PROGRESS IN
HETEROCYCLIC CHEMISTRY Volume 16
Related Titles of Interest
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BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS
PROGRESS IN
HETEROCYCLIC CHEMISTRY Volume 16 A critical review of the 2003 literature preceded by two chapters on current heterocyclic topics Editors
GORDON W. GRIBBLE
Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and
JOHN A. JOULE
Department of Chemistry, The University of Manchester, Manchester, UK
2004
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ISBN: ISBN:
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Contents
Foreword
vii
Editorial Advisory Board Members
viii
Chapter 1: Lamellarins: Isolation, activity and synthesis Pablo Cironi, Fernando Albericio, and Mercedes Alvarez, Biomedical Research
Institute, Barcelona Scientific Park, University of Barcelona, Barcelona, Spain.
Chapter 2: Radical additions to pyridines, quinolines and isoquinolines
27
David C. Harrowven and Benjamin J. Sutton,
School of Chemistry, University of Southampton, Southampton, UK.
Chapter 3: Three-membered ring systems
54
Albert Padwa, Emory University, Atlanta, GA, USA and Shaun Murphree, Allegheny College, Meadville, PA, USA.
Chapter 4:
Four-membered ring systems
82
Benito Alcaide, Departamento de Quimica Org6nica I, Facultad de Quimica,
Universidad Complutense de Madrid, Madrid, Spain and Pedro Almendros, Instituto de Quimica Org6nica General, CSIC, Madrid, Spain.
Chapter 5: Five-Membered Ring Systems Part 1.
Thiophenes & Se, Te Analogs
98
Venkataramanan Seshadri, Fatma Selampinar, Gregory A. Sotzing
University of Connecticut, Storrs, CT, USA.
Part 2.
Pyrroles and Benzo Derivatives
128
Tomasz Janosik and Jan Bergman, Department of Biosciences at Novum,
Karolinska Institute, Novum Research Park, Huddinge, Sweden, and SOdertOrn University College, Huddinge, Sweden and Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA.
Part 3.
Furans and Benzofurans
]56
Xue-Long Hou, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, Zhen Yang, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beij'ing, China Kap-Sun Yeung, Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, CT, USA, and Henry N. C. Wong, Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Chinese University of Hong Kong, Hong Kong, China and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, Shanghai, China.
vi
Part 4.
With More than One N Atom
198
Larry Yet, Albany Molecular Research, Inc., Albany, NY, USA.
Part 5.
With N & S (Se) Atoms
228
Mark G. Saulnier, Upender Velaparthi and Kurt Zimmermann,
Bristol Myers Squibb Company, Walling)Cord, CT 06492-7660, USA.
Part 6.
With O & S (Se, Te) Atoms
272
R. Alan Aitken, University of St Andrews, UK.
Part 7.
With O & N Atoms
283
Stefano Cicchi, Franca M. Cordero and Donatella Giomi,
Universith di Firenze, Italy.
Chapter 6: Six-Membered Ring Systems Part I.
Pyridines and Benzo Derivatives
309
Daniel L. Comins and Jason Dinsmore, Department of Chemistry,
North Carolina State University, Raleigh, NC, USA and Sean O'Connor, A TK Thiokol, Inc., Brigham City, UT, USA.
Part 2.
Diazines and Benzo Derivatives
347
Michael P. Groziak, California State University at Hayward, Hayward, CA, USA.
Part 3.
Triazines, Tetrazines and Fused Ring Polyaza Systems
385
Carmen Ochoa, Pilar Goya and Cristina G6mez,
Instituto de Quimica M~dica (CSIC), Madrid, Spain.
Part 4.
With O and/or S Atoms
405
John D. Hepworth, James Robinson Ltd., Huddersfield, UK and B. Mark Heron,
Department of Colour and Polymer Chemistry, University of Leeds, Leeds, UK.
Chapter 7: Seven-Membered Ring Systems
431
John D. Bremner, Department of Chemistry, University of Wollongong,
Wollongong, NSW, Australia.
Chapter 8: Eight-Membered and Larger Ring Systems
451
George R. Newkome, The University of Akron, Akron, OH, USA.
Index
469
~ Vll
Foreword
This is the sixteenth annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2003 on most of the important heterocyclic ring systems. References are incorporated into the text using the joumal codes adopted by Comprehensive Heterocyclic
Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews.
The first, by Mercedes /klvarez, Pablo Cironi, and Femando Albericio
covers 'Lamellarins: Isolation, activity and synthesis' a significant group of biologically active marine alkaloids. The second, by David Harrowven and Benjamin Sutton, discusses the increasingly important topic of 'Radical Additions to Pyridines, Quinolines and Isoquinolines'. The remaining chapters examine the recent literature on the common heterocycles in order of increasing ring size and the heteroatoms present. This year, following a consultation exercise involving members of the Editorial Board, and partly in the interest of getting the Volume published as soon as possible after the end of the year being reviewed, the Index is less comprehensive than formerly. It now includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under 'pyrroles'; wherever
'pyrido[3,4-b]indoles' are mentioned an indexed entry under that
name will be found; similarly 'aceanthryleno[1,2-e][1,2,4]triazines', 'azirines', '2H-pyran-2ones', 'l,2,4-triazoles' etc. etc. are listed.
But, subjects like'4-ethyl-5-methylpyrrole', '5-
acylazirines', '6-alkyl-2H-pyran-2-ones', '3-alkylamino-l,2,4-triazoles', are not listed as such in the Index. 'Diels-Alder reaction' or 'Heck coupling' etc., are also not indexed. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to Derek Coleman of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modem heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics.
Gordon W. Gribble John A. Joule
viii
Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2 0 0 3 - 2004 PROFESSORY. YAMAMOTO(CHAIRMAN)
Tohoko University, Japan
PROFESSOR D. P. CURRAN
PROFESSOR G.R. NEWKOME
PROFESSORA. DONDONI
PROFESSORR. PRAGER
University of Pittsburgh USA
University of Akron USA
University of Ferrara Italy
Flinders University Australia
PROFESSOR K. FUJI
PROFESSORR.R. SCHMIDT
Kyoto University Japan
PROFESSORT.C. GALLAGHER
University of Bristol UK
PROFESSORA.D. HAMILTON
Yale University USA
University of Konstanz, Germany PROFESSOR L. TIETZE
Georg-August University Germany
PROFESSORS.M. WEINREB
Pennsylvania State University USA
PROFESSORM. IHARA
Tohoku University Japan
Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://webdb, unigraz, at/~kappeco/ISHC/index, html
Chapter 1
Lamellarins" Isolation, activity and synthesis Pablo Cironi, Fernando Albericio, Mercedes Alvarez Biomedical Research Institute, Barcelona Scientific Park-University of Barcelona, 08028 Barcelona, Spain
[email protected],
[email protected],
[email protected] 1.1
INTRODUCTION
The lamellarins constitute an important group of natural products isolated from marine invertebrates such as sponges, molluscs and tunicates with structures without precedents in natural or synthetic compounds. They are characterized for possessing important biological activities. The aim of this review is to provide an overview of the work published since the isolation of the first group of lamellarins from the marine prosobranch mollusc Lamellaria sp, until the beginning of 2004.
1.2
I S O L A T I O N AND STRUCTURE
More than thirty lamellarins have been characterized since the isolation of the first group of lamellarins A-D . The structure of lamellarin A was established by X-ray crystallographic analysis , as was that of lamellarin E isolated together with lamellarins H-G from the marine ascidian Didemnum chartaceum collected in the Indian Ocean on the atoll of Aldabra. Six new polyaromatic alkaloid lamellarins I-M, the triacetate of lamellarin N, and four known alkaloids lamellarins A-C were isolated from the marine ascidian Didemnum sp . Since molluscs from the family Lamellariidae had been described as specific predators of colonial ascidians, it was speculated that the lamellarins mollusc had most likely sequestered the alkaloids from a colonial ascidian food source. The re-isolation of lamellarins A-D, which had been previously obtained from the prosobranch mollusc Lamellaria sp. supported this idea. The presence of lamellarins in molluscs, tunicates and sponges gives rise to speculations about the role of symbiotic organisms associated with the invertebrates and represents a target for new investigations . The first pyrrole non-fused alkaloids of the family were lamellarins O and P isolated from a marine sponge Dendrilla cactos . Later on, from a specimen of Dendrilla cactos collected in Australia two new pyrrole derivative lamellarins Q and R were isolated. A new pentacyclic alkaloid, lamellarin S together with the known lamellarin K were isolated from a tunicate Didemnum sp. . Lamellarin S was the first example that demonstrated atropoisomerism with a positive [Ct]D, which can indicate an enantiomerically enriched mixture. Repeated optical rotation measurements of lamellarin S over several months suggested slow racemization with a half-life calculated to be ca. 90 days. The first sulfates of lamellarins, the 20-sulfate derivatives of lamellarins T-Y, were extracted from an unidentified
2
P. CironL F. Albericio and M. Alvarez
ascidian from the Arabian Sea . From the same organism the non-esterified lamellarins T-X were also isolated. Later, from the ascidian Didemnum chartaceum, the 20sulfated lamellarins B, C, and L, the 8-sulfated lamellarin G plus a non-sulfated compound, lamellarin Z were identified . An investigation of the prosobranch mollusc Corioeella hibyae provided two known compounds; lamellarins C and U . A n e w ester, lamellarin c~ 20-sulfate was isolated from an unidentified ascidian collected from the Arabian Sea. From a purple unidentified Didemnum sp (other than D. chartaceum) lamellarin [3 was identified . Structures of pentacyclic lamellarins Unsaturated
A C E
Ra
R1 R2
RR 7 ~
F G I I aeet.
J
O R5~R4~-~R30
K K triacet.
L L triaeet. S
T Tsulf. U U sulf.
V V sulf. Y sulf.
a7
R1
R2 Z
RR 6 ~ R4~
O
Saturated B D H M N
W X o~
R3
R4
R5
OH H
OMe OMe OH OH H OMe OMe H OH OAc H H H OMe OMe H H OMe OMe H H H
OMe OMe OH OMe OMe OMe OMe OMe
Rl OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OMe OMe OH OH
R2 OH OH OH OH OMe OH OAc OH OH OAc OH OAc OH OH OSO3Na OH OSO3Na OH OSO3Na OSO3Na OMe OH
OMe OMe OH OMe
OMe H H OH H OH OMe OH OH OH OSO3Na H
OMe OMe OMe OMe
OH OH OH OH
H
H H H H
H H H
H H H
H H H H OH OH H H H
R6
R7
R8
OMe OMe OMe OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OH OMe OMe OMe OMe OMe OH OMe OAc OMe OH OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OMe OH OH OMe OH OH
OMe OMe OH OMe OH OMe OMe OMe OMe OMe OH OAc OH OH OMe OH OH OH OH OH OH OH
OH OH OMe OMe OMe OMe OMe OMe OH OAc OMe OMe OH OMe OH OMe OMe OMe OMe OMe OH OMe
OMe OH OH OMe OMe OMe OMe OMe
OH OH OH OH OMe OMe OMe OMe
OMe OMe OH OMe OH OH OH OH
The structures of the lamellarins, except for A and E, were established by a combination of 1H and 13C N M R analyses using heteronuclear correlation techniques. New procedures for differentiation of H M B C at two- and three-bond correlation in combination with ADEQUATE experiments and with O~l-refocused 1,1-ADEQUATE < 9 6 J M R 2 9 5 > experiments were developed for a comprehensive identification of 2JcH and 3JcH
Lamellarins : Isolation, activity and synthesis
3
correlations. The distinction between 2JcH and 3JcHconnectivities facilitates the assignment of complex structures. The apparent biogenetic origin of these metabolites is from two, three or more tyrosine and/or Dopa units and the relationship between them is clear. Looking at the structures, two important groups of lamellarins can be recognised. The most important group in number possess a common pentacyclic structure linked to a new phenyl ring. The differences between the members of this group are in the number and positions of OH/OMe substituents on the benzene rings and in the oxidation level of ring D. This ring can be saturated or unsaturated and/or hydroxylated. Structures of lamellarin pyrrole derivatives
HO.
OH HO
HO
HO/x__ BrBr OH Br-~\ //3 ~( ~ ~ ' 7--- Br
,OH
HO
Br
~
~
Br
HO
OH
O
@
OH
OH
OH
Lukianol A
Ningalin B
OH
Polycitone A
Structures of related natural products
HO
OH
HO.
OH
Me ~R
Lamellarin O R = H Lameilarin P R = OH
~.~OH
Me H Lamellarin Q
OH
HO
+
OH Lamellarin R
Less numerous is the group of lamellarins in which the pyrrole is not fused to another aromatic ring, known as pyrrole derivatives. These alkaloids are probably tyrosine derived metabolites, structurally closer to the lukianols , ningalines , polycitones and polycitrines than to the pentacyclic lamellarins. Chemical transformations between these groups of natural products have been described. Thus, dimethoxylamellarin O was transformed into the enol-ether lactam (ring B of pentacyclic lamellarins) and after cleavage of methoxy groups gave lukianol A . The open diaryl pyrroles were also chemically transformed into the pentacyclic alkaloids, for instance ningalin B into lamellarin G trimethyl ether . Again, the ease of chemical
4
P. Cironi, F. Albericio and M./ilvarez
transformation between compounds of these families could indicate their close biogenetic origin. Lamellarins O and P displayed a double family of signals corresponding to the aromatic carbon ortho to the phenolic functions, presumably due to the restricted rotation that generates chirality in these molecules .
1.3
ACTIVITY
While for the pyrrole derived lamellarins and related compounds no activity has been described, several pentacyclic lamellarins show important cytotoxic activities. Lamellarin D at a concentration of 19 ~tg/ml caused a 78% inhibition of cell division in the fertilized sea urchin egg assay while lamellarin C caused 15% inhibition but lamellarins A and B were inactive . Lamellarins I, K and L present significant cytotoxicity against P338 and A549 cultured cell lines and lamellarins K and L also exhibit immunomodulatory activity . The effects of several members of the family of lamellarins on the growth of several tumor cell lines and on P-glycoprotein (P-gp) mediated multidrug resistance (MDR) was tested . The use of lamellarins either alone against MDR tumors or in combination with other anti-tumor drugs as effective treatments against MDR cells has been described after testing an important group of natural lamellarins and derivatives. A nonnatural lamellarin derivative proved to have an important potency as a MDR reversal agent causing hypersensitivity towards vinblastine in the HCT/VM 46 MDR cell line . Lamellarin N tested in the NCI on a cell-line panel showed some selectivity towards the melanoma cell lines SK-MEL (LCs0 1.87 x 10-7 M) and UACC-62 (LCs0 9.88 x 10-6 M). Several lamellarins were tested as HIV-1 integrase inhibitors and the a 20-sulfate displayed a very favorable therapeutic index . Lamellarin a 20-sulfate inhibits integrase terminal cleavage activity with an IC50 of 16 ~tM and strand transfer activity with an IC50 of 16 l,tM and possesses a low toxicity with an LDs0 of 274 ~tM whereas other sulfated lamellarins (lamellarin U 20-sulfate and lamellarin V 20sulfate) were toxic in the 100 ~tM range and lamellarins T and N without the sulfate ester were more toxic. The site of action of lamellarin a 20-sulfate was mapped and it was postulated that it binds to a site composed of multiple integrase domains. A molecular modeling analysis suggested that the planar chromophore of lamellarin D can intercalate between a DNA base pair and that the appended methoxyphenol substituent oriented at a right angle with respect to the main chromophore may serve as a hook to trap proteins . DNA binding measurements by absorbance, fluorescence, and electric linear dichroism spectroscopy showed that lamellarin D is a weak DNA binder that intercalates between the double helix. Topoisomerase I was efficiently trapped on DNA by lamellarin D in P388 and CEM leukemia cells. The results identify lamellarin D as a novel lead candidate for development of topoisomerase I-targeted antitumor agents.
1.4.
SYNTHETIC STRATEGIES
From a synthetic point of view, lamellarins are rather complex molecules. In the literature, there are described several approaches, which fall into two main synthetic categories: (i) by pyrrole formation as the key step of the synthesis and (ii) by transformation of a pre-existent pyrrole derivative through cross-coupling reactions. Although and due to the structural
Lamellarins: Isolation, activity and synthesis
5
characteristics of these kinds of molecules, most of the syntheses have been carried out in solution, recently some synthesis carried out in solid-phase has also been described.
1.4.1 SOLUTION STRATEGY 1.4.1.1 Pyrrole ring formation approaches Fiirstner et al. synthesized lamellarin O dimethyl ether following their previous research on carbon-carbon double bond formation from carbonyl compounds by catalytic titanium coupling reactions . A new titanium-mediated approach to pyrrole synthesis, based on the cyclization of a 3-acylamino-enone, was reported .
R1
R1
.-,
r" "?r O 1. v NH R2.~_~O
Iow-valenttitanium
=
...
R2 H
In order to adapt this strategy to the synthesis of lamellarin O dimethyl ether, a 3unsubstituted keto-enamine 4 was prepared by hydrogenolysis of precursor isoxazole 3.
O
H202, NaOH
Ar'~-~Ar
98%
1
O O
~ Ar
r 2. NH2OH.HCI,
2
Ar = p-MeOC6H4 Ar, Ar ~O
Ti-graphite
NHR 4R=H 5 R =
52%
Ar. Ar P; ~ ~N )~/ H2 (1 atm), Pd (5%)
1. BF3.Et20
Ar.
67% (both steps) ~OMe
Ar
OMe H
O
r 91%
94%, (7):(E)- 11
3 K2CO3},-
Ar, Ar ~/OMe O
6 FOrstner intermediate
".~/F~O ~ O
OMe
CIOCCOOMe' Py 73% (Z):(E) = 2.5:1
lamellarin O dimethyl ether
Intermediate 3 was readily prepared from commercially available 4,4'-dimethoxychalcone 1 which by standard oxidation conditions afforded the epoxy ketone 2 in high yield. Compound 2 underwent a clean pinacol/pinacolone-type rearrangement with an excess of BF3"Et20. The crude 1,3-keto-aldehyde thus formed was trapped by hydroxylamine leading to isoxazole 3 in good yield. Reductive cleavage of its N-O bond gave the desired keto-enamine 4 (as a ~ 1:1 mixture of the (E)- and (Z)-isomers). Acylation of this mixture with oxalic acid half acid chloride half methyl ester afforded the coupling precursor 5. The (Z) isomer was used for the subsequent titanium-induced ring closure. Upon treatment with preformed Ti-graphite (TIC13: CsK =1:2) in DME, compound 5 bearing three different carbonyl groups
6
P. CironL F. Albericio and M. ,4lvarez
underwent a chemo- and regioselective oxo-amide coupling reaction with formation of pyrrole 6 in good yield without the ester group interfering. N-Alkylation of 6 with 4-methoxyphenacyl bromide 7 proceeded smoothly affording lamellarin O dimethyl ether in 15% overall yield. In work aimed at achieving a regiocontrolled preparation of unsymmetrical 2,3,4trisubstituted pyrroles, Gupton and Sikorski tested the condensation of different substrates (9, 10, 11) with glycine methyl ester, glycine ethyl ester and Nmethylglycine ethyl ester under acidic (HOAc), neutral (DMF) and basic conditions (Nail, DMF). The Firstner intermediate 6 was obtained when glycine methyl ester reacted with chloropropeniminium salt 10 (basic conditions, 77% yield) or with the [3-chloroenal 11 (neutral conditions, 82% yield), but no attempt at lamellarin synthesis was published. MeO
OMe
OMe
MeO
MeO
OMe MeO
OMe
MeO.,,T.. OMe
POCl3 ~
/N\
91%
w
/
8
H20 = THF
/ PF6
9
1 Glycine methyl Nail ester 77%
10
A similar approach was described by Kim et al. to build the Firstner synthon from the vinylogous amide 9, previously described, and the commercially available dimethyl aminomalonate hydrochloride as building block for pyrrole systems. The cyclocondensation reaction between the vinylogous amide 9 and dimethyl aminomalonate hydrochloride was performed in acetic acid at room temperature to yield the presumed intermediate 12 via an acid-catalyzed nucleophilic substitution reaction. The mixture was then diluted with additional acetic acid and heated under reflux to facilitate the intramolecular ring closure and the loss of the methoxycarbonyl moiety to produce the desired pyrrole. Formation of lamellarin O dimethyl ether was achieved as in the Firstner approach .
\N /
HOAc
Ar = p-MeOCsH4 9
,.
K2003 MeO2C
CO2Me 12
]
60%
90%
lamellarin O dimethyl ether
__J
Following on from their previous work on the biomimetic synthesis of marine natural products, Steglich et al. proposed a biomimetic lamellarin synthesis in which an oxidative dimerization of an arylpyruvic acid and condensation of the resulting 1,4-dicarbonyl compound with a suitable 2-arylethylamine would be the key steps of the synthesis. Thus, the synthesis of lamellarin G trimethyl ether was achieved by coupling two molecules of 3-(3,4dimethoxyphenyl)pyruvic acid and the appropriate 2-phenylethylamine . The use of a mixture of two different arylpyruvic acids afforded the unsymmetrical lamellarin L .
Lamellarins: Isolation, activity and synthesis
7
The 1,4-dicarbonyl compound 15, a key intermediate for pyrrole ring formation, was obtained in a one-pot procedure by oxidative coupling, for the symmetrically substituted pyrroles , or a deprotonation of ethyl ester 13 with sodium hydride and reaction of the resulting enolate with tx-bromoketone 14 . The 1,4-dicarbonyl compound 15 thus formed was directly transformed into the pyrrole 17 by adding the amine 16 at room temperature. Secondary reactions interfered in the coupling between 13 and 14 performed with the lithium enolate instead of the sodium enolate. A mixture of coupling products was observed due presumably to bromine exchange between the two coupling partners with the n-BuLi used for the enolate generation. A selective nucleophilic substitution on the methyl ester group of 17 on treatment with NaCN in 1,3-dimethyl-3,4,5,6tetrahydropyrimidin-2(1H)-one (DMPU) afforded the monocarboxylic acid 18 leaving the ethyl ester group unchanged. Subsequent oxidative lactonization of the carboxylic acid 18 with lead tetracetate, in refluxing benzene furnished the lactone 19 in 97% yield. As reported before, this reaction forms exclusively the desired regioisomer by attack of the carboxy radical at the ortho position which carries no adjacent alkoxy substituent. Hydrolysis of the ethyl ester group was achieved by treatment of 19 with 40% aqueous KOH, and removal of the ethanol by distillation. The Pd(0)-catalyzed Heck cyclizations of bromide 20 proceeded with concomitant decarboxylation, a reaction type hitherto not observed in Heck reactions. Treatment of 21 with A1C13 in dichloromethane removed the isopropyl protecting groups and afforded lamellarin L in almost quantitative yield.
co2,
V
0
1. Nail OMe Oi-Pr 2. B ~ oCo2Me 13
1,= ~ "OMe Oi-Pr
MeO' ~ O/-PrOMe Oi-Pr //~.~" ~'\ // 0 ~ 2 Et ?
\
~)
o,-Prl"Pr~
OMe
16
I i-PrO" ":/ ) \ OMe I NH2 I~ L EtO2C--~O O/~-CO2Me ~ Molec.Sieves A ) 5 3 (4 %
"~ "Oi-Pr OMe NaCN,~,. 17 R=Me DMPU 18 R = H 98%
~-
15
. ,., Oi-PrMeO ,.,. ,., Meu~N /~Ul-I-'r ~
1
O ~ R Pb(OAc)4R 97% r ?
Br-.~
ar
\
~
MeO
OR1
O CH3CN'PPh3, ~ NEt3, Pd(OAc)2 O 97% M e O ~
Br-~~ "~ "Oi-Pr OMe 40%aq.K O , ~ 19 R=Et then p-TsOH 20 R = H 80%
R1 0 ~ "
OMe OR1
~ '0
, R = Me : lamellarin G trimethyl ether AlCl3[_~ 21 RI=i-Pr 96% lamellarinL, R1 = H
Boger et al. developed a common strategy useful for the synthesis of related natural products and analogues . Their approach employs an aza Diels-Alder reaction using as diene the dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 25 to
8
P. CironL F. Albericio and M. Alvarez
assemble the substituents onto a six-membered 1,2-diazine core followed by a reductive ring contraction reaction . This method provided a tetrasubstituted pyrrole, a five membered heteroaromatic system, assembled by a [4 + 2] cycloaddition reaction followed by a ring contraction.
A•r
RO2C
Ar ~
I-Ar
Ar
Zn Ar'k~Ar DielsAlder N-N reduction , ~>MeO2C~(~ ~CO2Me , > MeO2C---( / \~)~CO2Me CO2R N-N N=N
H
Pd(0) '~~>
Ar
+ ArOTf
or
R3Sn - - SnR3 + 2 ArBr
Significantly, the oxygenation pattern found in the two aryl groups, as in 24, would be expected to increase the nucleophilic character of the acetylene and improve what is a typically poor reactivity of alkynes toward 1,2,4,5-tetrazine derivatives for an inverse electron demand Diels-Alder cycloaddition.
BnO--~
~
22
BnO--@l
Pd(PPh3)2CI2, Cul, Et3N
N-N
BnO---~
~
~~~--OBn
OBn
~~---~ MeO2C
N-N
BnO.
OBn
Zn, HOAc ~ ~ 7 72% ~ ' ~ 2Me MeO2Cf\ N~CO2 Me H
26
TFA~29 R=CO2H
Br
~o
OBn
0
30 R = H
HO
H2, Pd/C Me 100% "
25
BnO
OBn
K2CO3 ~ OMe
~
,,. oo%
-
// \\
_
MeO2Cf\N~CO2Me 28
27
BnO
LiOH 76% "
N TM
85%
24
75%
23
BnO
Me02C --.~/ \~--C02Me
L-~ O
OH OMe L ~0 1
97%
Me
lamellarin O
OMe
OMe
The acetylene 24 was allowed to react with 1,2,4,5-tetrazine 25 to give the desired pyridazine 26 in excellent yield. Zinc reductive ring contraction followed by N-alkylation of
Lamellarins: Isolation, activity and synthes•
9
the resulting pyrrole 27 with commercially available 4-methoxyphenacyl bromide 7 gave the pentasubstituted pyrrole 28. The symmetrical diester 28 was subjected to a selective hydrolysis with LiOH to provide the monoacid 29 which by decarboxylation afforded the appropriately substituted and functionalized pyrrole core 3t1 found in lamellarin O. This key intermediate could be quantitatively converted into lamellarin O by catalytic hydrogenolysis of O-protecting groups or, more simply, by conducting a TFA treatment of 29 or 30 at more elevated temperatures. Later, working on the synthesis of the natural product ningalin B, based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to pyridazine to pyrrole) the same group synthesized 36 a lamellarin derivative with a 7-membered ring instead of 6. The synthesis of the product 34 was achieved by N-alkylation with the phenethyl bromide 32 then subsequent MOM deprotection with concomitant lactonization provided lactone 34. Selective conversion of the methyl into the carboxylic acid 35 was achieved by reaction witn LiI. Attempts to promote decarboxylation under acidic conditions resulted in either no reaction (neat TFA) or Friedel-Crafts acylation (neat Eaton's acid ) giving 36 in 66% yield.
MeO OMe OMeOMe MeO~Me ~ OMe ~ ~ K2003 ~lOOJOMe ~ \~_/ HCI-EtOAc '%__/ \ 95% = R-~N _ // ~ OMOM 94% 0 MeO2C~\N~CO2Me MeO2C~\N~CO2Me H 31 33
M e O ~
Br
OMe
32
;
P205,MeSo3HMe~O OMe OMeOMe 66% - O ~ N ~ ' O MeO~ MeO
36
MeO
MeO
OMe
OMe Lilt---34 R=CO2Me 80%1---35 R CO2H
O
A different methodology was used by Iwao and co-workers to achieve the first total synthesis of the pentacyclic lamellarins D and H . The strategy was also used to produce a small library of 10 compounds for cytotoxicity evaluation in an effort to examine their structure-activity relationships . The common pentacyclic lamellarin skeleton was constructed by N-ylide mediated pyrrole ring formation and subsequent lactonization. The precursor 40 was obtained by a condensation of the known benzylisoquinoline 37 and the substituted benzoate 38 followed by N-alkylation with ethyl bromoacetate. Benzylisoquinoline 37 required for the synthesis of lamellarins was prepared according to a well known procedure . The 4-benzyloxy-3-methoxy-6methoxymethoxybenzoate 38 was readily obtained by a four-step synthesis from methyl 2,4dihydroxybenzoate in 49% overall yield . Metalation of benzylisoquinoline with LDA was chosen and gave better results than other tested bases on condensation with 38 to give 39 as a tautomeric mixture. Construction of the
l0
P. CironL F. Albericio and M..~lvarez
lamellarin framework from the mixture of 39a and 39b involves: i) quaternization with haloacetate, ii) removal of the MOM protecting group, and iii) pyrrole ring formation and subsequent lactonization. Although the three-step sequence can be operated virtually in a onepot procedure, high temperature or prolonged reaction times decreased the yield of 42. The synthesis of lamellarin D was accomplished by hydrogenolysis of the benzyl groups of 42 over
BnO
B n O ~
MeO~---~~
N
38
B n O ~
MeO~~~ N >- M e O ~ O
LDA 63%
BnO~
37 Q Br
MeO~.~.~
I ~ / 0 0 2 Et
BrCH2CO2Et M e O . . ~ @ O
"
BnO/X"--~ ~
"~
39b MeO"
OBn
RO
R
1
RO~
.
OMOM "~
OBn
R10
0
~
OR
Et3N
~ ./J ..1...OR " 3-~o BnO" ""~ ~ ~ (3steps) MeO"
M e O ~ - ~ ' ~ ' t N'H M e O ~ O
~/OMOM
39a MeO"
B n O ~
==
'~ OBn
40 R = MOM cat. HCI F-L_~ 41 R=H
~
0
H2, r-- 42 R = Bn, R1= Me Pd(OH)2/CI-=- lamellarin D R = H, R1 = Me 82% larnellarinH R=H, RI = H
BBr3 68%
Pearlman catalyst . Cleavage of both methyl and benzyl ether linkages in 42 using six molar equivalents of boron tribromide afforded lamellarin H. In a similar approach, Ruchirawat et al. first prepared an o-mesyloxyphenacyl Br
MeO
MeO
OMs R'~'~ ~ K2CO3
MeO" v
"1
.. . .. ... . .. . R= (~Me
OMe R
R
Me
I~
Ms
DMF, POCI3
63% MeO" ~ MeO
M
OMeR
=
R
e
e OM R
MeO
~
O
~
46 R1 = OMs KOH 47 R1 OH 77% series a 81% series b
~
R Pd(OAc)2, PPh3'
or
=e
e
O 45
MeO ~
OMe R
R
K2CO 3, PhBr
R1 ~ =_
=e M
80%
v 43
MeO~ . - ~ . ~ ~ ~ 48
HO
80%
= M
eO
MeO~ ~ . .
,,
N' ~-
'
O,' 0
49 R = H (from series a) larnellarin G trirnethyl ether, R = OMe (from series b)
Lamellarins: Isolation, activity and synthes&
11
bromide 44a as one of the building blocks, which was further condensed with 3,4dihydropapaverine hydrochloride 43 in the presence of potassium carbonate and acetonitrile as solvent. The expected mesyloxy pyrrolo[2,1-a]isoquinoline 45a was produced presumably due the intramolecular reaction of the derived enamine from the isoquinolinium salt and the ketone as found in the Knorr pyrrole synthesis . The introduction of the formyl group on the pyrrole ring to give 46a was accomplished by Vilsmeier reaction, using DMF in phosphorus oxychloride at room temperature. The O-mesyl protecting group in the derived aldehyde intermediate was easily removed by heating with potassium hydroxide in ethanol to give 47a. Finally, an oxidation of 47a with manganese dioxide in dichloromethane yielded the lamellarin derivative 49 presumably via the hemiacetal intermediate 48a. The same approach was applied again to the synthesis of lamellarin G trimethyl ether as shown in series b. The first three steps proceeded as expected, however the oxidation of compound 47b with manganese dioxide gave lamellarin G trimethyl ether in a disappointing yield (20%). The by-product was found to be the quinone derivative 50 formed by the preferred oxidation of the electron-rich phenolic ring. For this reason the oxidation was carried out with bromobenzene, palladium acetate and triphenylphosphine using DMF as the solvent and potassium carbonate as the base. Lamellarin G trimethyl ether was formed in 80% yield.
50 Later developments from the same group brought some changes to their previous routte. One of the drawbacks of the previous sequence was the use of a mesyl protecting group, which added two synthetic steps. A better approach was found using a hydroxyl protecting group on the phenacyl bromide synthon that can act as a directing group for the remote deprotonation at the C-2 position of the pyrrole as well as being the source of the lactone group in the subsequent lactonization of the resulting anion without the need for a separate formyl group equivalent. This strategy was pioneered by Snieckus and termed DreM (for directed remote metalation) . The directing group is typically a carbonate or a carbamate group. Alternatively, the intermediates 53 or 54 could be selectively brominated at the 2-position of the pyrrole to give the bromo compounds 55 or 56 which could undergo metal-halogen exchange to provide an anion similar to the one from the DreM strategy after initial remote deprotonation. Reaction between the benzyl-3,4-dihydroisoquinoline hydrochloride 43 with the carbamates 52a and 52b in the presence of NaHCO3 afforded the pyrrole carbamates 54a and 54b in 91 and 81% yields, respectively. The carbonates 51a and 51b were also coupled with 43 under similar conditions to give the pyrrole carbonates 53a and 53b in 72 and 60% overall yields. Lamellarin 49 was synthesized with just 35% yield after some exploratory work on the DreM methodology. In addition to the low yields, the DreM/cyclizations reactions were not highly reproducible and partial deprotonation of the starting material was frequently found. A more direct way to generate the C-2 pyrrole anion would be via metal-halogen exchange and require the C-2 halo pyrrole. To this end, the pyrroloisoquinolines 53a, 53b, 54a and 54b were
12
P. CironL F. Albericio and M. /ilvarez
selectively brominated with N-bromosuccinimide (NBS) to give the bromo pyrroles 55a, 55b, 56a and 56b in excellent yields (> 95%). Subsequent lithium-halogen exchange of carbamates using tert-BuLi, gave only the 2-(N,N-diethyl)amido-pyrroles 57a and 57b in virtually quantitative yield. Other attempts to achieve ring closure of these amido-pyrroles failed . However, lithium-halogen exchange of carbonates 55a and 55b with tertBuLi, proceeded smoothly to give the desired lamellarins 49 and lamellarin G trimethyl ether in 72 and 67% yields, respectively.
o Br O ~ O'Jt"x
MeO.~. MeO'- ~ MeO" ~
OMe R
R
~--'~'R
"]
MeO. ~ ~ ~
MeO
NHQC( ~
J
a
,Me
NaHCO3
M
51 X = OEt, 52 = NEt2 a R = H or b R = OMe
v
43
~O x e
O
DreM
~
53 X = OEt, 54 X = NEt2
M-halogen exchange
[
bromination MeO
MeO
OMe R
R
MeO
OMe R
M-halogen H ~exchange Me "~J/~\N/~CONEt2 57
lamellarins
R
o~X b
56 X = NEt2
55 X = OEt,
Recently, Ruchirawat et al. proposed a more convergent strategy which envisioned that the lamellarin skeleton could arise from condensation of the benzyldihydroisoquinoline with a Michael acceptor, such as 61 or 62, which essentially would install the lactone or the ester group on the 2-position. Since imines, which exist in equilibrium with their enamines, have been shown to react with 13-
R40
R50
OR6
R30
R40 B
R
3
R50 0
~
'
OBn
T
o 58
R40
59
A~,
R30
R20~ R10~
OR5 /OR6
+ 60
N+ O2N
60
~,OR5 /OR 6
O 61
O2N
CO2R 62
Lamellarins: Isolation, activity and synthes&
13
nitrostyrene to give the corresponding pyrroles , it seemed that Michael addition of an enamine derived from a benzyldihydroisoquinoline with a powerful Michael acceptor, followed by ring closure and aromatisation might provide a more direct route to the lamellarin alkaloids than previous methods. Modelling the Michael addition/ring closure reaction, a simple D-nitrostyrene and 3,4dihydropapaverine hydrochloride were reacted under basic conditions resulting in complete consumption of both starting materials but gave no desired product. The ester nitrostyrenes are more powerful Michael acceptor than the simple nitrostyrenes due to the additional electronwithdrawing effect provided by the ester group; this allows the ester nitrostyrenes to react under milder reaction conditions. Consequently, the authors planned to use a coumarin derivative as the ester nitrostyrene which would offer a significant advantage in that the structure already contained the lactone moiety. Unfortunately, such a reaction gave the desired lamellarins in only 5-6% yields. These results prompted the use of an acyclic ester nitrostyrene like 62. From the structure of compound 59, it was apparent that the desired lactone moiety could be formed by unmasking the benzyloxy-protected phenol by hydrogenolysis and subsequently initiating base-mediated lactonization.
R10
X
~CHO
EtO2CCH2NO2 B n O ~ O B n Et2NH.HCl . ,,. . ,..,II I NO2
BnO\ ~ / O B n .~ .~I 65; 3 steps=
R20 / ~
MeO'- -"7-- - - - C H O
63 X=OBn, R I = R 2 = M e
MeO/~x'~""x~
66
CO2Et
67
64 X = R2 = H, R 1= Me 65 X = R 1= H, R2 = Me 63-65, 7 steps
R30"~'~
M e O ~ N
R10~1 ~ X
R40 ~ x
R50 / ~
f/ \~L
NaHCO3,67 M e O . . ~ x OBn 70% "~/ / ' ~ \ N / - ' - C O 2 E t
R~ O ~ ~ ~ . J X
~ R40
OR6
Nail M e O ~ N . ~ O 93%
RI 0 ~ X
68 X = OBn, R1 = R3 = Me, R4 = Bn 70 X = OBn, R1 = R3 = Me, R4 = Bn 69 X = H , R I = R 3 = B n , R 4=Me ~ - 71 X = H , R I = R 3 = B n , R 4=Me H2, Pd/C
,~~ RSo
OR6
0
Lamellarins K LamellarinsL
72 X = OH, R1 = a 3 = Me, R4 = H 73 X = R1 = R3 = H, R4 = Me
The Michael addition/ring-closure reaction of the imines 68 and 69 with the ester nitrostyrene 67 proceeded smoothly in refluxing anhydrous acetonitrile in the presence of NaHCO3 to give pyrroles 70 and 71. The syntheses were completed by subjecting pyrroles 70 and 71 to hydrogenolysis to give compounds 72 and 73 quantitatively, followed by base-mediated lactonization with sodium hydride in dry THF to produce lamellarin K in 93% and lamellarin L in 87% yield over two steps. Lamellarins K and L were successfully prepared in three steps in 65% and 61% overall yields, respectively.
14
P. CironL F. Albericio and M. Alvarez
Iwao et aL developed a short and flexible route to 3,4-diarylpyrrole marine alkaloids applying a new strategy to the synthesis of lamellarin G trimethyl ether and related marine compounds . The synthetic strategy involved two key reactions: i) Hinsberg-type condensation of the aminodiacetates 75 with dimethyl oxalate to produce 3,4dihydroxypyrrole-2,5-dicarboxylates 76, and ii) palladium-catalyzed Suzuki cross-coupling of the bis-triflate derivatives 77 with arylboronic acids. 2-Arylethylamines 74a and 74b were alkylated with methyl bromoacetate in acetonitrile in the presence of NaHCO3 to give the aminodiacetates 75a and 75b. Condensation of 75a and 75b with dimethyl oxalate using NaOMe as a base afforded 3,4-dihydroxypyrrole-2,5dicarboxylates 76a and 76b in modest yields. This pyrroles were converted into the bis-triflates 77a and 77b in good yields. R10 NH2
OR 1
MeO2C~N~CO2Me MeO2C (CO2Me)2 MeONa =R 49%
BrCH2CO2Me, NaHCO3 =~ R OMe 74a R = H 74b R = OMe
91%
MeO CO2Me MeO. _ ~
L,, ""l
78
B(OH)2
Pd(PPh3)4,Na2CO3
/
[ ~
OMe
78%
=~ 79
R OMe
75a 75b
76a R = R 1= H
(0F3SO2)20 86%
76b
R = OMe, R1= H
R = H, R1= Tf 77b R = OMe, R1= Tf 77a
The bistriflate 77b was coupled with 1 equivalent of 3,4-dimethoxyphenylboronic acid 78 to give the mono-arylated 79 in 78% yield, accompanied by 11% of the di-arylated product. The second cross-coupling, of 79 with 4,5-dimethoxyphenylboronic acid 80, was found to be somewhat inefficient due to rapid decomposition of the boronic acid 80 under the coupling conditions. However when the reaction was carried out using excess (2.0 equiv) of 80 and 8% of Pd(PPh3)4, the coupling product 81 and its lactone 82 were obtained in 58 and 12% yields, respectively. Elimination the O-MOM protecting group of 81 by treatment with hydrochloric acid in methanol caused at the same time lactonization to give 82 with an excellent yield. Alkaline hydrolysis of 82 methyl ester followed by heating with p-TsOH produced the acid 83 which by Cu20-mediated decarboxylation in hot quinoline afforded permethyl ningalin B 84. The ring closure of 84 to furnish the lamellarin G trimethyl ether was cleanly effected by application of Kita's oxidative biaryl coupling conditions with good yield. Examination of a straightforward ring closure of 83 to lamellarin G trimethyl ether through a Pd(II)-mediated decarboxylative cyclization also afforded the same lamellarin G trimethyl ether in 65% yield, accompanied by 12% of 84. The ring closure was found to be regioselective at C-6 of the pendant aromatic ring. This novel cyclization may proceed via initial decarboxylative palladation of the pyrrole ring, followed by electrophilic palladation of the electron-rich aromatic ring and reductive elimination of Pd(0).
Lamellarins: Isolation, activity and synthesis
MeO
,
MeO :M' O e OMOM
MeO2Cf\ N~CO2Me
MeO2CJ\N~-CO2Me -
B(OH)2 ~ T ~OMOM
M~O"'f"
OMe
OMe
.o
+
OMe
L
OMe
811
OMe OMe OMe MeO
MeO2C.~ N ~ "
~
Pd(PPh3)4,Na2C03 OMe
79
MeO
15
0
0
OMe I 82
conc. HCI 90%
OMe OMe OMe
"1
O
OMe
0
HO2C-~ N~"~~ O ~N~ O MeO ?Me OMeoM e 1. KOH 400/0 L..... O Cu20' quinoline L.~ 0 Phl(OCOCF3)2' ~ ~ / 76% -
~J i~L
93%
-
"~\OMe
~
_
I~
'~
OMe 83 I
L
"OMe
. ...~\ ~ MeU " ~
OMe Pd(OAc)2,MeCN
84
2-%
86% M e O ~ O
l
N
\~
lamellarin G trimethyl ether
65% A new, convergent and straightforward approach was first developed by Banwell et al. in their total synthesis of the parent ring-system lamellarin K. The pivotal step in their approach to lamellarin ring systems involves construction of the central pyrrole moiety via an intramolecular [3 + 2] cycloaddition of an isoquinoline-based azomethine ylide to a suitably tethered bisarylacetylene, a hitherto unknown process. The reaction sequence leading to the alkyne 85 involved a palladium-mediated cross-coupling reaction between the appropriate alkynylzinc chloride and the aryl iodide , or a Sonogashira crosscoupling between the corresponding arylacetylene and the aryl iodide . The bis-aryl acetylene 85 was subjected to a Baeyer-Villiger reaction using mCPBA as oxidant. The resulting formate ester 86 was readily hydrolysed to the phenol 87 with excellent yield. DCC-mediated condensation of the phenol and ot-iodoacetic acid then provided ester 88 which was used for the quaternization of 3,4-dihydro-6,7-dimethoxy-5isopropoxyisoquinoline 89 to give the salt 90. This last compound was not isolated but immediately treated with Htinig's base. The resulting mixture was heated at reflux in 1,2dichloroethane to bring about the cycloaddition followed by in situ aromatisation to give lamellarin K triisopropyl ether 91. Treatment of this last compound with A1C13 resulted in the formation of the target compound lamellarin K. Applying the same methodology they also synthesized other pentacyclic lamellarins with the isoquinoline core in the dihydro form or in the oxidized form using," for the oxidation step, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) .
16
P. CironL F. Albericio and M. Alvarez
I-- MeO
Oi-Pr
MeO
,_Pro-
MeO~
OMe
-
o,-Pr
/ R
m-CPBA I NaHCO3 I
M e O ~ 89
I
-
N
"~ l
85 R= CHO 92% two steps --- 86 R = OCHO ' s7 R = OH -I NH3, MeOH
ICH2COOH, DCC DMAP 97% I
OMe
MeO.
MeO~,~ O/-Pr
O./N(~I~=
O
_
90
= 88 R = OCOCH21 Oi-Pr
MeO
.
\
OH
.Oi-Pr
re"ux M e o M e O
X.--,
MeO
, OH
\
,0,96O, o O
MeO
O
OH
O/-Pr 91
lamellarin K
Using a similar strategic procedure Faulkner et aL synthesized and evaluated 20-sulfate analogues of lamellarin ct. OM e /
-
P
r
MeO O
OM e
.OiPr
BCI 3
92
.OR
RO
~ 93%
MeO ~ . . ~ . ~ ~ ~
MeO
O
Me
MeO ~ j ~ ~
O
DMF-SO3 r--I_ 9 3 R = H 83% - 94 R = SO3Na
Lamellarins I and K were also synthesized by Guiti~n et aL with a new approach based on the 1,3-dipolar cycloaddition of a nitrone to an alkyne. The key cycloaddition step yielded an isoxazoline which rearranged to afford the central pyrroloisoquinoline core. N-Oxides 96a and 96b were obtained from dihydroisoquinolines 95a and 95b, which were prepared using standard isoquinoline alkaloid synthetic procedures. Reduction of the imine double bond 95 with sodium borohydride, followed by a non-optimised oxidation with sodium tungstate , afforded N-oxides 96. The key intermolecular cycloaddition step was carried out by heating a mixture of nitrone 96 and alkyne 97 at high temperature in a sealed tube. Under these conditions compounds 99 were obtained in moderate yields. The cycloaddition appears to produce the expected regiochemistry and form the isoxazoline 98, which upon heating undergoes rearrangement to the corresponding pyrroles 99. Finally, lamellarins I and K were obtained from 99a and 99b respectively, by removal of the isopropyl protecting groups with concomitant acid-catalyzed lactonization.
Lamellarins: Isolation, activity and synthesis
OR M e O ~ MeO~-~
OR M e O ~
OR O-~OMe MeO~ ~- "' ~- ~- - % OCO2Et\ ,, vMe
98a 98b
.CO2Et
,_PrO~[ ~ OM, 120~ "
96a R = Me 96b R = H
95a R = Me 95b R = H
MeO/"--~ ~OkPr
Oi-Pr
96% MeO 2. H202,Na2WO4=MeO'~~ 45% RO" "~
N
]7
MeO----~\ /> MeO.
~ ~
OR
OR
"OMe
MeO ~'/ \~)
"71 "/ ~"h-'/\N/~'CO2Et MeO~ ~ / ~ ' y 99a OR 99b
OR
MeO
MeO----~~ I
II
M e O ~
....
~_ N
\0
O
lamellarin I, R = Me lamellarin K, R = H
1.4.1.2 Approaches starting from the pyrrole core At about the same time as the Steglich report, Banwell et aL published a convergent synthesis for the open lamellarin systems: lamellarin O, lamellarin Q, lukianol A and some more highly oxygenated congeners . In each case, the key synthetic step involves Stille or Suzuki or Negishi cross-coupling reactions of readily available pyrrole-2-carboxylic ester derivatives with the appropriate arylstannane, -boronic acid or-iodide. The pivotal dibromopyrrole 102 required for all the syntheses was prepared from pyrrole itself using procedures developed by Muchowski and co-workers . Thus, the Ntriisopropylsilyl derivative of pyrrole 100 was subjected to reaction with NBS in THF to prepare the tribromo-derivative 101, which by reaction with PhLi followed by C1CO2Me afforded the previously unreported compound 102. Stille cross-coupling of pyrrole 102 with the t-BuMe2Si (TBDMS) protected stannane using Pd(PPh3)2C12 as catalyst gave the expected product 103. Elimination of N- and O-silyl protecting groups of 103 with Bu4NF afforded lamellarin Q. The synthesis of lamellarin O followed very similar lines. Thus, compound 102 was desilylated and the resulting pyrrole 104 coupled with the arylstannane. In this manner, the two-fold coupling product 105 was obtained. Reaction of this with 4-methoxyphencaylbromide in the presence of base then gave the N-substituted pyrrole which was deprotected with Bu4NF to afford lamellarin O. Two-fold cross-coupling of pyrrole 104 with p-MeOC6H4B(OH)2 under standard Suzuki conditions afforded lamellarin Q dimethyl ether. This route was shown to be more efficient than Ftirstner's route . Stille and Suzuki cross-coupling reactions failed when the authors tried to obtain the monoarylated pyrrole under different conditions. As a consequence, these types of coupling reactions would not seem to be useful in providing access to differentially di-arylated pyrrole systems
18
P. CironL F. Albericio and M. .4lvarez
that would be required for the synthesis of the more complex lamellarins. This limitation was overcome by regioselective lithiation of compound 102 followed by transmetallation and Negishi cross-coupling reaction. HO R1
R1
3x
~
TBDMSO~--~/k--SnMe 3
-
Ar
R2 Pd(PPh3)2Cl2 (10 mol%)9
66%
Si~Pr3
BrB ~ ;
H
78%
,.,r
3x T B D M S O ~ - - S n M e 3
Bu4NF(10 mol%), then 0.5 M aq. HCI
~N,,>L---CO2Me ~
98%
Me
9
Si~Pr3
100 R 1 = R2 = H NBS ]91% R1 R2 = = Br PhLi then I _ _ _ . 101 9 ~ ~ R 1 R CICO2Me = Br, 2 = CO2Me 99% Bu4NF (10 mol%), then 0.5 M aq. HCI
Ar
~''
OH
H
103
lamellarin Q HO\ _ ~~
Ar, ~
-
Ar
1. p-MeOC6H4COCH K2CO3, Bu4NCl _
_ / OH (~-~ (~,,N,~CO2Me
CO2MePd(PPh3)2CI2 (10 mol~ - \ N / ~CO2Me 2. Bu4NF (10 mol% ), 66% H then 0.5 M aq. HCI 104 105 83% 3x M e O - ~ -
B(OH)2
I Pd(PPh3) , sat. aq. Na2CO3 MeO
OMe
OMe lamellarin O
Me H lamellarin
Q dimethyl
ether
Thus, reaction of 102 a t - 7 8 ~ with PhLi afforded the mono-lithio-derivative 106 which was transmetallated with ZnC12 to give the organozinc 107. This last species was, in tum, cross-coupled with the aryl iodide 108 to give the mono-arylated pyrrole 109. Compound 110 was subjected to a further lithiation-transmetallation sequence and the intermediate 111 then cross-coupled with aryl iodide 112. This material was desilylated using Bu4NF thereby affording the target pyrrole 113. A similar reaction sequence where compound 107 was coupled with aryl iodide 112 and the resulting mono-arylated pyrrole subject to metallation and coupling with aryl iodide 108 afforded, after deprotection, the isomeric system.
Lamellarins: Isolation, activity and synthesis
OMe
MeO/ ~
MeO~j/OMe
BrR ~
, lo8 R2 Pd(PPh3)4_ ~
1
,
OMe 1, ~OTBDM OMe S
~OMe
19
MeO
MeO
.OMe
~ 11l H O ~ O M e Pd(PPh3)4
CO2Me 69% from 102 ~..NJ~----CO2Me 2. Bu4NF (10 mol%), ti then 0.5 M aq. HCI Si Pr3 ~;iipr3 68% 102 R'= Br - - 109 R2= Br PhLi I ~ 106 R1= Li BuLi L_~ 110 R2= Li ZnCll = 107 R1= ZnCl ZnCl[ ~_111 R2= ZnCl
"-..N/"--CO2Me H 113
A similar approach was used by Liu et aL for the synthesis of 2,3,4trisubstituted-lH-pyrroles with 1-protected 3,4-bis-(trimethylsilyl)-lH-pyrroles as pivotal precursors. They introduced the 1-(N,N-dimethylaminosulfonyl) protecting group for enhancing the acidity of the pyrrole ot proton and also stabilizes an ortho-lithium through coordination with its nitrogen or oxygen atoms. These factors therefore combine to facilitate formation of the a-carbon anion. The lithium salt, generated with n-BuLi, reacted with methyl chloroformate to give the sulfonamide 115. The mono-ipso-iodination of 116 was achieved with iodine and silver (I) trifluoroacetate. Steric and electronic factors played an important role in controlling the regioselecvity, C-4 is more nucleophilic as well as less sterically hindered. Suzuki reaction between 116 and p-methoxyphenylboronic acid gave 117, which was also allowed to undergo an ipso-iodination followed by another slightly modified Suzuki crosscoupling reaction with p-methoxyphenylboronic acid to yield the symmetrical compound 119. Deprotection of 119 with Bu4NF led to 120 but in a low yield. An alternative deprotection method using Mg in MeOH at room temperature gave a much higher yield of 120. Finally, Nalkylation of 120 with p-methoxyphenacyl bromide 7 was accomplished to furnish lamellarin O dimethyl ether. The regioselective methodology would be also suitable for the synthesis of unsymmetrical open lamellarin derivatives.
Me3Si'., __5/SiMe3 _70 % yield < 03T4767, 03SL1479>.
R2)~N,~
~OMe
1
_ ~ _ 1 ~ ~_~ (~
2
3
"Photo-Bergman" cyclization have been carried out on diethynyl sulfides 4 to produce 3, 4disubstituted thiophenes 5. Matzger reported this as being the first five-membered ring cycloaromatization reaction . The reaction is found to produce many side products thereby lowering the yield of the desired heterocycle.
hv > . ~ . P h j ~ S ~ " Ph
Ph!~
H S Ph
4
H
> ph~-~ph 5
While cyclohexadiene or y-terpinene (hydrogen donors) gives -~30% of the thiophene, alcohols were found to produce thioesters and acetylenes along with a lower yield of thiophene. The major side reaction reported is the oligomerization of the intermediate thiophene diradical. A one-pot synthesis of substituted 2-arylbenzo[b]thiophene has been described by Kolasa and co-workers.
~A~/
R~
R2 + H S R 4 ~ ~ X R3 X = F, Cl, NO2 R2= H,Ar A=CH, N
K2CO3 DMF,A
R2
~,4
R3
Aromatic nucleophilic substitution of a benzyl thiol to an aromatic ketone, nitrile or aldehyde followed by addition/elimination results in solely the formation of 2-arylbenzo[b]thiophenes 6 .
1 O0
v. Seshadri, F. Selampinar and G.A. Sotzing
One pot syntheses.
O
O
(i) K2CO3/DMF
RI'~~
O
R2 (ii)Ph-NCS
O R2
p 7
X'CH2-Y 1 K2CO3/DMF . .O~ J~. O
O R1-~2 Ph-HN" "S" Y -~ 8 X = halogen Y = e withdrawing group (-CN, -COOEt)
RI "1/ R2 Ph-HN/~S~Y R1 and R2 = Me, OEt, Ph Scheme 2
Ketene thioacetals 7 have been used to synthesize thiophene with a carbonyl in the 3-position 8 (Scheme 2) . In the reported procedure u-oxoketene dithioacetal is converted to the substituted thiophene 9 upon reaction with diiodomethane in the presence of Zn-Cu. Simple formylation or acetylation of thiophenes only produces the 2- or 5derivatives and, hence, this is a useful technique to produce the 3- or 4- derivatives. This method also has been studied to synthesize substituted selenophenes 10 . MeO.
OMe
O~1 H
CH212/Zn'Cu~ Et20, reflux "-
OHC
SMe
MeS" "SMe
O R1
H
@
O I
R2 e
Na2Se X'CH2-Y
MeS
Y 10
A [3,3] Claisen rearrangement of thiomorpholides has been reported to produce 2,3,5trisubstituted thiophenes 11 . H
O Ar-'JLCH3
(~~+S
i/'"O ~./X-Br + K2CO3 ~ A r - " ~ N-...~ Microwave, 10 min S 120-130[]3, o-dichlorobenzene
Ar
r . CH3 11
Ar= Phenyl,4-chlorophenyl,4-bromophenyl 4-biphenyl,2-naphthyl,4-methoxyphenyl
Five-Membered Ring Systems: Thiophenes & Se, Te Analogs
l 01
Microwave assisted Gewald synthesis of 2-acyl aminothiophenes 13 on solid support has been carried out by Gauvin and co-workers , wherein the solid support was a
Solid phase synthesis of highly substituted thiophene derivatives 15 using a cyclic malonic acid ester resin 14 was also reported. Highly pure thiophene derivatives were reported to have been prepared by this solid phase synthesis . While alkyl or aromatic substitutions on the 13 position to the carbonyl yielded the corresponding 5-alkyl/aryl substituted 2-acyl aminothiophene, acetaldehyde did not produce the corresponding 2,3-disubstituted thiophene.
2-aminothiophene-3-carboxamide synthesized via Gewald's route has been used to synthesize thieno[2,3-b]pyridines 16 and thieno[2,3-d]pyrimidines 17 . In an unprecedented reaction between triethylamine and disulfur dichloride in the presence of DABCO in chloroform, thienopentathiepin 18 and heptathiocane 19 were obtained .
Ar
R ~S"s
16
17
18
S NEt2
.[ _S_~ NEt2 19
4, 5-Dithenyl[1,3]dithiol-2-one 20-21 have been used to synthesize 6-arylthieno[3,4b]thiophene 22-23 and 2,3,4,5-tetrathiophen-2-ylthiophene 24 < 03JOC7115>.
102
V. SeshadrL F. Selampinar and G.A. Sotzing
S ~
a,b,c R
~
S
R
R=3-thienyl 20 R=2-thienyl 21
R=3-thienyl 22 R=2-thienyl 23
(a) hv, 6 h (b) (i) NaBH4, EtOH (ii) Mel, Na2CO3, rt (c) Mel, D
~~
=O
(i) hv, 5h (ii) AcOH, H202
24
Reactions of 2-trifluoromethylchromones with ethyl mercaptoacetate have been carried out to give trifluoromethyl containing 1,2-dihydrothieno[2,3-c]chromen-4-ones 25-28. Two thieno[2,3-c]coumarins have been prepared from the corresponding sulfoxides using the Pummerer rearrangement followed by aromatization . O CF3
CF 3
R2OOC
s
I ,,r
COOR2
-
S
" 0 R = H or Me 25, 26
0 R = H or Me 27, 28
R1, R3 = H or alkyl R2 = alkyl
29
H
H
30
A similar mercaptoacetate addition reaction to 5-acyl-4,7-dioxo-4,7dihydrobenzo[b]thiophene-2-carboxylates followed by cyclization and oxidation to give benzo[1,2-b:5,4-b ']dithiophene-4,8-dione derivatives 29 has been shown . Nitrogen bridged heterocycles, 3-(benzylthio)thieno[3,4-b]indolizine derivatives 30 have been synthesized and intramolecular arene-arene interactions within these compounds were reported . The arene-arene interaction leads to significant shifts in the proton NMR signals and red shifts in the absorption maxima. Benzo[c]selenophene 32 has been prepared by the aromatization of dihydrobenzo[c]selenophene 31 following the bromination of the selenium using molecular bromine and a subsequent elimination in the presence of an aqueous or non-aqueous base . Furthermore, the dialdehyde and dicarboxylic acids on the ot positions of benzo[c]selenophenes have been synthesized.
103
Five-Membered Ring Systems: Thiophenes & Se, Te Analogs
So + Br2
~
S
31
r
32
Some porphyrin and octaphyrins consisting of selenium will be discussed later in this chapter. To the best of our knowledge there have been no reports on the synthesis or chemistry of tellurophenes over the last one year.
5.1.2.2 Ring Closures Carried out on Thiophene Starting Materials
The synthesis of tetrasubstituted naphthalenes consisting of thiophene 33 were reported using palladium catalyzed reactions of aryl iodides and intemal alkynes .
~ ~-
COOEt COOEt ~ "COOEt COOEt /
33
S S
R1 R
H
R1, R2 - -H, -H -OMe, -H -OMe, -OMe
34
H
35
H ~
R
R2 1
R1, R2 = -H, -H -OMe, -H -OMe, -OMe
36
Thieno[3,2-c] or [2,3-b]carbazoles 34-35 and indolo[3,2-b]benzo[b]thiophenes 36 and derivatives have been synthesized by palladium catalyzed amination and subsequent palladium catalyzed cyclization reactions . While blocking the ~- and 13- position of thiophene gives thienocarbazoles the unsubstituted thiophene undergoes ring-closure on the b face of thiophene to give the indolobenzo[b]thiophenes. One pot borylation of benzo[b]thiophene followed by palladium catalyzed Suzuki coupling with aryl halides to make thienocarbazole compounds have been reported . 1,3,5,7-tetramethyl-4,8-dihydrobenzo[1,2-c:4,5c']dithiophene-4,8-dione 37 was synthesized from 2,5-dimethyl-3,4-dicyanothiophene and the diones were then converted to the mono- 38 and dithiones 39 in modest yield . The monothione has been prepared reproducibly using Davy's reagent in a 42 % yield.
104
14. Seshadri, F. Selampinar and G.A. Sotzing
Me
X
Me
O
Me
Me
~
Me
O
Me
X,Y=O,O 37 S,O 38 S,S
40
39
Increasing the reaction time lead to the formation of the dithione in only very low yield (5 %). Also, the synthesis of 40 has been reported to have been accomplished using the same procedure starting from phthaloyl chloride and 2,5-dimethyl thiophene. Conversion of this to the mono- and di-thiones has been reported to be unsuccessful. Thiophene containing fused 6, 7 and 8 membered ring systems 41-46 have been prepared from in situ generated azomethine imines followed by cycloaddition to N-methyl maleimide and subsequent Pd(0) catalyzed cyclizations . Me
O...~/N ~ "0 \
H ~ ~ -'~H /S ~.>.(..N.N.co2Me
41
Me
0 N-/.0 \
H~ H /S~N.N.co2Me
42 Me
Me
O ~ Nx~.O I
H H H,,. .N.co2Me
43 Me
I
Me
I
I
o
44
45
N
o
46
Thiophene analogs 47 of isatoic anhydride have been synthesized and their chemical reactivity towards nucleophiles have been studied . Unlike the reaction of isatoic anhydride with a nucleophile wherein both 2-ureidobenzoic acid and 2-carbamoylbenzoic acid are obtained, 6- and 7-arylthieno[3,2-d][1,3]oxazine-2,4-diones have been shown to give only the ureidothiophen carboxylic acid 48.
105
Five-Membered Ring Systems: Thiophenes & Se, Te Analogs
o
o
H Nu = Benzylamine, Butanol 47
O~,.Nu 48
Meldrum's acid 50 was found to react with 3,4-bis(bromomethyl)-2,5-dimethylthiophene 49 in the presence of triethylamine to give a C, O-dialkylation product, namely, 1,3,7,7-tetramethyl4H, l OH-6,8,9-trioxa-2-thiabenz[/]azulen-5-one 51. Upon heating this compound in the presence of a catalytic amount of potassium iodide in acetonitrile at 100~ the lactone 52 is produced and heating in butanol led to trapping of the ketene intermediate resulting in 53 .
0
.- t.~uO/../
51
5.1.3
O,~C02_t_B u 0
THIOPHENE RINGS, CAGES AND MISCELLANEOUS
5.1.3.1 Conjugated Macrocycles Shape-persistent macrocycles consisting of thiophenes alone or with other aromatic rings have been synthesized.
o
1 16
106
v. Seshadri, F. Selampinar and G.A. Sotzing
A "gigantocycle" with a diameter of 12 nm was synthesized in a 38% yield for the ring closing step wherein thiophenes have been used as the angular unit and the rest of the cycle was comprised of phenylethynyl. The open chain hexadecamer with terminal acetylenic group was cyclized using copper(II) acetate under very dilute conditions to produce the cyclic hexadecamer 54 . Bauerle and co-workers have synthesized a macrocycle consisting of 8 thiophenes in conjugation by an oxidatively induced elimination of platinum complexes . The platinum complexes 55 were obtained by reaction of terthiophene with terminal acetylenic groups with cis-Pt(dppp)C12 in the presence of CuI and Et3N. C-C bond formation was effected by oxidatively induced elimination using iodine and the diacetylene bridged thiophene macrocycle 56 was converted to an all thiophene macrocycle 57 by reacting with sodium sulfide.
t-Bu
t-Bu t-Bu
t-Bu
t-Bu
, ph.,.7x..q~ "~\,-,/\-Ph, I uP~ P~ t
t-Bu t-Bu
t-Bu
2eq. 12 ~
h"
h
60~ 24 h
S t-Bu"
55
t-Bu~
t-Bu
t-Bu t-Bu" t-Bu
"t-Bu
56
t-Bu
Na2S9.H20 xylene, ROH
140~ 20 h
t - B u ~ t _ B u 57 5.1.3.2
Porphyrin Analogs
Ravikanth et al have reported meso- or [3-furyl porphyrins with N3S and N2S2 cores 58-62. Porphyrins have generated a lot of interest as they can be good acceptors for efficient energy transfer in donor-acceptor type architectures.
107
Five-Membered Ring Systems: Thiophenes & Se, Te Analogs
0
R
--C N 58-60
61
9 5% regioselectivity
~SiMe3 " H
A Heck-type coupling of 2,3-dihydrofuran with a secondary chloroacetamide produced the two double bond isomers in about 2:1 ratio . A palladium-catalyzed Heck-type coupling between the heterocyclic iodide shown below and 2,3-dihydrofuran was used as the key step in the synthesis of C-nucleosides. Conditions were optimized to include Ag2CO 3 to prevent double migration and thereby obtain a good yield of the desired 2,5-dihydrofuran products .
166
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
Pd(OAc)2 AsPh3
~,'Y-CI
Ag2CO3 Et3N-DMF 45~ 48 hr 81%
Excellent enantioselectivity and double-bond regioselectivity can be achieved in an asymmetric Heck reaction between 2,3-dihydrofuran and aryl triflates by using a combination of chiral diphosphine-oxazoline ferrocenyl ligand and Pd catalyst , as shown below. Chiral diphosphine-containing (arene)tricarbonylchromium(0) complexes were also used as ligands for this reaction to obtain the 2,3-isomer, however, both the yield and enantioselectivity were modest .
~
Pd(OAc)2 (1.5 mol%) Pd(dba)2-dba Ligand Ugand ", ~+PhOTf - ~ "Ph/.Pr2NEt_PhMe (CH2CI)2 Ph 60 ~ 36 hr 68% conversion 67% conversion 92%ee
Ligand O..../ ~ ...J Fe'PPh2N ",t.Bu ,~;~~PAr 2 Ar = p-MeOCsH4
Magnetic isotopic effects on the endo/exo diastereoselectivity were observed in the Patern6-Biichi photocycloaddition between 2,3-dihydrofuran and an aldehyde . 2,3-Dihydrofuran was used to trap the acyloxyketene that was generated from the unstable mesoionic 1,3-dioxolylium-4-olate to form the bicyclic cyclobutanone product . The acid-catalyzed addition of soft nucleophiles to the dienyl acetal system of tonghaosu analogs produced 1,6-adducts exclusively . 2,5-Dihydrofuran was transformed to a C 14-C20 segment for the total synthesis of marine macrolide peloruside A . TMSOTf-promoted condensation of trans-3-hydroxymethyl-2-phenyl-2,3-dihydrofuran with anisaldehyde dimethyl acetal was used in the synthesis of exo-endo and exo-exo isomers of furofuran skeleton of lignan natural products . Regioselective oxidation at C3 (versus C7) of the tetrahydrofuran ring in buergerinin F under Sharpless conditions provided buergerinin G . An unusual oxidation of hexahydro-benzofuran-3a-ol using a catalytic amount of RuO 4 provided a medium sized keto-lactone. The usual regioselectivity was reversed in this example where the tertiary C7a-H was oxidized selectively over the secondary C2-H . The chemoselective addition of tetrahydrofuran radical to an aldehyde or an aldimine was dependent on the radical initiators used. As shown in the scheme below, dimethylzinc-air promoted the addition to C=N bond, while triethylborane-air conditions favored the addition to C=O bond .
OMe
Conditions
"-
Me2Zn, air, r.t., 21 hr ~ Et3B, air, r.t., 16 hr
/1~ 74% 10%
OMe +
H 75%
Triethylborane / tert-butyl hydroperoxide was found to efficiently generate the tetrahydrofuran radical for addition to aldehydes, providing the threo-alcohol products with moderate to high selectivity and in good yields . This method was applied to the synthesis of cytotoxic (+)-muricatacin . Allyl 2-tetrahydrofuryl ether was transformed into diol under Pd(OAc)z-catalyzed, EtzZn-promoted allylation conditions . Nucleophilic zinc species derived from tetrahydrofuran added to various aldehydes to provide C-glycals of the furanose type . The tetrahydrofuran-
167
Five-Membered Ring Systems : Furans and Benzofurans
containing spiroketal moiety found in some steroid derivatives could be ring-opened to give a dihydrofuran ring in high yield under mild conditions using trifluoroacetyl trifluoromethanesulfonate . An F3B ,OEt2-promoted ring expansion reaction of spiro tetrahydrofuran to dihydrobenzopyran was a key step in the synthesis of the sesquiterpene heliannuol E . A 2-(iodomethyl)tetrahydrofuran derivative underwent a stereoselective ring expansion when treated with p-iodotoluene difluoride to give a fluoropyran as shown below .
H1105'~O'~, , , ~ I k__/
p-Tol-IF2 Et3N-5HF C H2CI2 r.t., 1 hr 70%
5.3.2.3 Benzo[b]furans and Related Compounds Treatment of 5-trimethylsilylthebaine with L-selectride gave 10-trimethylbractazonine. In this reaction, a rearrangement of a phenyl group took place, and the generated compound was desilylated to give (+)-bractazonine. A mechanistic interpretation for this reductive rearrangement was provided . Me
Me I
N-Me
L-Selectride ~ M
Me3Si
THF - )~k ~ Me reflux MeO" bH 92%
TFA bMe
CH2CI2= 96% M
Me
A catalytically enantioselective synthesis of benzofuranones bearing quaternary stereocenters at the C-3 position was achieved using a chiral catalyst as shown below . Another catalytic process of Sharpless asymmetric dihydroxylation was applied to determine the absolute configuration of some natural products (such as remirol, remiridiol, angenomalin, and isoangenomalin), which have an isopropenyldihydrobenzofuran skeleton .
O Ph O
Catalyst ,- ~ ~ ~ = O CH2C12 35~ 81% (97% ee)
~ OCMe2(CCI3)
Catalyst ~l~~~,,Ph ph--- ~IF- 7-.h Ph
A highly regio- and stereoselective Diels-Alder reaction was achieved by the AuC13 catalyzed reaction between benzofurans and phenylacetylenes with carbonyl groups at ortho positions .
168
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
+
OH
" Ph
61%
OH
O'/"Ph
Anodic fluorination of ethyl (3-benzofuranyl)acetate was applied to the syntheses of 2,3difluoro-2,3-dihydrobenzofuran derivatives, together with 2-fluoro-3-hydroxy derivatives as minor products . F ~'~,,""'~302Et
Et4NF'4HF- ~~~.O.~F ,
MeCN-H20 1.8 V, 4F/mol
HO ~-~CO2Et
-I-~~~'O~
40%
5.3.3 SYNTHESIS 5.3.3.1 Furans
(_)-Dihydrospiniferin-1, with the skeleton of a 1,6-methano[10]annulene and a 2,3disubstituted furan, was synthesized and the furan ring was formed via cyclization of a 1,4dicarbonyl precursor . Suzuki-Miyaura coupling of furan-3-boronic ester with a vinyl triflate derivative was adopted to introduce the furan unit in the total synthesis of nakadomarin A . A Stille coupling reaction was used in the synthesis of metabolites of the prodrug 2,5-bis(4-o-methoxyamidinophenyl)furan , a DNA minor groove dimer binding model , and antimicrobial active compounds . 3Lithiofuran derived from bromine-lithium exchange of 3-bromofuran was used in natural product synthesis . C-N Cross-coupling of a bromo-substituted furan with various amides, carbamates, and lactams catalyzed by CuI furnished 2- and 3-substituted amidofurans in 45-95% yields . Arylboronic acids were used as aryl sources in the synthesis of 2-arylfurans under Mn(II) acetate-promoted radical reaction conditions. Although the yields were not high, they were better than in the phase-transfer Gomberg-Bachmann synthesis using arenediazonium ions . Reaction of furan and N-tosyl imines produced in situ from TsN=S=O and aldehydes in the presence of ZnC12 gave no Diels-Alder reaction products. Instead, furyl sulfonamides were separated in high yields . This procedure provides an efficient synthesis of 2-substituted furans and is general with respect to the aldehydes. Additionally, it is possible to synthesize 2,3-disubstituted furans by an intramolecular aromatic substitution of N-tosyl imines at the 3-position of furans. A regioselective arylation of a 3-furoate using Pd(PPh3) 4 as catalyst in toluene was developed . Interestingly, 5-aryl products were generated predominantly when Pd/C was used as catalyst and NMP as solvent.
d~
gr
CO2Et
CO2Et
Pd(PPh3)4, PhMe, KOAc: 73% (,6, : B = 50 : 1 ) Pd/C, NMP, KOAc 55% ( A : B = 1 : 3)
As illustrated below, the reaction of cyclic carbinol amides with triflic anhydride provided et-trifluoromethyl-sulfonamidofurans in high yields. , , . A wide range of lactams was used and the reaction proceeded under mild conditions. ~,-Keto amides were also suitable substrates in these reactions.
169
Five-Membered Ring Systems : Furans and Benzofurans
O
C5H5N 83%
~O20 F3
2-Butene-l,4-diones and 2-butyne-l,4-diones were converted into 2,5-diaryl- and 2,3,5triarylfurans in high yields in the presence of HCOOH and a catalytic amount of Pd on carbon under microwave-irradiation conditions . This procedure provides a new approach to the starting material used in the Paal-Knorr furan synthesis, as unsaturated diones are reduced to saturated diones in situ by formic acid and palladium. The solid-phase synthesis of 2,3,5-trisubstituted furans from 1,4-diketones was also reported .
HCO2H, 5% Pd/C conc. H2SO4 (cat.)
O p h ~ P h
PEG-200 microwave 95%
..
~ ' ~ Ph
h
..
HCO2H, 5% Pd/C conc. H2SO4 (cat) PEG-200 microwave 93%
O ~\ Ph/r
Ph / ~O
Double aldol reaction followed by a series of tandem reactions of a Co-complex of bisacetal of acetylenedicarbaldehyde afforded furyl-a-pyrone. The quantity of Lewis acid was shown to affect the result greatly. As shown below, a quantitative amount of furan product was provided when 6 equivalents of F3BoOEt 2 were used. However, a mixture of alkylation products as well as furan was provided if 2 equivalents of BF 3 ~ 2 were used .
OTMS EtO H
(oet OEt
',
H
co2(CO)6
Ph
~ Ph
6 BF3"OEt2 CH2CI2 quantitalive
h
A simple one-pot method for the synthesis of 2,5-diformylfuran was developed from fructose via dehydration followed by catalytic air-oxidation. This procedure used air, the most economical oxidant, in a second step and obviated the costly isolation of 5(hydroxymethyl)furfural and thus would be practical . The most expanded annulene system known so far was synthesized from a 1,6-bisfuryltriene and an aldehyde using Ca(NO3) 2 as an inducing reagent albeit the yield was low and a number of linear oligomers were also formed . Acid-catalyzed cyclization of a 5-oxo-akyne provided the furan-containing intermediate in the total synthesis of (+)-citreofuran, and TsOH turned out to be optimal in terms of yield and reaction rate .
O MeO
~o
p-TsOH 85%
-'-
,,o OMe
170
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
Chiral furfuryl alcohols were prepared via high-pressure Friedel-Crafts reaction of 2methylfuran and alkyl glyoxylates using (salen)Co(lI) complex as a catalyst, although the enanfioselectivity was not very high (up to 76% ee) .
Ca,a, s, ( ) Catalyst (5 mol~
+.J%O2Bu
._~~_
"NO~ ~
PhMe, 10 kbar
~
B
CO2Bu
47%
~H
But
u
(R)-, 76% ee
\tBu
tBu/
Symmetrical and unsymmetrical 2,5-bis-acetylenic furan derivatives were produced in high yield using Pd-catalyzed cross-coupling reaction of 2,5-bis(butyltelluro)furan, which was prepared from furan through lithiation-transmetallation and alkylation .
/._ / uH
1. n-BuLi, TMEDA hexane
2. Te (2.5 eq.)
3. BuBr (3 eq.) 90%
400 mol%
BuTe
eBu
,,,/~ ~,,=
PdCI2(20 tool%) MeOH, Et3N 82%
a-Acetyl or ct-acetonyl radicals, generated by reaction of dilauroyl peroxide (DLP) on xanthates, added to 2-acetylfuran in a conjugate addition manner to produce the corresponding 2,5-disubstituted furans . The furan ring subunit of a natural product was synthesized from a dihydrofuran using a dehydrogenation procedure. The formation of tanshinone IIA is shown below . The dihydrofuran was obtained by reduction of the corresponding lactone . o
DDQ 1.
benzene, rt 95%
The first example of nucleophilic aromatic substitution of 2-methoxyfurans with Grignard reagents was reported . In this reaction, the Grignard reagents derived from allylic and benzylic halides gave lower yields and the presence of an ester group at the 3position was important. If the group was an acetyl, or an ester at the 5- or 4-position, the reaction provided the alcohol exclusively or as a main product derived from the addition of Grignard reagent to these groups. Conjugated ene-yne-carbonyl compounds were employed again as 2-furylcarbene precursors that were allowed to react with allyl sulfides to form S-ylides followed by [2,3]sigmatropic rearrangement to provide the corresponding tetrasubstituted furans in high yields .
H+CH O
z
CH2C,-"
2.5 mol%
reflux 98%
Rh]
Five-Membered Ring Systems : Furans and Benzofurans
171
Reaction of diacetyl ketones in the presence of F3B.OEt 2 and water afforded bisfuryl methanes in good yields. When the reaction was carried out in dry THF and in the presence of 2,4-pentanedione, tri- and tetrasubstituted furans were delivered . As depicted in the following scheme, 2,3,4-trisubstituted furans were provided with high regioselectivity and high yields through Pd-catalyzed isomerization of alkylidene cyclopropyl ketones . The reaction is quite general and shows a dramatic salt effect. The reaction provided furans in the presence of sodium iodide, or 4H-pyrans in the absence of NaI.
PdCl2(CH3CN)2 (5 mol%)
PdCl2(CH3CN)2 5 ~ 0 2 Et_.. (5acetonemOl%1507 )H ~ C O 2 E t _ _ C7H1 e O/~'-Me r.t. 80%
acetoneNalC7H15~ 2 ~ t reflux 74%
Ma and coworkers reported an elegant regioselective synthesis of 2,3,4-trisubstituted furans using a Cu--catalyzed ring-opening cycloisomerization reaction of cyclopropenyl ketones . It is noteworthy that the regioselectivity of this reaction can be tuned using different catalysts. 2,3,5-Trisubstituted furans can be produced from the same starting material using a Pd catalyst with excellent regiocontrol.
2C•
EtO P h "
conditions
~ Ph
A
.CO2Et Ph ~ e
CO2Et Cul (5 mol%), CH3CN,reflux: A : B = 1 : 99, 89% e PdCI2(CH3CN)2(5 mol%),CHCI3, reflux 9
%% B
A
9
B =99"1,73%
Full details for the synthesis of 2,3,5-trisubstituted furans via an oxypalladation-reductive elimination domino reaction were given . Under an atmosphere of CO, the reaction afforded furan derivatives with incorporation of a carbonyl group.
O EtO
Pd(PPh3)4 (0.5 mol%)
+
~
K2003, DMF 60 ~ 55%
Radical cyclization of divinyl ethers prepared from the reaction of 1,3-dicarbonyl compounds and ethyl propynoate gave rise to trisubstituted furans as shown in the following example .
~CO2Et
Bu3SnH ~ AIBN 63%
CO2Et
Regioselective synthesis of substituted furans utilizing allene derivatives is still a focus of attention this year. An efficient procedure for the synthesis of 3-thio-substituted furans was developed using thioallenyl ketones via 1,2-migration of the thio group from an sp 2 carbon atom in allenyl sulfides . Propargyl sulfides gave similar results. If thiopropargyl
172
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
aldehydes were used as starting materials, 2,3-disubstituted furans were generated. This protocol therefore provides a simple means for the preparation of di- and trisubstituted furans.
BUs~:=:(c~2)3 Ph MOMO
Cul (5mo1%), P h ~ O
r.t. 36 h 82%
Bu
CH2)3OMOM
Another example of the regioselective synthesis of substituted furans using Pd-catalyzed coupling cyclization reactions of allenyl ketones with organic halides was reported . This methodology shows high substituent-loading capacity and functional group tolerance, as well as generality and versatility. If one of the substituents of the allenyl ketone is H, 2,3,4- and 2,3,5-trisubstituted furans were also formed.
HllC5
Bu
Phi (2 equiv) Pd(PPh3)4(5 mol %) K2CO3 (2 equiv) TBAB(0.2 equiv) DMA, 100 ~ 72%
Ph Bu ) ~ , H11C
Isomerization of an a-allenylcyclopentenone, obtained from a propargyl ether and a mopholino a,13-unsaturated amide, in the presence of Hg-catalyst to a furanyl cyclopentenone provided another example of the conversion of allenyl ketones to furans .
Me HO
Ph O
Ph
Hg(O2CCF3) 2
~ v t-Bu 0H2CI2 71%
M~~t_Bu
Another approach to tetrasubstituted furans via allenes also appeared . In this reaction, cumulenes were produced as an intermediate from alkynyl epoxides and SmI 2 and the allyl group was incorporated regioselectively.
OAc /Bu ipr
1. Sml2,THF 2. , ~ B r Pd(PPh)4(10 mol%) 2,2-dimethyloxirane K2003
. i
B
u
~
~r
Me Me
70%
Tri- and tetrasubstituted furans were provided via Ru- and Pt-catalyzed sequential reactions of propargylic alcohols and ketones . In this synthesis, two different kinds of catalysts sequentially promoted each catalytic cycle in the same medium and gave the products with high regioselectivity and good yields.
Cp*RuCl(~t2-SMe)2RuCp*CI (10 mol%) PtCl2 (20 mol%) NH4BF4 (20 mol%) reflux, 36 hr (Cp*= TI5-C5Me5) 75%
Five-Membered Ring Systems 9Furans and Benzofurans
173
Substituted furo[2,3-b]pyridones were assembled by a Pd-mediated sequential crosscoupling Sonogashira reaction-Wacker-type heteroannulation and deprotection reactions of pyridones, alkynes and organic halides in an one-pot operation . The coupling products of pyridones and alkynes could be separated and a single palladium catalyst intervened in three different transformations.
~~O2Me OBn
OBn
CO2Me PdC12(PPh3)2 (4 mol%)
+
.,,,t~ .,~ I
Cul (4 mol%) MeCN-Et3N 60~ 24 hr 63%
I
Me
O
-"-
O2Me Me
Furo[3,2-b]pyrroles were synthesized from commercially available 5-bromofuran-2carbaldehyde via a 4-step transformation . These procedures show the divergence and allow for the potential for the construction of compound libraries. 5.3.3.2 Di- and Tetrahydrofurans
Extensive efforts have been given to the synthesis of di- and tetrahydrofurans in 2003. Like before, Williamson cycloetherization continues to be one of the most popular and practical methods. In the total synthesis of muconin, Takahashi converted the tosylate as shown below into the tetrahydrofuran . Marshall , Fleet , Lewis and Paquette also synthesized tetrahydrofuran rings in their respective works employing the same strategy .
O H25012
1.
~
-
OH
5Ts
6H
13"(x = 93" 7
H
NaOMe MeOH r.t. to 50 ~
H25012 " 2. (MeO)2CMe2 HO CSA CH2CI2 78%
In addition to a "real" leaving group like a tosylate, treatment of 1-iodomethyl-l,5-bisepoxides with zinc also afforded substituted tetrahydrofurans. An example is illustrated below . o Me
"
I~
O
H
"~
Zn EtOH reflux 95%
Me~,,O ........
dr = 90" 10
H LOH
On the other hand, treatment of the benzenesulfonate depicted below with 3 equivalents of LDA gave an intermediate propargyl alkoxide through a double elimination. Then a concomitant intramolecular nucleophilic substitution led to the formation of the tetrahydrofuran ring .
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X.-L. Hou, Z Yang, K.-S. Yeung and H.N.C. Wong
OBs =
F . ~
O
0~~'"
x3;~
LDA
~ c l
THF -40~ 1 hr 600/0
F
Another way in which a tetrahydrofuran ring can be constructed is via the opening of an epoxide . Xu studied the synthesis of methyl isosartortuoate employing an epoxide opening route , and Yadav also prepared both enantiomers of altholactone and isoaltholactone utilizing a similar approach . In the total synthesis of malayamycin A, a diol cyclization step was used to construct the tetrahydrofuran skeleton . Ambeflyst has also been reported to induce diol cyclization . Highly enantioselecfive mercuriocyclizafion of ,t-hydroxy-cis-alkenes was reported by Kang who generated optically active 2-monosubstituted tetrahydrofurans in up to 95% ee . Kang later reported a catalytic enantioselecfive iodocyclizafion of y-hydroxy-cis-alkenes, but the ee% was not as good as those obtained from the mercufiocyclization route . An efficient preparation of a trisubstituted tetrahydrofuran in >90% de was reported by Snider en route towards his synthesis of ent-haterumalide NA methyl ester, and this key reaction is shown below . Several similar applications of iodoethefizafion approach were also recorded in 2003 and .
OH OH
OSiMe2t-Bu
OSiMe2t-Bu
12
NaHCO3 Et20 0 ~ 4 hr 81%
|"H HO
As can be seen in the following scheme, bromoetherization was also employed to form tetrahydrofurans with a 3:1 diastereoselectivity. Selenoetherization of (E)- and (Z)-2-ene-l,5-diols, on the other hand, reportedly produced a mixture of tetrahydrofurans and oxetanes .
HO~Me2t-Bu
OH
NBS 0 - 23 ~ 91%
J
,
~
Me2t'Bu
NO
Prins-pinacol condensation of a (Z)-a,13-unsaturated aldehdye and an (S)-carvonederived alkynyl dienyl diol as illustrated below provided the formyl tetrahydroisobenzofuran as a single diastereomer in 84% yield in two steps .
.CHO ipr3SiO HO tBuPh2SiOi Me3S
~
1. p-TsOH.H20 MgSO4 CH2CI2 ,OH -78~ -20~ 2. SnCI4 (0.1 equiv) CH2CI2 -78~ ---, r.t. 84% (2 steps)
ipr3SiO
~
tBuPh2SiO
O
SiMe3
Other syntheses of tetrahydrofurans involving cationic mechanisms were also recorded in 2003 . Michael addition was also extensively studied in tetrahydrofuran ring formation. As an example, the unsaturated ester shown below was converted into a tetrahydrofuran by treatment with TBAF in THF through Michael addition.
Five-Membered Ring Systems : Furans and Benzofurans
175
After reduction and protection steps, a mixture of diastereomers was obtained in a ratio of 1:1 .
-r~ '-' H
B n O " ~
CO2Et
/
1. n-Bu4NF THF r.t., 1 hr
2.DIBAL-H
BnO~~.-,-~.~
OSiMe2t Bu
CH2CI2 -78 ~ 1 hr 3. t-BuMe2SiCI imidazole, DMF r.t., 3.5 hr 43% Construction of tetrahydrofuran frameworks by Michael addition was also employed in the synthesis of 15-epi-haterumalide NA methyl ester , pentacyclic derivatives , diquinanes and other functionalized tetrahydrofurans . A structural analog of podophyllotoxin was prepared utilizing a strategy in which a phenylsulfonyl group was used to promote the dearomatizing Michael-type cyclization of tethered organolithiums onto aromatic tings . A novel cycloaldol approach to the isobenzofuran core common to many eunicellin diterpenes was reported . An unusual reaction route leading to the formation of a 2,2,5,5-tetrasubsfituted is shown below . In this procedure, a bicyclic aziridine was proposed to be an intermediate.
HO ~ " H
HO N a O M e O ~ Ph -OMs MeOH r.t O
3,5-(CF3)2C6H3COCI Ph
Et3N CH2CI2
CO2Me I,~CO2Me
C
F3 \ \ "F CO2Me ~,__7 - ~ 3 Y F3C' Radical versions of the bromo- and iodoetherization reactions of bis(homoallyl alcohols were reported by Hartung in 2003 . Other radical procedures that led eventually to tetrahydrofurans were also reported . Two examples in which alkoxy radical cyclizations and gallium-or indium-promoted radical cyclizations were involved are illustrated in the following schemes. I1
~lJ~Br
n-Bu3SnH Ac
C6H6 reflux 40%
O
HInCI2 THF r.t., 30 min 92%
A cobalt(II)-catalyzed oxidative cyclization converted a secondary alcohol to the trans2,5-disubstituted tetrahydrofuran . Oxidants such as vanadium(V) complex , ruthenium tetroxide and osmium tetroxide were all employed to convert either homoallyl alcohol or polyenes to molecules that contain
176
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
tetrahydrofuran structural units. Other transformations from which tetrahydrofurans can be obtained are by starting from tetrahydrofuran-containing precursors like tetrahydrofuran , lactols and lactol acetates . The following example depicts a pathway showing the preparation of a substituted tetrahydrofuran from a spiroketal .
~~_
,,hiI~
H
Et20 590/0
HO
Iq
HO
Stereoselective synthesis of tetrahydrofuro[3,2-c]benzothiopyrans was achieved by an intramolecular [4+2] cycloaddition of o-thiobenzoquinone methides that were generated from bis(2-formylphenyl)disulfide and alkenols in the presence of iodine . In Chiu's approach towards the total synthesis of pseudolaric acids, a tandem rhodium carbene cyclization--cycloaddition was employed to afford pivotal intermediates containing tetrahydrofuran rings . Five catalyst precursors and thirteen phosphorus ligands were screened to lead to the favorable combination. In this manner, the palladium-catalyzed cyclization of bisdienyl ethers shown below proceeded smoothly to give essentially a single diastereomer .
Bn f-~/~~"""~'~'nC5H11 ~N~"~,.,~
Pd2(dba)3 (2,4-di-t-butylphenyl)phosphite Bn ... N-hydroxyphthalirnide . O ~ THF-MeCN ( 1 " 1 ) 25 ~ 3 hr 67%
ONPht ' ' ' ' ' ~ nC5H11
k,,.~..,,~
The cyclization of the dianions of some 1,3-dicarbonyl compounds with l-bromo-2chloroethane led to the generation of a number of 2-alkylidenetetrahydrofurans with good regioand E/Z-diastereoselectivity. An example is shown in the following scheme . O
O
1. LDA (2.3 equiv) 2. CICH2C H2BrTHF --78 ~ --, 20 ~ 14 hr 68 ~ 2hr E: Z>98:2 58%
High chemo- and regioselectivity were observed for the metal complex-catalyzed cycloisomerization of readily available 4-propargyl-cyclohexanediones, leading to the formation of fused oxabicycles. As can be seen in the reactions below, a proper choice of metal catalyst can provide the 2-alkylidenetetrahydrofuran almost exclusively .
R ,MjoV LvLv
~
THF" ~ r.t.
. A
Ro +
R B
177
Five-Membered Ring Systems : Furans and Benzofurans R
[M] (mol%)
Time
Product
H Pd(OAc)2(5) 2 min H W(CO)5-THF (10) 0.5 hr Me Pd(OAc)2(5) 8 hr Me PdCI2 (5) 9 hr
Yield
A A A : B= 8 : 1 A : B= 1 : 14
85% 85% 75% 91%
A novel chemo-, regio-, and stereoselective cascade featuring an isoxazole benzoisoxazole rearrangement was uncovered by Suzuki. The reaction below illustrates the preparation of a polycyclic molecule having an embedded 2-alkylidenetetrahydrofuran moiety from readily available fused isoxazoles . Br
Br
,,~ 9
",,~ CO2Et
LD A
CO2Et ,
55 ~ hr 38%
As shown below, a simple way to construct 3-alkylidenetetrahydrofurans was the Lewis acid promoted reaction between alkylidenecyclopropanes and diethyl ketomalonate . Wittig reaction of a 3-ketotetrahydrofuran expectedly led to the formation of a 3vinyltetrahydrofuran .
P Ph+
O
EtO2C'~O2Et
Ph Yb(OTf)3 (5 mol%) .. ~ Ph C ICH2CH2CI 40~ 24 hr 84%
Et
t
Mikami reported a procedure as shown below which concerned a highly effective Cl-symmetric N,P-ligand for the enantioselective palladium(II)-catalyzed carbocyclization of allyl propargyl ethers, affording a variety of 3-alkylidene-4-alkenyltetrahydrofurans . Zhang also reported his approach towards similar products in >99% ee by employing [Rh(COD)C1] 2 and (S)-BINAP . A subsequent Suzuki reaction of the intermediate during the palladium(0)-catalyzed cyclization of allyl propargyl ethers was also possible, furnishing more diversified products . CO2Me ~~1
Ligand ._ / ~ ~ _ _ ~ 0 0 2 I [(MeCN)4Pd](BF4)2 (5 mol%) .... ~) HCO2H (0.2 equiv) DMSO 88 % e e 80 ~ 24 hr (S)-(+) 8 7%
Me
~ ~ N " ~ . Ligand
"
--~ "" ~ ~ P h 2 ~
(10 mol~
On the other hand, hydroxylative cyclization of allyl propargyl ethers was catalyzed effectively by Hg(OTf) 2 to generate 3-methylenetetrahydrofurans in good yields . Structurally more elaborate bicyclic alkylidenetetrahydrofurans could be realized via Pauson-Khand-type reactions. Thus, Chung reported the rhodium-BINAP complex catalyzed enantioselective Pauson-Khand reaction under phase-transfer conditions with sodium dodecylsulfate (SDS) . Chung also used an entrapped Rh complex prepared by a
178
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
sol-gel process , as well as immobilized heterobimetallic Rh/Co nanoparticles in similar Pauson-Khand processes. Vaska's complex [IrCI(CO)(PPh3)z] was shown to efficiently catalyze the intramolecular Pauson-Khand reaction of ethers tethered with an allyl group and a propargyl group . In the presence of a catalytic amount of [Rh(COD)C1] 2, the allenene illustrated below underwent cycloisomerization to form the 3methylenetetrahydrofuran in a meager yield and 84% purity .
[Rh(COD)CI]2 P(O-o-Tol)3
/-,..,~"
O
dioxane 110 ~ 24 hr 32%
For precursors containing a methylenecyclopropane, palladium-catalyzed reactions led to cycloadducts with an exocyclic double bond, and an example is shown in the following scheme .
Pd2(dba)3 P(O/-Pr)3 O~.~-~" CH2OSii'BuMe2
dioxane 100 ~ 0.5 hr 67%
O ~ II
CH2OSii.BuMe 2
A palladium(II)-catalyzed three component coupling reaction was established by Lu, who performed the intermolecular carbopalladation involving propargyl alcohols and alkenes, and this was followed consecutively by allylic chloride insertion to the C-Pd bond and its quenching by 13-heteroatom elimination in the presence of an excess of chloride ions. An example is shown below .
Me c, Me
II
I%
H
1. n-BuLl 2. Pd(OAc)2
oc,
, , MeO2C / r - - / _ M eO2C~ ~ '
CH2=CHCH2CIrt.(5 equiv) 47%
Phil)/
A simple way to form 2,3-dihydrofurans is by utilizing an organoselenium approach . Elimination of water from a ~,-lactol is also a viable route towards 2,3dihydrofurans . Intriguing transformations of 2-nitro-3-substituted-2,3dihydrofurans in the presence of F3BoOEt 2 led to the formation of 3-formyl-5-hydroxy-2,3dihydrofurans . It was shown by Karade that a variety of alkenes react with 1,3dicarbonyl compounds in the presence of diacetoxyiodobenzene to provide polysubstituted 2,3dihydrofurans as displayed in the following scheme . Similar conversions were reported using other oxidants such as ceric ammonium nitrate (CAN) , ceric tetra-n-butylammonium nitrate , Mn(OAc)3o2H20 . Miiller, on the other hand, investigated the enantioselective rhodium-catalyzed reactions between 2-diazocyclohexane-l,3-diones and alkenes, which led to products with similar structures . Palladium-mediated coupling of alkenes and a 1,3-dicarbonyl derivative was utilized in the total synthesis of (+)brevione B .
179
Five-Membered Ring Systems : Furans and Benzofurans
o
. . ~
+
PhI(OAc)2
ph,,~,,,"~Ac
MeCN
0~ lhr 77% Nacci, whose procedure involved the use of the ionic solvent n-butylpyridinium tetrafluoroborate, reported a stereoselective synthesis of 2,3-dihydrofurans . O +
O
Me(CH2)12CHO
bpy+BF4-
P'n-~"~'O~\//Ph
K2003 50 ~ 38 hr 82%
Me(OH2)12'S~ S ~ ~ E: Z> 99 : 1
]
A ruthenium complex catalyzed an oxidative cyclization reaction as depicted below to give 2,3-dihydrofurans with PPh 3 as ligand, and in the presence of allyl acetate and CO .
Me Ph H O ~
+ 77"',,f OAc
Ru3(CO)12 PPh3 K2CO3 CO (5 atm) PhMe 160 ~ 20 hr 99%
"
Meh...a/~/.,,O f~" Me P
The most obvious method for synthesizing 2,5-dihydrofurans is by employing ring-closing metathesis reactions. Along this line, Wallace reported the first example of a quadruple ring-closing metathesis reaction. Thus, the polyene shown below underwent a ruthenium complex catalyzed reaction to afford a mixture of two cyclic compounds . Trost , Liu and North also made use of similar metathesis approaches to synthesize 2,5-dihydrofurans.
--~o
o--~
CI. PCY3 "Ru CI" i~Cy3:~ph CH2C12 r.t., 24 hr
,"
-I65%
xxT 12%
A manganese carbyne complex was found to catalyze the cyclization of dipropargyl ether in the presence of i-Pr2NEt and catalytic amounts of CuBr and LiI to give the manganese enediyne complex. Upon air oxidation, the free enediyne was generated in excellent yield . Dipropargyl ether also reacted with 1,3-butadiene in the presence of 10% [CpRu(MeCN)3PF 6] and 10% EtaNC1 to furnish a 2,5-dihydrofuran fused with an 1,3,5cyclooctatriene . In Pattenden's synthetic study towards the total synthesis of phomactin A, deprotection of the MOM ether group of the precursor shown below using camphorsulfonic acid was accompanied by cyclization to give a 2,5-dihydrofuran .
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
LO
HO
o.MOM CSA
0 ~..,,"~,,.
OSiMe2t-Bu
CH2CI2 0oc
OSiMe2t-Bu
As can be seen in the scheme below, a mixture of allenylcarbinols was found by Burger to undergo a cyclization reaction catalyzed by AgNO 3 to lead to a mixture of 2,5-dihydrofurans in good yield . Hoppe also reported similar cyclizations employing an iodoetherization procedure . H
. , ~ -/ . ~ ~,-,.,,., CF3~2Me H,f, OH n-Pr
H
oJ~ C FCO#Me 3 AgNO3 ,, "n,,.]~ +H,,f OlH acetone_H20n.Prr n-Pr 90% 1:12
\,., C"r 3
H,,./~ \,,,GU21VI .... e n.p r4~',O/'~C F3
+
1:12
Wills investigated the intramolecular cyclizations of alkylidene carbenes and showed that the ketone depicted below was converted to a 3.6:1 mixture of two 2,5-dihydrofurans utilizing the Shiori protocol .
0SiMe2t-Bul~~
Me3SiC(Li)N2 DME-C6H14 -78 ~ --* r.t. 64%
OSiMe2t'Bu
H HO
= t. BuMe2SiO/ ' " y
+ t.BuMe2SiO / ,,.
....
OSiMe2t-Bu
OSiMe2t-Bu
3.6:1
Nair described a reaction in which the 1:1 zwitterionic intermediate generated in situ from dimethyl acetylenedicarboxylate and cyclohexyl isocyanide reacted with a quinone to furnish the spiro-iminolactone as illustrated in the following scheme .
Cy ~N O
CIO2Me + II I
I
O2Me
+
Cy-N=C"
06H6 80 ~ 4 hr 92%
CO2Me O2Me
J-
O
5.3.3.3 Benzo[b]furans and Related Compounds The palladium-catalyzed Sonogashira reaction of aryl bromide and aryl acetylene gave non-symmetrical diarylethynes, which can spontaneously cyclize to give 2-arylbenzo[b]furans in a modest yield as shown below . Other types of 2-alkyl/aryl substituted benzo[b]furans were also obtained by the palladium--catalyzed coupling reaction of oiodophenols (even o-iodophenols with a base-labile nitro group) with a variety of alkynes in the presence of prolinol as base in water. This environmental friendly procedure does not need a phase transfer catalyst or water-soluble phosphine ligands and is free from the use of any organic co-solvent . A similar process was also reported with an amphiphilic polystyrene-polyethylether (PS-PEG) resin-supported palladium-phosphine complex as a catalyst in water to give the corresponding aryl-substituted alkynes in high yields under copper-free conditions . In the total synthesis of pterulinic acid, the core 2-
Five-Membered Ring Systems : Furans and Benzofurans
181
substituted benzofuran structure was generated by the palladium-catalyzed heteroannulation of an o-iodophenol derivative with methyl 3-butynoate .
A c O " ~ ~ ,-OAc Br" v -t-
~~
Me
v
AcO.~,l~T,,OAc Pd(OAc)2 ~ Cul "-
~
Me(3
KOH HO.,~lf~.-O \
DIPA 50~ 95"/o
O --../
62%
In the total synthesis of (_+)-linderol A, the 6,5,5-tricyclic cyclopenta[b]benzofuran was made by a tandem reaction of a 3-ethoxycarbonylcoumarin derivative with dimethyl sulfoxonium methylide .
OMe
H2C=S(O)Me2NaH ~ DMF 76%
~ O O E t MeO"- ~
-"u N
H
A variety of biologically interesting dihydrofurocoumarins were synthesized in high yields by a palladium-catalyzed annulation of 1,3-dienes with o-iodoacetoxycoumarins. This is a general, regio-and stereoselective reaction, and a wide variety of terminal, cyclic, and internal 1,3-dienes can be selected as substrates. A syn-zc-allyl palladium intermediate was proposed in this synthetic transformation . To establish the absolute configuration of some naturally occurring furocoumarins, 4-methyl-8-(2-E-phenylethenyl)-8,9-dihydro-2H-furo[2,3h]-l-benzopyran-2-one was synthesized as shown below, resolved, and its absolute configuration investigated . Other similar work was also described .
Pd(dba)2(5 mol%) dppe Ag2CO3 ph/ I
dioxane-H20 (5:1) 24 hr
O
~
p
h
N-Acyltetrahydro-l-aza-9-oxafluorenes were synthesized by cycloaddition of 3-acyl1,4-dihydropyridines with p-benzoquinone under acid catalysis, the generated N-acyltetrahydro1-aza-9-oxafluorenes can undergo further oxidation to give 1-aza-9-oxafluorenes, a novel type of cyclin-dependent kinase inhibitor . The synthesis of optically active 2,3dihydrobenzofurans was also achieved through a combined strategy by ferric ion-catalyzed cycloaddition of styrene with quinone, followed by lipase-catalyzed enantioselective acylation . A similar process for the synthesis of some interesting dihydrobenzofuran derivatives was developed by nucleophilic addition of stilbene to 1,4-benzoquinone, followed by an intramolecular cyclization. A biomimetic approach was proposed to account for the stereochemistry of the generated molecules . InC13-catalyzed [3+2] cycloaddition was also applied to the synthesis of 2,3-dihydrobenzofurans employing a similar concept .
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X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
HO
Ph O
.%
Me+
HO ~
Ph O~e
doi xaneHCIO ,.4 o
~
Pb(OAC)4THF ---~N
70%
,,-L-,o
~
"~T ''Me
0.r
84%
A tandem cyclization approach was applied to the synthesis of mescaline analogs via a direct C-H activation followed by an olefin insertion .
nN
H
[RhCl(coe)2]2 FcPCy2 PhMe 150~ 75%
s
OMe
Titanium benzylidenes based arylboronates were generated from thioacetals with low valent titanium species, CP2Ti[P(OEt)3] 2, which reacted with Merrifield resin-bound esters to give enol ethers. The remaining boronate then underwent further Suzuki cross-coupling to give diversified 2,5-disubstituted benzofurans, which eventually were released from the solid support by 1% TFA . The same concept was applied to generate a 2-substituted benzofuran library with Wang resin-bound esters as starting materials .
1-.o
T,c,
,. oro..r., o
PG
._
2. Arl, Pd(0) 3. TFA-CH2CI2 4.10%HCI-MeOH
8-Nitro-2-dimethylamino-l,2,3,4-tetrahydro-2-dibenzofuran was prepared by an acid--catalyzed [3,3]sigmatropic rearrangement of an O-aryloxime as a key step as depicted below . A similar pathway was also presented for the synthesis of other dihydrobenzofurans . N Me2
O2N
HCI-HOAc
O2N~
5
/ NMe2
ip
90-110 ~ 7.5hr 95% In the total synthesis of (-)-ephedradine A, the key intermediate, transdihydrobenzofuran, was prepared by Davies catalyst catalyzed C-H insertion with high diastereoselectivity . In another total synthesis of (+)-epi-conocarpan, the key intermediate 5-bromo-cis-2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzofuran was also made by ruthenium-porphyrin--catalyzed intramolecular C-H insertion using an aryl tosylhydrazone salt as a carbene source . o-Alkenylphenols were oxidized with VO(acac)2/TBHP to the corresponding o-hydroxybenzyl ketones under mild reaction conditions, which eventually led to 2-substituted benzo[b]furans by a series of reactions . 3-Aryl substituted benzo[b[furans were generated from the aryl ketones shown below. In this reaction, the
183
Five-Membered Ring Systems : Furans and Benzofurans
substrate was treated with MeLi for a halogen-metal exchange process, and the resulting aryllithium underwent an intramolecular nucleophilic addition to the ketone. Elimination of water then gave 3-aryl substituted benzo[b]furans, being the key intermediate for the total synthesis of natural products malibatol A and balanocarpol . OMe MeO
~CHO/
OM e OMel
OMe
OMe
' , 2 p-TsOH 75%
OMe OMe
The palladium-catalyzed three-component reaction depicted below was reported for the creation of polysubstituted bicyclic molecules (including dihydrobenzofurans) in good yields from readily available substrates. A mechanistic interpretation was also presented .
{~
O-~'~
1
+
Pd(OAc)2 PPh3
~
0S2003
.,,,CO2t-Bu I1 + n-Bul
norbornene DME 80 ~ 85%
I
n
-gU \
CO2t-Bu
2-Hydroxy-l,2,2-triphenylethanone based carboxylic esters upon irradiation with a medium pressure mercury lamp resulted in a rapid and quantitative photolysis to afford the carboxylic acid and benzo[b]phenanthro[9,10-d]furan. No yield was reported for this synthetic transformation .
.-~O'2CR Ph , , ~ P h Ph" J] u
hv
,. -RCO2H
r[~y~
Ph
ll-"~'~
hv [O]
_--
SmI2-H20-amine mediated diastereoselective intramolecular couplings were reported for the synthesis of dihydrobenzofuran, and a radical mechanism was proposed to account for this reaction . A similar approach for the synthesis of pyridine-fused polycyclic amines was also developed by use of AIBN/Bu3SnH as a reducing system . Me
Me
H
H20-amine 72%
Dibenzofurans were synthesized from 6-substituted-3-alkoxycarbonylhex-3-en-5-ynoic acids. An interesting mechanistic interpretation was given .
184
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
O2H
NaOAc hydroquinone "~
Ac20 reflux 77%
CO2Et
Oxygen-bridged phenyl morphans were synthesized by an intramolecular phenolic hydroxyl based SN2 displacement of bromine as shown below . Two other phenylmorphans were also synthesized by almost identical conditions . Closely related benzo[b]furan based oxaspirocyclic molecules were made by a similar approach .
1. NaBH4 H O
N~-CH3
~Bt
H
~ r
MeOH
"r (\ ~ N-CH3 ~" ~,~..,,,,,L__/ MeOH-H20 " O ~" 11%
2. KOH
The Sonogashira coupling reaction was applied to the synthesis of phenyl acetylenes, which were used as substrates in the synthesis of spirodihydrobenzofurans, a central motif of some natural occurring antibiotics .
OMOM /
OMe [~,OMOM /II%~,,~jCHO
1. n-BuLi THF 2. H2, Pd/C K2CO3 EtOAc
OMe
3. TPAP NMO 4. Me3SiBr CH2Cl2 83%
3-Nitrocoumarins underwent intermolecular Diels-Alder reaction with substituted dienes, followed by sequential hydrolysis / decarboxylation / Nef reaction / cyclodehydration to afford dihydrodibenzo[b,d]furans. All these reactions were carried out in an aqueous medium .
I ..
1. NaOH neat
heaUng
c,
2. H2S04
0~
As depicted below, Swem oxidation and acid-catalyzed ring closure reactions were employed to construct fully functionalized benzo[b]furan, a key intermediate for the total synthesis of natural product kendomycin .
185
Five-Membered Ring Systems : Furans and Benzofurans
Me 9
Me
E,N
OMOM
:
1. (COCI)2
Me
Me
-78 ~ to r.t. e
2. TfOH, 4,/x,MS PhMe-EtOH 60 ~ 81%
9
Me
M
e
~k tBuPh2S i O - - j
Cycloalkanonaphthofurans were obtained by acid catalyzed cyclization of naphthols with cycloalkadienes . In a similar ring formation pathway, a variety of substituted 2,3dihydro-5-benzofuranols was realized . Amberlyst-15 was utilized to induce intramolecular cyclization to afford polycyclic benzo[b]furans, which were key intermediates in the total synthesis of Stachybotrys spirolactams . The palladium-catalyzed intramolecular Heck reaction was applied to functionalized heterocyclic molecules, e.g. methyl 4-(6-chloro-2-iodopyridin-3-yloxy)butenoates as shown below . The same reaction was also employed in the synthesis of tetracyclic benzo[b]furans with Pd2(dba)3/HP(t-Bu)3BF4 as a catalyst under mild conditions . The 3,3-disubstituted-2,3-dihydrobenzofuran scaffold was made from iodophenol and methyl bromoacrylate by an intermolecular Heck coupling . CI
N
Pd(OAc)2 HCO2Na Na2CO3
_1 R
CI ~
O
2
Me
n-Bu4NCI DMF 80~
The palladium-catalyzed carbonylative annulation of o-hydroxyphenylacetylene was employed to generate methyl benzo[b]furan-3-carboxylate, a key intermediate for the total synthesis of the natural product wedelolactone .
d n__ OBn
MeO
Pdl2~ rea CBr4
HO OB n
B
OBn
CO MeOH-THF 50 ~ 87%
OBn ..... M eO ~
~
o_ .OBn
~)~,%\ ~
BnO
~ ~ C02Me
"OBn
In the total synthesis of furaquinocins A, B, and E, the key intermediate dihydrobenzofurans were synthesized by the reductive Heck cyclization with sterically hindered pentamethylpiperidine (PMP) as a base .
~ I
O
HCO2H PMP, DMF 5O ~ 2. Ac20 Et3N-DMAP CH2CI2 81%
"
N
~ "OAc 87% ee
186
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
A radical cyclization approach was developed to synthesize dihydrobenzofurans, which were converted to benzofurans by dehydrogenation (aromatization) .
OH
0
phl(OAc)2
0
0
HoaX
OH 56%
OMe
oM
Mc~' 1 ~
An intramolecular Wittig reaction was employed to synthesize furotocopheryl derivatives . +
PPha Br-
R2COCI Et3N
H
+
R
PPha Br-
u~j~,f~
PhMe reflux 62% A one-pot procedure to construct the key intermediate of natural product egonol was developed using carbene-alkyne coupling and oxidative aromatization as key steps . Novel tetracyclic psoralen derivatives were synthesized from commercially available 2methoxyresorcinol through a series of synthetic transformations .
(OC)3CFj~.OMe 0~~
+
~
iMe3
12
470
An improved procedure for the rapid synthesis of aryl dihydrobenzofurans with a boron tribromide-mediated cyclization was discussed and is shown below . In the second total synthesis of diazonamide A, the late key step accounting for the dihydrobenzofuran formation was a DIBAL-H mediated lactam reduction and cyclization . R
OH MeO2C~R MeO..~ v
~OMe "CHO
OH BBr3 .
..~0
0H2CI2 0 ~ 2 hr OHC
C02Me
5.3.3.4 Benzo[c]furans and Related Compounds 1-Oxaspiro[4.5]deca-6,9-dien-8-one showed strong n-facial stereoselectivity in its Diels-Alder cycloaddition with in situ generated benzo[c]furan, leading to the formation of the bridge ether in 63% yield as shown below, together with minor amounts of other isomers. The
187
Five-Membered Ring Systems : Furans and Benzofurans
relatively high stereoselectivity was attributed to an efficient electrostatic control by the tetrahydrofuran ring .
diglyme heat
Structurally intriguing furanophane derivatives were obtained by employing an [8+2] cycloaddition of dienylisobenzofurans and dimethyl acetylenedicarboxylate (DMAD). The pivotal dienylisobenzofurans were in turn obtained through reactions between alkynylbenzophenones and alkenyl chromium carbene complexes. An example is shown in the following scheme .
"~[~
Bu +
Cr(CO)5 .,% MeO
Ph
OMe
Bu
Bu
OMe
DMAD
,,. dioxane 85 ~
.._ dioxane 85 ~ 1-2 hr 76~176
Ph
Me
CO2Me
A one-pot synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with chromium cyanocarbene complexes was reported. The reaction involved formation of an isobenzofuran first, which then underwent intramolecular Diels-Alder cycloaddition with the nitrile. One important feature of this process was the deoxygenation of the initial adduct to give the isoquinoline ring .
I(CO)3Cr H [ ~
+ Me2N HO NC"4M H
Me2N H
Me2N ,,
-I
Bu 100 ~_-PhMe 59%
The generation of azuleno[5,6-c]furan, 4-chloroazuleno[4,5-c]furan and naphtho[1,2-c:5,6-c]difuran , as well as their cycloaddition reactions were reported. These molecules were shown to be relatively stable compounds, whose spectroscopic data could be recorded.
o,
kVq
Sarkar and coworkers reported a route from which heterocyclic analogs of 1arylnaphthalene lignans were synthesized via a sequential Pummerer-Diels-Alder pathway, featuring furo[3,4-c]pyridines as intermediates. An example is depicted below .
188
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
Cl ~ O P h
p-TsOH.
~
CI
C
l
~
C F,CO) O
PhMe
C6H4-p-OMe reflux, 1 hr
SPh dimethyl maleate .CI~ 40%
CI
C6H4"P'OMe
SPh
~"~ Y CI
,CO2Me "CO2Me
C6H4-P-OMe
A simple synthesis of dihydrobenzo[c]furans was recently reported by Yus by starting from the lithiation reactions of 4-heterosubstituted dibenzothiins . Another way in which dihydrobenzo[c]furans can be prepared was recorded by Cheng who made use of a CoI2(PPh3)JZn catalyzed [2+2+2] ene-diyne cycloaddition of 1,6-heptadiynes with allenes as illustrated below. It was shown that these conversions were highly regio- and chemoselective. .
/
ON,
~
Ph
+
= O CI(CH2)2CI 80~ 8hr 71%
+ 94 : 6
Rhodium--catalyzed [2+2+2] cyclotrimerization of alkynes in an aqueous-organic diphasic system was also employed in the formation of dihydrobenzo[c]furans as depicted in the scheme below. Medium- and large-sized rings could be obtained by utilizing this approach .
[RhCl(cod)]2 tppts
= H20-Et20 24 hr
+ 50%: 11%
Cobalt-cycloheptyne complexes tethered with propargylic ethers were found to undergo also intermolecular as well as intramolecular [2+2+2] reactions to provide polycyclic benzocycloheptanes .
toluene reflux, 3 hr 60~ Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, China (Project No. AoE/P-10/01) for financial support. XLH acknowledges with thanks support from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. KSY thanks Dr. Nicholas A. Meanwell for support. 5.3.4 REFERENCES 03ACR48 03AG(E)98 03AG(E)184 03AG(E)948 03AG(E)1387
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Five-Membered Ring Systems 9Furans and Benzofurans
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03H(60)939 03H(60)1133 03H(60)1367 03H(60)1433 03H(60) 1633 03H(60) 1787 03H)60)2767 03HCA91 03HCA343 03HCA474 03HCA484 03HCA733 03HCA760 03HCA787 03HCA2164 03HCA3164 03HCA3320 03HCA3394 03JA36 03JAl192 03JA2058 03JA2374 03JA3682 03JA4684 03JA5642 03JA5757 03JA6650 03JA7484 03JA7784 03JA8112 03JA9016 03JA9282 03JAl1472 03JAl1514 03JA12386 03JA12694 03JA12720 03JA12994 03JA13155 03JA14149 03JA14702 03JA14884 03JA15748 03JMC1449 03JMC4761 03JNP30
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
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Five-Membered Ring Systems 9Furans and Benzofurans
03JNP73 03JNP80 03JNP357 03JNP416 03JNP438 03JNP461 03JNP532 03JNP558 03JNP572 03JNP634 03JNP638 03JNP703 03JNP735 03JNP772 03JNP804 03JNP968 03JNP987 03JNP990 03JNP996 03JNP1010 03JNP1128 03JNP1221 03JNP1259 03JNP1369 03JNP1416 03JNP1517 03JNP1554 03JNP1578 03JNP1586 03JNP1623 03JOC387 03JOC578 03JOC625 03JOC770 03JOCl150 03JOC1216 03JOC1521 03JOC1633 03JOC1771
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Five-Membered Ring Systems 9Furans and Benzofurans
03S2169 03S2530 03SC213 03SL51 03SL411 03SL573 03SL711 03SL732 03SL735 03SL955 03SL1631 03SL1707 03SL1969 03SL2005 03SL2092 03T77 03T755 03T1277 03T1389 03T1483 03T1501 03T1599 03T1613 03T1627 03T2083 03T2423 03T2471 03T3231 03T3433 03T3643 03T4603 03T4661 03T4739 03T4939 03T5033 03T5055 03T5609 03T6627 03T7365 03T7509 03T8027 03T10181 03T10279 03TA765 03TA1363 03TA1455 03TA1665
195
W.H. Suh, M. Choi, S.I. Lee, Y.K. Chung, Synthesis 2003, 2169. P. Le M6nez, J.D. Brion, N. Lensen, E. Chelain, A. Pancrazi, J. Ardisson, Synthesis 2003, 2530. G. Bar, F. Bini, A.F. Parsons, Synth. Commun. 2003, 33, 213. J. Hartung, P. Kunz, S. Laug, P. Schmidt, Synlett 2003, 51. F. Doi, T. Ogamino, T. Sugai, S. Nishiyama, Synlett 2003, 411. T. Shibata, S. Kadowaki, M. Hirase, K. Takagi, Synlett 2003, 573. S. Raghavan, K. Anuradha, Synlett 2003, 711. L. Chen, Z. Li, C.-J. Li, Synlett 2003, 732. I.B. Masesane, P.G. Steel, Synlett 2003, 735. P. Le M6nez, J.D. Brion, J.-F. Betzer, A. Pancrazi, J. Ardisson, Synlett 2003, 955. K. M. Dawood, T. Fuchigami, Synlett 2003, 1631. X. Jia, H. Lin, C. Huo, W. Zhang, J. Lu, L. Yang, G. Zhao, Z.-L. Liu, Synlett 2003, 1707. C. Schultz-Fademrecht, M. Zimmermann, R. Fr6hlich, D. Hoppe, Synlett 2003, 1969. S. Serra, C. Fuganti, Synlett 2003, 2005. A.G. Cs~ikS?, M. Mba, J. Plumet, Synlett 2003, 2092. H. Nambu, G. Anilkumar, M. Matsugi, Y. Kita, Tetrahedron 2003, 59, 77. S. Onitska, H. Nishino, Tetrahedron 2003, 59, 755. Y.-L. Lin, H.-S. Kuo, Y.-W. Wang, S.-T. Huang Tetrahedron 2003, 59, 1277 A.S. Golubev, N.N. Sergeeva, L. Hennig, A.F. Kolomiets, K. Burger, Tetrahedron 2003, 59, 1389. X.-J. Wu, S. Toppet, F. Compernolle, G.J. Hoornaert, Tetrahedron 2003, 59, 1483. X.-C. Li, D. Ferreira Tetrahedron, 2003, 59, 1501. J.S. Yadav, B.V.S. Reddy, J.S.S. Reddy, R.S. Rao, Tetrahedron 2003, 59, 1599. T. Kubota, M. Tsuda, J. Kobayashi, Tetrahedron 2003, 59, 1613. S. Takahashi, A. Kubota, T. Nakata, Tetrahedron 2003, 59, 1627. M. Yus, F. Foubelo, J.V. Ferr~indez, Tetrahedron 2003, 59, 2083. R.M. van Well, M.E.A. Meijer, H.S. Overkleeft, J.H. van Boom, G.A. van der Marel, M. Overhand, Tetrahedron 2003, 59, 2423. J.K. Harper, A.M. Arif, E.J. Ford, G.A. Strobel, J.A. Porco, Jr., D.P. Tomer, K.L. Oneill, E.M. Heider, D.M. Grant, Tetrahedron 2003, 59, 2471. C. Adelw6hrer, T. Rosenau, W.H. Binder, P. Kosma, Tetrahedron 2003, 59, 3231. A. Naoe, M. Ishibashi, Y. Yamamoto, Tetrahedron 2003, 59, 3433. A. Baran, C. Kazaz, H Seqcen, Y. Stitbeyaz, Tetrahedron 2003, 59, 3643. D. Tadic, J.T.M. Linders, J.L. Flippen-Anderson, A.E. Jacobson, K.C. Rice, Tetrahedron 2003, 59, 4603. A. Arcadi, S. Cacchi, G. Fabrizi, F. Marinelli, L.M. Parisi, Tetrahedron 2003, 59, 4661. G. Hobley, K. Stuttle, M. Wills, Tetrahedron 2003, 59, 4739. A. Pdwas, A. Zanka, M.P. Cassidy, J.M. Harris, Tetrahedron 2003, 59, 4939. A. Arnone, G. Candiani, G. Nasini, R. Sinisi, Tetrahedron 2003, 59, 5033. S. Kosemura, Tetrahedron 2003, 59, 5055. J. Zhang, Y. Zhang, Y. Zhang, J.W. Herndon, Tetrahedron 2003, 59, 5609. K. Takami, S. Mikami, H. Yorimitsu, H. Shinokubo, K. Oshima, Tetrahedron 2003, 59, 6627. P. Van de Weghe, S. Bourg, J. Eustache, Tetrahedron 2003, 59, 7365. Z. Nov~ik, G. Time'-i, A. Kotschy, Tetrahedron 2003, 59, 7509. M.M.G. Saad, T. Iwagawa, M. Doe, M. Nakatani, Tetrahedron 2003, 59, 8027. J. Raczko, Tetrahedron 2003, 59, 10181. V. Nair, A.U. Vinod, N. Abhilash, R.S. Menon, V. Santhi, R.L. Varma, S. Viji, S. Mathew, R. Srinivas, Tetrahedron 2003, 59, 10279. M. Schinnerl, C. B6hm, M. Seitz, O. Reiser, Tetrahedron: Asymmetry 2003, 14, 765. M.K. Gurjar, A.M.S. Murugaiah, P. Radhakrishna, C.V. Ramana, M.S. Chorghade, Tetrahedron: Asymmetry 2003, 14, 1363. S.E. Gibson, H. Ibrahim, C. Pasquier, V.M. Swamy, Tetrahedron: Asymmetry 2003, 14, 1455. G. Rassu, L. Auzzas, V. Zambrano, P. Burreddu, L. Battistini, C. Curti, Tetrahedron: Asymmetry 2003, 14, 1665.
196
03TA3643 03TL225 03TL467 03TL725 03TL835 03TL961 03TL1161 03TL1387 03TL1445 03TL2073 03TL2125 03TL2145 03TL2221 03TL2637 03TL2795 03TL2827 03TL2971 03TL2995 03TL3151 03TL3167 03TL3175 03TL3263 03TL3641 03TL3839 03TL4081 03TL4117 03TL4257 03TL4351 03TL4467 03TL5137 03TL5235 03TL5499 03TL5751 03TL5781 03TL5831 03TL5847 03TL5853 03TL6335 03TL6513 03TL6729 03TL6879 03TL7187 03TL7341 03TL7411
X.-L. Hou, Z. Yang, K.-S. Yeung and H.N.C. Wong
P. Kwiatkowski, E. Wojaczynska, J. Jurczak, Tetrahedron: Asymmetry 2003, 14, 3643. V. Ledroit, C. Debitus, C. Lavaud, G. Massiot, Tetrahedron Lett. 2003, 44, 225. G.-S. Liu, X.-Y. Lu, Tetrahedron Lett. 2003, 44, 467. B.M. Mathes, S.A. Filla, Tetrahedron Lett. 2003, 44, 725. A. Massa, M.R. Acocella, M. De Rosa, A. Soriente, R. Villano, A. Scettri, Tetrahedron Lett. 2003, 44, 835. N. Zanatta, R. Barichello, M.M. Pauletto, H.G. Bonacorso, M.A.P. Martins, Tetrahedron Lett. 2003, 44, 961. W.H. Miles, K.B. Connell, Tetrahedron Lett. 2003, 44, 1161. G. Zeni, C.W. Nogueira, D.O. Silva, P.H. Menezes, A.L. Braga, H.A. Stefani, J.B.T. Rocha, Tetrahedron Lett. 2003, 44, 1387. S.-L. Zheng, W.-Y. Yu, M.-X. Xu, C.-M. Che, Tetrahedron Lett. 2003, 44, 1445. Y.Y. Jiang, Q. Li, W. Lu, J. C. Cai, Tetrahedron Lett. 2003, 44, 2073. J. Tae, K.O. Kim, Tetrahedron Lett. 2003, 44, 2125. D.J. Wallace, Tetrahedron Lett. 2003, 44, 2145. J.S. Yadav, B.V.S. Reddy, G. Satheesh, A. Prabhakar, A.C. Kunwar, Tetrahedron Lett. 2003, 44, 2221. L.R. de Carvalho, M.T. Fujii, N.F. Roque, M.J. Kato, J.H.G. Lago, Tetrahedron Lett. 2003, 44, 2637. R. Ballini, D. Fiorini, M.V. Gil, A. Palmieri, E. Rom~in, J.A. Serrano, Tetrahedron Lett. 2003, 44, 2795. K.H. Park, S.U. Son, Y.K. Chung, Tetrahedron Lett. 2003, 44, 2827. H. Abe, Y. Arai, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 2003, 44, 2971. S. Richard Baker, M. Cases, M. Keenan, R.A. Lewis, P. Tan, Tetrahedron Left. 21103, 44, 2995. M.A. Ashraf, M.A. Jones, N.E. Kelly, A. Mullaney, J.S. Snaith, I. Williams, Tetrahedron Lett. 2003, 44, 3153. J.R. Hwu, T. Sambaiah, S.K. Chakraborty, Tetrahedron Lett. 2003, 44, 3167. T. Saitoh, T. Suzuki, M. Sugimoto, H. Hagiwara, T. Hoshi, Tetrahedron Lett. 2003, 44, 3175. J.M. Aurrecoechea, E. P6rez, Tetrahedron Lett. 2003, 44, 3263. A.V. Varlamov, F.I. Zubkov, E.V. Boltukhina, N.V. Sidorenko, R.S. Borisov, Tetrahedron Lett. 2003, 44, 3641. M. Shi, B. Xu, Tetrahedron Lett. 2003, 44, 3839. T. Itoh, K. Kawai, S. Hayase, H. Ohara, Tetrahedron Lett. 21103, 44, 4081. T. lnagaki, Y. Nakamura, M. Sawaguchi, N. Yoneda, S. Ayuba, S. Hara, Tetrahedron Lett. 2003, 44, 4117. K.L. Milkiewicz, D.J. Parks, T. Lu, Tetrahedron Lett. 2003, 44, 4257. M. Sasaki, C. Tsukano, K. Tachibana, Tetrahedron Lett. 2003, 44, 4351. Y. Fall, B. Vidal, D. Alonso, G. G6mez, Tetrahedron Lett. 2003, 44, 4467. D. Fokas, J.E. Patterson, G. Slobodkin, C.M. Baldino, Tetrahedron Lett. 2003, 44, 5137. H. Takikawa, M. Hirooka, M. Sasaki, Tetrahedron Lett. 2003, 44, 5235. G. Bifulco, T. Caserta, L. Gomez-Paloma, V. Piccialli, Tetrahedron Lett. 2003, 44, 5499. F. Glorius, Tetrahedron Lett. 2003, 44, 5751. M.R. Iesce, M.L. Graziano, F. Cermola, S. Montella, L.D. Gioia, Tetrahedron Lett. 2003, 44, 5781. J.S. Yadav, G. Rajaiah, A.K. Raju, Tetrahedron Lett. 2003, 44, 5831. G.J. Sanjayan, A. Stewart, S. Hachisu, R. Gonzalez, M.P. Watterson, G.W.J. Fleet, Tetrahedron Lett. 2003, 44, 5847. M.P. Watterson, A.A. Edwards, J.A. Leach, M.D. Smith, O. Ichihara, G.W.J. Fleet, Tetrahedron Lett. 2003, 44, 5853. T. Makino, K. Itoh, Tetrahedron Lett. 2003, 44, 6335. T. Saito, T. Horikoshi, T. Otani, Y. Matsuda, T. Karakasa, Tetrahedron Lett. 2003, 44, 6513. N.N. Karade, S.G. Shirodkar, M.N. Patil, R.A. Potrekar, H.N. Karade, Tetrahedron Lett. 2003, 44, 6729. A.H. Banskota, F. Attamimi, T. Usia, T.Z. Linn, Y. Tezuka, S.K. Kalauni, S. Kadota, Tetrahedron Lett. 2003, 44, 6879. S. Mukherjee, K.W.C. Poon, D.L. Flynn, P.R. Hanson, Tetrahedron Lett. 2003, 44, 7187. K.L. Milkiewicz, I.B. Neagu, D.J. Parks, T. Lu, Tetrahedron Lett. 2003, 44, 7341. A.R. Rodriguez, B.W. Spur, Tetrahedron Lett. 2003, 44, 7411.
Five-Membered Ring Systems 9Furans and Benzofurans
03TL7945 03TL8157 03TL8221 03TL8227 03TL8365 03TL8433 03TL8553 03TL8657
197
M. Hamaguchi, N. Tomida, E. Mochizuki, T. Oshima, Tetrahedron Lett. 2003, 44, 7945. D. Banti, M. North, Tetrahedron Lett. 2003, 44, 8157. M. Pal, V. Subramanian, K.R. Yeleswarapu, Tetrahedron Lett. 2003, 4, 8221. U.M. Krishna, G.S.C. Srikanth, G.K. Trivedi, Tetrahedron Lett. 2003, 44, 8227. D. Dabideen, D.R. Mootoo, Tetrahedron Lett. 2003, 44, 8365. A.M. G6mez, A. Barrio, A. Pedregosa, S. Valverde, J.C. L6pez, Tetrahedron Lett. 2003, 44, 8433. A. Plaza, G. Bifulco, A.I. Hamed, C. Pizza, S. Piacente, Tetrahedron Lett. 2003, 44, 8553. M. Szlosek-Pinaud, P. Diaz, J. Martinez, F. Lamaty, Tetrahedron Lett. 2003, 44, 8657.
198
Chapter 5.4
Five Membered Ring Systems" With More than One N Atom Larry Yet Albany Molecular Research, Inc., Albany, N Y USA larryy@al b mo le cular, co m
5.4.1
INTRODUCTION
The synthesis and chemistry of pyrazoles, imidazoles, 1,2,3-triazoles, and 1,2,4-triazoles continue to be actively pursued in 2003. Publications relating to tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of these ring systems have not been heavily investigated as in past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year.
5.4.2
P Y R A Z O L E S AND R I N G - F U S E D D E R I V A T I V E S
A review on the synthetic utility of N-acylpyrazoles has been published . 1,3-Difunctional systems are good substrates to react with various hydrazines to prepare pyrazole derivatives. Tetrasubstituted pyrazoles 2 were synthesized regioselectively in good yields from the reaction of Baylis-Hiliman adducts 1 with various hydrazine hydrochlorides in 1,2-dichloroethane . 3-Aminophenylpyrazoles 4 were prepared from c~-oxoketene O,N-acetals 3 using montmorillonite K-10 under sonication conditions . The one-pot three-component reaction of polyethylene glycol-supported acrylate 7 with aldehydes 5 and hydrazines 6 in the presence of chloramine-T followed by methanolysis afforded pyrazolines 8 in good yields and in high purities . Cyclocondensation of alkenones 9 with phenylhydrazine under microwave irradiation furnished 5-trichloromethyl substituted pyrazoles 10 in excellent yields . Reactions of ot,13-unsaturated ketones 11 with hydrazinediium dithiocyanate gave in one-pot 1-thiocarbamoyl-2-pyrazolines 12 or 1-formyl-2pyrazolines 13, in different ratios depending on the structure of the ketone .
199
Five Membered Ring Systems: With More than One N Atom
/ R1
OH ~
R3NHNH2.HCl
O
ClCH2CH2Cl 50-60 ~
R2
NHR
R1
O
R2~ ' ~ " R 3 11
R1
hydrazine, ultrasound
Ph""L]""~OEt ,3
)'
R2
R1 = Ph, C5Hll R2= Me, Et, cycloalkenone R3 = Ph, t-Bu
1
O
R3 'N-N Me 2
H N-N
_-.
montmorillonite K-10, 25 ~
NHR
PIi 4
R = H, Me, Ph, Bn, allyl, CH(Me)Ph
[H3N-NH3] 2+ 2SCNQ
,DMF, reflux R1 = Me, i-Pr, Ph, Ar
H2N'.~S
R1R2 ~ -N./ N
+
~ R2
R3
R 2= H, Me
R3 = Me, Ph, Ar
I CliO .N. N
R1
12
/ R3
13
Pyrazolidine derivatives 16 were obtained from the intermolecular [3+2] cycloaddition between hydrazones 14 and olefins 15 . A convenient method for the synthesis of 1H-pyrazole-4-carboxylic acid esters 18 from 13-ketaminoesters 17 has been reported using
200
L. Yet
conventional and microwave assisted Vilsmeier reactions . N-Alkyl-substituted phthalimides 19 were easily converted to di-, tri-, and tetrasubstituted pyrazoles 20 via a one-pot addition-decyclization-cyclocondensation process . Regioselective synthesis of several ethyl pyrazolecarboxylates could be prepared from different precursors . Cyclocondensation of diacetylenic ketones 21 with hydrazines afforded alkynyl-substituted pyrazoles 22 . Treatment of nitropyrimidine derivatives 23 with various hydrazines under very mild conditions gave 4-nitro-3,5-diaminopyrazoles 24 for new efficient and insensitive explosives synthesis . A practical approach of continuous processing was utilized in the nitration of substituted pyrazole-5-carboxylic acids .
N
NHBz
S
R4 '~
R~]~.
R3 R2
14
15
Bz = .N R4
BF3oOEt2 0H2012,0 ~
"
R H I ~ R R3 16
R1 = PhCH2CH2, Ph, CO2Et R2, R3, R4 = cyclopentadiene, dienes, eneyne
NO2
O2N
DMF, POCI3 reflux or microwave ,. R1 = Me, Ar
o
RI~.~OR
3
R2 = H, NO2 R3 = Me, Et
R2~ N-N // _\ R1 CO2R3
17
18
R2
i
O ~ N - R O 19
1
1. (Me)H~CMgBr THF, 0 ~ ,. 2. H20 3. R2NHNH2, EtOH
Me L~ /.L H (Me) ~ ~CONHR 1
R1 = Me, Et,/-Pr, t-Bu R2 = H, Ph, Ar
20
R2
O R2NHNH2.H2O R I ~ C O 2 E t 21
EtOH, 80 ~
N-N"
R I ~ C O 2 E t
R1 = Ph, Pr, Bu, CO2Et R2= H, Ph
22
201
Five Membered Ring Systems: With More than One N Atom
R1 O2N~N
NH2 R3NHNH2
R2.-L.~N~J
O2N~,
MeOH, 25 ~
H2N- -NRN
R I = R 2 = CI, NR2, OMe R3 = H, Me, Bn, SO2Ph
23
24
Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3-phenyl- or 3-pyridylpyrazoles 27 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-(pyridyl)acetylene with diazo compounds 26 generated in situ from aldehydes 25 has been reported . Cyclization of ortho(arylethynyl)benzene diazonium salts 28 having substituents at the para-position of the aryl ring furnished indazoles 29 .
O R..JL.H 25
1. TsNHNH2,CH3CN,25 ~
2.5M NaOH R = Ph, Ar, 3-pyridyl
=
I~
X = CH, N
R"J~H
50 ~ 48 h
26
Ar
Ar NaNO2, HCl acetone/H20 " -10 ~
N-NH R _~//~..~/'~X/,~X - "~" -'~/~/
"
27
~ N A r ,.
Q Q 28
29
H
Many pyrazole-type compounds have been elaborated further. Zirconium(IV) nitrate was found to be a versatile oxidizing agent for the aromatization of 1,3,5-trisubstituted pyrazolines 30 to the corresponding pyrazoles 31 in acetic acid at ambient temperature . 4Iodopyrazole derivatives 33 were efficiently synthesized in high yields from 32 at room temperature by the combined reagents iodobenzene diacetate (or polymer-supported (PS) iodobenzene diacetate) with iodine . 4-Iodopyrazole 34 was protected with ethyl vinyl ether to pyrazole 35, which underwent palladium-catalyzed cross-couplings with substituted alkynes and deprotection to afford 4-alkynyl-substituted pyrazoles 36 . 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 . Ruthenium-catalyzed reaction of 1-arylpyrazoles 37 with carbon monoxide and ethylene resulted in the regioselective carbonylation at the ortho C-H bonds to 38 via the directing role of the pyrazole group .
202
L. Yet
R I - - - . ~ ~ R2 N-N 3O
R2
Ph
Zr(N03)4 HOAc 25 ~
RI"'~~ N-N
"
R1 = Ph, 4-CIC6H4 R2= Ar, 2-thienyl
Phl(OAc)2 or PS-PhI(OAc)2
R2 Ph
31
R2
I
12, CH2CI2, 25 *C RI= H, Ar R2 = Me, Ph R3 = Me, Ph
32
I
N.N ~1 H
ethyl vinyl ether
Phil, HCI (1 drop)
34
Me.."L',.OEt 35
33
1. R~C-CH, Phil, 80 *C PdCI2(PPh3)2, Cul or Pd(OAc)2, Cul 2. HCI, H20, CHCI3 R = Ph, Ar, CMe2OH
Ru3(00)12 CO, CH2=CH2 N,N-dimethylacetamide 20atm, 160oC R =Me, OMe, CF 3, CO2Me D
R 37
Oi
R
H 36
~'.~/~
L.,_.L L
R~ V
~-Me O
38
5-Aminopyrazoles 39 were readily converted to 4,5-diaminopyrazoles 40, which were selectively condensed with isocyanates to yield 5-amino-4-pyrazolyl ureas 41 . 3Aminopyrazoles 42 could be selectively protected at the N-2 position to Boc-protected pyrazoles 43, which reacted with various acyl chlorides followed by Boc removal to provide 3-acylated pyrazoles 44 . Other protecting groups such as Cbz, Bn and SEM could be introduced at the N-2 position with biphasic conditions using potassium hydroxide as the base. A parallel synthesis route to 3-acylaminopyrazolinones from 3-aminopyrazolinones was accomplished using a sequence of functionalized polymers, both as stoichiometric and purification reagents to allow for the clean formation of the desired target compounds . The synthesis and chemistry of 3-tert-butyl-l,5-diaminopyrazole has been discussed .
203
Five Membered Ring Systems: With More than One N Atom
R2
NaNO2, HCl; SnCI2"2H20 = H20, 0 ~
NH 2 i~1 39
N"N ~.~~
R3NCO EtOH 25 ~
R2, ~ N H - - ~ O
r_
40
NH2
N~'~ .Boc HMDS, Me3SiCl .. Me\ , i . ~~.'N Boc20,MeCN i )--f \ 130, C ~NH2
42
NHR 3
N- N-2"" N H2 I~1 41
R 1 = R2 = R 3 = alkyl, Ar
H
Mex
R2 NH 2 N.N~ NH2 I~1
H
1" RC(O)CI, i-Pr2NEt, CH2CI2, 25 ~ 2.4N HCI, dioxane
Mex. i N~..~ - N
43
44
.-. .u N"JJ~" H R
Reaction of 2-bromoacetophenone 45 with dimethylformamide dimethylacetal (DMF-DMA) to the intermediate enaminoketones followed by reaction with various arylhydrazines afforded diarylpyrazoles 46, which underwent Mizoroki-Heck palladium-catalyzed intramolecular couplings to give pyrazolo[ 1,5-fl]phenanthridines 47 . o
~ B r
45
Me
. NHNH 1. DMF-DMA 2. R1
_-.
- - ~
Pd(OAc)2, K2CO3, LiCI TBAF, DM F, 110 ~
_
R2
R1 = R2 =R3 = OMe, H, Me
R3 46
"N R3 47
Nucleophilic substitution reactions of 5-chloropyrazoles 48 with amines and thiols under mild conditions provided 5-alkyl amino and thioether pyrazoles 49 as selective COX-2 inhibitors . 4-Chloromethylpyrazoles 50 reacted readily with amides, carbamates, urea, azoles, alcohols, and thiols under neutral conditions to give substituted benzylic products 51 in moderate yields . SO2Me
.SO2Me or
Et3N (1.2-2.0 eq), CH2CI2,40 ~ N~ F3C
48
~CI R
or8CICH2CH2CI 0= ~NR2R 3, SR ( 2 R = H,
CHO
N q ~ ~ R1 F3C
49
R
204
L. Yet
Me.
/~CI
N.N. ~
M e x / _ ~ ~ Nuc nucleophile=_ DMF, 80 ~
I
Ph
N'N'~ I
Ph
50
51
Pyrazolidinediones 52 were oxidized with manganese(III) acetate in the presence of alkenes 53 at elevated temperatures to produce 4,4-bis(alkenyl)pyrazolidinediones 54 in good yields . Photolysis of chiral trisubstituted pyrazolines 55 afforded cyclopropanes 56, in which the mechanism and stereospecificity were studied in detail .
O"~'~ ~O
+
R3 ===~
,N-N.R 2 R1
R4
52
53
0•0
N,! R 2N"/" N" 55
R3
Mn(OAc)3 HOAc, reflux.
R4
R1 = R2 = Et, Me, Ph, Bn R 3 = R4
Me, Et, Ph, Ar
=
hv
- N2 ,.
R3 R4
R
='_~'~-N.R2 54
0"~0
~.,1~1
acetone or
CH2CI2
R1 = R2 = Me, NO2, CO2Me,NHCbz
/R 2 56
Biarylphosphine ligands 57 were found to have fairly broad substrate applications in the palladium-catalyzed amination reactions of aryl halides . Chiral bis(pyrazolyl)methanes were employed as catalysts in the asymmetric Diels-Alder reactions of 1acryloyl-3,5-dimethylpyrazole with cyclopentadiene in the presence of magnesium perchlorate .
PR2 Ph 57 R =/-Pr, t-Bu
Amino polystyrene pyrazolone linker resin 58 provided various amide products 59 with a high conversion rate and good purity under mild conditions; the resin linker was stable under the reaction conditions, resistant to hydrolysis, and reused repeatedly without loss of activity . The preparation of pyrazoline derivatives 61 was accomplished with traceless solid-phase sulfone linker 60 with phenylhydrazine . Aniline cellulose-bound enaminones 62 reacted with phenylhydrazine under microwave irradiation to produce pyrazo|ocarboxylic acid derivatives 63 in high yields .
Five Membered Ring Systems: With More than One N Atom
205
Several reports on syntheses of unique fused-pyrazole heterocyclic systems have been published in 2003. Pyrazolinyl derivatives of protoporphyrin IX and chlorins related to chlorophyll a have been reported . N-Aroyldihydrocyclopenta-pyrazolidinols underwent unusual reactions with ketenes to give 1,3,4-oxadiazoles . The synthesis and dopamine receptor binding of some pyrazolo[3',4':6,7]azepino[5,4,3-cd]indoles has been reported . Desulfurization of 3,4-dimethyl-4H-1,3,4-thiadiazines under acidic thermal conditions provided entry to 5-imino-l,2-dimethylpyrazoles by valence isomerization into thia-6-homopyrazoles . Several synthetic approaches to a new class of 7amino-3-pyrimidinyl-pyrazolo[1,5-a]pyridine scaffolds has been published . Two different synthetic approaches led to the synthesis of a novel class of 1-(thiazol-2-yl)-lHpyrazolo[3,4-b]quinoxalines . Reaction of hydrazines with dimethyl 2-pyrrolidino-4oxo-2-pentenedioate 64 in the presence of acid provided N-substituted pyrazole-3,5dicarboxylates 65, which could be further elaborated to bicyclic pyrazoles 66 if R is an alkyl amine or alcohol side-chain . 1-Phenyl-5-arylcarboxamidopyrazoles 67 reacted with phosphorus halides to give 5-(aminopyrazol-4-yl)-phosphonic acid derivatives 68 . Reaction of N-aziridinylimino carboxamides 69 with triphenylphosphine in carbon
206
L. Yet
tetrachloride provided access to pyrazole-fused heterocycle 71 via thermal rearrangement of Naziridinylimino ketenimines 70 . 4-Benzoyl-3-chloropyrazoles 72 were converted to the intermediate oximes followed by intramolecular base-promoted cyclizations to give 3phenyl-6H-pyrazolo[4,3-d]isoxazoles 73 . 5-Hydroxypyrazoles 74 were acylated at the C-4 position followed by acid-catalyzed cyclizations to afford 5,6-dihydropyrano[2,3c]pyrazol-4-ones 75 .
O
O
MeOH
RNHNH2,
MeO2C-'~-~CO2Mev 64
2N HCl, 25 ~
N ~ N
PI~
N
Me/'J~~
O
NHR
69
Ph
72
5.4.3
N-J~.Ar H
1. NH2OHM = 21 Nail, F R1 = Me, Ph R2 = H, Me
-"
65
N'N'~--O I~1 73
"~)"n "N
CO2Me
X = NH, O 66
R
PBr3~ ~I~0 pyridine, 25 ~ = NN I~N/_.J....Ar R = Br (from PBr3) Pl~ R = Ph (from PhPBr2) 68
PPh3, CCl4 Et3N, CH2Cl2 .. reflux R = Me, Ph, Ar
Ph
N.N.~"--CI i~1
R
Me
0
67
CO2Me
,N-N
R = H, Me, Bn, Ph, 2-pyridyl, (CH2)nNH2, (CH2)nOH Me
N"
MeO2C~
"
Ph-.,.~__7 ~N"N R] Jl c_.R 3
/ ~ R1
112
R1 = H, Me, OMe, NO 2
R2 = Me, i-Pr, Ph R3 = Me, Ph
Benzimidazoles have been used as precursors to give other compounds. Microwave irradiation strongly accelerated the rhodium-catalyzed intramolecular coupling of benzimidazoles 113 C-H bond to pendant alkenes to afford tricyclic compounds 114, which are currently difficult to access by alternative methods . Reaction of 2-aminoimidazole 115 with isatoic anhydride gave benzamide 116, which then reacted with orthoesters to provide benzimidazolyl quinazolinones 117 under microwave irradiation . R3 R2~R
1
(7)o
RhCI(PPh3)3 (10 mol%) o-dichlorobenzene, acetone 250 ~ microwave
113
n=1,2 RI=H, Me R2 = R3 = H R2=R 3=Ph,H,Et
satoicao,,~176 NH2 H 115
m=crowave(300 VV) ~ N,N-dimethylacetamide
y
N//'~R3R2 114
icrowave,000 -"N H
H2N 116
N,N-dimethylacetamide" R1 = H, Me, Et, Pr, Bu R2 = Me, Et
R 117
4,5-Dihalo- and 4-vinyl imidazoles have been useful precursors in several reactions. 4,5Diiodoimidazole 118 underwent selective efficient Grignard-type coupling to give imidazoles 119, whose subsequent Sonogashira or Heck-type cross-couplings gave diverse imidazoles 120 as part of a MAP kinase inhibitors study . The same diiodo imidazole 118 was converted to the bis(allyl) imidazole 121, which underwent ring-closing metathesis reactions to give fused bicyclic imidazoles 122 . Novel bicyclic imidazole 123, an effective imidazoline anion equivalent, underwent regioselective halogen-metal exchange followed by reaction with various electrophiles to give bicyclic imidazoles 124 . 4,5-
212
L. Yet
Dibromoimidazoles were employed as precursors to syntheses of 6-substituted imidazol[4,5d]pyridazin-7-ones . 4-Vinyl imidazoles participated in intermolecular DielsAlder reactions with N-phenylmaleimide and in intramolecular Diels-Alder reactions . I.~N> i / -"N SO2NMe2 118
1. EtMgBr, THF,-20 *C
I-~N>
2. CuCN.2LiCI 3. electrophile
E"
"
N
R
Heck Couplings
Br
N~~O
Br
N
SO2NMe2 120
Grubbs catalyst CH2CI2, 25 ~ 121
N 122 SO2NMe2
SO2NMe2 R = H, Me
Me 1. n-BuLi, THF
"~N>
E/ -'N
SO2NMe2 119
1. EtMgBr, THF,-20 *C 2. CuCN~ , I N 3. allyl bromide 118 SO2NMe2 4. repeat steps 1-3
123
Sonogashira and
Me
=
-78 ~
2. electrophile
E~N/" ~ Br
E = H, CHO, CO2Me, Ph2COH
N 124
5-Hydroxymethyl imidazoline 125, prepared from 2,3-diaminepropionic acid in four steps, underwent Mitsunobu reaction with a series of phenols to give imidazolines 126; phthalimide and N-benzyl trifluoroacetamide also reacted under these reaction conditions . 4Cyanoimidazole 128 was prepared from commercially available 4-imidazolecarboxaldehyde 127, which readily reacted with various alkylmagnesium bromides followed by acidic conditions to give acyl imidazoles 129 without need for N-protecting groups . ROH or R N H 2
___(--OH
DIAD,PPh3
BoctN,,~N
THF, 20 ~
125
OHC.II~ NN>1. NH2OH.HCI, H 127
pyridine, 25 ~
2. Ac20, 80 ~
X =
O, NH
,__.~XR
/
\
--- Bocl N,,~ N 126
O 1. RMgBr, THF, 10 ~ 2. H2SO4
11,
128
R = alkyl
N
129
H
Five Membered Ring Systems: With More than One N Atom
213
The concept-guided development of selective new C-arylation methods for imidazoles via CH bond functionalization has been reported . By judicious choice of the proper catalyst, 2-phenylimidazole 130 can be selectively arylated at the 4-position to imidazoles 131 (palladium catalyst in presence of magnesium oxide and triphenylphosphine) or at the 2'-position to produce imidazoles 132 (ruthenium catalyst in the presence of cesium carbonate). R
Pd(OAc)2 (5 mol%)
~
I~__~--'k R
PPh3 (20 mol%) MgO (1.2 eq) dioxane, 150 ~
(1.8 eq)
CpRu(PPh3)2CI (5 mol%) Cs2CO3 (1.2 eq), DMF, 130 ~ 130
131
132
An efficient synthesis of tertiary amides 134 from carbamoylimidazolium salts 133 and carboxylic acids has been published . Highly enantioselective catalytic asymmetric epoxidation of ot,13-unsaturated carboxylic acid imidazolides in the presence of lanthanideBINOL complexes have been developed . Chiral 1,2-diamines were prepared by lithiation, subsititution, and hydrolysis of Boc-substituted imidazolidines in the presence of chiral ligand (-)-sparteine . Ytterbium triflate was found to effectively catalyze the reactions of various epoxides with substituted imidazole in high yields . Tartaric acid was transformed into imidazole-4,5-dicarboxylic acid, followed by esterification, hydrazinolysis, and condensation with aromatic aldehydes to furnish imidazole-4,5diacylhydrazones . O
RI.N~L.~ ~(~) IC) 1~2
'~L.~jN-Me -'~ 133
R3CO2H, Et3N ,. MeCN, 25 ~
0
RIN-~R3 i~2
R1 = R2 = morpholinyl; Bn, Me; 134 piperdinyl R3 = various alkyls, amino acids, Bn
The reactivity of 6-haloimidazol[1,2-a]pyridine 135 towards different azoles can be modulated to give ipso product 136 in the presence of copper(I) catalyst or to yield cine product 137 in the absence of copper catalyst . Imidazo[1,2-a]pyrimidine 138 can be arylated at the 3-position with aryl bromides in the presence of cesium carbonate with catalytic palladium(II) acetate to give 139 .
214
L. Yet
azole (1 equiv) Cul (5 mol%)
~"~'N
~~NN~~ F
K3PO4(2equiv) "PhMe,110~ 24h
c,,~NHMe L J,,. (15 mol~ V",NHMe X=l
136
azole
F
X 135
(1 equiv)
Cs2CO3 (2 equiv)
DMF, 110 ~ 24 h X= Br cine Substitution
F
~/N.~
137
ipso Substitution
9
~
HBr
ArBr, Pd(OAc)2 PPh3, Cs2CO3 (2 equiv) dioxane, 100 ~
N....// 138
----~FN"r~% N~ ' Ar 139
Imidazole-containing compounds have been utilized as ligands and catalysts in some reactions. Chiral 2-(hydroxyalkyl)imidazolines 140 were employed in the study of the ligand electronic effects in enantioselective diethylzinc additions to aldehydes . Peptidebased catalysts of the type 141 were evaluated for their potential regioselective acylation of carbohydrate monomers and enantioselective Baylis-Hillman reactions . Palladium(lI) bisimidazole ligand 142 was proven to be an effective catalyst for the Heck reaction under phosphine-free conditions using ionic liquids as solvents . lmidazolium salts 143 were utilized in the palladium-catalyzed borylation process with aryldiazonium ions and in the carbonylative amidation with boronic acids, aryl diazonium ions, and ammonia . Imidazolium salt 144 was employed in the palladium-catalyzed Sonogashira coupling of aryl halides . R2
O BocHN-v~peptid e : N - ~N ~ ",,R1
140 R1 = Bn,/-Pr, t-Bu R2 = CF3, Me, OMe
9
Me
141
MeaN zlN. ~ d'CI J/ Me"N N Me 142
x|
/-q|
R~N,,,~N-R 143 R = Ar, X = CI 144 R = naphthyl, X = PF6
5-Thioxo(or oxo)-6H-imidazol[ 1,2-c]quinazolines 147 were prepared from reactions of 2isothio(or oxo)cyanatobenzonitrile 145 with various ct-aminoketones 146 .
Five Membered Ring Systems: With More than One N Atom
1. Na2CO 3, H20, CN N~.C.. X 145
R2 +
H2 N 146
CH2CI 2, 20 ~ R1
O
2. reflux ,. R 1 = Me, t-Bu, Ar R 2 = H, Ph X=O,S
215
R1
/ .,~,...j./~-~ v
-N~-"X H 147
Solid-supported u-bromoketone 148 was condensed with various 2-aminopyridines or 2aminopyrimidine derivatives to give imidazo[1,2-a]pyridines or imidazo[1,2-a]pyrimidine derivatives 149 after cleavage with acid . An abnormal aza-Wittig reaction on solid-phase parallel synthesis of 3-aryl-2,4-dioxo-l,3,5-triazino[1,2-a]benzimidazoles was observed . New spiroimidazolidinone derivatives 151 were prepared from SynPhase lanterns from dipeptides anchored on the solid-supports 150 .
5.4.4
1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES
A review on the 1,2,3-triazole formation via 1,3-dipolar cycloaddition of acetylenes with azides under mild conditions has been published . The synthesis of a benzotriazole azo dye phosphoramidite and the subsequent use in solid phase synthesis of oligonucleotides has been reported . The chemical reactivity of [ 1,2,3]triazolo[ 1,5a]- and [1,5-c]-pyrimidinium salts has been published . A review on the use of benzotriazole as an ideal synthetic auxiliary has been disclosed . 1,2,3-Triazole derivatives could be synthesized from different starting substrates. Various triazoles 155 were synthesized from nonactivated terminal alkynes 152, allyl methyl carbonate 153 and trimethylsilyl azide 154 in a [3 + 2] cycloaddition with the use of the Pd(0)-Cu(I) bimetallic catalyst . The allyl group of 155 was efficiently deprotected by ruthenium-catalyzed isomerization followed by ozonolysis to give 4-substituted triazoles 156. tz-Aminoacetophenones 157 were reacted with hydrazines in acetic acid to give an efficient
L. Yet
216
preparation of 2,4-disubstituted-l,2,3-triazoles 158 . N-(Uracil-6-yl)-S,Sdiphenylsulfilimine 159 reacted with aryldiazonium salts to give arylsulfilimines 160, which were thermolyzed to the 1,2,3-triazolopyrimidine diones 161 in good yields . A domino sequence of reactions of 2-azidoindole led to the syntheses of indolo[3,2e][ 1,2,3]triazolo[ 1,5-a]pyrimidines .
R m
H
+
~OCO2Me
152
R
Pd2(dba)3-CHCI3 (25 mol%) CuCI(PPh3)2 (10 mol%) + TMSN 3 P(OPh)3 (20 mol%) 154 EtOAc, 100 ~
153
R 1. HRuCI(CO)(PPh3)2
N'N'N 2.03; Me2S 155 ~1
R = t-Bu, Ph, At, C6H13, BnOCH2, 1-naphthyl
156 i
0 R2NHNH2
157
reflux, 2 h
-
R 1 = CI, Br, OMe, F R 2 = Me, Ph
R1
o
158
o
N2C
Me-N NN
O L. .:Sp. H OO F Me 159
R2
N---N +
Me.N
N.~.N
L
THF, 5 ~
I~le 160
P.Mere,ux
Me-N N
; O LN NN
R = H, Me, OMe, CI, NO 2
Me
161
(z,13-Unsaturated systems are good substrates for azide additions to prepare 1,2,3-triazole derivatives. A series of 5-fluoroalkylated IH-1,2,3-triazoles 163 were prepared in good yield by the regiospecific 1,3-dipolar cycloaddition reaction of (~-ethyl 3-fluoroalkyl-3pyrrolidinoacrylates 162 with awl azides . Benzyl azides also participated in these reactions but sodium carbonate was required to provide good yields of the triazoles. 4Acyl-lH-1,2,3-triazoles 165 were formed from diethylaluminum azide and ct,13-unsaturated ketones 164 by [3+2] cycloaddition of azide, followed by 1,5-hydride transfer to the 13carbon of the triazoline side chain and fragmentation of the tertiary amino group . Rf ArN 3, 80 ~ = Rf/.~./.CO2Et
162
CO2Et /
~
ArIN'N'~N
163 Rf = CICF 2, BrCF2, CF3, CI(CF2)2CF2 Ar = Ph, 4-OMeC6H4, 4-NO2C6H4
217
Five Membered Ring Systems: With More than One N Atom
R1 B n 2 N ~ R
Et2AIN3 2
O 164
PhMe 25 ~
N=N
.
R I ~ ' N H O
R1 = i-Pr, Bn R2 = Me, Bn, i-Pr
R2 165
Many benzotriazole-based methodologies were utilized in the synthesis of variety types of compounds. N-Acylbenzotriazoles 166 were efficiently acylated with primary and secondary cyanides 167 to give the corresponding t~-substituted f3-ketonitriles 168 in good to excellent yields . N-Acylbenzotriazoles 170 reacted with pyrrole or N-methylpyrrole 169 in the presence of titanium(IV) chloride to yield 2-acyl pyrroles 171 . Similarly, indoles were acylated at the C-3 position using these conditions. N-Acylbenzotriazoles 166 and acyclic sulfones 172 were utilized in the synthesis of ]3-ketosulfones 173 . NAcylbenzotriazoles, when treated with samarium diiodide in tetrahydrofuran, underwent a selfcoupling reaction to afford 1,2-diketones; however, reactions in acetonitrile underwent ringopening reaction to afford 1-acylamido-2-alkyl(or aryl)benzimidazoles . NAcylbenzotriazoles were also intermediates in the efficient conversions of carboxylic acids into O-alkyl, N-alkyl, and O,N-dialkylhydroxamic acids .
[~
N CN n-BuLi,THF, -78 ~ 'IN + t1... or N RI~------.O R2 R3 KOt-Bu, DMSO, 25 ~ 166
167
~2~R 1 CN R 3
R1= alkyl, Ar, 2-thienyl, 2-furyl R2=H, Me R3 = H, Ph, Bn, Ar
[~
N N
R1 166
02 R2.S~R3 172
168
N
+ RI (Me) 169
R/~----O 170
TiCl 4 CH2CI2 25 ~
R (Me) IR
O 171
R = Ar, 2-furyl, 2-pyridyl, 2-indolyl
n-BuLi, THF
02 R2.S..
R3
-78 ~
R 1= alkyl, Ar, 2-thienyl, 2-furyl R2= Ph, Me, Et R3 = H, Ph, Me, vinyl
173
Reformatsky reaction of ethyl bromodifluoroacetate with N,N-(dibenzyl)-lH-benzotriazolyl1-methylamine 174 gave the fully protected t~,~-difluoro-13-alanine 175 . Hydrogenolysis and hydrolysis furnished t~,t~-difluoro-13-alanine 176. This methodology was also applied to the synthesis of N-protected 3,3-difluoroazetidin-2-ones .
218
L. Yet
"N N' ~'NBn2 174
Zn, TMSCI, THF " 25 ~ 3 h
Bn2N
F
F 175
OEt
0.5N HCI, 25 ~ 2. Dowex, NH4OH
=
H2N
F
F
OH
176
Benzotriazole-based methodologies were also used to convert 3-substituted pyrroles to indoles , to give facile N-derivatization of t~-amino esters and amides via benzotriazolylmethyl derivatives , and to provide substituted 2H-azirines from benzotriazolylmethyl ketones . Benzotriazole-based methodologies have been utilized in the syntheses of various ring-fused heterocycles, such as 1,2,3,4tetrahydropyrazino[l,2-a]indoles , imidazo[1,2-a]pyridines and pyrimidines , and other complex systems . There have been two published reports on the use of polymer-supported azide reagents in the 1,3-dipolar cycloadditions of alkynes. Various alkyl bromides reacted with Merrifield resin supported ammonium azide 177 to give various alkyl azides 178, which were reacted with methyl propiolate to give 1,2,3-triazoles 179 in excellent yields . The monomethylether of poly(ethylene glycol)- or MeOPEG-bound azide 180 was utilized in the 1,3dipolar cycloadditions with various alkynes to afford regioisomeric mixtures of 181 and 182 . The 1,2,3-triazoles could be cleaved with formic acid in dioxane in one example (R = COEMe).
Merrifield 1,2,3-triazole resins 183 and 184 were prepared and utilized in the BAL (Backbone Amide Linker) strategy to synthesize amides 185 via sequential reductive aminations, amide couplings, and traceless resin cleavage with trifluoroacetic acid .
219
Five Membered Ring Systems: With More than One N Atom
5.4.5
1,2,4- TRIAZOLES AND RING-FUSED DERIVATIVES
Several synthetic routes to 1,2,4-triazole derivatives have been reported in 2003. A novel one-pot synthesis of 1,2,4-triazole-3,5-diamine derivatives 189 and 190 from isothiocyanates 188 and monosubstituted hydrazines has been published; derivatives 190 were obtained with higher regioselectivity when aromatic and sterically bulky hydrazines were used . Cyclocondensation of C-acetyl-N-arylnitrilimines 191 with various benzoylhydrazones 192 furnished 1,2,4-triazoles 193 . Three-component condensation of acid hydrazides 194 in the presence of S-methyl isothioamide hydroiodide 195, silica gel and ammonium acetate under microwave irradiation afforded 1,2,4-triazoles 196 in good yields . Unusual hydrazinolysis of 5-perfluoroalkyl-l,2,4-oxadiazoles 197 provided an expedient route to 5perfluoroalkyl-l,2,4-triazoles 198 . N-Tosylamidrazones 199 can react either with acid chlorides or with ethyl chloroformate to give tosylated 1,2,4-triazoles 200 or 1,2,4-triazole3-ones 201, respectively . R2
R1NCS 188
1. NaNHCN, DMF, 25 ~ R 1HN.~.~N.N..R2 2. R2NHNH2, EDC, Et3N = - YN - ~ 60 ~ R 1 = Ph, CH3CH2CH 2 R 2 = t-Bu, Ph, C6H 11, Ar
i
R 1HN.~/N, , +
NH 2 189
NH2 190
220
L. Yet
COPh
|174
'
N'N"H
CH3COC---N-N-Ar
RI-J~R2
191
192
|
O 194
RI
197
RI~,N,~ O H 201
u
Ar R2 -- Me, Ph
R
91
Z!
>
R~ =H, Me
R2 = Me, Et R1 = R2 = cycloalkyl
R 1 = Me,
NH2NH2 MeOH 25 ~
~,JN
CHC'3,0 ~
NNHTs 199
"N
R2
HN..cOPh
193
N-N RI-ff~.N ~.~--R2 H 196
198
R2COCI, pyridine CHCl 3, 0 ~
RJ~'NH2
R1 = Ph, Bn, i-Pr, 4-MeC6H4
,-,1
R ,/N-~'~ RI'Iq'N" N H
Rf = OF3, 03H7, 07H15 R = Ph, C11H23
CICO2Et, pyridine
Ar
iexv.j ~ ~.K
,|
195
iTs
THF, 25 ~
NH2 silica gel, NH4OAc R2"JJ"SMe Et3N, microwave (900 VV)
RI"J~'NHNH2
N-N
N-N'
R1 = Ph, Bn,/-Pr, 4-MeC6H4 R2 = Me, Bn,/-Pr
N-N
/ms
200
Urazoles 202 were easily converted to their corresponding triazolinediones 203 with silica sulfuric acid and sodium nitrite . 3-Phenylthio-l,2,4-triazoles 204 were alkylated to their triazolium salts 205, which under aqueous basic conditions provided 2,4-disubstituted1,2,4-triazol-3-ones 206 . HN-NH O.~ N/~ O R 202
silica/sulfuricacid
NaNO2 CH2Cl2, 25 ~
R = alkyl, Ar
N=N O~X. N / ~ O R 203
221
Five Membered Ring Systems: With More than One N Atom
N--~ P h S ' ~ N -N
R2X EtOAcor = CHCl 3 or neat
R2 ~ X Q /N--~ PhS-14~,N.N
K2CO3 = water
R2 IN--~ O'"~N" N
80 oc
204
R 1 = Me, Et, Bn R2 = Me, Bn, allyl, Bu
205
206
[1,2,4]Triazoline-3,5-dione 207 was an effective fluorous dienophile in scavenging excess diene after the Diels-Alder reactions have been completed . 0
N~N---~--C8F17 II
O
207
There have been two published reports on the syntheses of stable 1,2,4-triazolyl carbenes. Thermal decomposition in v a c u o of 5-methoxytriazoline 208 provided in quantitative yield 1,2,4-triazol-5-ylidene 209, a stable carbene in the absence of oxygen and moisture . This nucleophilic carbene 209 could react with a variety of alcohols, thiols, amines, oxygen, sulfur, selenium, isocyanantes, and metal carbonyls to form a myriad of addition products. Reactions of 1,2,4-triazolyl perchlorate salts 210 with base afforded stable nucleophilic 1,2,4triazol-5-ylidenes 211, which could react with acetonitrile and elemental sulfur and selenium to yield addition products .
,Ph
N-.N
, ~ >--OMe Ph N Ph 208
90 ~ 0.01 m b a r neat
Ph
N--N
ph/JL.N~> 9 Ph 209
CI04Q Q , Ad
KOt-Bu, Phil or
/~~\>---H Nail (60%), CH3CN R1 R1 = Ph, 4-BrC6H4 ~2 R2 = Ph, 4-BrC6H4 210 Ad = 1-adamantyl
Ad R 1N Z : > ~2 211
Reaction of resin bound S-methyl-N-acylisothioureas 212 with hydrazines followed by acidic cleavage yielded 3-amino-l,2,4-triazoles 213 under mild conditions . 3,4,5Trisubstituted 1,2,4-triazoles 215 were synthesized on solid-phase from various thioamides 214 and hydrazides leading to peptidomimetic scaffolds .
9
222
L. Yet
Several unique heterocyclic fused-l,2,4-triazole structures have been published. Pyridine amination of 216 with O-mesitylenesulfonylhydroxylamine followed by condensation with various aryl and heterocyclic aldehydes and subsequent cyclization and oxidation gave triazolopyridines 217 . Triazolopyridines 217 were utilized in the direct conversion to the triazolopyridine amides 218 with methylaluminoxane premixed with amines in a combinatorial library synthesis. A convenient synthesis of novel 4-(l,2,4-triazol-l-yl)-2pyrazolines and their derivatives has been reported . A novel triheterocyclic ring system, thieno[2,3-f] [ 1,2,4]triazolo[ 1,5-a]azepines, has been published .
,.O-
MeO...~O
es,t,,enesu,,on,,-
25hydr~176
dioxane, ,.
2. R1CHO, 100 ~ H2N -N- NH 2 3. KOH, MeOH, 0 2 216
methylaluminoxaneR2R3NH, dioxane 90 H2N N ~-N
I~1"~-"
~ O FBF3~ RI\\ N'; .~ ~Z 2. MnO2 Et3N/ MeOH / ~ O ~ 117E lO ( = " E ozM e ) E ~_~CO2Et F~CO2Et o 1.Tf20 BrCCi3 S"~~ MeHN.~/ 2. L-Cysteine % N DBU > SAN
S I
9
"
O'"
1
"
12 (E = CO2Me)
HO
NC-~OMe 16
13
14
D-Cysteine
15
HO
,...._
17
230
M.G. Saulnier, U. Velaparthi and K. Zimmermann
cysteine . Intramolecular nucleophilic attack of sulfur follows electrophilic activation of amide with bis-(triphenyl)oxodiphosphonium trifluoromethanesufonate (Tf20 + Ph3PO) or TIC14 and provides a "biomimetic" synthesis of thiazolines from which the corresponding thiazoles are obtained by MnO2 oxidation. Condensation of nitrile 16 with D-cysteine at pH 6 generates thiazoline 17, an iron chelating agent . Aldehydes react with [3-aminothiols to give thiazolidines which are oxidized to thiazoles with MnO2 . 1,3-Thiazolidinones arise from 2-mercaptoacetic acid cyclization onto imines and an interesting spiroannulation strategy exploits this chemistry under microwave-irradiation (e.g. 18 to 19) . When nitriles 20 are substituted for imines, reaction with 2-mercaptoacetic acid esters 21 produces 4-oxothiazolines 22 . Three component reactions of 2-mercaptoacetic acid, ArNH2, and Ar'CHO give 2,3-diaryl-l,3-thiazolidin-4-ones 23 as anti-HIV agents . Multicomponent synthesis of 4-carboxy-2-acylaminomethylthiazoles 25 on solid support utilize a precondensation of aldehyde (RICHO) and the Rink amide resin followed by thiocarboxylic acid (RZCOSH) and 3-(N,N-dimethylamino)-2-isocyanoacrylate 24 . Related multicomponent syntheses of 2,4-disubstituted thiazoles have been described . Katritzky has described a solid phase synthesis of 2amino-4,5-substituted thiazoles 26 using thiourea resins, linked to the support via the phenol of 26 before TFA-induced cleavage . Solid phase synthesis of benzothiazoles has also been reported . R
NAt
__{ll~ SH s/~O O EtO2C--~ X H O R-'j'CO2H._._X--t~ ~ ~ N N~rO R/~.CN + )--HSCO2Et 18
19 H
R
N
o..N.~R 2 O
RICHO MeO2c'~--/NMe2 + 24 -~ ~NH 2 O R2"J~sH
s '~ -~A r
22
23
TFA
=
21
NC
O~_N"Ar
COR
EtO2
20
~-
S"~ RI~N~CO2Me HN-,,~ R2 o 25
.o
N / ~ T R3 ~1
26
Other methods for the synthesis of thiazoles than those discussed above have been reported during the past year. The 2-bromo-N-methylthiazolium bromide (BMTB) 29 is synthesized by cyclization of thiocyanate 27 with HBr to give 2-bromothiazole 28 in quantitative yield . Methylation of 28 provides BMTB which serves as a thiazolium peptide coupling reagent that works more efficiently than HATU for the coupling of two sterically hindered N-methylated amino acids. 1,4-Bis(cyanothioformamido)benzene 30 is cyclized with 2-aminothiophenol to bis-benzothiazole 31 . Bis-
231
Five-Membered Ring Systems: With N and S (Se) Atoms
benzothiazoles also arise from 2-aminothiophenol and bis-aromatic acid chlorides, but with 2,6-pyridinedicarboxylic acid chloride, the resulting bis-amide (bearing free thiol groups) fails to further cyclize . Flash vacuum pyrolysis of 1,2,4-benzotriazine 32 generates a low-yielding mixture of benzothiazole 33 and isobenzothiazole 34 . 4Vinyl-l,3-thiazolidin-2-one 36 is the major product of the rearrangement of the Salkyloxazoline 35 in refluxing acetonitrile . The synthesis and nitration of 2chloromethylbenzothiazole has been described and a rebuttal of a previously published benzothiazole synthesis (from ArSH and Ar'CN) also appeared .
O HBr __~N~I NCS..,.,~ "~ 27
CN S'~NH CH3Br ~"S/~Br ~~" 29
28
O
SH ~ N / ~
NH
NH2
HN...~S
,___ N.,.~NH
30 N(~
/~_~S
31
_
N~N F.V.P.750~ [~N/~SCH3 I
[~
33 +
Sv_.
32
O
S
c H3oN
reflux
Ph
36
34 5.5.2.2
Reactions of Thiazoles and Fused Derivatives
Substitution at the C-2 position of 2-bromothiazole 37 and 2-chlorobenzothiazole via palladium-catalyzed amination (e.g. 37 to 38) has been reported by Hartwig and Padwa has disclosed the copper(I)-catalyzed amidation of 37 to give 39 . While the former reaction does not proceed without palladium catalyst, amination of ethyl 2bromo-l,3-thiazole-5-carboxylate occurs directly (e.g. 40) . Alkoxide nucleophiles react readily with 2-chlorobenzothiazole, allowing access to the 2benzothiazolyloxy products . Suzuki coupling of 2-bromobenzothiazole with aryl boronic acids gives 2-arylbenzothiazoles and related chemistry with 2chlorothiazoles and N-tosyl-3-indolylboronic acid yields a 2-thiazoyl-substituted indolyl library . An interesting palladium-catalyzed annulation to similar 2-thiazolylsubstituted indoles has been reported by Cacchi (e.g. 41 to 42) . Direct C-H bond functionalization of thiazoles and benzothiazoles has received considerable attention during the past year. For example, the t-Bu-P4 phosphazine base, t-Bu-P4 (pK = 42.7) induces the C-2-H deprotonative functionalization of benzothiazole 33, in the presence of benzophenone, to generate alcohol 43 in quantitative yield: This reaction has been extended to the direct C-4H functionalization of 3-bromopyridine in the presence of both aldehydes and ketones, but only succeeds with zinc iodide present as an additive . The combination of polymethylhydrosiloxane (PMHS) and CsF facilitates the direct palladium/copper-catalyzed C-2-H cross-coupling of 33 with aryl halides to 2-arylbenzothiazoles . 2(Trimethylsilyl)-thiazole directly reacts with aldehydes to yield 2-thiazolyl alcohols related to
232
M.G. Saulnier, U. Velaparthi and K. Zimmermann
43 . An elegant cobalt-catalyzed [Co(OAc)2] method for the direct arylation of thiazole 44 with iodobenzene in the presence of the ligand, 1,3-bis-mesitylimidazolylcarbene (IMes), has tuneable regioselectivity: The exclusive C-5 arylation product 45 switches to the sole C-2 aryl analog 46 simply by the addition of CuI to the reaction mixture . Similar palladium-catalyzed tandem thiazole C-H substitution chemistry has also appeared . Direct substitution at C-4-H of the thiazole ring occurs if C-2 and C5 hydrogen atoms are not present. Br S
HNMePh ._ N
37
Pd(O2CCF3)2 (t_Bu)3P
~NMePh ~ ' ~ NH S ~
NaOt-Bu
N 38
O
Ph 45
Cul/K3PO 4 1,2-diamine
S
33
,...-
41
~
ligand
37
Pd(0) NHCOCF3 Cs2CO3
._
37
HN-"'%Ph
~
O EtO2C\~~/~)~ N
N O N_.__/
39
40
PhCOPh > t-Bu-P4 base
Ph ~
~S 43
42
Co(OAc)2 / IMes Cs2CO3 / DMF
Ph
44
Co(OAc)2 /IMes / Cul Cs2CO3 / dioxane
Ph 46
Simultaneous disclosures by Liebeskind and Guillaumet describe the palladium(0)-catalyzed cross-coupling of 2-(methylthio)benzothiazole 47 with heteroarylstannanes (e.g. 47 to 48) in the presence of copper(I) salts (CuMeSal complex in the case of Liebeskind). A palladium(II) / copper(I) catalyst system allows for a tandem onepot aminovinylation of 5-bromo-2-nitrothiazole 49 with acetylenes in the presence of secondary amines to give, for example, the 5-(aminovinyl)thiazole 50 in moderate yield . Base-induced intramolecular aminovinylation of C-2 acetylene-substituted thiazoles 51 accomplishes a particularly creative route to 2-(1,3-thiazol-2-yl)-lH-indole 52 . Lithiation of 2-(methylthio)thiazole 53 with n-butyllithium occurs at C-5 and subsequent quenching with aromatic nitriles yields 5-thiazolyl ketones (e.g. 54) . C-5 lithiation of N-Boc-2-aminothiazoles with LDA provides access to C-5-1ithio-2aminothiazole 55, an intermediate en route to C-5-ct-(2-aminothiazolyl)-C-nucleosides . A novel radical-mediated route to benzothiazole sulfonyl ethyl C-glycosides and the synthesis of 2-(mercapto)benzothiazole S-nucleosides have also been disclosed during the past year. New sulfonyl-substituted 2benzylthiazoles are reported via the well established C-2 lithiation of benzothiazole . Alpha-lithiation of 2-(chloromethyl)thiazoles 56 with n-butyllithium at -78~ followed by quenching with imines (or ketones) provides aziridines (or oxiranes) 57 with moderate to good diastereoselectivity . Samarium diiodide mediated Barbier-type reaction of related 2-(chloromethyl)-benzothiazoles 58 with ketones or aldehydes yields the 2-(13-hydroxyalkyl)-benzothiazoles 59 .
Five-Membered Ring Systems: With N and S (Se) Atoms
.__•\• ~
MeS
Pd(Ph3P)4 2.2 CuMeSal
47
H2N~
N
Me\
S
CI
N
~ ~SMe
pyrrolidine
50
1. n-BuLi M e S a s
=
|1 iX/~
53
Ar
Boc
%)
54
S~
j
Li
55
Y
1. n-BuLi Me -~ 2. R1R2C=X X = O, NPh
Ph
HccPh_
49
52 ~ j
R 56
HN ,~
Bsr/~ ~ N
48
KH
51 ~
ONe( ~ S
233
N 57
R1
S, /, N 58
CI
"Sml2/ THF ~
S. /, N
Y = H, Cl
5
R1
Olefination of carbon substituted thiazoles with carbonyl substrates has been achieved via standard Wittig chemistry, as exemplified by the use of 60 with a homochiral ketone in the context of epothilone A synthesis , by Horner-Emmons reaction with a phosphonate such as 61 , or by Knoevenagel-type condensation between 2methylthiazole 62 and aldehyde 63 to give olefin 64 . Base-induced condensation of 2-methylbenzothiazole with aromatic aldehydes is also a useful olefination protocol . Various condensation reactions of aldehydes with ring methylene nucleophiles alpha to carbonyls in thiazolidinones , 4-thioxo-thiazolidin-2-ones , and thiazolidine-2,4-diones (e.g. 65 to 66 ) have been reported during the past year. Such 5-benzylidinethiazolidine-2,4-diones as 66 represent key intermediates for the synthesis of peroxisome proliferator-activated receptor ~, (PPARv) antagonists such as rosiglitazone, an important antidiabetic drug (see section 5.5.2.5 for more details). An interesting report of an asymmetric tandem Michael-aldol reaction of homochiral 1,3-thiazolidine-2-thione 67 with 4-chlorobenzaldehyde gives 68 (and its C8 epimer) as confirmed by X-ray analysis . N-Acylations of N-unsubstituted thiazolidinethiones with carboxylic acids and DCC / 4-DMAP give products related to 67 . Rearrangement of 2-alkylidene-4-oxothiazolidine 69 by reaction with Lawesson's reagent (LR) presumably proceeds via intermediacy of the dithione, followed by ring opening-closing to the 1,2-dithiole 70 . A novel rearrangement of 5-(tertbutylamino)-3-N-methyl-2-phenylthio-4-phenylthiazolium chloride to imidazolium-4-thiolate 71 is initiated by thiophenol in the presence of triethylamine .
234
M.G. Saulnier, U. Velaparthi and K. Zimmermann
H s
P"Bu~c,- ,.-.-Z,"ii
o..( ~'.-~L ~ Etd \OEt 7 "
6O
o,~ HN
S.
S-~
61
R1R2C= Opiperidine"HOAc
o
"S"~ s N~ . , . ~
s
O
H
69
Ph
ArCHO BF3 Et20 9
H
LR
,S,
to,uer,:
Ph
S--S
t-Bu,
R I ~ N~~.~ R2
A
70
S
H
67
O H
2.HCl "-H264N. -1'4
63
Ar
O
66
RL,r_-s
BocHN
62
H,H~N~2R1
65
1.Ac20 N .-,,. S
+
S"
/~~N +
H
71
68
I CHa
Ph
Asymmetric hydrogenation of a 5-benzoylthiazole using a homochiral RuC12 catalyst gives the corresponding alcohol 72 quantitatively and in 99.4% ee. Other 5-benzoylthiazoles are similarly processed to their alcohols in 92-99% ee . 1,3-Dipolar cycloadditions of 2-dialkylaminothioisomunchnones 73 with aliphatic aldehydes proceed via the initial [3+2] cycloadduct 74, which fragments to 13-1actams 75 or thiiranes 76 depending on the electronic character of the aryl substituents on the nitrogen atom of 73 . An interesting thiophene synthesis proceeds from 2-(mercaptomethyl)benzothiazole 77, 4phenyl-3-butyn-2-one, and DBU to generate biheteroaryl 78 . Symmetrical benzothiazole C-2-disulfides have been prepared using CsF-Celite as a solid base . N-Benzyl-3-cyanopyridinium chloride reacts with 4-substituted-2aminothiazoles at the open C-5 position of the aminothiazole and the 4-position of the
F3C
Ph
F 3 C ~ OMOM
H3C..~
S-~-N
Bn
HO",
)"--O-H-'JJ'-.Ar2
F
~ Ph
Ar1 S N--Bn
Ar~ 74
75
CH3 Bn--N-,~ O
F2CHO k ~ ( 99.4% ee via ketone hydrogenation ) 72
?H 77
o
Ar2/J-- N,,ArI
73
O
H3C..N..Bn
CH3
Ph --
COCH3 [ ~ N
DBU / CH3CN
S~/ S J ~ ~] 78 H3C
Ph
AF 1. N,,,~O
S~'~Ph H" "A~
76
235
Five-Membered Ring Systems: With N and S (Se) Atoms
pyridinium to give 1,4-dihydropyridine addition products . Nonselective anodic fluorination of (4-arylthiazole-2-yl)acetonitriles generates 5-fluorinated products in addition to fluorination alpha to nitrile . 5.5.2.3
R i n g A n n u l a t i o n on T h i a z o l e s
The synthesis of thiazole[4,5-c]quinoline-4(5H)-ones 80 derives from palladium(0)catalyzed coupling of 5-chlorothiazole-4-carboxylate 79 with 2-aminophenyl boronic acid. The intermediate amino ester cyclizes under the reaction conditions . Dibromoethane serves as a 2 carbon fragment to transform 5-amino-2,3-dihydro-lH-1,2,4triazole-3-thione 81 into intermediate 82. Base-induced cyclization of 82 gives 2-amino-5,6dihydrothiazolo[3,2-b][1,2,4]triazole 83, however heating 82 in the absence of base affords isomeric 3-amino-5,6-dihydrothiazolo[2,3-c][1,2,4]triazole 84 . Annulation of 2-aminothiazole 85 with 2H-pyran-2-one 86 yields the thiazolo[3,2-a]pyrimidine 87 . Thiazolo[3,2-a]pyrimidines related to 87 are also prepared from thiourea via double annulation, wherein a dimethylformamidine derivative of a 2-aminothiazole serves as useful intermediate . A related pyrimidine ring annulation onto 2aminothiazoles provides an entry to 6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-ones under microwave irradiation and solvent free conditions . The same laboratory also has described a similar synthesis of thiazolo[3,2-a]triazine C-nucleosides 88 and pyran-annulated thiazoles 89 . A synthesis of thiazolo[4,5-d]pyrimidine-7(6H)thiones, via annulation of an isothiocyanate onto a 2,4-diarninothiazole intermediate, was also reported . Br
N~ S
S..~ ~
1)" ArB(OH)2' Pd(Ph3P)4
O~' 2). 2-NH2C6H4B(OH)2"OEt CI
~
H
79
NH2
+
SMe
..~CN Ar
85
~
80
Br(CH2)2.S
S
HN~ BrCH2CH2Br N~, HI~I-~N Hl~l'~N NaOMe ~ NH2 NH2 82 81 heats ,
NC~,,L~S -~ - cO2 Ar N A
O 86
~2
87
84
N'N/'~NH2 83
Ar1
NvNH 88 (R -
D-arabinobub/I, D-ribobutyl)
O//'\O / -'N Ar 89
Rapid entry to the imidazo[2,1-b]thiazole ring system 90 has been described using thiourea as starting material . This same ring system is also fashioned via an Ugi three-component coupling of 2-aminothiazole 85, benzylisocyanide, and 2naphthaldehyde catalyzed by scandium triflate . The isomeric imidazo[5,1b]thiazole ring system is derived by annulation of the 2-(aminomethyl)thiazole (e.g. 91 to 92) . Pyrrolo[2,1-b]thiazoles 94 are obtained by Vilsmeyer-type formylation of
236
M.G. Saulnier, U. Velaparthi and K. Zimmermann
thiazolones 93 . Bergman has reported an intramolecular SNAr reaction of a thiourea anion which serves as an interesting annulation procedure for the synthesis of the thiazole[4,5-b]pyridine ring system, even when the site of ring halogen substitution is not particularly activated (e.g. 95 to 96) . Condensation of the aldehyde moiety of D-arabinuronolactone 97 with L-cysteine methyl ester precedes intramolecular attack of nitrogen on the lactone carbonyl, resulting in ring expansion to the bicyclic thiazolidinelactam 98 . S
R2
CO2Et
90
91 NC
NC
O
L~
92
Ar
O
Br
S\ ~jNMe2
DMF / POCI3
Br NaOMe
0
93
,CO2Et
Ar" " O
o
HN
CI NMP / 120 ~
94
~==S PhCOHN 95
N.,.,S 96 NHCOPh
OH NH3+CI- .~ 97
Ho~,N 98 O
CO2Me
The benzylidene derivative of 4-thiazolidinone 99 (formed by condensation of the parent thiazolidinone with benzaldehyde and sodium methoxide) undergoes initial 1,4-Michael addition with the Wittig reagent, methoxycarbonylmethylenetriphenylphosphorane, to give an intermediate which cyclizes to the furo[2,3-d]thiazolidine 100 via intramolecular displacement of triphenylphosphine by the thiazolidinone oxygen . A Russian group has reported a novel synthesis of various annulated sulfur heterocycles (e.g. 102) via activation of aromatic and heteroaromatic substrates bearing pendant methylthioalkyl side chains (e.g. 101) with triflic anhydride. The presumed electrophilic intermediate trifluoromethane-sulfonylsulfonium salt cyclizes to an isolable methyl sulfonium salt which is readily demethylated to the fused sulfur heterocycle (e.g. 102) by triethylamine . The thiazole o-quinodimethane 104 is generated from tribromide 103 and undergoes Diels-Alder addition to indoloquinone 105 to give a 52:48 unseparable mixture of regioisomeric tetracyclic quinone adducts of which only the major isomer 106 is shown . The pyrazolo[3,4-d]-l,3-thiazolino[2,3-f]pyrimidine 108 results via annulation of intermediate 107 with triethyl orthoformate. Intermediate 107 is synthesized from malononitrile and cyanoacetophenone in two steps . Dehydrogenative cyclization of thiazole 109 with chloranil leads to the novel thiazolo[2,3-c][1,2,4]triazole 110 . The synthesis of a new 3,5-dithia-l-aza-norbornane was also reported .
237
Five-Membered Ring Systems." With N and S (Se) Atoms
R S,,~N.-Ar Ph S-~/R ~ O " N,,Ar Ph3P=OHOO2Me ;h,~ O
tf, o
"-
101
100 CO2Me
99
o
CH2Br I-N CH2 -] N/fS~~ l_~ CHBr2 DMFNal / 60 ~> [/~.S~ CHBrj 103
NH
NHBoc
Ph CH(OEt)3
N.~
107
102
0
N.
0
oc
106
~.(Ar
N.~N~--~Ar \ SHN'~~~,/~, , N chlorani/ N I
H2N~N-N ~~/NH2 >-H2N~, ~ ~/ N N-N 5.5.2.4
N
104
/=( Ph
S L___.J
L,,,,/SMe 2. Et3N
108
1 0 ~
110
Thiazole Intermediates in Synthesis
Perhaps the most widely reported use of the thiazole ring system as a synthetic intermediate for the synthesis of non-thiazole containing molecules is the application of the 2-sulfonyl- 1,3benzothiazole moiety in the Julia olefination, and several reports on this topic have appeared during the past year. The use of the Julia olefination in the total synthesis of natural products includes its application in the syntheses of proteasome inhibitors , the antitumor macrolide Rhizoxin D , the 14-membered unsaturated macrolide cineromycin B , enantiopure 19-norvitamin D3 analogues , phorboxazole A , and (+)-cassiol . The Julia olefination protocol allows a convenient one-step synthesis of fluoroethylidene derivatives 112 using 2-(1fluoroethyl)sulfonyl- 1,3-benzothiazole 111 , as well as an efficient synthesis of substituted vinyl ethers 114 from a-alkoxy sulfones 113 . The 6-nitro-2benzothiozoate 115 serves as a highly efficient donor for 13-stereoselective glycosylation of acceptors bearing primary hydroxyl groups (e.g. 116). For example, Mukaiyama reports that ~-glycoside 117 results from activation of 115 with triflic acid in the presence of 116. The anomeric [~:ct ratio is 96:4 at -78 ~ and donor 115 gives [~-saccharides with better [3stereoselectivity than other typical glyosyl donors, such as imidates or fluoride, under the same conditions . Related S-benzoxazolyl (SBox) glycosides serve as versatile glycosyl donors for stereoselective 1,2-cis glycosylation and thus complement the Mukaiyama method . The influence of the benzothiazolyl moiety to enhance the
238
M.G. Saulnier, U. Velaparthi and K. Zimmermann
leaving group ability of sulfur and oxygen heteroatoms attached at the 2-position is further exemplified by Mukaiyama in the Friedel-Crafts phenethylation reaction. Herein, thiocarbonate 118 reacts with anisole catalyzed by scandium triflate to yield 119 as an equal mixture of ortho and p a r a isomers . The use of 2-thiobenzothiazolyl (2-SBtz) ethers as a leaving group for
[[.,~"'.,J I[ N~ - s - O( , ~S
F
R1COR2
O
>
O CH3 base/THF 111
Bn~.IoO---,, O Bn.. , _ . . - ~
BnO'~BnO ~
113
HO,,,--~_..-O
N-
I~~ NO2
Ph
o1(CH2)2 S Ph
118
CH3 112
BnO\_~.-,..T~
115 S
S/~N ~
F
PhOMe Sc(OTf)3
'OMe
119; 1:1 olp
OR
s__/ ~
BnO~Bns~)Me 116 ._ TfOH/ CH2CI;
,.._
R
RCOR' LiHMDS"-RO/~I"'R1 114
BnO--,,
BnO"~XI~O\ .O O
BnO-"~_ L~'~ ~..,~-~O ~nu ~nu \~.~...~ 117 BnO"~BnE)OMe
o. ~ "/cH3
H3C Ph,,,/~ ~
s/J~N _ PhCHO.._ I S " ~ O (~ Bu4NBr"- S/~N CH3
120
~
121
"R +'' generation and trapping in synthesis has also been described . The role of the 2-SBtz moiety as a leaving group in synthesis is further demonstrated by the conversion of 120 to 121. The 2-SBtz group is cleaved with ethylmagnesium bromide to yield the free vinyl SH group . Benzothiazole also serves as a formyl group equivalent via reductive processing of its C-2 ring carbon . The use of thiazolidinethiones in the asymmetric aldol addition reaction has seen two very elegant applications during the past year. Evans has reported an enantioselective, syn diastereoselective aldol reaction of N-propionylthiazolidinethione 122 using 10 mol % of [Ni((S,S)-t-BuBox)](OTf)2 to give syn aldol adduct 123 in 94% ee. While a 97% ee results from substituting TESOTf with TMSOTf in this reaction, the TES adducts (e.g. 123) are directly converted to Weinreb amides (e.g. 124) . Liotta has described a diastereoselective addition of the chlorotitanium enolate of thiazolidinethione 125 with Omethyl oximes to give the anti azetine isomer 126 as the major product. The formation of the azetine presumably results via cyclization of the initially-formed bis-titanium intermediate 127. Treating azetinyl thiazolidine-2-thione 126 with benzoyl chloride provides the a,13disubstituted 13-amino carbonyl adduct 128 . Thiazolidinethione 125 is similarly transformed into anti aldol adducts using titanium enolate chemistry with dibenzyl acetals in lieu of imines or aldehydes . Remote functionalization of a non-activated C-H bond (e.g. 129 to 130) results from treating thiazolethione 129 with bromotrichloromethane and AIBN. Homolytic cleavage of the nitrogen-oxygen bond in 129 leads to 130 and 131 . Functionalization of the double bond of 2(3H)-thiazolone provides a new route to chiral synthons for 2-amino thiols .
239
Five-Membered Ring Systems: With N and S (Se) Atoms
S
[Ni((S,S)_t_Bu_Box)](OTf)2 ~
PhCHO/2,6-lutidine TESOTf
0
O
OTES
& ' ~
Ph Me(OMe)NH2Cl
[ ~
123
122
0
N..OMe
S
R/J~H S
CI3Ti ~
124
cla
m
Ti
oi"s
R.-". %
TiCI4 / CH2CI2 (-)-Sparteine
125
, ~ Ss PhCOCI~R
\" -
127
OTES
imid~uzole ~ M e O . N ~ ~ J . ~ p h
s
....
126
-
0 HN"~
128
Ar
H3C
129
5.5.2.5
I
f ,O -.[~
S
BrCCl3 .~ AIBN / Phil
4"
~/ S H3C
130
SCCI3
131
Biologically Important Thiazoles
The thiazole ring system is found in a wide variety of medicinally important compounds and many such examples have been reported in the 2003 literature. For example, thiazolidine2,4-diones (TZD's, glitazones) constitute an important class of antidiabetic drugs which control hyperglycemia by enhancing tissues' sensitivity to insulin. These agents, most notably represented by the approved drug rosiglitazone 132, are known as PPAR 7 agonists as they target the nuclear receptor known as the peroxisome proliferator-activated receptor ), (PPAR?). Several reports in the TZD/PPAR domain have appeared during the past year . Thiazolidinones possess anti-inflanmlatory activity and also show inhibition of the synthesis of dTDP-rhamnose which is an essential component of the M y c o b a c t e r i u m tuberculosis cell wall . Ureas of 2-aminothiazole inhibit growth of grampositive bacteria . The aminothiazole class itself is highly prevalent in several important areas of medicinal chemistry , particularly as kinase inhibitors, including the Src-family kinase p56 lck (Lck) . For example, 2-aminobenzothiazole 133 (BMS-35075 l) is an exceptionally potent, non-cytotoxic inhibitor of Lck (ICs0 = 0.5 nM) . 4-Acylamino-l,3thiazoles are described as selective inhibitors of CDK5, a serine/threonine kinase that is required for normal neuronal development, and thus are potential agents for the treatment of Alzheimer's disease . 2-Arylaminothiazoles are corticotrophin-releasing factor-1 receptor (CRF1R) antagonists (e.g. 134; Ki = 8.6 nM) and display anxiolytic activity in a mouse canopy model . Orally active, dual ErbB-2/EGFR tyrosine
240
M.G. Saulnier, U. Velaparthi and K. Zimmermann
kinase inhibitors of the 6-(2-(aminomethyl)thiazolyl)quinazoline class (e.g. 135) show significant antitumor activity against both erbB-2 and EGFR over-expressing human tumor cell lines in mouse xenografl models . Thiazole 136, a 0.71 nM inhibitor of farnesyltransferase, potentially useful as an antitumor agent, has also been reported . Furthermore, thiazole-containing molecules are reported to have in vitro and/or in vivo antitumor activity , anti-HIV activity , antifungal activity , antibacterial activity by inhibition of peptide deformylase (PDF) , and inflammatory activity useful for the treatment of asthma via inhibition of phosphodiesterase-4 (PDE4) or inhibition of mast cell leukotriene release . Benzothiazoles also are reported as selective inhibitors of cyclooxygenase-2 (COX-2), an enzyme which is induced and expressed during the inflammatory process . Two other important targets, both useful for the development of antithrombotic agents, which are inhibited by thiazole-containing molecules are factor VIIa and factor Xa . Some of the factor Xa analogs are not only active against factor Xa, but selective over thrombin . The argthiazole analog 137 is one of the most potent factor Xa inhibitors, with IC50of 0.9 nM.
O
H ~ 0
9H3
O ~ N N ~~
132 Rosiglitazone PPAR7 agonist
/
H CI S/~T~N--~ ---~F3~C~NC l ~ C I
H3C
HN HO~N~ H
133
N H
BMS-350751 Lck ICs0 = 0.5 nM
~N HO N 172
S-"SO3Na 169
>
NH3
S 170
n-BuLi DMF
Br N PPh3 N > BrPh3+p. 173
174
246
M.G. Saulnier, U. Velaparthi and K. Zimmermann
2-Alkyl-(or aryl)-isothiazol-3-ones 178 are formed by oxidative cyclization of dithiopropionic amides 177 with SO2C12. These can be further rearranged into 3-alkyl(or aryl)-aminoisothiazoles 181 and then oxidized to the corresponding 1,1-dioxides 184. Harsher treatment of 177 with SO2C12 leads to 5-chloro- and 4,5-dichloro derivatives 179 and 180, which are transformed by the same series of steps to give chlorinated compounds 185 and 186. Bromination of the isothiazole dioxide 184 (Rl=R2=H) gives (via an addition / elimination sequence) the 4-bromo-derivative 187 .
(SCH2CH2COOH)2
SOCl2 (SCH2CH2COCI)2 RNH2> (SCH2CH2CONHR)2 SO2Cl2
175
RI~~ R R2
176
~2) 1)NH3 POC'3
S
NHR RI~, N
177
rn--CPBA ~
R2~S
178 RI=R2=H 179 RI=H, R2=CI 180 RI=R2=Cl
R~~HR ,,/~ ,.,,' R" (~/~\x0
181 RI=R2=H 182 R1=H, R2=Cl 183 RI=R2=CI
1, Br2=
NHR Br~ # ~ N O
2) NEt3 or heat
O
184 RI=R2=H 185 RI=H, R2=Cl 186 RI=R2=CI
187
In a very similar sequence, fluorobenzophenone 188 reacts with potassium benzylthiolate, followed by S-chlorination and cleavage of the benzyl group with SO2C12 to give the corresponding sulfenyl chloride. Quenching with ammonia yields benzo[d]isothiazole 189. The isolated benzo[d]isothiazoles are oxidized to the corresponding S,S-dioxides with potassium permanganate . A more environmentally friendly and processchemistry appropriate procedure uses hydrogen peroxide to facilitate ring closure between an imid-nitrogen and an oxidized sulfur atom to give 1,2-benzoisothiazolin-3-one. The published experimental procedure, "one-pot" from 2,2'-dithiodibenzoic acid methyl ester, synthesizes eighteen kg 1,2-benzoisothiazolin-3-one . Chloramine-T and hydroxylamine-Osulfonic acid were used for S-amination of thiosalicyl amides, followed by cyclization to give N-substituted benzoisothiazole-3-ones . 2-Alkylthio-3-acyl-4-quinolinones
R1
R1 O
O
O
_
2) SO2012 3) NH3
S
R2 188 0/
R2 189
0
O~NH MeO ~---Br ~---/~ 192
H 190
191
0 MeNH2MeOOC~'~ NH >
MeH
193
MeOOC MeOOC'~ O.,,L./ Na2S II "NH Br ~ MeHN ~ ( / ~ ~ NaS 194
H202 or12>
M e~N . ~,'" N ~;--~
195
247
Five-Membered Ring Systems: With N and S (Se) Atoms
190 (and the related quinolines) can be cyclized to the corresponding annelated isothiazols 191 by treatment with O-mesitylenesulfonylhydroxylamine (MSH) . 1HPyrrolo[3,2-c]isothiazole-5(4H)-ones 195 are formed via oxidative cyclization of pyrrolidinones 194 with hydrogen peroxide or iodine. Further stepwise oxidation by H202 in AcOH affords first the corresponding sulfinamides and then the sulfonamides, depending on reaction time. These sulfinamides are shown to insert Pt into the S-N bond . Two examples of ring-closure by formation of the C3-N bond have been published in 2003. Spirocyclic isothiazolidine 196 is formed via N-oxidation of N-methoxy-2-(pmethoxyphenyl)-ethanesulfonamide 197 (n=2) with hypervalent iodine reagents via an ipsocyclization. Examples without the strong electron donating group on the aromatic ring give ortho-cyclization in good yields, leading to cyclic sulfonamides of general structure 198 . Oxidation of benzene-sulfonamides 199 bearing a 2-vinyl or 2-allyl function in the presence of chiral rhodium catalysts results in nitrene formation and aziridination of the carbon-carbon double bond in 55-76% e.e. and up to 75% yield of 200 .
O•.•
O~ N /(3 ~S-,~ O
196
PhI(OH)OTs R I . ~ ~ ] -" -" ~, ~ R' =OCH3 n=2
H N .O 802 197
n
PhI(OH)OTs R I ~ "~ "R'=H,F,Cl,OH 3 n= 1 or2
198
SO 2
n
Cyclization via formation of the C3-C4 bond has also been described. Indium mediated alkyl radical addition-cyclization-trap reactions of N-allyl-vinyl-sulfonamides 201a proceed smoothly in aqueous media. The electrophilic vinyl sulfonamide group of 201 reacts with nucleophilic alkyl-carbon radicals, generating electrophilic sulfonamide-stabilized radicals, which show excellent reactivity towards the vinyl group to give cyclic sulfonamides 202a, in low cis-trans selectivity. The analog radical addition-cyclization reaction of vinylsulfonamide-hydrazone 201b gives the 4-hydrazino-functionalized cyclic products 202b .
~T/SO2NH2 ~ ' ~ R 199
[Rh2(L*)4] ~-oxidant
O~ R 200
~ O2S. N/ R' 201
RI, In a) X=CH2, Y=CH21 b) X=NNPh2, Y=NHNPh2
I~' 202
Cyclization by formation of the C4-C5-bond is demonstrated by intramolecular alkylation of the dianion of methylsulfonamide 203 to give sultam 204. This method has been applied towards the synthesis of chiral sultams, which are valuable auxiliaries . The required [3-chloroalkanesulfonamides 203 are easily accessible from ~-aminoalcohols via bismesylation and displacement of the O-mesyl group by chloride.
248
M.G. Saulnier, U. Velaparthi and K. Zimmermann
02
HN--S\
~
H ..N.~SO 2
LDA
S
NH2 CH3SO2NSO
X
Cl
203
N"S~s+ Cl,~ Cl 209 .-----Cl
O Xy~
207 X=Br
O
O NC
s
y
~N~
O"~N ~ ~
Nu
X~~~d
NH2
X = 208(y
206 X=H
205
204
I
O'~ 210 ./'~'~
211
O
R. H
CN _
O
212
I
NC.
S
N-S /
S
NC , O" 215 216 213 214 Only few examples of ring formation by combination of 2 fragments (= formation of 2 bonds in 1 reaction) were published in 2003. N-sulfinylmethane sulfonamide (CHaSO2NSO) reacts with 2,4-dimethylaniline 205 to form 2,1-benzoisothiazole 206, which is further brominated at the methyl group (using NBS) or at C5 (using BuLi, Br2) to give 207. These intermediates can be further transformed into nucleoside transport inhibitors . Keto-enamines 208, e.g. 6-amino-l,3-dimethyluracil, react with Appel's salt (4,5-dichloro1,2,3-dithiazolium chloride, 209) to form 5-cyanoisothiazoles 210. The uracil-based cyanoisothiazoles undergo substitutive replacement of the cyano group with various nucleophiles to give 211, whereas pyrone-isothiazoles 210 undergo ring-opening of the pyrone-ring to form monocyclic isothiazole derivatives 212 when treated with primary amines . Another example of an isothiazole formation by combination of multiple fragments in one reaction is the treatment of 213, a 13-bromo-ot,13-unsaturated aldehyde, with 2 equivalents of NH4SCN, which gives isothiazole 214, without interference from the free nitroxyl radical . Treatment of thien-2-yl-methylene-malonitrile 215 with $2C12 gives 3-chloro-4-cyano-5-(2-thienyl)isothiazole 216 . The 3thienyl regioisomer undergoes the same reaction. ~).
5.5.3.2
Reactions of Isothiazoles
3,5-Dichloro-isothiazole-4-carbonitrile 217 undergoes a regiospecific Suzuki coupling replacing only the C-5 chloride when reacted with aryl- or methyl-boronic acid to form 3chloro-5-(aryl or methyl)-isothiazole-4-carbonitrile 218 . Commercially available ethyl-5-amino-3-methyl-isothiazole-4-carboxylate 219 can be converted to 4aminomethyl-3,5-dimethyl-isothiazole 220 via diazotization and conversion to the iodide, palladium (II) catalyzed methylation with Sn(CH3)4, reduction of the ester with LAH, conversion of the alcohol to azide and reduction to the amine . Isothiazolemalonate 222 can undergo debenzoylation to give 223 when treated with NaOH in a water/benzene two-phasic system, and both of these compounds (222 and 223) can undergo
249
Five-Membered Ring Systems: With N and S (Se) Atoms
ring expansion to 1,3-thiazin-4-one 224 and 225, respectively, upon treatment with triethylamine in chloroform . N-S
N-S
217
218
N-S
N-S
219
220
Ph SOCl 2,~ O
HN)__E E
NaOH,.~
E
221
Et3N~
O
E/I,.. E E 222
MeOOC S ,,~ MeO0 O 224 R=H 225 R=PhCO (from 222)
223
Isothiazolium salts 226, which are prepared from 13-thiocyanatovinyl aldehydes and anilines, can be oxidized with magnesium monoperoxyphthalate (MMPP) in water or alcohols to give 2-aryl-3-hydroxy-sultames 227 . This publication also reviews, in its introduction, a variety of other methods to form highly oxidized isothiazoles and their biological properties.
~S
N+._~__R1
MMPP ROH
226
RO
/.s.- o
O
221
An interesting difference in regioselection in the reaction of an allyl-palladium complex 228 with either a sulfonamide 231 or an amide 232 is reported by Cook and coworkers . The differential outcome is explained by the steric difference between the planar amide and tetrahedral sulfonamide nucleophile.
250
M.G. Saulnier, U. Velaparthi and K. Zimmermann
Ph Ph
Ph
Ph
O ' ~ N-H
: L/
O " ~ NH
-I-
-
7
Nu
,k
Nu
229
228
230
O II O~S-NH Nu =
~
Nu =
231
0
"
100
232
88
"
12
Sharp and coworkers report two decomposition reactions of ziprasidone 234, an antipsychotic drug. The benzoisothiazole portion of this molecule can be photoisomerized to the corresponding benzothiazole 233. This reaction does not involve the oxindole part of the molecule, as was shown by the similar conversion of 3-(piperazin-l-yl)benzo[d]isothiazole to the corresponding benzothiazole . The same group showed further that ziprasidone and other benzoisothiazoles can undergo reductive ring opening to form 235 or its isobaric isomer dihydrobenzoisothiazole 236. This transformation can be accomplished synthetically by treatment with benzyl mercaptan but it was also observed in the dithiothreitol-dithioerithritol matrix that is commonly used for FAB-mass spec analysis. FAB-mass spectra of several benzoisothiazoles show only the reduction product (2 units heavier) when this reducing matrix is used .
N N
hu
~'~
Cl
0 233
N
BnSH
/Cl
0
N
or
Cl
DMSO, 100~
0 234
Cl
0 235
236
251
Five-Membered Ring Systems: With N and S (Se) Atoms
The anion generated by deprotonation of 1-methyl-3-chloro-l,3-dihydro-2,1benzoisothiazole-2,2-dioxide reacts in a vicarious nucleophilic substitution reaction with nitrobenzenes 239 to give compounds 240. It is advantageous to use an equimolar mixture of non-chlorinated 237 and dichlorinated 238, which form the mono-chloro-compound in situ, rather than to attempt selective mono-chlorination of 237 . Prikryl and coworkers report the formation of triazenes rather than the expected diazo-dyes when reacting 5-nitro2,1-benzoisothiazole-3-diazonium salts 241 with N-alkyl-anilines 242 or diphenylamine. Anilines are ambivalent nucleophiles, which can be attacked at nitrogen, but for nonbenzoisothiazole based diazonium salts this is a reversible reaction (under acidic conditions), which ultimately leads to reaction between the diazonium component and the C4-carbon of the aniline. Triazene 243 is protonated at the isothiazole-nitrogen rather than the anilinenitrogen, making the kinetically favoured attack of the diazonium ion on nitrogen irreversible . /
/
/ +
R" ~
\
+
--,,7"" H
R" x~
237
7""Cl Cl
238
NaOH
x
_
Y
NO2
DMSO
R"
Q = N or CH
239
X 240
Y
NO2
~ K N,s
O2N
~ 241
5.5.3.3
-~ N2+
H
4-
N-R
O 2 N ~
s N= N
/,~
%
N-- R 242
243
~
R=CsH5 or alkyl
Isothiazoles as Auxiliaries and Reagents in Organic Syntheses
Oppolzer's camphor sultam is a well known chiral auxiliary and several interesting examples of its use have been published in 2003 . (S,E)-2-Methylhex-4-enal 245 reacts with high anti-selectivity with the silyl enol ether 244 to form, after hydrolysis, acid 246 .
252
M.G. Saulnier, U. Velaparthi and K. Zimmermann
~
O
O
O
Z>N OTBS §
> H 245
244
y
o o
S~ N" I~--~NII
247
x
O
249
N'~Br
Q
~ 246
\7 ~ o ~ .IS"; R - \
RI Zn
X = OBn or NPh2
Ar,N000 02
OH
250> 251
248
NHX
O
jar
H eO' A t
H,"~N'''H ~lpp
NH2 252
Paintner et al. prepare a chiral glycine analog based on the camphor sultam by deprotonation with n-BuLi and alkylation (98% d.e.) in the context of their synthetic approach to biphenomycin antibiotics . Sultam based glyoxylic oxime ether and hydrazones 247, when treated with alkyl iodide and zinc in aqueous media, undergo alkyl radical addition to form chiral ot-aminoacid derivates 248 in good enantiomeric excess . Asymmetric aza-Darzens reactions of bromoacylated champhor sultam 249 with N-diphenylphosphinyl-arylaldimines 250 give substituted aziridines 251 with high level of enantiomeric purity . Cleavage of the N-P bond with BF3etherate, followed by hydrogenolytic opening of the aziridine and hydrolysis of the amide converts these intermediates into "unnatural" aminoacids 252 without loss of stereochemical integrity.
253
Five-Membered Ring Systems: With N and S (Se) Atoms
N-Chlorosaccharin 254 has been shown to undergo electrophilic Ritter-type reactions with alkenes (e.g. 253) in acetonitrile. The resulting labile [3-chloro sulfonylamidines can be ringopened and cyclized to imidazolines 255. Overall this provides a one pot method for the electrophilic diamination of alkenes. Competing aziridine formation as well as allylic chlorination are also observed depending on the nature of the alkene used . Norbornene-based sultam 256 can be used as a starting material for ring opening metathesis (ROM) mediated phase trafficking purification. The polymer formed via ROM is soluble in dichloromethane and allows most reactions to be performed in homogenous solution, but can be precipitated by addition of methanol to separate from excess reagents and byproducts . 0
>
253
5.5.3.4
2) KOEt
pfi
255
256
Pharmaceutically Interesting Isothiazoles
Isothiazoles and their saturated and/or oxygenated analogs play an important role in pharmaceutical research. Isothiazoloethenyl side chains were incorporated into carbapenems , isothiazolidine-l,l-dioxide into HIV integrase inhibitors , isothiazoles into HIV protease inhibitors and 1,2-benzoisothiazol-3-one1,1-dioxide into repinotan (BAYx3702 257), a potent 5-hydroxytryptamine antagonist . Benzo[d]isothiazoles e.g. 258 show promising inhibition of human 2,3oxidosqualene cyclase and efficacy in lowering plasma cholesterol levels . Indolyl-glyoxylamides of 3-methyl-5-aminoisothiazole 259 are active (in vitro) against several cancer cell lines and show in vivo activity against P388 murine leucemia . Condensation of 2-ethylisothiazolidine-l,l-dioxide 261 with substituted benzaldehydes 260 is used in the synthesis of S-2474 262 (R=H), an anti-arthritic drug candidate and its metabolites . One of the two major pathways of metabolic degradation of this compound is N-deethylation of the isothiazolidine-dioxide , the other one being oxidation of the t-butyl group (262 R=H to 263 R=OH). This publication also describes the synthesis of sulfonimide 264 and its reduction product 265.
254
M.G. Saulnier, U. Velaparthi and K. Zimmermann
257
H 02 ..../N~/~/~N.S Repinotan O ~
R--k N ~
s--N
~
N~O'--.T;../~ I
R
L ~ ~ CHO
H
258
02
~S~N--~ ~J
,.,_
261
R=HorOTHP
259
N
. o ON
'264
5.5.4
THIADIAZOLES
5.5.4.1
1,2,3-Thia diazoles
~
B
O
R
~
HO" "~
/
HO" ~
r
2
N-~
262 S-2474R=H 263 R=OH
2651CHO
The Hurd and Mori reaction is undoubtedly the most popular method for the construction of 1,2,3-thiadiazoles, and many applications of this reaction have been reported during the past year . For example, the reaction of 266 and 267 with semicarbazide affords the corresponding semicarbazones 268 and 269, which are transformed to 1,2,3-thiadiazoles 270 and 271 upon treatment with thionyl chloride. Interestingly, when there are no methyl groups on the cyclohexenone ring, oxidized fully aromatic tricyclic 1,2,3-thiadiazoles are obtained . The 1,2,3thiadiazole 273 is also synthesized by the reaction of N-acylhydrazone 272 with thionyl chloride. A novel series of a-substituted phenoxy-N-methyl-1,2,3-thiadiazole acetamides 274 is obtained through the reaction of compound 273 with several phenols, and the resultant phenoxy derivatives were evaluated against heptatitis B virus (HBV) .
255
Five-Membered Ring Systems: With N and S (Se) Atoms
O
O~. NH2
~ ~ ~ X ph NH2NHCONH2
266 X=O 267 X=S
SOCI2
N"NH
N~N "~ ~ X
268 X=O 269 X=S
270 X=O 271 X=S
0.,,%/NHMe N~ N O ,N~ N O O =S ~ ? EtO/jj'" N" N~-~Cl SO012 NHMe ArOH S ~ N H M H CI OAr 272
ph
273
e
274
Thiadiazole-naphthalimides are synthesized and evaluated in the context of a new family of photonucleases. For example, ortho-bromo nitrobenzene 275 is transformed into the 2thiobenzyl aniline 276, which is then diazotized to obtain 1,2,3-thiadiazole 277 . These thiadiazoles intercalate into DNA efficiently and damage DNA at as low as 10 ~tM under photochemical conditions. Zeleska et al. have shown that thioanilide 278 is transformed into phenyl hydrazone 279 which subsequently undergoes oxidative heterocyclization with H202 to yield the 1,2,3-thiadiazole 280 .
a) BnSH, K2CO3 NO2 275 Br
NaNO2,HCI
b) SnCI2, HCI 276
NH2 S'Bn
Ph MeO NHPh S PhNHNH2 N"N. H MeOH - - . ~ ~ S O,,,H,N-.Ar reflux O,,H..N~Ar
~
278
279
86%
N 277 S-N /
Ph
H202 N "~N MeOH" ~ S O
N~Ar 280
Tumkevicius et al. report the formation of the novel benzimidazole[ 1,2-c][ 1,2,3]thiadiazole 283 by refluxing 281 with thionyl chloride. When the reaction is performed at room temperature, compound 282 is isolated instead. Refluxing the compound 282 with thionyl chloride also furnishes thiadiazole 283. The formation of 283 is explained by Hurd-Mori's mechanistic model, wherein the first step is presumably formation of the thiadiazole-S-oxide which undergoes a Pummerer-like rearrangement, initiated by the attack of thionyl chloride followed by subsequent elimination of HC1 to give 283. Following the addition of sodium bicarbonate, the fused chloro thiadiazole 284 is then obtained. These chloro thiadiazoles are suitable substrates for SNAr reaction with various amines, and for instance heating with morpholine yields 285 .
256
M.G. Saulnier, U. Velaparthi and K. Zimmermann
SO012 =,, I~Nx~/CI 281
rt SOCl2
NH2
SOCI2 reflux
N .HCI
r~0 1 ~
Morpholine/J"
NaHCO3 ,. N
"N~S .HCl
283
5.5.4.2
N
~
/
~CI
85%
II
"~'~'~N~~/~"O N Nv" j
:282 ~IH2
/
N
EtOH,reflux
N= S 285
II
"N~-S
284
1,2,4-Thiadiazoles
Several methods are known to form 1,2,4-thiadiazoles via dimerization of thioureas. A novel method has been reported this year that involves oxidative azacyclization of 1monosubstituted thioureas. In this reaction, thiourea 286 reacts with [bis(acyloxy)iodo]arenes (BIA) to form 3,5-bis-phenylamino-l,2,4-thiadiazole 287. A reaction mechanism is proposed wherein the polyvalent iodo intermediate 288 undergoes elimination of iodobenzene to form 289. BIA-initiated oxidative azacyclization of 289 yields 1,2,4thiadiazole 287 .
PhHNVNH2 II S 286
2 PhI(OAc)2 .- PhHN -20~ 30 min ~/I N 55% N'SX~--NHPh 287
H
H
2 PhHN~ NH2 -CH3Co2HPhI(OAc)2 PhHN~ S\I"Na " ~ NHPh S NH Ph S 286
PhI(OAc)2 -CH3CO2H
-PhI_s = PhHN..]I/N..~ NHPh NH S
288
PhHN..~NyNPh I~I/S |
289
-CH3CO2H,.PhHNN/~sX/~__ _N -Phi NHPh
Oxidative cyclization of dithiobiuret under basic conditions provides bis(5-amino-l,2,4thiadiazolyl)-3,3'-disulfide 293 via oxidative dimerization of intermediate 5-amino-3mercapto-l,2,4-thiadiazole 292. However, alkylation of 293 under basic conditions gives the thioalkyl- 1,2,4-thiadiazole 294 .
SH H 291
N"2 2N NaOl~
/~--S H2N 292
.
NZ-
H2N~ s " N
SR RX N N N N,,S~ NH2 KOH ~ H2N
293
294
2-Amidinobenzothiazoles 298 are prepared in high yield by a thermally-promoted rearrangement of thiadiazolium salts 296 or thiadiazolines 297. Addition of base to the rearrangement of the thiadiazolium salts 296 can improve the yield by the prior conversion of
Five-Membered Ring Systems: With N and S (Se) Atoms
257
the diazolium salts to the corresponding thiadiazoline free bases 297. The authors speculate that thiadiazolines 297 may go through an electrophilic aromatic substitution or free radical pathway to furnish 2-amidinobenzothiazoles 298 .
[~
S "-y=' NHR2 NBS
o---N+ R2
295
296
~
~
,
F~2
s-.
2971
'
~--N
+
,p='
A R2HN
EtOH,reflux
I 298
Morel et al. report the preparation of 5-chloro-l,2,4-thiadiazol-2-ium chlorides 301 by treatment of formimidoyl isothiocyanates 299 with a twofold excess of methanesulfenyl chloride. These salts show interesting chemical behavior toward several nitrogen and carbon nucleophiles. The nature of the N-substituent determines the stability of the salt 301, and especially when the substitutent on nitrogen is t-butyl, the salt 301 decomposes in solution into 5-chloro- 1,2,4-thiadiazole 302 .
RIs~
--N
N"C+s
299
FR'S . ~ ]
MeSC,/.~~ / esc' / 'C-S /-Me2S; L C" L..SMeJ 300
RIs + ~
Y-' c,--t-BuC'
NyS C, 301
"
R'S
'~N NyS C, 302
2-Hydroxylamino-4,5-dihydroimidazolium-O-sulfonate 303 is prepared by reacting 2chloro-4,5-dihydroimidazole with hydroxylamine-O-sulfonic acid. Reaction of 303 with carbon disulfide in the presence of triethylamine presumably proceeds via intermediate 304 to yield the 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione 305 by a tandem nucleophilic addition-electrophilic amination reaction . In an interesting photochemical reaction, irradiation of 5-phenyl-1,2,4-thiadiazole 306 results in the formation ofbenzonitrile 307 . s
-
s
O'N-H CS2/DMF ~ ' N ~ - / HN~NH+ Et3N H ~ L_J 303
304
-]
-SO4-2
H
N ~" ~; S
305
N~ N ~--~ 306
hv 307
Several biological applications of 1,2,4-thiadiazoles have been reported during the past year . For instance, a novel class of cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol trapping pharmacophore. Within this series, compound 310 is the most potent inhibitor. The requisite 1,2,4-thiadiazole moiety 309 is assembled by treating amidine 308 with perchloromethyl mercaptan . The 1,2,4-thiadiazole moiety has been incorporated in 13-1actam antibacterials to modulate pharmacokinetic properties. The 1,2,4thiadiazolo cephem 313 displays the best balance of serum stability and in vitro activity. The 1,2,4-thiadiazole intermediate 312 is synthesized from 3-aminoisoxazole 311 by a sequence of reactions . In addition, 2,3-diaryl-5-anilino[1,2,4]thiadiazoles are found to
258
M.G. Saulnier, U. Velaparthi and K. Zimmermann
be potent and selective melanocortin-4-receptor (MC4) agonists for potential use for nerve regeneration and drug addiction .
NH cc,3sc,.NaO MeO .,
H2N"J~OMe
CH2Cl2,H20-
308
O
Me . N
CI
309
N-OTr
I=
311
5.5.4.3
OH
310
a) KSCN, MeOCOCI
b) MeOH, 60~ NH2 c) CH3CO3H d) MeOH, SOCI2
,oro
N
L~N- ~ O MeO" " O
OMe
H2N-"~/Ns._N
312
O 313
% + S R O
O/~__OH
1,2,5-Thiadiazoles
Alkyl and aryl N-substituted 1,2,5-thiadiazolidine-1,1-dioxides 316 are synthesized in good yield from the reaction of sulfuryl chloride with 2-chloroethylamine. 2-Chloroethylamine hydrochloride is heated at 80~ with sulfuryl chloride in acetonitrile, and corresponding mono(chloroalkyl)sulfamyl chloride 314 is then extracted with diethyl ether to separate from unreacted amine hydrochloride. This ether solution is added to a solution of primary amine, and the resultant N-aryl (chloroalkyl)sulfamide 315 is treated with potassium carbonate in DMSO to afford N-substituted 1,2,5-thiadiazolidine- 1,1-dioxides 316 . o
CI~/~
NH2
SO2012= CH3CN 75-80~
.
~Cl Ns. H / ci 314
Et3N -7~176
=
,S..N" H
R,Nrj
K2CO3 O~ ,,/O = R.. N.S~N.. H
DMso
cI 315
316
Caram et al. report that 3,4-diphenyl-l,2,5-thiadiazole-l,l-dioxide 317 serves as a Michael acceptor and addition of amides, ureas and aromatic amines to the carbon-nitrogen double bond proceeds in aprotic solvents such as DMF. For example, 3a,6a-diphenyl-tetrahydro-lHimidazo[4,5-c][1,2,5]-thiadiazol-5-one-2,2-dioxide 318 is readily formed upon treatment of urea with 317 in DMF at room temperature . Interestingly, compound 319, which is prepared from corresponding Ar-N=S=O on treatment with Li(SiMe3)2, undergoes smooth SNAr type intra-molecular ring closure to furnish 4,5-difluoro-2,1,3-benzothiadiazole 320 .
259
Five-Membered Ring Systems: With N and S (Se) Atoms
Ph H2NNH2 HNHN NHNH O
Ph N.s..N O" "O .,.
O
DMF,RT
~..
" Ph > ( Ph
317
CsF
F
(~/S\xO
" -ae3SiF N=S=NSiMe3
318
319
S 320
In the study of novel fluoroionophores as receptors for transition metal cations, 1,2,5thiadiazole-l,l-dioxide 322 is used as an intermediate to produce the 4,5-dicyano analog 323. Upon treatment of compound 321 wth sulfamide and HC1 in anhydrous ethanol, 1,2,5thiadiazole-l,l-dioxide 322 is obtained. Vacuum pyrolysis of compound 322 yields 1-nitro4,5-dicyanonaphthalene 323 .
N'S"N Sulfamide= HCl, EtOH 321
NO2
CN CN I I
vacuum ~ 220~ 322
NO 2
NO2
323
1,2,5-Thiadiazoles have also been used in pharmaceuticals, especially as M1 (muscarinic) selective agonists for the treatment of Alzheimer's disease. The synthesis of a series of alkylsulfanyl bioisosteric congeners of xanomeline is described by Jung et al. . The cyanohydrin 324 is converted to aminonitrile 325, which upon treatment with sulfur monochloride in DMF furnishes 1,2,5-thiadiazole 326. The 1,2,5-thiadiazole 326 is further transformed into compounds such as 327 as bioisosters of xanomeline . Merschaert et al. have reported palladium-catalyzed cross coupling reactions of commercially available 3,4-dichloro-1,2,5-thiadiazole under Stille and Suzuki conditions .
HO.. ..CN N~/N 324
5.5.4.4
NH4CI NH4OH
H2~~i]CN N~/N 325
S2CI2 DMF
~\
S CI
N~/N 326
- ~SN - N
SR
HN.~ N~ 327
iS-N . O(CH2)5CH3 ~
N~
Xanomeline
1,3,4-Thiadiazoles
The reaction of substituted thiosemicarbazides 328 with aldehydes yields the corresponding thiosemicarbazones 329, which upon oxidative cyclization with iron(III) chloride furnish substituted 1,3,4-thiadiazoles 330 in good yields . A solid phase synthesis is also developed to produce several 1,3,4-thiadiazoles . In addition, a solid phase synthesis of 2-alkylthio-l,3,4-thiadiazoles is also devised. Accordingly, treatment of di-(2-pyridyl)thionocarbonate with thiosemicarbazide 331 affords the immobilised 1,3,4thiadiazole-2-thione 332, which was selectively mono-S-alkylated to yield resin-bound 2alkylthio-l,3,4-thiadiazoles 333. Acidic cleavage of the resin with TFA yielded 2-alkylthio1,3,4-thiadiazoles in good yields 334 .
260
M.G. Saulnier, U. Velaparthi and K. Zimmermann
S
RL N ~J~N ~NH2 H
328
H
H
H
R2CHO
R~
-H20
S
S
N H
~J~ 329
N" H
DPT, DOM=
N" ~ N" NH2
N~/R 2
H R1.N%S/~ R2 N-N
FeCi3 EtOH
330
ONH S O/~HN._._~S.. ~
R2X Dioxane
N..-NH
O
332
331
H
IP
N-N
TFA, DCM
33:3
H2N",,.,,-f~ J/N-N\L
R2
334
A new cyclizing reagent is used for the synthesis of 5-unsubstituted 1,3,4-thiadiazoles 336 in an efficient manner. The reaction of oxamic thiohydrazide 335 with Vilsmeier reagent (POC13/DMF) produced 5-unsubstituted carbamoyl-l,3,4-thiadiazole 336 in rather low yield. However, yields are significantly improved by using diethyl chlorophosphate in DMF as a one carbon source effecting cyclization to afford 5-unsubstituted 1,3,4-thiadiazoles 336 . Reaction of phenyl isothiocyanate with various hydrazides gives thiosemicarbazides 337, which further react with phosphorus oxychloride to provide 1,3,4thiadiazoles 338 . The 1,3,4-thiadiazolidine-2-thiones 339 are readily obtained on exposure of tributylphosphine and carbon disulfide adduct to dialkyl azodicarboxylates and aromatic aldehydes .
O S CI--P-OEt ~R ,,i __ R/JL NHNH2 OEt S N DMF ,~1~1 335
NHPh / N HNH2 PhNCS S - ~ NH O::~ i " O.~NH R
H 336
Bu3P+
CS 2
POOl3 =
R 337
S Bu3§
PhHN
-
N SN/~N R 338
RO2C_N=N-CO2 R RO2C. ~CO2R = N-N ArCHO Ar-~s/~S 339
A novel series of 2-substituted-l,3,4-thiadiazoles 342 were synthesized and evaluated against NCI cancer cell-lines. The 1-(4-chlorophenyl)-4-hydroxy-lH-pyrazole-3-carboxylic acid hydrazide 340 is treated with various isothiocyanates, and the resultant semicarbazides 341 are exposed to cold sulphuric acid to afford 1,3,4-thiadiazoles 342 . Chauviere et al. report the synthesis and biological activity of analogs of Megazol (344) as anti-infective agents against protozoal parasites. The synthesis of Megazol involves oxidative cyclization of thiosemicarbazone 345 with ferric sulfate, and Megazol is also obtained by condensation of carbonitrile 343 with thiosemicarbazide in TFA .
261
Five-Membered Ring Systems: With N and S (Se) Atoms
O\ NH2 HO~/_~HN" N"
0
H 346
~8 O2N
H
O'~
347
1NH, S ,.•
N"
NH2
349
R-
O"~
348
N..N~__NH2 Fe(NH4)(SO4)2=~ S ~'s H20 350
O
CO2H
I~-N,~-SCH2CO R
J J
O2N
__
O2N
351
262
M.G. Saulnier, U. Velaparthi and K. Zimmermann
SELENAZOLES AND SELENADIAZOLES
5.5.5
A number of selenium heterocycles are prepared utilizing carbon-selenium double bonds as 2n dienophilic intermediates for [4+2] cycloadditions. However, Koketsu et al. reported a novel hetero Diels-Alder reaction wherein selenoazadienes 353 serve as 4n components. Accordingly, compound 353 reacts with dimethyl acetylenedicarboxylate to yield 4selenazolone 354. The proposed mechanism involves the formation of hetero Diels-Alder adduct 355, which is converted into 4-selenazolone 354 following purification on silica gel. Protonation of cycloadduct 355 presumably affords the selenoamidine 356, which is converted into 357 by nucleophilic recyclization . R2N
Se Me2NCH(OMe)2 Se H MeO2C ~ R2N.,~ NH2 " R2N.~ N~'~ NMe2 rt 352
CO2Me "
353
N.~ 4-II = )N"~CO2Me NMe2 CO2Me H+ ~-" ( i~lMe2
3s3
355
354
~Se N~__.~CO2Me 0 CHO
=_ -MeOH N ] HI ~ C O 2 M e l O
/
3s. J
I,~N+/
35 1
Reaction of 1,4-dicyanobenzene 358 with potassium selenocarboxylate 359 affords the corresponding cyanoselenoamides 360 and diselenoamides 361. The obtained cyanoselenoamides (e.g. 360) are reacted with potassium selenocarboxylate 359 again to afford the corresponding diselenoamides 361 in higher yields. When cyanoselenoamide 360 is reacted with chloroacetyl chloride, malonyl chloride, and phenacyl bromide 362, the corresponding selenazol-4-one, selenazin-4-one and selenazole 363 are respectively formed . In a separate publication, Geisler et al. report that 2-benzoyl-l,3-selenazoles 366 are obtained by cyclization of 2-bromoketones 362 with selenophenylacetic amide 364 that can be fragmented to fumish 2-unsubstituted 1,3-selenazoles 367 . These same authors also report the synthesis of 4-chloromethyl-l,3-selenazole 371, which is subjected to nucleophilic displacement reactions to obtain double-functionalized, ionic and multivalent 1,3-selenazoles . The cyclization of cx,ct'-dichloroacetone 369 with phenylselenourea 368 affords semi-aminal 370, which upon treatment with acetic anhydride fumish the 1,3-selenazole 371 . Selenium compounds are also used in the class of porphyrazines, and for instance selenadiazole in the presence of 9,10-phenanthrenequinone or 2,3-butanedione results in the formation of pyrazines .
263
Five-Membered Ring Systems." With N and S (Se) Atoms
NC 358
Se
4"
H2
360
364
NC
359
NC
p
BF3Et20,0~
CN 4- R . ~ S e K
362, EtOH
H2
reflux
Se
p
365
H2 360(36%)
H2N
x~/ NH2 361(24%)
Ph
362
363
SeO2 Ph
Se
O
dioxane p
acetone C,~seN~ reflux
369
370
NaOH S/.e~ Ph
366
OH
H2N"~NHPh-I-CI~CI
S e n S e
Br
,~.(Sel-]
O
368
O
••e
+
EtOH
~NJL'- Ph 367
Ac20. C,'~N/~_..N(Ac)Ph Se
NHPh
371
There are few reports on the synthesis of 1,2,3-selenadiazoles from the corresponding semicarbazones during 2003 . For example, Attanasi et al. report the synthesis of 1,2,3-selenadiazole 374 by treatment of hydrazone 373 with selenium dioxide in acetic acid. However, under mild conditions (selenium oxychloride in dichloromethane), the aromatization process does not occur, and only the 2,3-dihydro compound 372 is observed . Sterically congested 1,3,4-selendiazolines 376 are obtained upon treatment of tetramethylindanone hydrazone 375 with diseleniumdibromide .
MeO2C
.CO2Me
~SS 372
MeO2C
4H...~ .,SeOC'2 OtBu CH2CI2
//~_
0
CO2Me NN__~O O 373
,NH2 375
Et3N
MeO2C, SeO2" AcOH
~u
CO2Me
/~/.N
374
~e
S 376
5.5.6
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03AG(E)83 03AG(E)1255 03AG(E)2889
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M.G. Saulnier, U. Velaparthi and K. Zimmermann
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Five-Membered Ring Systems: With N and S (Se) Atoms
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03JOC1947 03JOC2609 03JOC2861 03JOC2929 03JOC4215 03JOC4406 03JOC4791 03JOC4855 03JOC4912 03JOC6338 03JOC6424 03JOC6745 03JOC6775 03JOC7407 03JOC7887 03JOC8693 03JOC9116 03JOC9506 03JPO220 03NNN1281 03NNN2039 03NNN2061 03OBC381 03OBC1342 03OBC2900 03OL15 03OL197 03OL455 03OL507 03OL543 03OL801 03OL803 03OL1281 03OL2785 03OL2809
M.G. Saulnier, U. Velaparthi and K. Zimmermann
J.J. Parlow, T.A. Dice, R.M. Lachance, T.J. Girard, A.M. Stevens, R.A. Stegeman, W.C. Stallings, R.G. Kurumbail, M.S. South, J. Med. Chem. 2003, 46, 4043. J.J. Parlow, B.L. Case, T.A. Dice, R.L. Fenton, M.J. Hayes, D.E. Jones, W.L. Neumann, R.S. Wood, R.M. Lachance, T.J. Girard, N.S. Nicholson, M. Clare, R.A. Stegeman, A.M. Stevens, W.C. Stallings, R.G. Kurumbail, M.S. South, J. )Wed. Chem. 2003, 46, 4050. L.J. Perez, D.J. Faulkner, J. Nat. Prod. 2003, 66, 247. A. Rudi, L. Chill, M. Aknin, Y. Kashman, J. Nat. Prod. 2003, 66, 575. P.G. Williams, H. Luesch, W.Y. Yoshida, R.E. Moore, V.J. Paul, J. Nat. Prod. 2003, 66, 595. Y. Sera, K. Adachi, K. Fujii, Y. Shizuri, J. Nat. Prod. 2003, 66, 719. M. Inagaki, S. Matsumoto, T. Tsuri, J. Org. Chem. 2003, 68, 1128. A.S. Karpov, F. Rominger, T.J.J. Muller, J. Org. Chem. 2003, 68, 1503. W. Wang, F. Nan, J. Org. Chem. 2003, 68, 1636. A.P. Kozikowski, W. Tuckmantel, G. Bottcher, L.J. Romanczyk, Jr., J. Org. Chem. 2003, 68, 1641. S.M. Baum, A.Trabanco, A.G. Montalban, A.S. Micallef, C. Zhong, H.G. Meunier, K. Suhling, D. Phillips, A.J.P. White, D.J. Williams, A.G.M. Barret, B.M. Hoffman, J. Org. Chem. 2003, 68, 1665. Q. A. Attanasi, L.D. Crescentini, G. Favi, P. Filippone, G. Giorgi, F. Mantellinini, S. Santeusanio, J. Org. Chem. 2003, 68, 1947. A. Padwa, K.R. Crawford, P. Rashatasakhon, M. Rose, J. Org. Chem. 2003, 68, 2609. M.W. Hooper, M. Utsunomiya, J.F. Hartwig, J. Org. Chem. 2003, 68, 2861. V. Calo, A. Nacci, A. Monopoli, S. Laera, N. Cioffi, J. Org. Chem. 2003, 68, 2929. J.A. Lafontaine, D.P. Provencal, C. Gardelli, J.W. Leahy, J. Org. Chem. 2003, 68, 4215. V. Calo, F. Scordari, A. Nacci, E. Schingaro, L. D'Accolti, A. Monopoli, J. Org. Chem. 2003, 68, 4406. F. Saczeswki, J. Saczewski, M. Gdaniec, J. Org. Chem. 2003, 68, 4791. J.W. Pavlik, C. Changton, V.M. Tsefrikas, J. Org. Chem. 2003, 68, 4855. C. Landreau, D. Deniaud, J.C. Meslin, J. Org. Chem. 2003, 68, 4912. M. Avalos, R. Babiano, P. Cintas, F.R. Clemente, R. Gordillo, J.L. Jimenez, J.C. Palacios, J. Org. Chem. 2003, 68, 6338. M. Ueno, T. Nabana, H. Togo, J. Org. Chem. 2003, 68, 6424. H. Miyabe, Y. Yamaoka, T. Naito, Y. Takemoto, J. Org. Chem. 2003, 68, 6745. W.P. Gallagher, R.E. Maleczka, Jr., J. Org. Chem. 2003, 68, 6775. K. Ono, A. Yoshida, N. Saito, T. Fujishima, S. Honzawa, Y. Suhara, S. Kishimoto, T. Sugiura, K. Waku, H. Takayama, A. Kittaka, J. Org. Chem. 2003, 68, 7407. M. Ochiai, Y. Nishi, S. Hashimoto, Y. Tsuchimoto, Y.; D.-W. Chen, J. Org. Chem. 2003, 68, 7887. A.D. Jordan, C. Luo, A.B. Reitz, J. Org. Chem. 2003, 68, 8693. Z.-L. Wei, A.P. Kozikowski, J. Org. Chem. 2003, 68, 9116. S.-L You, J.W. Kelly, J. Org. Chem. 2003, 68, 9506. J.A. Caram, S.L. Aimone, M.V. Mirifico, E.J. Vasini J. Phys. Org. Chem. 2003, 16, 220. F. Lecubin, M. Devys, J.L. Fourrey, J.-S. Sun, R. Benhida, Nucleotides, Nucleosides and Nucleic Acids 2003, 22, 1281. C.W. Liang, M.J. Kim, L.S. Jeong, M.W. Chun, Nucleotides, Nucleosides and Nucleic Acids 2003, 22, 2039. A.I. Khodair, N.A. AI-Masoudi, J.-P. Gesson, Nucleotides, Nucleosides and Nucleic Acids 2003, 22, 2061. H. Miyabe, K. Fujii, T. Naito, Org. Biomol. Chem. 2003, 1, 381. Y. Misu, H. Togo, Org. Biomol. Chem. 2003, 1, 1342. I.C. Christoforou, P.A. Koutentis, C.W. Rees, Org. Biomol. Chem. 2003, 1, 2900. A.M. Harned, S. Mukherjee, D.L. Flynn, P.R. Hanson, Org. Lett. 2003, 5, 15. B.K. Albrecht, R.M. Williams, Org. Lett. 2003, 5, 197. A.V. Demchenko, N.N. Malysheva, C. De Meo, Org. Lett. 2003, 5, 455. Y.-G. Chang, H.S. Cho, K. Kim, Org. Lett. 2003, 5, 507. V. Nair, A. Augustine, Org. Lett. 2003, 5, 543. M. Egi, L.S. Liebeskind, Org. Lett. 2003, 5, 801. F.-A. Alphonse, F. Suzenet, A. Keromnes, B. Lebret, G. Guillaumet, Org. Lett. 2003, 5, 803. J. Chen, C.J. Forsyth, Org. Lett. 2003, 5, 1281. A.G.J. Commeureuc, J.A. Murphy, M.L. Dewis, Org. Lett. 2003, 5, 2785. A. Cosp, I. Larrosa, J.M. Anglada, J.M. Bofill, P. Romea, F. Urpi, Org. Lett. 2003, 5, 2809.
Five-Membered Ring Systems: With N and S (Se) Atoms
03OL2911 03OL3313 03OL3607 03OL3835 03OL4163 03OL4175 03OL4421 03OL4851 03OL5039 03OPP401 03 PNA6712 04S17 03S195 03S371 03S728 03S1079 03Sl112 03Sl191 03S1215 03S1361 03S1503 03S2265 03S2395 03S2559 03S2632 03S2851 03SC535 03SC563 03SCl109 03SC1433 03SC1943 03SC2053 03SC3551 03SC4339 03SL166 03SL227 03SL522 03SLl109 03SLl175 03SLl195 03SL1500 03SL1731 03SL1898 03SL1967 03SL2033 03SL2167 03SL2351 03SL2410 03SUL17
03SUL35 03SUL67
269
K.J. Hodgetts, M.T. Kershaw, Org. Lett. 2003, 5, 2911. K.I. Booker-Milburn, D.J. Guly, B. Cox, P.A. Procopiou, Org. Lett. 2003, 5, 3313. B. Sezen, D. Sames, Org. Lett. 2003, 5, 3607. M. Ueda, H. Miyabe, A. Nishimura, O. Miyata, Y. Takemoto, T. Naito, Org. Lett. 2003, 5, 3835. P.L. DeRoy, A.B. Charette, Org. Lett. 2003, 5, 4163. J. Lee, Y.-L. Zhong, R.A. Reamer, D. Askin, Org. Lett. 2003, 5, 4175. M.C. Bagley, J.W. Dale, X. Xiong, J. Bower, Org. Lett. 2003, 5, 4421. S. Surprenant, W.Y. Chan, C. Berthelette, Org. Lett. 2003, 5, 4851. C. Chen, R.A. Reamer, J.R. Chilenski, C.J. McWilliams, Org. Lett. 2003, 5, 5039. A. Dandia, R. Singh, K. Arya, Org. Prep. Proced. Int. 2003, 35, 401. J.S. Welch, M. Ricote, T.E. Akiyama, F.J. Gonzalez, C.K. Glass, Proc. Natl. Acad. Sci. USA 2003, 100, 6712. V.N. Yarovenko, A.V. Shirokov, I.V. Zavarzin, O.N. Krupinova, A.V. Ignatenko, Synthesis 2004, 17. Y. Liu, X. Chen, M. Xue, R. Cao, L. Liu, Synthesis 2003, 195. O.A. Fedorova, E.N. Andryukhina, S.P. Gromov, Synthesis 2003, 371. S. Cacchi, G. Fabrizi, D. Lamba, F. Marinelli, L.M. Parisi, Synthesis 2003, 728. L.D.S. Yadav, R. Kapur, Synthesis 2003, 1079. A. Heynderickx, R. Guglielmetti, R. Dubest, J. Aubard, A. Samat, Synthesis 2003, 1112. N.E. Shevchenko, V.G. Nenajdenko, E.S. Balenkova, Synthesis 2003, 1191. K. Geisler, W.-D. Pfeiffer, C. Muller, E. Nobst, E. Bulka,, P. Langer, Synthesis 2003, 1215. G. Kulcsar, T. Kalai, J. JekO, K. Hideg, Synthesis 2003, 1361. K. Wojciechowski, H. Modrzejewska, Synthesis 2003, 1503. K. Taubert, A. Siegemund, A. Eilfeld, S. Baumann, J. Sieler, B. Schulze, Synthesis 2003, 2265. L.D.S. Yadav, A. Singh, Synthesis 2003, 2395. B. Zaleska, B. Trzewik, J. Grochowki, P. Serda, Synthesis 2003, 2559. A.V. Tverdokhlebov, E.V. Resnyanska, A.A. Tolmachev, A.P. Andrushko, Synthesis 2003, 2632. A.V. Golovchenko, S.G. Pilyo, V.S. Brovarets, A.N. Chernega, B.S. Drach, Synthesis 2003, 2851. G.H. Elgemeie, S.H. Sayed, Synth. Commun. 2003, 33, 535. S.C. Jain, J. Sinha, S. Bhagat, W. Errington, C.F. Olsen, Synth. Commun. 2003, 33, 563. R. Xuan, W. Hu, Z. Yang, Synth. Commun. 2003, 33, 1109. T. Kalai, J. Jeko, E. Osz, K. Hideg, Synth. Commun. 2003, 33, 1433. T.C. Harrop, K. Rodriguez, P.K. Mascharak, Synth. Commun. 2003, 33, 1943. K. Pan, A.B. Reitz, Synth. Commun. 2003, 33, 2053. X. Xu, Y. Zhang, Synth. Commun. 2003, 33, 3551. S. Hamilakis, A. Tsolomitis, Synth. Commun. 2003, 33, 4339. J.H. Choi, E.B. Choi, C.S. Pak, Synlett 2003, 166. J. Hartung, T. Gottwald, K. Spehar, Synlett 2003, 227. F.F. Paintner, K. GOrier, W. Voelter, Synlett 2003, 522. A. Cosp, I. Larrosa, I. Vilasis, P. Romea, F. Urpi, J. Vilarrasa, Synlett 2003, 1109. A. Yoshida, K. Ono, Y. Suhara, N. Saito, H. Takayama, A. Kittaka, Synlett 2003, 1175. K. Geisler, A. Kunzler, H. Below, E. Bulka, W.D. Pfeiffer, P. Langer, Synlett 2003, 1195. T. Deba, F. Yakushiji, M. Shindo, K. Shishido, Synlett 2003, 1500. A.N. Kurchan, E. Wade, A.G. Kutateladze, Synlett 2003, 1731. N.E. Maguire, A.B. McLaren, J.B. Sweeney, Synlett 2003, 1898. C.K. Jin, J.-K. Moon, W.S. Lee, K.S. Nam, Synlett 2003, 1967. D. Quintard, P. Bertrand, S. Vielle, E. Raimbaud, P. Renard, B. Pfeiffer, J.-P. Gesson, Synlett 2003, 2033. G. Morel, Synlett 2003, 2167. C.K.Z. Andrade, R.O. Rocha, O.E. Vercillo, W.A. Silva, R.A.F. Matos, Synlett 2003, 2351. B. Henkel, B. Westner, A. Domling, Synlett 2003, 2410. V.L.M. Guarda, M.A. Pereira, C.A. De Simone, J.F.C. Albuquerque, S.L. Galdino, J. Chantegrel, M. Perrissin, C. Beney, F. Thomasson, I.R. Pitta, C. Luu-Duc, Sulfur Lett. 2003, 26, 17. A.M. Salah El-Din, Sulfur Lett. 2003, 26, 35. Y. Njoya, A. Gellis, M.P. Crozet, P. Vanelle, Sulfur Lett. 2003, 26, 67.
270
03SUL127 03T851 03T1317 03T1381 03T1571 03T2679 03T2701 03T2713 03T4851 03T5411 03T5475 03T5685 03T6363 03T6579 03T6637 03T6979 03T7141 03T7445 03T7521 03T7803 03T9399 03T9979 03T10187 03T10231 03TA239 03TA717 03TA2857 03TA3827 03TL13 03TL391 03TL1379 03TL1559 03TL2087 03TL2117 03TL2199 03TL3679 03TL3745 03TL3915 03TL4369 03TL4393 03TL5355 03TL5483 03TL5917 03TL6073
M.G. Saulnier, U. Velaparthi and K. Zimmermann
S.I. E1-Desoky, S.B. Bondock, H.A. Etman, A.A. Fadda, M.A. Metwally, Sulfur Lett. 2003, 26, 127. Z. Reidl, G. Hajos, W.J. Pelaez, I.T. Gafarova, E.L. Moyano, G.I. Yranzo, Tetrahedron 2003, 59, 851. N. Ikemoto, J. Liu, K.M.J. Brands, J.M. McNamara, P.J. Reider, Tetrahedron 2003, 59, 1317. F. Bona, L. De Vitis, S. Florio, L. Ronzini, L. Troisi, Tetrahedron 2003, 59, 1381. C. Koradin, W. Dohle, A.L. Rodriguez, B. Schmid, P. Knochel, Tetrahedron 2003, 59, 1571. K. Kato, T. Sasaki, H. Takayama, H. Akita, Tetrahedron 2003, 59, 2679. B. McKeever, G. Pattenden, Tetrahedron 2003, 59, 2701. B. McKeever, G. Pattenden, Tetrahedron 2003, 59, 2713. X. Huang, J. Tang, Tetrahedron 2003, 59, 4851. L.D.S. Yadav, S. Dubey, B.S. Yadav, Tetrahedron 2003, 59, 5411. A. Khrimian, A.K. Margaryan, W.F. Schmidt, Tetrahedron 2003, 59, 5475. A. Yokooji, T. Okazawa, T. Satoh, M. Miura, M. Nomura, Tetrahedron 2003, 59, 5685. L.F. Frey, K.M. Marcantonio, C. Chen, D.J. Wallace, J.A. Murry, L. Tan, W. Chen, U.H. Dolling, E.J.J. Grabowski, Tetrahedron 2003, 59, 6363. H. Sugiyama, F. Yokokawa, T. Shioiri, Tetrahedron 2003, 59, 6579. S. Jayaprakash, G. Pattenden, M.S. Viljoen, C. Wilson, Tetrahedron 2003, 59, 6637. A. Bertram, A.J. Blake, F.G.-L. de Turiso, J.S. Hannam, K.A. Jolliffe, G. Pattenden, M. Skae, Tetrahedron 2003, 59, 6979. V.J. Ram, P. Srivastava, A. Goel, Tetrahedron 2003, 59, 7141. A.-S.S.H. Elgazwy, Tetrahedron 2003, 59, 7445. E.A. Mamaeva, A.A. Bakibaev, Tetrahedron 2003, 59, 7521. R. Markovic, M. Baranac, Z. Dzambaski, M. Stojanovic, P.J. Steel, Tetrahedron 2003, 59, 7803. F. Clerici, A. Contini, M.L. Gelmi, D. Pocar, Tetrahedron 2003, 59, 9399. T. Ganesh, J.K. Schilling, R.K. Palakodety, R. Ravindra, N. Shanker, S. Bane, D.G.I. Kingston, Tetrahedron 2003, 59, 9979. E. Meyer, A.C. Joussef, H. Gallardo, A.J. Bortoluzzi, R.L. Longo, Tetrahedron 2003, 59, 10187. K.L. Erickson, K.R. Gustafson, D.J. Milanowski, L.K. Pannell, J.R. Klose, M.R. Boyd, Tetrahedron 2003, 59, 10231. M. Kosior, M. Malinowska, J. Jozwik, J.-C. Caille, J. Jurczak, Tetrahedron Asymmetry 2003, 14, 239. M.I. Colombo, J. Zinczuk, M.L. Bohn, E.A. Ruveda, Tetrahedron Asymmetry 2003, 14, 717. M. Ueda, H. Miyabe, A. Nishimura, H. Sugino, T. Naito, Tetrahedron Asymmetry 2003, 14, 2857. S. Orlandi, M. Caporale, M. Benaglia, R. Annunziata, Tetrahedron Asymmetry 2003, 14, 3827. A. Dondoni, A. Marra, Tetrahedron Lett. 2003, 44, 13. D.M. Volochnyuk, A.N. Kostyuk, A.M. Pinchuk, A.A. Tolmachev, Tetrahedron Lett. 2003, 44, 391. Y. Chen, H.V.R. Dias, C.J. Lovely, Tetrahedron Lett. 2003, 44, 1379. T.R. Sharp, K.R. Leeman, D.E. Bryant, G.J. Horan, Tetrahedron Lett. 2003, 44, 1559. Y. Xiao, X. Qian, Tetrahedron Lett. 2003, 44, 2087. T.R. Sharp, J.F. Lambert, S.W. Walinsky, Tetrahedron Lett. 2003, 44, 2117. J.-M. Navarre, D. Guianvarc'h, A. Farese-Di Giorgio, R. Condom, R. Benhida, Tetrahedron Lett. 2003, 44, 2199. B. Henkel, M. Sax, A. Domling, Tetrahedron Lett. 2003, 44, 3679. P.V. Ramachandran, B. Prabhudas, D. Pratihar, J.S. Chandra, M.V.R. Reddy, Tetrahedron Lett. 2003, 44, 3745. A. Armstrong, N.G.M. Davies, N.G. Martin, A.P. Rutherford, Tetrahedron Lett. 2003, 44, 3915. S.M. Ireland, H. Tye, M. Whittaker, Tetrahedron Lett. 2003, 44, 4369. R. Wischnat, J. Rudolph, R. Hanke, R. Kaese, A. May, H. Theis, U. Zuther, Tetrahedron Lett. 2003, 44, 4393. K.S.K. Murthy, A.W. Rey, M. Tjepkema, Tetrahedron Lett. 2003, 44, 5355. P.D. Johnson, S.A.Jewell, D.A. Romero, Tetrahedron Lett. 2003, 44, 5483. J.-L. Liang, S.-X. Yuan, P.W.H. Chan, C.-M. Che, Tetrahedron Lett. 2003, 44, 5917. C. Benedi, F. Bravo, P. Uriz, E. Fernandez, C. Claver, S. Castillon, Tetrahedron Lett. 2003, 44, 6073.
Five-Membered Ring Systems: With N and S (Se) Atoms
03TL6635 03TL6789 03TL7087 03TL7445 03TL7825 03TL8127 03TL8153 03TL8535 03TL8563 03TL8905 03TL8947 03TL8951 03TL9219
271
S. Tumkevicius, L.Labanausks, V. Bucinskaite, A. Brukstus, G. Urbelis, Tetrahedron Lett. 2003, 44, 6635. S.T.A. Shah, K.M. Khan, M. Fecker, W. Voelter, Tetrahedron Lett. 2003, 44, 6789. R. Markovic, M. Baranac, S. Jovetic, Tetrahedron Lett. 2003, 44, 7087. X. Gai, R. Grigg, I. Koppen, J. Marchbank, V. Sridharan, Tetrahedron Lett. 2003, 44, 7445. J.P. Kilbum, J. Lau, R.C.F. Jones, Tetrahedron Lett. 2003, 44, 7825. D. Chevrie, T. Lequeux, J.P. Demoute, S. Pazenok, Tetrahedron Lett. 2003, 44, 8127. J.E. Clare, C.L. Willis, J. Yuen, K.W.M. Lawrie, J.P.H. Charmant, A. Kantacha, Tetrahedron Lett. 2003, 44, 8153. V.J. Majo, J. Prabhakaran, J.J. Mann, J.S.D. Kumar, Tetrahedron Lett. 2003, 44, 8535. J.L. Gross, Tetrahedron Lett. 2003, 44, 8563. M. Seki, M. Kimura, M. Hatsuda, S. Yoshida, T. Shimizu, Tetrahedron Lett. 2003, 44, 8905. B. Henkel, B. Beck, B. Westner, B. Mejat, A. Doemling, Tetrahedron Lett. 2003, 44, 8947. L.D.S. Yadav, R. Kapoor, Tetrahedron Lett. 2003, 44, 8951. T. Takahashi, H. Watanabe, T. Kitahara, Tetrahedron Lett. 2003, 44, 9219.
272
Chapter 5.6 Five-Membered Ring Systems: With O & S (Se, Te) Atoms
R. Alan Aitken
University of St. Andrews, UK (e-mail: raa@st-and, ac. uk)
5.6.1
1,3-DIOXOLES AND DIOXOLANES
A comprehensive review chapter on 1,3-dioxolium salts has appeared . New catalysts for the reaction of carbonyl compounds with ethanediol to give 2,2disubstituted dioxolanes include sulfuric acid-derivatised polyaniline , trimethylsilyl triflate in the presence of a trimethylsilyl ether and K]0 montmorillonite under solvent-free conditions . A one-pot oxidation-Wittig reaction approach has been used to convert primary alcohols, RCH2OH into products 1 involving reaction with MnO2, the phosphonium salt 2 and the tricyclic guanidine base 3 . Compound 3 is also an effective catalyst for reaction of epoxides with CO2 to give 1,3-dioxolan-2-ones and other new catalysts investigated for this process include 8-hydroxyquinolinates of trivalent metals in the presence of Ph3PO , (Ph3P)2NiC12/Ph3P/Zn/Bu4NBr and a range of magnesium-containing heterogeneous catalysts . The process may also be carried out with supercritical CO2 in an ionic liquid .
0
+ 0
1 R3
O
~
5
2 R1
MeO"%--O~ CO2Me
rll
R2 O_.~al
Ph'~ O 0 9
R1 R ~ . , j O - ~ R2
6
Me Me O'~O
~_. 10
0
OH
[~,,.CO2Et
01~0~/ 11
R2
Me 3
4
O
R3Si'~OCH2Ph N2
'1
O~o PhCH 2
R1
273
Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms
Treatment of tx-hydroxyketones, R1CH(OH)COR 2 with triphosgene, (C13CO)2CO, gives the 1,3-dioxol-2-ones 4 in moderate yield and palladium-catalysed reaction of propargylic acetates 5 with CO in methanol results in cyclisation to give the dioxolanes 6 . Rhodium-catalysed reaction of the diazo esters 7 with carbonyl compounds, R1COR2, provides a new route to silyl dioxolanones 8 in a process involving an intermediate carbonyl ylide . Reaction of mandelic acid with aldehydes and ketones to give 1,3-dioxolan-4-ones 9 is efficiently achieved by microwave irradiation with anhydrous CuSO4 under solvent-free conditions . An improved synthesis of the key synthetic intermediate 10 from D-mannose in 23% overall yield has been described and baker's yeast reduction of the corresponding ketone gives the chiral building block 11 . An enantioselective synthesis of the dioxolane-containing bicyclic amino acids 12 from erythrose has been reported and an asymmetric total synthesis of the marine natural product attenol B 13 has appeared . The synthesis and unexpected stability of a range of 2-pyridyl-l,3-dioxolanes have been reported .
0
R2N\ O%/~'"CO2H 12
Me
Ph 0.../R ph/~O]
Me 15 Me
16
Li 14 ~OH
~
Ph Ph R 17
The reactivity of lithiated benzodioxole 14 with a variety of electrophiles has been examined in detail . Transformations of compounds 15 with the 6,8dioxabicyclo[3.2.1]octane skeleton have been reviewed . Cleavage of 2,2disubstituted 1,3-dioxolanes to give carbonyl compounds can be achieved using T-picolinium chlorochromate and a study of ceric ammonium nitrate in the same process reveals that it is required only in a catalytic amount and acts as a Lewis acid rather than an oxidising agent . Rhodium-catalysed reductive cleavage of 2-substituted 1,3dioxolanes with PhSiH3 gives 2-hydroxyethyl ethers while aerobic oxidation of the same starting materials catalysed by Co(OAc)2 and N-hydroxyphthalimide gives 2hydroxyethyl esters . A novel thermal isomerisation process occurs upon flowpyrolysis of 2-alkylidene-l,3-dioxolanes such as 16 to give the butyrolactone products 17 . Reaction of chiral 1,3-dioxolan-4-ones with base and either nitroaryl fluorides or acylsilanes followed by deprotection has been used in asymmetric synthesis, and compound 18 is an effective chiral catalyst for the asymmetric epoxidation of alkenes with Oxone | . Samarium iodide-promoted conjugate addition of the chiral dioxolane nitrone 19 has been used in a formal asymmetric synthesis of (S)-vigabatrin . Conjugate addition of organozinc compounds to chiral dioxolanones and dioxolanes such as 20 and 21 has been examined , as has the hetero Diels-Alder reaction of methylenedioxolanes 22 to give products such as 23
274
R.A. Aitken
. Inclusion complexes with TADDOLs such as 24 have been used to direct enantioselective Diels-Alder reactions in aqueous solution . Chiral cyclopentadienes such as 25 have been introduced for use as transition metal ligands .
Me .0.,
M~.'
:o
Me
0
~O
Bu t
Me
N+-CH2Ph t
18
0
20
Me
O'~Ar R ~ "~O O Ar Me~O~ "~ ---~O"J'"Ar AoNH"'I"~O-_~ Me O"~ ~ 22
O...~Me RO2C~-~.~-../O
23
Ar
21
Ph Ph "---/ '0..--J.... OH
p./p,
25
24
The chiroptical properties of the benzodioxole 26 have been examined and the photochromism of compound 27 has been studied . Anti-diabetic activity is claimed for compound 28 and the spiro indolone/dioxolanes 29 have monoamine oxidase inhibiting and psychostimulant properties . 0
27
5.6.2
Me O
~
29
R1
1,3-DITHIOLES AND DITHIOLANES
A comprehensive review chapter on 1,3-dithiolium salts as well as selenium and tellurium and benzo annulated analogues has appeared . Reaction of 2-substituted 1,3-dioxolanes with ethanedithiol in an ionic liquid results in transthioacetalisation to afford the corresponding 2-substituted 1,3-dithiolanes and the combination of 2,4,6-trichloro-l,3,5-triazine and DMSO in CH2C12 results in cleavage of 2-substituted 1,3dithiolanes to give the corresponding carbonyl compounds in high yields . The asymmetric synthesis of various analogues of nucleosides in which the ribose is replaced by a 1,3-dithiolane has been reported . In a rather remarkable process involving 3+2 cycloadditive dimerisation of a transient thiocarbonyl ylide, treatment of the oxidised trithiocarbonate 30 with Me3Si-CHN2 gives the product 31 whose structure was established by X-ray diffraction . Reaction of phenylacetylene with sulfur and KOH in DMSO leads to direct formation of the dithiole 32 in low yield while the salt 33 reacts with long chain alkyl iodides to give mainly the dithioles 34 . Formation of the chiral dithiolane sulfoxides 35 by the action of a genetically-engineered yeast containing cyclohexanone monooxygenase, on the corresponding achiral dithiolanes, has been described .
275
Five-Membered Ring Systems." With 0 & S (Se, Te) Atoms
S ~~Cl PhSO2.~S 30
Me3Si~SiMe3 PhSO2 - ~+ S C,. ~ S ~ o 2Sh~S~ ' ~ ~ C '
Ph-,..,~s
U
Ph
32
31
O
II
K+K+-s~-sNo2R-I = RS...S ~ ~ ' s NO2 L-.. S/r~ S~C~ 33
= ~s/~'R%CO2Et
34
35
A convenient new synthesis of 1,3-diselenole-2-thione which avoids the use of CSe2 has been reported and a new synthesis of the useful building block 36 has been described . A detailed mechanistic study of the reaction of compounds 37 with PzS5 or Lawesson's reagent to give 38 and 39 has appeared . A series of benzodithiole/ferrocene compounds 40 have been prepared , an iron complex of the ligand 41 has been examined as a spin crossover material and further studies on compounds 42 related to molybdopterin have been described . New dithiole-containing donor-spacer-acceptor compounds include the furan compound 43 and the heptacyclic spacer compound 44 . R
36
S
S/"~SCH2C(O)R
sO.~
37
38
S
39
s
Fe
Me "~--0 42
Me
S
I R s~
F3C
R
43
A great deal of work involving tetrathiafulvalenes has again appeared and there have been reviews of their application for molecular devices , 2nd order nonlinear optical materials and advanced materials . An X-ray diffraction study of a complex between donor 45 and Re6Ses(CN)6 shows an unexpectedly complex structure of formula (45+')4 (45~ Re6Ses(CN)44- (CH2C12)2 (MeCN)2 and isomer-dependent packing is observed for the E and Z isomers of TTF 46 . A range of polyfluorobenzyl TTFs have been described and the TTF-based tetranitroxyl 47 has been prepared and its electrochemical and magnetic properties examined . Other new TTF donors reported include 48 and 49 which show interesting patterns of hydrogen- and halogen-bonding in the solid state . A range of new annulated tetraselenafulvalenes 50 and 51 have been prepared and
276
R.A. Aitken
superconductivity has been observed for the tetrafluoroborate salt of the dihydro-TTF 52 . s
s
S S~/sAr ArS'~ S~~SLsA r ArS/ -O~, Me ~, ~ //N :J/__Me Ar= ~~--"k~_~/~k.N..J%Me O' Hex
s
( S ~ S~~S~]jcOaaMe 018H3,..S~ 45
y CN
~S~s
48
46
S~
47
49
/S~ Se Se_ Se Se.~S\ (CH2)n (CH2!~;/~Se/~Se~ (CH2/,)~~]~ Se/~Se I-~S,, 50 n = 1,2,3
s .
52
51 n = 1,2,3
Electron transfer through the TTF bridge is observed in the radical anion of the diquinone 53 and 3rd order non-linear optical properties are observed for the compounds 54 . The new donor 55 has also been reported . TTF-fused porphyrins have been used as anion sensors and as fluorescence switches and a TTF/diquat cyclophane has shown donor/acceptor character . Further examples of donor-acceptor diads are the nitrofluorene-based compound 56 and the TCNQ-based compound 57 . The latter is remarkable in having the lowest gap between first oxidation and reduction potentials of any organic compound (0.17 eV) and it shows an ESR signal at RT due to thermal population of the charge-separated diradical state.
O o
ORv S 53
o
OR
NO2NO2 O2N
o
54
OR
55
CN O NC,,'L~v,'~v,"~~O~ S s~C5H11 "~[~~CN Me.~ S~)~SLOsH,,
CN
S..~..~ N~ S s~C5H11 .)Me/~ 02 PhCl.[12 I S~=~SL 05H11
57
56
Further studies on TTF-type systems linked in various ways to C60 and C60F18 have appeared. A number of bis(TTF)s have been described with the two units linked either directly , by-SCH2CH2S, by one or two-SCH2-2,6-pyridine-CH2S- units or by a perylenediimide linker .
277
Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms
New extended TTFs include the anthraquinone type compound 58 , a series of bridged link compounds 59 and compounds such as 60 and 61 and 62 .
MeS S HexS.
S
SMe
R
S
R
S
S
R
S
R
S
exs S
s 58
Ar
RO C" 2 - ~ S ~
,~
MeS
SMe
'~--/~~CO2R -\ CO2R
R
"rr" J/ S~ /~ - / /E ' " s/ R/ ~ S 61
S
Ar
~ R
R
62
A variety of other annulated TTF systems have been studied including 63 , 64 , 65 and 66 , 67 whose salts remain metallic down to 4K and 68 which despite lacking a TTF function gives a superconducting salt with GaC14- as counterion .
O~
Sv
S
S-- ~ SeMe
~~~===~S.~ S ) = ~ S L SeMe 63
(i s
s_ se,
S~:~(S'~ S 65
Se
S e n S e lSe/~S
, S ~ . . . S[e ~
Sf ~S
sel~ SeMe
sere
S
s-J
S
S
S
SEt
67
Se'~SeMe
66 5.6.3
64
68
1,3-OXATHIOLES AND OXATHIOLANES
Comprehensive review chapters on 1,3-oxathiolium salts and 1,3oxaselenolium salts have appeared. Scandium triflate has been introduced as an efficient catalyst for reaction of aldehydes with mercaptoethanol to form 2-substitued 1,3oxathiolanes . Protection of c~-mercaptocarboxylic acids is readily achieved by
278
R.A. Aitken
reaction with hexafluoroacetone to give oxathiolanones 69 which are resistant to a variety of acidic and basic conditions but are readily hydrolysed back to the starting materials with water . Reaction of substituted o-phthalimidosulfanylphenols with isocyanides directly affords the 2-iminobenzoxathioles 70 . The phosphonate-substituted iminooxathiole 72 is formed by treatment of the ot-haloaldehydes 71 with a metal thiocyanate followed by heat or base . A variety of 1,3-oxathiolanes have been prepared and evaluated as flavouring agents .
O S~/.. CF 3
o
R'
F3c
69
~ ( P r"' O ) 2 P ~ o
X 71 X = CI, Br
70
pri_/S \
o
NR2 (P~O)21~L/CliO 1
R4
R2
S...~' 72 NH
R1
O-r-~O 73
R2k~/ " S j ' 74
R4
=" =H, Me
R3
75
h
Cleavage of 2-substituted 1,3-oxathiolanes to give the corresponding carbonyl compounds may be achieved using H202 in acetonitrile or NaNO2/AcC1 followed by water . Conversion of amino acid esters into the amides with mercaptoacetic acid can be carried out by treatment with the oxathiolanone 73 . Titanium tetrachloride-mediated reaction of ct,13-unsaturated oxathiolanes 74 with styrene or ~-methylstyrene gives the dihydrothiapyrans 75 . 5.6.4
1,2-DITHIOLES AND DITHIOLANES
A comprehensive review chapter on 1,2-dithiolium salts has appeared . Synthesis of compound 76 which contains the core functionality of the antibiotic leinamycin has been reported and cycloaddition of the dithiolanethione 77 with DMAD results in generation of the thioacyl chloride function of 78 in an unusual way . The thiazolidinones 79 react with Lawesson's reagent to give 3-imino-l,2dithioles 80 . The bis(1,2-dithiole) 81 has been prepared and is shown by X-ray diffraction not to have a significantly delocalised structure while a series of oxime-functionalised dithiolethiones 82 undergo S-methylation to give the nitroso products 83 .
279
Five-Membered Ring Systems: With 0 & S (Se, Te) Atoms
s. Ss
0 HO(CH2)7
76
R
S O
0
77 S
/CO2Me
S
CI
0 S' S
S-S
S
I 78 S-S
81
80
79 5.6.5
~
MeO2C.,
1,2-OXATHIOLES AND OXATHIOLANES
Comprehensive review chapters covering 1,2-oxathiolium salts , 1,2oxaselenolium salts and 1,2-oxatelluronium salts have appeared. Full details of the asymmetric synthesis of chiral ~/-sultones 84 have been described . Reaction of the sultines 85 with bromine results in loss of SO2 to give 86 and the 1,3-dipolar cycloaddition of nitrones to the sultone 87 has been reported . OH S-S N ~ S R1
=
0N . . .@ . S-S II ~
R2
R1
82 Ar~,~ O-SO
Ar2
85
5.6.6
Br
86
O-O
SMe
R2
83
Br
NHz Oz
CO
84 R1-O
RZ
88 (Me3Si)2CH I 1 ~ i
02
87
89 n = 1 (Me3Si)2CH CH(SiMe3)2 90n=2 91X=S 9 2 X = Se
THREE HETEROATOMS
A wide range of di- and tri-spiro 1,2,4-trioxolanes have been evaluated as antimalarial agents and some such as 88 show good activity . New molybdenum and tungsten catalysts have been reported for the oxidation of the cyclic sulfites 89 to give sulfates 90 and the products 90 have also found use in synthesis . A review including coverage of benzotrithioles has appeared and the first 1,2,3-trithia- and tri-selenagermolanes 91 and 92 have been prepared .
5.6.7
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282
03SL1423 03SL1527 03SL1759 03SL 1793 03SL2185 03SL2325 03SM(133)309 03SM(133)317 03SM(133)321 03SM(133)329 03SM(133)333 03SM(135)627 03SM(135)775 03T341 03T1773 03T2159 03T4843 03T5251 03T5719 03T6353 03T8107 03T8989 03T10255 03TL853 03TL2573 03TL2931 03TL2979 03TL4415 03TL4701 03TL7087 03WOP2550
R.A. Aitken M.B. Nielsen, Synlett 2003, 1423. G. Masson, W. Zeghida, P. Cividino, S. Py, Y. Vall6e, Synlett 2003, 1527. J.-G. Jun, Synlett 2003, 1759. S. Palaniappan, P. Narender, C. Saravanan, V.J. Rao, Synlett 2003, 1793. D. Enders, A. Lenzen, Synlett 2003, 2185. G. Blay, L. Cardona, I. Fernfindez, R. Michelena, J.R. Pedro, T. Ramirez, R. Ruiz-Garcia, Synlett 2003, 2325. J. Becher, J.O. Jeppesen, K. Nielsen, Synth. Met. 2003, 133-4, 309. M. Fourmigu6, O.J. Dautel, T. Devic, B. Domercq, Synth. Met. 2003, 133-4, 317. T. Shirahata, T. Mori, R. Kato, K. Takahashi, Synth. Met. 2003, 133-4, 321. G.G. Abashev, E.V. Shklyaeva, A.G. Tenishev, O.N. Kazheva, G.V. Shilov, O.A. Dyachenko, Synth. Met. 2003, 133-4, 329. T. Matsumoto, T. Kominami, K. Ueda, T. Sugimoto, H. Yoshino, K. Murata, E. Negishi, S. Endo, H. Matsui, N. Toyota, K. Takahashi, M. Shiro, Synth. Met. 2003, 133-4, 333. M. Ashizawa, H. Nii, T. Kawamoto, T. Mori, Y. Misaki, K. Tanaka, K. Takimiya, T. Otsubo, Synth. Met. 2003, 135-6, 627. S. Kojima, H. Nishikawa, T. Kodama, I. Ikemoto, K. Kikuchi, Synth. Met. 2003, 135-6, 775. P. Leeming, C.A. Ray, S.J. Simpson, T.W. Wallace, R.A. Ward, Tetrahedron 2003, 59, 341. T. Tachihara, T. Kitahara, Tetrahedron 2003, 59, 1773. T.K.M. Shing, Y.C. Leung, K.W. Yeung, Tetrahedron 2003, 59, 2159. X. Guo, D. Zhang, H. Zhang, Q. Fan, W. Xu, X. Ai, L. Fan, D. Zhu, Tetrahedron 2003, 59, 4843. A. Trabocchi, G. Menchi, M. Rolla, F. Machetti, I. Bucelli, A. Guarna, Tetrahedron 2003, 59, 5251. T.J. Chow, N.-R. Chiu, H.-C. Chen, C.-Y. Chen, W.-S. Yu, Y.-M. Cheng, C.-C. Cheng, C.-P. Chang, P.-T. Chou, Tetrahedron 2003, 59, 5719. A. Sarhan, Y. Nouchi, T. Izumi, Tetrahedron 2003, 59, 6353. F. Turksoy, J.D. Wallis, U. Tunca, T. Ozturk, Tetrahedron 2003, 59, 8107. A. Ates, A. Gautier, B. Leroy, J.-M. Plancher, Y. Quesnel, J.-C. Vanherck, I.E. Mark6, Tetrahedron 2003, 59, 8989. J.K. Bjernemose, E. Frandsen, F. Jensen, C.Th. Pedersen, Tetrahedron 2003, 59, 10255. S. Kerverdo, L. Lizzani-Cuvelier, E. Dufiach, Tetrahedron Lett. 2003, 44, 853. R.R. Ferrett, M.J. Hyde, K.A. Lahti, T.L. Friebe, Tetrahedron Lett. 2003, 44, 2573. A. Barbarini, R. Maggi, A. Mazzacani, G. Mori, G. Sartori, R. Sartorio, Tetrahedron Lett. 2003, 44, 2931. A. Ploug-Sorensen, M.B. Nielsen, J. Becher, Tetrahedron Lett. 2003, 44, 2979. G. Harada, T. Jin, A. Izuoka, M.M. Matsushita, T. Sugawara, Tetrahedron Lett. 2003, 44, 4415. H.S.P. Rao, L. Sakthikumar, S. Vanitha, S.S. Kumar, Tetrahedron Lett. 2003, 44, 4701. R. Markovic, M. Baranac, S. Jovetic, Tetrahedron Lett. 2003, 44, 7087. V. Akella, O.R. Gaddam, M.R. Siripragda, M. Gutta, N. Dussa, R.S. Mamillapalli, PCT Int. Appl. WO 2,550 (2003) [Chem. Abstr. 2003, 138, 73249].
283
Chapter 5.7
Five-Membered Ring Systems with 0 & N Atoms Stefano Cicchi, Franca M. Cordero, Donatella Giomi Universith di Firenze, Italy donatella, giomi@unifi, it
5.7.1
ISOXAZOLES
Interest in this class of heterocyclic compounds is well documented by many different applications, especially in the pharmacological domain. The development of new methodologies for facile isoxazole synthesis enhances even more the attractiveness of this system as a platform for the synthesis of complex molecules. Solid phase synthesis using the 'catch & release' approach allowed the efficient preparation of libraries of substituted isoxazoles. Starting from aniline-cellulose 1 as solid support, N-formylimidazole dimethyl acetal 2, and different [~-ketoesters or 13-ketoamides 3, the one-pot generation of cellulose-bound enaminones 4 was performed in quantitative yields. The following reaction with hydroxylamine hydrochloride afforded pure isoxazoles 5 in high yields directly in solution, restoring the starting resin . Microwave-assisted synthesis was also reported .
Cyclocondensation of malonyl derived O-acyl hydroxamic acid derivatives 6, in the presence of phosphazene super base P2-t-Bu 7, gave rise to isoxazolone carboxylic esters 8 .
284
S. CicchL F.M. Cordero, and D. Giomi
Lanost-8-en-3-one 9, as well as methyl oleanonate, afforded regioselectively the corresponding [2,3-d]isoxazole 10, and not the [3,2-c]fused systems previously reported. The first synthesis of a new lanostane triterpenoid 11 with a cyano enone moiety in ring A, interesting from the perspective of biological activity, was also achieved .
O••-=H .
1. HCO2Et,NaOMe Phil, 94% ,, 2. NH2OH.HCI aq. EtOH, 89%
9
j~_ H
10
1. NaOMe,MeOH Et20, 93% = 2. DOG, Phil 72%
11
A base-promoted cyclocondensation of cyclic 1,3-diketones 13 with C-chloro oximes, derived from oximes 12, gave rise to functionalised isoxazoles 14, under mild reaction conditions and with notable functional group tolerance . The above 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 base, suggesting a key role for enolate species in the ratelimiting carbon-carbon bond forming step, either via nucleophilic addition to the nitrile oxide or 1,3-dipolar cycloaddition (1,3-DC) . Anyway, molecular sieves (MS 4A) can even act as efficient promoters, broadening the scope of this simple approach . Isoxazoles 14 can be directly converted to a variety of polyketide-derived polycyclic structures. Moreover, ester 14a gave rise, via dianion 15, to new chemo-, regio-, and stereoselective cascade reactions involving a novel base-induced isoxazole-benzisoxazole rearrangement, alkylation by dibromides 16, and SN2' cyclization with tetrahydrofuran ring closure. Compounds 17, obtained as single diastereomers, can be converted by different reducing agents to complex, structurally diverse polycyclic molecules .
R1 N"OH [ ~
+
O
O ~
12
R1 1. NCS,cat. py ',,R3 2. base
',,R 3
R 2 13
OH N~O [ ~ ~ 14a
_
O-
N~O
LDA (20 equiv) i ~ E Ii.
E
NmO
...... DME,-78~
E=CO2EtR,R'=H,Me
2
R
]
Br~ ...L~ ~
,l
, 78--~ 55 ~ 38-45%
......
15
RI=Br,OH,OMe polycyclic R2=H,CO2Et = polyketides R3=H,Me
16v
'r" - i ~ , Br
O~N
O
~
tessst
R
Reductive cleavage with TMSC1/NaI of fused systems such as pyrano- and furo[3,4c]isoxazole derivatives 18 gave predominantly polysubstituted isoxazoles 19, as key intermediates for further elaborations . Pyranoisoxazole derivatives 18a have been prepared by intramolecular 1,3-DC of nitrile oxides 21, obtained by treatment with n-
285
Five-Membered Ring Systems with 0 & N Atoms
BuLi and Ac20 of nitrooxaheptynes 20, generated in high yields from nitroalkenes and hydroxy alkynes . Domino [3+2] cycloaddition/annulation reactions of aminophenyl-ynones 23 with nitrile oxides, generated in situ from chloro oximes 22, allowed the synthesis of isoxazolo[4,5c]quinolines 24, in satisfactory yields . Bromine substituents on naphthoquinones activate and orient 1,3-DC with nitrile oxides. Compound 25 reacted with halo oximes 22 to give regioselectively only unsymmetrical naphthoquinones 26, as polyketide building blocks .
Ar
Ar
~ N
TMSCIINaI L ~ N ecm
R
18
80 ~ n=1,2
I R 19 26-87% O
A
Ar~ "N- ~
24 23-77%
~
Ar /'~~D ~ O
+ ~N-O 21
18a 37-46%
OMe O
r
~
.. 23 H 2 N ~
R
Ar ~ O
" ~ ' ~ ] I I"n-BuL. -18 ~ Ar ,. 2. Ac20 NO2 20
MeO~.Br
OMeO
R.,.~XN..
TEA
,,
OH
~II ~ I ~ N
TEA
OMe O
xyleneor toluene, A 22 X=CI,Br DCM, rt, 2-3 h
R
26 78-99%
[3+2] Cycloadditions of in situ generated nitrile oxides 28 with alkynols 27 provided isoxazolylalcohols 29 directly. Their catalytic hydrogenation under mild conditions, followed by acidic hydrolysis, afforded 3(2/-/)-furanones 30, through [3-aminoenone cyclization . Reductive ring opening by breaking of the N-O bond was also exploited for the synthesis of different pyrido-condensed heterocycles 33, containing from five to eight atoms in the fused ring. 4,6-Dichloroisoxazolo[4,5-c]pyridine 31 reacted regioselectively with nitrogen and sulfur bis-nucleophiles, affording 4-substituted derivatives 32, easily converted to 33 with Mo(CO)6 in refluxing methanol. The same ring opening/ring closure strategy was also applied to 4-chloro-3-methylisoxazolo[5,4-b]pyridine . a 1
R2
~>
40-74% -I-
HO
27
C'
N
"('~nNH2__ CI
31
/ ~N-O R3 28
R3 ~. N ~ o ~ ~ R 29
1 1. H2, Pd/C 10%=. R3 R2
Z'~n NH2
N
n=0,1,2,3
Z=NH,S
HO
O
Mo(CO)6,.
CI MeOH, A
32 54-85%
~
2. H +
63-88% N'~nZ
R1 "O" "R 2
30
RI
N CI
33 35-67%
R2
34 n=0,1,2
R3
286
s. CicchL F.M. Cordero, and D. Giomi
3,5-Diarylisoxazoles were easily halogenated at the C-4 position with N-halosuccinimides in acetic acid (37-97% yields) . The Dess-Martin periodinane oxidation of or-, 13-, and ~,-hydroxy isoxazoles into the corresponding ketones 34 was easily performed in good to excellent yields . As previously reported for the corresponding 5-substituted compounds, 3-isoxazole carbaldehydes 35 gave rise to fast and efficient Baylis-Hillman (BH) reaction with a variety of activated alkenes 36 in the presence of DABCO and in the absence of any solvent, leading to adducts 37 in excellent yields. Analogous results were also obtained on solid phase . On the contrary, 4-isoxazole carbaldehydes were less reactive electrophiles in the same reaction and in general gave the desired adducts only in modest yelds, after longer reaction times . Acetates of BH adducts produced from 5-formylisoxazoles reacted with DABCO and phenol in aqueous media to give the corresponding 3-phenoxy prop-2-enoates 38 in good yields . Isoxazolo[3,4-d]pyrimidine 39 when treated with cyanoolefins 40, in the presence of TEA as catalyst, gave biologically interesting pyrido[2,3-d]pyrimidine oxides 41 in excellent yields. Probably, a [4+2] cycloaddition of the azadiene moiety of 39 with keteneimine intermediates, derived from 40 and TEA, is involved in the process . Starting from 4- or 5-tributylstannanyl isoxazoles, prepared via 1,3-DC with chlorooximes and tributylethynyltin in the presence of base, a series of isoxazolyl tetrahydropyridinyl oxazolidinones 42 were synthesised and their in vitro antibacterial activity evaluated .
O-N Ar~OHO 35
O
~EWG 36
O-N
DABCO" Ar rain. EWG=CO2R,CN,CONH2 15-30
Ar.
CN
AF
O
O.~ N..~N,O 40k~EWG Me" N cat TEA " OJ", " ",K 39 Me EtOH,• 41 Me O
5.7.2
N'O~co2R 38 OPh
EWG OH 37 77-95% R
F,
0
42 R=Me,CI,CF3,CN,CO2Et, NHAc CONH2,CONMe2
ISOXAZOLINES
Chiral dipolarophiles such as 43 and 45 , derived from carbohydrates, react with nitrile oxides to afford spiro- and bicyclic-isoxazolines 44 and 46, respectively, with high regio- and diastereoselectivity.
287
Five-Membered Ring Systems with 0 & N Atoms
R
N_
AF
OTBDMS
+
""
O ~'~OBn OBn OBn 43
DCM
OBn
O
OBn OBn R = Me, Ph 44 76-85% Ar = 2,4,6-Me3C6H2 dr > 95:5
....OR1 45
OTBDMS
RC-N-O DCM"
O
" OR1 '. . . . . . . H
R-J-~N.O R = Me, Et R1 = Et, c-C5H9, c-C6Hll 46 78-89%
The chiral isoxazoline derivatives 49 were prepared in a highly enantioenriched form by 1,3-DC of benzonitrile oxide and pivalonitrile oxide with acrylate 47 followed by reductive removal of the D-glucose-derived auxiliary R*OH which was recovered in high yields . O "~OR* 47
R-C-N-O DCM, rt R=Ph
N"O~f cO2R* LiB(Et)3H N"O~ cH2OH R
48
THF, rt
96%; dr 9 9 1
R = t-Bu 90%; dr 9 9 1
R
T#OO-
49
TBSO
99%
98%
89%
92%
OMe
R*OH
The cycloaddition of carbethoxylformonitrile oxide with different alkenes was shown to be easier when performed in an ionic liquid such as [bmin][BF4] or [bmin][PF6] . A parallel array of 16 differently substituted isoxazoline diamides 53 was prepared through a three-step procedure (Schotten-Baumann, 1,3-DC, ester amidation with A1C13) using [bmin][BF4] as common phase without isolation of any of the intermediates. The final products were extracted with diethyl ether in 38-51% overall yields, pure by NMR analysis . CI ~_COCI
50
CO2Et
CONHR 2
N R2NH2toluene R1NH2 = ( \CONHR1 He.. N~.~CO2Et ~ ~ O KHCO3 ,,,, KHCO3 Me3A, in [bmin][BF4] [bmin][BF4] CONHR 1 [bmin][BF4] 51
52
R1, R2 = c-Hex, Ph, Bn,/-Bu
N
6 CONHR 1 53
38-51% overall yields
Isoxazolines 54, prepared by stereoselective 1,3-DC of nitrile oxides and enantiopure allylic alcohols, were converted into 13-amino acids 56 and 58 by nucleophilic addition to the C=N bond followed by reductive cleavage of the N-O bond and oxidative cleavage of the diol moiety. The facial selectivity in the nucleophilic addition was dictated by the C-5 substituent in either a directed (hydride addition) or a sterically (Grignard reagents addition) controlled manner .
288
S. CicchL F.M. Cordero, and D. Giomi
a1 ~'"'NHBoc
R1 i)LiAIH4 ....NHBoc NalO4 RuCI3 /,~qOH ii) BoC20 CO2H HO--~ 56 59-76% 55 40-64% 7-15"1 dr
R1
R2MgCI R2,,,71 i) LiAIH4 R1 N BF3"OEt2 H"~//E-NHii)BOC20_ R2,,?NHBoc THF - 78 ~
iii) Nal04 iv) NaClO2 CO2H
/ , HO
58
57 81-95% 9->20"1 dr
54
48-69%
An electrocatalytic method for the reductive N-O bond cleavage of 3-methoxyisoxazoline in the presence of Ni~ was studied. The nickel complex, generated in situ, acts as the actual electron source. Under these conditions, isoxazoline 59 afforded a mixture of [3hydroxyester 60 and ]3-hydroxynitrile 61 in high overall yields, and in different ratios depending on the amount of Ni~ used .
N-'O Ph 1) Ni~ / DMF O OH OH N~/~ Zn anode / 2e~ + .,,j,,, " MeO Ph N.-..C Ph Me 2) 0.2 M HCI 60 61
"~" CO2Me ~1~ %Fe(CO)2eeh3 + ..~
~
O2N" 62
(OC)3Fe
63
Nillbpy (%) Yield (%) 6 0 61 7 15 30 100
90 99 90 99
TBSO, ~)3
MeO2C ?TBS
TEA Ph3P(OC)2Fe., 63%
4:1 1.9 1 2.2 1 13 1
N-O
64
Fe(CO)3
The bimetallic tetraene isoxazoline 64 was prepared through a highly diastereoselective intermolecular nitrile oxide-olefin cycloaddition and used as an intermediate in the synthesis of the C7-C24 segment of macrolactin A. The addition of the nitrile oxide on the less hindered face of the s-trans triene rotomer of 63 was the key to controlling the absolute configuration of the new formed stereocenter . The isoxazoline skeleton is frequently present in biologically active compounds and is used as a building block in the synthesis of new potential drugs. New libraries of isoxazoline derivatives have been recently prepared by solution-phase or solid-phase synthesis and their activity as factor Xa inhibitors , antibacterial or antifungal agents was evaluated. 3,3-Disubstituted 4-isoxazolines 65 were easily converted to ct,[3-enals 66 by treatment with MeI in THF at reflux temperature. When the same reaction was performed in polar solvents such MeOH, DMF or MeCN the formation of minor amounts of t~,13-unsaturated amides 68 was observed. The amides 68 were obtained as sole products in high yields by heating the preformed isoxazolinium salts 67 in MeOH. The new process is believed to proceed through the heterolytic cleavage of the C3-N bond of 67 assisted by the solvent with formation of an allylic tertiary carbocation intermediate .
289
Five-Membered Ring Systems with 0 & N Atoms
R2
2
CO2Et Mel R1 reflux
66
65
O2EtTfOMe
oc;
rt, 2 h
Rl co2Et 2
MeOH reflux 1h
67
O2Et R1
CONMe2 68
95-100%
R1, R2:-(CH2)5-; Ph, Me; p-MeOCsH5, Me; Some stable azomethine ylides were prepared by photochemical excitation of a series of differently annulated 4-isoxazolines. For example, irradiation of a ca. 10-3 molar solution of 69 in C6H6 with a high-pressure mercury lamp afforded the azomethine ylide 72 in 88% yield after chromatographic purification. The proposed pathway for the transformation is based on the photochemically induced N-O bond cleavage of 69 to the diradical 70 followed by bond reorganization to aziridine 71, which undergoes C-C cleavage to afford the final product 72 .
H
A
Phil
P h ~ H
36 min
O
69
5.7.3
o
hv
70
O 71
hv Ph
H O
O 72
88%
ISOXAZOLIDINES
Isoxazolidines are useful and versatile intermediates in the synthesis of highly functionalized compounds. Frequently, they are prepared by 1,3-DC of enantiomerically pure nitrones derived from compounds belonging to the chiral pool such as carbohydrates, amino acids, and hydroxy acids. Several examples have been reported also this year, and among them there are the total syntheses of the natural products (+)-hyacinthacine A2 (73) (for an analogous approach to 73 see ), (-)-monatin 77 , and (+)-heliotridine 81 . In all these cases, the reductive opening of the N-O bond of cycloadducts 75, 79, and 83 was followed by a spontaneous cyclization to afford 7-1actam 74, 3t-lactone 78, and pyrrolizidine 82, respectively. The cycloaddition of the enantiopure nitrone 85 with diversely substituted dipolarophiles 86 afforded bicyclic isoxazolidines 87 with a very high anti-facial selectivity .
290
S. CicchL F.M. Cordero, and D. Giomi
/...j~OH
/ . . . ~ 0 Bn
H OBn BnO OBn .. (a) Me2NOC. / ~ ~ L-xylose ....OH::=:>HO" ~ OH:~:>Ph"~NYZ=> IS)-phenylglycino 77
aN--~ i78
9
HQ _H /--OH t-Bu~CO2Et ~:> 81
~""ILI"~OH
800
t.Bu~CO2Et ::~
t-BuQ
~ N - d ....\Br ~
+"0- ==> L-malicacid
82 83 84 (a): reductivecleavageof the N-ObondbyZn/AcOH,H2/Pd(OH)2and 1-12/RaNi
+ R2" ,,,H OBn ~R' O- OBn
D-glyceraldehyde
85
R2 =- ',',..R, /L-C~
OBn
OBn
87
86
N-Benzyl-C-glycosyl nitrones reacted with acrylate to give glycosyl isoxazolidines which were easily converted to glycosyl pyrrolidines by reduction of the N-O bond with Zn in acetic acid. The best result was obtained with pyranosyl nitrone 88 which quantitatively afforded the cycloadduct 89 with complete regio- and stereoselectivity .
~CO2Me Sug Zn Sug /~ AcOH,H20 /~ neat ,- Bn-N lJ ,. Bn-N O "',C02Me60 ~ 5 h ~OH - o..N.Bn 25 ~ 4 h 100% 89 90% O 90 88
Sug~] +
CO2~ a O-
91
92
DCM
rt, 24h
OZHP
:
CO2 ,z
93
CO2Me oO/~ C'}
Sug=
92
~-",/>C 02-7~ le----~n es ~N"d reflux 94 7h
O,,,"o~O
OH O CO2Me
95 42% overallyield
Insoluble polymer-supported dipolarophiles such as 92 were used to mask the nitrone moiety of the chiral pyrroline N-oxide 91 to prevent racemization at the vicinal stereogenic center by temporary formation of the resin linked isoxazolidines 93. A thermally induced 1,3dipolar cycloreversion was used to cleave the product from the resin and restore the 1,3dipole functionality which underwent intramolecolar 1,3-DC to afford the enantiomerically pure tricyclic isoxazolidine 95 .
291
Five-Membered Ring Systems with 0 & N Atoms
Some approaches to chiral 5-isoxazolidinones, useful precursors of [3-amino acids, have been studied. Diastereomeric 5-isoxazolidinones 97 were prepared by cyclization of chiral hydroxylamines 96, separated and then converted to enantiomerically pure cz-substituted-[3amino acids by hydrogenolysis of the N-O bond and concurrent removal of the chiral auxiliary .
ph/~N ~ O
phi..N~.~.CO2R,LiHMDS OH
R
97a
THF
96
P
R
:. hO ~ N: & 97b
1) 10% Pd/C
HCO2NH4 FmooHN~'~-CO2 H
2) Fmoc-OSu
98a
R
1) 10~ Pd/C HCO2NH4 F m o c H N / ~ / C O 2 H ~
%
:
2) Fmoc-OSu
R
98b
15,
Chiral nitrone 99 reacted with ynolates such as 100 at low temperature to give 5isoxazolidinones with good diastereoselectivity. The 4,4-dimethyl-5-isoxazolidinone 103 could be obtained in high yield and with good diastereoselectivity by treating the initially generated enolate 101 with MeI .
o / ~
H,
i) THF
~N+
-78 oc l~n
103 95% dr: 94:6
ii) Mel
o-
O ~ ,O 99
Oki
iiI -=8 oc
+ [
100
O
H,
THF [---~ 0
O
13n 101
t-BuOHO
J
H, "
= / I~
Bn
102 91% dr: 84 : 10::6
A stereoselective synthesis of 5-isoxazolidinones was achieved through addition of lithiated chiral oxazolidines to nitrones followed by intramolecular addition of the resulting lithiated hydroxylamines to the oxazoline C-N double bond and acidic hydrolysis of the resulting spiro-fused isoxazolidines. For example, the 2-oxazolidinyloxirane 104 gave the epoxy 5-isoxazolidinone 106 which was quantitatively reduced to the epoxyamino acid 107 . Upon treatment with LDA, the 4-chloro spiro-fused isoxazolidine 108 underwent stereoselective ring contraction to give oxazolidinyl[1,2]oxazetidine 109 which is a masked form of an cz-hydroxy-[3-amino acid .
292
S. CicchL F.M. Cordero, and D. Giomi
,s.uu
TMEDA -98 ~ THF _ t-Bu +..O 104 ii) "N I_ dr 98:2 ILL. Ph ee > 99%
_
_NH O O ~ t.B/L) J [- t-Bu
t-BuI 106 60%
t-BuI 105
"~NH O THF I H,,,N--O ,Li Okr"k--J'~ H Ar -98~ ~Ar ~1/~ ~ J \ J~ C
NH t-BUll07
ee > 99%
-I
108
O _O H2 __~H+O"N~eh ed HO2C...~ Ph ee >
,t-Bu
,,o ,,~-~H/~r 109
MeOH,. - ~ O 20 bar
O~
99%
H
,~,r \t-Bu 110
The highly strained 5-spirocyclopropane isoxazolidines show a peculiar reactivity caused by the presence of the small ring spiro-fused next to the weak N-O bond. The thermal rearrangement of spirocyclopropanated isoxazolidines has been recently used to prepare a variety of tetrahydropyridone derivatives with up to three spiroannelated cyclopropane rings. For example, compound 111 was cleanly converted into 112 upon heating at 140 ~ . In the presence of a protic acid 3,4-cis ring fused 5-spirocyclopropane isoxazolidines 113 underwent ring contraction to 3,4-cis-fused bicyclic azetidin-2-ones 114 with concomitant extrusion of ethylene . Both processes are believed to occur through the homolysis of the N-O bond of the neutral and protonated isoxazolidine, respectively.
TFA 70-110 - v - - ~-
oc, , , p-xylene 111
112
I~ H 113
80%
02H4
O HH~~.N
114 47-92%
A variety of N- and C-nucleoside derivatives in which the sugar unit has been replaced by a functionalised isoxazolidine have been synthesized. The synthetic approaches to different classes of nucleoside analogues such as 115 were all based on 1,3-DC of nitrones .
115a
'"B
"O
115b
,CO2Et
B
OH 115e
N~N..o/ ..../ 115d
oH
B = nucleobase
Isoxazolidines 118, prepared from enantiopure cyclic nitrones 116 and isolevoglucosenone 117, were used as key intermediates in the synthesis of a new class of directly linked (1--*3)imino-C-disaccharides belonging to D-gulo and D-allo series such as 119 and 120.
293
Five-Membered Ring Systems with 0 & N Atoms
o o
,+ O116
O
o ~
Ho ~
o
RO
=
>
(RO)"~118
117
OH
HO
OH or HO
(HO~"
119 D-gulo series
(HO~"
120
D-allo series
During the last year, new aspects of enantioselective synthesis of isoxazolidines using chiral auxiliaries derived from sugar , and by chiral induction of either cationic Co(Ill) complexes and organocatalysts in the reaction of simple acyclic nitrones with ct,13-unsaturated aldehydes have been analysed. The enantio- and diastereoselectivity of 1,3-DC of nitrones with 3-crotonyl-2-oxazolidinone catalysed by Ni(II)-binaphthyldiimine complexes have been studied . 5.7.40XAZOLES 2,4,5-Trisubstituted oxazoles 123, widely distributed as subunits of biologically active natural products, have been efficiently synthesized from various carbonyl compounds 121, using sequential treatments with [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB) and amides, under solvent-free microwave irradiation conditions. These regioselective reactions proceed in high to excellent yields in short reaction times through sulfonyloxy carbonyl intermediates 122 . Trisubstituted derivatives were also obtained through a new silyl-promoted variant of the Passerini reaction. New multiple component condensation (MCC) reactions of unsubstituted isocyanoacetamides 124 with aldehydes and ketones, or their derived iminium ions, led to 2-substituted-5-aminooxazoles 126 and 125, respectively . From 124, a one-pot four-component process affording 127 has been developed based on the in situ hydroxyarylation and acylation of 126 with aromatic aldehydes and acid chlorides, respectively . O 0 HDNIB _~ RI.J~R 2 MVVl 20-40 sec 121
NR1R2 R3R4~NI~ 125
R2
R1
ODNs 122
R3R4CO
O R1., HNR1R2 I~N..R2 N T~.HCI NO ,1 2 MeOH, rt 73-92% 124
R3
NH2 R D. MW! 1-2 min
O
,R3=Me,Ar R2 R2=H,Me,Ph,COMe,CO2Et,CONEt2 DNs=2,4_(NO2)2CsH3SO 2
R1 123 58-94%
OSiR3 R5CHO R3-~)-....j O R1 R3R4CO OSiR3 R3SiCI R3SiC' R3~-..../O R1 o r = !~ [ N I ~ N , R2 Zn(OT~2 R4 I N I ~ ~ R 2 R5COC, R5 ~yX NEM 35-72% X! Y= O DCM, rt 126 29-84% X=H Y=OSiR3 127
294
S. CicchL F.M. Cordero, and D. Giomi
N
s~~O 1.n-BuLi,THF,-78~
n-Be
CuON
3. RX (X-Br, I) 128
N~R
TBSOA
n_,,ujLO
R= Me, allyl,propargyl 129
o ,,CliO o
,o
6
47-96%
Copper salts such as CuCN, CuBr'SMe2 and CuCN'2LiC1 were demonstrated to mediate the regioselective allylation, alkylation, and propargylation of the lithium anion of nbutylthiooxazole 128 providing 2,5-disubstituted systems 129. Desulfurization with deactivated W2-Raney nikel produced 5-substituted derivatives . #
H H ~O Z~I1/ O 132
PY , R (RCO)20
R
20-98%
(,~,
133
134
R1
R2~X_ DMF-
OLN ~ k~
24-61%
135
55-65 oc ,7K2CO3 ~~ _ - : - j ,
R1
The synthesis of oxazole C-nucleosides in moderate yields by Tosmic addition to sugar derived aldehydes and concomitant cyclization has been reported. In particular, aldehyde 130 gave 131 in 48% yield . 5,5'-Bisperfluoroalkyl-2,2'-bisoxazoles 133, with different alkyl and aryl spacers Z, were obtained by treatment of diamides 132 with perfluoroalkyl anhydrides . Reactions of tx-oxo-oximes 134 with electrophiles (X - Br, I, OSO3Me) in the presence of anhydrous K2CO3 gave 2-substituted benzoxazoles 135 in a new general route . 2-Substituted oxazolo[4,5-b]pyridines 138 (and quinolines) were synthesised in high yields from zwitterion or hydroxyamidine derivatives 137, obtained by treatment of nonenolisable amides 136 with the complex base NaNH2-t-BuONa, via hetaryne intermediates. Intramolecular cyclization and NH3 elimination to give 138 were performed in dimethylacetamide by heating or microwave irradiation . Different approaches to oxazolo[4,5-c]quinoline-4(5H)-ones from ethyl 2-chlorooxazole-4-carboxylate have also been described .
Bro N 136 H
NaNH2-t-BuONaI " ~ ~ q NH2 ~"'i1/O NH2* DMA R (2 equiv) '~N"~%N//"" a N R Aor MWl R=t-Bu,Ar, Het 137 45-80% H -NH3 138 55-88%
295
Five-Membered Ring Systems with 0 & N Atoms
R3
R3
OH O
o R 4 ~ R2= 100 ~ O+ 120 ~ 1 II I. I 1 ~ R ~"~..O ~.,~O.,."% O Rs=OH R1 R5/ ~"~-/~O"~O RI=Me,Bn RI=Me r~ NHBz 141 61-91% 139 140 R2=H
.lAr 0;r H20 ~ ' ~ O
139a
N.R4
60_6;O/oH N ~ , o H
MeCN, A Ph 16-24h 1
- u u Bz 14240-80%
Ph
r
144
J
R4
N OO H
+~I/~--()I R3/~-R~ NX/--R 3
R~
O
145
146
Solventless reactions of 5(4H)-oxazolones 139 with hydroxycoumarins 140 exhibited excellent control of chemoselectivity leading to O- and C-acylation products 141 and 142 . 4-Arylideneoxazolones 139a behaved as imines in [2+2] cycloaddition with benzyne, generated from benzenediazonium carboxylate, to afford mainly benzoxazepine-2-ones 144, through ring-opening of the cycloadduct 143, followed by water addition . 1,3-DC of imines and mtinchnones 145, in situ generated by treatment of 5(4H)oxazolones with chlorotrimethylsilane, allowed a diastereoselective multicomponent synthesis of highly substituted imidazolines 146, containing a four-point diversity and two stereocenters. The process is applicable to aryl, alkyl, acyl, and heterocyclic substitutions and only the trans distereomers (with respect to R 2 and R 3) of 146 were observed in almost all cases .
RI~O 148 v v= AcOD-x~~ K2CO3Me2CO ~nUBr , 147a 147b
2OAc ARI~sBox
Bzg(,OH
BzO~SEt OBn OBz RI=OAc,R2=H 149a92% Box=- - < O ~ 150 R1=H, R2=OAc 149b 90%
OAc AcO~O AcO--~~ 149a AgOTf B Z ~ Q DCM B z O ~ S E t 98~ otonly 151 OBz
BnOo
Novel glycosyl donors, 1,2-trans-S-benzoxazolyl (SBox) glycosides 149a,b have been synthesized by reaction of D-glucopyranosyl bromide 147a and D-galactopyranosyl bromide 147b with 2-mercaptobenzoxazole 148. They allow selective 1,2-cis glycosylation of Opentenyl and thioglycosides, such as 150 that reacted with 149a to give 151 with complete stereoselectivity .
296
S. CicchL F.M. Cordero, and D. Giomi
R I ~O N C.~CO2R2Me2AI - H
51-91%
R~'3 R1~\~ I~CO R3
2R2
152
153
iPr, ~,.
RI=Me,Ph,C6H11,PhtN~,,H,'~ R2=H,n-Bu,allyl R3=C6H13,Ph,TMS,CH2OMe o
~~N
+roc
~N'x,/~CONH2 o~ ~NH
154
155 (-)-muscorideA
An iterative oxazole assembly via ot-chloroglycinates 152, obtained from primary amides by treatment with glyoxylate esters and SOC12, has been reported. Compounds 152 reacted rapidly with dimethylaluminium acetylides to give oxazoles 153. This technique allows polyoxazole construction and has been exploited for the total synthesis of (-)-muscoride A 155, by application of the same sequence to the intermediate oxazole amide 154 .
Ph ph~N
1. t-BuOK CI- H3~I E N-protected-aa R2 H THF, -78 ~ T t-BuOCOCI ,~NTE ~--E 2.Fm0c-aa-CI O'~~. NHgmOc NMM'THF'-20~ R3HN O .~v..NHFm0c 156 3. HCI,-78 ~ to rt 157 R1 57-73% 158 O |1 68-82% R E=CO2Me AIlO2q O Ph3P R3HN
THF, 0 ~
N...,./E
159 63-85%
i~1
N
NHFmoc
MeO2C
NHBoc
O~"')~NH H N - - ~ ~ N
160
NHZ
The synthesis of a new family of densely functionalised oxazole-containing amino acids 159 has been described starting from imine 156. Treatment with t-BuOK and acylation of the anion with Fmoc protected amino acid chlorides afforded intermediates 157, converted to 158 by coupling with N-protected amino acids. Cyclization allowed the construction of the oxazole ring with diverse functional groups orthogonally protected. These behaved as useful building blocks for the preparation of macrocyclic peptides such as 160 . The total synthesis of the peptide derived macrocycle dendroamide A 163 has been accomplished in 19% overall yield from appropriately protected heterocyclic amino acids. The oxazole amino acid 162 resulted from cyclodehydration of ]3-ketodipeptide 161 with bis(triphenyl)oxodiphosphonium triflate, with notable chemo- and stereoselectivity . A highly stereocontrolled total synthesis of the cytotoxic 18-membered macrolide (+)leucascandrolide A has been reported as well as the second total synthesis of
297
Five-Membered Ring Systems with 0 & N Atoms
diazonamide A . The first enantiospecific total synthesis of pseudopteroxazole 164 allowed the revision of the previously assigned stereochemistry .
FmocHN
~]~0~_.1 ~
Ph3PO
OBn
1,1~." ~
Tf20
_
Frn~
N
/2
oc~,_~0o~ 1,~% ~ ~-~~
o _~ O,4. N > ,,,'"~NH
0~~
5.7.5
i
n "..~ HN/'~O
N~S~I~' dendroamide A
164
J'~
OXAZOLINES
Several new ligands containing the oxazoline nucleus were synthesized in enantiopure form. Compounds of general structure 165 were obtained from L-serine or L-threonine and found application as catalysts for the zinc addition to aldehydes or were derived from f3-amino alcohols and used in diethylzinc addition to N-(diphenylphosphinoyl) imines . Also, compound 166 was derived from a commercially available amino acid and afforded good selectivity in allylic alkylation .
Ar
0--" 165 HO
R 1, R2 - Me, Ph, H R 3 = H, Ph
166
167 X = Ar, H
R = alkyl R1= Ph, H
;~ R
169
R
R
170
171
'R 1
~ 0 1.
R1
R
R 1= Cbz, Boc,Ac, Ts
R2 = Me, i-Pr
9
o
172/)'-~-~
.~
R R
R
175
R
173
R
298
S. Cicchi, F.M. Cordero, and D. Giomi
Compound 167 was obtained by aziridine expansion, a known synthetic transformation, applied on ferrocenyl derivatives . The new bisoxazoline ligands 168 were decorated with secondary binding sites to enhance the selectivity in asymmetric cyclopropanation of furans . Ligand 169 also found application in cyclopropanation reactions . Ligand 170 is a new example of the small family of sulfur-containing oxazoline ligands . Compound 171 was used in the synthesis of a series of iridium-carbene complexes for the asymmetric hydrogenation of arylalkenes . High selectivity and yields were obtained in Nozaki-Hiyama allylation and methallylation catalyzed by chromium complexes with ligand 172 . Compound 173 found application in the formation of rhodium(II) catalysts for the preparation of aziridines and in the cyclopropanation of olefins with ethyl diazoacetate . The well known bisoxazoline ligands of general structure 174 found application in several new reactions forming complexes with different metals. Copper complexes were used in asymmetric polymerization of 2,3-dihydroxynaphthalene , Mannich reactions of glycine derivatives with imines , enantioselective Henry reactions , enantioselective Diels-Alder reactions , asymmetric Michael reactions , Nazarov reactions and [3+2] cycloadditions with azomethine imines . Nickel complexes were used in the enantioselective syn aldol reactions of N-propionylthiazolidinethiones in the presence of silyl triflates , while mercury complexes found application in the enantioselective mercuriocyclization of y-hydroxy-cis-alkenes The C2-symmetric bisoxazolinate 175 formed complexes with lanthanides for the catalysis of enantioselective intramolecular hydroamination/cyclization .
Pyridine bisoxazoline ligands of general structures 176 were widely used and only the most outstanding results are reported here. Samarium and gadolinium complexes were employed to catalyze quinone Diels-Alder reactions while other lanthanide(II) triflates were used in enantioselective Diels-Alder reactions . Scandium(III) triflate complexes were used for enantioselective indole Friedel-Crafts alkylations . A derivative of the pyridine-bisoxazoline ligand was linked to a polymer to afford compound 177, used for the silylcyanation of benzaldehyde . A pyridine bis(oxazoline)-copper(II) complex was able to perform amino acid recognition in aqueous solution . Some interesting applications of oxazoline derivatives in supramolecular chemistry were also described in the literature. Compound 178 was revealed as an efficient receptor for fluorescence sensing of ammonium and organoammonium ions . Bisoxazoline
299
Five-Membered Ring Systems with 0 & N Atoms
179 showed a highly biased P-type helical conformation in solution and in the solid state . Compound 180 was used as a ligand for palladium and copper to obtain supramolecular helical stacking of metallomesogens .
R
N.-,, 0
Cl
O./.N
HO
O
0 R,,.~~O~
0
R ~O~~f'Njo~
178
C12H250" "lv, 180 O012H25
179
MeO,.,~N~ OMe \ /
"-~ 90% (optimized)
R1 = H, OMe
R2 = H, OMe, CI R3 = H, OMe, F
R1 R2*~~~'~
Ar O
R3" R~~4~N~"~"SM e
R4= H, OMe Ar = C6H5, 2-BrC6H4 (best yields)
A polyhalogenated quinoline C-nucleoside is assembled by reaction of a 2-aminophenone with a ketene ylide, through an intramolecular Wittig reaction. The nucleoside unit is already attached and is evidently not damaged under reaction conditions . CI,,,~~NH2
o• RO._~
H Ph3P=C=C=O benzene, reflux 50%
O
I
I
R = TBDMS
Ionic liquids (imidazolium salts) were utilized as "green" solvents in the Friedlander synthesis. Reactions of o-amino-substituted aromatic carbonyls with a variety of ketones (cyclic, acyclic, aromatic) result in the desired quinolines in uniformly high yield. Conditions are mild and no hazardous acids or bases are used . O R ~ R 2 v
-NH2
RI= H, CI R2 = Me, Ph
R2
O J~R R4+
Ionic Liquid= 3
R
100 *C > 90%
~ ~
R3 ~N"/~R 4
R3 = CH3, CH2R', Ar R4 = H, CO2Et, COCH3, CH2-R'
Attempts to cyclize unsaturated Fischer chromium carbenes to quinolines met with mixed results. The yields are poor, and the products were often mixed with tetrahydroquinolines and indoles. It appears there are too many competing side reactions for this to be an effective synthetic method .
Cr(CO)5 H
)t--Me
toluene. 90 ~
Me
+
+ Me
H 15%
21%
H 12%
Me
321
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Two separate methods for preparation of quinolinophanes were described. The reactions are straightforward and proceed in good yields .
I
NH2
NaOH-acetone
N
O
hv,12
95%
O
80% Ph
ROOOH2OOOH3 NH2
EtOH
=-
@I
N~ CH3 PPA ID-
reflux 2 h 93-95%
N ,,CH3
120 ~ 75-80%
Nucleophilic ring-opening of benzoxazinones by enolates of arylacetic esters followed by deacylation of the amine group resulted in cyclization to the desired 3-arylquinolin-2-ones . O O O R' " ~ N H O O OH
R3"v~oR4
O
LDA, THF
R1
R2
R4
lira
-78 ~
R2
MeONa
D
toluene reflux
R2= H, CI R3 = Ph, 3-MeOPh, 4-MeOPh
R2
H 57-93% overall
The Baylis-Hillman reaction has been carded out to synthesize 3-carboalkoxyquinolines in two steps. Previous efforts in this area have yielded indoles, 2-quinolines, 4-quinolines, unsubstituted quinolines, and dihydroquinolines . The yields are only fair, but the reaction is very clean, with only unreacted starting material found with product.
~_.I~N R1
OH O2,,R2 A cOl/pyridine 71-99%
R 1 = H, CI, di-MeO R2 = CO2Me, CN
OAc ~
__.~I~N R1
R2
[Cp*Fe(CO)2]2 10 mol%
R2
CO, 6 atm, 42 h, 150 ~ 39-89%
Isomerization of enyne-isonitriles to enallene-isonitriles resulted in a formal [4 + 1] cycloaddition to indenoquinolines . Starting material is prepared in two steps. Application to other related systems resulted in low yields and/or exclusive formation of indoles.
322
D. L. Comins, J. Dinsmore and S. O'Connor
H "- ' ~ 1
H
.fo
H
Poc,3. i-Pr2NH ph 1 h, 0 *C
Pd(PPh3)2CI2,2 mol % Cul, Et3N, DMF
| @ ~C'.
N ~ . ~ p
h
t-BuOK t-BuOH 5h, rt 51% overall
Fluorine-substituted quinolines can be formed in good yields from readily available starting materials. The reaction proceeds by generating nucleophiles through addition to multiple bonds, in this case, nitriles and isonitriles . R1
R1
F2C~
R2M, toluene, -_
c..N- v
r.t., 15 min
R1 = n-Bu, sec-Bu R2 = n-Bu, Et,/-Pr, t-Bu
toluene, HMPA, 0 *C, 1 h, then r.t., 4 h ._
F2 C |
v
R1 F R
R2
M= Mg, Li
Readily available thiocarbamates, thioamides, and thioureas provide direct routes to quinolines in moderate to good yields . The reactive intermediate postulated is the synthetic equivalent of an imidoyl radical, but with greater utility.
tris(lrime~ylsilyl )silane N H
44-88%
X = O, CH2, NH A synthesis of quinolines from reaction of 2-isopropenylaniline hydrochloride with cyclic ketones was described. The method employs a hydrothermal process with no organic solvents involved . The authors suggest this as an environment-friendly process. The product yields and side product formations are heavily dependent upon reaction temperature. NH2 I~.~J HCI
O~)n H20, heat
C5Hll 64% n=3 200 ~
C3H7 27% n =1 100 ~
36% n =2 150 ~
323
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
The cyclopentaquinoline core of a series of alkaloids has been reported. An intramolecular hetero Diels-Alder reaction proceeds with high diastereoselectivity and forms up to four contiguous stereocenters . Care was taken to avoid formation of undesirable regioisomers.
x
/Y
MeOy.~~~
,
TsOH, 5 mo160. %'79% 80 ~ lh =
NH2
MeoX~H~,:/'~,/~~IVle "
Me racemic
A solventless synthesis of substituted quinolines occurs when anilines are reacted with alkyl vinyl ketones in the presence of indium(Ill) chloride on silica gel and with microwave radiation . The mechanism proposed involves Michael addition of aniline to the vinyl ketone followed by cyclization and aromatization under the catalysis of InC13/SiO2. The reactions are fast, clean, and high-yielding.
O RI~NH2
+
R4R2~I R3
R4
InCl3/SiO2 microwave 5-30min 45-87%
RI~
~ R3 q/-.~...R2
R1= H, Me, OMe,OH, Cl, Br, CO2Me,OTs R2 = H, Me,n-Pr,di-Me2 R3 = H, Et R4 = Me, 4-OMeC6H4 A successful ruthenium-catalyzed oxidative coupling and subsequent cyclization between 2aminobenzyl alcohol and secondary alcohols in the presence of KOH and 1-dodecene leading to quinolines has been reported . After optimization of conditions, yields were fair to good. The reaction is widely applicable to a large series of 2-substituted quinolines.
~ g H 2
+
OH
r
R
[Ru], KOH
1-dodecene, dioxane, R = Ph, 2-, 3-, 4-MeC6H4,4-MeOC6H4, 80 ~ 20 h 4-FC6H4,4-pyridyl,2-thienyl,2-furanyl, 42-90% 2-naphthyl,Me,i-Pr, phenethyl,pentyl
R
An efficient, diverse synthesis of oxazolo[4,5-c]quinoline-4-ones and thiazolo[4,5c]quinolines-4-ones is carried out in two steps from readily available starting materials . The Suzuki-Miyaura coupling reaction was employed.
324
D. L. Comins, J. Dinsmore and S. O'Connor
EtO2C
2.NH2C6H4B(OH)2
Br
Ph Pd(PPh3)4,DME, H20 K2CO3, 80 ~ 78%
i
EtO2C.
/
N ~p
O~kPh
NH2
H
A rapid, high-yielding procedure for the conversion of o-nitrobenzaldehydes to quinolines (a modification of the Friedlander synthesis) has been reported . The method appears to be limited in that the ketones utilized must be symmetrical. An example is shown below.
H R
~
O O
+
I~
SnCI2 (5 equiv)' ZnCI2(5 equiv)=
R2"/""'~"~'NO 2 R1 = H, OH, OMe,
R2 = H, OMe
EtOH, 70 ~ 4 A mol sieves 70-98%
R
~
R
CI
N-Phenyldiazoketolactams cyclized via carbenoid insertion to a pyrrolo[ 1,2-a]quinoline-l,4dione. The reactions are highly regioselective and proceed in good yields, though the C-H insertion does not always occur at the same location on the phenyl ring . The "normal" insertion product is shown below. R1
R1
O
"'~,r
CH2CI2 67-71%
N '"H O-"J'Nv---~ :-"Ar :H"
RI= Me, F, CI R2= H, F, CI Ar = C6H5,2-thienyl, 2-naphthyl, 2-furyl Because the 2'-aminochalcones are known to form 2-aryl-4-quinolones, the authors undertook an investigation of possible reductive coupling reactions of 2'-hydroxy-2-nitrochalcones . With a limited number of examples, the reactions were carried out via a one-pot synthesis. Quinoline-N-oxides formed as side products are likely intermediates and can be carried on to the final material.
325
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
R2
R2
nc, 2H20
OH O
NO 2
HCI (Conc.), AcOH, 90 ~ 23-66%
OH N / ~ , , .
R1 = H, OH, OCH 3, OBn R2= H, Br
A mild, highly efficient, scalable synthesis of 4-arylquinolin-2-ones from 2aminobenzophenones was reported . By reacting the starting material with lactones and two equivalents of LiHMDS, the desired compounds are formed in good to excellent yields. O RI__~~.~ ,~
NH2 O
~_jO R3
H ,2-4.5 eq
LiHMDS,1 M in THF, 5-7.5 eq, 0 *C to r.t., then H20, r.t., 2-3 h 65-96%
R
I
~
R2
O R3
R1 = H, 4-Me, 5-CI, 5-CF3 R2= H, 5'-CI R3 = H, OMe, OBn, MOM
The Buchwald-Hartwig palladium-catalyzed aryl-amino coupling reaction was applied to the synthesis of functionalized N-phenyl-2-quinolinones . This was especially powerful because known methods of cyclization preclude anilines with electron-withdrawing groups para, or any ortho substituents, for steric reasons.
326
D. L. Comins, J. Dinsmore and S. 0 'Connor
R3 R2..~
~
O
R1
1. NaOEt, EtOH, reflux, 4 h = 2. Tf20, Et3N, CH2Cl2, r.t., 2 h
R
I
~
NH2 o
R3
OEt
.
Pd2(dba)3(25 mol %), (• Cs2CO3, toluene, reflux 38-80%
R3
R2
RI~
R4
f,~,OTf
NaOMe, MeOH,
N~
refluxr 1-4 h ,, 43-84%
OEt
R2
R1
N~O
R1 = H, 6-Me, 6-NO2, 7-Me, 7-OMe R2=H, Cl R3 = H, CO2Me R3 = H, OMe
O
6.1.3.2 Reactions of Quinolines
Singh and co-workers have repeated an earlier reported quinoline annulation reaction and obtained a different product. A mechanism is proposed . CH3
CH3
N-N--C-Ar H H
A = AcOH
~NII~"N~N
NaNO2 AcOH 72-80% C H3 Ar = C6H5, 4-CH30-C6H 4, 4-C1-C6H4, 4-C H3-C6H4, 3,4-(OCH20 )-C6H3, alpha-Naphthyl t
Oxazoloquinolines were obtained from 2-amino-3-bromoquinolines by successive acylation, amination, and cyclization .
327
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
R-COX
~
81%
heat (90-96%) or microwave
(85-94%)
B
r
O
"ComplexBase"
N'JI'-R H
81%
~ O \ I[~..N~L,.N//~--R
.o~ |
NH2
N"~R H
R = t-butyl, Ph
The Sonogashira cross-coupling reaction was applied to p-phenylethynes and 2chloroquinoline. The resulting compounds are blue-green emitters. Their electrogenerated chemiluminescence properties were reported .
,PPh,,,P0C,,,cu,
9
R = H, Me, OMe, NMe2, NEt2 N-pyrrolidinyl, N-piperidinyl N-morpholinyl
"-O
_
THF, TEA, reflux, 24 h
Asymmetric hydrogenation of quinolines by iridium catalysis was explored . Nineteen compounds were reported with excellent yields and enantiomeric excesses.
R
~
[Ir(COD)Cl]/(R)-MeO-Biphep R1
toluene/12/H2(700 psi), r.t. 86-94% ee mostly > 90%
RR1 H
R1 = Me, Et, n-Pr, n-Bu, 3-Butenyl, n-Pentyl, 2-ethylaryl, Ph, CH2OH, i-Pr, CHOCOCH3 R2 = H, F, Me, MeO
A regioselective transformation of quinolines to indoles was developed. The 1,4-dihydro Meisenheimer salts were prepared, to the exclusion of the 1,2-isomer. Yields were poor to excellent .
328
D. L. Comins, J. Dinsmore and S. O'Connor
PO(OPh)2
A
R1 ~ / ~ ~ ~ , v
/CHO
R1 = H, 6-Me, 7-Me, 6-MeO
i~1 I
CO2Ph Pyrrolo[3,4-c]quinolines are synthesized by ],5-electrocyclisation of azomethine ylides. 2Aryl-3-formylquinolines were reacted with sarcosine in refluxing xylene. The products were purified in fair yields. Trapping with N-phenylmaleimide showed presence of the azomethine ylide intermediate.
R2",,,~CHO sarcosine(2 eq)=
R2~~.
O ~ ,,CH3
xylene, 140 *C 40-60%
R']R1 -N- -Ph
L
'
CH3 2 R
-H2 =
~ R~I "N-
R1 = H, CH3 R2 = H, OCH3 -Ph
6.1.4 ISOQUINOLINES
6.1.4.1 Preparation of Isoquinolines The preparation of 3,4-disubstituted isoquinolines by a general process involving the palladium-catalyzed cross-coupling of N - t e r t - b u t y l - 2 - ( 1 - a l k y n y l ) a r y l b e n z a l d i m i n e s and organic halides was examined . Conditions were optimized to prevent the formation of 3phenylisoquinolines. The method was generally successful, except in the cases where the aryl halides were electron-rich or o-substituted. Forty-seven examples are given.
~-
+ R2X
~'~R1
R1 = Ar, n-Bu, 1-cyclohexenyl R2= Ar, allyl, alkynyl, vinyl X = I, Br, CI, OAc
K2CO3, 100 *C, 12 h 23-80%
R'~
R1
329
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
A route to 4-(1-alkenyl)isoquinolines and 4-alkyl-3-arylquinolines via palladium(II)-catalyzed cyclization, followed by olefination, was developed through many trials. Substrates were chosen for their ability to stabilize the Pd(II) intermediate, and to promote the Pd-catalyzed cyclization. An o-methoxy substituent on the aryl group was found to be necessary . Forty-one examples are given.
H2C=CHR (5 eq) PdBr2 10 mol %, CuCI2 10 mol %
0 ~~--~N-'t-Bu
~ ~Tii~-~"~N
NaHCO3 (3 eq), DMSO, 70 *C, 02, 5-24 h 48-89%
OMe
R
R = CO2-t-Bu, CONMe2, CH(OH)CH3 The application of zirconocene-copper-mediated coupling of benzocyclobutadiene with nitriles was shown to be effective in one specific case . The only successful transformation is shown below. In contrast, benzonitrile only yielded traces of 3phenylisoquinolines.
{~~Br
1.Mg
Me , CP2Zr~
1. t-BuCN toluene 70*0
2. Cp2ZrMeCI
2. CuCI/THF 61%
[~~.~
t-Bu
'/ 95% de A 2-aminoalkylfuran was utilized as starting material in a synthesis of a piperidine-containing natural product. The desired stereochemistry is attained by taking advantage of A(l'3)-strain .
~ O~
~ Ph N.-.j Ph
1. n-BuLi,THF, BrCH2CH2CH2OTBDPS
86%
.,
2. HCl 95% 3. TsCI, NEt3,CH2CI2 90%
OTBDPS m-CPBA , NH Ts'
CH2CI;
CH2 4 steps HO'"
"~ Ts TBDPSO
v
Ts
~OTBDPS
A ring-closing metathesis (RCM) strategy was utilized in the synthesis of 5-hydroxypiperidin2-ones . Stereoselectivity is observed with optically active amino acid derivatives as starting materials.
336
D. L. Comins, J. Dinsmore and S. O'Connor
Ph
O
L"NH
O
Ph
CH2CI2
Ph
ph/~.N.,~.,J
4oo,o-
Ph
"Grubbs' Catalyst" 78%
Ph O O l,..N.,-~A.ph oxone, NaHCO3 p h ~ [ ~ ~ . p h Me2CO, H20 54% Grubbs' Catalyst =
O
O Ph p h ~ . . . , ~ ./J
LDA, THF,-78 ~ 91%
OH
PCy3 Cl,,, I Ru=~
CIS I Ph PCy3
Polyhydroxylated piperidines are valued as inhibitors of carbohydrate-processing enzymes. Dioxanylpiperidine, identified as a precursor, is synthesized in good yield, stereoselectively, in 5 steps from Garner's aldehyde. The key step is a ring-closing metathesis with Grubbs' catalyst .
HO O~NBoc Me Me
~ZnBr,
THF
78% after ReX 92% de
,.
"~
,.N/~O Boc
"~Me
9 O. NBoc Me/NMe
HCI
Grubbs' Catalyst CH2CI2,r.t. "excellent yield"
~
Boc
o . fe
e
i=
Nail, THF 0~ 76%
Me
Boc dioxanylpiperidine
Highly-functionalized piperidines are available from readily-available pyrazinones by way of Diels-Alder cyclization and acid-catalyzed methanolysis. Products are reported as single stereoisomers .
337
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Bn
H2C=CH2.
Ph~ N ~ O CI
N
R
Bn
P h ~i ~
35 atm toluene
H30 |
Bn Ph. ~ O
82-92% O" Noverall H
CI
R = H, Me, Ph
-R
0Ph
H|
0
BR
N i
";
84-94%
Me
R
NH3§
el"
A variety of piperidines are formed by intramolecular cyclization of y-aminoolefins via bromination of the double bond. Chiral secondary amines provide diastereoselectivity . H N
1. Br2, CH2CI2,-78 ~ "R 2. K2CO3, Acetone, 70 *C= 70-85%
)m R
R = protecting group It.,.,.~II
,It
Ph N.~Me HH
1. Br2, CH2CI2, -78 ~ 2. K2CO3, Acetone, 70 ~ 74% one diastereomer
~H'J" ~IyHh '~ Me
Enantiomerically pure 2-azetidinones are applied to the asymmetric synthesis of nonracemic 2-piperidones. This is a novel application of 2-azetidinones . Because 2-azetidinones are valued as antibacterials and chiral building blocks for amino acids, peptides and 2pyrrolidinones, they are readily accessible for application to this transformation.
O~ R 1 ,,,R2 LiAIH4 ,. BnO RR2 BnO; , THF, 0 oc H O ~ ) ~ ' ~ N -'Boo "Boc 87% H BnO RR2 N~MHe "B~
BnO IBX " . ~ ~ , RR2 93%~O = = ( ~ N-Boo H
Ph3P=CHCO2Me y
87%
1. TMSOTf r,~,,,OBn ... 2'6-1utidine'0 ~ ~ . ~ N ~ . , R a 1 2. DMAP O 2 95%
Enantioenriched radical precursors are trapped by amines intramolecularly to give 2substituted piperidines with 60% ee. The authors propose a tight radical ion pair mechanism to account for these results .
338
D. L. Comins, J. Dinsmore and S. O'Connor
0 ~jO
OPh Bn MejNO2 'Pk~o OPh Bu3SnH
6 steps
AIBN 41%
70% overall
II(PhO)~,P'/NI oHI|~ L
"/'
1I
,H
"Bn J
Tight RadicalIon Pair
T r a n s - 2 , 6 - d i s u b s t i t u t e d piperidines are building blocks for complex bioactive alkaloids and are available in good yield from an acyclic polyfunctional sulfinimine . The authors suggest that an intermediate alkoxy aluminum species shields one face of the imine bond during the reduction to afford the observed stereoselectivity.
P-T~
OH i
OMe
HO
Me--I~lLi 90%"
Ph~OMe
P-T~
OH i
HO Ph~N'Me
C)Me
MeMgBr 88~176
OH I
P-T~
ph- v
.,~"~ILH "O 1. HCI _v -Me 2. NH4OH 0 *C
~ Ph" -N- Me
DIBAL-H ~ H n-BuLi 68% Ph" -N- '"Me H
Because many 4-benzylpiperidines are physiologically and pharmacologically active, an efficient route to these compounds was developed . Cyclization of imines containing an allylsilane with aldehydes in a one-pot reaction resulted in 4-methylenepiperidines in good yields. Heck-type arylation of arylboronic acids with 4-methylenepiperidines afforded the styryl derivatives, which gave the desired piperidines on reduction.
O ~NH2
1. LewisAcid, r.t. I ~ 2. TsCI, pyridine 73-96%
"i's
ArB(OH)2
_-
R 10 mol%Pd(OAc)2 02, Na2CO3, DMF 62-88%
10% Pd/C Ts
R MeOH,H2 85-90%
"i's
R = H, CH(OCH3)2,n-Pr, i-Pr, t-Bu, C6H5, Ar = C6H5,4-t-BuC6H4,4-MeOC6H4,4-FC6H4, 4-MeOC6H4,4-CIC6H4,PhCH=CH2,2-pyridyl 4-Me2NC6H4, 4-MeCOC6H4 Ring-closing metathesis of N-acyl-2,6-dialkenylpiperidines has been applied to the synthesis of bridged azabicyclic structures .
339
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
H O~,~.O
1. NaBH4, H EtOH,HCl O ~ S O 2 P h 2. PhSO2Na, HCO2H
THF,RMgX-20 ~
c~z ~
~o,~,., " -7800
H
1. n-BuLi, -78 ~ 2. Cbz-CI,-78 ~ 76-92%
63-74%
70%
O ~ ) n
O
PCy3 =-
h
c~z~
c,~-tu; ''c' i ~k~---Ph
~ ) + n
2. AllyI-TMS, BF3OEt2, -78 ~ 59-67%
Cy3P
_
~1)
trans isomer CH2CH2, r.t.
N'Cbz n
82-91% (yield includes
trans-precursor)
6.1.5.2 Reactions of Piperidines An entry to cyclopentane-annulated piperidines, ubiquitous in natural products, is available from 4-nitroalkyl-3-allylthiolactams . As shown, the 2-nitropropyl group adds trans to the substituent at C-6 if either the substituent at C-6 or the N-substituent is bulky.
" • -NO2 R2
i~1
-22 ~ 24 h
R2
~..o~
2. Et3N
~'
z7-89O/o
" ~ . NO2
80-90%
-~__ ~o~
R2
~'
~.,,i e pe~
R2
41
72-80% R2 R1 = CH2COCH3, CH3 R2 = Bu, H
I~1
AIBN toluene 100 ~ 39-43%
R2- "N" ~'O i~1 84 82
R2- "N" ~'O " "
16 18
340
D. L. Comins, d. Dinsmore and S. 0 'Connor
The nitrone of piperidine reacts with phenyl vinyl ether to yield a 1,3-dipolar cycloaddition product. Benzylation led to a ring-opened product which was converted to a hydroxamic acid. This is desired functionality in medicinal chemistry because it is a metal-binding ligand .
oI+
~_~
~/OPh O :_ ~ , ~
OPh
oh
OPh
BnBr
OyOPh
500OD.
58%
Ph O~NHOH
NH2OH.
65%
9O%
Arylation of piperidine by Ni-catalyzed coupling of aryl nitriles proceeds in good yield. An amidine intermediate is suggested .
R~N-Li
; I.-CN :I' ]
+ PhCN
Ni catalyst Cs salt
R
--~/N
-Ph
THF 61-73%
A precursor to the pharmaceutical Paroxetine was obtained in good yield and 96% ee. Addition of phenyl Grignard to a chiral et, 13-unsaturated enoylsultam followed by epimerization to the thermodynamically more stable C-3, C-4 t r a n s isomer provides the desired compound . Other chiral auxiliaries gave lesser or negligible ee.
F
F
CMe
O O~.o. II ~..~Me Me 1. F - - ~ - - M g B r 2. KO-t-Bu 75%
Ii.1
o o
0 ~3~Me
O'k
....~0~ 0
Me
H
- HCI
Paroxetine Starting from a common precursor, either c i s - or t r a n s - 2 - m e t h y l - 4 - a r y l p i p e r i d i n e s can be prepared . Yields and selectivity depended on the aryl group, reaction time, temperature and amount of catalyst used.
CH3 OH Boo--N~ ~ ~ A r
H2 N._toluene i/SiO2
CH3 Boc-N/~~'~Ar
trans-2,4 CH3 OH Boc..
N ~
H2
A
r
Pd/C
EtOH
CH3 Ar BoC..N~ ~
cis-2,4
Ar = 2-naphthyl,Ph, (2-CH3)-Ph (4-OCH3)-Ph, (4-CF3)-Ph
341
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
The authors desired cis-3-hydroxy-2-phenylpiperidines as starting materials for the synthesis of a large number of bioactive products. They accomplished this task, starting with protected 3hydroxyglutarimide, available in 5 steps from S-glutamic acid . The epimeric hydroxyl compound is converted to the cis-phenyl through an acyliminium ion, thus the two isomers did not need to be separated, simplifying the synthetic route.
. ~~omgges
O" N"OI~MB
NagH4
=
O ~
MeOH, 940/-20 0 *C
OmegeS eF3.OEt2 "
PMBOH
"'Ph THF,r.t. 81% PMB
CH2012, r.t.800/o
,,,O-S'~ u
?'-NM B"Ph - ~
""Ph I~MB
i
A three-step synthesis of a precursor of paroxetine is described. An aza double Michael reaction was used to form the piperidine ring .
0
O ~ Bn
NHBn 1. methyl acrylate, TBSOTf, Et3N,
t-BuOH,DCE,r.t.
.
.
.
.
.
"'CO2Me LAH,THF,reflux,,
,,,,/OH
.
2. NaOMe,58% MeO e,overall H-toluen reflux F
0 ~ . ~Bn
~
quantitative F
F
Enantiopure cis- and trans-2,6-dialkylpiperidines were synthesized from the same 6alkylpiperidine-2-one. In order to relieve A (~'2) strain in the intermediate iminium ion, the 6-alkyl substituent is in a pseudo-axial disposition and nucleophilic attack occurs from the axial direction to give the cis product .
342
D. L. Comins, J. Dinsmore and S. O'Connor
R2G"
1
R1
~ ~ 6 H5
C6H 5 "H
H C6H5,1/"'OH
OR
~
R = H, MgBr R 1 = CH 3, n-Pr R 2 = H, alkyl
C~H~H~.1oH
R 3 = alkyl, when R 2 = H, R 3 = H, when R 2 = alkyl
The synthesis of spirocyclic aminochromans are described. From an optically active oxazolopiperidine, the desired compounds are realized in eight steps, with 32% overall yield and greater than 99.5% enantiomeric purity .
Boc i
NC~.~o,s.e0s~HO~ Ph,
Boc i
THFHO~
" OTBMS Bu,;Foo _-
~~oc R
TFA, CH2CI2
Ph3P, DEAD toluene, reflux 85%
R
72%
The key step in a synthesis of rigid azabicyclic piperidines was a ring-closing metathesis . Starting from 3-hydroxypiperidine, the transformation was accomplished in six steps, each in good yield.
343
3ix-Membered Ring Systems: Pyridines and Benzo Derivatives
~
~/Br OH 2steps
H
~ O ~
~
~ I
O .,~
Br
OH
Mg,-60 ~ THF, 1 h
11,
KHMDS, THF -78 ~ to reflux 69%
74% /-Pr
..•
(F3C)2MeCO'"~i~~ ~J'%Ph (F3C)2MeCO _-
Bu3SnH, AIBN toluene, 80 ~
O
Br
CH2Cl2, r.t., 1 h 54%
N
79%
Syntheses of new analogues of diphenylpyraline are described. The strategy is flawed by a non-stereospecific hydrogenation. This results in a 50:50 mixture of diastereomers requiring purification by HPLC . R1 R1 R1 MeS Nt .R 2 Raneynickel W-2, N0 R2 2~ 1" N--~-H CH3I' CHCI3' ~11-0~C~ r't"2 h18 h I ~ R3 EtOH' r.t.,306 psi h (H2)-" ~ HN - N "(:;OR 2 29a, R2 = H
29b, R2 = Me
R2 = H, Me
29a I -HCHO
Ar N_N ~ R~CO--( / > N=N
30 6.3.2.2. Reactions
A series of chlorotetrazines 31 reacted with different terminal alkynes 32 under Sonogashira coupling conditions to furnish alkynyltetrazines 33 in good to moderate yields . R1 N ~
5% (PPh3)2PdCl 2
I
II
.
__
.2
2 eq. TEA DMA
CI
31
,.cu,
32 R1 = morpholinyl, pyrrolidinyl, diethylamino R2 = C(CH3)2OH, Ph, n-C4H9
N=N
,>
N 33
__
.2
391
Triazines, Tetrazines and Fused Ring Polyaza Systems
A variety of 1,6-dihydro-3,6-dialkyl-l,2,4,5-tetrazines have been obtained from the corresponding perhydrotetrazines . Novel bridgehead nitrogen heterocyclic systems containing the 1,2,4,5-tetrazine ring have been synthesized from 1,2,4,5-tetrahydrospiro3-( 1',7',7'-trimethylspiroadamantan-2'-yl)-1,2,4,5-tetrazine-6-thione , . Inverse electron demand Diels-Alder reactions of 3,6-bis(3,4dimethoxybenzoyl)-l,2,4,5-tetrazine have been studied. This represents the first systematic study of the [4+2] cycloaddition reactions of 3,6-diacyl-l,2,4,5-tetrazines . Reaction of 3,6-disubstituted-l,2,4,5-tetrazines with fullerene C60 yielded the first nonclassical fullerene C62 incorporating a 4-membered ring . Oxidation reactions of 3,6-diaryl1,2-dihydro-l,2,4,5-tetrazines afforded the corresponding bis-substituted tetrazines with two pendant 2-pyrrolyl or 2-thienyl groups, which are precursors of new conjugated polymers .
6.3.3.
FUSED [6]+[5] POLYAZA SYSTEMS
New dinuclear phosphane complexes stabilized by 8-thiotheophylline have been described . The metal ion complexes Co(II), Ni(II), Cu(II) and Cd(II) of some azopyrazolopyrimidine derivatives have been prepared and characterized . Coordination chemistry of aminomethylphosphine derivatives of adenine has been studied . The DNA binding properties of imidazo[4,5-b]pyridines have been evaluated . Novel series of arylpyrazolo [3,4-b]pyrimidines , , arylpyrazolo[3,4-b]pyridazines and heteroarylpyrazolo[3,4b]pyridines have been identified as potent inhibitors of Glycogen Synthase Kinase-3 (GSK-3).
6.3.3.1. Synthesis The synthesis of a panel of pyrrolo[2,1-d][1,2,4,5]tetrazinones of type 36, which present potent antitumor activity, has been accomplished by reaction of 2-diazopyrroles 35 with isocyanates, using the most convenient method to obtain azolotetrazinones .
R2~N NaNO2ICH3COOH, R~R .~ Na co
34
35
R1 R3NCOIDMF R2~N R
36
The synthesis of 7-benzoyl-3,4-dihydroisoxazolo[4,3-d][1,2,3]triazin-4-one has been achieved from 4-diazo-5-benzoylisoxazole-3-carboxamide . Treatment of a 3amino-(2'-thiazolyl)-4-amino-6-styryl-l,2,4-triazin-5-one derivative with ethyl chloroformate afforded the corresponding N-substituted triazolotriazinone . Other triazolo-l,2,4triazin-5-one derivatives have been synthesized by cyclization reactions of diaminotriazoles . Reactions of 3-bromoacetylazulene with 2-amino-l,2,4-triazines gave the corresponding imidazo[1,2-b][1,2,4]triazine substituted azulenes . A highly diastereoselective synthesis of 6-functionalized dihydroimidazotriazines has been described . The synthesis of (14C)-labeled vardenafil hydrochloride, an imidazotriazinone derivative with selective phosphodiesterase inhibitory activity, has been reported .
392
c. Ochoa, P. Goya and C. G6mez
Synthesis of 4-amino-3-(2'-pyridyl)pyrazolo[5,1-c][ 1,2,4]triazine and some of its derivatives has been achieved from appropriate pyrazolohydrazones . A 2,6-diaminoimidazo[3,4a][1,3,5]triazine has been synthesized as a constitutional isomer of the natural nucleobase 2,6diaminopurine . Reaction of 2-hydroxylamino-4,5-dihydroimidazolium-Osulfonate with phenyl isothiocyanate gave the corresponding tetrahydroimidazo[1,2a] [1,3,5]triazine-4-thione derivative . A pyrazolo[2,3-a][1,3,5]triazine derivative has been synthesized as a nonpeptide radioligand used to visualize corticotropin-releasing hormone type-1 . Pyrazolo-, thiazolo- and tfiazolo[1,3,5]triazines have been prepared in a straightforward one-step procedure by a ring chain-transformation reaction from the corresponding 2-aminoazoles . Pyrazolo[ 1,5-a][1,3,5]triazines were prepared, as corticotropin-releasing factor (CRF) receptor ligands, by couplings of aminopyrazoles with aroylthioimidates . Novel solution-phase and solid-phase synthesis of pyrazolo[1,5-a][ 1,3,5]triazin-4-ones and pyrazolo[ 1,5-a][ 1,3,5]triazines have been described . Syntheses of thiadiazolo-l,3,5-triazines have been performed by cyclizations of aminothiadiazole derivatives and ammonium thiocyanate. Their antiviral activity has been evaluated . Preparation of a dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylate has been described . Some triazolopyrimidine derivatives have been synthesized , , , . Many examples of the synthesis of diverse purine derivatives have been reported , , , , , , , , , , . Other imidazopyrimidines have been described , . Syntheses of several pyrazolopyrimidine derivatives have been developed , , 03IJC(B)343>, , , , , . Palladium catalyzed reaction of 4-amino-6-chloro-5nitropyrimidine 37 with arylacetylenes 38 afforded the corresponding 1-(4-amino-5-nitro-6pyrimidinyl)-2-arylacetylenes 39, which in dry pyridine underwent smooth cyclization to give pyrrolo[2,3-d]pyrimidine 5-oxides 40 . NH2
37
38 R = H , Me, F
R
o
Py R
40
One-pot synthesis of 9-deazaxanthines from 1,3-di-n-propyl-5-nitro-6-arylvinyl-pyrimidine2,4-dione has been accomplished . Syntheses of new azolopyrimidines , , isothiazolopyrimidines and thiazolopyrimidines have been reported. Efficient preparation of imidazo[4,5-d]pyridazin-7-ones and imidazo[1,2-b]pyridazines have been described. Synthesis and antihistaminic activity of new imidazo- and triazolopyridazines have been reported . A new approach to the synthesis of fused pyrazolopyridazines, triazolopyridazines and
393
Triazines, Tetrazines and Fused Ring Polyaza Systems
tetrazolopyridazines has been attempted . Synthesis and SAR evaluation of oxadiazolopyrazines as selective Haemophilus influenzae antibacterial agents have been described . Some 1,2,4-triazolothiadiazine derivatives have been synthesized . Syntheses of diverse imidazopyridine derivatives have been reported , , , . Synthesis of 1H-pyrazolo[3,4b]pyridines 46, as inhibitors of Cyclin-Dependent Kinases, has been carried out following the pathway shown in Scheme 2 .
CN
I~
0
a,b
~N,N i)c HCIH2N O PMB ii) d, Ph~ C 0 2 E t 42
41
0
e v,.._
~
p h ~ \Nf~
H
43 ~OEt
CI
P h ~ N
f, g
0
N ~
PMB
44 0
X-Y
P h ~ ~ N ~ N/~'~ N' H 46
PMB 45
PBM =p-methoxybenzyl; X = S, NMe, O Y = n-butyl, n-propyl,n-pentyl, (1-methyl)butyl,cyclohexyl,benzyl,phenyl, (2-hydroxy)ethyl, (2-dimethylamino)ethyl a) NH2NH2H20(1 equiv), THF,0-25 ~ 2 h; thenp-methoxybenzaldehyde(1 equiv)25 ~ 2 h; b) nBuONa (1 equiv)/n-BuOH,25-120 ~ 3 h then HC1,42% fromacrylonitrile;c) 10%K2CO3;d) 43 (1 equiv), 120 ~ 1.5 h then Ph20, 250 ~ 1.5 h, 40%; e) POC13,110 ~ 60%; f) NaX-Y,CH2C12,25 ~ 6 h; g) TFA, 65 ~ 2.5 h, 50-80%from45 Scheme 2 New pyrazolopyridine derivatives have been synthesized , , . An elegant one-step synthesis of 5,6-disubstituted isoxazolo[4,5-b]pyridine Noxides has been carded out . 6.3.3.2. Reactions
Several 2-arylthio-5-(4-oxo-benzo[d][1,2,3]triazin-3-ylmethyl)cyclopentane carboxylates and the corresponding carboxylic acids have been prepared from the appropriate benzotriazines and arylthiocyclopentanes as specific matrix metalloproteinase inhibitors . Intramolecular [4+2] cycloaddition reactions of suitable thieno[2,3-c][1,2,4]triazines yielded new condensed thienopyridine ring systems . Reaction of some 8aminopyrazolo[1,5-a][1,3,5]triazine derivatives with various acyl chlorides has been developed as a general approach towards the synthesis of 8-acylamido-pyrazolo[1,5-a][1,3,5]triazines, which could be applied to high-throughput synthesis . Glycosylation reactions of 2aryl-l,3,4-oxadiazolo[3,2-a][1,3,5]triazine-5,7-dithione with different sugars have been described . Selective C-arylation of free (NH)-purines via catalytic C-H bond functionalization has been developed . Substitution at the 2 or 8 positions of 9-ethyladenine with a variety of side-chains was accomplished in order to obtain non-xanthine adenosine receptor antagonists
394
c. Ochoa, P. Goya and C. Grmez
. An unusual oxidative ring transformation of purine to imidazo[ 1,5-c]imidazole has been described . SNAr Displacement reactions of 2,6-disubstituted-purines with weakly nucleophilic substituted anilines were dramatically accelerated in the presence of trifluoracetic acid in trifluoroethanol . Regioselective N-9-arylation of purines using arylboronic acids in the presence of Cu(II) has been carried out . 2Aminoalkyl-6-aminoaryl-9-isopropyl-8-substituted purines were obtained from the corresponding 2,6,9-trisubstituted purines as new CDK1 inhibitors . Other substituted purines have been synthesized from appropriate purine derivatives as MAP kinase inhibitors , interferon inducing agents and selective phosphodiesterase type-4 inhibitors . Alkylation of 2-amino-6-chloropurine with allyl-protected bromohydrins afforded 7-hydroxy(phenyl)ethyl-guanines . Preparation of 2,6,9-trisubstituted purines 50 from 2,6-dihalogenopurine 47 has been carried out as novel inhibitors of Src Tyrosine Kinase .
OH
CI
CI
FJ~N/~L~N" -N'I~N -..-
>
R1-NH2(1 eq.) DIEA/DMSO, 110 *C
DIAE/PPh3/THF
FJLLN//L-N H
47
,.
48
N, N>
R~NH
R~NH
N,I~N >
R2-NH2(excess)
F/LLN//L..N 49 ~
"-
DIENDMSO,110 *C
,,. R2 N ,~N//I~N H
Rl, R2= aryl, phosphonicacids Reaction of 9-benzyl-6-iodopurine 51, in toluene at -80 ~ with i-PrMgC1 gave, almost quantitatively, the purine-derived Grignard reagent, which reacted selectively with aldehydes 52 affording the corresponding alcohols 53 in 25 to 62% yield .
HO _Ar
'
51
"Ph
ii) ArCHO/toluene 52
~"Ph 53 (25-62%)
Application of a phase-transfer catalysis procedure on 2-amino-6-chloropurine afforded 6O-benzylguanine derivatives . Cross-coupling reactions of 2,6-dichloropurines yielded carba-analogs of myoseverin and 2-substituted 6-methylpurine bases and nucleosides . Electrocyclization of 8-hydrazino derivatives of caffeine yielded 3substituted 1,2,4-triazolo[4,3-e]purines . N 1 / N 9 Alkylation of different purine nucleobases has been carried out using potassium fluoride-doped natural phosphate as catalyst . Coupling reactions between p a r a - mono or bis-amino calix[4]arenes and thymin-
395
Triazines, Tetrazines and Fused Ring Polyaza Systems
1-ylacetic acid afforded mono or bis-thymine-substituted calix[4]arenes . New (S,Z)-2-aminopurine methylenecyclopropane analogues have been synthesized, from 2-amino6-chloropurine derivative, as anti-herpes viruses agents . A method for preparation of 6-alkylpurines via [2+2+2] cyclotrimerization of 6-alkynylpurines with diynes has been developed . S-Alkylation of 2-acetamido-9-(2-acetoxyethoxymethyl)-6oxo-8-thioxopurine yielded new 8,9-disubstituted guanine derivatives . Substitution reactions on adenine and guanine have been reported. Several transformations on pyrazolo[3,4-d]pyrimidines to yield new cyclindependent-kinase-2 inhibitors , Staphylococcus aureus DNA-polymerase III inhibitors and antimicrobial agents have been reported. One-pot two-step microwave-assisted reactions of 4,5-dihalogen substituted pyrazolo[3,4-d]pyrimidines to obtain new 4,5-disubstituted derivatives have been developed . Substitution reactions on pyrrolopyrimidines , and pyrrolopyrazines have been described. The reaction of an 8-carbohydrazide derivative of tetrazolo[1,5-b]pyridazine with aromatic aldehydes gave the corresponding 8arylidenecarbohydrazide derivatives . A detailed thermodynamic and kinetic study of the reaction of 4,6-dinitrotetrazolo[1,5-a]pyridine with water and methanol has been carded out . Transformations of imidazo[4,5-b]pyridines afforded new derivatives which act as corticotropin releasing factor receptor ligands .
6.3.4.
FUSED [61+[61 POLYAZA SYSTEMS
The mechanism by which benzo[1,2,4]triazine 1,4-dioxides, a class of anticancer drugs, produce oxidizing radicals following their one-electron reduction has been investigated . In relation with protein dimerizers, a flexible methotrexate dimer has been synthesized and the crystal structure of this bis-MTX in complex with E. coli DHFR published . Analogs of methotrexate (MTX) encompassing bridging ester groups have been synthesized and evaluated as DHFR inhibitors .
6.3.4.1. Synthesis Some new 1,2,4-triazin-5-ones fused to 1,2,4-triazines 54, 1,2,4-triazin-5-ones 55, 1,2,4,5tetrazines 56 and 1,2,4,5-tetrazin-3-ones 57 have been synthesized from 4-amino-6-styryl-3thioxo- 1,2,4-triazin-5(4H)-ones .
N-N N"U"NH
%-.N-,N 2 O"J"N'J"N'" HL.J
-o
%N-,N O N'LNH
I'~ N ~ R' 3
R4 54
55
R1 OH
H=CH'-
56
H
NH
%'
N,,.R3
O
57
R2 = 4-(NH2SO 2)C6H 4, R3 = H, 2,4-(NO2)2C6 H3, R4 = 2-furyl 4-CIC6H 4
396
c. Ochoa, P. Goya and C. G6mez
The synthesis and biological activity of pyrimido[1,2-b]-l,2,4,5-tetrazin-6-ones as HCMV protease inhibitors has been reported . Novel 6-azapteridines from bifunctional 1,2,4-triazines have been synthesized . Pyrimido[5,4-e][1,2,4]triazines with oral tyrosine phosphatase inhibitory activity have been described . In order to establish structure-activity relationships, analogs of tirapazamine (1,2,4-benzotriazin-3-amine 1,4-dioxide), a bioreductive hypoxic cytotoxin currently in clinical trials, have been synthesized . Efficient solid-phase syntheses of 1,2,3-benzotriazin-4-ones using t-butyl nitrite and with SynPhase TM lanterns have been published. Solid phase syntheses have also been reported for pteridines . In an example, a traceless reaction starts by linking pyrimidines to polystyrene supports via either a 2- or a 4thioether. Oxidative cleavage (dimethyldioxirane) followed by nucleophilic substitution by amines, azides or water completes the synthesis . Tetrahydropteridinediones 59 were obtained in a ring transformation reaction of diazepines fused to uracil rings 58 .
o
H
I~le ~
Heat
MeoN
-'-
0
H
~e
~02
le 58
59
R=Ts, H
A novel and versatile solid-phase synthesis of pyrimido[4,5-d]pyrimidine-2,4-diones has been reported . The key step is the reaction of the support-bound pyrimidine with isocyanates, involving formation of a carbamate intermediate, followed by a base-catalyzed intramolecular ring closure to give the polymer-bound pyrimidopyrimidines which are used in subsequent reactions providing 1,3-disubstituted 7-amino derivatives. 6.3.4.2. Reactions
Wittig reactions using 2-thioalkyl-6-formylpteridines as substrates were the first step in providing highly functionalized 6-substituted pteridines . Rearrangement of 5,8dihydro-6H-pteridin-7-ones into pteridin-6-ylideneacetic acids has been described . In an extensive paper, Pfleiderer has reported on the improvement of the solubility of pterins by preparing the N-2-acyl- or N-2-[(dimethylamino)methylene]-derivatives, and on the use of 2-(4nitrophenyl)ethyl (npe) as a suitable blocking group . The reactivity of pyrazino[2,3c] [1,2,6]thiadiazine 2,2-dioxides, sulfur dioxide analogs of pteridines, has been studied . N-Oxide and 3-amino derivatives of pyrimido[4,5-c]pyridazinedione 60 have been shown to react with primary alkylamines in the presence of an oxidant to produce condensed imidazolines 61 based on a nucleophilic aromatic substitution of hydrogen (SNH) strategy. Heterocyclic analogues of the still unknown dibenzo[a,o]picene 62 were obtained as by-products .
Triazines, Tetrazines and Fused Ring Polyaza Systems
O
~e
397
?NH2 AgPy2MnO4
60
O
Me I
o.
I~le
61a, R = n-Pr (19%) 61b, R : n-Bu (14%)
6.3.5.
R
Me
R
62a, R = n-Pr (11%) 62b, R = n-Bu (2.5%)
MISCELLANEOUS FUSED RING POLYAZA SYSTEMS
6.3.5.1. Synthesis Derivatives of thienotriazine, thienoimidazotriazine, thienotriazolotriazine and thienotetrazolotriazine have been synthesized . Several reports have dealt with pyridothienopyrimidines and pyridothienotriazines, synthesis , and synthesis and evaluation as antimicrobial and as antiprotozoal agents . A new quinoxalino[1,2-c][1,2,3]benzotriazine system has been obtained through an anomalous course of the reduction of 2-(3-oxo-3,4-dihydroquinoxalin-2-yl)benzene diazonium salt . Two new heterocyclic systems, 3-phenyl-3,4-dihydrobenzimidazo[2,1-~[1,2,4]triazine and 8,9,10,11-tetrahydroindolo[2,1-c]benzo[1,2,4]triazine have been described. The synthesis and reactivity of 8-fluoro-4-hydroxy-lH-[1,2,4]triazino [4,5-a]quinoline-l,6(2H)-dione has been reported . Bridgehead nitrogen heterocyclic systems containing a triazolo-l,3,5-triazine moiety have been prepared . Derivatives of [1,2,4]triazino[4,3-a]benzimidazole have been synthesized as constrained analogs of high affinity ligands at the benzodiazepine receptor . Novel annelated 2,3-benzodiazepine derivatives containing [1,2,4]triazines have been synthesized . Synthesis of 9-substituted tetrahydroazepinopurines as asmarine analogs has been described . In relation to adenosine receptor antagonists, new derivatives of pyrazolo[4,3e][1,2,4]triazolo[1,5-c]pyrimidines have been synthesized . A one-pot synthesis of 1,2,4-triazolo[ 1,5-c]quinazoline thiones 65, consisting of a domino cyclization of 2isothiocyanatobenzonitrile 63 with hydrazides 64 has been published .
398
C. Ochoa, P. Goya and C. G6mez
0 ~
S"yr":" N solv64ent > wN N"N~R 2-6 refluhx II/~~HIHIHI~O 1 l II~J~/H~ 63
R1 H
--~
H 65
The aza-Wittig reaction of resin-bound iminophosphoranes 66 with aryl isocyanates has been studied. Depending on the temperature and on the nature of isocyanate employed, a significant amount of 2,4-dioxo-l,3,5-triazino[ 1,2-a]benzimidazoles 68 were formed along with the normal aza-Wittig products 67. The mechanism of the reaction may involve the loss of triphenylphosphinimide instead of triphenylphosphine oxide, resulting in the formation of isocyanates instead of carbodiimides as intermediates .
6.3.5.2. Reactions
Cleavage of [ 1]benzofuro[2,3-e][ 1,2,4]triazine ring was employed to obtain oxygen, nitrogen and sulfur derivatives of 1,2,4-triazines . The formation of highly reactive triazinium-imidothiolate zwitterions 70 and their role as key intermediates for novel SN(ANRORC) reaction pathways has been reported. These intermediates, isolated from the reaction between bis([ 1,3,4]thiadiazolo)[ 1,3,5]triazinium halides 69 and benzylamines can yield unusual bis([ 1,2,4] triazolo) [ 1,3,5] triazinium halides 72, [1,2,4]triazolo[1,3,4]thiadiazolo[1,3,5]triazinium halides 73, or highly substituted guanidines 71 , .
399
Triazines, Tetrazines and Fused Ring Polyaza Systems
1
--~
2
N~N,,,,,~N,,~~ R 1" \ \ u H..N..R3"N---N 71
a1 N~ ~
,S ~|
69
H2NR3
9
R1
.J...., ,,.
H..N.,,~N-~S"
"
72
70
R1 X -
R4_SH
6.3.4.
h3
~3
73
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03BMCL129
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C. Ochoa, P. Goya and C. G6mez
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402 03JMC1229 03JMC1531 03JMC1769 03JMC1824 03JMC3455 03JMC3559 03JMC3758 03JMC3840 03JMC4287 03JOC276 03JOC367 03JOC1097 03JOC2882 03JOC3367 03JOC3559 03JOC3593 03JOC4345 03JOC4791 03JOC5773 03JOU753 03KGS274 03KGS722 03KGS730 03KGS948 03KGS949 03KGS950 03KGS1376 03KGS1584 03M565 03MI21 03MI109 03MI156 03MI365 03MI373 03MI452 03MI620 03MI629 03MI1019 03MI 1805 03MI1825 03MRC183
C. Ochoa, P. Goya and C. G6mez
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Triazines, Tetrazines and Fused Ring Polyaza Systems 03MRC324 03NJC172 03OBC664 03OBC1354 03OBC 1909 03OBC2764 03OL 117 03OL507 03OL637 03OL1245 03OL2067 03OL2271 03OL2359 03OL3495 03OL3587 03OL4265 03OL4289 03OL4595 03OM976 03OM3781 03PHA372 03PJC1001 03POL205 03PS89 03PS199 03PS279 03PS549 03PSll01 03PSl143 03PS1211 03PS1413 03PS1549 03PS1795 03PS1987 03PS2055 03S63 03S413 03S1201 03S1739 03SC253 03SC403 03SC941 03SC1245 03SC2095 03SC2599 03SC2769 03SC3077 03SLl151 03SL1459 03SRI775
403
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404 03SRI1351 03T47 03T607 03T2297 03T2539 03T4495 03T4761 03T6493 03T7141 03T7397 03T7669 03T8489 03TA429 03TA1345 03TL693 03TL703 03TL785 03TL1123 03TL1267 03TL1359 03TL2125 03TL2421 03TL2919 03TL3359 03TL3705 03TL3755 03TL5539 03TL6141 03TL6265 03TL7493 03TL8361 03TL8689
C. Ochoa, P. Goya and C. G6mez
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405
Chapter 6.4 Six-Membered Ring Systems" With O and/or S Atoms
John D. Hepworth James Robinson Ltd., Huddersfield, UK Email."j. d.hepworth@tinyworld,co. uk B. Mark Heron Department of Colour and Polymer Chemistry University of Leeds, Leeds, UK Email:
[email protected] 6.4.1
INTRODUCTION
Reviews of the thio-Claisen rearrangement , the application of Lawesson's reagent in synthesis and the role of 1,3-dithianes in natural product synthesis have been published. Reviews of biosynthetic Diels-Alder (DA) reactions , cycloaddition reactions of vinyl oxocarbenium ions , the synthesis of 6-membered heterocycles from alkoxyethylenes and of new antimalarial drugs include much O-heterocyclic chemistry. Material pertinent to this chapter can be found in reviews of the ring opening of heterocycles by arenecatalysed lithiation , natural product hybrids as new leads for drugs and synthetic efforts toward the phomoidrides . An account of bicyclic ketals discusses not only their synthesis and functionalisation, but also their transformation into a range of useful products ; a one-pot synthesis of frontalin is illustrative . Work on naturally occurring spiroketals includes the total synthesis of attenol A and B , aspects of the synthesis of the spongistatins , azaspiracid , y-rubromycin , spirofungin A and tautomycin . An account of the desymmetrisation of centrosymmetric molecules as a tool for asymmetric synthesis includes its application to tetracyclic tetrahydropyrans ; a synthesis of an intermediate pyranopyran in a route to hemibrevitoxin B is illustrative of this approach . Developments in marine ladder polyethers include synthetic studies on brevetoxin , ciguatoxin , gambierol , gymnocin-A , and yessotoxin . A divergent synthesis of tetracyclic ethers of varying ring size
406
J.D. Hepworth and B.M. Heron
involves the neutral coupling of an alcohol and an a-chlorosulfide derived from the same precursor . Total syntheses of the macrolides phorboxazole A , phomactin , leucascandrolide A, and apicularen A have been published. 6.4.2
HETEROCYCLES CONTAINING ONE OXYGEN ATOM
6.4.2.1 Pyrans Spiro-cyclobutene derivatives prepared from the intramolecular Wittig reaction of DMAD with ethyl oxo-(2-oxocycloalkyl)ethanoates yield cycloalka[b]pyrans via a thermal electrocyclic ring-opening ring-closing sequence (Scheme 1) . Cycloalka[b]pyranones result from the one-pot reaction of DMAD, dimedone and Ph3P at room temperature . A trans-annular DA of a pyranophane pseudobase is the key feature of a total synthesis of (+)-chatancin, a soft coral metabolite . O
O
O CO2Et
n = 3- 9
(i)
CO2R ~J..,,,./ CO2R
CO2Et CO2R
=
L;I-12)n CO2R
Reagents: (i) Ph3P, DMAD, CH2CI2,-5 ~ Scheme 1
\(0H2r n
CO2Et 8 examples 77- 94%
RT; (ii) PhMe, reflux
Depending upon reaction conditions, the Pd-catalysed isomerisation of alkylidene cyclopropyl ketones can lead to furans or pyrans. In acetone and in the absence of added salts, proximal bond cleavage occurs exclusively and 4H-pyrans are formed . The 4H-pyran unit has been spiro-linked into the indanoparacyclophanes . 1
R . ~ _ _ < ~ R2 C)~/~R3
5 mol% [PdCI2(MeCN)2] . . ~ Me2CO RT -" ' R1
R2 R3
8 examples 60 - 91%
Good yields of 3,4-dihydropyrans are produced with high regioselectivity in a ring closing metathesis (RCM) and double bond isomerisation sequence using a Ru complex activated by the addition of a hydride donor (Scheme 2) . A chiral Moadamantylimido alkylidene complex catalyses the asymmetric ring-opening- RCM reaction of the norbornyl triene 1 which leads to the chiral spirocyclic dihydropyran . The first example of a quadruple RCM is high yielding and exhibits both regio- and stereoselectivity; octaene 2 produces mainly the bis-spirocycle 3 .
407
Six-Membered Ring Systems." With 0 and~or S Atoms
(i) 5 mol% Grubbs' cat. PhMe, 20 ~ I" I"1 14 examples --Ph 36- 95% (ii) 30 mol% Nail MeO_J--hoy 100 ~
""
MeO--
Scheme
~~~~--~/~"
2
5mol%chiralMocat.= 22 ~
O,,~
96%ee
Phil, 3 h.
80%
1
--o,_
ru,,s' ca,.
65%
C H O,2, T,24 . 2
3
Cyclobutenes possessing an angular O-functionality, obtained from a Lewis acidmediated [2+2] cycloaddition of cyclic silyl enol ethers to ethyl propynoate and subsequent reduction and butenylation, undergo a ring-opening metathesis that produces a substituted dihydropyran that forms part of a cis-diene. After desilylation, an oxy-Cope rearrangement leads to the fused tetrahydropyran 4 .
_OTBS
O -
H
j
H-
~.
(ii), (iii)
-
4
Reagents: (i) 2 mol% cat. 5, Phil, 60 ~ lh., (83%); (ii) TBAF; (iii) KHMDS, 18-crown-6,-40 ~ then MeOH (64%)
.esN
NMes
Cl~" P C y 3 Ph 5
The in situ reaction of aldehydes with a chiral amine generates chiral enamines that function as electron-rich alkenes in an enantioselective hetero Diels-Alder (hDA) reaction with enones (Scheme 3) . An elimination- addition sequence is proposed to account for the production 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans rather than the 3-trifluoroacetyl derivative during the DA reaction of [3-trifluoroacetylvinyl ethers with heterodienes (Scheme 4) . Vinyl allenes with an aldehyde function tethered at the allene terminus undergo an intramolecular hDA reaction; the stereochemistry of the tricyclic dihydropyran adduct is consistent with an exo approach of the C=O to the dienic portion of the vinyl allene (Scheme 5) . Functionalised 3,4-dihydro-2H-pyrans have been obtained through e n d o - s e l e c t i v e hDA reactions using supported vinyl ethers . The Cu-catalysed hDA reaction between cyclohexadiene and ethyl glyoxalate occurs with high ee using a Cl-symmetric sulfoxime ligand . a-Hydroxyalkyl dihydropyrans are formed with high enantio- and diastereo- selectivity in a one-pot, three component reaction. An initial hDA involving 3-boronopropenal and ethyl vinyl ether affords a cyclic allylboronate and an allylboration reaction ensues on addition of an aldehyde. Oxidation of the allylboronate provides the 4-hydroxydihydropyran (Scheme 6) .
408
J.D. Hepworth and B.M. Heron
O ,~
O'-~/CO2 R3 (i) 10 mol% cat. 6, silica -15 ~ - RT, CH2CI2
4-
R1
(ii) PCC, CH2CI2
/ O ' . ~ 002R3
R1~
10 examples
-
80- 94% ee
I~ 2
65 - 81%
Scheme 3
/COCF3
R32"~fCHO RIo ~
R
R2 R3~/~
sealed tube 140 ~ 8 h.
J
R10'~O /
Scheme 4
R
II
COGF3
5 examples 30 -42%
R
BF3.OEt2
R = Me, 45% R = t-Bu, 48%
CH2CI2, RT O
+
H
H202, NaOAc I THF " BPin
BPin ~O
H
Scheme 5
~ OEt
Cr cat., mol. sieve_RT
6 examples OEt
,
RCHO
BPin = mB~o
OH
40 ~
24 h.
,, R
8 examples OEt 61-92%
~H H
Scheme 6
There are several examples of annulation of a dihydropyran on to other ring systems using cycloaddition methodology. Thus, 4-hydroxypyranones react with t~,]3-unsaturated iminium salts to give pyrano[3,2-c]pyranones in a formal [3+3] cycloaddition. The pyran ring behaves as a diene with DMAD and gives aromatic compounds . This approach features in a total synthesis of (+)-arisugacin and in the synthesis of the ABD ring system of phomactin A . AcO
/___~/
R
O
4-
HO
sealed tube EtOAc, 85 ~ 24 - 48 h.
O
>
R
25 examples 52 - 84%
The conjugate addition of dithiols to hexa-l,4-diyn-3-ones yields [3,[Y-bis-l,3-dithiane ketones, masked 1,3,5-triketones, which have been converted into dihydro- and tetrahydropyrans . The enol triflates derived from tetrahydropyran-2-ones undergo a cross-coupling with benzenethiols catalysed by Ni(0) that gives the 6-arylsulfanyl-3,4-dihydro-2H-pyrans, readily oxidised to the stable sulfoxides. The latter undergo facile conversion to the t~-lithiated enol ethers .
409
Six-Membered Ring Systems: With 0 and~or S Atoms
R
O (i) - (iii),. R
S..ph
,.
,.
3 examples, 61 - 80% Reagents: (i) PhN(Tf)2 and KHMDS, THF, -78 ~ (ii) PhSNa, 10 mol % Ni(0), -78 ~ - RT; (iii) m-CPBA, NaHCO3, CH2CI2, -78 ~ (iv) n-BuLi, THF,-78 ~ (v) MeOH,-78 ~
The Heck arylation of 2-substituted 3,4-dihydro-2H-pyrans with diazonium salts exhibits and leads to the 2-aryl-5,6-dihydro-2H-pyrans (Scheme 7) . Tris(dihydropyranyl)indium undergoes Pd-mediated cross coupling reactions with aryl halides to give mainly 6-aryl-3,4-dihydro-2H-pyrans (Scheme 8) . trans-diastereoselectivity
R.~
(i) = R , , . ~ ~ A r
6 examples 71 - 83% Reagents: (i)[ArN2]BF4, Pd2(dba)3.CHCI3, NaOAc, MeCN, 20 ~
Scheme 7
(i)
~ 3
~ A
In
r 17 examples 27 - 100% Reagents:(i)ArBr, (PPh3)2PdCI2, THF, reflux
Scheme 8
A Nazarov cyclisation of 1-(3,4-dihydro-2H-pyran-6-yl)-3-phenylpropenones affords cyclopenta[b]pyranones (Scheme 9) and the conjugated ethoxytriene 7 derived from tetrahydropyran-2-one also yields a fused cyclopentenone . O
O
OEt
O
O
12 examples 40- 92% Reagents: (i) 10% AlCl 3, CH2Cl2, RT
Scheme 9
7
62%
Reagents: (i) Amberlyst 15, CHCI3, 25 ~
Homoallenic alcohols 8 yield 3,4-dimethylidenetetrahydropyrans in a Prins reaction with aldehydes and an intramolecular Prins cyclisation occurs in water using a Lewis acidic surfactant . Application of the Prins reaction to alkynols instead of alkenols yields 5,6-dihydro-2H-pyrans (Scheme 10) . =_ RI~"'/J~SiMe3 19 examples 60 - 100% Reagents: (i) R2CHO, TMSOTf, Et20, -78 ~
FeX3 RCHO
CH2X2, Rs
8
X 8 examples 30 - 98%
Scheme 10
An iterative sequence of propargylation, enantioselective epoxidation of the resulting silylated skipped enynes, an endo selective hydroxyepoxide cyclisation and protodesilylation in which a SiMe3 group plays a pivotal role produces the tris-tetrahydropyran 9 in 18 steps . The stereoselectivity of the endo selective oxacyclisations of 1,4-di- and
410
J.D. Hepworth and B.M. Heron
1,4,7-tri- epoxides is controlled by the nature of the terminal nucleophile; a tert-butyl carbonate affords the cis-fused bis-tetrahydropyran, but the N,N-dimethylcarbamate gives the trans-fused bicycle . A key feature in a convergent approach to trans-fused tetracyclic ethers is a SmIz-induced intramolecular reductive cyclisation .
o H
H
H
H -
H
,,,OH (i) = ,,,OH
OH
79%
O
+
sttl
HO O
9
10
OH
OH
Reagents: (i) (+)-L-DET, Ti(O/-Pr)4, t-BuOOH
Sharpless asymmetric oxidation of the meso 1,4-diol 10 results in its desymmetrisation to the pyran-3-one, which exists as a mixture with the dihydrofuran, and the doubly oxidised bis-pyranone. Each of these hemiacetals can be individually trapped in good yield by careful choice of reaction conditions . 6.4.2.2 [1]Benzopyrans and Dihydro[1]benzopyrans (Chromenes and Chromans)
In a variation of the RCM approach to chromenes, allylphenols are isomerised to the vinylphenol prior to O-allylation and subsequent treatment with a Grubbs' second generation Ru catalyst. Application to bis(O-allylated)catechols affords 1,4-benzodioxins .
~~OH~
(i),(ii)~~O~......~ =
(iii)= ~
Reagents: (i) RuCIH(CO)(PPh3) 3, PhMe, 80 ~ (90%); (ii) allyl bromide, K2CO3, Me2CO, reflux (86%); (iii) Grubbs' cat. 5, CDCI 3, RT (>80%)
The Mitsunobu reaction of o-vinylphenols with chiral epoxyalcohols, derived from allylic alcohols using Sharpless methodology, affords epoxyethers 11. Removal of the epoxy function, which serves as a protecting group for the vinylic double bond, and a ring-closing metathesis gives 2-substituted chromenes with good enantiomeric purity. It is noted that the chiral chromenes are photoracemised, presumably through the light-induced opening of the pyran ring . Both 2H-chromen-4-yl and thiochromen-4-yl enol phosphates have been synthesised using RCM . Aryl vinyl ethers also undergo RCM, affording 4H-chromenes in high yields (Scheme 11) . [~~OH
+ O , , . ~1OH ~ R
(i),(ii)= ~~~,,o~O".,,R1 (iii)= ~~]~O"]",R1
11 6 examples Reagents: (i) DEAD, PPh 3, THF (63 - 72%); (ii) Zn, CP2TiCI2, N2 (44 -62%) (iii) Grubbs' cat. 5, CH2CI2, RT (88 - 97%)
Six-Membered Ring Systems: With 0 and~or S Atoms
411
R1
R
R 5 examples, 80- 98% Reagents: (i) Grubbs' cat. 5, CH2CI 2, RT
Scheme 11
O '~R 2
R1 I R2 8 examples, 13 - 87%
Reagents: (i) PtCI4, 1,2-DCE, RT- 70 ~ Scheme 12
No racemisation is observed during the Pt(IV)-catalysed cyclisation of chiral propargyl ethers to chromenes. The PtC14 catalyst appears to activate selectively the triple bond to nucleophilic attack by the arene and enables this well-established route to chromenes to be carried out under mild, neutral conditions and with a variety of substrates (Scheme 12) . A Pt-catalysed 6-endo hydroarylation of an alkynone combined with an intramolecular Michael addition are the key steps in a synthesis of the rotenoid deguelin . In the synthesis of 2H-naphtho[1,2-b]pyrans from 1-naphthols and 1,1-diarylprop-2-yn-1ols, initial protonation and loss of water from the latter generate an alkynyl carbocation, normally converted to the aryl propargyl ether. However, the concomitant formation of the highly coloured propenylidenenaphthalenones 12, a new class of merocyanine dyes, suggests attack of the allenic form of the cation at the 4-position of the naphthol followed by a 1,7-H shift . R Ar, Ar OH O I + R = H , Me
Ar
Ar
OH
PhMe, reflux
Ar
12
Ar
A Suzuki coupling of 2,6-dimethoxyiodobenzene with the dihydroaromatic boron compound 13 forms the basis of a synthesis of the dibenzo[b,d]pyran ring system and naphtho[2,3-c]chromenes result from an intramolecular dehydro DA reaction on the diarylalkynes 14 .
PhMe.
13 Reagents: (i) PdCl2(dppf), 2,6-dimethoxyiodobenzene, aq. NaOH, THF; (ii) DDQ, Phil (83%); (iii) TMSI (97%)
R
160 oc14
3 examples 54 - 72%
A study of the synthesis of chromans from allylic carbonates involving Pd-catalysed asymmetric allylic alkylation has established that the addition of acetic acid results in a pronounced increase in enantioselectivity. Furthermore, (E) allylic carbonates afford (R) chromans and the (Z) substrates the (S) heterocycle (Scheme 13) . This approach to chromans has been combined with a radical epoxide cyclisation in a total synthesis of (-)-siccanin .
412
J.D. Hepworth and B.M. Heron
R
Br
"'//" R 9 examples 73 - 89% ee 62 - 99% Reagents: (i) 2 mol% Pd2dba3. CHCI3, ligand, AcOH, CH2CI2 (i)
".
RI
R2 ~ R -N
1. Br 2 (1.0 equiv). 2. Me OH },3. aq. K2CO 3
1 "R 3
R
1
R2 ~
MeO"
10
a: R 1 = tBu, R2 = a 3 = H R1
-N-
b: R 1 = H, R 2 = R3 = tgu c: R 1 = H, R 2 = tBu, R3 = OMe
"R 3
d: R 1 = H, R 2 = Me, R3 = OMe
11
tBu
tB u
tBu
tBu
1. Br2 (0.5 equiv). ,....._
OMe
12
2. aq. K2CO 3
~
Br
OMe
13
1. NBS (0.5 equiv.) 2. aq. K2CO 3
NBS (1.0 equiv.) tBu
Br
tBu Et3N
O
-HBr
~ O
~. O OMe
OMe
15
16
The bacterial translocase 1 inhibitor, A-500359C, 17 (and a methoxy analogue A-500359A), isolated from Streptomyces griseus SANK 60196, has been shown to incorporate a tetrahydro azepin-2-one unit .
434
J.B. Bremner
OH o
H
#..r
.
H(~
"OH
17 7.2.2
Fused azepines and derivatives
A combination of ruthenium-mediated isomerisation and ring closing metathesis has been applied to the synthesis of the benz[c]azepine derivative 21 in moderate yield from 20 via 18 and 19 . H/~O
/ ~ C MeO" ~ .
v
-,~
.-,,, ,.,Ts
(0' (ii) ~".v- ~ MeO
O~Pr
O~Pr
18
20
/--q
19
Ts
O~Pr
0i0' ('v)-' '~
/Ts
Catalyst 1:
MesINyN'Mes CI..... ~ Ph Cl~ u PCY3
Catalyst 2:
[RuCIH(CO)(PPh3)3]
O~Pr 21
Reagents: (i) TsNH2, toluene, 110 ~ 4 d, 8 20% and recovered 3 78%; (ii) catalyst 2 (1%), toluene, 80 ~ quantitative; (iii) NaBH4, MeOH, 0 ~ 30 min, 98%; (iv) allyl bromide, Nail, THF, 6 h, r.t., 64%; (v) 5% catalyst 1, toluene, 60 ~ 2 h, quantitative.
A ring interconversion strategy has been used to access the functionalised benz[c]azepinones 23 from 22. The key ring expansion is initiated by lithium-bromine exchange in 22 followed by internal carbanion attack on the lactam carbonyl group; trapping of the ring expanded lactam intermediate by various electrophilic species then gave 23 in moderate to good yields . None of the isomeric benz[c]azepinones 24 expected from the lithium enolate intermediate were observed.
Seven-Membered Rings
435
,GH3
CH3
EI-X
- 78 ~ to r.t. CH3 ~ . ~ - l r "
H''-
o
tert-BuLi
23
THF,-45 ~
CH3
Br
, CH3
EI-X
~-OLi
22
H3C 24
CH3
EI-X = CH31 (74%) EI-X = CH2=CH-CH2Br (50%) EI-X = PhCHO (64%)
Silver ion-promoted ring enlargement of the 1-tribromomethyl-dihydroisoquinoline 26, from 25, provides a concise approach to [3]benzazepinones 27 .
~ N
(i) =
~ N
O,., | bn Br
25
(ii)= [ ~ N
(iii) = "Bn CBr3
26
[
~
O
N-Bn
RO
27a:R = Me b:R=H
Reagents: (i) PhCH2Br (1.1 equiv.), MeOH, reflux for 2 weeks (quant.); (ii) 25 dissolved in CH3CN/H20 (1/1) then HCBr3 (1.3 equiv.) and aq. KOH (1.2 equiv.), r.t., 45 min (89%); (iii) 26 in MeOH at-40 ~ then aq. AgNO3 (3 equiv.), up to r.t., 16 h (44%).
A key step in the asymmetric synthesis of the angiotensin converting enzyme inhibitor, benazepril HC1 32, was the reduction of the ketoester 28 with baker's yeast to afford the chiral a-hydroxy ester 29 in high chemical yield and ee. Formation of the benz[b]azepinone 31 directly from 29 proceeded in 42% yield (without racemization at C-3) or in 74% yield in two steps via 30, again with no racemization .
436
J.B. Bremner O ~NO2
O (i) =
O
(ii)
~ C O 2 E t --.7 -NO 2
O
@
28
OH
C02Et
29
(iv)
OH OH
.HCI ....
~
(v)
~ N O ~ cO2Et
C02Et Et
32
30
31
Reagents: (i) diethyl oxalate, NaOEt, THF, 0 ~ (99%); (ii) baker's yeast, phenacyl chloride, Et20/H20, 30 ~ (85%); (iii) H2, Pd-C, HCI, MeOH, then HOAc/toluene, 80 ~ (42%); (iv) NaBH(OAc)3, THF, 0 ~ (v) H2, Pd-C, HCI, MeOH, then HOAc/toluene, 80 ~ (74%, two steps).
Lactim ether formation from 2,3,4,5-tetrahydrobenz[b]azepin-2-one on reaction with dimethyl sulfate and triethyloxonium tetrafluoroborate has been described, and its reaction with a variety of primary amines assessed . Dibenzazepine systems also received some attention in 2003. Treatment of the Nmethoxyamide 33 with phenyliodine(III)bis(trifluoroacetate) (PIFA) afforded the dibenzazepinone 34 in high yield (84%) in hexafluoroisopropanol (HFIP) as solvent; ipso cyclisation of the nitrenium ion intermediate to afford a spirocyclic system is suppressed in this case without the stabilising para-methoxy group in the aryl ring in 33. When trifluoroethanol (TFEA) was used as the solvent both benz-annulation and spiro-cyclisation was observed . Similarly, when TFEA was used as a solvent in the case of 35, benzannulation was observed with the benz[b]azepinone 36 being isolated in 50% yield, together with the spiro-cyclized product 37 in 48% yield.
PIFA HFIP 1 min
H3CO
33
34 P,F
O OCH 3 35
TFEA 15 min
H3CO 36
H
,
H3CO 37
\, O
Seven-Membered Rings
437
Ring closing methodology was also used to access the axially chiral dibenz-fused lactams 39 and 4t1 from the unsymmetrically substituted biphenyls 38 and (R)-phenylglycinol; high yields and diastereselectivities were obtained. The relative stereochemistry of the minor diastereomer 40 was established via a NOESY experiment . hoe H
Ph/,.~/~'- 0 hi ,l,~Me
COOR
38
Ph/,.
N--~ Me
39
40
Reagents: (i) (R)-phenylglycinol, toluene, reflux 18 h (R = H) or 38 h (R = Et). A new Stemona alkaloid sessilifoliamide C, 41 (from Stemona sessilifolia) has been described with a fused azepine skeleton; a butanolide analogue (sessilifoliamide B) was also isolated .
0 O H
0 41
7.2.3
Oxepines and derivatives
Ring-closing olefin metathesis has been extended to vinyl chloride precursors, resulting, for example, in the preparation of the chloro-substituted oxepine derivative 43 from 42 in high yield (88%) .
Phil, 65 ~ Grubbs' catalyst* 42
*Catalyst:
Ph(H2C)2~ 43
/--1
M e s ~ N y N--Mes CI~ R ~ P h CI~ i u
PCY3
CI
438
J.B. Bremner
RCM methodology was also at the heart of the synthesis of the dihydro-7H-oxepin-4-one 45 from the Boc-protected D-phenylalanine derivative 44 . H2C---CH---CH2---O
O
ph~JJ~~~CH2
tBu-- O--C-- ~H II 0
tBu--
O----C-- NH II
O
O
44
45
A new and efficient approach to oxepine derivatives based on singlet oxygen oxidation of a furan ring has been described . Synthetic interest continues in the 7-membered oxaheterocyclic systems of marine natural products, and Crimmins and DeBaillie have published a chiral synthesis of rogioloxepane A, 46 .
6r
#
Cl 46
7.2.4
Fused oxepines and derivatives
The benzoxepine 49 was accessed in 18% overall yield from the diene 47 via a base induced isomerisation to 48 and a subsequent RCM reaction .
MeO
~
"~. O~Pr
(28~
MeO-
'~ ",,,~ -~ O~Pr I
47
9
48 (ii)
r (64%)
Ru catalyst: MeO
O~Pr
M e s I N y N-Mes CI\-.Ph C i / iRu ~ / PCY3
49 Reagents: (i) t-BuOK, DMF, r.t., 18 h, quantitative; (ii) 5 mol% Ru catalyst, toluene, 2 h at 60 ~ h at 80 ~
then 2
The spirocyclic benzoxepines 50 (R = Ph, p-MeC6H4, t-butyl) were obtained unexpectedly by isomerisation of the vinyl carbonyl ylide intermediates obtained from reaction of indanetrione with vinyl diazo compounds, and subsequent cyclisation and a 1,5-hydrogen shift.
Seven-Membered Rings
439
This reaction sequence was not observed however with six-membered cyclic tricarbonyl compounds .
o
HO~ R
='-
Me
o o
CN 50
Me~8~,Me Me'Me
51
52
An elegant enantiocontrolled, five-step, total synthesis of the sesquiterpenoid plant product (+)-heliannuol D 51 has now been realised starting from (-)-xanthorrhizol and utilising a palladium-catalysed cyclisation to form the seven-membered ring . A racemic synthesis of 51 was also reported . The reaction of Meldrum's acid with 3,4-bis(chloromethyl)-2,5-dimethylthiophene (or the bromomethyl analogue) proceeds under kinetic control to afford the bis-fused oxepine 52 . A novel quinolone-ring fused oxepine 56 (n = 1), reported by Joseph et al., was accessed by a ring-closing metathesis reaction on the precursor 55, which was made in turn from 53 via 54, and a Claisen rearrangement on the last compound. An aza analogue of 56 (n = 1) was made in a similar direct approach .
J.B. Bremner
440
OH O . ~ / O C H 3 CH30/[~
1) Nail (2 equiv) DMF, 0 ~ 2) allyl bromide (2 equiv) Nal, 90 ~
CH3
71%
Of O
/OCH3
2 h
CN3 54
53
xylene, 200 ~ 24 h sealed tube OCH3
CH~30 -
i;~ OH3
. PCY3 CI/,.~ ~,I-90 %) the tetrahedral coordination cage 39 in 5 h at 25 ~ . Dendritic molecular squares with 16 ferrocene groups on the bridging ligands derived from perylene bispyridinyl imides and with [[Pt(dppp)][(OTf)2]] corners have been self-assembled in high (68 - 77 %) yields . A series of enantiomerically pure multinuclear metallacalixarenes has been constructed with Pd comers and 1,2-diamino-cyclohexane and substituted 2-hydroxypyrimidine components . The magnetism of related tetranuclear complexes of the [FeUnLn](Xs) [2x2]-grid-type [L = 4,6-bis(2',2"-bipyridin-6'yl)-2(substituted)pyrimidine] was shown to possess spin translation behavior; the phenomenon depends directly on the substituent at the 2-position on the central pyrimidine . Chirally twisted porphyrin-based molecular capsule and polymeric capsule have been synthesized from chiral cis-Pd[(R)-(+)-2,2'-bis(Ph2P)-l,l'-binaphthyl] with porphyrins bearing either four (for a capsule) or eight (for the polymeric counterpart) pyridinyl moieties . 8.14
C A R B O N - P H O S P H O R U S - M E T A L RINGS
The self-assembly of two tripodal caps, such as tris[4-(trans-Pt(PEt3)2(NO3))phenyl]phosphine oxide, with three 1,8-bis(4-pyridinylethynyl)anthracene connectors afforded a nanoscopic prism 40 in an incredible 98 %; the C- and Si- capped analogous were also reported . 8.15
CARBON-OXYGEN-NITROGEN-METAL
RINGS
The b/s-mono-dentate ligands, constructed from a PEG moieties (n = 3 or 4) with pyrazolyl end groups, afforded either mono or binuclear silver metallomacrocycles; X-ray diffraction of single crystals confirmed their structures . Bowl-shaped, water-soluble, C2v symmetric superstructures have been assembled by intra-clipping of resorcin[4]arene, capped with (pyridinylOCH2) moieties, upon treatment with (en)Pd(NO3)2 . Treatment of cis-l,8-bis(pyridin-8-oxy)oct-4-ene-2,6-diyne (cis-bpod) with either Cu(ll) or Zn(ll) in a 2.1:1 ratio gave the corresponding [Metal(bpod)2] complexes; the photo-Bergman cyclization of the [Cu(bpod)2] afforded (87 %) a ring-contacted 1,2-bis(2'-pyridinyloxymethyl)benzene . 8.16
REFERENCES
02AC(E)3554 K. Mikami, M. Terada, H. Matsuzawa, Angew. Chem. Int. Ed. 2002, 41 (19), 3554-3571. 02CCR159 W. Levason, S. D. Orchard, G. Reid, Coord Chem. Rev. 2002, 225 (1-2), 159-199. 02CCR171 S.-S. Sun, A. J. Lees, Coord Chem. Rev. 2002, 230 (1-2), 171-192. 02CCR255 A. lngham, M. Rodopoulos, K. Coulter, T. Rodopoulos, S. Subramanian, A. McAuley, Coord. Chem. Rev. 2002, 233-234, 255-271. 02CCR289 P.D. Harvey, Coord. Chem. Rev. 2002, 233-234, 289-309. 02CHC261 A.A. Abramov, A. V. Anisimov, A. A. Bobyleva, Chem. Heterocycl. Compds. 2002, 38 (3), 261273.
Eight-Membered and Larger Rings
02CHC763
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G.R. Newkome
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469
INDEX 2,5-bis-Acetylenic furans, 170 N-Acyl oxazolidin-2-ones, 300 N-Acyl-5,5-dimethyloxazolidin-2-one, 304 2-Alkylidene-l,3-dioxolanes, 273 3-Alkylidene-4-alkenyltetrahydrofurans, 177 2-Alkylidenetetrahydrofurans, 176 3-Alkylidenetetrahydrofurans, 177 2-Alkyl-substituted benzo[b]furans, 180 2-Alkynylchromanones, 419 3-Alkynylflavones, 418 3-Alkynyltetrazines, 390 2- Amidofurans, 168 3-Amidofurans, 168 3-Amino- 1,2,4-triazines, 386 3-Aminoisochroman-5,8-diol, 413 3-Am inomethylenedihydrofuran-2-ones, 165 5-Aminooxazoles, 293 Anthocyanins, 414 Artemisinin, 423 3-Aryl- 1,2,4-triazines, 388 2-Arylbenzo[b]furans, 180 4-Arylideneoxazolones, 295 6-Aryl sul fanyl-3,4-dihydro-2H-pyrans, 408 6-Aza-(2'-deoxy)isocytidine, 388 6-Aza-5-methyl-(2'-deoxy)isocytidine, 388 2-Azabicyclo[2,2,0]hex-5-enes, 83 Azabicyclo[2,2,1 ]heptane, 88 Azacoumarins, 45 Aza-Diels-Alder, 7 Azazirconacyclobutanes, 92 2H-Azepin-2-imine, 432 2H-Azepin-2-one, 433 2H-Azepine, 433 Azetidines, 83,84 3-Azetidinones, 82 2-Azetidinones, 84-91,292 Aziridines,86,289,298 Azocino[ 1,2-a:6,5-b ]indoles, 150 Azomethine ylides, 289 Azuleno[4,5-c]furan, 187 Azuleno[ 5,6-c] furan, 187 Benz[4,5]imidazo[1,2-c]pyrido[3',2':4,5]thieno[2,3e]pyrimidine, 363 Benz[b]azepinones, 435,436 Benz[c]azepine, 434 Benz[c]azepinones, 434 Benz[f]indenone, 165 [3]Benzazepinones, 435 Benzimidazo[2,1 -f][ 1,2,4]triazine, 397 Benzimidazole[ 1,2-c] [ 1,2,3]thiadiazoles, 254 Benzo[ 1,2,4]triazine 1,4-dioxides, 395 Benzo[1,2-b:4,3-bqdithiophenes, 108 Benzo[ 1,2-b:4,5-b ]dithiophenes, 110
Benzo[ 1,2-b:5,4-b ~]dithiophenes, 102 Benzo[ 1,2-c:4,5-c']dithiophenes, 103 Benzo[4,5]thieno[2,3-d]pyrimidines, 362 5H-Benzo[6,7]cyclohepta[ 1,2-d]pyrimidines, 359 Benzo[b]furan natural products, 158,159 Benzo[b]furan-3-carboxylate, 185 Benzo[b]furans, 2-substituted,182 Benzo[b]phenanthro[9,10-d]furan, 183 tris-(2-Benzo[b]thienyl)methane, 421 Benzo[b]thiophenes, 98, 99, 112 Benzo[c]phenanthridines, 40 Benzo[c]pyrylium salt, 414 Benzo[c]selenophenes, 102 Benzo[d]azepin-3-ones, 333 Benzo[d]isothiazoles, 246, 250, 252 Benzo[/]isoquinolines, 45 Benzo[h]isoquinolines, 39, 43, 44, 331 1,4-Benzodiazepin-2-one, 441 2,3-Benzodiazepine, 397 Benzodiazepinium, 441 1,4-Benzodioxanes, 422 1,4-Benzodioxepin-3-yl-5-fluorouracil, 448 1,4-Benzodioxins, 410,422 Benzodioxoles, 273,274 Benzofurans, 2,5-disubstituted, 182 Benzofurans, Diels-Alder reaction, 167 [ 1]Benzofuro[2,3-e] [ 1,2,4]triazine, 398 2,1-Benzoisothiazoles, 248 1,2-Benzoisothiazolin-3-ones, 246 Benzonitrile oxides, 284 1H-2-Benzopyran-5,8-diones, 413 2,1,3-Benzothiadiazoles, 257 Benzothiazoles, 230,213,232, 250 Benzothiazolines, 241 Benzothieno[2,3-d]pyrimidines, 368 [ 1]Benzothieno[3,2-b]pyrans, 98 [ 1]Benzothienol[3,2-d]pyrimidin-4-ones, 370 Benzothiopyano[2,3-b]indol- 11-ones, 144 1H-2-Benzothiopyrans, 421 2-Benzothiopyrylium salts, 421 1,2,4-Benzotriazines, 231 Benzotriazoles, 146 Benzotrithioles, 279 [ 1,4]Benzoxathiin-2-ones, 426 4//- 1,2-Benzoxazines, 412 S-Benzoxazolyl (SBox) glycosides, 295 Benzoxepine, 438 2,2'-Biindoles, 142 Bithiazoles, 228, 229 Bithiophenes, 117, 121 2,6-Bridged pyran-4-ones, 415 5-Bromofuran-2-carbaldehyde, 173 4-Bromopyran-2-ones, 416
470
Index
Bromopyrroles, 21 ),-Butenolides, 160 2,5-bis(Butyltelluro)furan, 170 C60, 276 C60, 391 C60F18, 276 Calix[2]bipyrrole[2]thiophenes, 107 Calix[4]arenes, 121 Camptothecin, 38 Carba-2-oxacephem, 88 Carbacephams, 89 4a-Carbafuranoses, 160 Carbapenam, 87,88 Carbazoles, 148 B-Carbolines, 142, 146, 147, 363 y-Carbolines, 146, 148 Carbon suboxide, 415 Cephalosporins, 87,88 Chalcones, 419 ot-Chloroglycinates, 296 6-Chloropyran-2-ones, 416 2H-Chromen-4-yl enol phosphates, 410 2H-Chromenes, 110 Chromone-3-carboxaldehydes, 418 Coumarins, 164 1-Cyanocyclopropancarboxamides, 165 Cyanuric chloride, 389 Cycloalka[b]pyrans, 406 Cycloalkanonaphthofurans, 185 Cyciobuta[b]pyran-4-one, 415 Cyclobuta[b]pyrano[2,3-d]pyran-2,5-diones, 415 Cyclobuta[b]thieno[2,3-J][ 1]benzothiophenes, 110 Cyclopent[b]indoles, 147, 150 Cyclopenta[b]pyranones, 409 Cytotoxicity, 4 8-Deazapteridines, 387 3- Deazapuri nes, 387 9-Deazaxanthines, 392 Dendrilla sp,, 1 3-Deoxyanthocyanidins, 414 2,5-Dialkylfurans, oxidation, 161 4,6-Diamino- 1,2-dihydro- 1,3,5-triazines, 387 2,6-Diaminoimidazo[3,4-a][ 1,3,5]triazine, 392 2,5-Diarylfurans, 169 3,4-Diarylpyran-2-ones, 415 [1,3,2,4]Diazadiboretidine, 92 1,4-Diazepan-3-one, 440 1,4-Diazepin-2-ones, 442 1,4-Diazepinol, 44 I 1,3-Diazetidin-2-ones, 92 1,2-Diazetidine, 92 Dibenzo[b,d]pyran, 411 3,5-Dibromopyran-2-one, 416 Didemnum sp,, 1 Difluoro-2,3-dihydrobenzofuran, 168
2,5-Diformylfuran, 169 1,4-Dihydro- 1,2,4,5-tetrazines, 390 1,6-Dihydro- 1,2,4,5-tetrazines, 391 4,5-Dihydro- 1,2,4-triazin-6-one, 388 4,5-Dihydro- 1,3-oxazin-6-ones, 299 1,2-Dihydro-4(3H)-carbazolones, 142 6,7-Dihydro-5 H-imidazo[2,1 -c][ 1,2,4]thiadiazole-3thiones, 256 Dihydrobenzo[b]furan natural products, 158,159 Dihydrobenzo[c]furan natural products, 158,159 Dihydrobenzo[c] furans, 18 Dihydrobenzoxanthenes, 420 Dihydrodibenzo[b,d]furans, 184 Dihydrofuran natural products, 156,157 2,3-Dihydrofuran Patem6-Biichi rection, 166 2,3-Dihydrofuran, Heck coupling, 165,166 2,3-Dihydrofuran-2,3-diones, 415 Dihydrofurocoumarins, 181 3,4-Dihydroisoquinolines, 1l 3,4-Dihydroisoquinoliniums, 22 3,4-Dihydroisoxazolo[4,3-d][ 1,2,3]triazin-4-ones, 391 5,6-Dihydropyrano[2,3-c]pyrazol-4-ones, 205 tris(Dihydropyranyl)indium, 408 1,2-Dihydropyridine, 83 Dihydrotetrazolo[ 1,5-a]pyrimidines, 392 5It, 10H-Diimidazo[ 1,5-a; l ',5'-d]pyrazine-5,10-dione, 374 1,3-Dioxanes, 422 Dioxetanes, 91 1,3-Dioxoi-2-ones, 273 ! ,3-Dioxolan-2-ones, 272 1,3-Dioxolan-4-ones, 273 1,3-Dioxolium salts, 272 N-(Diphenylphosphinoyl) imines, 297 2,2'-bis(5,6-Diphenyl- 1,2,4-triazin-3-yl)-4,4'-bipyridine), 385 1,3-Diphosphacyclobutane, 93 1,3-Diphosphacyclobutane-2,4-diyl, 93 Dipyranone, 162 2,4,6-(Dipyridin-2-ylamino)- 1,3,5-triazine, 3 85 1,3-Diselenole-2-thione, 275 3A-1,2,3,4-Disiladigermetene, 93 Disilagermirenes, 93 Distannoxanes, 93 1,3-Ditelluretane, 93 1,3-Dithianylium triflate, 424 1,3-Dithiaphosphetane-2,4-disulfide, 93 Dithiatricyclo[4,2, I, 1]deca-3,7-dienes, 114 1,2,3-Dithiazoliums, 248 1,4-Dithiepines, 442 1,3-Dithietanones, 92 [ 1,2]Dithiete- l, 1-dioxides, 92 1,2-Dithiins, 424 Dithiolane sulfoxides, 274 1,3-Dithiolanes, 274 1,3-Dithiolium salts, 274
Index
1,2-Dithiolium salts, 278 DNA binder, 4 3-Ethoxycarbonylcoumarin, 181 Fluoropyran, 167 3-Formyl-5-hydroxy-2,3-dihydrofurans, 178 Furan natural products, 157,158 3(2H)-Furanones, 285 Furanophane, 187 Furans from allenes, 171,172 Furans, [4+3] cycloadditions, 163 Furans, cyclopropanation, 161 Furans, Diels-Alder reactions, 162 Furazano[3,4-b]pyrazines, 347 Furo[2,3-b]pyridones, 173 Furo[2,3-d]pyrido [ 1,2-a] pyrimidines, 357 Furo[2,3-d]pyrimidines, 347 Furo[2,3-d]thiazolidines, 236 2H-Furo[2,3-h]-l-benzopyran-2-ones, 181 Furo[3,2-b]pyridines, 314 Furo[3,2-b]pyrroles, 133,160,173 Furo[3,4-c] isoxazole, 284 Furo[3,4-c]pyridines, 187 Furobenzopyrandione, 420 Furyl sulfonamides, 168 Furyl-ot-pyrone, 169 2-Furylcarbenes, 170 1,6-bisFuryltriene, 169 Gelsemoxonine, 83 2-Geranylfuran, 160 Germabenzene, 447 Heptathiocanes, 101 Hexahydrobenzofuran-3a-ol, 166 Hexahydrocyclonona[ 1,2-b:4,5-b'qtriindoles, 149 3-Hydrazino- 1,2,4-triazin-5(2H)-one, 388 3-Hydrazino- 1,2,4-triazin-5-ones, 387 2-Hydroxychromanone, 419 3-Hydroxychromanone, 419 4-Hydroxycoumarin, 418 Hydroxycoumarins, 295 (R)-2-Hydroxyethyl- 1,3,5-triazine, 386 Imidazo[ 1,2-a][ 1,3,5]triazine-4-thione, 392 Imidazo[ 1,2-a]pyrazin-3 (7H)-ones, 372, 374 Imidazo[ 1,2-a]pyridines, 212, 213,216, 311-313,349 Imidazo[1,2-a]pyrimidines, 213,356-358 Imidazo[ 1,2-b][ 1,2,4]triazine, 391 Imidazo[ 1,2-b]pyridazinones, 352 Imidazo[ 1,2-b]pyridazines, 350 Imidazo[ 1,2-c]pyrimidines, 353, 357 6H-Imidazo[ 1,2-c]quinazolines, 213 5H-Imidazo[ 1,5-a]pyrazin-8-ones, 372 Imidazo[2,1 -b]thiazoles, 235 Imidazo[4,5-b]pyridines, 391 Imidazo[4,5-c]pyridines, 387 Imidazo[4,5-d]pyridazin-7-ones, 210, 350 Imidazo[ 4,5-d] pyri dazin- 7-ones, 392
471
Imidazo[4,5-f]pyridazines, 3 74 Imidazo[5,1 -b]thiazoles, 235 Imidazolines, 206 3-Imino- 1,2-dithioles, 278 2-Iminobenzoxathioles, 277 Imino-sugars, 162 Indazoles, 201 5H-Indeno[ 1,2-c]pyridazin-5-ones, 352 Indenopyrrolocarbazoles, 147 Indol-2-yl- 1H-quinolin-2-ones, 142 Indol-2-yl-2-pyridones, 142 3H-Indol-3-ones, 144 Indole-2,3-diones, 148 Indolizidines, 41, 150 Indolo[2,1-c]benzo[ 1,2,4]triazine, 397 Indolo[2,3-a]carbazoles, 142, 150 Indolo[3,2-b]benzo[b]thiophenes, 103 Indolo[3,2-b]carbazoles, 149 Indolo[3,2-b]quinolin-6-ones, 148 Indolo[3,2-e] [ 1,2,3 ]triazolo [ 1,5-a] pyrimidines, 214, 357 2-Indolones, 91 Integrase inhibitors, 4 o-Iodoacetoxycoumarins, 181 3-Iodoflavones, 418 lsatins, 148 Isobenzopyrylium, 162 Isobenzothiazoles, 231 Isochromans, 412 Isochromenoquinone, 413 Isocyanoacetamides, 293 Isomunchnones, 234 Isopropenyldihydrobenzofuran, 167 Isoquinolines, 9,15, 49 Isothiazolo[3,4-d]pyrimidines, 361 3-Isoxazole carbaldehydes, 286 Isoxazole-benzisoxazole rearrangement, 177, 284 Isoxazoles, 5,75, 88 Isoxazolidines, 89 5-Isoxazolidinones, 291 Isoxazolines, 16 Isoxazolo[3,4-d]pyrimidines, 286 Isoxazolo[4,5-b]pyridine N-oxides, 393 Isoxazolo[4,5-b]pyridines, 310 Isoxazolo[4,5-c]pyridine, 285 Isoxazolo[4,5-c]quinolines, 285 Iso xazolo [5,4-b ]pyri dine, 285 13-Lactams, 83-87,89-91 13-Lactones, 91 Lamellaria sp,, 1 Lamellarins, bioactivity, 4 Lamellarins, biogenesis, 3 Lamellarins, structures, 2,3 2-Lithio-2,3-dihydrofuran, 165 3-Lithiofuran, 168
472
Index
Loracarbef, 88 Lukianols, 3 Melamine, dendrimers, 389 (Menthyloxy)(3-furyl)carbene, 160 Merocyanine dyes, 411 2-Methoxyfuran, 162 2-Methoxyfurans, with Grignards, 170 3-Methoxyisoxazoline, 288 Methylazetidin-3-ones, 84 Methylenedioxolanes, 273 3-Methylenetetrahydrofurans, 177 Multi-drug resistance, 4 M~inchnones, 208,295 Naphth[3,2,1-cd]indoles, 147 Naphtho[ 1,2-b] furan, 414 Naphtho[ 1,2-b]pyran-4-one, 419 2H-Naphtho[ 1,2-b]pyrans, 411 Naphtho[ 1,2-c:5,6-c]difuran, 187 Naphtho[2,3-c]chromenes, 41 l 1,8-Naphthyridinyl-3 (2H)-pyridazinones, 350 Ningalines, 3,14 8-Nitro-2-dimethylam ino- 1,2,3,4-tetrahydro2-dibenzofuran, 182 2-Nitro-3-substituted-2,3-dihydrofurans, 178 3-Nitro-4-nitromethylchromans, 412 Nitrocoumarins, 184,417 Nitrones, 289-293 Oligothiophenes, 115, I 16, I 17 10-Oxa-3-aza-tricyclo[5,2, 1,01'5]dec-8-en-4-ones, 162 Oxabenzonorbornadienes, 164 1,3,4-Oxadiazoles, 205 1,2,4-Oxadiazoles, 304 1,3,4-Oxadiazolo [3,2-a] [ 1,3,5 ]triazi ne-5,7-dithiones, 393 [ 1,2,3]Oxadigermetanes, 93 [ 1,2]Oxaphosphetane 2-oxides, 93 1,2-Oxaphosphetanes, 93 1-Oxaspiro[4,5]deca-6,9-dien-8-one, 186 1,2-Oxastibetanes, 93 Oxathianes, 425 Oxathiins, 425 Oxathiolanes, 278 Oxathiolanones, 278 1,3-Oxathiolium salts, 277 1,2-Oxathiolium salts, 279 Oxazaphospholes, 75 1,4-Oxazepin-7-ones, 445 1,2-Oxazepines, 442,443 1,2-Oxazetidines, 92 Oxazole amino acids, 296 Oxazole C-nucleosides, 294 Oxazoles, 90 Oxazolidin-2-ones, 293,302,304 Oxazolidin-2-ones, 302 Oxazolidin-4-ones, 301 Oxazolidin-5-ones, 302 2-Oxazolidinethiones, 300
Oxazolidinones, 74, 300 Oxazolidinyl[ 1,2]oxazetidine, 291 2-Oxazolidinyloxirane, 29 l bis-Oxazoline ligands, 298 Oxazolines, 68 Oxazolo[ 3,2-a] pyrazin- 5-ones, 373 [ 1,3]Oxazolo[3,2-a]pyrimidinones, 363 Oxazolo[4,5-b]pyridines, 294 Oxazolo [4,5-c] quinoline-4(5//)-ones, 294 Oxazolo[4,5-c]quinoline-4-ones, 323 Oxazolones, 208 5(4H)-Oxazolones, 295 Oxazoloquinolines, 326 7H-Oxepin-4-ones, 438 Oxetanes, 90,91 4-Oxoazetidines, 89 Paclitaxel, 83,161 Papaverine, I l, 13 Pentathiepine, 446 Pentathiophenes, I 15 5,5'-bis-Perfluoroalkyl-2,2'-bisoxazoles, 294 Perhydrofuro[2,3-b]oxepine, 164 Phenanthrolines, 59 N-Phenyitriazolinedione, 92 Piperidine-2-thiones, 420 Platina[1,2]diphosphetane 1-oxide, 93 Platinaoxetanes, 93 Polycitones, 3 Polyketides from isoxazoles, 284 Polythiophenes, 119 Porphyrins, 85, 105,276,451,452, 456 Pteridines, 396,44 l Purine Grignard reagent, 394 Purines, 392-395 (2H-Pyran-6-yl)-3-phenylpropenones, 408 Pyrano[2,3-d]pyrimidines, 356 Pyrano[ 3,2-c]pyranones, 408 Pyrano[3,4-c]isoxazole, 284 Pyranoanthocyanins, 414 bis-Pyranone, 410 Pyranophane, 406 Pyrazino[ 1,2-a] indole- 1,4-diones, 375 Pyrazino[ 1,2-a]indoles, 146, 147, 216 Pyrazino[2,1 -b]quinazoline-3,6-diones, 347 Pyrazino[2,3-c][ 1,2,6]thiadiazine 2,2-dioxides, 396 l H-Pyrazino[2,3-c][ 1,2,6]thiadiazine, 374 Pyrazino[2,3-fl][ I, 10]phenanthrolines, 374 Pyrazolines, 201 Pyrazolo[ 1,3,5]triazines, 392 Pyrazolo[ 1,5-a][ 1,3,5]triazines, 392,393 Pyrazolo[ 1,5-a]pyrimidin-7-ones, 369 Pyrazolo[ 1,5-fl]phenanthridines, 202 Pyrazo Io[3 ',4':6,7] azepi no[ 5,4,3-cd] indoles, 205 Pyrazolo[3,4-b]pyridazines, 353,391 Pyrazolo[3,4-b] pyridines, 391
Index
Pyrazolo[3,4-b]pyrimidines, 391 1H-Pyrazolo[3,4-b]quinoxalines, 205 Pyrazolo [3,4- d]- 1,3-thiazolino [2,3-J] pyrim id in e s, 236, 362 Pyrazolo[3,4-d]pyrimidines, 353,363,368-370 Pyrazolo[ 3,4-d] pyrimidines, 395 Pyrazolo[4",3":5,6][4',3'-e]pyrido[3,2-c]pyridazines, 350 2H-Pyrazolo[4,3-c]isoquinoliniums, 333 6H-Pyrazolo [4,3-d]isoxazoles, 205 Pyrazolo[4,3-d] pyrimidin-7(6H)-ones, 358 Pyrazolo[4,3-d] pyrimidin-7-ones, 362 Pyrazolo[4,3-d]pyrimidines, 369 Pyrazolo[4,3-e]- 1,2,4-triazolo[ 1,5-c]pyrimidines, 369 Pyrazolo[ 5,1 -c][ 1,2,4]triazine, 392 Pyrazolopyridines, 42 tris(Pyrazolyl)- 1,3,5-triazine gold(I), 385 tris(Pyrazolyl)- 1,3,5-triazine palladium(II), 385 Pyridazines, 8 Pyridazino[3,4-h]psoralens, 349 Pyridazino[3,4-j]angelicins, 349 Pyridazino[ 4',3 ':4,5]thieno[ 3,2-d][ 1,2,3]triazines, 349 Pyridazino[ 4,3-h]psoralens, 350 Pyridazino[4,5-b][ 1,4]oxazine-3,8-diones, 350 Pyridinium salts, 415 Pyridino[2,3-d]pyrimidin-4-ones, 363 Pyridino[2,3-d]triazolino[4,5-a]pyrimidin-5-ones, 363 Pyrido[ 1',2': 1,2]imidazo[4,5-d]pyridazines, 349 Pyrido[ 1,2-a]pyrimidin-2-ones, 361 Pyrido[ 1,2-a]pyrimidines, 357, 364 1H,2H-Pyrido[ 1,2-c]pyrimidine- 1,3-diones, 353 Pyrido[2,3-b] [ 1,4]oxazin-2-ones, 310 Pyrido[2,3-d]pyrimidin-7-ones, 360, 369 Pyrido[2,3-d]pyrimidine oxides, 286, 358 Pyrido[2,3-d]pyrimidines, 356, 367, 368,370 Pyrido[ 2,3-d] pyrimidines-2,4(1H,3 H)diones, 365 Pyrido[3',2':4,5]pyrrolo[ 1,2-c]pyrimidines, 361 Pyrido[3',2':4,5]thieno[2,3-e]pyrrolo[1,2.a]pyrazines, 373 5H-Pyrido[3',2':5,6]thiopyrano[4,3-d]pyrimidines, 367 Pyrido[3,2-d] pyrimidin-4-ones, 387 Pyrido[3,2-d]pyrimidine-2,4-diones, 358, 362 Pyrido[3,4-b]pyrazines, 372, 375 Pyrido[4',3':4,5]thieno[2,3-d]pyrimidines, 357, 362 Pyridotriazines, 51 2-Pyridyl- 1,3-dioxolanes, 273 Pyrimido[ 1,2-b]- 1,2,4,5-tetrazin-6-ones, 396 2H,6H-Pyrimido[2,1-b][ 1,3]thiazines, 362 Pyrimido[4',5':4,5]thieno[2,3-c]pyridazines, 349 1H-Pyrimido[4,5-b][1,5]diazepine-2,4-diones, 354 Pyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones, 351 Pyrimido[4,5-c]pyridazines, 351
473
Pyrimido[4,5-d]pyrimidine-2,4( 1H,3H)-diones, 356 Pyrimido[4,5-d]pyrimidine-2,4-diones, 396 Pyrimido[ 5,4-e] [ 1,2,4]triazines, 396 Pyrroles, 3,5-14,17 Pyrrolidines, 83,88 Pyrroline N-oxide, 290 Pyrrolizidines, 150, 289 Pyrrolo[ 1,2-a]pyrazines, 375 Pyrrolo[ 1,2-a]quinoline- 1,4-diones, 324 Pyrrolo[ 1,2-c]pyrimidin- 1(5H)-ones, 364 Pyrrolo[2,1-a]isoquinolines, 11 Pyrrolo[2,1-b]thiazoles, 235 Pyrrolo[2, I-d][ 1,2,4,5]tetrazinones, 391 Pyrrolo[2,3-d]pyridazinones, 351 Pyrrolo[2,3-d]pyrimidine 5-oxides, 392 Pyrrolo[2,3-d]pyrimidines, 363,367, 369 1H-Pyrrolo [3,2-c] isothiazole-5 (4H)-ones, 247 Pyrrolo[3,2-c]pyridines, 136 1H-Pyrrolo[3,2-d]pyrimidines, 360 Pyrrolo[3,4-b]pyrazines, 373 Pyrrolo[3,4-c]quinolines, 328 6H-Pyrrolo[ 3,4-d]pyridazines, 348 Pyrylium salts, 414 Quadruple ring-closing metathesis, 179 Quarterthiophenes, 117 Quinazolinones, 210 Quinolizidines, 41 Radical bromo- and iodoetherizations, 175 1,2,3-Selenadiazoles, 261 1,3-Selenazoles, 260 Selenophenes, 451 Sexithiophenes, 108, 117, 461 5-Silabicyclo[3,2,0]heptatrienes, 93 Silacyclobutanes, 93 Silacyclobutenes, 93 4-Silatriafulvenes, 93 Siletanes, 93 2-Silyloxyfuran, 160,161 Solid-phase synthesis, 22,24 Solid-phase, in situ monitoring, 24 Spiro[ 1,3] oxazino[2,3-a]isoquinolines, 333 Steroidal [2,3-d]isoxazole, 284 3-Styrylchromones, 418 13-Sultams,92 T-Sultones, 279 Taxane, 91 Taxinine, 83 Taxol,90 Tellerophenes, 451 Tellurophenes, 102 Terthiophenes, 117, 121 Tetra(p-m elamin-2-ylphenyl)methane, 385 Tetraboranes, 93 4,4',6,6'-Tetracyano-2,2'-bis-triazine, 388 Tetrahydro- 1,2,4,5-tetrazines, 390
474
Index
Tet rahydro- 1H-imidazo[4,5-c] [ 1,2,5 ] -thiadiazol-5 ones, 257 Tetrahydrobenz[b]azepin-2-one, 436 Tetrahydrocarbazoles, 144 Tetrahydrofuran natural products, 156,157 Tetrahydrofuran radical, 166 Tetrahydrofuro[3,2-c]benzothiopyrans, 176,421 Tetrahydroimidazo[ 1,2-a] [ 1,3,5]triazine-4-thione, 392 Tetrahydropyrano[3,2-c]benzothiopyrans, 421 Tetrahydropyrrolo[3,2-e][ 1,2,4]triazines, 388 Tetraselenafulvalenes, 275 Tetrathiafulvalenes, 275,276, 277 1,2,4,5-Tetrazines, 7,8 Tetrazolo[ 1,5-a]pyridine, 395 Tetrazolo[ 1,5-b]pyridazines, 351 Tetrazolo[5,1 -a]-isoquinolines, 332 2-Thia- 1-phospha-bicyclo[3,2,0]heptane, 93 1,2,3-Thiadiazoles, 253 1,2,4-Thiadiazoles, 254 1,2,5-Thiadiazoles, 257 1,3,4-Thiadiazoles, 258,259, 368 bis([ 1,3,4]Thiadiazolo)[ ! ,3,5]triazinium halides, 398 [ 1,3,4]Thiadiazolothieno[3,2-e]pyrimidin-5(4H)ones, 368 Thianthrene, 442 1,2-Thiaphospholes, 93 1,4-Thiazepin-5-ones, 444 1,2-Thiazetidines, 92 1,3-Thiazin-4-ones, 249 Thiazole[4,5-c]quinolin-4(5 I/)-ones, 235 Thiazolidinethione, 82 1,3-Thiazolidinones, 230, 233 2H-A2-Thiazolines, 89 1,3-Thiazolium-4-olates, 85 Thiazolo[ 1,3,5]triazines, 392 Thiazolo[2,3-c][ 1,2,4]triazoles, 236 5H-Thiazolo[3,2-a]pyrimidin-3-ones, 353 Thiazolo[3,2-a]pyrimidines, 235,362 Thiazolo[3,2-a]triazines, 235 Thiazolo[3,2-b][ 1,2,4]triazoles, 235 Thiazolo[3,2-c]pyrimidines, 362 Thiazolo[4,5-b] pyridines, 236 Thiazolo[4,5-c]quinolines-4-ones, 323 Thiazolo[4,5-d]pyrim idine-7(6t/)-thiones, 235 Thiazolo[4,5-d]pyrimidines, 367 2(3H)-Thiazolones, 238 Thieno[2,3-b]carbazoles, 103 Thieno[2,3-b]pyrazines, 373 Thieno[2,3-b]pyridines, 101 Thieno[2,3-c][ 1,2,4]triazines, 393 Thieno[2,3-c]chromen-4-ones, I 01 Thieno[2,3-c]coumarins, 101 Thieno[2,3-c]pyridazines, 349 Thieno[2,3-d]pyrimidine-2,4-diones, 369
Thieno[2,3-d]pyrimidines, 101,362, 363 Th ieno[2,3-J] [ 1,2,4]triazolo[ 1,5-a] azepines, 220 Thieno[3,2-b]thiophenes, 119 Thieno[3,2-c]carbazoles, 103 Thieno[3,2-d] [ 1,3]oxazines, 104 Thieno[3,4-b]indolizines, 102 Thieno[3,4-b]thiophenes, 101 Thienocarbazoles, 141 Thienopentathiepins, 101 Thietanes, 92 Thietes, 92 o-Thiobenzoquinone methides, 421 Thiobutyrolactones, 92 2H-Thiochromen-4-yl enol phosphates, 410 Thiohydantoins, 92 Thioisomiinchones, 85 Thiophene- 1-imides, 92 3-Thio-substituted furans, 171 1,2,4,6-Thiotriazine 1, l-dioxide, 387 5-Thioxo-3,4-dihydro-2H- 1,2,4-triazin-3-one, 388 Topoisomerase I, 4 2,4,6-Triamino- 1,3,5-triazines, 387 2,3,5-Triarylfurans, 169 1,2,3-Triazin-5-ones, 386 1,2,4-Triazin-5-ones, 391,395 1,3,5-Triazine-2,4,6-trione, 385 2H- 1,2,4-Triazine-3,5-diones, 388 4H- 1,2,4-Triazine-5,6-di ones, 388 1,2,4-Triazines, 386 1,2,3-Triazinium salts, 387 1,3,5-Triazino[ 1,2-a]benzimidazoles, 213 [1,2,4]Triazino[4,3-a]benzimidazole, 397 1tl-[l,2,4]Triazino[4,5-a]quinoline-l,6(2H)-dione, 397 1,2,4-Triazoline-3,5-diones, 92 bis([l,2,4]Triazolo)[l,3,5]triazinium hal ides, 398 [ 1,2,4]Triazolo[ 1,3,4]thiadiazolo[ 1,3,5]triazinium halides, 398 Triazolo[ 1,3,5]triazines, 392 [ 1,2,3]Triazolo[ 1,5-a]pyrimidinium salts, 214, 365 [ 1,2,3]Triazolo[ 1,5-c]pyrimidinium salts, 214, 365 1,2,4-Triazolo[3,4-b] [ 1,3,4]quinolinothiadiazepines, 448 Triazolo[4,3-a]pyrimidines, 358 1,2,4-Triazolo[4,3-a]pyrimidines, 361 1,2,4-Tri azolo[4,3-b] [ 1,2,4]triazinones, 388 2H- 1,2,3-Triazolo [4,5-d] pyrim idine-5,7-d iones, 358 1,2,4-Triazolopyridines, 311 1,2,4-Triazolothiadiazine, 393 5-Tributylstannanyl isoxazoles, 286 4-Tributylstannanyl isoxazoles, 286 3-Trichioroacetyl-4,5-dihydrofuran, 165 Trichlorooxazolines, 299 2,4,6-Tricyano- 1,3,5-triazine, 388 6,5,5-Tricyclic cyclopenta[b]benzofuran, 181 N-Triisopropylsilylpyrrole, 17 5-Trimethylsilylthebaine, 167
Index
4H, 10H-6,8,9-Trioxa-2-thiabenz[/] azulen-5-ones, 104 1,3,5-Trioxanes, 32 1,2,4-Trioxanes, 423 1,2,4-Trioxolanes, 279 Tris(3',5'-dim ethylpyrazol- 1-yl)- 1,3,5-triazine, 385 1,2,3-Triselenagermolanes, 279 Tris-tetrahydropyran, 409 2,3,4-Trisubstituted furans, 17 l, 172
475 2,3,5-Trisubstituted furans, 172 1,2,3-Trithiagermolanes, 279 TTFs, 275,276,277 Uracil, 90 Uridine, 83 5-Vi nyloxazolidin-2-ones, 303 Zirconocene benz[t]indene complex, 165
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