [2þ3] Two-Component Syntheses Selenothioacetic acid S-butyl ester 226 was treated with epichlorohydrin 227 followed by tetrabutylammonium fluoride to give the product 199 (R1 ¼ H, R2 ¼ CH2Cl) (Equation 47) .

ð47Þ

Reaction of 1,3-benzodithiole-2-selone 228 with benzyne (obtained from 2-carboxybenzenediazonium chloride 229 as precursor) in refluxing 1,2-dichloroethane afforded the sulfonium salt 9aH-9-selena-10-thia-4b-thioniaindeno[1,2-a]indene chloride 118?Cl in 82% yield (Equation 48) .

ð48Þ

Treating the quinoline 230 with selenourea gave 1,3-thiaselenolo[5,4-c]quinoline 231 (Equation 49) . Similarly, 232 was converted into compound 233 (Equation 50) .

ð49Þ

ð50Þ

The acid 234 was condensed with 2-(benzoyloxy)acetaldehyde 235 to give the lactone 126 (Equation 51) .

ð51Þ

Synthesis of compound 82 by dilithiation of compound 112 followed by treatment with 1,2-bis(selenocyanato)methane is also an example of a [2þ3] two-component synthesis . Regarding synthesis of 1,3-selenazoles and derivatives hereof, one general method deserves mention here as it has provided a large selection of compounds, namely the reaction between an -halo-carbonyl compound of general structure 236 (in most cases, X ¼ Br) and selenoamides 237 (Equation 52) . The parent 1,3-selenoazole (R1 ¼ R2 ¼ R3 ¼ H) was obtained by


pyridine-mediated cyclization of selenoformamide with bromoacetaldehyde in a yield of 3% as a brownish, unstable oil . Employing selenourea (R3 ¼ NH2), 2-aminoselenazoles were obtained.

ð52Þ

4.14.9.4 Multicomponent Syntheses Efficient one-pot syntheses of 1,3-diselenole-2-selones were developed . Treating alkynes 239 with butyllithium followed by selenium and carbon diselenide gave, after quenching with water, compounds of general structure 240 (Equation 53). Treatment with MeSCN instead of water in the final step gave disubstituted products (Equation 54). Thus, 239 (R ¼ SMe) was converted into 4,5-bis(methylthio)-1,3-selenole-2-selone 241. Yet, trimethylsilylacetylene (239: R ¼ SiMe3) gave the expected product 242 in only 2% yield, while instead 241 was the major product, followed by compounds 243a and 243b. Macrocycles of general structure 244 were obtained according to Equation (55).

ð53Þ

ð54Þ

ð55Þ

1147

1148 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Selenium or Tellurium In a similar way, compound 245 was prepared .

Compound 246 was prepared in a yield of 83% by treating lithium trimethylsilylacetylide with tellurium and carbon diselenide followed by water in the final step .

Halogen-substituted 1,3-diselenole-2-selones 191a–c were prepared from trimethylsilylacetylene according to Equation (56) . (Z)-1-Bromopropene 247 served as precursor for the halogenated compounds 248a–c according to Equation (57) .

ð56Þ

ð57Þ

Alk-2-yn-1-ols 249 served as precursors for 4-alkylidene-1,3-oxaselenolanes 250 by treatment with selenium and isocyanides (Equation 58) .

ð58Þ

Reaction of 3-aminoalkynes 251 with carbon monoxide and selenium yielded 5-alkylideneselenazolin-2-ones 252 stereoselectively via cycloaddition of in situ-generated carbamoselenoates to the carbon–carbon triple bond (Equation 59) .

ð59Þ


The 1,3-ditellurole derivative 149 was prepared from trimethylsilylacetylene according to Equation (60) . Thus, lithium trimethylsilylacetylide was reacted with tellurium, whereupon the resulting tellurolate was protonated to give 149. This compound suffered extensive decomposition during purification and could not be desilylated. Instead, it was subjected to Vilsmeier–Haack formylation giving a stable dialdehyde 150 (Equation 22).

ð60Þ

Treating the dilithium salt of o-hydroxybenzeneselenol, generated in situ from 2-bromophenol 253, with (dichloromethylene)dimethylimmonium chloride (Viehe’s salt), followed by sodium hydrogenselenide gave benzo-1,3-oxaselenole-2-selone 153 (Scheme 13) .

Scheme 13

4.14.10 Ring Syntheses by Transformations of Another Ring The conversions along the sequence 137–138–102a–108–117–109–110/111 (Equations (10), (11), (17), and (18); Scheme 4) are all ring syntheses by transformation of another ring . Another example is the preparation of the cation 102b by treating the 1,3-diselenole-2-selone derivative with methyl triflate . The 1,2,3-selenadiazole route to 1,3-diselenole-2-chalcogenones (i.e., 1,3-thiaselenole-2-thione ) was described in detail in CHEC-II(1996). Here one more recent example is shown. 1,2,3-Selenadiazole 254 was treated with isoselenocyanatobenzene and potassium tert-butoxide in N,N-dimethylformamide and tert-butanol to provide 2-phenylimino-1,3-diselenole 25 in 50% yield (Equation 61) . Compounds 37, 38, and 255 were made in a similar way by cycloaddition reactions .

ð61Þ

1149


4.14.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available The synthesis of the zinc complex 115 according to Scheme 3 presents an efficient alternative to the previous method based on reduction of carbon diselenide by sodium metal . Compounds 22, 98–101, and 116 containing either (2-methoxycarbonyl)ethyl or 2-cyanoethyl as thiolate protecting groups are versatile compounds for the synthesis of a large selection of functionalized tetraselenafulvalenes via the (1) base-promoted deprotection and (2) thiolate alkylation protocol. The efficient one-pot syntheses of 1,3-diselenole-2-selones described in Equations (53)–(57) also deserve special attention. Overall, the chemistry of fulvenes and fulvalenes evidently dominate this chapter. Most of the parent, unsubstituted Se/Te-containing five-membered heterocycles with a nonadjacent heteroatom are still unknown. Figure 3 shows those heterocycles that are known today; the references to their synthesis are: 256 , 257 , 258 , 259 , 260 , 261 , and 262 . It transpires that only one new parent compound has been made during the decade under review, namely 1,3-selenazole. It was prepared according to Equation (52).

Figure 3

4.14.12 Important Compounds and Applications The conducting properties of tetrachalcogenafulvalenes have already been treated in Section 4.14.4.1 as well as in CHEC(1984) and CHEC-II(1996). Moreover, the review articles cited in Section 4.14.1 provide an overview of this application. Oxaselenolane nucleosides exhibited potent anti-HIV and anti-HBV activities . The activities of compounds 27 and 263–265 are collected in Table 6.

Table 6 Anti-HIV and anti-HBV activities of racemic oxaselenolane nucleosides in vitro Toxicity, IC50 (M) Compound

Anti-HIV activity in PBM cells, EC50 (M)

27 () 263 () 264 () 265 ()

0.51 0.88 2.4 >10

a

PBM, peripheral blood mononuclear. ND, not determined.

b

a

Anti-HBV activity in 2.2.15 cells, EC50 (M)

PBM

CEM

Vero

1.2 1.2 NDb ND

>100 >100 >100 >100

>100 >100 >100 >100

>100 >100 >100 >100


4.14.13 Further Developments Syntheses of benzo-1,3(2H)-thiaselenole and 1,3(2H)-diselenole have been reported . Moreover, several reports (mostly dealing with conductivity measurements) on tetraselenafulvalenes have been reported .

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Biographical Sketch

Mogens Brøndsted Nielsen was born in 1972 in Gren˚a, Denmark. He received his Ph.D. degree in 1999 from the University of Southern Denmark in Odense under the supervision of Professor Jan Becher. During his Ph.D. studies, he spent one year in the group of Professor J. Fraser Stoddart at the University of California in Los Angeles (UCLA). After postdoctoral work with Professor François Diederich at ETH in Zu¨rich from 2000 to 2002, he returned to the University of Southern Denmark as assistant professor. In 2004, he moved to a position as associate professor at the University of Copenhagen. His research topics cover heterocyclic chemistry (mainly tetrathiafulvalene), acetylenic scaffolding, conjugated biochromophores, as well as macrocyclic and supramolecular chemistry – targeting new redox-active molecules, photoswitches, and devices for molecular electronics. He has been awarded the 2004 Knud Lind Larsen prize for his contributions to synthetic and supramolecular chemistry.

1153

4.15 Five-membered Rings with Two Adjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony K. Karaghiosoff Ludwig-Maximilians Universita¨t, Munich, Germany ª 2008 Elsevier Ltd. All rights reserved. 4.15.1

Introduction

1155

4.15.2

Spectra, Structure, and Bonding

1156

4.15.2.1

Theoretical Methods

1156

4.15.2.2

X-Ray Diffraction

1157

4.15.2.3

NMR Spectra

1158

4.15.3 4.15.3.1 4.15.3.2

1H-1,2-Azaphospholes

1158

Synthesis

1158

4.15.4

1,2-Oxaphospholes

4.15.5

1,2-Thiaphospholes

4.15.5.1 4.15.5.2

1158

Properties and Reactivity

1160 1161

Properties and Reactivity

1161

Synthesis

1163

4.15.6

1,2-Thiarsoles

1163

4.15.7

1H-1,2-Diphospholes

1163

4.15.8

1,2-Diphospholide Anions

1164

4.15.8.1

Reactivity

1164

4.15.8.2

Synthesis

1164

References

1165

4.15.1 Introduction This chapter deals with heterophospholes, phosphorus-containing five-membered heterocycles with six delocalized p-electrons . To allow full cyclic conjugation, the phosphorus ring member must be two coordinate. In general, compounds with three-coordinate and four-coordinate phosphorus ring members are therefore not included in this chapter. Two-coordinate phosphorus perfectly imitates a CH-ring member and likewise contributes one p-electron. The five-membered ring, if neutral, must in addition to the phosphorus atom contain one more heteromember such as NR, O, S, Se, or Te contributing two p-electrons. The same applies to heteroarsoles and heterostiboles. The two heteroatoms of the ring can be adjacent as in this chapter, or nonadjacent as in Chapter 4.16; the corresponding chapters of CHEC-II(1996) are 3.15 and 3.16 . Heterophospholes with more than two heteroatoms are dealt with in Chapter 6.13, heteroarsoles and heterostiboles with more than two heteroatoms in Chapter 6.14; the corresponding chapters of CHEC-II(1996) are 4.22 and 4.23 . Also included in this chapter and Chapter 4.16 are five-membered rings with two two-coordinate P-, As-, or Sb-atoms or with combinations thereof. In these cases, to complete the 6p-system, the ring must be negatively charged as in diphospholides. The situation is the same as in the case of phospholides, covered in Chapter 3.15, arsolides (Chapter 3.16), tri-, tetra-, and pentaphospholides (Chapter 6.13), or diphosphaarsolides and diphosphastibolides (Chapter 6.14).

1155

1156 Five-membered Rings with Two Adjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony As first examples of unsaturated five-membered ring systems with one additional heteroatom adjacent to phosphorus, 1,2-azaphospholes became known in 1986 . CHEC-II(1996) also mentioned 1,2-benzazaphospholes and 1,2-thiaphospholes as well as 1,2-diphospholides and 1,2-benzodiphospholides ; a review of 2001 in addition describes 1,2-oxaphospholes and 1,2-selenaphospholes. Thus phosphorus ring systems to be covered in this chapter are those shown in Figure 1. In 2000, 1,2-thiarsole was added as the first example of an arsole with one heteroatom adjacent to arsenic .

Figure 1

Several reviews have appeared in which 1,2-heterophospholes are mentioned. .

4.15.2 Spectra, Structure, and Bonding 4.15.2.1 Theoretical Methods The electronic structure and the aromaticity of 1,2-azaphosphole, 1,2-oxaphosphole, 1,2-thiaphosphole, and 1,2diphosphole have been theoretically investigated in terms of aromatic stabilization energies (ASEs), resonance energies (REs), magnetic susceptibility exaltations, and nucleus-independent chemical shift (NICS) indexes , as well as based on isodesmic reactions . The molecular geometry and the frontier orbital energies of 3,5-diphenyl-1,2-thiaphosphole were obtained from density functional theory (DFT) calculations at the B3LYP/6-311þG** level of theory . For 1,3dipolar cycloadditions with diazo compounds, the dominant frontier interaction was found to be between the highest occupied molecular orbital (HOMO) of the diazo compound and the lowest unoccupied molecular orbital (LUMO) of the 1,2-thiadiphosphole. Because of the high energy of the HOMO (thiaphosphole), its interaction with LUMO (diazo compound) was also shown to be important . The geometry and bonding situation of 1H-1,2-diphosphole have been theoretically investigated by several authors. The inversion barrier at the pyramidal three-coordinate phosphorus atom in 1H-1,2-diphosphole was estimated to about 8.2 kcal mol1 , suggesting that 1H-1,2-diphospholes are close to planarity. The ˚ respectively, with the formal P–C P–P, P–C, and PTC bond lengths were estimated to be 2.08, 1.72, and 1.75 A, single bond being shorter than a formal PTC bond . Calculations at the B3LYP/aug-cc-pVTZ level of theory for the three possible tautomers of 1,2-diphosphole showed that the 3H-tautomer is the most stable . The aromaticity and bonding situation of the 1,2-diphospholide anion have been the subject of theoretical investigations. The calculations suggest that the 1,2-diphospholide anion has 80% of the aromaticity of the

Five-membered Rings with Two Adjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony

cyclopentadienide anion . For a series of phosphaferrocenes CpFe(CH)5nPn (n ¼ 1–5), analysis of the electron localization function (ELF), calculated at the DFT/B3LYP level of theory, revealed the importance of the shape and the extension of the phosphorus lone pair, which influences the electron-withdrawing capability of the phosphole ring. Based on these data, a model for the electrophilic reactivity of these complexes was proposed .

4.15.2.2 X-Ray Diffraction The 1,2-heterophospholes, which have been structurally characterized in the period 1996–2006, together with selected structural parameters are listed in Table 1. All structures were determined by single crystal X-ray diffraction except that of the parent 1,2-thiarsole, which was determined by electron diffraction of the vapor at a nominal temperature of 24 C and which was further refined taking into account spectroscopic and quantum-chemical data. In all cases, a planar five-membered ring was found. The atom distances within the ring are in between those typical for single and double bonds. Both are consistent with the presence of a delocalized p-system. Table 1 Bond angle at phosphorus or arsenic ( ) and selected bond lengths (pm) in neutral and anionic 1,2-heterophospholes and in 1,2-thiarsole Angle

Bonds

Reference

91.5(2)

PN 172.8(4), PC 171.3(5)

2000S417

90.2(1)

PN 170.6(1), PC 171.2(1)

1998ICA(270)273

89.8(5) 89.5(4)

AsS 219.8(3), AsC 182.9(4) 219.3(1) 182.0(3)

2000JA7012 2004JTC778

87.7(2)

PP 207.4(3), PC 176.0(3)

1996CB1083

95.0(1) 94.9(1)

PP 207.7(1), PC 177.0(3)

1996CEJ221

94.9(2)

PP 211.1(3), PC 177.1(4)

2005OM2233

In 1,3-di(tert-butyl)-5-phenyl-1H-1,2-azaphosphole, the phenyl ring is oriented almost orthogonal to the azaphosphole ring, indicating no interaction between the p-systems of the two rings . The only structurally characterized 1H-1,2-diphosphole is the 1-methyl derivative. The diphosphole ring is essentially planar. The three-coordinate

1157

1158 Five-membered Rings with Two Adjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony phosphorus atom displays a pyramidal coordination (sum of angles 339 ). The endocyclic PC bond to the threecoordinate phosphorus atom is shorter than that to the dicoordinate phosphorus atom , in accord with quantum-chemical calculations on the parent 1H-1,2-diphosphole .

4.15.2.3 NMR Spectra 1,2-Heterophospholes have been extensively studied by multinuclear nuclear magnetic resonance (NMR) spectroscopy. The NMR signal of the dicoordinated phosphorus atom in 1,2-heterophospholes is generally found at low field . Characteristic 31P ranges are 168–193 for 1H-1,2-azaphospholes and 208–242 ppm for 1,2-thiaphospholes . For a 1,2-oxaphosphole, a 31P chemical shift of 303.1 ppm was reported . 31P of the 2-phosphorus atom in 1,2-diphospholides was found between 152 and 286 ppm . 1JPP in these anions is large with values between 436 and 466 Hz . In 1H-1,2-diphospholes, the two-coordinate (31P ¼ 267.3, 279.0) and the three-coordinate phosphorus atoms (31P ¼ 141.8, 147.2) can be clearly distinguished and show a large one-bond coupling constant (468.5, 483.7 Hz) . 5-Complexation of a 1,2-diphospholyl anion is accompanied by a strong shielding of the two phosphorus atoms and by a decrease of 1JPP (to 384 Hz) . In 1H-1,2-azaphospholes, the NMR signal of the proton at the 4-position appears at low field between 6.4 and 6.8 ppm; 3JPH ranges between 5 and 7 Hz. Characteristic for the carbon atom adjacent to the two-coordinate phosphorus atom is a large coupling constant; 1JPC: 39–45 Hz for 1H-1,2-azaphospholes and 55–60 Hz for 1,2-thiaphospholes . The P,C coupling constants to C-4 (5–7 Hz for 1H-1,2-azaphospholes and 7–12 Hz for 1,2-thiaphospholes ) are larger than to C-5 (0–4 Hz for 1H-1,2-azaphospholes and 3–9 Hz for 1,2-thiaphospholes ). The 1H and 13C NMR data of the parent 1,2-thiaphosphole have been reported .

4.15.3 1H-1,2-Azaphospholes 4.15.3.1 Properties and Reactivity The 1H-1,2-azaphospholes are colorless to yellow solids or oils and are stable at ambient temperature . Most of the reactions reported so far involve the dicoordinated phosphorus atom, which represents the reactive center of the molecule. 1,3-Di(tert-butyl)-5-phenyl-1H-1,2-diazaphosphole reacts under mild conditions with alkyl triflates CF3SO3R (R ¼ Me, Et) to afford the P-alkylated 1,2-azaphospholium compounds 1a and 1b in quantitative yields. With an equimolar amount of iron nonacarbonyl, the 1-complex 2 was selectively formed in 63% yield (Scheme 1) . 1,3-Di(tert-butyl)-5-phenyl-1H-1,2-diazaphosphole reacts with diethyl azodicarboxylate by a double [4þ1] cycloaddition reaction at the phosphorus atom yielding the zwitterionic adduct 3 with a hexacoordinate phosphorus . Toward electron-poor acetylenes, 1H-1,2-azaphospholes behave like dienes and azaphosphanorbornadienes 4 are obtained as the formal products of a [4þ2] cycloaddition reaction (Scheme 1) .

4.15.3.2 Synthesis When the 1:1 cycloadducts, generated in situ by addition of an equimolar amount of a phosphaalkyne R3CUP to an imidovanadium(V) complex RNTVCl3, are treated with an excess of an acetylene R4CUCR5, quantitative formation of the corresponding 1H-1,2-azaphospholes 5 is observed (Scheme 2). Compounds 5 are isolated pure in 31–71% yields and the reaction is regiospecific. A large number of 1H-1,2-azaphospholes have been prepared by this route. The formation of the 1,2-azaphospholes proceeds via an insertion of the acetylene into the P–C bond of the vanadium cyclobutene derivative, followed by a reductive elimination . The Schiff base 6, resulting from the condensation of ()-(R)-myrtenal with (þ)-(R)-phenylethylamine, reacts with MePBr2 in the presence of -picoline to give, after dehydrohalogenation of an intermediate McCormack product, the 1,2-azaphospholium bromide 7. Reduction of 7 with 2 equiv of sodium in tetrahydrofuran (THF) yields the chiral 1H1,2-azaphosphole 8 (Scheme 3). The reaction takes place at low temperatures (20 to 0 C) and can be accelerated by ultrasonic irradiation .


Scheme 1

Scheme 2

The P,P-bis-W(CO)5 complex 10 was obtained as a red crystalline solid by reaction of the phosphinidene complex 9 with benzonitrile at ambient temperature (Scheme 4) . A P-W(CO)5 complex of a 1-unsubstituted 1H-1,2-azaphosphole was assumed to be an intermediate in the [3þ2] cycloaddition of a nitrilium phosphane ylide P-W(CO)5 complex, with dimethyl acetylenedicarboxylate. It reacts further with another equivalent of dimethyl acetylenedicarboxylate to give a 7-aza-1-phosphanorbornadiene as the final product .

1159

1160 Five-membered Rings with Two Adjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony

Scheme 3

Scheme 4

Treatment of the 2H-1,2-azaphosphole P-W(CO)5 complex 11 with t-BuOK in THF at 0 C cleaves the exocyclic P–C bond to the substituent R and yields the 1,2-azaphospholide W(CO)5 complex 12. Methylation of 12 with MeI takes place at the ring nitrogen atom forming the 1H-1,2-azaphosphole W(CO)5 complex 13 (Scheme 5); however, both 12 and 13 were only characterized by 31P NMR spectroscopy .

Scheme 5

4.15.4 1,2-Oxaphospholes The 1,2-oxaphosphole 16 was formed quantitatively in the reaction of the oxadiphosphole 14 with dimethyl acetylenedicarboxylate (Scheme 6). It is highly sensitive and could not be isolated in a pure state by distillation or column chromatography .

Scheme 6


The reaction takes place even at 20 C and is assumed to proceed via the oxadiphosphanorbornadiene 15, which is formed by the [4þ2] cycloaddition of the acetylene to the oxadiphosphole 14 acting as the diene. Elimination of MesCP from the norbornadiene 15 yields the oxaphosphole 16 (Scheme 6) .

4.15.5 1,2-Thiaphospholes 4.15.5.1 Properties and Reactivity 1,2-Thiaphospholes are colorless or yellow crystalline solids or yellow oils and are stable at ambient temperature . Their reactivity toward diazo compounds, dienes, and acetylenes has been extensively investigated. The PTC bond in 3,5-diphenyl-1,2-thiaphosphole 17 is an excellent acceptor for the diazo dipole and cyclopropanation of this bond occurs easily. Reaction of 17 with diphenyldiazomethane furnishes the (1,2-thiaphospholo)phosphirane 18 in good yield (Scheme 7) .

Scheme 7

The reaction of 3,5-diphenyl-1,2-thiaphosphole with (1-diazo-2-oxoalkyl)silanes is complete within 15–28 h at 20 C and is accompanied by evolution of N2. In all cases, the tricyclic compounds 19 are isolated by column chromatography as the major product (36–83%). In the case of i-Pr3Si-substituted diazo derivatives, the bicyclic alkylidenephosphiranes 20 were also isolated in low yields (4–8%) (Scheme 8) .

Scheme 8

In contrast to the high dipolarophilic reactivity toward diazo compounds, the PTC bond of 1,2-thiaphospholes does not act as a dienophile toward cyclopentadiene. No reaction of 3,5-diphenyl-1,2-thiaphosphole with cyclopentadiene was observed at 20–80 C. However, heating this thiaphosphole with a large excess of cyclopentadiene at 120 C in a sealed tube produced a mixture of the polycycles 21 and 22, which represent the formal 4:1 and 3:1 cycloadducts with cyclopentadiene (Scheme 9) .

1161


Scheme 9

Acceptor-substituted 1,2-thiadiphospholes react with electron-rich alkynes. When a diethyl ether solution of the 1,2-thiaphospholes 23 was treated at 78 C with a 1.5–2-fold excess of an electron-rich acetylene, [2þ2] cycloaddition of the acetylene to the PTC bond occurred exclusively. The reaction proceeds with high chemo- and regioselectivity (Scheme 10). The [2þ2] cycloadducts 24 were isolated as pale yellow solids or pale yellow to red oils with yields of 55–92% .

Scheme 10

Acceptor substitution at the PTC bond appears to be essential, since 3,5-diphenyl-1,2-thiaphosphole does not react with bis(diethylamino)acetylene under analogous conditions . Heating a solution of the 1,2-thiaphospholes 25 with a twofold excess of cyclooctyne in toluene at 100 C results in the formation of the polycyclic compounds 26 and 27 as well as the phosphinine 28 (Scheme 11). Compounds 26 and 27 were isolated as pale yellow and colorless crystals, respectively .

Scheme 11


4.15.5.2 Synthesis A number of 1,2-thiaphospholes 23 were prepared by the reaction of 1,2,4-thiadiphospholes 29 with activated acetylenes. The reaction proceeds most probably via the intermediate formation of the heteronorbornanes 30, resulting from a [4þ2] cycloaddition of the acetylene to the thiadiphosphole (Scheme 12) .

Scheme 12

4.15.6 1,2-Thiarsoles The parent 1,2-thiarsole 32 was prepared according to the reaction sequence shown in Scheme 13. Commercially available allylmercaptan was first lithiated with BuLi/TMEDA and then reacted with dimethyltin dichloride to afford crystalline 2,3-dihydro-2,2-dimethyl-1,2-thiostannole 31 (TMEDA ¼ tetramethylethylenediamine). Heating 31 with AsBr3 in diglyme followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) yielded the 1,2-thiarsole 32, which was isolated by distillation in 56% yield .

Scheme 13

The thiarsole 32 is a pale yellow air-sensitive liquid, which on standing at ambient temperature for several days decomposes with the formation of a white solid .

4.15.7 1H-1,2-Diphospholes The only well-characterized 1H-1,2-diphosphole, 34, was prepared by methylation of the corresponding diphospholide ion in 33 with methyl triflate (Scheme 14). It was isolated in the form of yellow crystals .

Scheme 14

1163

1164 Five-membered Rings with Two Adjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony The corresponding 1-phenyl derivative 36 was obtained by chloride abstraction from the parent 2-chloro diphosphole 35 by aluminium chloride (Scheme 14); however, it was only characterized by 31P NMR spectroscopy.

4.15.8 1,2-Diphospholide Anions 4.15.8.1 Reactivity Reaction of the lithium diphospholide 37 with the cationic iron complex 38 resulted in the formation of the diphosphaferrocene 39 (Scheme 15) .

Scheme 15

The diphospholide anion 40 is readily halogenated by SO2Cl2, Br2, or I2, yielding the 1,2-dihalodiphosphole derivatives 41 (Scheme 15) .

4.15.8.2 Synthesis The phosphetenes 42 react with PCl3 at low temperatures to give the dihydro 1,2-diphospholes 43, resulting formally from the insertion of a chlorophosphinidene into a P–C bond of the four-membered ring. It is assumed that the reducing agent for this step is the starting phosphetene 42. Reduction of 43 with lithium metal in THF at ambient temperature cleaves both the P–Cl and the exocyclic P–C bonds, yielding the lithium diphospholides 37 (Scheme 16) .

Scheme 16

Reaction of 2-phenyl-1,3-bis(triphenylphosphonio)propenide bromide 44 with PCl3 and a base in the presence of Ph3P as a reducing agent results in the formation of the 1,2-dichloro diphosphole derivative 45. Reduction of 45 with Bu3P causes the cleavage of both P–Cl bonds and yields the corresponding bis(phosphonio) 1,2-diphospholide cation, which can be isolated as the chloride 46 or, on addition of NaBPh4, as a tetraphenylborate (Scheme 17) .


Scheme 17

The salts of the diphospholide form colorless crystals and are reported to be stable toward air and water . The sodium salt 48 of the 3,4,5-triphenyl-1,2-diphospholyl anion was isolated in 59% yield from the reaction of the triphenylcyclopropyl nickel complex 47 with sodium pentaphospholide in THF/diglyme at ambient temperature (Scheme 18) . It was isolated as a light brown powder. Nickel(II) plays an important role in the formation of the diphospholide ring, as no reaction was observed between triphenylcyclopropenyl bromide and NaP5 in diglyme, even at 90 C .

Scheme 18

References K. Karaghiosoff, H. Klehr, and A. Schmidpeter, Chem. Ber., 1986, 119, 410. K. Karaghiosoff and A. Schmidpeter, Phosphorus Sulfur, Silicon Relat. Elem., 1988, 36, 217. N. Maigrot, N. Avarvari, C. Charrier, and F. Mathey, Angew. Chem., 1995, 107, 623. J. F. Nixon, Coord. Chem. Rev., 1995, 145, 201. G. Jochem, A. Schmidpeter, and H. No¨th, Chem. Eur. J., 1996, 2, 221. G. Jochem, H. No¨th, and A. Schmidpeter, Chem. Ber., 1996, 129, 1083. A. Schmidpeter; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 3, p. 709. 1996CHEC-II(3)715 A. Schmidpeter; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 3, p. 715. 1996CHEC-II(4)771 A. Schmidpeter; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 4, p. 771. 1996CHEC-II(4)819 A. Schmidpeter; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 4, p. 819. 1996JPC6194 L. Nyulaszi, J. Phys. Chem., 1996, 100, 6194. 1997CCR1 L. Weber, Coord. Chem. Rev., 1997, 158, 1. 1998IC4413 A. Dransfeld, L. Nyulaszi, and P. v. R. Schleyer, Inorg. Chem., 1998, 37, 4413. 1998ICA(270)273 K. Angermund, A. Eckerle, J. Monkiewicz, C. Kru¨ger, and G. Wilke, Inorg. Chim. Acta, 1998, 270, 273. 1999AGE215 U. Rohde, F. Ruthe, P. G. Jones, and R. Streubel, Angew. Chem., Int. Ed. Engl., 1999, 38, 215. 1999EJO587 A. Mack, U. Bergstra¨ßer, G. J. Reiß, and M. Regitz, Eur. J. Org. Chem., 1999, 587. 2000JA7012 A. J. Ashe, III, X. Fang, M. Schiesher, A. D. Richardson, and K. Hedberg, J. Am. Chem. Soc., 2000, 172, 7012. 2000S417 Ch. Peters, F. Tabellion, M. Schro¨der, U. Bergstra¨ßer, F. Preuss, and M. Regitz, Synthesis, 2000, 417. 2001AG3520 M. Schiffer and M. Scheer, Angew. Chem., 2001, 113, 3520. 2001CRV3549 R. K. Bansal and J. Heinicke, Chem. Rev., 2001, 101, 3549. B-2001MI1 K. B. Dillon, F. Mathey, and J. F. Nixon, ‘Phosphorus: The Carbon Copy’, Wiley, Chichester, 1998. 2002EJO1664 J. Dietz, Th. Schmidt, J. Renner, U. Bergstra¨ßer, F. Tabellion, F. Preuss, P. Binger, H. Heydt, and M. Regitz, Eur. J. Org. Chem., 2002, 1664. 2002HC568 G. Maas; in ‘The Chemistry of Heterocyclic Compounds’, A. Padwa and W. H. Pearson, Eds.; Wiley, Chichester, 2002, ch. 6, p. 568. 2002JOC1333 M. K. Cyranski, T. M. Krygowski, A. R. Katritzky, and P. v. R. Schleyer, J. Org. Chem., 2002, 67, 1333. 2002PCA5653 G. Frison, F. Mathey, and A. Sevin, J. Phys. Chem. A, 2002, 106, 5653. 1986CB410 1988PS217 1995AG623 1995CCR201 1996CEJ221 1996CB1083 1996CHEC-II(3)709

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2002SOS(11)493 2002SOS(12)679 2002SOS(12)705 2003CC2794 2003EJO512 2003EJO1894 2003JPO504 2003OM5427 2003T1657 2003ZNB44 2004HAC271 2004JTC778 2005CPH(313)123 2005OM2233 2005SOS(15)1097

D. Gudat; in ‘Science of Synthesis’, E. Schaumann, Ed.; Georg Thieme Verlag, Stuttgart, 2002, vol. 11, p. 493. A. Schmidpeter and K. Karaghiosoff; in ‘Science of Synthesis’, R. Neier, Ed.; Georg Thieme Verlag, Stuttgart, 2002, vol. 12, p. 679. F. Mathey; in ‘Science of Synthesis’, R. Neier, Ed.; Georg Thieme Verlag, Stuttgart, 2002, vol. 12, p. 705. T. Jikyo and G. Maas, Chem. Commun., 2003, 2794. J. Dietz, J. Renner, U. Bergstra¨ßer, P. Binger, and M. Regitz, Eur. J. Org. Chem., 2003, 512. J. Kerth, T. Jikyo, and G. Maas, Eur. J. Org. Chem., 2003, 1894. T. Jikyo, J. Schatz, and G. Maas, J. Phys. Org. Chem., 2003, 16, 504. R. Streubel, N. Hoffmann, G. von Frantzius, C. Wismach, P. G. Jones, H.-M. Schiebel, J. Gunenberg, H. Vong, P. Chaigne, C. Compain, N. H. T. Huy, and F. Mathey, Organometallics, 2003, 22, 5427. M. K. Cyranski, P. v. R. Schleyer, T. M. Krygowski, H. Jiao, and G. Hohlneicher, Tetrahedron, 2003, 59, 1657. Ch. Peters, U. Fischbeck, F. Tabellion, M. Regitz, and F. Preuss, Z. Naturforsch. B, 2003, 58, 44. R. K. Bansal, N. Gupta, and N. Gupta, Heteroatom Chem., 2004, 15, 271. Yu. I. Tarasov, I. V. Kochikov, D. M. Kovtun, N. Vogt, B. K. Novosadov, and A. S. Saakyan, J. Struct. Chem., 2004, 45, 778. W. P. Oziminski and J. Cz. Dobrowolski, Chem. Phys., 2005, 313, 123. V. Miluykov, A. Kataev, O. Sinyashin, P. Lo¨nnecke, and E. Hey-Hawkins, Organometallics, 2005, 24, 2233. F. Mathey and P. le Floch; in ‘Science of Synthesis’, D. Black, Ed.; Georg Thieme Verlag, Stuttgart, 2005, vol. 15, p. 1097.


Biographical Sketch

Konstantin Karaghiosoff received his Ph.D. in 1986 from Munich University under the supervision of Alfred Schmidpeter. In his thesis, he developed the synthesis of many new heterophospholes. Further interests of his include phosphorus selenide-derived anions and cations, as well as the analysis of NMR spectra of high order. He is Professor of Chemistry at the University of Munich.

1167

4.16 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony J. A. Joule The University of Manchester, Manchester, UK ª 2008 Elsevier Ltd. All rights reserved. 4.16.1

Introduction

1169

4.16.2

Theoretical Methods

1170

4.16.3


1171

4.16.3.1

X-Ray Diffraction

1171

4.16.3.2

Nuclear Magnetic Resonance Spectroscopy

1174

4.16.3.3

Mass Spectrometry

1175

4.16.4

Reactions of Fully Conjugated and Some Dihydro Derivatives

4.16.5

Ring Synthesis

1175 1179

4.16.5.1

From Nonheterocyclic Precursors

1179

4.16.5.2

Ring Synthesis from Another Heterocyclic Ring Compound

1181

4.16.5.3

Miscellaneous Methods of Ring Synthesis

1183

4.16.5.4

Applications

1186

References

1186

4.16.1 Introduction This chapter on the chemistry of heterocycles with ‘two nonadjacent heteroatoms with at least one phosphorus, arsenic, or antimony’, is an update to the earlier review in CHEC-II(1996) . It has been assembled by the Volume Editor at a late stage in the absence of a contribution from the originally commissioned author. As a consequence, there has been insufficient time for as thorough an assessment of the available literature, as would have been desirable. There has not been time to assemble detailed tables of data. Additionally, the subdivisions in this chapter do not follow completely the pattern in the rest of this volume, partly because of the short timescale and partly because this group of heterocycles does not lend itself fully to those subdivisions. However, it is the belief that all the most important information in the decade since 1995 has been summarized, and leading references to spectroscopic and X-ray data have been cited, but apologies are offered to any workers in this field whose contributions may not have been properly included or as fully described as they merit. The heterocycles that are discussed in this chapter are 1,3-heterophospholes (which include 1,3-diphospholes, by far the most studied) and 1,3-heteroarsoles, specifically 1,3-azaphospholes 1 and 5, 1,3-oxaphosphole 2, 1,3-thiaphosphole 3, 1,3-selenaphosphole 4, 1,3-diphosphole 6, the 1,3-diphospholyl anion 7, 1,3-azarsoles 8 and 12, 1,3thiarsole 9, 1,3-selenarsole 10, and 1,3-phospharsoles 11 and 13.

1169

1170 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony

Systems with a fused aromatic carbocyclic ring which have been studied, either theoretically or synthetically, in the period under review include 1H-1,3-benzazaphospholes 14 and 15, [1,3]azaphospholo[1,5-a]pyridine 16, [1,3]azaphospholo[1,5-a]isoquinoline 17, and [1,3]azaphospholo[1,5-a]quinoline 18.

Several of the systems reviewed in this chapter have been the subject of chapters in The Science of Synthesis series which deal in detail with the synthesis of those systems: 1,3-azaphospholes and 1,3-azaarsoles , 1,3-oxaphospholes and benzannulated analogues , 1,3-thiaphospholes , 1,3-diphospholes , and 1,3-selenaphospholes .

4.16.2 Theoretical Methods It was demonstrated earlier that 3H-1,3-azaphosphole and 3H-1,3-azarsole are not aromatic, indeed not planar (unlike the 1H-isomers), with the phosphorus or arsenic atom out of the plane. A study by ab initio methods using Hartree–Fock (HF) and MP2/6-311þþG(2d,p) levels of theory of lithium 1,3-azaphospholides (i.e., LiC3H3NP) showed that the most stable ‘molecule’ is an 5-Li-azaphosphole , though it is not clear how this relates, if at all, to the known and useful lithiation chemistry of 1,3-azaphospholes, by which chemically useful substitutions can be achieved .

Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony

The HeI photoelectron spectra of 2-t-butyl-5,6,7,8-tetrahydro-4H-cyclohepta[d]-1,3-thiaphosphole 19 and 2-tbutyl-4,5,6,7-tetrahydrocyclohexa[d]-1,3-selenaphosphole 20 were recorded and interpreted using Koopmans’ theorem. MP2/6-31G* optimized geometries of 1,3-thiaphosphole 3 and 1,3-selenaphosphole 4 themselves showed them to be planar, indicating that they are aromatic .

The aromaticity of five-membered heterocycles, including those considered in this chapter, has been the subject of several studies. In one study, statistical analyses of quantitative definitions of aromaticity were evaluated: it was concluded that the various manifestations of aromaticity are related and that ‘‘aromaticity can be regarded statistically as a one-dimensional phenomenon’’ . The use of isodesmic reactions produced aromatic ‘resonance energies’ which had flaws and did not take proper account of other contributions to the energy – hybridization, homoconjugation, etc. . The aromaticity of phospholes becomes larger as the number of dicoordinate atoms in the ring increases. The aromaticity of polyphosphaphospholes decreases with the pyramidality of the tricoordinate phosphorus . A comparison of phosphaferrocenes and azaferrocenes, including 1,3-diphospholide sandwiches, utilized the electron delocalization function at the DFT/B3LYP level of theory . The ‘shape’ of the heteroatom lone pair was found to be important. An examination of tautomerism in 1,3-diphospholes using DFT/B3PW91/aug-cc-pVTZ calculations provided convincing evidence that the 2H-tautomer, that is, 21, is always the most stable . In such tautomers, the ring is planar, as opposed to those with a P–H bond where the phosphorus is pyramidal and the ring not planar.

Density functional theory (DFT) calculations at the B3LYP/6-311þG** level were carried out on the 1,3dipolar cycloadditions of various heterophospholes, including 1,3-azaphosphole, with diazo compounds across the PTN bond . In most cases, the dominant frontier orbital interaction is between HOMO(diazo) with LUMO(heterophosphole); however, 1,3-azaphosphole has a HOMO of high energy and for it, HOMO(heterophosphole)–LUMO(diazo) is also important (HOMO ¼ highest occupied molecular orbital; LUMO ¼ lowest unoccupied molecular orbital). Gradient-corrected (BP86) density functional calculations have been carried out on various P-heterocyclic carbene metal complexes, including where the carbene was derived from a 1,3-azaphosphole and quantum-mechanical calculations at the DFT level were used to analyze metal-ligand interactions in mixed iron(II) metallocenes where, in one instance, one of the ligands was a 1,3-diphospholide anion . Correlated ab initio calculations showed that the 20 kcal mol1 inversion barrier about phosphorus in a phosphole is reduced by incorporating other phosphorus atoms (as in 1,3-diphosphole) into the ring .

4.16.3 Experimental Structural Methods 4.16.3.1 X-Ray Diffraction The disubstituted 1H-1,3-benzazaphosphole 22 was examined by X-ray crystallography. The molecule is planar; some key dimensions are shown in Figure 1 (distances in angstroms; angles in degrees) . The crystal structure of 2-tert-butyl-1H-1,3-benzazaphosphole was also reported later . X-Ray crystallographic examination of 23 displayed a completely planar (and therefore aromatic) molecular structure .

1171


Figure 1

X-Ray single crystal structure determinations have been described for the (1-2-phosphaindolizine) chromium complex 24 . The heterocyclic ring system is planar with a trigonal planar coordination at the phosphorus, and with the metal slightly out of the plane. The structure of the aerial oxidation product 25 was established by crystallography: the four-coordinate phosphorus signifies loss of aromaticity in the heterocyclic ring .

The 1-oxo-1H-diphospholes 26 and 27 were obtained from a diphosphacyclobutane-2,4-diyl and their structures established by crystallographic measurements .

The potassium and lithium salts of the 2,4,5-tri-t-butyl-1,3-diphosphacyclopentadienide anion (a 1,3-diphospholide anion) 28 were examined crystallographically . Short bond lengths in the ring were taken to indicate extensive electron delocalization. Crystallographic examination of the ketone 29 showed the planarity and intermediate bond lengths in the fivemembered heterocycle to be expected of an aromatic 1,3-oxaphosphole system .


The 3,4-dihydro-1,3,4-triphosphacyclopenta[a]indene 30 was shown by crystallographic determination to have an essentially planar tricyclic nucleus, with the 2,4,6-tri-t-butylphenyl (Mes* ) groups twisted out of that plane due to severe steric interactions .

The planarity of the 10p-electron system of the 2-phosphaindolizine 31 was revealed in a crystal structure determination .

The phosphorus ylide 32 with a P–H bond was shown by crystallography to have a planar five-membered ring with the substituent phosphorus atom also in that plane . The corresponding fulvene analogue 33, from which 32 was made, was also examined by crystallography .

The 1,3-diphosphole ring in the tin derivative 34 is essentially planar, but because the tin-bearing phosphorus is significantly pyramidal, the tin atom is 2.48 A˚ out of that plane .

The crystal structure of 2-lithiated 1-methyl-1,3-benzazaphosphole 35 showed it to have a dimeric structure with two THF molecules associated with each lithium. The two lithium atoms and the two C-2 atoms form a fourmembered ring . In contrast, the N-lithiated derivative of 2,5-dimethyl-1H-1,3-benzazaphosphole exists as a monomeric species 36 in the solid state . The carbene-type complex 37 derived from the lithiated species 35 on reaction with tungsten hexacarbonyl was also studied by X-ray crystallography.

1173

1174 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony A four-membered ring was also found in the complex 38 formed by the reaction of 2-tert-butyl-5-methyl-1H-1,3benzazaphosphole with nickelocine . The structure of the indium phospholyl [In(5-P2C3-t-Bu3)] 39 was studied by X-ray diffraction, photoelectron spectroscopy, and using DFT .

4.16.3.2 Nuclear Magnetic Resonance Spectroscopy The proton and 13C nuclear magnetic resonance (NMR) spectra of the parent 1,3-thiaphosphole 3 and 1,3-thiarsole 9 compounds themselves have been measured (Figure 2) – the proton signals are downfield of those of thiophene; especially low field are the signals of the protons on the carbons adjacent to the group 15 heteroatoms . These data, together with measurements of UV spectra (3: 215 (12 000), 249 (3000), and 274 nm (5000); 9: 225 (14 000), 267 (6200), and 290 nm (9800)) allow the conclusion that these two heterocycles are aromatic. The gas-phase bond lengths of 1,3-azarsole, measured by electron diffraction, are intermediate in values and thus are also consistent with aromaticity in this heterocycle .

Figure 2 Proton and 13C chemical shifts measured in CDCl3 in ppm.

Detailed 1H and 31P NMR data were assembled for the phosphaindolizines ([1,3]azaphospholo[1,5-a]pyridines) 40 and for a group of complexes 41 derived from this heterocyclic system . Full 1H, 13C, and 31P NMR data were given for the 1,3-azaphospholo[5,1-a]isoquinolines 42 .


The zwitterions and salts 43 and 44 were examined and detailed .

A full analysis of the .

31

P and

13

31

P,

77

Se,

13

C, and proton NMR data reported

C signals of the tricyclic systems in the Diels–Alder products 45 has been given

4.16.3.3 Mass Spectrometry The mass spectrometric fragmentation of 1,3-thiaphosphole and 1,3-thiarsole themselves has been analyzed – the major loss is of acetylene . A detailed analysis of the fragmentation pathways observed for the diester 46 was given .

4.16.4 Reactions of Fully Conjugated and Some Dihydro Derivatives Phosphaindolizines ([1,3]azaphospholo[1,5-a]pyridines) 40 reacted with hydrogen sulfide and elemental sulfur to produce zwitterionic systems 43. No reaction was observed with sulfur alone. The thiolate was trapped with iodomethane in a couple of cases (to give 47, Scheme 1) . An analogous P-diselenate was obtained from 48 using 1,3,2,4-diselenadiphosphetane-2,4-diselenide 49, but under different conditions and in the presence of base the C-substituted product 50 was obtained (Scheme 2). There are several example of Diels–Alder-type additions across the PTN bond of various 1,3-azaphospholes. For example, treatment of the tricyclic compound 51 with a diene in the presence of oxygen, sulfur, or selenium produced the adducts 52 (Scheme 3) .

1175


Scheme 1

Scheme 2

Scheme 3

In a similar way, microwave heating was used to aid the synthesis of compounds 53 from the 1,3-azaphospholo[5,1-a]isoquinolines. When iodomethane was used as coreactant, instead of sulfur, the analogous phosphonium methiodides were obtained .

On protonation of the mixture of diphospholyl anion 28 and triphospholyl anion 54 generated by Na/Hg-treatment of t-BuCUP, a spontaneous Diels–Alder reaction occurred between the two systems and the tricyclic compound 55 was formed, the structure of which was determined by X-ray crystallography (Scheme 4) .


Scheme 4

A variety of organometallic complexes have been made from systems containing the ring systems of this chapter. In some cases, the neutral heterocycle is reacted with a metal complex, but in others a strong base is first used to deprotonate and then the resulting anion interacted with the metal source. Thus, for example, reaction of the lithium derivative from 2-t-butyl-1,3-benzazaphosphole 56 (R ¼ t-Bu) with [CpW(CO)3Cl] gave complex 57 which was oxidized by air to 58 (Cp ¼ cyclopentadienyl; Scheme 5) . Conversely, direct reaction of 56 with tungsten hexacarbonyl (to give 59), by reaction also at the phosphorus, and then lithiation and further reaction gave 60.

Scheme 5

Complexes of 1,3-benzazaphosphole systems with other metal carbonyl compounds (Cr, Mo, as well as W) also follow the same pattern, reaction at phosphorus , and exactly comparable behavior was seen in the formation of complexes 61 and 62 from dihydrothiazole-fused and dihydrooxazole-fused 1,3-azaphospholes, respectively .

In other related studies, it was confirmed that both the 1,3-benzazaphospholes themselves, and their tungsten complexes, are deprotonated with t-BuLi losing the N-hydrogen and leaving the lithium associated with the nitrogen . The lithiated species react with alkyl halides at the phosphorus atom giving 3H-3-alkyl-1,3benzazaphospholes, for example, 63. Silylation can occur on either phosphorus or nitrogen depending on steric factors.

1177


Strong base deprotonation of the dihydro-1,3-diphosphole 64 and then reaction with Ph2PCl allowed the introduction of the phosphorus substituent (to give 65). Further deprotonation generated the corresponding diphospholide anion from which the two P-phenyl substituents were removed, rather surprisingly, by treatment with lithium giving the phosphorus-substituted diphospholide anions 66 (Scheme 6) .

Scheme 6

The dihydro-1,3-diphosphole 67 reacted with 2 equiv of [TiCp2(P(OMe)2)2] to give the complex 68. This was rather unstable, reacting with water to give 69 (Scheme 7) . Reaction of 67 with zirconecene gave a complex comparable to 68, but more stable.

Scheme 7

C-Lithiation (to give 71) of the 1,3-benzazaphospholes 70 was achieved with t-BuLi and the C-lithiated reagents proved to be synthetically very useful, reacting with a variety of electrophiles to produce 2-substituted derivatives 72 as indicated in Scheme 8 .

Scheme 8

The 1,3,6-triphosphafulvene 73 reacted regioselectively with nucleophiles at the external phosphorus to give the corresponding phosphinodiphospholide anions, and, as shown in Scheme 9, reaction of these with iodomethane occurred on a ring phosphorus, giving 74 .


Scheme 9

However, when acetic acid was used to quench the anion, protonation occurred on the external phosphorus, producing the ylide 32 .

4.16.5 Ring Synthesis 4.16.5.1 From Nonheterocyclic Precursors A rather general synthesis has been developed for ‘2-phosphaindolizines’ ([1,3]azaphospholo[1,5-a]pyridines). In this approach, a pyridinium salt is reacted with phosphorus trichloride. There are two variants: one in which there is no pyridine -substituent and one in which there is an alkyl group at the pyridine -position. Scheme 10 illustrates the former sequence and Scheme 11 the latter . Thus, pyridinium salt 75 gives bicycle 76, probably via the intermediates 77 ! 78 ! 79, as shown in Scheme 10.

Scheme 10

1179


Scheme 11

When the pyridinium salt carries an -alkyl group, as in 80, it is believed that reaction with the phosphorus halide proceeds first at that carbon to give 81, ring closure subsequently producing 82 (Scheme 11). It should be noted that in the former sequence (Scheme 10), the two five-membered ring substituents are necessarily identical. If the methylene group on nitrogen is insufficiently acidic, for example 83, the reaction can take an alternative course , involving reaction at the pyridinium salt -carbon twice, giving 84 and thereby leading to dichlorphosphinyl-substituted products 85 (Scheme 12).

Scheme 12

This ring synthesis has been extended for the synthesis of azetidinone-containing products 86 , and to products 87 derived from an isoquinoline and 88 from a quinoline .

The reaction of t-BuCUP 90 with LiCH3n(SiMe3)n produced mixtures containing a 1,3-diphospholinyl anion . The same phosphaalkyne on reaction with -keto diazo compounds 89, in the presence of Rh2(OAc)4 as catalyst, produced 1,3-oxaphosphole-ketones 91 via elimination of nitrogen (Scheme 13) . Exposure of 2,2-dibromo-1-(2,4,6-tri-t-butylphenyl)-1-phosphaethene 92 to t-BuLi led to the formation of the 1,3,6-triphosphafulvene 33 (a formal trimer of the starting material) and the tricyclic 93 (Scheme 14) ; see also and . Reduction of ortho-acylaminoaryl phosphonic acid esters 94 with LiAlH4 produced 1,3-benzazaphospholes 95 (Scheme 15) .


Scheme 13

Scheme 14

Scheme 15

4.16.5.2 Ring Synthesis from Another Heterocyclic Ring Compound 1,3-Thiaphosphole 3 and 1,3-thiarsole 9 were prepared by comparable sequences summarized in Scheme 16 . Treatment of 3,3-dibutyl-2,3-dihydro-1,3-thiastannole 96 with phosphorus or arsenic tribromides, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), allowed the parent heterocycles to be distilled from the resulting reaction mixtures in 10% and 22% yields, respectively.

Scheme 16

1181

1182 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony The dipolar cycloaddition reactions of mesitylphosphaacetylene 97 with the mesoionic heterocycles 98 or 99 produced the 1,3-aza- or 1,3-thiaphospholes, 100 or 101, following loss of CO2 and COS, respectively, from the initial adducts (Scheme 17) .

Scheme 17

In a similar process, the isomu¨nchnones 102, either preformed, or generated in situ, reacted with phosphalkynes to give 1,3-oxaphospholes 103 (Scheme 18) .

Scheme 18

In another electrocyclic sequence (Scheme 19), dimethyl acetylenedicarboxylate reacted with a 1,2,4-selenadiphosphole 104 to give a mixture of 1,2-selenaphosphole 105 and 1,3-selenaphosphole 106. Quantum-chemical calculations suggested that a [3þ2] cycloaddition of the acetylene via a single transition state structure leads to the 1,3-isomer .

Scheme 19

When 1,3,5-triphosphabenzenes 107 are treated with an alkyllithium, adducts 108 are formed which release phosphinidene when heated, thus producing 1,3-dipohospholide anions 109 which can be trapped by P-alkylation with primary alkyl halides, thus producing 1H-1,3-diphospholes 110 (Scheme 20) . When 2-pyridyllithium, prepared by reaction of 2-bromopyridine with n-butyllithium, was used, the n-BuBr produced in the


halogen-exchange process served as the P-alkylating agent and thus 110 (R1 ¼ R3 ¼ n-Bu) was obtained directly. A comparable sequence allowed the synthesis of 1-triphenylstannyl-2,4,5-tri-t-butyl-1,3-diphosphole 34 using chlorotriphenylstannane as the electrophile with KP2C3-t-Bu3 .

Scheme 20

Reacting the methyllithium adduct 108 (R1 ¼ t-Bu, R2 ¼ Me) with iron(II) chloride produced two compounds, one of which was the deep red sandwich compound 111, the structure of which was determined by the X-ray method .

When 107 (R1 ¼ t-Bu) was reacted with the gallium heterocycle 112, the diphospholyl anion 109 (R1 ¼ t-Bu) was produced directly (Scheme 21) .

Scheme 21

The anionic complexes [cyclo-[P(Mes* )–C(SiMe3)–P(Mes* )–C(O)–C[M(CO)5]]] where M is Cr or W, 113, formed from 1,3-diphosphacyclobutane-2,4-diyl-2-ide 112, reacted with electrophiles to give neutral complexes [cyclo-[P(Mes* )–C(SiMe3)–P(Mes* )–C(OR)–C[M(CO)5]]], 114 or 115, where R is either Me or SiMe3, or H (Scheme 22) . Reduction of 2,4,6-tri-t-butyl-1,3,5-triphosphabenzene 107 (R1 ¼ t-Bu) with potassium generates the 2,4,5-tri-tbutyl-1,3-diphosphacyclopentadienide anion, isolated as its potassium salt 116 in the form of a white powder (Scheme 23) . The anion has aromaticity comparable to that of the cyclopentadienyl anion. Earlier, this anion had been produced by Na/Hg-treatment of t-BuCUP .

4.16.5.3 Miscellaneous Methods of Ring Synthesis The reaction of bis(2-ethylene)(6-toluene)iron 117 with t-butylphosphaethyne, at a temperature no more than room temperature, produced, in addition to cyclodimerization of the ethyne, a mixture of a coordinated 1,3-phosphete in (4-2,4-di-t-butyl-1,3-diphosphete)(6-toluene)iron 118 and penta-t-butyl-(1,2,4-triphospholyl)(1,3-diphospholyl)iron

1183

1184 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Phosphorus, Arsenic, or Antimony 119 (Scheme 24) . The reaction of 119 with an equivalent of Bu4N[Ir4(CO)11Br] in the presence of AgBF4 gave a good yield of [Ir4(CO)11(1-L)] where L is the iron sandwich linked to iridium through phosphorus .

Scheme 22

Scheme 23

Scheme 24

The reaction of iron(II) chloride with [K(THF)(P2C3t-Bu3)] produced the orange ferrocene 120 . The molecular and electronic structure of the complex was studied by photoelectron spectroscopy and DFT.


Co-condensation of vanadium vapor with t-BuCUP 90 produced the paramagnetic complex [V(5-P3C2t-Bu2)(5P2C3t-Bu3)] 121, the structure of which was determined by X-ray crystallography (Scheme 25) .

Scheme 25

Later, a similar metal vapor reaction with cobalt produced 122, among other products, which was structurally established using the X-ray technique; the yields in such processes are low, typically 30 ppm for the 11B NMR signals. The conversion of bis(dimethylamino)borane 128 into the bis(methoxy)borane 101 results in only a small shift in either the 11B or the 31P NMR spectra. However, reduction of 101 to the dihydride 129 takes place with concomitant ring closure. A large upfield shift in the 11B NMR spectrum and a downfield shift in the 31P NMR spectrum indicates the change in coordination. The 11B and 31P are strongly coupled in 129 but not in 128 and 101 .

Scheme 1

Five-membered Rings with Two Adjacent Heteroatoms with at least One Boron

4.17.4 Thermodynamic Aspects 4.17.4.1 Aromaticity of 1,2-Heteroborolyl Rings The concept of aromaticity is central to organic chemistry in general and heterocyclic chemistry in particular. A good concise description of the application of aromaticity to heterocycles is contained in the Handbook of Heterocyclic Chemistry . The most frequently used criteria of aromaticity are: (1) energetic, a stability due to aromaticity; (2) structural, the tendency of conjugation to favor planar rings with equalized bond lengths; and (3) magnetic, the tendency to display an exaltation of diamagnetic susceptibility and the consequent ring current. The anionic 1,2-azaborolyl 9, 1,2-oxaborolyl 17, and 1,2-thiaborolyl 22 are formally aromatic six p-electron rings. However, there have been no studies which bear on the energetic or the magnetic criteria for aromaticity of these ring systems. On the other hand, all three ring systems form Cp-like transition metal complexes for which several crystal structures have been obtained (as discussed in Section 4.17.3). These ligands are close to planar. The C–C and the C–heteroatom bond lengths are consistent with partial multiple p-bonding. Thus 9, 17, 22, and their fused benzocyclic derivatives have been described as aromatic ligands.

4.17.4.2 Equilibria between 1,2-Azoniaboratoles and their Open-Chain Isomers The 1,2-azoniaboratolidines 26 are internal amine–borane complexes. Analogous acyclic complexes have been studied since the classical work of H. C. Brown in the 1940s . Qualitative data suggest that many 1,2-azoniaboratolidines are in equilibrium with their open-chain isomers 130, as illustrated in Equation (5). The position of the equilibrium is a function of the Lewis acidity of the boron atom and steric hindrance about both boron and nitrogen.

ð5Þ

Quantitative data are available for a few cases, some of which are compared in Table 5. It has been found that the H and 13C NMR signals of the diastereotopic groups of 48, 51, and 54 average on heating toluene solutions of these compounds. It has been assumed that these processes involve rate-determining B–N bond cleavage followed by fast rotation about the B–C bonds and ultimately re-formation of the B–N bond. Heating optically active 45 in hexane causes racemization. The mechanism of racemization has been assumed to involve rate-determining B–N cleavage as above. Although the values of the H* are not identical to the thermodynamic values for the B–N bond dissociation energies, they may approximate them for these endothermic ring openings. 1

Table 5 The activation parameters for ring opening of 1,2-azoniaboratolidines and related compounds (Equation 5) Compound

H* (kcal mol 1)

S* (cal mol 1 K )

G* (356 K )(kcal mol 1)

Solvent

Reference

51 54 48 45 80

14.4 18.9 23.7

14.6 14.9 16.6

11.2a 13.6a 17.8a 27.8 1.8a,b

C7D8 C7D8 C7D8 Hexane C7D8

1990BCJ1168 1992BCJ1832 1992BCJ1832 2004CL206 1997OM163

a

6.0b

22.0b

Extrapolated value. H , S , or G .

b

The 11B NMR chemical shift values of 80 are highly temperature dependent. These values have been interpreted as being due to a weighted average of the ring-closed and ring-open forms. This has allowed evaluation of the thermodynamic values of H and S . The data in Table 5 clearly show that electron-donating groups at boron and steric hindrance at boron decrease the strength of the B–N bonds.

1203

1204 Five-membered Rings with Two Adjacent Heteroatoms with at least One Boron

4.17.5 Reactivity of Fully Conjugated Rings 4.17.5.1 Electrophilic Attack at Carbon As was noted in CHEC-II(1996) , 1,2-azaborolyl lithium salts generally react with electrophiles with substitution at C-3. New examples of this reaction include silylation of 131 and of ringfused 12 . Interestingly, 1,2-thiaborolyllithium 132 undergoes silylation at C-5 under the same conditions, perhaps for steric reasons . These reactions are shown in Scheme 2.

Scheme 2

1,2-Azaborolyllithium salts such as 131 react with methylene chloride and base to give 1,2-dihydro-1,2-azaborines 134, as shown in Scheme 3 . The reaction appears to be general and is the best method for preparing this six-membered ring aromatic heterocycle. It has been used to prepare a B,N analogue of naphthalene 135 . The proposed mechanism involves attack of the electrophilic chlorocarbene on 131 to give 133 followed by ring expansion to 134.

Scheme 3

4.17.5.2 Reaction with Transition Metals The extensive pioneering work of Schmid and co-workers on transition metal complexes of 1,2-azaborolyl ligands was thoroughly covered in CHEC-II(1996) . More recent work has reported additional complexes


with different metals and different substituents on the ligands . Representative examples are illustrated in Scheme 4.

Scheme 4

1,2-Thiaborolyls and 1,2-oxaborolyls have been converted into complexes of early and late transition metals as illustrated in Scheme 5 .

Scheme 5

4.17.6 Reactivity of Nonconjugated Rings 4.17.6.1 Deprotonation of Nonconjugated Dihydro Rings The dihydro-1,2-azaboroles 4 , 2,5-dihydro-1,2-oxaboroles 14 , and dihydro1,2-thiaboroles 19–21 can be deprotonated by strong, bulky bases as in Equation (6), the most widely used bases being lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidide (LTMP), and KN(SiMe3)2.

ð6Þ

1205


4.17.6.2 Reactivity of Rings 4.17.6.2.1

Reversible ring opening

Many 1,2-azoniaboratolidines 26 have been shown to be in equilibrium with their ring-opened isomers 130 as illustrated in Equation (5). Similar equilibria have been described for 1,2-thioniaboratatoles 31 and 1,2-phosphoniaboratatole 88 . Typically, the reactions are observed via NMR spectroscopy by an increase in the symmetry consistent with the process illustrated for 88 in Scheme 6. Intermediate 136 has been trapped by reaction with PdCl2 .

Scheme 6

The above reactions can be described as proceeding via an SN1 type of mechanism. In certain geometrically favorable cases, an SN2 type of mechanism is competitive. Thus the equilibration of the nonequivalent B–ethyl groups of the boron–nitrogen heterocycle 39 (Equation 3) is much faster than that of 138 . Similar equilibration of the B–ethyl groups of boron–sulfur compound 41 (Equation 4) is much faster than that of 139 . Compounds 138 and 139 must equilibrate by a process similar to that illustrated in Scheme 6, while 39 and 41 can equilibrate via a pentacoordinated boron transition state as illustrated in Equations (3) and (4). In the case of 1,8-disubstituted-9-boraanthracenylboranes 77–79, 91, and 95, equilibration is too fast to observe on the NMR timescale. For the boron–oxygen heterocyles 98–100, the X-ray structures show that the compounds have a pentacoordinated boron .

4.17.6.2.2

Transformation into another ring system

1,2-Dichloro-1,2-diborolane 140 undergoes an easy thermal reaction with bis(trimethylsilyl)acetylene to afford the seven-membered ring 3,7-diboracycloheptene 141 in good yield . 1-Sila-2-boracyclopentane 142 reacts with acetylenes in the presence of Pd(II) catalysts and isonitriles to give 3-sila-7-boracycloheptenes 143 and 144 , as shown in Scheme 7.

4.17.6.2.3

Transformations into acyclic products

1-Sila-2-boracyclopentane 142 is easily cleaved by warming with alcohols as illustrated in Equation (7). . Like their acyclic relatives, many boron-containing heterocycles can be oxidized with the loss of boron to produce alcohols. Two applications are illustrated in Equations (8) and (9) .


Scheme 7

ð7Þ

ð8Þ

ð9Þ

1,3-Dihydro-1-hydroxy-2,1-benzoxaborole 102 and its derivatives have been employed as substrates in the Suzuki reaction . Equation (10) illustrates the use of 102 to add an o-hydroxymethyphenyl unit to an aryl halide . Pearson’s 1,2-thioniaboratole 145 continues to be used in organic synthesis . Equation (11) illustrates this use in Grieco’s synthesis of ()-lycopodine .

ð10Þ

1207


ð11Þ

4.17.7 Reactivity of Substituents at Ring Carbon Atoms Reactions involving substituents at ring carbon atoms have not been well investigated. A straightforward conversion of a nitrile to an aldehyde group in a 1,2-azoniaboratatolidine has been reported (Equation 12) .

ð12Þ

4.17.8 Reactivity of Substituents at Ring Heteroatoms 4.17.8.1 Substituents at Boron There are many examples of nucleophilic substitution at boron. 1,2-Dichloro-1,2-diborolane 140 can be reversibly converted into its 1,2-bis(dimethylamino) derivative 146 (Equation 13) . The dimethylamino group of 1,2-silaboracyclopentane 147 can be exchanged for a diethylamino group simply by heating with diethylamine in toluene (Equation 14) . The chloro group of 46 can be exchanged for a pentafluoropropionate, as in Equation (15). Fu and co-workers report that the chloro group of 1-t-butyl-2-chloro-2,5-dihydro-1H-1,2-azaborole 148 can be exchanged for a variety of nucleophiles to afford 149. Subsequent reaction of 149 with base and metal reagents gives the appropriate B-substituted 1,2-azaborolyl metal complexes as shown in Scheme 8 . The same research group has found that 1-t-butyl-2-chloro-1,2-azaboraferrocene 150 can be converted into triflate 151, which can be exchanged for a large number of nucleophiles (Scheme 8) .

ð13Þ

ð14Þ

ð15Þ


Scheme 8

Like most organoboronic acids, 1,3-dihydro-1-hydroxy-2,1-benzoxaborole 102 is readily converted into esters by treatment with alcohols and to the anhydride on drying (Scheme 9) . Boronic acid derivatives are also readily substituted at boron , as shown in Scheme 10. Indeed, nitrogen-coordinated boronic acids are more readily esterified by diols, particularly sugars, than boronic acids without internal coordination . A useful functionalization of an arylboronic derivative is shown in Scheme 11. Spiro compound 153 formed from 152 allows glycosidation of sugars .

Scheme 9

Scheme 10

1209


Scheme 11

4.17.9 Ring Syntheses from Acyclic Compounds 4.17.9.1 Formation of One Bond 4.17.9.1.1

Formation of a boron–heteroatom bond

The only preparation of a 1,2-silaboracyclopentane 142 involves a hetero-Wurtz type of coupling of dichloride 154 (Equation 16) . The reaction is very similar to prior preparations of 1,2-diborolanes . An example of this precedent is illustrated in Equation (17) .

ð16Þ

ð17Þ

The formation of heterocycles 25–35, which are internal Lewis base–borane complexes, is dependent on the borane substituents. An increase in the Lewis acidity of the borane can result in ring formation. For example, bis(methoxy)borane 101 has no B–P bond, but treatment with boron trichloride results in the formation of 1,2phosphoniaboratole 156, presumably via 155 (Scheme 12) .

Scheme 12

The formation of a B–O bond has been observed on the removal of a protecting group; thus, 157 does not ring-close until it is heated to form 158 (Equation 18) . On removal of the THP group from 160, an internal ester 103 forms (Scheme 13) . For related reactions see: .


ð18Þ

Scheme 13

4.17.9.1.2

Formation of a boron–carbon bond

The reaction of 161 with lithium metal involves a reduction, a trimethylsilyl migration, and formation of a boron– carbon bond to afford 162. Subsequent reaction with trimethylsilyl chloride gives 1,2-diborolane 146 (Scheme 14) .

Scheme 14

Heterocyclic BPC3 and BNC3 rings have been formed by internal hydroboration of alkenes. Reaction of allyl t-butylphosphine 163 with borane dimethyl sulfide gives the phosphine–borane complex 164, which gives 165 on warming. Subsequent flash vacuum pyrolysis produces the highly labile 24 (Scheme 15) . For related internal hydroboration of a homoallylic phosphine, see . The older literature has several related internal hydroborations, for example, the preparation of 168 from 166 via 167 (illustrated in Scheme 16) .

Scheme 15

2,3-Dihydro-1H-2,1-benzazaborole derivative 170 can be prepared by an intramolecular Friedel–Crafts reaction of 169 , as illustrated in Equation (19).

1211


Scheme 16

ð19Þ

4.17.9.1.3

Formation of a carbon–heteroatom bond

Examples of syntheses involving the formation of a carbon–heteroatom bond are rare. Equation (20) shows one such reaction .

ð20Þ

4.17.9.1.4

Formation of a carbon–carbon bond

No syntheses involving a ring closure through formation of a carbon–carbon bond were noted in CHEC-II(1996). Two such syntheses have been reported subsequently. The most important and general synthesis is the application of the Grubbs’ ring-closing metathesis (RCM) to the preparation of unsaturated boron–nitrogen, boron–oxygen, and boron–sulfur heterocycles. A more specialized reaction, involving a nucleophilic aromatic substitution, has been applied to the preparation of a benzo-fused boron–nitrogen heterocycle. Upon treatment of (allylthio)vinylborane 172 with 1 mol% Grubbs’ catalyst, (Cy3P)2(PhCH)RuCl2 173, in methylene chloride, cyclization occurred smoothly to afford a 95% yield of the 2,5-dihydro-1,2-thiaborole 174 as shown in Scheme 17. The precursor 172 is itself readily available from the reaction of allylthiol with diisopropylaminochlorovinylborane 171 . Essentially, the same reaction of allyloxyvinylborane 175 with 2% Grubbs’

Scheme 17


catalyst afforded the analogous 2,5-dihydro-1,2-oxaborole 176 in 92% yield . In the same manner, the reaction of B-vinyl, N-allylboramines 178 with 5% 173 gave an 85% yield of the 2,5-dihydro-1,2-azaboroles 120 and 179 . Compounds 178 are easily prepared by treating the corresponding allylamine with phenylvinylboron chloride 177. The above Grubbs’ RCM procedure has been adapted for the preparation of fused ring azaboroles 8 and 185 but not 182 . RCM on boramine 180 afforded a 79% yield of a single ring closed product 181. However, even under forcing conditions, none of the double ring closed product 182 could be detected. On the other hand, Grubbs’ RCM on 183 gave a 35% yield of the fused ring product 18. It seems reasonable therefore to suppose that the ring strain which would be present in 182 makes the RCM closure from 181 unfavorable. In this context, it is interesting to note that the double RCM of 184 to 185 is favorable (Scheme 18).

Scheme 18

On treatment with LDA, bis(pentafluorophenyl) derivative 186 gave the ring closed product 188. Apparently, the reaction proceeds through a nucleophilic aromatic substitution in the presumed intermediate 187 (Scheme 19) .

Scheme 19

4.17.9.2 Formation of Two Bonds 4.17.9.2.1

From [1þ4] atom fragments

The most common method of preparing 1,2-aza-, 1,2-phospha-, 1,2-thia-, and 1,2-oxaboraheterocyles has been the reaction of a suitable -heterolithium reagent with a boron compound. This method is particularly efficient since the required lithium reagents can usually be prepared by direct ortho-assisted lithiation as illustrated in Equations (21)

1213

1214 Five-membered Rings with Two Adjacent Heteroatoms with at least One Boron and (23) . Alternatively, the lithium reagent can be prepared by a lithium/halogen exchange as in Equation (22) . A selection of recent examples of the preparation of 1,2-azaboraheterocyles are shown in Equations (23) , (24) , and (25) ; see also . For 1,2-phosphaboraheterocycles, see Equation (26) . For 1,2-thiaboraheterocyles see Equation (27) , and also , and for 1,2-oxaboraheterocycles see Equation (28) .

ð21Þ

ð22Þ

ð23Þ

ð24Þ

ð25Þ

ð26Þ

ð27Þ

ð28Þ

Closely related to the above are the reactions of 1,4-dilithio compounds with suitable boron compounds. As noted in CHEC-II(1996) , t-butyl- and trimethylsilylallylamines can be dilithiated . Subsequent reaction with methylboron dibromide gives 2,5-dihydro-1,2-azaboroles (Scheme 20) . Analogous reactions have been used to prepare boron–sulfur heterocycles (Scheme 21 ) and boron–oxygen heterocycles (Schemes 22 and 11 ).

Scheme 20

Scheme 21

Scheme 22

The hydroboration of heteroallyl derivatives often produces boron–heteroatom rings. These reactions are very closely related to the internal hydroborations discussed in Section 4.17.9.1.2. The hydroboration of 2-vinylpyrrole affords boron–nitrogen heterocycle 189 (Equation 29) . Two important hydroborations of allyl methyl sulfide and the allene 190 are shown in Equations (30) and (31), respectively. The reduction/ hydroboration of 191 probably occurs via the intermediacy of 192 (Scheme 23) .

ð29Þ

ð30Þ

ð31Þ

Scheme 23

1215

1216 Five-membered Rings with Two Adjacent Heteroatoms with at least One Boron The reaction of triethylborane with the silylacetylene 193 produces the boron–nitrogen heterocycle 194 (Equation 32) .

ð32Þ

4.17.9.2.2

From [2þ3] atom fragments

The syntheses from [2þ3] atom fragments are neither as general nor as important as those from [1þ4] atom fragments. Wrackmeyer et al. have found that cis-2-boryl-1-stannylalkene 195 reacts with carbodiimides, isocyanates, and isothiocyanates as shown in Scheme 24 . The reaction of 9-cyclopentyl-9-borabarbarlane 196 with acetone takes place with rearrangement to cyclooctatriene derivative 197 (Equation 33) .

Scheme 24

ð33Þ

Fischer carbene 198 reacts with bis(1,2-dimethylpropyl)chloroborane to give 200. It seems likely that the initial reaction occurs to form intermediate 199, which then undergoes an internal CH insertion to give 200 (Scheme 25) .

Scheme 25


4.17.10 Syntheses from Other Ring Systems 4.17.10.1 Syntheses from Organotin Heterocycles Many organoboron heterocycles have been prepared via a B/Sn exchange reaction from the corresponding organotin heterocycles . This general route has been used to prepare 2,5-dihydro1,2-azaboroles. Fu and co-workers reported that 2,5-dihydro-1,2-azastannole 201 undergoes exchange with boron trichloride to afford a good yield of 148 . Compound 201 itself is readily available via dilithiation of allyl-t-butylamine followed by reaction with dimethyltin dichloride (Scheme 26) . In a similar manner, Pan and Ashe reported that the reaction of 202 with phenylboron dichloride gave a good yield of 203 . Again, the tin heterocycle is prepared via dilithiation of the corresponding allylamine followed by reaction with dibutyltin dichloride (Scheme 27) .

Scheme 26

Scheme 27

2,5-Dihydro-1,2-oxastannole 204 undergoes a similar exchange with phenylboron dichloride to afford 2,5-dihydro1,2-oxaborole 205 . This synthesis is particularly convenient since the tin compound can be easily prepared by the hydrostannation of propargyl alcohol (Scheme 28) .

Scheme 28

4.17.10.2 Other Ring Transformations Two older ring transformations which were omitted from CHEC-II(1996) should be mentioned. Herberich et al. reported that 2,5-dihydroborole 206 will generally react with ketones and ketenes to produce 1,2-oxaborolanes 207 and 208, respectively (Scheme 29) . Benzoxaborine 209 reacts with iodine and base to give the ringcontracted product 104. The reaction may proceed through proposed intermediate 210 (Scheme 30) .

1217


Scheme 29

Scheme 30

4.17.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available 4.17.11.1 Syntheses of 2,5-Dihydro-1,2-azaboroles 2,5-Dihydro-1,2-azaboroles 4 are important compounds, since they are the precursors of the aromatic 1,2-azaborolyl anions 9. Three routes to derivatives of 4 have been reported: (1) the dilithiation of t-butyl- or trimethylsilylallylamines followed by reaction with organoboron dihalides (usually methylboron dibromide) which is illustrated in Scheme 20; (2) the reaction of 2,5-dihydro-1,2-azastannoles with boron halides as illustrated in Schemes 26 and 27; and (3) the RCM of B-vinyl, N-allylboramines shown in Scheme 17. Routes (1) and (2) are closely related since both start with dilithiation of the same amines. Although route (2) involves an extra step, it is generally preferable to route (1). The 2,5-dihydro-1,2-azastannoles are more robust and more easily purified than the 2,5-dihydro-1,2-azaboroles. They are easy to store until needed. Furthermore, the Sn/B exchange reaction to produce 4 is very clean. It is harder to make a straightforward choice between routes (2) and (3), since they have been applied to the preparation of different compounds. The azastannole routes are short and efficient. They are limited to N-t-butyl and N-trimethylsilyl substituents, although the Fu procedure, outlined in Scheme 8, shows that many different B substituents are available. The RCM procedures appear to offer a wider choice of both B and N substituents. One drawback of the RCM procedures is that it is necessary to prepare the precursor B-vinyl, N-allyl boramine. Clearly, the RCM procedures are excellent for preparing fused ring compounds as shown in Scheme 18.


4.17.12 Important Compounds and Applications 4.17.12.1 1,2-Azaborolyl Zirconium(IV) Complexes as Alkene Polymerization Catalysts Metallocene derivatives of the early transition metals have important uses as catalysts for the Ziegler–Natta polymerization of alkenes . Intense research has centered on the syntheses of modified versions of zirconocene dichloride 211 in order to tune the reactivity of the Ziegler–Natta catalysts. One noteworthy development has been the use of zirconocene-like complexes in which a boron-based anionic heterocyclic ligand has been substituted for Cp. For example, on activation by excess methaluminoxane, boratabenzene–zirconium complexes 212 and 213 have a similar polymerization activity toward ethylene as does 211 . Furthermore, the nature of the boron substituent in such complexes controls the mode of action of the catalyst . Since 1,2-azaborolyl 9, 1,2-thiaborolyl 22, and 1,2-oxaborolyl 17 are isoelectronic with Cp, their zirconium(IV) complexes have been prepared and studied as possible polymerization catalysts. Zirconium complexes of various derivatives of 9 and for 1,2-thiaborolyl complex 211 show significant activity as for the polymerization of ethylene. To date, no data have been reported for complexes of 17. Since there are no standard polymerization conditions, it is very difficult to compare data from different laboratories . Fortunately, ethylene polymerization data for complexes 108, 111, 112, 213, and 214 were all run under the same conditions in the Midland, Michigan, laboratory of the Dow Chemical Company. The polymerization activity of 213 was also measured, but under somewhat different conditions and can be compared with less precision . These data are collected in Table 6. The three 1,2-azaborolyl zirconium complexes 108, 111, and 112 are significantly better catalysts than the 1,2-thiaborolyl complex 214 and the bis(boratabenzene) complex 212. Since 212 had previously been found to have approximately the same activity as 211, albeit under different conditions, it is safe to conclude that the 1,2-azaborolyl complexes are more active than zirconocene dichloride. Indeed, the high activity of complex 108 approaches the activities of commercial catalysts.

Table 6 Comparison of the efficiency of ethylene polymerization for selected zirconium complexes of boron heterocycles Compound

Efficiency (kg polymer/mol Zr atom)

Reference

211 212 213 214 111 112 108

[200]a 204 [100]a 60 660 1200 2340

1996JA2291 1996JA2291 1996JA2291 200OM4935 2006OM513 2006OM513 2005POL1280

a

Estimated value.

1219


4.17.13 Further Developments Fu and coworkers have extended their work on B-functionalized 1,2-azaborolyls which was outlined in Section 4.17.8.1. In particular they have prepared enantiopure 1,2-azaborolyl iron complexes ()-151 and (þ)-218 which have been used on asymmetric syntheses. Complex (þ)-218 was prepared from 148 as illustrated in Scheme 31. The reaction of 148 with Fe(CO)5 followed by I2 afforded complex 215 . Selective reduction of this iodide with sodium amalgam followed by reaction with TMSCl gave 216. Hydrolysis of 216 followed by resolution using chiral HPLC afforded ()-217 for which an X-ray structure has been obtained. This hydroxyl compound was then sequentially converted to chloride ()-216 using oxalyl chloride and tosylate (þ)-218 using AgOTs.

Scheme 31

1,2-Azaborolyl complex (þ)-218 has been used in a stereoselective Mukaiyama aldol reaction as illustrated in Scheme 32 . Complex (þ)-218 reacts with electron rich aromatic aldehydes and silyl ketene acetals to generate adduct 220. X-ray structures indicate the stereochemistry is as illustrated. This stereochemistry is

Scheme 32


consistent with a mechanism involving exo-addition of the silyl ketene acetal to putative intermediate 219, in which the coordinated aldehyde is held coplanar with the 1,2-azaborolyl ring and oriented away from the But group. Reaction of 220 with TBAF liberates the uncoordinated aldol 221. The reaction of ()-151 with imines such as 2-methyl-1-pyrrolidine illustrated in Scheme 33 affords complex 222. An X-ray structure of 222 shows that the coordinated imine is oriented perpendicular to the 1,2-azaborolyl ring. This orientation which contrasts with that assumed for 219 must be due to the greater steric bulk of the imine. Reaction of 222 with allylmagnesium bromide gives 223 with excellent stereoselectivity. Hydrolysis affords the free amine 224. The reactions illustrated in Schemes 32 and 33 demonstrate that 1,2-azaborolyl iron complexes can efficiently transfer chirality to B-bound organic substrates. The development of catalytic versions of these stoichiometric reactions would be a highly desirable extension of this work.

Scheme 33

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1221


B-1992MI417-01 1993CB297 1993CB1551 1993CB2211 1993JOC1443 1993JOC7679 1993JOM139 1993OM3225 1993ZNB1248 1994CC477 1994JOM9 1995CC2499 1995AGE1143 1996CB1541 1996CHEC-II(3)739 1996CHEC-II(3)753 1996CHEC-II(3)755 1996CHEC-II(3)759 1996CHEC-II(3)761 1996CHEC-II(3)763 1996JA2291 1996OM387 1997CC197 1997CC1899 1997JA9305 1997JOM323 1997JOM181 1997MGC141 1997OM163 1997OM1884 1997OM2492 1997ZFA1093 1998HAC79 1998JA5128 1998JOC3599 1998OM2379 1998OM4155 1999AGE429 1999BCJ1879 1999CAP2225014 1999CEJ2584 1999JA2315 1999JA8776 1999JOM234 1999NJC683 1999TL6705 2000AGE4055 2000CC1587 2000CRV1167 2000JA1371 2000JA3047 2000JPR666 2000MI14 B-2000MI43 2000OL2089 2000OM206 2000OM4681 2000OM4935 2000ZFA2081 2001CHE1396 2001CL1104 2001J(P1)3269 2001J(P2)727

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2001OL1311 2001OM143 2001OM5413 2001USP6228958 2001USP6228958 2002AGE174 2002AGE1526 2002AXEo1389 2002BCJ1319 2002CEJ2976 2002J(P2)303 2002OM4323 2002OM4578 2003BML3813 2003JOM257 2003MI417-01 2003MI417-02 2003NJC1419 2003OM2298 2004AXEo2270 2004BCJ2081 2004BML2209 2004CEJ3792 2004CL206 2004EJI3063 2004HAC241 2004ICA1103 2004JA11046 2004JFC975 2004JOC4094 2004OM5088 2004OM5626 2004PS711 2004TL2859 2005AOM377 2005BCJ323 2005JA4354 2005JA15352 2005JOM4784 2005POL1280 2006OM197 2006OM513 2006OM3463 2006T11343 2006USP7074865 2007OM1563

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1223

1224 Five-membered Rings with Two Adjacent Heteroatoms with at least One Boron Biographical Sketch

Arthur J. Ashe, III, is a professor of chemistry and professor of macromolecular science and engineering at the University of Michigan, Ann Arbor. He is a native New Yorker and grew up in suburban New York. In 1962, he received a B.A. in chemistry from Yale University, where he did a senior project with William Doering. He then spent a year on a Henry Ford Fellowship at Cambridge University where he worked in the laboratory of F. G. Mann. After returning to Yale as an NSF Graduate Fellow, he received his Ph.D. in organic chemistry under the supervision of Kenneth B. Wiberg. In 1966, Ashe joined the faculty of the Chemistry Department of the University of Michigan where he remains. He was chairman of the department during a crucial period of planning for a new chemistry building. He has been a Fellow of the A.P. Sloan Foundation. Ashe has supervised the research work of more than 30 doctoral and postdoctoral fellows as well as many undergraduates. He has published 150 scientific publications, most of which are in the area of heterocycles of boron and group 15 elements.

4.18 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Boron G. Varvounis University of Ioannina, Ioannina, Greece ª 2008 Elsevier Ltd. All rights reserved. 4.18.1

Introduction

1225

4.18.1.1

History and Relation to Corresponding Chapter in CHEC-II(1996)

1225

4.18.1.2

Types of Ring, Nomenclature

1226

4.18.2

Theoretical Methods

1226

4.18.3


1226

4.18.3.1

Molecular Structure

1226

4.18.3.2

NMR Spectroscopy

1228

4.18.3.3

Mass Spectrometry

1230

4.18.3.4

Ultraviolet and Fluorescence Spectroscopy

1231

4.18.4


1231

4.18.5


1231

4.18.5.1

Introduction

1231

4.18.5.2

Formation of 1,3-Diborolyl Ligands

1231

Synthesis of 1,3-Diborolyl Ligand Complexes

1231

4.18.5.3 4.18.6


1232

4.18.6.1

Introduction

1232

4.18.6.2

Synthesis of Dinuclear Complexes

1232

Insertion of Carbon Monoxide in B–C Bonds

1233

4.18.6.3 4.18.7


1233

4.18.8


1233

4.18.9


1234

4.18.9.1

Introduction

1234

4.18.9.2


1234

4.18.9.3


1235

4.18.10


1239

4.18.11


4.18.12


1240


1240

References

1240

4.18.1 Introduction 4.18.1.1 History and Relation to Corresponding Chapter in CHEC-II(1996) A discussion of five-membered rings with two nonadjacent heteroatoms and at least one boron atom appeared for the first time in CHEC-II(1996) . Up to 1995, the interest in this class of rings was rather small – a trend that has continued right through to the first half of 2006.

1225

1226 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Boron

4.18.1.2 Types of Ring, Nomenclature The five-membered rings discussed in this chapter have two nonadjacent heteroatoms where one heteroatom is boron and the second heteroatom is boron, nitrogen, silicon, or tin. No other examples of five-membered rings with the second heteroatom being other than boron, nitrogen, silicon, or tin have been found. Thus the heterocycles discussed are: 1,3-diborolanes 1, 2,3-dihydro-1H-1,3-diboroles 2, 1,3-diboryl radicals 3 (derived in situ by dehydrogenating 2,3dihydro-1H-1,3-diboroles), 1,3-azaborolidines 4, examples of which exist as 8-borafluorazenes, 2,3-dihydro-1,3-thiaboroles 5, 1,3-thiaborole anions 6, 2,3-dihydro-1H-1,3-silaboroles 7, and 2,3-dihydro-1H-1,3-stannaboroles 8.

H

B

B

B

H

H

B

H

H

B

S

B

H

S –

5

B

H

H

B

6

H

B

N

H

4

3

2

1

H

B

Si

H H

H

H Sn H

B

8

7

4.18.2 Theoretical Methods Albrecht and Kaufman carried out ab initio calculations for 9H-pyrrolo[1,2-a][1,3]benzazaborole (8-borafluorazene) 9 and two other related ring systems and calculated bond distances fully optimized at the B3LYP/ 6-31G level. By comparing the calculated bond distances, the Mullikan charge distributions and the spectroscopic data of the atoms in 9a, it was concluded that the benzopentalene-type structure 9b contributes significantly to the overall structure of 9. Minkin and co-workers calculated the total energies (Etot, a.u.), relative energies (E, kcal mol1), numbers of negative Hessian eigenvalues (), zero-point energies (ZPEs, a.u.), relative energies with account taken of ZPE (EZPE, kcal mol1), and lowest or imaginary harmonic frequencies ( 1/i, cm1/cm1) for structures 9a and 9b using nonempirical RHF/6-31G** and MP2(full)6-31G** methods. N

N

B

B

H

9a

H

9b

4.18.3 Experimental Structural Methods 4.18.3.1 Molecular Structure The single crystal X-ray analysis of 1,3-diiodo-4,5-dimethyl-2-(2,4,6-trimethylbenzyl)-2,3-dihydro-1H-1,3-diborole 10 represents the only molecular structure of a diborole to be analyzed in this way. There are however several single crystal X-ray analyses of transition metal complexes of 1,3-diborolyl radical derivatives. Sandwich complex 11 formally contains 16 valence electrons (VEs). The diborolyl ring is severely folded along the B(1)–B(3) vector by an angle of 41.3 with the carbon atoms closer to the iron atom. The coordination of C-2 deviates from that of an sp2 carbon atom in a p-complex, tending toward an sp3 geometry with a small B(1)–C(2)–B(3) angle of 89.5 and a very short Fe–C(2) distance of 1.899(6) A˚ . Triple-decker complex 12 has a terminal carborane ligand. The best planes through the cyclopentadienyl and the 1,3-diborolyl ligands exhibit an interplanar angle of 6.1 . The short Co–Co distance of 3.32 A˚ is in agreement with the 30-VE configuration of the molecule . The X-ray crystal structure analysis of 13 confirmed the triple-decker arrangement with a bridging 1,3-diborolyl ring and a terminal thioborane ligand. The Co–Co distance of 3.22 A˚ is similar to that of the related 30-VE triple-decker 12 .

Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Boron

Co

Co Me

Me

Me

Me

Me I

B

B

Me

I

H Me

Me

B

Me

Pr i B

Et Me

Me

B

B

B B

B

S B B H B H B B

H

B

11

10

Me Me

S B B

Me

B

Co

H

Et

B

Me

Co B

Pr i

Me

Me

Me Me

Me

Fe

Me

B

13

12

The molecular structures of the four sandwich complexes 14 are very similar. The best planes though the 1,3diborolyl and arene ligand are almost parallel (angles between the planes 1–3 ). The distances from the Rh atom to ˚ and to the heterocyclic plane (1.790–1.815(3) A) ˚ differ only slightly. The diborolyl the arene plane (1.788–1.796(3) A) ring is folded along a line through the boron atoms (7–10 ) .

R4 R3 B H

R5 B R1 R2 Rh

R

R

R1

R2

R3

R4

R5

Me

Me

CH 2 SiMe

Me

Me

Me

Me

Me

Me

Me

Et

Et

Me

t -Bu

Me

t -Bu

Me

Me

H

Me

H

Me

Me

Me

14 Ashe III et al. described the synthesis and obtained an X-ray structure of the first (5-N,Ndiisopropyl-3-amino-1,3-benzothiaborolyl)(5-pentamethylcyclopentadienyl)ruthenium(II) complex 15. In complex 15, the thiaborolide ring is 5-bound to the Ru atom while the benzene ring shows a diene-like CC bond ˚ than to the thiaborolide ring alternation. Furthermore, the Ru atom is closer to the cyclopentadienyl ring (1.793 A) ˚ ˚ ˚ (1.867 A). The C–S bonds (average 1.76 A) and the C–B bonds (average 1.55 A) are typical of those found for transition metal complexes of thiophenes, boratabenzenes, and other heterocycles containing both boron and ˚ is longer than those of the aminoboratabensulfur atoms. On the other hand, the exocyclic B–N bond (1.443 A) ˚ Ashe III et al. presented the synthesis and X-ray structure zene complexes (1.39–1.41 A). determination of (5-N,N-diisopropyl-3-amino-1,3-thiaborolyl)(5-pentamethylcyclopentadienyl)ruthenium(II) complex 16, as a follow-up to the work on complex 15. The thiaborolide ring in 16 is 5-bound to the Ru atom and is a p-coordinated aromatic ring, analogous to the thiaborolide ring of complex 15. In isonitrile sandwich complexes 17, described by Siebert and co-workers , the isonitrile group is bonded to the Rh atom causing a tilt of the cyclopentadienyl and the 1,3-diborolyl ligands. The best planes through cyclopentadienyl and 1,3diborolyl rings form an angle of 28.6 . The isonitrile is located near one boron atom. The 1,3-diborolyl ligand is not planar, but is folded along the B(1)–B(3) vector by 16.2 . The Rh–B distances are significantly larger than those to C and are all in the expected range for this type of complex. The octadecahedral geometry of the closoRhC3B7 cluster framework of the air-stable triple-decker complex 18 was described by Siebert and co-workers . The ligands in complex 18 are almost planar and parallel to each other and the 1,3-diborolyl ring does not have the folded structure along the B(1)–B(3) vector that was observed in the isonitrile complex 17. The distances from the Rh and Ru atoms to the 1,3-diborolyl atoms are almost identical. In (5-1,3-di-t-butyl2,4,5-trimethyl-2,3-dihydro-1,3-diborolyl)(6-toluene)-rhodium sandwich 19, the 1,3-diborolyl ring is folded along ˚ the B(1)–B(3) vector by 15.1 and the diborolyl–Rh and toluene–Rh distances are 1.816(2) and 1.810(2) A, respectively .

1227


Me

Me

Me

Me

Me

Me

Me Me

Me

Me

Me

Me

Ru

Ru

B N

15

Me

Me

R R

R B

B

Pr i

N

16

B

R

Me

Bu t

B

Me Bu t

Rh

Me

Me B

B

Me

Pr i

Me

Ru

Me

Me

B Pr i

Me

Me

CN Bu t

Rh

S

Me

Me

Me

S

Pr i

Me

Me

Rh

17

Me

19 H

H3C B

R = Et, Me B

B

B B

B H

B

18


H, 13C, 11B, 119Sn, and 29Si nuclear magnetic resonance (NMR) spectral data provide information about the electronic and structural properties of the five-membered rings and their complexes, described in this chapter. In the 1H NMR spectra of 2,3-dihydro-1H-1,3-diboroles 20 (R2 ¼ H, R29 ¼ H, Me, PhCH2, or MeSCH2) in C6D6, H-2 is in the range of ¼ 0.322.42 ppm . The chemical shift is influenced by the substituent on the boron atoms, electron-withdrawing groups such as iodine or ethoxy cause an upfield shift while alkyl groups cause a downfield shift. In the 13C NMR spectra of these compounds, the C-2 signal appears at ¼ 3552.7 ppm, the nature of the substituents on the boron atoms having no influence on the chemical shift. Carbon atoms at positions 4 and 5 resonate in the range of 167 177 ppm, while the presence of an ethoxy group on the boron atoms causes a sharp upfield shift up to 10 ppm. In the 11B NMR spectra, the signal due to the two boron atoms appears at ¼ 50.170 ppm, where ethoxy substituents on the boron atoms give the most upfield signal.

In the proton NMR spectrum of 1,2,3,4-bis(19,39-diborole-29,39-dihydro)-5,6-bis(boryl)benzene 21 in C6D6 , H-2 and H-7 of the 1,3-diborole rings appear at 3.5 ppm while the 13C NMR spectrum features three signals at ¼ 7.8, 9.8, and 10.9 due to the three different methyl groups. The resonances of the methylene carbon atoms are found at ¼ 24.2 and 25.6 while C-2 and C-7 give a signal at ¼ 67.8. The signal due to the arene carbon atoms is seen at ¼ 154.0. In the 11B NMR spectrum, one broad signal is seen at ¼ 77.0.

In the 1H NMR spectrum of 2-(2,2-dimethylpropylidene)-4,5-diethyl-1,3-diiodo-2,3-dihydro-1H-1,3-diborole 22 in CDCl3, triplets at ¼ 1.06 and 1.07 and quartets at ¼ 2.49 and 2.60 correspond to the ethyl groups .


The nine protons of the t-butyl group resonate at ¼ 1.34, whereas the alkene proton resonates at ¼ 2.60. In the 13C NMR spectrum, a signal at ¼ 150 corresponds to C-2, at ¼ 172.1 to the exocyclic alkene carbon, and at ¼ 173 and 184 to C-4 and C-5, respectively. In the 11B NMR spectrum, a broad signal due the two boron atoms appears at ¼ 61.8.

The chemical shifts of the signals in the 1H and 13C NMR spectra in C6D6 solution of 9-mesityl-9Hpyrrolo[1,2-a][1,3]benzazaborole 23 are comparable to the corresponding signals found in boron-substituted five-membered heterocycles where intramolecular interaction between boron and a donor atom occurs via the aromatic ring. Furthermore, the 11B NMR chemical shift of 23 in C6D6 solution is at ¼ 58.4, close to zwitterionic-type triorganoboranes, the 11B signals of which are in the range of ¼ 5060.

The 1H and 13C spectra of 2,3-dihydro-1,3-benzothiaborole 24a (R ¼ H) in THF-d8 solution show that the isopropyl C–H groups are nonequivalent, resonating as broad signals at 3.58 and 4.50 ppm, due to slow rotation about the B–N bond . The CH2 protons at C-2, however, appear as a singlet at 2.70 ppm and the boron signal is at 47.1 ppm. In the 1H NMR spectrum of 2-methyl-2,3-dihydro-1,3-benzothiaborole 24b (R ¼ Me) run in C6D6 solution, the isopropyl C–H groups are nonequivalent and give a broad signal centered at 3.87 ppm while the C-2 proton is also a broad signal and resonates at 3.87 ppm. No 13C and 11B NMR spectra of this compound were recorded. The 1H, 13C, and 11B NMR spectra of 1,3-benzothiadiborole 25 in THF-d8 show that the carbanion is strongly stabilized by p-bonding to boron. The BCH group shows a 1H NMR signal at 60.9 ppm, far downfield from those of sp3-hybridized organolithium compounds, which indicates that the carbon is sp2 hybridized. The 11B NMR signal of compound 25 at 43.6 ppm is upfield relative to compound 24a (47.1 ppm) due to the enhanced electron density at the boron atom. The 1H and 13C NMR spectra of compound 25 at ambient temperature show that the two isopropyl groups are identical due to rapid rotation around the B–N bond. In the1H NMR spectrum of 2,3-dihydro-1,3-thiaborole 26 run in CDCl3 solution, the two nonequivalent isopropyl C–H groups are found to resonate at 3.48 and 3.61 ppm, while the protons at C-2 resonate as doublets at 6.15 and 7.64 ppm . From the 1H, 13C, and 11B NMR spectra of 1,3-thiaborole 27 in THF-d8, it can be deduced that the carbanion is strongly stabilized by p-bonding in the same manner as that found for compound 25. H-2 resonates at ¼ 2.89 and in the 13C NMR, C-2 is at ¼ 59.8. The 11B NMR signal at ¼ 35.1 indicates an upfield shift relative to compound 26 ( ¼ 43.9) consistent with enhanced electron density at boron. As in compound 25, the two isopropyl groups in compound 27 are identical. Interestingly, the 1H NMR signals at ¼ 6.19 and 6.95 and the 13C NMR signals at ¼ 126.8 and 132.2 for C-4 and C-5 in compound 27 are in the normal aromatic/olefinic region. Apparently little negative charge is transferred to these atoms which is as expected from consideration of the resonance structure of 27. The 11B NMR signals of compounds 24, 25, 26 and 27 are not comparable and resonate at 47.1, 43.6, 43.9, and 35.1, respectively.

1229


S

R

S

B

H

B

N(Pr i)2

24

Li +

(Pr i )2 N

B

S

(Pri)2 N

B

S Li +

N(Pr i)2

25

26

27

The proposed structure of 3,4-diallyl-2-but-3-enylidene-1,1,5-trimethyl-2,3-dihydro-1H-1,3-silaborole 28 is strongly supported by 1H, 13C, 11B, and 29Si NMR data . The characteristic chemical shifts are a singlet corresponding to six equivalent protons of the SiMe2 group in the 1H NMR spectrum at ¼ 0.19, signals for C-2, C-4, C-5, and the exocyclic alkenyl carbon in the 13C NMR spectrum at ¼ 142.3, 163.2, 174.2, and 163.8, respectively, a signal at ¼ 64 in the 11B and a signal at ¼ 23 in the 29Si NMR spectra. The 1H, 13C, 11B, 29Si, and 119Sn NMR spectra of 2,3-dihydro-1H-1,3-stannaboroles 29 and 30 fully support their structures. In the 1H NMR spectrum of compounds 29a and 29b, the two methyl groups attached to the stannole atom are not equivalent, resonating at ¼ 0.14 and 0.37, and 0.17 and 0.25, while H-2 resonates at ¼ 1.55 and 1.62, respectively. In the 13C NMR spectra of these compounds, C-2, C-4, and C-5 resonate at ¼ 27.7, 159.3, and 169.4, and 31.2, 167.4 and 165.0, respectively, in the 11B NMR spectra the boron atoms resonate at ¼ 75.0 and 78.8, while in the 119Sn NMR spectra the tin resonates at ¼ 7.5 and 0.7, respectively. Singlets in the 1H NMR spectra of compounds 30a and 30b corresponding to the six equivalent protons of the SnMe2 group are at ¼ 0.33 and 0.33 with 2J (119Sn, 1H) ¼ 53.8 and 53.9, respectively, whereas in the 13C NMR spectra the chemical shifts deviate more than 2 ppm for C-2, C-4, C-5, and the exocyclic alkenyl carbon, resonating at ¼ 152.4, 162.4, 172.3, and 156.6, and 180.3, 181.7, 170.2, and 159.4, respectively. The signals in the 11B NMR spectra are at ¼ 62.4 and 64.4 and the 119Sn signals appear at ¼ 38.9 and 78.8 for these two compounds, respectively. In the 29Si NMR spectrum of 30b, two signals appear at ¼ 5.9 and 10.2. Characteristic peaks in the 1H NMR spectra of 2-ethylidene-2,3-dihydro-1H-1,3-stannaboroles 30c and 30d are a singlet at ¼ 0.18 corresponding to the 36 protons and singlets at ¼ 0.11 and 0.14 each corresponding to the 12 protons of the methyl groups attached to the silicon atoms, respectively. Carbons C-2, C-4, C-5, and the exocyclic alkenyl carbon resonate at ¼ 157.7, 175.3, 160.6 and 155.3, and 154.4, 171.3, 164.1, and 157.9, respectively. The boron signals are at ¼ 68.6 and 64.6, in the 15N NMR spectra at ¼ 341.4 and 344.4, the 119Sn signals at ¼ 96.7 and 72.3, and the 29Si signals at ¼ 4.9 and 16.4, respectively.

4.18.3.3 Mass Spectrometry 1,3-Diboroles have been routinely analyzed by electron impact mass spectrometry. The method has been used to confirm only molecular masses when 2,3-dihydro-1,3-thiaboroles and 2-(2,2-dimethylpropylidene)-4,5-diethyl-1,3-diiodo-2,3-dihydro-1H-1,3-diborole 22 were measured. When the molecular masses of other 2,3-dihydro-1H-1,3-diboroles, 1,3-azaborolidines, 2,3-dihydro-1H-1, 3-stannaboroles, and 2,3-dihydro-1H-1,3-silaboroles were measured, fragmentation patterns of these compounds were also recorded.


4.18.3.4 Ultraviolet and Fluorescence Spectroscopy The ultraviolet–visible absorption spectrum of 8-mesityl-8-borafluorazene 25 in hexane shows maxima at 226, 265, 328, and 410 nm as expected for its pentalene-type structure, and this can be compared to only two maxima at 226 and 322 nm for dimesityl(2-pyrrolyl)borane.

4.18.4 Thermodynamic Aspects Thermodynamic aspects of 1,3-diborolanes, 2,3-dihydro-1H-1,3-diboroles, 1,3-azaborolidines, 2,3-dihydro-1,3-thiaboroles 2,3-dihydro-1H-1,3-stannaboroles, or 2,3-dihydro-1H-1,3-silaboroles are only sparsely mentioned. It has been found that the 12p-electron antiaromatic heterocycle 23 is stabilized by electron delocalization via the boron atom (cf. compound 9) . Noteworthy is the comparison between the 8p-electron antiaromatic 2,3dihydro-1,3-benzothiaborole 24 or 4p-electron antiaromatic 2,3-dihydro-1,3-thiaborole 26 and the corresponding 10p-electron 25 or 6p-electron 27 aromatic lithium compounds, the latter forming stable p-coordinated transition metal complexes.

4.18.5 Reactivity of Fully Conjugated Rings 4.18.5.1 Introduction 2,3-Dihydro-1H-1,3-diboroles can be transformed into 2,3-dihydro-1H-1,3-diborolyl transition metal complexes. 1,3Diborolyl radicals are formed from 2,3-dihydro-1H-1,3-diboroles by the loss of a hydrogen atom from C-2. The resulting 1,3-diborolyl ring systems cannot exist independently but, as three-electron donors to metal atoms through the C p-electrons and electron acceptors of metals through the two B atoms, can form complexes with one or two transition metal atoms.

4.18.5.2 Formation of 1,3-Diborolyl Ligands There are two possible 1,3-diborolyl ligands that lead to the formation of complexes with metals. In the first case, strong bases such as an alkyllithium or sodium hydride are used at low temperature to deprotonate the 2,3-dihydro1H-1,3-diborole derivative. The 1,3-diborolyl anions thus produced react with the metal complex. In the second case, 1,3-diboryl radicals are formed by reaction with the metal complex itself, which then coordinates to the 1,3-diborolyl ligand generated. Overall, this interaction corresponds to oxidative addition with elimination of a hydrogen atom .

4.18.5.3 Synthesis of 1,3-Diborolyl Ligand Complexes Siebert and co-workers reported the reaction of 2,3-dihydro-1,3-diborolyl ligands with ruthenium complexes . 2,3-Dihydro-1H-1,3-diborole derivatives 31a–d were treated with MeLi at –55 C and then reacted with [(C5Me5)RuCl]4 to give the violet mononuclear (5-pentaalkyl-2,3-dihydro-1,3-diborolyl)5-pentamethylcyclopentadienyl)ruthenium complexes 32a–d (Equation 1). The synthesis of (5-pentaalkyl-2,3-dihydro1,3-diborolyl)(5-1-ethyl-2,3,4,5-tetramethyl-cyclopentadienyl)ruthenium complexes 33a and 33d (Equation 2) required treatment of 2,3-dihydro-1H-1,3-diboroles 31a and 31d with MeLi at –55 C and then with [(C5Me4Et)RuCl]4, generated in situ by the reaction of [(C5Me4Et)RuCl2]2 with [Li(Et3BH)]. The interesting dinuclear complex bis[(5-pentamethyl-2,3-dihydro-1,3-diborolyl)-(5-pentamethylcyclopentadienyl)ruthenium carbon disulfide], with two carbon disulfide molecules connecting the ruthenium centers, has been synthesized .

1231


Me

R3

i, MeLi ii, [(C5Me5 )RuCl] 4

R5

R4 B

B

H

R2

Me

Me

Me Me Ru

R1 R4 B

R3

31

ð1Þ

R5 B

R1

R2

32

i, MeLi ii, [(C5 Me4 Et)RuCl 2] 2 [Li(Et 3 BH)]

31

Me

Me Me

Me Me Ru R4

a: R1–R5 = Me b: R 1 –R 3 = Me; R 4 , R 5 = Et c: R1, R 3 = CH2 SiMe 3 ; R2, R4, R5 = Me d: R1, R 3–R 5 = Me; R 2 = Et

R3

ð2Þ

R5

B

B

R1

R2

33

4.18.6 Reactivity of Nonconjugated Rings 4.18.6.1 Introduction 1,3-Dialkyl-2,3-dihydro-1H-1,3-diboroles act as four-electron donor ligands to metals through coordination of the H-2 atom and the CTC bond. This occurs when the H-2 atom is not removed. In CHEC-II(1996) , two other modes of metal coordination with 1,3-dialkyl-2,3-dihydro-1H-1,3-diboroles were also described.

4.18.6.2 Synthesis of Dinuclear Complexes An example of the H-2/CTC ligand metal coordination was reported by Siebert and co-workers , who reacted 2,3-dihydro-1H-1,3-diborole derivatives 31a–c with dirhodium-m-dichlorotetraethylene in tetrahydrofuran (THF) at room temperature to give the dinuclear complexes bis{5-[1,3,4,5-tetramethyl-2-(2,4,6trimethylbenzyl)-2,3-dihydro-1,3-diborole]- and bis[5-(4,5-diethyl-1,2,3-trimethyl-2,3-dihydro-1,3-diborole)rhodium chloride 34a–c, respectively (Equation 3). R4 R5

R4

R3 [(C 2 Me 4 ) 2 RhCl] 2

R

3

B

B

H

R2

R

1

THF

31 1

R5

B

B

H

R

Rh

Cl

34 3

5

2

a: R , R –R = Me; R = CH 2SiMe b: R1–R3 = Me; R4, R 5 = Et c: R 1, R3 = t -Bu; R 2, R 4, R 5 = Me

R1

2

ð3Þ 2


4.18.6.3 Insertion of Carbon Monoxide in B–C Bonds Siebert et al. have reported that bubbling carbon monoxide into a solution of 1,3,4,5-tetraethyl-2-methyl-2,3-dihydro1H-1,3-diborole 35, under dry conditions, resulted in insertion of carbon monoxide into the B–C bonds and formation of two products, which were identified as 2,4,5,6-tetraethyl-3-ethylidene-3,6-dihydro-2H-1,2,6-oxadiborinine 36 and 2,3,4,5-tetraethyl-6-ethylidene-5,6-dihydro-2H-1,2,5-oxadiborinine 37 (Equation 4) . This reaction was not mentioned in CHEC-II(1996) .

ð4Þ

4.18.7 Reactivity of Substituents Attached to Ring Carbon Atoms The only reaction relevant to this section is the abstraction of H-2 from 2,3-dihydro-1H-1,3-diboroles to form the 1,3diborolyl ligands which are used in the formation of metal complexes, as described in Section 4.18.5.

4.18.8 Reactivity of Substituents Attached to Ring Heteroatoms Siebert and co-workers exchanged iodine for methyl or trimethylsilylmethyl in 1,3-diiodo-2,3-dihydro-1H-1,3-diboroles 38a and 38b by reacting compound 38a with trimethylaluminium and compound 38b with trimethylsilylmethyllithium, in pentane at low temperature, to give the corresponding 1,3-dialkyl-2,3-dihydro-1H-1,3-diboroles 20a and 20b (Scheme 1) . Siebert et al. exchanged iodine for methyl in 1,3-diiodo-1,3-diboroles 35c–e

Scheme 1

1233

1234 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Boron carrying out the reactions in hexane at 30 C and treating compounds 38c and 38d with trimethylaluminium and compound 38e with methyllithium . The very sensitive 1,3-dimethyl-1,3-diboroles 20c–e were obtained in moderate yields. Siebert and co-workers failed to alkylate directly 1,3-diiodo-2,3-dihydro-1H-1,3-diboroles 38f and 38g with t-BuLi and obtain the corresponding t-butyl derivatives 20f and 20g . The explanation given was the high Lewis acidity of the B–I bonds. Therefore, the 1,3-diiodo compounds 38f and 38g were first transformed into the 1,3-diethoxy derivatives 39f and 39g and then treated with t-BuLi in pentane at 0 C to provide the 1,3-di-t-butyl-2,3-dihydro-1H-1,3-diboroles 20f and 20g in 47% and 58% yields, respectively. Bayer and Siebert tried to exchange methyl for iodine in 2-(2,2-dimethyl-propylidene)-4,5-diethyl-1,3-diiodo-2,3dihydro-1H-1,3-diborole 22 by reacting with trimethylaluminium in pentane at –15 C . However, due to the instability of the 1,3-dimethyl derivative 40, it was detected only by 1H NMR spectroscopy before rearranging into nido-C4B2 carboranes 41 and 42, as well as to polymeric materials (Scheme 2).

Me B But

Et Et

B

H Me

Et I

B

B

Et

AlMe3 Me(CH 2 )3 Me

Et I

Me

t

H

Bu

Et

B

B

H

Bu

41 + Me

Me B

t

H

Et

22

40

Polymeric material

Et

Bu t

B Me

42 Scheme 2

4.18.9 Ring Synthesis Classified by Number of Ring Atoms in Each Component 4.18.9.1 Introduction The synthesis of rings containing two nonadjacent heteroatoms with at least one boron is readily accomplished by the simultaneous formation of two heteroatom–carbon bonds.

4.18.9.2 Formation of One Bond Since 1996, there are only two syntheses that apply to this section. There is however another example mentioned in CHEC-II(1996) that involves the synthesis of two 2,3-dihydro-1H-1,3-diborole derivatives . Wrackmeyer et al. described how (Z)-2-chloro-(dimethyl)stannyl-3-diethylborylpent-2-ene 44, obtained by reacting chlorodimethyl(prop-1-ynyl)stannane with triethylborane, isomerizes into (Z)-3-chloro-(dimethyl)stannyl-2-diethylborylpent-2-ene 45 when treated in THF with powdered sodium amide at 65 C (Scheme 3) . Pure 3,5-diethyl-1,1,2,4-tetramethyl-2,3-dihydro-1H-1,3-stannaborole 29a was obtained by the reaction of 45 in hexane with a suspension of lithium diisopropylamide (LDA) in toluene at 78 C. The reaction goes to completion by allowing the reaction mixture to reach room temperature and then by briefly heating to reflux. The yields of compounds 45 and 29a were 78% and 93%, respectively. Keeping pure liquid 29a in an ampoule, or in C6D6 solution in a sealed NMR tube for several months at room temperature, led to a mixture containing 29a and a small amount (5%) of isomer 47. The authors also found that


Scheme 3

when a pure sample of 47 was prepared , it too isomerized slowly to give a mixture containing 29a and a small amount of isomer 47. Since the interconversion between 29a and 47 takes place at comparable rates in the pure liquid and in solution, an intramolecular mechanism must be assumed. As shown in Scheme 4, structures with p ! delocalization and migration of the stannyl group can account for the isomerization.

Scheme 4

Recently, Wrackmeyer et al. synthesized 2,3-dihydro-1H-1,3-stannaborole 29b by treating (E)-2-chloro(dimethyl)stannyl-3-diethylboryl-N,N-dimethyl-2-pentenylamine 48 with LDA in THF (Equation 5) . The cyclization owes its success to the high basicity of LDA that abstracts a proton from one of the ethyl groups at boron; the resulting carbanion acts as a nucleophile attacking the tin atom. Diisopropylamine and lithium chloride are eliminated from the reaction.

ð5Þ

4.18.9.3 Formation of Two Bonds Several research groups are working in this area of chemistry. Siebert and co-workers have synthesized 2,3-dihydro-1H-1,3-diborole, 2-(2,2-dimethylpropylidene)-2,3-dihydro1H-1,3-diborole and 1,2,3,4-bis(19,39-diborole-29,39-dihydro)-5,6-bis(boryl)benzene derivatives. Albrecht and Kaufmann have synthesized the first 9H-pyrrolo[1,2-a][1,3]benzazaborole (8-borafluorazine), Ashe III et al. have synthesized the first lithium 1,3-benzothiaborolide and lithium 1,3thiaborolide derivatives, and Wrackmeyer et al. have synthesized 1,2dihydro-1H-1,3-stannaborole, 2-alkylidene-1,3-silaborolene, and 2-alkylidene-1,3-stannaborolene derivatives.

1235

1236 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Boron The most common synthesis of 1,3-diboroles (Scheme 5), such as 38, starts by the hydroboration of monosubstituted ethynes using dichloroborane formed in situ to give 1,1-bis(dichloroboryl) derivatives 49. Dichloroborane can be produced by reacting trimethylsilane with boron trichloride. 1,1-Bis(dichloroboryl) derivatives 49 are then converted into 1,1-bis(diiodoboryl) derivatives 50 and these are reacted with but-2-yne to give the corresponding 1,3-diiodo-4,5dimethyl-2,3-dihydro-1H-1,3-diboroles 38. In an earlier publication, Siebert and co-workers reacted 1,1-bis(diiodoboryl)propane 49a with but-2-yne in pentane at 0 C and obtained 2-ethyl-1,3-diiodo-4,5-dimethyl-2,3dihydro-1H-1,3-diborole 38a in 81% yield. Two years later Siebert et al. reported that hydroboration of phenyl- and mesitylethyne with dichloroborane formed in situ leads to an isomeric mixture of 1,1-bis-(dichloroboryl)-2phenylethane 49b and 1,1-bis(dichloroboryl)-1-phenylethane 49c in a 3:1 ratio and regioselectively to 1,1-bis(dichloroboryl)-2-mesitylethane 49d. Treatment of compounds 49b/49c and 49d with boron triiodide in hexane at 78 C gave the corresponding tetraiodo compounds 50b/50c and 50d in excellent yields. Compounds 50b/50c and 50d undergo redox reactions with but-2-yne in a mixture of hexane and toluene to afford an isomeric mixture of 38b/38c and 38d in 74% and 43% yields, respectively.

Scheme 5

Bayer and Siebert reported the reaction of 3,3-dimethyl-1-butyne with n-BuLi in pentane, followed by the addition of boron trichloride to afford the intermediate dichloro(3,3-dimethylbut-1-ynyl)borane that was hydroborated with dichloroborane formed in situ to give 1,1-bis(dichloroboryl)-3,3-dimethylbutene 51 (Scheme 6) . When the latter was subjected to halogen exchange with boron triiodide, it was converted into the corresponding tetraiodide 52, which underwent a redox reaction with hex-3-yne to give the 2-(2,2-dimethylpropylidene)-1,3diborole 22 in 73% yield.

Scheme 6


Binger reported the first synthesis of the derivative 1,3,4,5-tetraethyl-2,3-dihydro-2-methyl-1H-1,3-diborole, which involved thermolysis of cis-3,4-diethyl-3,4-bis(diethylboryl)hexane at 160 C . Recently, Siebert and co-workers heated hexakis(diethylboryl)benzene 53 at 180 C in a stream of argon and isolated 1,2,3,4-bis(19,39diborole-29,39-dihydro)-5,6-bis(boryl)benzene 21, accompanied by evolution of ethane (Equation 6) . This compound represents the first example of a benzo derivative with two condensed 1,3-diborole rings.

ð6Þ

The only compound so far known containing a 1,3-azaborolidine ring is 9-mesityl-9H-pyrrolo[1,2-a][1,3]benzazaborole 23 . This compound was synthesized by treatment of 1-(2-bromophenyl)-1H-pyrrole 54 with n-butyllithium in ether to give 2,29-dilithio-1-phenylpyrrole 55, which was subsequently reacted with dimethoxymesitylborane to afford 23 in 76% yield (Scheme 7).

Scheme 7

1,3-Thiaborolide 6 is an aromatic anion which is related to thiophene in the same manner that the boratabenzene anion is related to benzene. Although thiophene forms rather few stable p-coordinated transition metal complexes, the boratabenzene anion has a particularly rich transition metal chemistry. With this in mind, Ashe III et al. decided to synthesize the 1,3-thiaborolide ring in order to explore the coordination chemistry of this aromatic molecule. First, 3,3-dibutyl-2,3-dihydro-1,3-benzothiastannolene 57 was prepared by double deprotonation of thioanisole using n-butyllithium in hexane solution containing tetramethylethylenediamine (TMEDA) at 78 C, followed by reaction with dibutyltin dichloride. Further reaction of compound 57 with excess boron trichloride in heptane at room temperature followed by gentle warming up to 50 C gave the rather sensitive 3-chloro-2,3-dihydro-1,3-benzothiaborole 58. Compound 58 was not characterized but reacted immediately with excess N,N-diisopropylamine in dichloromethane at 78 C to afford N,N-diisopropyl-1,3-benzothiaborol-3(2H)amine 24a, in 92% yield from compound 57. Methylation of compound 24a to give its 2-methyl derivative 24b was accomplished by treating an ether solution of 24a at 78 C with t-butyllithium, warming to room temperature, cooling to 78 C and then adding methyl iodide. Compound 24a was dissolved in THF-d8 and reacted with t-butyllithium at room temperaure to afford the lithium anion 25, which was used for NMR and mass spectrometry measurements (Scheme 8). Comparable treatment of an ether solution of compound 24a with t-butyllithium was used for metal complexation with (5-pentamethylcyclopentadienyl)ruthenium(II) chloride. The synthesis of 2,3-dihydrodiisopropyl-1,3-thiaborol-3-yl-amine 26 and subsequently lithium diisopropyl-1,3thiaborol-3-ylamine 27 required a four-step synthesis starting from chloromethyl trimethylsilylethynyl sulfide 59 (Scheme 9). Desilylation of compound 59 with tetrabutylammonium fluoride (TBAF) in methanol afforded the labile chloromethyl ethynyl sulfide 60, which was treated with a solution of dibutylstannane and LDA in a mixture of THF and hexane at 78 C to give 3,3-dibutyl-2,3-dihydro-1,3-thiastannole 61, in 39% yield. Reaction of compound 61 with 2 equiv of n-butyllithium in THF at 78 C gave the dilithio reagent 62, which could be detected by NMR

1237

1238 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Boron spectroscopy when the reaction was conducted in THF-d8 solution. When compound 62 was reacted with N-(dichloroboryl)-N-isopropylpropan-2-amine in THF at 78 C, 2,3-dihydro-1,3-thiaborole 26 was isolated in 33% yield. The lithium salt 27 was obtained in quantitative yield as a yellow solid, after treating an ether solution of thiaborole 26 with t-butyllithium in hexane. SMe

S

i, ii

S

iii

Sn Bun Bun

56

B Cl

57

iv

58

S

R

vi

S

B

H

R=H

B

+ H Li

58

N(Pr i ) 2

N(Pr i ) 2

v

25

24a: R = H 24b: R = Me

i, n-BuLi, TMEDA, hexane, –78 °C; ii, n-Bu 2 SnCl 2 ; iii, BCl3, heptane; iv, (i -Pr) 2 NH, CH 2 Cl 2 , –78 °C; v, t -BuLi, Et 2O, –78 °C to rt, –78 °C, MeI; vi,t -BuLi, THF-d 8 Scheme 8

i Me3SiC CSCH2 Cl

59

Sn Bun

v

iv S Li LiH2C

S

61

60

iii

61

Bun

ii HC C SCH 2Cl

i

(Pr )2 N

B

S

(Pr i)2 N

B

S

Li+

H

62

26

27

i, TBAF, methanol, 0 °C; ii, Bu2SnH2, LDA, THF, hexane, –78 °C; iii, n -BuLi, THF, –78 °C; iv, (i -Pr)2 NBCl 2, THF, –78 °C; v, t -BuLi, Et 2O, –78 to 0 °C Scheme 9

Wrackmeyer et al. obtained (E)-3,4-diallyl-2-(but-3-enylidene)-1,1,5-trimethyl-2,3-dihydro-1H-1,3-silaborole 28 selectively by the reaction of dimethyldi(prop-1-ynyl)silane 63 with triallylborane in CDCl3 at room temperature for several days (Equation 7) . The reaction was monitored by 1H and 29Si NMR spectroscopy and is believed to take place via an intermolecular 1,1-allylboration followed by an intramolecular 1,2-allylboration.

ð7Þ


In a similar way, dimethyldi(prop-1-ynyl)stannane 64a reacted with triallylborane in CDCl3 at below 20 C to give, after warming up to room temperature, 3-allyl-1,1,4-trimethyl-2-(1-methylbut-3-enylidene)-2,3-dihydro-1H-1,3stannaborole 30a (Scheme 10). By monitoring the reaction of stannane 64b with triallylborane in CDCl3 using 119Sn, 29 Si, and 13C NMR spectroscopy starting from 40 C, it proved possible to identify an intermediate 65, which is the result of 1,1-allylboration. Although the stereochemistry of 65 is wrong for cyclization, allowing the reaction mixture to warm up to room temperature must allow rotation because the signals for 65 vanished and the signals for 1,3stannaborole 30b became dominant.

Scheme 10

Two further derivatives of the 1,3-stannaborole ring system 30c and 30d have been prepared from the corresponding stannanes 64c and 64d in an analogous manner .

4.18.10 Ring Synthesis by Transformation of Another Ring In CHEC-II(1996), there are two reactions involving the synthesis of 2,3-dihydro-1H-1,3-diboroles by transformation of other rings . One of these reactions involves thermal ring contraction of 1,4,5,6-tetramethyl-1,2,3,4-tetrahydro-1,4-diborinine 66 at 160 C to 4,5-diethyl-1,2,3-trimethyl-2,3-dihydro-1H-1,3-diborole 67. Uhm heated a solution of compound 66 in toluene in a pressure tube at the same temperature and obtained 1,2,3,4,5pentamethyl-2,3-dihydro-1H-1,3-diborole 68 (Scheme 11) .

Scheme 11

1239


4.18.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available The heterocycles discussed in this chapter are too diverse and the reported work too little to allow a meaningful discussion of either the synthesis of particular classes of heterocycles with ‘two nonadjacent heteroatoms with at least one boron’ or of the routes to such heterocycles.

4.18.12 Important Compounds and Applications The different classes of heterocyclic compounds described in this chapter are important in as far as their synthetic applications are concerned. The interest in the metal-complexing abilities of these compounds has to do with several group 4 metal complexes of five- and six-membered boron heterocycles that are an important class of homogeneous catalysts for the polymerization of alkenes . Furthermore, the synthesis of novel metal-containing polymers is important since this category of compounds has long been known for its electrical properties .

References P. Binger, Angew. Chem., 1968, 80, 288. J. Edwin, W. Siebert, and C. Kru¨ger, J. Organomet. Chem., 1981, 215, 255. W. Siebert, U. Ender, and W. Herter, Z. Naturforsch, B, 1985, 40, 326. S. Kerschi and B. Wrackmeyer, Chem. Ber., 1988, 121, 1451. W. Weinmann, F. Metzner, H. Pritzkow, W. Siebert, and L. Sneddon, Chem. Ber., 1996, 129, 213. R. Hettrich, M. Kaschke, H. Wadepohl, W. Weinmann, M. Stephan, H. Pritzkow, W. Siebert, I. Hyla-Kryspin, and R. Gleiter, Chem. Eur. J., 1996, 2, 487. 1996CHEC-II(3)767 G. Schmid; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 3, p. 767. 1997CB329 W. Weinmann, H. Pritzkow, W. Siebert, and L. G. Sneddon, Chem. Ber., 1997, 130, 329. 1998JOM107 S. Huck, A. Ginsberg, H. Pritzkow, and W. Siebert, J. Organomet. Chem., 1998, 571, 107. 1998OM2379 A. J. Ashe, III, X. Fang, and J. F. Kampf, Organometallics, 1998, 17, 2379. 1999EJI1685 T. Mu¨ller, M. Kaschke, M. Strauch, A. Ginsberg, H. Pritzkow, and W. Siebert, Eur. J. Inorg. Chem., 1999, 1685. 1999JCM264 K. Albrecht and D. E. Kaufmann, J. Chem. Res. (S) 1999, 4, 264. 1999OM1821 A. J. Ashe, III, X. Fang, and J. F. Kampf, Organometallics, 1999, 18, 1821. 2000EJI1177 C. Ester, A. Maderna, H. Pritzkow, and W. Siebert, Eur. J. Inorg. Chem., 2000, 1177. 2000JOM125 T. Mu¨ller, D. E. Kadlecek, P. J. Carroll, L. G. Sneddon, and W. Siebert, J. Organomet. Chem., 2000, 614–615, 125. 2000RJO965 T. N. Gribanova, P. M. Minyaev, and V. I. Minkin, Russ. J. Org. Chem. (Eng. Transl.), 2001, 36, 965. 2001JOM7 A. Ginsberg, H. Pritzkow, and W. Siebert, J. Organomet. Chem., 2001, 619, 7. 2001ZN73 W. Siebert, S. Huck, and H. Z. Pritzkow, Z. Naturforsch., 2001, 56b, 73. 2002JOM146 B. Wrackmeyer, M. H. Bhatti, S. Ali, O. L. Tok, Yuri, and N. Bubnov, J. Organomet. Chem., 2002, 657, 146. 2002JOM232 B. Wrackmeyer, A. Pedall, W. Milius, O. L. Tok, and Y. N. Bubnov, J. Organomet. Chem., 2002, 649, 232. 2002ZN1125 M. J. Bayer and W. Siebert, Z. Naturforsch., 2002, 57, 1125. 2002ZN1251 B. Wrackmeyer, S. Kerschl, and U. Klaus, Z. Naturforsch., 2002, 57b, 1251. 2003JOM188 B. Wrackmeyer, W. Milius, and S. Ali, J. Organomet. Chem., 2003, 682, 188. 2004JOM429 B. Bettina, Y. Nie, H. Pritzkow, and W. Siebert, J. Organomet. Chem., 2004, 689, 429. 2005JKC329 J.-K. Uhm, J. Korean Chem. Soc., 2005, 49, 329. 1968AG288 1981JOM255 1985ZNB326 1988CB1451 1996CB213 1996CEJ487


Biographical Sketch

George Varvounis was born in Alexandria, Egypt, in 1953. He received his B.Sc. (Honours) degree in chemistry and biochemistry in 1977 at the Polytechnic of Central London, UK, and his M.Sc. degree in applied heterocyclic chemistry in 1979 and Ph.D. degree in organic chemistry in 1982 at the University of Salford, UK. He was appointed lecturer at the Department of Chemistry of the University of Ioannina, Greece, in 1982, assistant professor in 1990, and associate professor in 2001. He spent several short periods on sabbatical leave working with Dr. G. W. H. Cheeseman at Queen Elizabeth College, University of London, in 1983–87, with Professor H. Suschitzky and Dr. B. J. Wakefield at the University of Salford, and with Professor J. A. S. Smith and Dr. C. W. Bird at King’s College London, University of London, in 1988–94. His research interests include the synthesis and properties of heterocyclic compounds, especially benzo- and naphtha-fused tricycles containing one, two, or three nitrogen, nitrogen and oxygen, or nitrogen and sulfur atoms.

1241

4.19 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element C. Cano-Soumillac Northern Institute for Cancer Research, Newcastle-upon-Tyne, UK ª 2008 Elsevier Ltd. All rights reserved. 4.19.1

Introduction

1243

4.19.1.1

Scope

1244

4.19.1.2

Nomenclature

1244

4.19.2

Theoretical Methods

1244

4.19.3


1244

4.19.3.1

X-Ray Diffraction Studies

1244

4.19.3.2

NMR Studies

1245

Ultraviolet and Infrared Spectroscopy

1246

4.19.3.3 4.19.4


1246

4.19.4.1

Physical Properties

1247

4.19.4.2

Conformational Studies

1247

4.19.5


1247

4.19.6


1247

4.19.7


1249

4.19.8


1249

4.19.9

Ring Syntheses – Fully Saturated or Partially Saturated Derivatives

1249

4.19.9.1

Group 6: Chromium, Molybdenum, and Tungsten

1250

4.19.9.2

Group 7: Manganese, Technetium, and Rhenium

1250

4.19.9.3

Group 8: Iron, Ruthenium, and Osmium

1253

4.19.9.4

Group 9: Cobalt, Rhodium, and Iridium

1257

4.19.9.5

Group 10: Nickel, Palladium, and Platinum

1260

4.19.9.6

Group 14: Silicon-Containing Heterocycles

1263

4.19.10


1265

4.19.11


4.19.12


1266


1266

References

1266

4.19.1 Introduction Ring systems with two adjacent heteroatoms and at least one other element were reviewed in (CHEC(1984) and CHEC-II(1996) ). This chapter covers reports up to the end of 2005. The literature was searched by groups within the periodic table.

1243

1244 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element

4.19.1.1 Scope In contrast to CHEC-II(1996) where only rings which have relatively strong -bonds between adjacent atoms were reviewed, syntheses of heterocyclic complexes are also be described in this chapter. The chemistry of such ‘chelates’ or ‘coordination compounds’ is very interesting as the carbon–metal bond is labile and subject to various reactions such as insertion, protonation, or substitution. However, even though the synthesis of these intramolecular complexes is described in Section 4.19.9, their physical properties are not reported in this chapter. As the cyclic complex is in equilibrium with its open-chain form, the structural properties of such compounds may not be indicative of the heterocycle ring at all.

4.19.1.2 Nomenclature IUPAC nomenclature is generally followed using the numbering shown in structure 1. The cyclic structure, when X is a nonmetallic heteroatom and M is a metal, is called a metallaheterocycle or a cyclometallic compound. Most metallaheterocyclopentanes have a stabilizing aromatic ring fused to the five-membered ring but a few cases of unfused stable metallaheterocyclopentanes are known.

4.19.2 Theoretical Methods There are no reports of ab initio or semiempirical methods being used on five-membered ring heterocycles of this class.

4.19.3 Experimental Structural Methods 4.19.3.1 X-Ray Diffraction Studies X-ray diffraction data have focused on determining the conformation of the five-membered ring or substituents, or the geometry around the metal atom. Over the past 10 years, X-ray crystallography has been used routinely and most of the new heterocycles synthesized have been examined by this method. Mention of these results is made in the appropriate sections dealing with the synthesis of the heterocycle. The crystals of compound 2 were submitted to single-crystal X-ray diffraction and the structure revealed a distorted pentagonal bipyramidal geometry around the tungsten center bearing one nitrosyl group, one hydride ligand, three PMe3 ligands, and the bidendate 2-benzylnaphthylamide ligand .

The structure of the pentacoordinate vinylcobalt(III) 3 (L ¼ trimethylphosphine) has been determined by an X-ray diffraction analysis . The cobalt atom is located above the base of a square pyramid and attains pentacoordination with two equatorial phosphorus atoms of trans-trimethylphosphine ligands, a carbon atom of the vinyl group, and an oxygen arom of the phenoxy group. The carbon atom of the acyl group is located at the apex of the square pyramid.

Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element

The molecular structure of compound 4 showed a hexacoordinate cobalt and three P-donor atoms lying in a plane, and two phenolate-O donors and an acyl group arranged in a plane perpendicular to the first .

˚ hydrogen atoms on The structure 5 was also determined by X-ray diffraction. The Rh–Si distance was 2.365(7) A, ˚ The rhodium and silicon were located and refined to provide Rh–H and Si–H distances of 1.541(3) and 1.456(3) A. small Si–Rh–C angle of 80.16(7) was indicative of some strain in the five-membered ring .

Conclusive evidence for the structure 6 was obtained from an X-ray analysis, which confirmed the presence of a spirocyclic unit, with the expected trans-disposition of C-2 and C-12 .

4.19.3.2 NMR Studies Structural characterization by nuclear magnetic resonance (NMR) methods is routine and, in general, mention of the results has been deferred to the sections dealing with the synthesis of particular heterocycles. This section includes results where sufficient work has been performed to suggest patterns and where more unusual techniques have been discussed. The 31P{1H} NMR spectrum of complex 7 showed an AM2X pattern at 13.8, 0.96, and 10.7 ppm, indicating two trans- and two cis-PMe3 ligands in an octahedral geometry. The 1H NMR spectrum showed three magnetically inequivalent PMe3 ligands at 0.90, 1.00, and 1.17 ppm .

1245


The 1H NMR spectrum of 3b showed a pseudotriplet at 1.0 ppm with strong coupling (j2JP,H þ 4JP,Hj ¼ 8.1 Hz) to the trans-PMe3 ligands. The signals of the two geminal protons in the alkenyl group were found in the range expected of alkenyl-CH groups, with coupling constants 2J ¼ 3 Hz. In the 31P NMR spectrum at 30 C, singlets for the transPMe3 groups were observed. The diamagnetic properties of 3b were compatible with a square pyramidal configuration .

In 1998, the structure of compound 8 was determined by various physical methods, including 1H–1H and 1H–13C correlation spectroscopy (COSY), HMBC, and nuclear Overhauser and exchange spectroscopy (NOESY) .

4.19.3.3 Ultraviolet and Infrared Spectroscopy Most of the studies have been carried out on nonstable metallacycles with one or more weak bonds in the intended five-membered ring. However, compound 2, previously described in Section 4.19.3.1, has been analyzed by IR spectroscopy . The spectrum revealed a band at 1535 cm1, which provided the evidence for the presence of an NO group in this complex. Complex 3 has also been analyzed by IR and its spectrum showed bands at 1659 and 1641 cm1 characteristic of the presence of CTO .

4.19.4 Thermodynamic Aspects Because of the wide range of atoms that can occupy sites in the heterocycle ring, it is not possible to make many generalizations about physical and thermodynamical properties. However, it is possible to conclude that many metal– carbon bonds are weak or subject to easy reactions such as protonation, insertion, or redox reactions. Many metal bonds to nitrogen, oxygen, sulfur, silicon, and phosphorus are also labile. Particular attention should be paid to the valence states of heteroatoms: those, whose normal valence state is satisfied without closure of the ring, or those whose valence is exceeded on ring closure, are generally in equilibrium with open-chain or polymeric structures (physical properties of such complexes are not covered in this section).


4.19.4.1 Physical Properties A common feature of many metallaheterocyclopentanes is their sensitivity to hydrolysis, insertion of carbon monoxide, or oxidation on exposure to air. Many are subject to dimerization reactions that are thermally induced or thermally reversed.

4.19.4.2 Conformational Studies There have been no conformational studies on metallaheterocyclopentanes over the period of this review.

4.19.5 Reactivity of Fully Conjugated Rings Metallaheterocycles with the metal atom capable of supporting a carbon–metal double bond, and with oxygen, nitrogen, sulfur, or selenium as the second heteroatom are the only structures capable of full conjugation. These compounds show furan-like aromaticity with the heteroatom p-electrons participating. No examples of this type of ring system were uncovered, undoubtedly due to the stability of the metalla-carbon double bonds required for their formation.

4.19.6 Reactivity of Nonconjugated Rings This section considers both reduced or partially reduced metallaheterocycles, that is, with one or no double bonds. Exposure of the thiaruthenacycle 9 to hydrogen gas (0.1 MPa) in C6D6 led to hydrogenolysis (Equation 1) .

ð1Þ

Treatment of the nickel complex 11 with carbon monoxide (5 atm) led to the formation of butadiene 12 and aldehyde 13 with the formation of Ni(CO)3(PCy3) . The scission of the nickel–oxygen bond of the alkoxy complex 11 was also achieved with ZnMe2 to afford 14 in very good yield (Scheme 1).

Scheme 1

1247

1248 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element Ring opening of azasilacycle 15 has also been observed (Equation 2) .

ð2Þ

Oxacyclopentene 17 underwent a variety of transformations, such as Tamao oxidation, yielding the -hydroxy ketone 18 efficiently, an epoxidation reaction, and transformation into 1,4-diene 20 (Scheme 2) .

Scheme 2

Reactivity of benzo[1,2]oxasilole 21 was also studied . Homoallylic alcohol 22 was obtained by treatment with tetrabutylammonium fluoride (TBAF). Tamao reaction provided the desilylated ortho-phenolic benzyl alcohol 23. Finally, treatment with methyllithium resulted in nucleophilic methylation on silicon and opening of the Si–O bond (Scheme 3).

Scheme 3

Instead of using Tamao conditions, Woerpel and co-workers have oxidized the C–Si bond with t-BuOOH, cesium hydroxide, and cesium fluoride . Oxidation of oxasilacyclopentanes with alkyl


hydroperoxides to provide 1,3-diols was also described . Silicon-tethered ynals were converted into allylic alcohols via a cleavage process that involved stereospecific protodesilylation of the vinyl functionality (Equation 3) .

ð3Þ

4.19.7 Reactivity of Substituents Attached to Ring Carbon Atoms Substituent chemistry is that expected from analogous reactions of those substituents on saturated cyclic hydrocarbons or on aromatic heterocycles.

4.19.8 Reactivity of Substituents Attached to Ring Heteroatoms Acylphenolato(hydrido)cobalt(III) complexes were found to react smoothly with 2-nitrophenol, according to Equation (4) .

ð4Þ

Formal insertion of propynoic acid ethyl ester into Co–H functions afforded pentacoordinate vinylcobalt(III) 3 (Equation 5) .

ð5Þ

4.19.9 Ring Syntheses – Fully Saturated or Partially Saturated Derivatives In general, ring-forming reactions which result in hypervalent heteroatoms give complexes, where one of the ring bonds is weaker than the other ring bonds, that is, formation of a ring bond between the metal atom and the heteroatom generates a formal charge on one or more atomic centers. As such, these complexes are in equilibrium with their openchain and polymeric structures. In contrast to CHEC-II(1996), where only rings that have relatively strong -bonds between adjacent atoms were reviewed, the syntheses of heterocyclic complexes are also described in this section.

1249


4.19.9.1 Group 6: Chromium, Molybdenum, and Tungsten Only one example of a chelated tetracarbonyl chromium-containing complex has been reported during the period under review . Molybdenum- and tungsten-containing complexes have also been studied. Imine insertion into the Mo–H bond of the tetrakis(trimethylphosphine)-molybdenum nitrosyl hydrido complex 29 was performed by Berke and co-workers . Treatment of complex 29 with an equimolar amount of N-naphthylideneaniline in toluene-d8, at room temperature during 4 days afforded the amido complex 30 as the only product (Scheme 4). When the reaction was carried out at 60 C, with 1 equiv of N-naphthylideneaniline, the amino complex 34 was obtained within 2 weeks. Scheme 4 presents a plausible pathway for the formation of product 34. The first step is imine insertion into the Mo–H bond to form the amido complex 30, which subsequently loses one PMe3 ligand and establishes an equilibrium with the agostic complex 31. When the system is heated to 60 C, other equilibria are assumed to come into play leading to the agostic species 32. Oxidative addition of the agostic C–H bond produces 33 and proton transfer to the amide ligand eventually gives 34.

Scheme 4

Similar studies have been investigated by the same research group, replaced the molybdenum with a tungsten atom . Indeed, an insertion reaction of the imine C10H7NTCHPh into the W–H bond of the hydridonitrosyltetrakis(trimethylphosphine)-tungsten(0) 35, followed by an oxidative addition of the C–H bond to the tungsten center gave the complex [W(NO)(H)(PMe3)3(C10H6NCH2Ph)] 2, which was studied by X-ray diffraction (Scheme 5). The insertion of an imine into the M–H bond transition metal hydride is believed to be an important step in the catalytic hydrogenation of such substrates. The reaction was observed when a toluene-d8 solution of 35 was heated at 50 C during 20 days with N-benzylidene-1-naphthylamine affording 2 in 78% yield.

4.19.9.2 Group 7: Manganese, Technetium, and Rhenium Many types of aromatic substrate are known to undergo a cyclometallation reaction when exposed to alkylpentacarbonylmanganese complexes under thermal conditions. It is well established that the treatment of ligand appended arenes with alkylmanganesepentacarbonyl complexes can lead to the formation of [C,Y] heterochelates of Mn(CO)4 (Y being a two-electron donor ligand) (Equation 6). For instance, aromatic compounds such as N,N-dimethylbenzylamine, alkyl benzyl thioethers, 2-phenylpyridine, acetophenone, benzaldehyde, and diazobenzene can be readily


Scheme 5

transformed into the corresponding cyclomanganated products when treated with alkyl-pentacarbonylmanganese complexes . The reaction of PhCH2Mn(CO)5 with the tertiary amine 3,4Me2C6H3CH2NMe2 38 in refluxing n-hexane afforded the corresponding neutral C,N-cyclometallated Mn(I) compounds of stoichiometry Mn(C–N)(CO)4 40a and 40b (Equation 7). The overall yield was 88% and the 40a:40b ratio was 1:2 . In this reaction, with two potential cyclometallation sites, the observed orientational preference was to avoid a steric interaction between the methyl group ortho to the Mn–C bond and a CO unit.

ð6Þ

ð7Þ

Cyclomanganation reactions of (6-acylaryl)tricarbonylchromium complexes have been investigated and the novel heterobimetallic complexes synthesized characterized by X-ray crystallography . Complementary studies have been carried by Djukic and co-workers , who studied the metallation with (6-arene)tricarbonylchromium substrates taking as a model the ortho-manganation reaction promoted by benzylpentacarbonylmanganese (Equation 8).

1251


ð8Þ

A thioether such as 43 also afforded a cyclomanganated product 44 (Equation 9).

ð9Þ

. Some examples of bis-cyclomanganation have also been reported . For example, the reaction of 2,3-diphenylquinoxaline 46 with PhCH2Mn(CO)5 afforded the dinuclear complex 47 (Equation 10).

ð10Þ

Reaction of the 1,5-diphenyl-3-(2-pyridyl)pentane-1,5-dione 47 with 2.5 equiv of benzylpentacarbonylmanganese in petroleum under reflux gave a small amount of the symmetrical di-aryl-manganated product 48 but mostly the complex 49, which is manganated at only one aryl carbon (by Mn(CO)4) but also (by Mn(CO)3 with N- and O-coordination) at the methylene carbon adjacent to the Mn(CO)4-coordinated ketone carbonyl (Scheme 6). The latter is a rare example of direct cyclomanganation at a saturated carbon and the only known case adjacent to carbonyl .

N

(OC)4Mn N

O

O

48

PhCH2Mn(CO)5

+ O

O

petroleum reflux overnight

N

47 (OC)4Mn

O O Mn OC COCO

49 Scheme 6

Mn(CO)4


The synthesis of cyclomanganated metallocycles has also been carried out by reaction between N-benzyl-benzylidene imines and the metallating agent MnMe(CO)5 . Complex 51 was characterized by FABMS and NMR analysis. The proton spectrum provided conclusive evidence on the metallation position: the methinic proton signal in 51 appeared at a value close to that of the methinic proton of the free imines, in agreement with an (E)-configuration for this ligand (Scheme 7).

Scheme 7

The preparation of tropidinyl transition metal complex 53 was achieved by reaction of 4-trimethylstannyltropidine 52 with M(CO)5Br, M ¼ Mn, Re . In complex 53, the tropidinyl ligand is coordinated through the nitrogen and the three–carbon allylic system which serve as a 2/4p-electron donor. It has been characterized by single-crystal X-ray diffraction analysis (Equation 11).

ð11Þ

Finally, pyrazole binding to manganese(I) has been achieved by photoinduced substitution of CO, and the adjacent N4-coordination pocket can accommodate a second metal ion (Equation 12). The heterodinuclear MnZn complex 55 was characterized crystallographically and its redox chemistry investigated by spectroelectrochemical methods .

OC OC

Mn

i, hν, THF

N

N

OC N H

N

ii, KOt-Bu, ZnCl2

N

N N Mn

N

54

N

ð12Þ

Zn

OC CO Cl

N

55

4.19.9.3 Group 8: Iron, Ruthenium, and Osmium The synthesis of only one iron-containing heterocycle was described between 1995 and 2006. The formation of paramagnetic 57 from a stable arylgold(I) phosphine, [Au(1-C-NCN)(PPh3)] 56 and anhydrous FeCl3 in toluene at

1253

1254 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element room temperature was confirmed by X-ray diffraction techniques . The reaction was carried out on millimolar scale and 57 was obtained in good yield. Moreover, the reaction was performed at room temperature, which underlines the nonreductive character of 56 giving an easy access to the formation of C–Fe(III) bonds (Equation 13).

ð13Þ

Komiya and co-workers have studied the successive O–H and sp3 C–H bond activation of ortho-substitued phenols by a ruthenium(0) complex . The reaction of Ru(1,5-cyclooctadiene)(1,3,5-cyclooctatriene) 58 with PMe3 and 2,6-xylenol in hexane caused immediate precipitation of [Ru(5-C8H3-2,6]þ [OC6H3Me2-2,6] 59 as a white powder (Scheme 8) . Treatment of 59 with PMe3 at 70 C for 15.5 h resulted in sp3 C–H bond cleavage of the ortho methyl group in the aryloxy anion giving an oxaruthenacycle complex cis-Ru[OC6H3(2-CH2)(6-Me)](PMe3)4 3b in 69% yield with concomitant formation of 1,3-cyclooctadiene and 2,6-xylenol. A small amount of 60 was also formed in the reaction. The 5-C8H11 moiety was considered to act as the hydrogen acceptor for the C–H bond activation liberating 1,3cyclooctadiene. Complex 3b has been characterized by NMR, IR and elemental analysis.

Scheme 8

With the O–H and sp3 C–H bond activation of ortho-substitued phenols methodology in hand, Komiya and co-workers carried their research forward by synthesizing a divalent thiaruthenacycle complex, the cis-Ru[SC6H3(2CH2)(6-Me)-2S,C](PMe3)4 62 (Scheme 9) . The synthesis, characterization, and reactivity of various ruthenium(II) complexes have been studied extensively by Koten and co-workers (Equation 14) .


Scheme 9

ð14Þ

Treatment of RuCl3?H2O with an equimolar amount of the bisphosphine ligand [2,6-(CH2PtBu2)2-C6H4] 65 in methanol at 80 C in a pressure vessel followed by reaction with carbon monoxide (1 atm) at room temperature resulted in the formation of the saturated complex 66 (Equation 15) . PBut2

i, RuCl3•3H2O MeOH, Et3N, Δ ii, CO, 1 atm, rt

PBut2

65

PBut2 CO Ru CO Cl PBut2

ð15Þ

66

In 2004, Baratta and co-workers achieved the synthesis of the five-coordinate complex RuCl[(2-CH2-6MeC6H3)PPh2][(CO)(2,6-Me2C6H3)-PPh2] 68, according to Equation (16) . The reaction of the 14-electron complex RuCl2[(CO)(2,6-Me2C6H3)-PPh2)]2 67 with formaldehyde in the presence of triethylamine proceeded in high yield via cyclometallation of an ortho methyl group and aldehyde decarbonylation.

ð16Þ

1255

1256 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element The cycloruthenation of substituted N,N-dimethylbenzylamines by [6-C6H6)RuCl(m-Cl)]2 in acetonitrile in the presence of NaOH and KPF6, which led to the formation of corresponding cycloruthenated complexes in good to moderate yields, has also been studied . For example, the work of Le Lagadec and co-workers is illustrated in Equation (17) . As shown in Equation (17), the cycloruthenation of the 3-substituted N,N-dimethylbenzylamine 69 afforded two positional isomers as a result of the Ru(II) attack at the C-2 or C-6 aromatic carbons.

ð17Þ

Treatment of RuHCl(CO)(PPh3)3 72 with [2-(2-pyridyl)phenyl]2Hg proceeded smoothly to form Ru[2-(2-(2pyridyl)phenyl)]Cl(CO)(PPh3)2 73 . In this complex, the [2-(2-pyridyl)phenyl] ligand is bound as a stable five-membered chelate ring (Equation 18).

ð18Þ

Similar transmetallation reactions using mercury reagents of the form Ar2Hg have been performed by Clark and coworkers to deliver osmium complexes Os[2-C,N-(2-phenylpyridyl)Cl(CO)(PPh3)2] 75 from 74 (Equation 19) .

ð19Þ

Preparation and spectroscopic characterization of OsCl(PPh3)(PCP) 76 (PCP ¼ 2,6-(Ph2PCH2)2C6H3) has been performed by Jia and co-workers . Treatment of OsCl2(PPh3)3 with 1,3-(Ph2PCH2)2C6H4 63 in 2-propanol led to the formation of the coordinatively unsaturated complex 76 (Equation 20). The spectroscopic data of the green compound 76 were consistent with a square–pyramidal complex with PPh3 occupying the apical position.

ð20Þ

An analogous complex 78 has been synthesized by Gauvin et al. , by reaction between the diphosphine 77, OsCl2(PPh3)3, and Et3N (Equation 21).


ð21Þ

Similar conditions have been used by Gusev et al. to synthesize complex 54 . From OsCl62, they obtained the 16-electron chloride square–pyramidal compound 54, using triethylamine and methanol as solvent (Equation 22).

ð22Þ

More recently, C–H bond activation and subsequent C-C bond formation promoted by osmium have been investigated by Esteruelas and coworkers . Treatment of OsH2Cl2(Pi-Pr3)2 with 2 equiv of 2-vinylpyridine in toluene under reflux gave rise to the release of H2 and [i-Pr3PH]Cl and the formation of the red complex 81, which was isolated in 70% yield as a 6:4 mixture of the isomers 81a and 81b shown in Equation (23).

ð23Þ

Complex 81 contains two substrate molecules. One of them is metallated, as a consequence of C(sp2)-H bond activation of the CH2 group of the vinyl substituent, whereas the other one is coordinated to the osmium atom by the nitrogen atom and the CTC double bond of the alkene.

4.19.9.4 Group 9: Cobalt, Rhodium, and Iridium Only a few syntheses of cobalt-containing metallacycles have been carried out over the period under review. In 1998, Klein and co-workers reported the synthesis of the 18-electron cobalt(I) complex 83, smoothly formed by an aldehyde reaction with a suitable methylcobalt(I) according to Equation (24) .

ð24Þ

From 1996 to 2005, this research group published extensively on the synthesis of such cobaltacycles . They notably described the reaction of the benzyldiphenylphosphine 84 with [CoMe(PMe3)4] at 70 C in THF affording the ortho-metallated complex 85 (Equation 25).

1257


ð25Þ

Analogously, the formation of the C-metallated complex 87 occurred at 70 C according to Equation (26).

N

Et

CoCH3(PMe3)4

Et N

THF, 20 °C, 18 h Co(PMe3) P Ph2

– CH4, PMe3 PPh2

86

ð26Þ

87

Rhodium-containing complexes have been extensively studied over the period review. Particularly, chelating ligand systems based on 1,3-disubstituted benzenes have been used to obtain the ortho-metallated complexes . The reaction of the chelating bis(phosphine)-3,5-bis((diphenylphosphino)methyl)pyridine 88 with Rh2Cl2(COE)4 (COE ¼ cyclooctene) and Pi-Pr3 in THF/Et3N (3:1) led to the formation of the mononuclear Rh(I) complex 89 (Equation 27) .

ð27Þ

As expected, compound 89 exhibited two signals in the 31P{H}NMR spectrum (intensity ratio 2:1) in accord with the X-ray structure determination (vide supra). A similar reaction has been carried out between the aromatic phosphine alcohol 90 and [RhCl(C8H14)3]2 in THF under a nitrogen atmosphere at room temperature affording the complex 91, as proved spectroscopically by 1H, 1H{31P} and 31P{H}NMR, IR, and FD-MS measurements (Equation 28) .

ð28Þ

When [Rh(Cl)(Nbd)(bipy)] (Nbd ¼ norbornadiene) 92 prepared in situ was treated with Ph2P(o-C6H4CHO) 93 in methanol, oxidative addition of aldehyde to rhodium followed by insertion of norbornadiene into the Rh–H bond occurred (Equation 29) . NMR spectroscopy, including two-dimensional (2-D) experiments, allowed complete characterization of complex 94.


ð29Þ

In addition, the reaction of [{Rh(cod)Cl}2] (cod ¼ 1,5-cyclooctadiene) with Ph2P(o-C6H4CHO) 93 in the presence of 1,2-phenylenediamine(daphen) 95 led to the formation of the chelate-assisted oxidative addition product [Rh(Cl)(H)[PPh2(o-C6H4CO)](daphen)] 96 with displacement of 1,5-cyclooctadiene as shown in Equation (30) .

ð30Þ

In 1998, Mitchell and Tilley described the synthesis of a new rhodium silyl complex . Reaction of (Me3P)3RhCl with (THF)2LiSiHMes2 (Mes ¼ 2,4,6-trimethylphenyl) in toluene resulted in formation of a light yellow solution, from which colorless crystals of compound 5 were isolated after work-up. The presence of both Rh–H ( ¼ 9.90) and Si–H ( ¼ 5.76) resonances in the 1H NMR spectrum and five separate methyl signals suggested the structure 5 shown in Equation (31). Me

Me

Mes

(THF)2LiSiHMes2

97

(Me3P)3RhCl toluene rt, 5 h

H Si H Me3 P Rh

ð31Þ

Me3 P PMe 3

5

Iridium-containing complexes have also been studied over the period reviewed . Treatment of the methoxy-functionalized ligand 98 with IrCl3?nH2O in 2-propanol/water gave the chlorohydrido complex 99 (Equation 32).

ð32Þ

In a similar way, Grimm et al. isolated the iridium hydrochloride complex 101, obtained by heating an isopropanol/ water solution of the ligand 100 in the presence of iridium(III) chloride to 80 C (Equation 33). The red complex 101 dissolved well in polar organic solvents but was air sensitive in solution, whereas in the solid state no decomposition was observed while handling in air.

1259


Bun P

Bun Bun

O2N P

Bun

P

H

IrCl3•nH2O isopropanol/water 80 °C

Bun

100

Bun

O2N

Ir

Cl

ð33Þ

P

Bun Bun

101

4.19.9.5 Group 10: Nickel, Palladium, and Platinum From 1996 to 2005, the synthesis of pincer nickel complexes has been widely described . For example, reaction of ligand 77 with a stoichiometric amount of NiI2 in ethanol at 130 C in a sealed pressure vessel led to the formation of the aryl-nickel complex 102 as shown in Equation (34) . Similar reactions were achieved by Castonguay et al. using different nickel halides (Cl and Br) .

ð34Þ

Kurosawa and co-workers have been studying the oxidative cyclization of 2:2-2-allylbenzophenone nickel complexes leading to the formation of nickelhydrofurans (Equation 35) .

ð35Þ The reaction of 2-allylacetophenone 103 with Ni(cod)2 and PCy3 gave an 2:2-1,5-enone nickel complex 104 quantitatively (Scheme 10). The following reaction of 104 with AlMe3 in C6D6 proceeded very rapidly to give a deep-orange solution of cyclized compound 105. Its structure was confirmed by X-ray diffraction analysis, showing a unique nickelacycle with a bridging methyl group .

Scheme 10

In addition, the synthesis of enolate complexes of nickel has been carried out by Campora and co-workers . Treatment of a THF solution of Ni(C6H4-o-C(O)CH3(Cl)(dippe) 106 with 1 equiv of KOt-Bu allowed the preparation of the nickel enolate 107 in good isolated yield (60%). O-Coordination of the enolate fragment could be proposed on the basis of the NMR spectra. Thus, the terminal methylene group gave rise


to two signals in the 1H spectrum at 4.62 and 4.79 ppm that correlated (1H–13C HETCOR experiment) with a resonance at 75.9 ppm which exhibited no coupling to phosphorus (Equation 36).

Pri2 P Me Cl Ni P Pri2

106

O KOt-Bu THF rt, 1 h

Pri2 P O

13

C

H H

Ni P Pri2

ð36Þ

107

Five-membered nickelacycles have also been investigated by Ceder et al. (Equation 37) .

ð37Þ

In 1998, Klein et al. showed that a methylnickel complex activates the C(O)–H function of 2-diphenylphosphinobenzaldehyde 93 to form a five-membered ring in which OC is axial and P equatorial in the trigonal bipyramidal configuration of nickel compound 110 (Equation 38) .

ð38Þ

Finally, the reaction of succinic anhydride 111 with a 1:2 mixture of (cod)2Ni and a monodentate phosphine generated a reactive monomeric nickelalactone, which underwent rapid aggregation to form cyclic oligomer 112 (Equation 39) .

ð39Þ

Palladacycles have also been investigated. They are a fascinating family of organometallic complexes with applications in many areas, including total synthesis, materials science, and biological and supramolecular chemistry. Moreover, they are often air-stable, are readily synthesized, and possess a range of types of metallated carbon and different types of donor groups bound to palladium (P-, N-, S-, and O-containing groups). Several pincer complex syntheses have been described over the review period . The most recent is the reaction of the cis-bis(di-t-butylphosphinomethyl)cyclohexane (cis-PCyP) 113 with palladium

1261

1262 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element chloride affording C8 and C1 symmetrical complex 114, where the PCyP ligands are coordinated in a meridianal fashion through the two phosphorus atoms and the cyclometallated C-1 carbon of the cyclohexane ring (Equation 40) . Me PdCl2,

PBut2

N

PBut2 Pd Cl

Me

dioxane, 100 °C

PBut2

ð40Þ

P But2

113

114

In addition, dimer palladacycles have been extensively studied over the last 10 years. Phosphapalladacycle and nitropalladacycle syntheses have been widely described . One of many examples is the successful cyclopalladation of compound 115 achieved using only Pd(OAc)2 as the palladation agent in acetic acid solution, followed by treatment with LiCl (Equation 41) . Me Me

O O Me

Bun N

i, Pd(OAc)2, AcOH 80–88 °C, 50 h ii, excess LiCl, Me2CO

Me

N Pd Cl

ð41Þ 2

25 °C, 12 h

115

116

Ferrocene-based palladacycles have also been investigated . Among several studies, Troitskaya and co-workers achieved the cyclopalladation of the Schiff base 117 with a chiral center (Equation 42), leading to a mixture of three products, two of which were planar chiral diastereoisomers formed from homoannular substitution into the aldehyde fragment. The third product was a result of an unusual heteroannular palladation of the nitrogen in the starting aldimine .

ð42Þ

Cyclopalladated sulfur-containing and oxygen-containing complexes have also been synthesized. The insertion of phenylacetylene 122 into the palladium–carbon bond of complex 121 yielded the palladacycle 123 (Equation 43).


+ BAr –

Pr i

4

N

Me Pd

N

Me

Pri CH2Cl2

+

–50 °C to 0 °C, 2 h

CO

N

4

Me Pd O

N

Me

ð43Þ

Pri

Pr i

121

+ BAr –

Ph

122

123

Ar = 3,5-(CF3)2C6H3

Similar reactions have been achieved with platinum. Syntheses of phosphaplatinacycles and nitroplatinacycles have been described using PtCl2(COD) or PtMeCl(COD). Intramolecular activation of C(aryl)–X bonds (X ¼ Br, Cl, F, and H) at platinum(II) has been achieved for amine– imine ligands such as RCHTNCH2CH2NMe2, in which R was an aryl group . A series of complexes with bipyridine ligands has also been described .The reaction between 6,69-diphenyl-2,29-bipyridine 124 and [Pt(Me)2(DMSO)2] was carried out with a platinum/ligand ratio of 2:1 in toluene at 80 C (Equation 44). The reaction was slow and led to the isolation of a yellow product that was insoluble in the reaction medium, was stable in air, and had high thermal stability .

ð44Þ

As previously observed for the palladium complexes, pincer ligand systems coordinated to Pt(II) centers have been described in the literature between 1995 and 2005 . Platinum-containing dimers have also been synthesized . Metallation of 2,6-diphenylpyridine 126 by potassium tetrachloroplatinate in acetic acid gave a monocyclometallated chloride-bridged dimer 127 (Equation 45) .

ð45Þ

4.19.9.6 Group 14: Silicon-Containing Heterocycles Silicon-containing heterocycles have been widely studied over the review period. Belzer et al. have studied nitrogencontaining silacycles and within their research work, they described the photolysis of a trisilane 128

1263

1264 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element in a hydrocarbon matrix at 196 C and observed an intense absorption at max ¼ 478 nm, which was attributed to the intramolecularly coordinated silylene 129 (Equation 46) .

ð46Þ

Nitrogen-containing silacycles have also been synthesized by thermolysis of bis(pentacoordinate) silicon compounds in the presence of butyllithium , by reaction of various (dichloromethyl)oligosilanes R(Me3Si)2–SiCHCl2 with alkyllithium derivatives , and have also been obtained by intramolecular silylformylation of 1-bis(dimethylsilyl)amino-3-octyne 130 in the presence of Rh2Co2(CO)12, in toluene at 60 C (Equation 47) .

Bun N(SiMe2H)2

130

Rh catalyst CO (10 atm)

Bun

benzene-d6 60 °C, 14 h

OHC

N Si Me Si H Me Me Me

ð47Þ

131

Oxasilacyclopentenes have been synthesized either by silacyclopropenation of alkynes utilizing Ag3PO4 as catalyst , or by reaction of ketones and alkynylsilanes in the presence of a catalytic amount of a nucleophilic initiator (Equation 48) .

ð48Þ

Oxasilacyclopentanes have been extensively studied over the period reviewed and many different methodologies have been developed for their syntheses. Intramolecular radical cyclizations , intramolecular silylformylation of silyloxyalkynes promoted by catalysts such as Rh , Ni , hydrosilylation of homopropargyl hydrodimethylsilyl ethers promoted by solvated Pt-atoms (Equation 49) , and also photoinduced intramolecular cyclisation of alkynyl-substituted pentamethyldisilanes have been reported .

ð49Þ

Analogously, intramolecular hydrosilation reactions have been carried out with alkenes: cyclization of alkenyloxysilanes catalyzed by thiols and by Pt has been described. In addition, intramolecular temporary silicon-tethered rhodium-catalyzed [4þ2þ2]-cycloisomerization reactions have been carried out by Evans and Bawn (Equation 50) .

ð50Þ


Silicon–oxygen heterocycles from thermal , photochemical , transition-metal-catalyzed and radical reactions have been extensively described from 1995 to 2005. Woerpel and co-workers have studied many different strategies to obtain oxasilacyclopentanes . Particularly, they reported the reaction of ,-unsaturated (or not) alkenes with silacyclopropanes: ZnBr2 , CuBr2 , AgOTf , AgOTf/ZnBr2 , AgOTf/CuI , AgOCOCF3 , AgOCOCF3/ZnBr2 catalyzed reactions have been reported. Another way to synthesize oxasilacyclopentanes is the thermal insertion reaction of 1-formylpyrrolidine 138 into silirane trans-139 which proceeded cleanly in hexanes at 120 C in a sealed tube to provide the N,O-acetal 140 as a single product (Equation 51) .

ð51Þ

Rhodium silyl complexes have also been investigated over the review period. As previously described in Section 4.19.9.4, Mitchell and Tilley have reported the reaction of (Me3P)3–RhCl with (THF)2SiHMes2 (Mes ¼ 2,4,6trimethylphenyl) in toluene to form the metallated species (Equation 31) . Finally, Benin et al. have synthesized the pincer silicon complex 142 from the ligand 141 in THF at room temperature (Equation 52) .

Me N Bu

Me Li Me N Me

t

141

N

Me2SiCl2

Bu

Me⎤

Me Me Si Me

t

THF, rt

N

+

Cl–

ð52Þ

Me Me

142

4.19.10 Ring Synthesis by Transformation of Another Ring Oxasilines have generally been found to be of limited stability . Indeed, by passing through a silica gel column or in CDCl3 solution, 143 was converted, by ring contraction and incorporation of an oxygen atom, into 5-acetyl-2,5-dihydro-1,2-oxasilole 144 (Equation 53).

ð53Þ

Oxasilacyclopentanes have been synthesized by insertion reactions of silacyclopropanes with carbonyl compounds . For example, copper-catalyzed insertion into silacyclopropane 145 is described in Equation (54) .

1265


ð54Þ

4.19.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available No update of this section, which was covered in CHEC-II(1996) , has been found necessary as no new classes of compounds have been described over the period reviewed. Syntheses of various heterocycles have been described in Section 4.19.9.

4.19.12 Important Compounds and Applications Cyclopalladated compounds, illustrated below, have been found to be excellent catalysts , and particularly effective for sp2–sp2 carbon coupling processes such as Heck and Suzuki reactions : Me Me

Me

S

Pd

Bun

Cl P 2

Dupont catalyst

Pd

O

CF3 O

2

(o -Tol)2

Hermann/Beller catalyst

Me

N

Pd

O

O

Pd N

O

O 2

2

Pri

Milstein catalyst

Blackmond/Pfaltz catalyst

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Organomet. Chem., 2002, 653, 54. A. Suzuki, J. Organomet. Chem., 2002, 653, 83. J. C. Ro¨der, F. Meyer, R. F. Winter, and E. Kaifer, J. Organomet. Chem., 2002, 641, 113. G. Ebeling, M. R. Meneghetti, F. Rominger, and J. Dupont, Organometallics, 2002, 21, 3221. C. Michon, J.-P. Djukic, Z. Ratkovic, J.-P. Collin, M. Pfeffer, A. De Cian, and J. Fischer, Organometallics, 2002, 21, 3519. M. Contel, M. Stol, M. A. Casado, G. P. M. Van Klink, D. D. Ellis, A. L. Spek, and G. Van Koten, Organometallics, 2002, 21, 4556. H. A. Y. Mohammad, J. C. Grimm, K. Eichele, H.-G. Mack, B. Speiser, F. Novak, M. G. Quintanilla, W. C. Kaska, and H. A. Mayer, Organometallics, 2002, 21, 5775. C. Michon, J.-P. Djukic, Z. Ratkovic, and M. Pfeffer, Tetrahedron Lett., 2002, 43, 5241. W. Baratta, S. Stoccoro, A. Doppiu, E. Herdtweck, A. Zucca, and P. Rigo, Angew. Chem., Int. Ed., 2003, 42, 105.

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2003CC1742 2003CC3002 2003EJI853 2003EJI2749 2003ICA179 2003JA1482 2003JA6532 2003JA11041 2003JCD3350 2003JOM112 2003JOM215 2003OL4325 2003OM2396 2003OM3967 2003OM5243 2003TA2331 2003ZFA2408 2004CC122 2004EJI1538 2004EJI4484 2004ICA1854 2004ICA2818 2004IC725 2004ICA4015 2004JA9522 2004JA11150 2004JA11802 2004JCD2957 2004JOC4007 2004JOC8101 2004JOM1739 2004JOM1806 2004JOM2382 2004JOM4820 2004JOM4889 2004OM224 2004OM5432 2004OM5653 2004OM5833 2004OM6264 2004PS955 2005CEJ2319 2005CEJ3268 2005EJI1671 2005IC2443 2005IC3863 2005JA2046 2005JA2388 2005JA12810 2005JCD580 2005JOC648 2005JOM3193 2005JOM3348 2005JOM3976 2005JOM4822 2005OL4995 2005OM77

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1269

1270 Five-membered Rings with Two Adjacent Heteroatoms with at least One Other Element Biographical Sketch

Celine Cano-Soumillac was born in Angouleme, France, in 1977. She studied Organic Chemistry at the University of Poitiers, France. In 1999, she went to Paris as a predoctoral fellow and worked on asymmetric synthesis of substituted piperazines from phenylglycinol derivatives, under the supervision of Prof. H.-P. Husson. In 2000, she moved back to Poitiers, where she worked on the synthesis of biomolecules by 1,3-dipolar cycloadditions with carbohydrates and received her Ph.D. degree in 2004. She then joined the group of Prof. John A. Joule at the University of Manchester, UK as a postdoctoral fellow and worked on the synthesis of analogues of cofactors of oxomolybdoenzymes. She now holds a research associate position in the Northern Institute for Cancer Research, at Newcastle University, UK, where she works on the synthesis of inhibitors of DNA-dependent protein kinase. Her research interests include heterocyclic chemistry, carbohydrates chemistry, asymmetric synthesis, and development of new synthetic methodologies.

4.20 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element C. Cano-Soumillac Northern Institute for Cancer Research, Newcastle-upon-Tyne, UK ª 2008 Elsevier Ltd. All rights reserved. 4.20.1

Introduction

1272

4.20.1.1

Scope

1272

4.20.1.2

Nomenclature

1272

4.20.2

Theoretical Methods

1272

4.20.3


1273

4.20.3.1

Electron Diffraction Studies

1273

4.20.3.2

X-Ray Diffraction Studies

1273

4.20.3.3

NMR Studies

1275

4.20.3.4

Ultraviolet and Infrared Spectroscopy

1279

4.20.4 4.20.4.1 4.20.4.2


1279

Physical Properties

1280

Conformational Studies

1280

4.20.5


1280

4.20.6


1280

4.20.7


1281

4.20.8


1281

4.20.9

Ring Syntheses – Fully Saturated or Partially Saturated Derivatives

1282

4.20.9.1

Group 6: Chromium, Molybdenum, and Tungsten

1282

4.20.9.2

Group 7: Manganese, Technetium, and Rhenium

1282

4.20.9.3

Group 8: Iron, Ruthenium, and Osmium

1282

4.20.9.4

Group 9: Cobalt, Rhodium, and Iridium

1284

4.20.9.5

Group 10: Nickel, Palladium, and Platinum

1285

4.20.9.6

Group 14: Silicon-Containing Heterocycles

1291

4.20.9.6.1 4.20.9.6.2 4.20.9.6.3 4.20.9.6.4 4.20.9.6.5

1,3-Disilacyclopentanes and 1,3-disilacyclopentenes 1-Sila-3-boracyclopentanes 1-Aza-3-silacyclopentanes 1-Oxa-3-silacyclopentanes 1-Thia-3-silacyclopentanes

1291 1295 1297 1299 1300

4.20.9.7

Germanium-Containing Heterocycles

1300

4.20.10


1302

4.20.11


4.20.12


1302


1302

References

1302

1271

1272 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element

4.20.1 Introduction Ring systems with two nonadjacent heteroatoms and at least one other element were reviewed in CHEC-II(1996) . This chapter covers reports up to the end of 2005. The literature was searched by groups within the periodic table.

4.20.1.1 Scope In contrast to CHEC-II(1996), where only rings which have relatively strong -bonds between adjacent atoms were reviewed, syntheses of heterocyclic complexes are also described in this chapter. The chemistry of such ‘chelates’ or ‘coordination compounds’ is very interesting as the carbon–metal bond is labile and subject to various reactions such as insertion, protonation, or substitution. However, even though the synthesis of these intramolecular complexes is described in Section 4.20.9, their physical properties are not reported in this chapter. As the cyclic complex is in equilibrium with its open-chain form, the structural properties of such compounds may not be indicative of the heterocyclic ring at all. Furthermore, as in CHEC-II(1996), the majority of the heterocycles which fall under the auspice of this chapter contain silicon and, where this is the case, it has been elected to group them together instead of using the general section headings employed in other chapters. Accordingly, to simplify access for the reader, it has proved easier to present other heterocycles in order of the position of their key heteroatom in the periodic table.

4.20.1.2 Nomenclature IUPAC nomenclature is generally followed using the numbering system shown in structure 1. The cyclic structure, when X is a nonmetallic heteroatom and M is a metal, is called a metallaheterocycle or a cyclometallic compound. Most metallaheterocyclopentanes have a stabilizing aromatic ring fused to the five-membered ring but a few cases of nonfused stable metallaheterocyclopentanes are known. 3

X

4

2 5

M 1

1

4.20.2 Theoretical Methods Most of the reported studies have been carried out on nonstable metallacycles with one or more weak bonds in the five-membered ring. However, the molecular structure of 3,3-dimethyl-3-silatetrahydrofuran 2 has been studied by ab initio calculations . Ab initio geometry optimization was carried out by using the GAUSSIAN-92 program with the HF/631G* basis set. The calculation was performed assuming C1 symmetry, no assumptions regarding the structure were made, and it converged to a single stable conformer very similar to the ‘O-envelope’. In addition, the methylene fragments were slightly tilted but the distortion of the Me2Si moiety was found to be negligible. The methyl groups had a staggered configuration with respect to the Si–CMe bonds. Me Si Me O

2 Wrackmeyer et al. have described the reaction of 1-boraadamantane 4 with the 4-methylene-3-borahomoadamantane 3 . The intermediate 6 was proposed, considering the highly Lewis-acidic character of the boron atoms in 5 (Scheme 1). The authors suggested that the conversion of 6 into 7, by a 1,2-shift of a CH2 group from the

Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element

boron to the neighboring carbon atom in each half of the molecule, should be straightforward. According to semiempirical AM1 calculations, they found that 7 is more stable than 6 by 18.9 kcal mol1 and 6 is higher in energy than 5 by 28 kcal mol1. Me

SiMe2 Me

Me Me

B

B

Si

B +

Me

3

4

Me B

5

Me Me Me Si

Me

Me Si

Me

– B

B B

+ +

Me

7

B Me –

6

Scheme 1

4.20.3 Experimental Structural Methods 4.20.3.1 Electron Diffraction Studies The molecular structure of 3,3-dimethyl-3-silatetrahydrofuran 2 has also been studied by gas-phase electron diffraction (GED) . Assuming a correlation between the barrier of inner rotation in aliphatic molecules and the sizes of torsional angles within the cyclic molecules, the half-chair cTc conformer could be predicted as the most stable form. Gromov et al. actually found that the resulting conformation was close to one obtained by ab initio calculation, that is, the ‘O-envelope’, slightly distorted.

4.20.3.2 X-Ray Diffraction Studies X-Ray diffraction data have focused on determining the conformation of the five-membered ring or substituents, or the geometry around the metal atom. Over the past 10 years, X-ray crystallography has been used routinely, and most of the new heterocycles synthesized have been examined by this method. Mention of these results is made in the appropriate sections dealing with the synthesis of the heterocycle. The structure of the methylene-substituted metallalactone 8 was determined by a single crystal X-ray study . Pale yellow monocrystals of this product were grown from a hexane/dichloromethane (90/10) solution at 30 C, and Cabon et al. described the structure of the metallacycle as quasi-planar. The presence in the metallacycle of the sp2 carbon linked to the methylene group was indicated by the high value of the C(5)–C(4)–O angle, 118.1(2) . Compared to other metallalactones, the presence of the exocyclic methylene group on the metallacycle of 8 induced significant modifications of interatomic distances. 3

O OC OC

2

O

4 5

Fe

1

O CO CO

8 The crystal structure of yellow metallacyclic–osmium(IV) complex 9 was also reported . The distribution of ligands around the osmium atom can be described as a four-legged piano-stool geometry with the carbon atom C-5 of the metallated phenyl group disposed transoid to the hydride ligand. The bidentate carbon donor

1273

1274 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element ligand acts with a bite angle of 75.5(2) . The five-membered metallacycle showed an envelope conformation with the osmium atom displaced by 0.217(8) A˚ from the plane defined by the oxygen and the carbon atoms.

2 1

Pri

3P

Os

H

5

Ph C H O3 4

9 An X-ray crystal structure of complex 10 indicated the absolute configuration of the metal-bonded sp3-hybridized stereogenic carbon as R, allowing assignment of the absolute configuration of the diastereomer 10 as (R,S,S) . Me

Me

Ph2P

PPh2 Pd

H

O

COOEt

10 The structure of palladacycle 11, an azaheterocycle analogue of 10, has also been determined by X-ray diffraction , showing the (S)-configuration of the palladium-bonded stereocenter.

Me2N

NMe2 Pd N Tf

COOEt H

11 A colorless single crystal of 12 for an X-ray diffraction study was successfully grown from a concentrated hexane solution . The structure of 12 was revealed to be a five-membered ring with a trans-relationship between the two phenyl substituents. The torsion angle of Ca–Cb–Cc–Cd was 63.4 .

SiMeCl2 Cl2Si

c b

SiCl2 a

d

12 In the research work of Wrackmeyer et al., the molecules of compound 13 were found in layers which were separated by dichloromethane molecules (disordered) . There were no evident intermolecular interactions and the endocyclic Sn–C bonds were slightly longer than the exocyclic Sn–C bonds. The boron atoms were trigonal planar, within experimental error. All the C–C bonds next to the boron atoms were found to be elongated relative to the other C–C bonds in 13.


Me Me Me3Si Sn B B Me3Si

13 Compounds 14a and 14b were structurally characterized by single crystal X-ray diffraction. They crystallized in the space group Pbca 14a and P21/c 14b and their molecular structures were reported . The sixmembered rings of the bicyclic heterocycles were almost planar, whereas the five-membered rings adopted envelope conformations. N O

N

OEt O

N

OEt

N

SiMe2

SiPh2

14a

14b

X-Ray crystal structure determination of compound 15 (from dimethylformamide (DMF)) revealed a trigonal bipyramidal coordination environment around the pentacoordinate silicon atom , distorted by 16% toward square pyramidal along the Berry pseudorotation coordinate . The observed bond lengths were in accordance with those previously reported for pentaorganosilicates , the apical Si–C bonds being distinctly longer than the equatorial bonds. There were no close contacts with the ammonium cation, which was disordered in one butyl chain. –

N Si Me N

(n-Bu)4N+

15 The X-ray structure of tetracycle 16 was reported by El Kettani et al., who noted the elongation of the two intracyclic Ge–C bonds due to high steric hindrance.

Me Mes2Ge MeOC O

N H

Ph

Mes =

Me Me

16

4.20.3.3 NMR Studies Structural characterization by nuclear magnetic resonance (NMR) methods is routine, and, in general, mention of the results has been deferred to the sections dealing with the synthesis of particular heterocycles. This section includes results where sufficient work has been performed to suggest patterns and where more unusual techniques have been discussed.

1275

1276 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element Previously described in Section 4.20.3.2, the metallacyclic–osmium(IV) complex 9 has also been characterized by NMR . In agreement with the presence of a hydride ligand in 9, the 1H NMR spectrum of this compound in benzene-d6 at room temperature contained at 13.94 ppm a doublet with an H–P coupling constant of 41.1 Hz. In the low-field region of the spectrum, the most noticeable resonance was a singlet at 8.36 ppm, corresponding to the OsC-hydrogen atom. These unusual chemical shifts seem to be a consequence of the ring current effect of the aromatic rings of this polycyclic system. The 31P{1H} NMR spectrum showed a singlet at 19.0 ppm.

2 1

Pri

3P

Os 5

H

Ph C H O3 4

9 Metallacycle 17 has been characterized by NMR . In the 1H NMR spectrum, the two alkene protons H-12 and H-13 appeared as two multiplets at 3.65-3.13. The 31P{1H} NMR spectrum was temperature dependent and at 90 C displayed three doublets. The high-field signal near 70 ppm was attributed to the P3 phosphonium atom coupled to the two phosphorus ‘nuclei’, P1 and P2, of the phosphonite ligands. +

EtO H12 EtO P3 C C H13 Ph Co P′1

P′ = PPh(OEt)2

P′2 CO

17 The 13C NMR spectrum of complex 18 displayed an acyl carbon at 259.6 ppm, a carbonyl (cyclic CO2 group) at 222.8 ppm, and an unresolved broad signal between 207.7 and 209.3 ppm for the other CO of the molecule. The resonance of the quaternary carbon of the metallacycle, substituted with an SCH3 group, was observed at 95.5 ppm . – O OC OC

OMe O Me Fe CO

O

SMe

O

18 Resonances at 5.50 and 5.17 ppm (t, J(1H–31P) ¼ 8.5–8.7 Hz) in the 1H NMR (500 MHz, CDCl3) spectrum of palladacycle 19a and 19b were assigned to the methine protons attached to the stereogenic metal-bonded carbons . The palladium-bonded methine carbons were found to resonate at 95.9 and 98.5 ppm (dd, J(13C–31P) ¼ 84.4–85.3, 5.4–5.7 Hz) in the 13C NMR (125 MHz, CDCl3) spectrum. Also, two pairs of doublets were detected in the 31P NMR (162 MHz, CDCl3) spectrum. Me

Me

O

O

H

H

Ph2P Pd O

PPh2 COOEt H

19a

Me

Me

O

O

H

H

Ph2P Pd

PPh2 CO2Et

O

19b

H


The structure of palladacycle 20, analogue of compound 19, was also elucidated by NMR spectroscopy . Thus, complex 20 displayed a 1H NMR signal for the methyl (Pd–C–CH3) resonance at 1.75 ppm, a 13C NMR signal for the Pd-bonded sp3-hybridized tertiary carbon (Pd–Csp3) at 93.5 ppm. By 31P NMR analyses of crude reaction mixtures, ligand displacement reactions of palladacycles (N,N,N9,N9-tetramethyl-1,2ethylenediamine bidentate)Pd-1-C6H4-2-OC(R1)COOEt with monodentate phosphines (PPh3 and PPh2Me) were also reported. Me2N

NMe2 Pd

COOEt Me

O

20 The structure of platinacycle 21 was determined by NMR measurements , which showed the aryl hydrogens between 5.99 and 6.92 ppm as multiplets coupled to 31P, with the expected satellites due to the coupling with 195Pt. The CH2 hydrogens appeared as a dd (3J(31P–1H) ¼ 4.4 and 2.9 Hz) with 2J(1H–195Pt) ¼ 49.5 Hz. The 13 C{1H} NMR spectrum of 21 showed the CH2 carbon at ¼ 85.99 ppm as a dd due to the coupling with two distinct phosphines (2J(13C–13C) ¼ 93.8, 5.3 Hz) with a corresponding coupling to 195Pt (1J ¼ 683.2 Hz). The 31P{1H} NMR spectrum showed a resonance at ¼ 28.36 ppm as a singlet, although the corresponding 195Pt satellites appeared as a pair of doublets corresponding to 1J couplings of two different 31P with 195Pt of 2146 and 1888 Hz and 2 31 J( P–31P) ¼ 14.2 Hz. O Pt Ph3P PPh3

21 The 13C NMR spectrum of metallacycle 22 revealed two resonances at 7.8 and 8.2 ppm, three resonances at 128.3, 132.4, and 148.1 ppm, and a single resonance at 191.2 ppm, due to Et2Si carbons, phenylene ring carbons, and alkene carbons, respectively . In addition, the 29Si NMR spectrum showed a single resonance at 2.7 ppm at much lower field that that of the silicon atoms in 5,6-benzo-1,4-disilacyclohexa-2,5-dienes, indicating that compound 22 must have a 4,5-benzo-1,3-disilacyclopent-4-ene structure. Et2 Si

Et2 Si

Si Et2

Si Et2

22 The configuration of compound 23 was characterized by analyses of 1H NMR data . The spectrum showed two singlets at 1.64 and 3.62 ppm for two protons of a methylene and for two benzylic protons, respectively, indicating a trans-relationship between the two phenyl substituents on the five-membered ring, that is, the two protons of the methylene and the two benzylic protons are in chemically equivalent environments. Cl2Si

SiCl2

23 Previously described in Section 4.20.2, the progress of the synthesis of the octacyclic 7-metalla-2,5-diboranorbornane derivative 7 was followed by 29Si NMR spectroscopy . The signals at ¼ 19.3 and 7.0 ppm were tentatively assigned to 3 and 5, present in the reaction mixture (Scheme 1).

1277


Me Me Me Si B B Me

7

The depicted structure of 24 came from 1H NMR observations . Examination showed a nuclear Overhauser effect (NOE) correlation between H-29 and one of the SiCH2 (11%) protons and between the 29-Me and H-39 (4%). H N

O

O

N

O TBDMSO MeO

Me

Si Me Me

24 The 29Si NMR spectrum of pentaorganosilicate 25 was recorded at 50 C to minimize signal broadening . 1H NMR, 13C NMR, heteronuclear multiple quantum correlation (HMQC), and heteronuclear multiple bond correlation (HMBC) spectroscopic measurements were also performed. The observed JC2,Si value of 86 Hz was similar to that of a typical Si(sp2)–C(sp2) bond, while the JC-29,Si value of 30 Hz was much smaller than that of a Si(sp3)–C(sp2) bond (64–70 Hz). –

5′

6′

4′

1′

3′ 3 2

4 5

N

2′

Si Me

[Li(THF)4]+

N

25 1

H, J-modulated 13C, and 29Si NMR spectra of compound 26 were reported . Its structure was proved by the signals of the diastereotopic protons of all three methylene groups and two signals of diastereotopic Me groups in the 1H NMR spectrum. O S Me2Si

26 Finally, the structures of 16 and 27 were deduced from their NMR data . El Kettani et al. reported that due to the hindered rotation of the two nonequivalent mesityl groups caused by the great steric hindrance, the four ortho-methyl groups of the mesityls appeared as broad signals. They were spread over a very large range (from 0.96 to 2.97 ppm) since the steric hindrance and the cyclic structure induced a special blocked position relative to the CR2 group. The spectroscopic data for 16 and 27 featured very surprising extremely low-field shifts (8.80 and 8.76 ppm respectively) of one proton of the fluorenylidene group.


Me

MeOC O

Mes =

Mes2Ge

Mes2Ge Ph

N H

(EtO)2P O

Ph

N H

16

Me Me

27

4.20.3.4 Ultraviolet and Infrared Spectroscopy There are no comprehensive studies reported on the ultraviolet (UV) and infrared (IR) spectra of 1,3-metallaheterocycles. Only studies on nonstable metallacycles with one or more weak bonds in the intended five-membered ring have been described in the literature. However, IR spectroscopy has been used as a routine method to characterize intermediates and products of several reactions. Thus, the synthesis of 8, characterized by X-ray crystallography (Section 4.20.3.2), was performed at 10 C and monitored by IR spectroscopy . Metallacycle 8 was characterized by three (CUO) bands at 2069, 2004, and 1987 cm1 and by (CTO) and (CTC) bands at 1678, 1639, and 1592 cm1. 3

O OC OC

O

2

4 5

Fe

O CO CO 1

8 Moreover, spectroscopic investigations on the protonation of alkynylcobalt complexes with HBF4?Et2O allowed Albertin et al. to propose a reaction path . Palladacycles have also been characterized by IR spectroscopy . Thus, to provide insight into the bonding mode of palladium enolates in complexes 28–30, IR spectroscopic analyses were performed by Lu et al. They revealed (CTO) bands at 1687, 1676, and 1676 cm1 for compounds 28, 29, and 30, respectively.

MePh2P PPh2Me Pd Me O

COOEt

28

MePh2P PPh2Me Pd Pri O

29

COOEt

MePh2P PPh2Me Pd Ph O

COOEt

30

4.20.4 Thermodynamic Aspects As previously mentioned in Chapter 4.19 of CHEC-II(1996), because of the wide range of atoms that can occupy sites in the heterocycle ring, it is not possible to make many generalizations about physical and thermodynamical properties. However, it is possible to conclude that many metal–carbon bonds are weak or subject to easy reactions such as protonation, insertion, or redox reactions. Many metal bonds to nitrogen, oxygen, sulfur, silicon, and phosphorus are also labile. Particular attention should be paid to the valence states of heteroatoms: those, whose normal valence state is satisfied without closure of the ring, or those whose valence is exceeded on ring closure, are generally in equilibrium with open-chain or polymeric structures (physical properties of such complexes will not be covered in this section).

1279


4.20.4.1 Physical Properties A common feature of many metallaheterocyclopentanes is their sensitivity to hydrolysis, insertion of carbon monoxide, or oxidation on exposure to air. Many are subject to dimerization reactions that are thermally induced or thermally reversed.

4.20.4.2 Conformational Studies There have been no conformational studies on metallaheterocyclopentanes over the period of this review.

4.20.5 Reactivity of Fully Conjugated Rings As previously mentioned in Chapter 4.19, metallaheterocycles with the metal atom capable of supporting a carbon– metal double bond, and with oxygen, nitrogen, sulfur, or selenium as the second heteroatom, are the only structures capable of full conjugation. These compounds show furan-like aromaticity with the heteroatom p-electrons participating. No examples of this type of ring system were uncovered, undoubtedly due to the stability of the metallacarbon double bonds required for their formation.

4.20.6 Reactivity of Nonconjugated Rings This section considers both reduced or partially reduced metallaheterocycles, that is, with one or no double bonds. Most of the bibliographic data appropriate to this chapter deal with the preparation and characterization of the metallacycles and, accordingly, there have been little data on their reactions. The only examples found in the literature concerned silicon-containing heterocycles. Stable silicates with five carbon substituents are extremely rare. Such pentacoordinate anions have been successfully synthesized by Couzijn et al. by reaction of 31 with methyllithium at 78 C (Equation 1) . – N N Si

MeLi, THF –78 °C

N

31

Si Me N

[Li(THF)4]+

ð1Þ

25

The relative stability of five-membered S-functional derivatives of 1,3-thiasilacycloalkanes has been studied by Suslova et al. (Scheme 2) . Oxidation of 3,3-dimethyl-3-sila-1-thiacyclopentane 32 with 1 equiv of m-chloroperbenzoic acid (MCPBA) in dichloromethane, at 20 C, proceeded to complete conversion into sulfoxide 33, which was not isolated due to its low stability. The only isolated product was disiloxane 34 formed by ring opening of sulfoxide 33. Oxidation of sulfide 32 with a twofold excess of MCPBA gave the corresponding sulfone 35, which also decomposed during aqueous work-up or column chromatography to afford disiloxane 36. The latter was found to be much more stable as compared to sulfoxide 33. Imidation and S-methylation were also investigated. Hoping to obtain five-membered cyclic sulfimide 37, imidation was carried in methylene chloride but afforded only silanol 38 as the major product. Finally, sulfonium salt 39 was prepared by treatment of sulfide 32 with methyl iodide in dry ethanol, and was found to be fairly stable under dry conditions.


O S Me2Si

MCPBA (1 equiv) CH2Cl2, –20 °C

H2O

(MeSOCH2CH2SiMe2)2O

33

34

O S O

MCPBA (2 equiv) CH2Cl2 –20 °C

aq. MeOH

Me2Si

(MeSO2CH2CH2SiMe2)2O

36

35

S Me2Si

32

PhSO2NNaCl 3H2O CH2Cl2 –5 °C

NSO2Ph S

NSO2Ph

Me2Si

CH3SCH2CH2SiMe2OH

37

MeI dry ethanol rt, 5 d

38

+ I– SMe Me2Si

39 Scheme 2

4.20.7 Reactivity of Substituents Attached to Ring Carbon Atoms Saponification of the ester group in 40 was successfully achieved by Vivet et al., using CaCl2 as an efficient additive to suppress 9-fluorenylmethyloxycarbonyl (Fmoc) cleavage under the basic conditions, yielding heterocycle 41 (Equation 2) . COOMe H

Fmoc N

Si Me Me

NaOH, CaCl2 i-PrOH, H2O (7/3)

COOH H

Fmoc N

ð2Þ

Si

rt, overnight

Me

40

Me

41

Demercuration of metallacycle 42 with an alkaline solution of sodium borohydride provided a C-methyl-substituted five-membered heterocycle 43 (Equation 3) . Me2Si

Me2Si

HgOAc N

NaBH4, NaOH

N

Ph

rt, 48 h

Ph

42

Me

ð3Þ

43

4.20.8 Reactivity of Substituents Attached to Ring Heteroatoms As previously described in Scheme 2 in Section 4.20.6, Suslova et al. investigated the oxidation, imidation, and S-methylation reactions of five-membered 1,3-thiasilacycloalkanes .

1281

1282 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element In addition, a simple Fmoc protection of the ring amine group of heterocycle 44 giving 40 has been performed by Vivet et al. (Equation 4) . COOMe H

H N

N

ð4Þ

Si

Si rt, overnight

Me Me

COOMe H

Fmoc Fmoc-OSu, i-Pr2NEt THF

Me Me

40

44

4.20.9 Ring Syntheses – Fully Saturated or Partially Saturated Derivatives In general, ring-forming reactions which result in hypervalent heteroatoms give complexes, where one of the ring bonds is weaker than the other ring bonds, that is, the intended ring bond, between the metal atom and the heteroatom, generates a formal charge on one or more atomic centers. As such, these complexes are in equilibrium with their open-chain and polymeric structures. Contrary to CHEC-II(1996), where only rings which have relatively strong -bonds between adjacent atoms were reviewed, the syntheses of heterocyclic complexes are also described in this section.

4.20.9.1 Group 6: Chromium, Molybdenum, and Tungsten No examples were found of relevant heterocycles containing elements from group 6 over the period of this review.

4.20.9.2 Group 7: Manganese, Technetium, and Rhenium No examples were found of suitable heterocycles containing elements from group 7 over the review period.

4.20.9.3 Group 8: Iron, Ruthenium, and Osmium Anionic nucleophilic reagents Nu ¼ CH3O, C2H5O, t-BuO, CH3S, and P(C6H5)2 were found to react with (CO)4Fe(CO2Me)[C(O)C(O)Me] 45 to afford two isomers of anionic trifunctionalized metallalactones 46, whose formation resulted from an addition of the nucleophile to the -carbonyl of the pyruvoyl ligand . In this reaction, the metallacycle formation occured via a further addition of the oxygen of the same -carbonyl onto a terminal carbon monoxide ligand (Scheme 3).

O OC

O

OC

C C

Me

Fe OC

COOMe CO

MeONa –30 °C, 1.5 h

OC OC MeO

O CO Fe

Me OMe

–

O

MeO OC +

OO

Fe

46

MeO

OC OC

–

HCl

O CO Fe CO

Me OMe O

O

47

– Me OMe O

CO O

45

Scheme 3

OC

OO


p-Allylcarbonyliron lactone complexes 49 are especially useful as they undergo a wide range of chemical transformations . Their real advantage is in the great selectivities achieved in stereocontrolled reactions and the extent of synthetically useful processes available for removal of the metal template by treatment of the acetoxy complex with lithium naphthalenide . p-Allylcarbonyliron lactone complexes can be obtained by the light-induced reaction of vinyloxiranes with Fe(CO)5 or by the sonochemical reaction with diiron nonacarbonyl in tetrahydrofuran (THF) (Equation 5) . O (OC)3Fe O

O Me

TBSO OTBS

O

O

Me

TBSO

Fe2(CO)9

49

THF, rt

14% +

OTBS

48

ð5Þ

O O

Fe(CO)3 O

Me OTBS

OTBS

50 48%

Similar metallacycle complexes, the p-allyltricarbonyliron lactam complexes 52, can be obtained in good yield by reaction between vinyl aziridinyl 51 and Fe(CO)5 in benzene under UV irradiation (Equation 6) .

NCO2Me

Fe(CO)5 benzene hν, 71%

O (OC)3Fe

ð6Þ

NCO2Me

51

52

A (3-allyl)ferralactam synthesis using Fe2(CO)9 has been reported by Aumann et al. . Schobert et al. have also studied the regioselective reactions of (4,6-3-pentadienyl)ferralactones 53 with primary amines to afford 3-(endo-vinyl)-(4,6-3-allyl)ferralactams 54 and 6-(exo-vinyl)-(4,6-3-allyl)ferralactams 55 (Equation 7) . O (OC)3Fe

1

O

4

MeNH2 THF rt, 16 h

O

O (OC)3Fe

(OC)3Fe 6

N CH3

6

H

7

3

H

5 6

8

H

ð7Þ

7

8

53

N Me

4

+

5

1

8

54

55

35%

41%

p-Allylcarbonyliron lactam complexes 57 have also been prepared by Ley and Middleton, by treatment of functionalized alkenyl aziridines 56 with Fe2(CO)9 under ultrasonication (Equation 8). This allowed the rapid, large-scale synthesis of p-allylcarbonyliron lactam complexes bearing carbonyl functionality in the side-chains, facilitating investigation into the potential of the lactam-tethered p-allylcarbonyliron units as chiral templates .

1283


Fe2(CO)9 benzene sonication

Bn H Me

N O

O Fe(CO)3 BnN

O

ð8Þ

30 °C, 3 h, 68%

Me

H

Me

Me

57

56

There was one publication on osmium-containing heterocycles in the period under review . Complex 58 was reacted with phenol 59 at room temperature to afford the hydride metallacyclic osmium(IV) complex 9 (Scheme 4). The structure of the complex was studied by NMR spectroscopy and crystallography. Initial addition of the oxygen of the phenol to the Os–C triple bond of 58 would give the hydride-alkoxycarbene intermediate 60. The subsequent migration of the hydride ligand from the metallic center to the C atom of the carbene ligand would then afford the unsaturated 61, which could evolve into 9 by C–H activation of one of the ortho-CH bonds of the OPh group.

OH

Pri

3P

rt

+

Os

66%

Ph

58

Os Pri

3P

Ph

H

O

59 60

Ph C H O

Os Pri3P

H

9

Os Pri3P H

H C Ph O

61

Scheme 4

4.20.9.4 Group 9: Cobalt, Rhodium, and Iridium Only cobalt- and iridum-containing heterocycles were described between 1995 and 2006. Protonation of the alkynylcobalt complex Co(CUCPh)(CO)[PPh(OEt)2]3 62 by HBF4?Et2O or CF3SO3H allowed the synthesis of [Co{2:1-C6H4P(OEt)2C(H)TC(H)Ph}(CO){PPh(OEt)2}2]BPh4 metallacycle 17, which was characterized crystallographically and spectroscopically . The mechanism proposed by Albertin et al. involves protonation of 62 to give the vinylidene complex 63, as confirmed by the highly deshielded C signal at 382.8 ppm in the 13C spectrum (Scheme 5). The vinyl phosphonium complex 64 was formed by intramolecular attack of one phosphonite on C of the vinylidene ligand. The proton-coupled and -decoupled 13C NMR spectra of 17 allowed clear assignment of the characteristic carbon atoms in the molecule: the carbonyl appeared as a multiplet at 207.7 ppm, the metallate C–Co at 168.4 ppm, and the two alkene carbons at 63.8 and 32.1 ppm. An Ir–O heterocycle, Fischer-type carbene 69, has been synthesized in 37% yield by Santos et al. . The process involved additionally ortho-metallation of the anisole ring; hence, three C–H bonds were sequentially broken, the last one in the course of an -H elimination reaction (Equation 9).


+

P′ P′ PhC C Co CO

P′ P′ H C C Co CO Ph P EtO OEt

H+

P′

62

+

H P′ C Co P′ H CO EtO P EtO

Ph

C

P′ = PPh(OEt)2

63

64

+

EtO EtO

H P

H

C C

Ph

+

H P′ C Ph C Co P′ CO EtO P EtO

H

Co P′ CO

P′

17

65

Scheme 5

Ir Ph

N2

Ph

66

O +

Me

C6H6 60 °C, 24 h

Ir

H H

Ir

C

ð9Þ

O

68

69

67 [Ir] = [hydridotris(3,5-dimethylpyrazol-1-yl)borate]Ir

4.20.9.5 Group 10: Nickel, Palladium, and Platinum Only palladium- and platinum-containing heterocycles were described between 1995 and 2006. Mateo et al. reported that iodoaryl stannane 70 reacts with Pd(PPh3)4 to afford palladacycle 71, as a result of an intramolecular Pd/Sn transmetallation of the intermediate oxidative addition arylpalladium(II) complex (Equation 10) . O I

70

SnBu3

Pd(PPh3)4 toluene 40 °C

O Pd Ph3P PPh3

ð10Þ

71

They also found that by using silanes instead of stannanes, the intermediate complexes were obtained as stable compounds, allowing one to study the transmetallation step of an important cross-coupling reaction systematically, separately from the oxidative addition and reductive elimination steps (Scheme 6). Importantly, the Pd/Si transmetallation was promoted by the formation of a transient Pd–O bond . Garcia et al. studied the reaction of the homochiral (R)-3-p-tolylsulfinyl propanone 75 with Pd(OAc)2 in acetic acid at 70 C under nitrogen for 48 h which yielded the enantiomerically pure trimer ortho-palladated compound 76 containing a stereogenic carbon directly joined to the Pd atom (Equation 11) .

1285


O

SiMe3

O

I

65%

I

Pd

O Pd

80%

Ph3As

AsPh3

Ph3As

72

TBAF 23 °C, 51 h

SiMe3

Pd(AsPh3)4

73

AsPh3

74

Scheme 6

Pd O

Et

O S

O

Pd

Pd(OAc)2

S

Et

O

Me

ð11Þ

AcOH, 70 °C Me

75

3

76

The microanalytical data for 76 were consistent with the empirical formula C10H1002SPd, which indicated the structure [LPd]n. The absence of the bridging acetates was confirmed by the lack of the two bands (1580 and 1420 cm1) in the IR spectrum. The CTO stretching frequency appeared 139 cm1 lower in complex 76 than in its corresponding ligand 75 (1711 cm1), which suggested that the carbonyl oxygen was involved in the coordination (coordination of CTO to palladium usually results in a slight shift of the CTO stretching mode to lower frequencies). The STO stretch was tentatively assigned to the strong band 1114 cm1, which suggested coordination via sulfur. Finally, the IR spectrum of 76 showed one weak band at 544 cm1 and a further stretch at 450 cm1, which were tentatively assigned to Pd–C and Pd–S bonds, respectively. Falvello et al. reported that the dinuclear complex [Pd(m-Cl){[C(H)PPh3]2CO}]2(ClO4)2 77 undergoes thermal rearrangement in refluxing acetonitrile, giving the ortho-metallated derivative [Pd(m-Cl)(C6H4-2PPh2C(H)COCH2PPh3)]2(ClO4)2 81 as a mixture of two diastereoisomers (RR/SS and RS/SR) (Scheme 7) .

2+

+ PPh3

+ Ph3P OC

Pd H 2 H

77

Cl

MeCN

+ + PPh3 Ph3P Cl OC Pd NCMe H H

+

+

H

Δ

Pd

Cl NCMe

Ph2P Ph3PH2CC + O

79

78

dimerization

+Cl– –Cl–

2+

H

Pd

Ph2P Ph3PH2CC + O

80 Scheme 7

Cl Cl

H

Pd

Ph2P Ph3PCH2C + O

81

Cl 2


The active species in the ortho-metallation reaction of complex 77 is the monocationic complex [PdCl){[C(H)PPh3]2CO}(NCMe)]þ 78 which ortho-metallated to give the monocationic solvate 79. This solvate 79 can dimerize to give 81 by addition of a precipitating agent (Et2O) or, through reaction with Cl can give 80. The ortho-metallation proceeded through a pathway involving electrophilic substitution at one of the phenyl rings and the formation of the C,C-chelating ligand (C6H4-2-PPh2C(H)COCH2PPh3) resulted from an intramolecular acid-base reaction in which the proton generated in the ortho-metallation reaction was captured by an ylide group (Scheme 8).

+ +

+ + PPh3 Ph3P Cl OC Pd NCMe H H

+

+ + Ph2P + Ph3P H Cl OC Pd – NCMe H H

+ Ph2P + H Ph3P Cl OC Pd NCMe H H

78

79

82 83

Scheme 8

The driving force for this reaction seems to be related to the steric repulsion between the two PPh3 fragments in the chelating bis(ylide) group and to the transformation of a four-membered ring into a five-membered ring. Palladium-catalyzed cascade reactions belong among the most powerful tools for the construction of carbon–carbon bonds. Over the past 10 years, new pathways for these transformations have been observed and rationalized by proposing palladacycles as intermediates . Particularly, diastereoselective formation of oxapalladacycles and synthesis of 2H-1benzopyrans have been studied extensively by Malinakova and co-workers . Stable oxapalladacycles 85 have been prepared and converted into a series of 2H-1-benzopyrans 86 via a regiocontrolled insertion of activated unsymmetrical alkynes (Scheme 9).

Pd(0), L base

I O

L L Pd O

Y

84

R1 H

R1

R2

R2

H

Y

O

85

Y

86

R1 = CO2Me, Me, n-Bu, 1-cyclohexyl, TMS R2 = CO2Me, CO2Et, COMe Y = CO2Et, CONEt2 Scheme 9

Iodopalladium complex 88 was obtained using commercially available enantiomerically pure phosphine ligand (4S,5S)-(þ)-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane (named (S,S)-DIOP) (Equation 12).

Me N Me

Me Me N Pd O

87

I COOEt

L–L CH2Cl2 rt

L

L Pd O

I

ð12Þ COOEt

88 L–L = (S,S)-DIOP

1287

1288 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element Treatment of 88 with t-BuOK afforded the corresponding palladacycles 89 in good overall yield, as a mixture of two diastereosiomers (Equation 13). The stereoselective event involved an intramolecular displacement of the iodide by a potassium ester enolate generated in situ .

L

L Pd O

L

L Pd

THF, t-BuOK

I COOEt

rt, 15 min

O

L

L Pd

Y H

+

H Y

ð13Þ

O

88

89a

89b

L–L = (S,S)-DIOP

44%

56%

Following the same strategy, Malinakova and coworkers synthesized a stable racemic benzannulated azapalladacycle 93 featuring a palladium-bonded sp3-hybridized stereogenic carbon . Here again, the reaction involved an intramolecular displacement of the iodide by an ester enolate (Scheme 10). Preparation of stable azapalladacycle ()-93 commenced with treatment of sulfonamide 90, accessible via N-alkylation of N-trifluoromethanesulfonyl-2-iodoaniline with palladium(0) (Pd2(DBA)3; DBA ¼ dibenzylideneacetone) and tetramethylethylenediamine (TMEDA) to afford palladium(II) complex 91. An easy ring closure of complex 91 provided palladacycle ()-92 in 92% yield via addition of t-BuOK (1 M in solution in THF, 1.2 equiv) at room temperature. Displacement of tetramethylethylenediamine with triphenylphosphine delivered palladacycle ()-93 in quantitative yield.

Pd2(DBA)3 TMEDA benzene

I N Tf

COOEt

Me Me

Me N

N Pd

55 °C, 1 h

I

N Tf

90

Me

COOEt

91 THF, t-BuOK rt, 15 min Me

Ph3P

PPh3 Pd N Tf

93

H COOEt

Ph3P CH2Cl2 rt, 24 h

Me

Me N

N Pd N Tf

Me H COOEt

92

Scheme 10

Intramolecular transmetallation of arylpalladium(II) and arylplatinum(II) complexes with silanes and stannanes has been studied by Echavarren and co-workers (Scheme 11) . As previously described, the oxidative addition of compound 94 to palladium(0) [Pd(DBA)(AsPh3)2] gave intermediate 95 which suffered a rapid transmetallation to form palladacycle 96 using TBAF. The reaction was also achieved with platinum(0) to provide the corresponding oxaplatinacycle 21: a solution of iodoaryl silane 94 and [Pt(PPh3)4] in toluene was heated at 70 C and the oxaplatinacycle 21 was obtained cleanly (isolated in 45% yield). In this case, no arylplatinum(II) complex could be observed upon performing the reaction at lower temperature and shorter reaction time, which demonstrated that the Pt(II)/Si transmetallation was faster than the oxidative addition of the aryl iodide to platinum(0) coordinated to PPh3. Therefore, in contrast with what was observed in the Pd(II)/Si transmetallation, the related Pt(II)/Si transmetallation is an easy process which took place in the absence of any additive. The synthesis of the platinacyclophosphazene 98 has been achieved by Fang et al. (Equation 14) . The unique Pt-N-P-N-P-C platinacyclophosphazene 97 was converted into its ortho-metallated isomer 98 quantitatively using a Lewis acid (AgOTf) or MeOTf (about 0.5 equiv). Both metallacarbaphosphazenes 97


O Pt

Pt(PPh3)4 toluene, 70 °C

Ph3P

PPh3

21 O

SiMe3

I

94 Pd(dba)(AsPh3)2 acetone, 23 °C

O

SiMe3

Pd Ph3As I

TBAF

O

AsPh3

Pd AsPh3 Ph3As

95

96

Scheme 11

þ and 98, which contain the [PTNTP] fragment, have been fully characterized spectroscopically and by X-ray crystallography. Analysis by NMR spectroscopy and mass spectrometry showed that the same product was formed in reactions mediated by either catalyst. Additionally, the conversion of 97 into 98 occurred without catalyst, but was extremely slow; heating a C6D6 solution of 97 to 65 C for 2 weeks gave less than 33% conversion. No intermediate was observed by in situ 31P NMR spectroscopy for either the catalyzed or uncatalyzed reactions. The precise role of the catalytic electrophile in this reaction remains poorly understood. It is possible that reversible association between electrophile and the imido N atom in 97 gave rise to a coordinatively unsaturated Pt center, which then undergoes ortho-metallation.

Me HN PPh2 + N

+N PPh2 CH2

Ph2P

N Pt Me

–

TfO

Ph P

rt, 24 h and then 70 °C, 7 h

97

CH2

ð14Þ

Pt

98

The synthesis of platinum(II) complexes has also been studied by Urriolabeitia and co-workers . Treatment of PtCl2(NCPh)2 with [Ph3PCH2COCH2PPh3]Cl2 (1:1 molar ratio, 2-methoxyethanol, reflux, 22 h) resulted in the formation of the C,C-ortho-metallated derivative 100, characterized by elemental analysis and mass spectrometry (Equation 15).

[Ph3PCH2COCH2PPh3]Cl2 2-MeOCH2CH2OH/reflux/22 h PtCl2(NCPh)2

99

–2NCPh/–2HCl

Pt

Ph2P

C H

Cl Cl O

PPh3

100

ð15Þ

1289

1290 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element The IR spectrum showed the carbonyl absorption at 1641 cm1. The 1H NMR spectrum showed a single set of resonances, in accord with the presence of only one isomer. Another example of their work is illustrated in Equation (16). The reaction of 101 with PtCl2(NCPh)2 in refluxing 2-methoxyethanol gave a pale yellow solid which was identified as the cycloplatinated derivative [Pt(C6H3-3-Ph-2PPh2CTC(Me)CH2PPh2-C,C,P)Cl] 102. This synthesis formally involved three C–H bond activations (one at the vinyl position and two in two different phenyl rings), one P–C bond activation, and one C–C bond coupling (Scheme 12) .

Me

Ph2 P

PtCl2(NCPh)2

Ph3P

PPh3

Cl2

MeOCH2CH2OH Δ, 24 h

Cl

PPh3

Ph3P

P Ph2

102

Ph2 P Cl2

ð16Þ

Pt

101

Me

Me

Ph2 P

H PPh3 Cl

PtCl2(NCPh)2 Pt Cl2

–HCl

Pt Cl2

Me

A

101

102

–HCl

Me PPh3

B

Ph2 P

Ph2 P Cl Pt

Me Cl

P Ph2

Cl Pt P Cl Ph2

D

Me

C

Scheme 12

Finally, reaction of carbodiphosphorane PPh3TCTPPh3 with platinum(II) derivatives has been investigated by Petz et al. . The complex [(COD)PtI2] 103 (COD ¼ 1,5-cyclooctadiene) reacted with 3 equiv of the hexaphenylcarbodiphosphorane Ph3TCTPPh3 104 in THF solution to give the novel Pt(II) complex [(3-C8H11)Pt(C6H4PPh2CPPh3)] 105 along with the salt [HC(PPh3)2]I (Equation 17).

PPh3 Pt

C PPh2

[(COD)PtI2]

103

+

3Ph3P=C=PPh3

104

–2[HC(PPh3)2]I

105

ð17Þ


In addition to the coordination of the ylidic carbon atom at the Pt atom, 105 contains two further Pt–C -bonds originating from H to Pt exchange in the ortho-position of one phenyl group of the carbodiphosphorane ligand and in the former COD ligand. The resulting C8H11 moiety was coordinated to the Pt atom in an 3-manner via a double bond and a -bond and contained a further uncoordinated double bond. The complex 105 was characterized by X-ray analysis and the usual spectroscopic methods.

4.20.9.6 Group 14: Silicon-Containing Heterocycles Of the ring systems that come under the purview of this chapter, the most widely studied are those containing silicon. In this section, ring formation of silicon-containing metallacycles is described and classified according to the heteroatom involved in the reaction. Therefore, various syntheses of disilacyclopentanes, disilacyclopentenes, silaboracyclopentanes, azasilacyclopentanes, oxasilacyclopentanes, and finally thiasilacyclopentanes are described.

4.20.9.6.1

1,3-Disilacyclopentanes and 1,3-disilacyclopentenes

While disilacyclopentanes and disilacyclopentenes are often unstable, numerous routes for their formation have been described in the literature. Most of the authors proposed reaction mechanisms and it is considered relevant to integrate them in this report. In 1996, Naka et al. described the synthesis of silicon–carbon unsaturated compounds via a nickel-catalyzed reaction . 3,4-Benzo-1,1,2,2-tetraethyl-1,2-disilacyclobut-3-ene 106 with bis(trimethylsilyl)acetylene 107 in presence of a catalytic amount of tetrakis(triethylphosphine)nickel(0) in a sealed glass tube at 150 C for 24 h gave 5,6-benzo-1,1,4,4-tetraethyl-2,3-bis(trimethylsilyl)-1,4-disilacyclohex-2,5-diene 108, 4,5-benzo-1,1,3,3tetraethyl-2-[bis(trimethylsilyl)methylene]-1,3-disilacyclopent-4-ene 109, 5,5,6,6,11,12,12-octaethyl-5,6,11,12-tetrasilanaphthacene 110, and 1,19-bis(3,4-benzo-2,2,5,5-tetraethyl-2,5-disilacyclopent-3-enylidene) 110, in 10%, 21%, 41%, and 9% yields (Scheme 13). Et2 Si

SiMe3

Et2 Si

Et2 Si

Si Et2

Si Et2

+ Si Et2 SiEt2

Ni(PEt3)4

SiMe3

111

108

+ Me3SiC CSiMe3 SiEt2

106

–Me3SiSiMe3

107 Et2 Si

SiMe3

Si Et2

SiMe3

Et2 Si

Et2 Si

Si Et2

Si Et2

+

109

110

Scheme 13

The formation of compound 109 can be explained in terms of oxidative addition of an sp-hybridized C–Si bond of the coordinated bis(trimethylsilyl)acetylene, in complex 113, to the nickel atom, followed by a shift of the trimethylsilyl group from the nickel atom to the trimethylsilyl-substituted sp carbon, giving vinylidenenickel complex 114 (Scheme 14). Evidence for the formation of intermediates 113 and 114 has not been obtained yet. Once, disilacyclopentene 109 was isolated and its structure analyzed by spectroscopic and elemental analyses. It was treated with dimethylphenylsilane again to afford 117, in 1% yield. The formation of 117 was explained by a series of intermediates shown in Scheme 14. Insertion of a nickel species into one of the two trimethylsilyl–carbon bonds in 109 gave nickel complex 115. This, it was proposed, is followed by a trimethylsilyl shift from the sp2-hybridized carbon to a nickel atom to give the reactive vinylidene carbene–nickel complex 116. The reaction of this nickel species with (dimethylphenyl)silane affords product 117.

1291


SiEt2

Ni(PEt3)4

106

SiEt2

Me3SiC CSiMe3 Ni(PEt3)2

SiEt2

Ni-SiMe3

Si Et2

113

Et2 Si

Ni(PEt3)4

115

SiEt2

SiMe3

Ni C C

Si Et2

SiMe3

SiMe3

SiEt2

109

Et2 Si C Ni Si Et2

SiMe3 SiMe3

114

Et2 Si

PhMe2SiH

SiMe3

C SiMe3

SiEt2

112

Et2 Si

SiMe3 C

Ni

H C

SiMe3

Si Et2

Me3SiSiMe3

116

SiMe2Ph

117

Scheme 14

Photochemical reaction of disilalkylene-bridged cyclic triacetylene 118 with (methylcyclopentadienyl)tricarbonylmanganese 119 in THF gave a variety of p-electron systems such as fulvene, dimethylcyclobutene, and biallene. The structures of these complexes were determined by the usual spectroscopic methods (Equation 18) .

Me

Me

Me Si Me

Si Si Me

Me

Me

Me

Me Me Si Me

Me

Me Me Si

Si

Si Me + Mn Me CO OC CO

118

Me Si Me Me Me Me Si Si Me +

Me Si

119

Me

Me

Si

Si

Si Si Me Me

Si Me Me

Me Si Me

Me Me Me

Si

Me Me

ð18Þ

Me

120

121

50%

8%

More recently, the same research group achieved another synthesis of disilacycles (Equation 19) .

OMe Br

Br

Br

Br

Cl +

Cl

OMe Me Si

Me

Me

123

Me Me Si

Me

OMe Me Si

Me

+

Me Si CH2 Si Me

OMe

122

i, Mg, THF ii, NaHCO3

Si

Me OMe Me

124

Me

Si Me

Si

Me OMe Me

125

ð19Þ


Another way to synthesize disilacycles has been investigated by Mise et al. . Compounds having two vinyldimethylsilyl groups on adjacent carbons have been successfully cyclized by ruthenium hydride catalysts via a metathetical reaction (Equations 20 and 21).

Me2 Si

Me2 Si

RuCl(CO)(PPh3)3(H) Si Me2

87%

126

Me2 Si Si Me2

128

ð20Þ

Si Me2

127

Werner’s hydride THF 60 °C, 24 h 83%

Me2 Si

ð21Þ

Si Me2

129

By using [RuCl(CO)(PPh3)3(H)] or Werner’s hydride [RuCl(CO)(Pi-Pr3)2(H)] as the catalyst precursor, cyclic compounds, for example 129, possessing an exo-methylene unit were obtained as the sole cyclization products. The existence of the methylene unit in the products was confirmed by NMR DEPT studies. More recently, examination of the cycloisomerization of 1,1,2,2-tetramethyl-1,2-divinyldisilane 130 in the presence of a ruthenium–diphosphine complex , ruthenium–DPPE, revealed a selective catalysis and 1,1,2,3,3-pentamethyl-1,3-disilacyclopent-4-ene 132 was isolated as the major product, in addition to 131 (DPPE ¼ bis(diphenylphosphino)ethane; Equation 22).

Me Me Si Si Me Me

130

cat. RuHCl(CO)(PPh3)(DPPE) 60 °C, 48 h

Me Me Si

Me +

Si Me Me

131

Me Si

Me

ð22Þ Si Me Me

132

Mise et al. proposed a mechanism for this selective formation of the five-membered silacycle 132 . Thus, initial hydroruthenation of 130 would give the sterically less congested complex E (Scheme 15). The ruthenium-assisted isomerization of E would be the key step in the sequence, which would lead to the formation of F. This process might have proceeded via the insertion of the Ru species to the Si–Si -bond, followed by the C–Si bond formation. Alternatively, -hydride elimination might have taken place, and then addition of Ru–H to the CTC bond in the alternative orientation, followed by the insertion of Ru–C to the CTSi bond would have led to the formation of the five-membered silacycle 132 as the product. Another synthesis of disilacycles using a ruthenium-containing catalyst has been developed by Delpech et al. . The bis(dihydrogen)ruthenium complex RuH2(H2)2(PCy3)2 G or the ethylene complex RuH(C2H4)[(P(3-C6H8)Cy2](PCy3) H efficiently catalyzed the silylation of ethylene with HSiMe2(CH2)2SiMe2H (Scheme 16). The reaction was carried out under 20 bar of C2H4 at room temperature using a catalyst (C or D)/disilane ratio of 1/100. The major product using C was 135 resulting from hydrosilylation of one Si–H bond. In contrast with this, the use of D as catalyst favored the formation of the cyclic compound 138. The one-step synthesis of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene 141 via a palladium-catalyzed dehydrogenative double silylation of phenylacetylene 140 with (methyldichlorosilyl)bis(dichlorosilyl)methane 139 has been performed by Phan et al. (Equation 23) .

1293


Scheme 15

Scheme 16

SiMeCl2 Cl2HSi

SiHCl2

139

+

H

Ph

Pd(PPh3)4 benzene reflux, 8 h 83%

140

SiMeCl2 Cl2Si

SiCl2

ð23Þ

Ph

H

141

Considering that (methyldichlorosilyl)bis(dichlorosilyl)methane 139 has two Si–H bonds, these workers first attempted to prepare the 1,3-disilacyclopentane. Surprisingly, 1,3-disilacyclopent-4-ene 141 was obtained in very good yield when tetrakis(triphenylphosphine)palladium was used as a catalyst. On the basis of the results, a plausible catalytic cycle for this dehydrogenative double-silylation reaction was proposed (Scheme 17). Platinum-catalyzed double silylations of alkynes with bis(dichlorosilyl)methane 142 have also been studied by the same research group . Indeed, bis(dichlorosilyl)methane undergoes the two types of reaction – double hydrosilylation and a dehydrogenative double silylation with an alkyne, in the presence of Speier’s catalyst, to give 1,1,3,3-tetrachloro-1,3-disilacyclopentane and 1,1,3,3-tetrachloro-1,3-disila-cyclopent-4-ene (Equation 24).


SiMeCl2 SiHCl2

Cl2HSi

139

SiMeCl2 Cl2Si

H Pd(PPh3)4

SiCl2

H

Pd(PPh3)2

Cl2Si

SiHCl2

Cl2MeSi

Ph

141

2 (PPh3) H2 SiMeCl2 Cl2Si

SiMeCl2

SiCl2 Cl2Si

Pd(PPh3)2

H

SiCl2 Pd (PPh3)2

Ph

H

Ph

140 Scheme 17

Speier’s catalyst Cl2HSi

SiHCl2

142

+

R1

R2

143

toluene 80 °C

SiCl2

Cl2Si R1

R2

144

+

Cl2Si

SiCl2

R1

R2

ð24Þ

145 traces

Thus, bis(dichlorosilyl)methane 142 reacted with alkynes [R1 ¼ H, R2 ¼ H (143a); R1 ¼ H, R2 ¼ Ph (143b); R ¼ R2 ¼ Ph (143c)] at 80 C to afford 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 144 as the double hydrosilylation products in fair to good yields (33–84%). Among these reactions, the reaction with 143c gave a trans-4,5diphenyl-1,1,3,3-tetrachloro-1,3-disilacyclopentane 144c in the highest yield (84%). Various catalysts, such as Speier’s catalyst, Pt(Cl2)(PEt3)2, Pt(PPh3)4, and Pt[ViMeSiO]4, were tested, but Speier’s catalyst was the best for such silylation reactions. Here again, Phan et al. proposed a plausible mechanism which accomodated the two pathways to afford the intramolecular double hydrosilylation and dehydrogenative double-silylation products (Scheme 18). The formation of 145 is explained by the same mechanism described in the previous catalytic cycle (Scheme 17). One patent about the preparation of heterocycle-substituted organosilicon compounds and their therapeutic applications has been published (Scheme 19) . 1

4.20.9.6.2

1-Sila-3-boracyclopentanes

The hydroboration of Me2Si(CUCMe)2 150 by adding diethyldiborane at room temperature furnished a mixture of 1,2-diethyl-2,4-bis(diethylboryl)-3,3,5-trimethyl-3-silaborane 151 and complex 152 (Equation 25) .

1295


Cl2HSi

SiHCl2

142 [Pt] R = H, Ph

H2 Cl2HSi

SiCl2

Cl2Si

143c

SiCl2

[Pt]

Cl2HSi Ph

[Pt]

SiCl2

Cl2HSi

[Pt] H

H R

SiCl2

[Pt] H

Ph Ph

Ph

H SiCl2

Cl2Si

Cl2HSi

[Pt] H

Cl2Si

SiCl2 [Pt]

R

SiCl2

[Pt] H H

H

Ph Ph

Ph

Ph

[Pt] SiCl2

Cl2Si

SiCl2

Cl2Si

[Pt] R

[Pt]

R

SiCl2

Cl2Si Ph

145

Ph

144

Scheme 18

Me Si CH2

O

+

O

Me

MeO

Me

Si

OMe O

MeO

Me i–iii

Me

146

147 OMe +

MeO

O

N H

Me

Me

Si Me

OMe

Si Me

NH2

Me

149

OMe

148 i, CpCo(CO)2, m-xylene, 14 h, reflux; ii, AlMe3, toluene, 10 min, –30 °C; iii, NH4OAc, H2O, 20 °C Scheme 19

Et

CH3 H3C

Si CH3

150

(Et2BH)2 CH3

Et Et

Me Me Et Si B Et B Et B Me Et

151

Et +

Me

Me Me B

Si B Et Si

Me B

Me Me Et

152

Et B

Et

ð25Þ


Another example of boration of Me2Si(CUCMe)2 150 was reported by Wrackmeyer et al. . 1-Boraadamantane 153 reacted with di(1-alkynyl)silicon compound 150 in a 1:1 ratio by intermolecular 1,1-alkylboration. This led to the novel octacyclic 7-metalla-2,5-diboranorbornane derivative 7 (Equation 26; Scheme 1). Me Me Me Si B

Me +

Me

B

Si

B Me

Me

150

153

4.20.9.6.3

ð26Þ

Me

7

1-Aza-3-silacyclopentanes

Of the ring systems which come under this silicon-containing heterocycles section, the most widely studied from 1995 to 2005 were those containing nitrogen and called 1-aza-3-silacyclopentanes. In 2000, Vivet et al. published an interesting asymmetric synthesis of a new silaproline surrogate (Scheme 20), incorporating a dimethylsilyl group at the 4-position of the proline, using Scho¨llkopf’s bis-lactim ether method . Deprotonation of the bis-lactim ester 154 with n-BuLi afforded a planar cyclic anion intermediate which reacted with bis(iodomethyl)dimethylsilane to give compounds 155 and 156. A mixture of acetonitrile, water, and formic acid (49:49:2) was effective in giving the silaproline methyl ester 44 along with dipeptide 161. Treatment of 156 with acidic conditions afforded the iodide intermediate 158 which was cyclized to the silaproline methyl ester, t-butoxycarbonyl (BOC)-protected, 159. Following their ongoing program aimed at replacing natural amino acids in peptides with nonproteinogenic counterparts to obtain new medicinal agents, Cavellier et al. reported the incorporation of non-natural silylated amino acids in substance P (H-RPKPQQFFGLM-NH2) . They also used the Scho¨llkopf bis-lactim ether method to synthesize the analogue, -(dimethylsila)-proline, in both enantiomerically pure forms. As in the research work of Vivet et al., new bicyclic sila-heterocycles were synthesized by Handmann et al. . Compound rac-164 underwent a thermally induced cyclization reaction to give rac7-ethoxy-2,2-dimethyl-2,3,5,7a-tetrahydro-1H-3a,6,-sila-inden-4-one 9a (Equation 27). The crystal structure of 9a and kinetic studies of the cyclization reaction have also been reported. Starting from 3,6-ethoxy-2,5-dihydropyrazine 163, metallation with 1 molar equivalent of n-butyllithium and subsequent treatment with 1 molar equivalent of the bis(chloromethyl)silane produced compound 164 in 50% yield. Heating neat 164 at 120 C gave the crystalline 9a in almost quantitative yield. N N EtO

OEt

N

i, n-BuLi ii, (CH3)2Si(CH2Cl)2

N

EtO

163

OEt

Δ

Si Me Me

N

OEt

Cl O

164

ð27Þ

N SiMe2

–EtCl

9a

Electrophilic cyclization of dimethyl(!-phenylaminoalkyl)alkenylsilanes has been studied by Kirpichenko et al. . They found that ring closure by vinyl(phenylaminomethyl)dimethylsilane 165 proceeded contrary to the Markownikoff rule (Equation 28). i, Hg(OAc)2, THF ii, NaBH4, NaOH

Me2Si

NHPh

Me2Si N

ð28Þ

Ph

165

166

The action of mercury(II) acetate on 165 in a THF solution followed by demercuration with an alkaline solution of sodium borohydride, gave a substituted 3-silapyrrolidine 166 in 58% yield. Analogously, under the same conditions of aminomercuration–demercuration, allyl(phenylaminomethyl)dimethylsilane 167 easily formed C-methyl-substituted five-membered heterocycle 43 (Equation 29).

1297


Pr i

N

MeO

N

OMe

Si Me

I

Me

155 Pr i MeO

N N

14%

OMe i, n-BuLi ii, (ICH2)2-SiMe2

+ Pr i

N

MeO

N

OMe

154

COOMe Si Me MeOH, HCl 10% Me (3/1)

I

+ H-(D)Val-OMe, HCl + H2N

157

I

156

H Si Me Me

158

86%

MeCN, H2O, HCOOH (49/49/2)

COOMe H

H H-(D)Val-OMe, HCl

157

+

i, i-Pr2NEt ii, BOC2O

Pr i

N

O +

Si Me Me

NH2 COOMe BOC COOMe N H N H BOC-(D)Val-OM + Si Si Me Me Me Me

44

Fmoc-OSu, i-Pr2NEt THF Pr i Fmoc N

COOMe H

O +

Si Me Me

40

N

COOH H

Si Me Me

41 Scheme 20

Fmoc N H COOMe H N Si Me Me

162 NaOH, CaCl2 i-PrOH, H2O (7/3)

Fmoc

159

161

BOC N

COOH H

Si Me Me

160


Me2Si Hg(OAc)2, THF Me2Si

HgOAc N

NHPh

167

Me2Si NaBH4, NaOH

N

Ph

Ph

42

43

Me

ð29Þ

The mode of cyclization of 2-sila-5-hexen-1-yl radicals generated from 6-(bromomethyl)dimethylsilyl-19,29-unsaturated uridines was investigated by Ogamino et al. (Equation 30) . H N

O O

N

TBDMSO MeO

Si Me Me Me BrH2C

168

O

H N

O

AIBN Bu3SnH

O TBDMSO

O

N

ð30Þ Si Me Me Me

MeO

24

When the radical reaction of 168 was carried out in refluxing benzene by adding a mixture of AIBN (0.2 equiv) and Bu3SnH (2.0 equiv) via a motor-driven syringe over 1 h at 80 C, only the 5-exo-cyclized product 24 was obtained in 41% yield. The structure of 24 was determined thanks to 1H NMR studies: NOE correlations were observed between H-29 and one of the SiCH2 (11%) and between the 29-Me and H-39 (4%). The result above can be rationalized by the formation of the intermediate I (Equation 31).

ð31Þ

The high preference for C-19 attack of the -silyl carbon radical derived from 24 could be due to the formation of an incipient tertiary C-29 radical A, although steric hindrance of the 29-methyl group cannot be ruled out. In 2004, the reaction of the N,N-bis(methoxyethyl)amide 169 with phenyldimethylsilyllithium was carried out by Buswell et al. and the formation of the 3-silapyrrolidine 174 was observed (Scheme 21). The reaction of N,N-bis(methoxyethyl)amide 169 with phenyldimethylsilyllithium gave the ‘normal’ product 171, small amounts of the elimination product 173, and the diastereoisomeric pyrrolidines 174. These products can be accounted for by proton transfer in 170, presumably intramolecular, followed by displacement of the phenyl group 172 ! 174 or -elimination 172 ! 173. Stable silicates with five carbon substituents are extremely rare. These pentacoordinate anions have been successfully synthesized by Couzijn et al. . Bis(1-phenylpyrrole-2,29-diyl)silane 31 was synthesized in 53% yield from 2-bromo-1-phenylpyrrole 175 in diethyl ether by treatment with 2 equiv of n-butyllithium (0 C) and 0.5 equiv of SiCl4 (reflux) (Scheme 22). Reaction of 31 with methyllithium in THF at 78 C afforded a pale yellow solution of lithium silicate 25, as indicated by the upfield shift of the 29Si NMR signal at ¼ 35 to 131 ppm (the NMR spectrum was recorded at 50 C to minimize signal broadening).

4.20.9.6.4

1-Oxa-3-silacyclopentanes

No synthesis of 1-oxa-3-silacyclopentanes has been described between 1995 and 2006.

1299


MeO

OMe

N

Pr i

PhMe2SiLi (2 equiv)

MeO

–

Pr i

O

OMe

N

MeO

+H+

H

Pr i

SiMe2Ph

SiMe2Ph

171

170

169

OMe

N

53% +H+

proton transfer MeO MeO NH

Pr i

OMe

N

+

–

+H

Pr i

SiMe2

SiMe2Ph

Ph

173

172

2% displacement of Ph– OMe

MeO

Pr i

SiMe2

174 16% (cis/trans = 62/38) Scheme 21

–

n-BuLi, SiCl4 Et2O, reflux Br

N N Si

MeLi THF

Si Me

[Li(THF)4]+

N

N N

175

31

25

Scheme 22

4.20.9.6.5

1-Thia-3-silacyclopentanes

Even though silicon-containing thiacyclopentanes with the two heteroatoms separated by one methylene group are known to be stable compounds, only a few examples of their synthesis were found in the literature in the period under review . Cabiddu et al. reported that the addition of n-butyllithium to (vinylthio)benzene 176 followed by an electrophilic quenching with dichlorodimethylsilane afforded the 2-methylene-3,3-dimethyl-1,3-benzothiasilole 178 containing an exocyclic double bond (Scheme 23) .

4.20.9.7 Germanium-Containing Heterocycles Very little work has been done regarding germanium-containing heterocycles from 1995 to 2005. The only research work found in the literature in this period is that of El Kettani et al. .


Li

S

S

2n-BuLi 0 °C, 2 h

176

Li

Me2SiCl2 –78 °C

S

overnight 30%

Si Me Me

178

177

Scheme 23

Addition of iminoester 180 or iminophosphonate 181 to an ethereal solution of germene 179 followed by overnight stirring at room temperature afforded nearly quantitatively the 3-germapyrrolidines 16 or 27, respectively, which were purified by fractional crystallization as air-stable compounds (Scheme 24). The structures of 16 and 27 were deduced from their NMR data and X-ray crystal diffraction study. One of the main features of this reaction is its complete regioselectivity and complete diastereoselectivity leading to the isomer with the Ph and ester (or phosphonate) groups in a pseudo-equatorial position. The stereochemical outcome suggested that the most reasonable mechanism is a [3þ2] cycloaddition reaction between the germene and the 1,3-dipolar azomethine ylide. The complete diastereoselectivity could be explained by the presence of 1 equiv of LiF in the crude solution of germene prepared from Mes2Ge(F)CHR2.

Mes2Ge

Me Mes =

179

Me

Ph(H)C=N-CH2COOMe

Ph(H)C=N-CH2P(O)(OEt)2

180

181

Ph

EtO EtO P

–

MeO

+ N

O

Li

+

– N

O

182

183 179

Mes2Ge O

Mes2Ge N H

16 Scheme 24

Ph

Li

179

MeOC

Me

Ph

(EtO)2P O

N H

27

Ph

1301


4.20.10 Ring Synthesis by Transformation of Another Ring As previously mentioned in Section 4.20.9.6.1, Naka et al. described the synthesis of silicon–carbon unsaturated compounds via a nickel-catalyzed reaction . The reaction between 3,4-benzo-1,1,2,2-tetraethyl-1,2disilacyclobut-3-ene 106 with bis(trimethylsilyl)acetylene 107 in presence of a catalytic amount of tetrakis(triethylphosphine)nickel(0) gave the four metallaheterocyles detailed in Scheme 13. In addition, photochemical transformation of disilalkylene-bridged cyclic triacetylene 118 with (methylcyclopentadienyl)tricarbonylmanganese 119 in THF gave a variety of p-electron systems (Section 4.20.9.6.1; Equation 18) .

4.20.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available No particular classes of compounds have been described over the period in review. Syntheses of various heterocycles have been described in Section 4.20.9.

4.20.12 Important Compounds and Applications In general, sila-heterocycles are believed to be promising candidates for the development of silicon-based drugs and agrochemicals. For example, the sila-proline ester 184 was prepared as part of a systematic study of silicon-containing amino acids and proteins . O

OEt

HN SiMe2

184

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1303

1304 Five-membered Rings with Two Nonadjacent Heteroatoms with at least One Other Element Biographical Sketch

Celine Cano-Soumillac was born in Angouleme, France, in 1977. She studied Organic Chemistry at the University of Poitiers, France. In 1999, she went to Paris as a predoctoral fellow and worked on asymmetric synthesis of substituted piperazines from phenylglycinol derivatives, under the supervision of Prof. H.-P. Husson. In 2000, she moved back to Poitiers, where she worked on the synthesis of biomolecules by 1,3-dipolar cycloadditions with carbohydrates and received her Ph.D. degree in 2004. She then joined the group of Prof. John A. Joule at the University of Manchester, U.K. as a postdoctoral fellow and worked on the synthesis of analogues of cofactors of oxomolybdoenzymes. She now holds a research associate position in the Northern Institute for Cancer Research, at Newcastle University, UK, where she works on the synthesis of inhibitors of DNA-dependent protein kinase. Her research interests include heterocyclic chemistry, carbohydrates chemistry, asymmetric synthesis and development of new synthetic methodologies.

Compr. Heterocyclic Chem. III Vol. 4 Five-membered Rings with Two Heteroatoms

Compr. Heterocyclic Chem. III Vol. 8 Six-membered Rings with Two Heteroatoms

Compr. Heterocyclic Chem. III Vol.13 Seven-membered Heterocyclic Rings

Compr. Heterocyclic Chem. III Vol. 9 Six-membered Rings with Three or more Heteroatoms

Compr. Heterocyclic Chem. III Vol. 6 Other Five-membered Rings with Three or more Heteroatoms

Compr. Heterocyclic Chem. III Vol.14 Eight-membered and larger Heterocyclic Rings, Other Seven-membered Rings

Compr. Heterocyclic Chem. III Vol. 2 Four-membered Heterocycles

Compr. Heterocyclic Chem. III Vol.15 Ring index

Compr. Heterocyclic Chem. III Vol. 1 Three-membered Heterocycles

Compr. Heterocyclic Chem. III Vol. 7 Six-membered Rings with One Heteroatom

Compr. Heterocyclic Chem. III Vol. 3 Five-membered Rings with One Heteroatom

Compr. Heterocyclic Chem. III Vol. 5 Five-membered Rings - Triazoles, Oxadiazoles, Thiadiazoles

Compr. Heterocyclic Chem. III Vol.11 Bicyclic 5-5 and 5-6 Fused Ring Systems with at least One Bridgehead Heteroatom,

Stereoselective Heterocyclic Synthesis III

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

Rings with generalized identities

Rings with Morita duality

Collected Papers, Vol. III

Dio's Rome, Vol. III,

IS Vol. III

Winnetou vol III

Selected Works, Vol. III

Pzkpfw Tiger Vol III

StuG III. Часть 4

Shreir's Corrosion vol III

Cognition, Vol. 4, No. 4

Encyclopaedia of Chess Endings, Vol 4 - Rook Endings, Part Two

Progress in Heterocyclic Chemistry, Vol. 17 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Tales and Novels, Vol III

Building Military Vehicles, Vol. III

Treatise on Analysis, Vol. III

Compr. Heterocyclic Chem. III Vol. 4 Five-membered Rings with Two Heteroatoms

Compr. Heterocyclic Chem. III Vol. 8 Six-membered Rings with Two Heteroatoms

Compr. Heterocyclic Chem. III Vol.13 Seven-membered Heterocyclic Rings

Compr. Heterocyclic Chem. III Vol. 9 Six-membered Rings with Three or more Heteroatoms

Compr. Heterocyclic Chem. III Vol. 6 Other Five-membered Rings with Three or more Heteroatoms

Compr. Heterocyclic Chem. III Vol.14 Eight-membered and larger Heterocyclic Rings, Other Seven-membered Rings

Compr. Heterocyclic Chem. III Vol. 2 Four-membered Heterocycles

Compr. Heterocyclic Chem. III Vol.15 Ring index

Compr. Heterocyclic Chem. III Vol. 1 Three-membered Heterocycles

Compr. Heterocyclic Chem. III Vol. 7 Six-membered Rings with One Heteroatom

Compr. Heterocyclic Chem. III Vol. 3 Five-membered Rings with One Heteroatom

Compr. Heterocyclic Chem. III Vol. 5 Five-membered Rings - Triazoles, Oxadiazoles, Thiadiazoles

Compr. Heterocyclic Chem. III Vol.11 Bicyclic 5-5 and 5-6 Fused Ring Systems with at least One Bridgehead Heteroatom,

Stereoselective Heterocyclic Synthesis III

Heterocyclic Compounds With Three- And Four-Membered Rings (The Chemistry of Heterocyclic Compounds, Volume 19)

Rings with generalized identities

Rings with Morita duality

Collected Papers, Vol. III

Dio's Rome, Vol. III,

IS Vol. III

Winnetou vol III

Selected Works, Vol. III

Pzkpfw Tiger Vol III

StuG III. Часть 4

Shreir's Corrosion vol III

Cognition, Vol. 4, No. 4

Encyclopaedia of Chess Endings, Vol 4 - Rook Endings, Part Two

Progress in Heterocyclic Chemistry, Vol. 17 (Progress in Heterocyclic Chemistry) (Progress in Heterocyclic Chemistry)

Tales and Novels, Vol III

Building Military Vehicles, Vol. III

Treatise on Analysis, Vol. III

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