General and Synthetic Methods (A Specialist Periodical Report, Vol 11)

General and Synthetic Methods Volume 11 A Specialist Periodical Report General and Synthetic Methods Volume 11 A Rev...

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General and Synthetic Methods Volume 11

A Specialist Periodical Report

General and Synthetic Methods Volume 11 A Review of the Literature Published in 1986 Senior Reporter G . Pattenden, Department of Chemistry, University of Nottingham Reporters K. Carr, University of Nottingham K. Cooper, Pfizer Central Research, Sandwich, Kent D.J. Coveney, University of Nottingham T. Gallagher, University of Bath L.M. Harwood, University of Oxford D.W. Knight, University of Nottingharn T.V. Lee, University of Bristol C.M. Marson, University of Sheffield K.E.B. Parkes, Roche Products Limited, Welwyn Garden City H erts. N. Simpkins, Queen Mary College, University of London S.E. Thomas, University of Warwick P.J. Whittle, Pfizer Central Research, Sandwich, Kent

SOClETY OF CHEMISTRY

ISBN 0-85 186-924-6 ISSN 0141-2140 Copyright 0 1989 The Royal Society of Chemistry All Riritrenpermission from the Royal Society of Chemistry

Published by The Royal Society of Chemistry, Thomas Graham House, Cambridge, CB4 4WF Printed by J . W . Arrowsmith Ltd, Bristol, England.

Introduction

This report on General and Synthetic Methods covers the literature published between January and December 1 9 8 6 . The aim of the Reports has been to provide a summary and assessment of reactions and methods in organic chemistry which are new (or useful variants of existing ones) and appear sufficiently general to be useful in synthesis. Interconversions between all the major functional groups are covered in five chapters (Chapters 1-S), and the applications of organometallic compounds in synthesis are treated in Chapter 6 . Two further chapters deal with developments in the synthesis of saturated carbocycles (Chapter 7) and saturated heterocycles (Chapter 8 ) and the final chapter provides a summary of 'Highlights in Total Synthesis of Natural Products'. A list of reviews on General and Synthetic methods is collected at the end of the Report. January 1 9 8 9

G. Pattenden

Contents

Chapter 1

1

Saturated and Unsaturated Hydrocarbons

By N. S i r n p k i n s

Chapter 2

Saturated Hydrocarbons

1

Olefinic Hydrocarbons

1

Conjugated 1,3-Dienes

16

Non-conjugated Dienes

23

Allenes

25

Alkynes

28

Enynes and Diynes

31

Polynes

34

Reference

38

43

Aldehydes and Ketones

By K.E.B.

Parkes

1

Synthesis of Aldehydes and Ketones Oxidative Methods Reductive Methods Methods Involving Umpolung Other Methods Cyclic Ketones

43 43 46 49 53 56

2

Synthesis of Functionalised Aldehydes and Ketones Unsaturated Aldehydes and Ketones a-Substituted Aldehydes and Ketones Dicarbonyl Compounds

63 72

Protection and Deprotection of Aldehydes Ketones

75

3 4

63

67

and

Reactions of Aldehydes and Ketones Reactions of Enolates Aldol Reacti&s Conjugate Addition Reactions

76 76 78 80

References

83

vii

Contents

viii

Chapter 3

Carboxylic Acids and Derivatives

89

By D.W. K n i g h t Carboxylic Acids General Synthesis Diacids and Half-esters Hydroxy-acids Keto-acids Unsaturated Acids Aromatic Acids Arylacetic Acids and Esters Acid Anhydrides Carboxylic Acid Protection

89 89 94 96 101 101 103

2

Carboxylic Acid Esters Esterification General Synthesis Diesters Hydroxy-esters Keto-esters Unsaturated Esters Aromatic Esters Thioesters, Selenoesters, and Related Compounds

108 108 110 113 116 124 130 144 144

3

Lactones p-Lactones Butyrolactones a-Methylenebutyrolactones Butenolides Tetronic Acids Phthalides Valerolactones Macrolides

148 148 148 159 161 165 165 168 173

4

Carboxylic Acid Amides

175

5

Amino-acids a-Amino-acids p-Amino-acids y-Amino-acids Unsaturated Amino-acids Asymmetric Hydrogenation Amino-acid Protection

179 179 185 188 188 189

References

191

Alcohols, Halogeno Compounds, and Ethers

208

1

Chapter 4

By L . M .

1

105

107 107

189

Harwood

Alcohols Preparation by Additions to Alkenes Preparation by Reduction of Carbonyl Compounds Preparation by Nucleophilic Alkylation Miscellaneous Methods Protection and Deprotection Reactions of Alcohols

208 208 211 215 227 231 235

ix

Contents

Oxidat Lon Deoxygenation Miscellaneous Reactions

235 237 239

2

Halogeno-compounds Preparation from Alcohols Preparation by Addition to Unsaturated Substrates Interhalide Conversions Halogenation of a- to Carbonyl Groups Miscellaneous Methods Reactions Elimination and Dehalogenation Coupling Reactions Miscellaneous Reactions

239 239 239 241 242 242 244 244 246

3

Ethers Preparation Reactions

248 248 250

4

Thiols

252

5

Thioethers

252

References

254

Amines, Nitriles, and other Nitrogen-containing Functional Groups

262

Chapter 5

By C.M.

MarSOn

1

Amines Primary Amines Secondary Amines Tertiary Amines Diamines Polyamines

262 262 272 280 282 285

2

Enamines

288

3

Allylamines, Homoallylamines, and Alkynlamines

290

4

Amino-alcohols

295

5

Amino-carbonyl Compounds

299

6

Amides and Thioamides

313

7

Nitriles and Isocyanides

332

8

Nitro- and Nitroso-compounds

342

9

Hydrazines and Hydrazones

355

10

Hydroxylamines and Hydroxamic acids

358

11

Imines, Iminium Salts, and Related Compounds

361

12

Oximes

368

13

Carbodi-imides

369

Conrents

X

14

Azides and Diazo-compounds

369

15

Azo- and Azoxy-compounds

373

16

Isocyanates, Thiocyanates, and Isothiocyanates

375

17

Nitrones

377

18

Nitrates and Nitrites

378

References

378

Organometallics in Synthesis

393

Chapter 6

By S.E. Thomas and T. Gallagher PART I:

The Transition Elements

393

By S.E. Thomas 1

Introduction

393

2

Reduction

393

3

Oxidation

398

4

Isomerisations and Rearrangements

401

5

Carbon-carbon Bond-forming Reactions via Organometallic Electrophiles via Organometallic Nucleophiles via Coupling and Cycloaddition Reactions via Carbonylation Reactions

401 401 410 420 427

6

Miscellaneous Reactions

432

References

432

Main Group Elements

437

PART 11:

By T. Gallagher

1

Group I Selective Lithiation Dianions, Alkenyl, and Alkynyl Anions Sodium and Potassium Sulphur and Selenium Stabilised Anions.

437 437 446 453 455

2

Group I1 Beryllium, Magnesium, and Calcium Zinc and Mercury

465 465 467

3

Group I11 Boron Aluminium and Thallium

471 471 478

xi

Contents

4

Group IV Silicon Allyl, Propargyl, and Benzyl Silanes Vinyl, Alkynyl, and Allenylsilanes Other Silicon-containing Reagents Tin and Lead

480 480 480 485 490 493

5

Group V Phosphorus Antimony and Bismuth

497 497 501

6

Group VI Sulphur Selenium and Tellurium

501 501 507

References

508

Saturated Carbocyclic Ring Synthesis

518

Chapter 7

By T.V. Lee 1

Three-membered Rings General Methods

518 518

2

Four-membered Rings

518

3

Five-membered Rings General Methods Fused Five-membered Rings

523 523 528

4

Six-membered Rings Diels-Alder Reactions Other Syntheses of Six-membered Rings Polyene Cyclisation

535 535 538 541

5

Seven-membered, Medium, and Large Rings

541

6

Ring Expansion Methods and Spiro-ring Compounds

543

References

543

Saturated Heterocyclic Ring Synthesis

547

Chapter 8

By K. Cooper and P.J. Whittle

1

Oxygen-containing Heterocycles Three-membered Rings Five-membered Rings Tetrahydrofurans Dihydrofurans Five-membered Rings containing more than One Oxygen Six-membered Rings Tetrahydropyrans and Dihydropyrans Pyrans Polyether Ionophores Medium Rings

547 547 551 551 554 557 557 557 560 560 563

Contents

xii

2

Sulphur-containing Heterocycles

565

3

Heterocycles containing more than One Heteroatom Nitrogen- and Oxygen-containing Rings Nitrogen- and Sulphur-containing Rings Oxygen and Sulphur, and Oxygen-, Nitrogen-, and Sulphur-containing Rings

568 568 571

4

Chapter 9

571 571 571

Nitrogen-containing Heterocycles Three-membered Rings Five-membered Rings containing more than One Nitrogen Six-membered Rings Six-membered Rings containing more than One Nitrogen Seven-membered Rings p- Lactams

600 603

References

607

Highlights in Total Synthesis of Natural Products

612

588 588

600

By K. Carr, D.J. Coveney, and G. Pattenden 1

Terpenes

612

2

Steroids

624

3

Alkaloids

624

4

Prostaglandins

637

5

Spiroacetals

641

6

Ionophores and Macrolides

645

7

Other Natural Products

649

References

656

Reviews on General and Synthetic Methods

659

Compiled by K. Carr, D.J.

Coveney, and G. Pattenden

1

Esters and Lactones

659

2

Fluoroorganic Compounds

659

3

Ketenes

659

4

Nitrogen-containing Functional Groups

659

5

Organometallics

660

6

Carbocyclic Ring Synthesis

661

Xlll

Contents 7

Heterocycles

662

8

Natural Products

662

9

Asymmetric and Selective Synthesis

663

10

Enzymic Reactions

664

11

Reduction

664

12

Photochemistry, Electrochemistry, and Sonochemistry 664

13

Radical Chemistry

665

14

General

665

15

Miscellaneous

666

Author Index

668

A

Saturated and Unsaturated Hydrocarbons BY N. SlMPKlNS

1

Saturated Hydrocarbons

A new radical method for the deoxygenation of secondary alchols has

appeared.'

The method consists of first reacting the alcohol with 2,2'-dibenzothiazolydisulphide in the presence of Bu3P leading to

the corresponding sulphide derivative ( l ) , which is then reacted with Bu 3 SnH to give the hydrocarbon product in excellent yield (Scheme 1). A wide variety of aryl aldehydes and ketones can be deoxygenated by a mixture of Zn12 and NaCNBH3 in dichloroethane.2 The reagent also gives good results with benzyiic, allylic and tertiary alcohols, although attempted reduction of u,@-unsaturated ketones gave complex mixtures of products. Highly efficient conjugate reduction of a,@-unsaturated ketones and aldehydes is possible by use of a three component system comprising a palladium catalyst, a hydrosilane, and zinc chloride (Scheme 2) .3

The same task of conjugate reduction can be accomplished on unsaturated esters, usually in near quantitative yield, using magnesium in methanol. 2

Olefinic Hydrocarbons

The protonolysis of alkenyldialkylboranes to give 2-alkenes can be conducted, in most cases, under neutral conditions using methanol. More hindered alkenyldisiamylboranes react less well, unless a small amount of a carboxylic acid is added. A variety of Z-alkenyl pheromones was prepared using this method.6 The synthesis of trans-alkenes

and unsymmetrical ketones was also accomplished

using vinylic organoborane chemistry.' Cross-coupling reactions are now possible between aryl (or vinyl) halides and trialkylboranes by the use of catalytic palladium (Scheme 3 ) . 8 The reaction appears not to suffer from side reactions due to 6-hydride elimination which are normally observed in such processes. The reduction of allylic acetates to the 1

2

General and Synthetic Methods

Bu3 SnH, AlBN

R’

\

R S H 2

Scheme 1

U

C

H

O

Scheme 2

Y

@

____) 9BBN THF

[fi

AcO

“‘Y/ Pd’,

Scheme 3

NaOH

3

1: Saturated and UnsaturatedHydrocarbons

(2)

(3) i RCHO ii H ~ O +

t

C02Et

Scheme 4

Ar3p+r-

SiR,

+

RIACHO

R2

+RIA/ OSi R3

R

'

r

S

i

R

1

OSiR,

+

R2

R2 anti ( L ]

R* syn ( L )

(51

Scheme 5

'yo R'

Li

CICH21, MeL;

CL

Scheme 6

Li

-+

General and Synthetic Methoak

4

68 ' l o

CO2Si Et2Me

05 iEt2 Me 70 'lo Scheme 7

P

h

S

G

C

N

Bu'Li,

TMEDA

75"/0

P h S \ O / M .

56Ole Scheme 8

Scheme 9

5

I: Saturated and Unsaturated Hydrocarbons

corresponding alkenes has been reported using Sm12 with a Pd(0) catalyst. The reaction gave high yields of deoxygenated products: unfortunately, mixtures of regioisomers usually result. Brandsma has illustrated the use of a new and highly potent basic mixture comprising ButOK, BuLi and TMEDA, by efficient generation of vinylpotassium from ethene. l o Warren's examination of the Horner-Wittig reaction continues with two more papers detailing the stereoselective reduction of The phosphorane (2) is normally rather a - ~ ~ p- o ketones.'' unreactive: however addition of NaH produces the ylide anion (3) which reacts with aldehydes to give predominantly ?-products (Scheme 4) .I2 The homologation of esters via a DIBAL reduction and phosphonate extension sequence is a commonly desired transformation.

The DIBAL reduction to give an aldehyde suitable

for homologation is often plagued by over-reaction problems,so that a reduction-reoxidation procedure is often required.

These

problems can be overcome by the neat trick of carrying out the ester reduction in the presence of the phosphonate anion.13 The Seyferth-Wittig reagent often gives vinylated by-products ( 4 ) , as well as the usually desired allylsilanes (5) (Scheme 5). Efficient and stereoselective formation of the syn-vinylated product (4) can be promoted by choice of suitable groups on silicon.l4 Wittig-type olefination reactions can be carried out using tungsten alkylidene complexes,15 and by the use of & I situ generated chloromethyl lithium (Scheme 6) .l 6 Diiodo alkenes have been prepared __ via a Wittig-like reaction which requires no base.17 Me3SiC1 accelerates the reaction of both catalytic and stoichiometric copper reagents with unsaturated carbonyl compounds to give the desired silylenol ethers. l8 An extensive study of the C ~ ~ ( C O ) ~ - c a t a l y sreaction ed of acetates and lactones with CO and HSiEt2Me has appeared." This reaction constitutes a very general, mild and high-yielding synthesis of siloxymethylidene products (Scheme 7 ) . Vinyl sulphides are available by reaction of phenylthiocarbenes with nitrile anions.20 Yields on the whole are fair to good, and with some modification several intramolecular versions are possible (Scheme 8). Vinyl sulphides, vinyl selenides and ketene seleno(thi0) acetals are formed in high yield by reaction of an appropriate vinyl bromide or dibromide with PhSe- or PhS- in the presence of a Ni (11) catalyst. 21 6-Phenylthio-nitro-olefins have been prepared as mixtures of stereoisomers as shown in Scheme 9.22

6


HR3, HR3 F

R’

6utLi

-120 R2

wR3

R’

PhSQN-BuL I

R’

OC

I

R2

Li

R2

F

71- 88% Scheme 10

H 66% Ref. 26 R’C=CR*+

MX e.g.X=F,Cl,I or SCN

hR1 RZ

Ref. 27

Ref. 28 Scheme 11

Ref. 29

7 3 *I. Scheme 12

Ref. 30


7

Me (PhMqSi)2 CuLi, THF

Me

Me

SiMe2Ph 96 *I*

-

Me Me>-,

Me

SiMe2Ph

99 Ye

Scheme 13

-RHHHH Bu3SnBEtjL i

RC=CH

R

+

THF, McOH, CuCN

SnBuJ

H

BusSn

H

(8 1 Scheme 14

L i-C=C

Et3B

-R1

Me3SnCI

Li+[Et3&CsC-R1]

D -

E128

SnMq

1

i. Bu"Li , CuBr SMeZ ii, R2 X

Et

?(%Me3

R1

Ref.35

- i , PriNMgBr

ii , TfZNPh

63 *I* Scheme 15

80% Ref. 36

8


Oxidation of the sulphide ( 6 ) to either the corresponding SulPhOxide or sulphone was also possible, and the products were used in Diels-Alder reactions. Alkenyl fluorides are available by reaction of the corresponding lithio compound with N-tert-butyl-N-fiuoro-benzene sulphonamide (Scheme 10) .23 Two new reports extend the chemistry of fluorinated vinyl organometallics. In the first, trifluorovinyllithium is shown to be much more stable in Et20 (up to -30°C) than in THF.24 Remarkably, the other research paper by the same group reports that the corresponding zinc reagent F C=CF-ZnC1 is stable for several days

"

in THF at room temperature. These findinqs a1 lowed considerable extension to the synthetic repertoire of these reagents. A variety of fluorinated products, including perfluoroalkylated alkenyl iodides are available y&i a palladium-catalysed reaction between perfluoroakyl iodides (RfI) and alkynes.26 This method and two other routes to alkenyl iodides are outlined in Scheme 1 1 . The use of bis(pyridine)iodotetrafluoroborate (7) in conjunction with various metal salts gave good yields of the desired 1,2-iodofunctionalised olefins.27 Curran's notable contributions to radical chemistry continue with a novel reaction which isomerises hex-5-ynyl iodides to the product (iodomethylene)cyclo-pentanes.2 8 2,2-Disubstituted vinylsilanes have been prepared in reqio and stereoselective fashion by reaction of aryl iodides with This and alkynyl silanes in the presence of a palladium catalyst." another palladium-catalysed transformation leading to aryl vinysilanes3' are outlined in Scheme 12. The latter process, involving arylation of trimethylvinylsilane with aryl iodides takes place smoothly if silver salts are included in the mixture; otherwise styrenes are formed y & a presumed addition-desilylpalladation. The scope of the palladium mediated addition of silylstannanes to acetylenes highlighted last year has been further examined.31 Allenes react with bis(phenyldimethylsily1)cuprate to give either vinylsilanes or

allylsilanes depending on the structure of the allene (Scheme 1 3 ) .32 The intermediate ally1 or vinyl copper reagents could also be reacted efficiently with other electrophiles such as MeI, CH3COC1, etc. The addition of PhMe2SiBEt3Li or Bu3SnBEt3Li to acetylenes occurs cleanly using CuCN as catalyst (Scheme 14) .33 This stereospecific *-addition

also exhibits good


9

BU"

SiMe,

y'""

Pd(OAd2, BujSnOAc

Ph

+

( 9 ) 81%, 97% E Ref. 38

v0vo W h 3 ,

Ph

V

(11)

O

V

(101 74%

O

Ref. 39

Me3Si &OAc (11 1

Scheme 16

Scheme 17

Ref. 42

MeMg-N

Y

~

OMe

HO@:Tr

OMe 94%, Ref. 43 Scheme 18

10


[ Rd] R'N=SePh

R

RNCS 'NH~

(14)

Scheme 19

Scheme 20 E

70%

Ref. 47

73%

Ref. 48


11

regioselectivity, especially if CoC12(PPh3)2 is employed in place of CuCN, in which case the terminal isomer (8) is the exclusive product. A related report from the same research group describes

another synthesis of vinyl silanes by reacting alkenyl halides with (R3Si)3MnMgMe.3 4 Two other notable entries to vinyl silanes have appeared and examples are shown in Scheme 15. The first sequence35 uses the known stereoselective boron to carbon migration of an alkyl group using Me3SnC1 as the electrophilic trap. The boron group is then selectively attacked using n-BuLi, CuBr-SMe2 to give the alkenyl copper which can then be coupled with either ally1 bromide or methyl iodide. In the other method36 enol triflates are coupled with distannanes in a similar fashion to the well-established reaction with organostannanes. A number of (1-cyclohexeny1)diphenylphosphine oxides were prepared by Diels-Alder reaction of 37 2 - ( d i p h e n y l p h o s p h i n y l ) - 1 , 3 - b u t a d i e n e with suitable partners. Allylically unsaturated cyclic ethers of the same general type have been prepared by the research groups of Overman3* and T r ~ s t . ~ ’ Thus suitably substituted vinyl silanes undergo Lewis acid mediated intramolecular attack on a methoxyethoxymethyl (MEM) ether to give cyclic products, e.g. (9) (Scheme 16). The preparation of (10) by use of the trimethylenernethane (TMM) reagent ( 1 1 ) (which will not normally react with carbonyl groups) was made possible by the addition of Bu SnOAc in catalytic quantities. 3 Allylic alcohols (12) are formed when a,fi-epoxy sulphides are treated with 3-5 equivalents of BuLi at - 7 0 ° C (Scheme 17) . 4 0 Interestingly, clean desulphurisation to give the epoxide product (13) was also possible by the use of less BuLi at - 1 0 0 ° C . Opening of vinylic epoxides by organomercurials, mediated by palladium also gives allylic alcohol^,^' as do two other new methods which use epoxides as starting materials (Scheme 18). Thus transformation of chloromethyl epoxides to 2-substituted allylic alcohols occurs on exposure to telluride ion.4 2 Methylmagnesium-N-cyclohexylisopylamide is a new, mild reagent for isomerisation of epoxides. 43 The scope of the synthesis of allylic amines and their protected derivatives via sigmatropic rearrangement of selenilimines ( 1 4 ) has been examined (Scheme 19) .44 The reaction works well unless very sterically conjested products are being formed, and has some advantages over the original Sharpless procedure which provided the products as sulphonamides. Allylic amines have also been prepared via palladium catalysed azidation of


12

Scheme 22

OBn +

Ph

phkIy-*

PhMezSi

OLi

PhMezSi

MeCHO

--+

P h Me2Si Ph$

Me

(16)

(15) Scheme 23

-

SiMe,

-

90O l O -~iMe,

95 %

Scheme 24

AryAr NaCHZ?, THF

OAc

Pd, Ligand

*‘cA z

e.9. Z=coMe or C02Me Scheme 25


13 Ph

PhYNvco2Me i , LDA

Ph

(17)

Scheme 2 6

99 'Ie d .e. , 96% e.e. Ref. 61

(20)

I

OH

bH Ref. 60

Scheme 27

Bu3SnH, AlBN

85 'Ie

Scheme 28

14


allylic acetatesI4’ and by an elegant nitrone route described by DeShong (Scheme 2 0 ) .46 Thus, reaction of nitrones with vinyl silanes followed by reduction provides Peterson - type or Eintermediates which can then be eliminated to either

z-

products. Homoallylic amines were also prepared using allylsilane in the initial cycloaddition. Substitution reactions of allylic nitro compounds have received considerable attention and some examples are outlined in Scheme 21. In each case, examination of the regiochemistry of the reaction was of paramount concern, the results using palladium being superior to the SnC14 mediated process. Allylic sulphides constitute yet another group of products accessible by palladium mediated allylation.50 Excellent yields of allylstannanes are obtained in a new ultrasound-promoted preparation, (Scheme 22) .” The method is highly attractive in its simplicity, and gives isomerically pure compounds in some cases. Fleming has described further work on the synthesis of allylsilanes. 52 Thus stereoselective aldol condensation of a @-silylenolate, e.g. ( 1 5 ) , with an aldehyde was followed by a decarboxylative elimination to provide the allylsilane stereoselectively (Scheme 23). The corresponding trans-allylsilane could also be prepared from (16) using an alternative elimination via the 6-lactone. Stereocomplementary sequences were also possible using the Z-enolate corresponding to (15). A survey of transition metal catalysts, and ligands identified [Ir-(COD) (PPh3)2] PF6 as the most efficient for the isomerisation of alkenyl silanes to allylsilanes (Scheme 2 4 ) .53 By-products of the reaction include vinyl silane and saturated silanes. A new electrochemical oxidative cleavage of allylsilanes and benzylsilanes produces allyl or benzyl ethers.5 4 Asymmetric modifications of the palladium-catalysed allylic alkylation reaction have appeared from several laboratories. Very good results were obtained in the reaction of racemic allylic acetates with soft carbon nucleophiles in the presence of optically active ferrocenylphosphine ligands (Scheme 25) .55 The products could be obtained in up to E. 90% ee and in high yield. Kinetic resolution of racemic allylic acetates was also found to be possible.56 A similar asymmetric process combines an allyl acetate with a prochiral nucleophile to give the chiral allylated product (Scheme 26) . 5 7 Using the Schiff base (17) derived from glycine, the allylated amino ester (18) was prepared in up to 5 7 % ee. Asymmetric preparations of homoallylic alcohols have also appeared, most notably by reaction of allylic tin complexes with aldehydes.58

I : Saturated and Unsaturated Hydrocarbons

- RT -MgBr, 0

RCECCH20H

Cur

H

w I

9 i,CI2ZnCpz, 2 k L i

H

p q o -

-

ii,CO

SiMe3

SiMe3

Scheme 29

87 Y o

4

B(OPr ' l2

Ph

59 ' l o

76 '10

Scheme 30

t

Scheme 31

other isomers

Ph


16

Metallic zinc or iron in the presence of BiC13 can be used to mediate the reaction between allylic halides and aldehydes to give homoallylic alcohols. 59

The method displays notable chemoselectivity betweeen aldehydes and ketones, and alcohol or

phenol groups can be incorporated in the substrates without protection. Both Roush6O and Brown61 have published studies of the stereoselective synthesis of homoallylic alcohols using various allylboron reagents (Scheme 27).

Thus Brown made use of

5- or

E-crotyl diisopinocamphenylborones, e.9. (19) prepared in situ, to

-

give any of the four possible isomeric 6-methylhomoallyl alcohol products in excellent de and ee.

Scheme 27 also highlights Roush's

results using tartrate-modified crotylboronates such as (20) with chiral aldehydes.

A number of cyclic homoallyl alcohols were

obtained using radical cyclisation of vinyl radicals onto trimethylsilylenol ethers (Scheme 28).

62

The problem of stereoselective construction of exocyclic alkenes has been addressed by two methods, both-starting with alkynes. Thus stereoselective allylmetallation of propargyl alcohols yielded intermediates capable of further elaboration by zirconium

-

promoted bicyclisation - carbonylation (Scheme 29) .63

The other approach used the stereospecific conversion of an alkynyl trialkylborate to a trisubstituted olefin,

the migration of an

alkyl group from boron to carbon.64 3

Conjugated 1,3-Dienes

Hydrodimerisation of terminal alkynes to give symmetrical trans, trans

-

1,3-dienes can be carried out straightforwardly by use of a A wide

CoC12/NaBH4/PPh3 system65: internal alkynes are unaffected.

variety of conjugated dienyl products are available by employing the palladium

-

catalysed coupling of alkenyl boronates with Both mono- and

various ary1,vinyl or ally1 halides (Scheme 30) . 6 6

disubstituted alkenyl boronates can be employed in this sequence, thus allowing for a high degree of flexibility.

The same group of

research workers has also published some closely related work

(z,?)

enabling stereoselective synthesis of -l-bromo-l13-dienes.67 Various dienyl alcohols and lactones were amongst the products prepared by reaction of allylic acetates with carbonyl compounds (Scheme 31) . 6 8 The method suffers from a lack of selectivity, both stereo - and regio-isomers being formed in most cases.

A

variety

of l-nitro-lI3-dienes were prepared by treatment of the corresponding dienes with trifluoroacetyl nitrate (prepared

&

1: Saturated and Unsaturated Hydrocarbons

17

Scheme 33

LiAIH4, THF

*

R

t

G

4

R*

R3

H

(21)

Ref. 72

-

Me3Si

SBBN

Me3Si

->‘iBD

me351

Me3Si (22)

or isomer Ref.

73

Scheme 34 0

SiMej Scheme 35

0


18

SiMe3 I

NMe,

(24)

(26)

Ref. 78 OAc

Me0

rCo /

\

Piperovatine

Scheme 37

Ref. 79

19


Rsk

RS

X = CL or F

Scheme 38

(27)

-p;

Scheme 39

-qp@cp

OCOzMe

Ph

74Ole Scheme 40

20


e )followed , by

an elimination step using KOAc (Scheme 32) .69 The dienyl products are sensitive to both acid and base but can be purified by distillation or by flash chromatography on silica gel impregnated with sodium carbonate. A new short route to dienyl-tin products proceeds via hydrozirconation of conjugated enynes, followed by transmetallation using Bu3SnCl . 7 0 Vinyl triflates can be coupled efficiently to various organotin compounds. Further details of this chemistry have now appeared including efficient preparations of trimethylsilyldienes (Scheme 33) .71 Two other routes to silyldienes are outlined in Scheme 34. Reduction of allenic alcohols ( 2 1 ) gave moderate yields of the dienyl products, although the stereoselectivity of the process leaves much to be desired. The second method, involving hydroboration of the allene ( 2 2 ) is much more stereoselective and enables either isomer of the final product to be obtained depending on the elimination conditions used. A key application for such dienes is in Diels-Alder reactions, where the products have vinylsilane functionality for further modification. This type of chemistry has now been explored with 2,3-bis(trimethylsilyl)buta-l, 3-dieneI itself readily available by dimerisation of organolithium ( 2 3 ) (Scheme 35) . 74 Diels-Alder chemistry of the silyl-substituted diene (24)7 5 and of 2-tributylstanny1-1,3-butadiene (25)7 6 , has also been reported (Scheme 3 6 ) . Reaction of (24) with a suitable dienophile gives an intermediate, e.g. (26) which, after elimination, undergoes a second cycloaddition. The scope of the sequence is quite broad, enabling heterocycloadditions and (3+4) cycloadditions to be incorporated. The vinylstannanes resulting from cycloadditions with ( 2 5 ) are rather versatile, as was demonstrated by conversion to an a,B-unsaturated acid. Double elimination reactions of B-substituted sulphones provides access to both unfunctionalised d i e n e ~and ~ ~ to dienamides.78 The method is shown in Scheme 37 along with another dienamide preparation which utilises M O ( C O ) ~in a key elimination step.79 Other syntheses of such unsaturated carbonyls include the acylation reaction of bisalky1thio-lI3-alkadienes, and the use of 3-phenylselenobutanal as a crotonaldehyde equivalent in phosphonate reactions (Scheme 38) The latter sequence proved superior to that using crotonaldehyde which gave poor yields of difficult-to-purify material. A number of a-methlene lactams unexpectedly furnished novel

1: Saturated and UnsaturatedHydrocarbons

21

SO2Ph

I

-+p+) R‘

Scheme 41

Scheme 42

RXZnBr

R
9 5 % ) , the carboxylic acids.' reactions are very rapid, often taking less than 10 minutes but most significantly, a variety of protecting groups including acetonides, TBDMS, ThP, MOM and benzyl ethers are unaffected by this reagent mixture.

A somewhat less mild method consists of treating an

aldehyde (RCHO) with t-butyl trimethylsilyl peroxide and a catalytic amount of trityl perchlorate resulting in the formation of a diperoxide species [RCH(02LBu)2] which is decomposed to the acid, RC02H, using either aqueous piperidine at 90°C or copper sulphate and

(L)-ascorbic acid at ambient temperature.

Yields are generally good;

isolated olefins and benzyl ethers at least are not affected.

This

method is clearly limited in scale whereas an alternative method for oxidising aldehydes to acids using sodium chlorite and 35% hydrogen peroxide does appear to have some potential for large scale work.3 Yields are especially high for oxidations of aromatic aldehydes, and for other conjugated aldehydes such as cinnamaldehydes, and saturated aliphatic aldehydes.

Isolated double bonds, amino groups and Bisulphite complexes of aldehydes are

sulphides are also attacked.

efficiently oxidised to carboxylic acids using a Moffatt-type oxidation with dimethyl sulphoxide and acetic a n h ~ d r i d e . ~Work up of the reaction mixture with methanolic methoxide or an amine gives the corresponding ester or amide. Both alcohols and aldehydes can be oxidised to carboxylic acids using ruthenium tetroxide;

an efficient, two-phase (CC14-aq.NaC1)

electro-oxidation method has been developed for the generation of Ru04 which could be especially useful f o r oxidations of carbohydrate derivatives, partly protected as acetonides. Zinc dichromate 89

General and Synthetic Metho&

90

R’ .‘CON

19 1

SiPh,Me

RAcop

Mez

(1 0 )

91

3: Carboxylic Acids and Derivatives

trihydrate is also capable of oxidising a variety of primary alcohols to the corresponding carboxylic acids. However, the acidic nature of the reagent makes it incompatible with ketals and probably many other acid-labile groups;

the reagent also oxidises aromatic systems and

can attack olefins and acetylenes. 1,2-Diols are efficiently cl?aved to the corresponding carboxylic acids, usually in excellent yields ( > g o % ) , simply by treatment with hydrogen peroxide (40% w/v) but in the presence of both tungstate (Na2W04.2H20) and phosphate (H3P04) catalysts at P H ~ .The ~ method could be especially useful for large scale preparations. A new method for obtaining chiral a-substituted carboxylic acids

consists of S,2' ring openings of the tartramide-derived acetals ( 1 ) by trialkylaluminum reagents followed by cleavage of the major products (2) using KMn04-Na104.8 Optical yields of the acids ( 3 ) are often essentially quantitative, but the method is clearly limited by the availability of the aluminum reagent and the wastage of two alkyl groups, as well as by the oxidative cleavage method which precludes, for example, the presence of other double bonds.

However, many useful

products can be obtained, and the ready availability of both enantiomers of the acetal ( 1 ) is an additional attraction. Rather more familiar ligands have also been used to direct asymmetric alkylations a- to carboxylic acid precursors. Thus the pyrrolidine (4) can be enolised and alkylated to provide the di-substituted cyano-acetic Such alkylations are acids (5) [80-90% eel after acidic hydrolysis.' often prevented by the bulky chiral ligand; in this case the small steric requirement. of the cyano group is presumably crucial to the success of the method.

During work towards a synthesis of the

ionophore antibiotic ionomycin, Evans has utilised his prolinol propionamide methodology to obtain acid ( 6 ) of very high optical purity . 10 Simple unsaturated acids [e.g. ( 7 ) l can be reduced in essentially quantitative optical yields to give butanoates (8) using an enoate reductase together with methyl viologen (paraquat) as an electron-transfer reagent, hydrogen and a modified Pd-C or Pt-C hydrogenation catalyst. The system looks particularly simple and will hopefully be effective with a variety of other substrates. The hindered cyclopropyl ester ( 9 ) , as well as the corresponding t-butyl ester, can be lithiated [using tBuLi in the case of ester ( 9 ) ] and homologated by reactive electrophiles such as allylic bromides and aldehydes : subsequent ester cleavage using KOtBu provides the


92

R’

f ‘2 H

OC Ph3

(18)

0

\I

Ph..

H

122)

(211

Ph

I

Ph/ (251

(241

(23)

R3 A r y S S H

CO,H

R2+C0,

0

H

S R’

(27)

(26)

,CO,Me R 1 CO,H 4

‘CO, H H (301

(29) H

HO,C

OR

’r H

OH Co2Et

“;ii

CO,H

02E

93


cyclopropanecarboxylic acids ( 1 0 )

.IL

Further routes to some useful

a-substituted acids have been reported.

Phenoxides adsorbed on

Amberlite IRA 4 0 0 resin react smoothly with sodium chloroacetate to give aryloxyacetic acids (11) in good yields.13 In common with other bulky silyl chlorides, diphenylmethylsilyl chloride C-silylates carboxylic acid dianions to give acids (12) which can be re-enolised and alkylated at the a-position.14 Further developments in the preparation of chiral O-substituted carboxylic acids using ligands derived from camphor have been described by Oppolzer.

For example, the sultam-imides (13) can be

hydrogenated with > 90% diastereofacial selectivity to give acids ( 1 4 ) and recovered ligand in excellent yields after hydrolysis. l 5 Despite some obvious limitations, this methodology seems certain to find many applications.

The same starting material (13) also undergoes

asymmetric conjugate addition of hydride when treated with L-selectride; trapping of the resulting enolate with methyl iodide followed by hydrolysis has been used to obtain the acid (15) in a single operation and in excellent optical yield.16

As with the

foregoing protocol, this method could find many applications. Further examples of the elaboration of chiral B-substituted acids [e.g. ( 1 4 ) l using Michael additions to sterically screened alkenoates An alternative to also derived from camphor have been reported.” this is the addition of nucleophiles to proline derivatives (16); depending upon the precise way the reactions are carried out, either enantiomer of the final product (17) can be obtained with up to 60% Somewhat better in this latter respect are the related derivatives (18) which undergo efficient Michael additions of Grignard reagents using CuBr.Me2S leading to acids (19) with enantiomeric enrichments of 77-97%. l9 Asymmetric Michael additions have also been effected with the aid of various enzymes using

2-(trifluoromethyl)propenoic acid as the substrate: [(20),

the products

X=O, NH(R‘) and S ] were obtained using water, alcohols, amines

and thiols as nucleophiles in usually good yields with optical purities of 39-70%.20 A group of rather different Michael acceptors are the chiral vinyl sulphoximines (21) which undergo conjugate additions with a variety of organometallic species to give, after carboxylation [LDA, (MeO)2CO], desulphurisation (AlHg), and hydrolysis, acids (19) with > 9 0 % ee in the optimum cases discovered.21 Loss of the chiral auxiliary is a drawback although on the credit side, the method can also be used to prepare chiral

94


hydrocarbons simply by desulphurisation of the initial Michael adduct, and presumably a range of other derivatives obtainable from the initial ionised sulphoxide. Removal of a chiral auxiliary can be a limiting factor in much of the foregoing methodology, especially where amide linkages are involved. In the special case of a-methylbenzylamine derivatives [e.g. (22)1, which are often usec for optical resolutions of acids RC02H, removal of the benzyl group can be efficiently performed with suitable substrates by reduction using the system Li-NH3-THF-H20.22 Racemisation a- to the carbonyl is reported not to occur under these conditions. The resulting primary amide can be hydrolysed to the acid (RC02H) using potassium hydroxide in hot ethylene glycol if no a-proton is present; with enolisable amides the best hydrolysis method found was that due to Olah, using nitrosonium tetraf luoroborate, NOBF4. A useful two-carbon homologation method involves alkylations of the carbanion (23) derived from the corresponding 2-methylimidazoline using n-butyl lithium, followed by acidic hydrolysis leading to acids (25) in generally good to excellent yields.23 The intermediates (24) could presumably also be useful as "protected" carboxylic acids. 6-Aroylthiopropionic acids (26) can be obtained by enantioselective hydrolyses of the corresponding racemic methyl esters using various microbial lipases.2 4 However, enantiomeric excesses of both the acids (26) and the recovered esters are variable (6-98%). An alternative route to racemic 4-alkylthiocarboxylic acids (27) in general consists of Michael additions to a,B-unsaturated acids by alkylthiolates, the novelty being that these are generated by hydrolysis of the corresponding z,z-dialkyl dithiocarbonates, (RS12C0, using a variety of aqueous basic conditions, thus avoiding the handling of an alkyl thiol at this stage; yields are generally excellent.25 Similar conjugate additions to acetylenic acids lead to the unsaturated acids (28), also in excellent yields. Epoxidations of a,B-unsaturated acids using potassium peroxymonosulphate [KHS05; oxonel in aqueous acetone are more conveniently conducted in the presence of excess sodium bicarbonate rather than continuously adding a base, to avoid low pH values, as originally reported. Yields of the epoxy-acids (29) are excellent on 26 small and large (multi-kilo) scales. Diacids and Half-esters. - A research group led by Gais has given full accounts of their work on the PLE-catalysed asymmetric


95

4M

HZSOL

KOH

acoO

n SPh

H 0,C

(421

(41)

Scheme 1

p:i

R'

i M e2 R

' 4 0 M e

CO,M e (L3)

96


hydrolysis of E -d i e ~ t e r s . ~ ~ method will doubtless find many The applications since useful chiral starting materials such as half-ester (30), which contains three readily distinguished functional groups, can be easily and efficiently produced on a relatively large scale, e.g. 200 g.

Various improvements both in the rate of reaction and

in the optical yields resultinc from this type of hydrolysis have been reported. 28 Similar hydrolyses using PLE, or better lipase-MY, have been used to obtain the a-fluoro-esters (31) with up to 91% ee; this transformation is somewhat unusual in that halogenated substrates are often incompatible with such enzymic systems.29

The

initial products (31) can be used to obtain chiral a-fluoroalkanoates.

PLE-catalysed hydrolysis has also been used to prepare 30

the useful tartrate derivatives [(32); R=Me or PhCH2].

A new route to racemic 2-arylsuccinic acids consists of condensations between D-nitrostyrenes (33) and the enamine (34); subsequent acidic hydrolysis of the resulting adducts (conc. HC1, reflux) then gives the diacids (35) in good to excellent yields.31 A milder hydrolysis procedure would clearly extend the scope of this method.

Dye-sensitised photo-oxygenation in methanol can be used to

prepare half-esters (36) in good yield from the corresponding 1 ,2-cyclopentanediones. 32

When applied to cyclic 1 ,2-diolsI the

cleavage method using hydrogen peroxide discussed above7 represents a useful approach to many a,w-dicarboxylic acids. Hydroxy-acids. - Once again the emphasis in this area has been on the development of asymmetric routes to a- and O-hydroxy-acids. Whitesell and co-workers have assessed the suitability of a variety of auxiliaries for controlling asymmetric ene reactions of chiral glyoxalates (37) leading to a-hydroxy-acid precursors (38).33 Optimum inductions are observed when the substituent R1 contains a phenyl group, e.g. the 8-phenylmenthol derivatives, indicating that complexation between the aromatic substituent and the Lewis acid is important.

Essentially complete asymmetric induction can be achieved

under optimum conditions.

The related method whereby asymmetric

Grignard additions to glyoxalates (37) and the corresponding pyruvates are used to establish a chiral centre a - to the ester carbonyl group has been reported in full34 and used to prepare both enantiomers of the aggregation pheromone Frontalin, from esters of 8-phenylmenthol . 3 5 As with the ene reactions, chiral induction is essentially complete. Both enantiomers of an a-hydroxy-acid (40) can be obtained from a

97


single a-keto-amide (39), derived from

( 5 )- p r ~ l i n e . This ~~

preliminary study has only been applied to two examples [ ( 3 9 ) ; R=Ph i or Bu] but has revealed that, in the presence of lithium halides, reduction using LiBH4 gives (5)-(40) (up to 80% ee) whereas when i Bu 2 A 1 H is used, (5)-(40) is obtained with an ee of 59% when R=Ph. Chiral acids (40) can also be obtained with optical yields in the range 60-95% by alkylations of enolates derived from chiral amides of glycolic and lactic acids.37

Dibenzyl peroxydicarbonate

[(PhCH O C 0 2 ) 2 ] ,prepared from aqueous hydrogen peroxide and benzyl 2 chloroformate, is yet another hydroxyl cation equivalent capable of directly introducing an oxygen function (in this case, a benzylcarbonate) a- to a carbonyl group, by condensation with an enolate of the latter.38 When applied to chiral enolates derived from oxazolidinone carboximides of the type developed by Evans, a-hydroxyacids (40) are obtained with almost complete optical purity in excellent yields. variable.

However, yields with other enolates are rather

The electro-carboxylation of nXzhydes, RCHO,

previously

regarded as impossible, can be effected using a sacrifical aluminum anode, to give a-hydroxy-acids, RCH(OH)C02H, in variable yields: aromatic aldehydes work best and the method is also applicable to aromatic ketones, in which cases yields are much higher (62-85%).39 One example has been given of a potentially useful version of the benzil-benzilic acid rearrangement in which a-acetoxy-ketones ( 4 1 ) , obtained by Pummerer rearrangement of the corresponding a-thio-ketone, undergoes ring contraction to give the a-hydroxy-acid (42), a precursor of the corresponding cyclopentanone, upon treatment with aqueous potassium hydroxide. 4 0 The (2.3]-sigrnatropic (Wittig) rearrangement of a-allyloxy esters or acids has been highlighted recently as a general route to a-hydroxyacids and esters.41 One problem associated with this methodology is the possibility of competing I3.31-sigmatropic (Claisen) rearrangements especially when esters are used as substrates (Scheme 1 ) . In general the Wittig rearrangement occurs at lower temperatures; for example, C-silyl-esters (43) are converted into the a-hydroxy-esters (44) when treated with fluoride (TBAF) at -85"C, whereas the corresponding g-silyl derivatives (45) simply revert to the starting ester when treated with fluoride.

(Thermolysis of ester enolates

(45) results in the expected Claisen rearrangement).42

It t h u s

appears that the "free" enolate of keten acetal (45) is not formed


98

& , gcozH & ?H

f"

OBn

(CO,H

-- 0

+

--0

+

H (53)

(52)

(57) 0

158)

99

3: Carboxylic Acids and Derivatives upon treatment with fluoride.

The pathway taken by ester enolates

(Scheme 1 ) depends remarkably on how these intermediates are generated; exclusiiJe [2.3]-Wittig rearrangements occur when the lithium enolate is generated using LDA, crucially in 20% HMPA-THF.43 The two rearrangements (Scheme 1) can however be complimentary. Thus, Wittig rearrangement of the steroidal acid (46) gives exclusively the threo-hydroxy-acid (47) whereas enolate Claisen rearrangement of the benzyloxy acetate (48), derived from the same alcohol, leads only to the erythro-isomer (49) 44 Chiral auxiliaries have been incorporated

.

into such rearrangements [at position "X" in Scheme 11 and although yields, either optical or chemical, are rather variable, some useful examples have been delineated.45 Zirconium enolates can be especially suited to these and also to chiral

rearrangement^^^

transfer in rearrangements of ethers (50) into hydroxy-esters ( 5 1 ) . The syn-isomer predominates ( > 6 0 : l ) and is almost optically pure.46 The unusual (?)-selectivity of the last examples is also observed when trimethylsilyl triflate and triethylamine are used to effect the transformation: the authors propose the intermediacy of an unusual oxygen ylide species.4 7 Heathcock and co-workers have given a full description of their extensive studies on the preparation of 6-hydroxy-esters and ketones by Lewis acid catalysed condensations of enol silanes with aldehydes. 48 Although the diastereoselectivi ties are in general rather moderate, some useful mechanistic rationales of this and other work are given. Similar selectivities (erythro:threo ca. 4 : l ) are _______ observed in preparations of 6-hydroxy-esters by crossed aldol condensations using a-silyl trimethylsilyl esters,49 and in condensations between the trianion derived from glycinol (52) and aldehydes in the presence of a titanium salt. In the latter cases, hydrolysis and a single crystallisation is reported to give enantiomerically pure a-hydroxy-acids (53). 5 0

The dilithio salt of

propionic acid condenses with the chiral aldehyde (54) to give the anti- (55) and syn- (56) isomers (1:l) accompanied by only traces of their enantiomers.51 This lack of selectivity is somewhat alleviated by the potential utility of both products. A synthesis of the highly substituted hydroxy-diacid Crispatic acid (57) features a previously reported route to 6-hydroxy-carbonyl compounds __ via isoxazolines, generated by [ 1 ,3 1 -dipolar cycloaddition reactions.5 2 This example serves to further illustrate the potential of this methodology.


0

H2°2 _____)

R

K2C03

162)

R

1c02h (63)

t (65)

(66)

0

TsCL

(69) Scheme 2

0 (EtO),P

II

; 9 5 % ee using a reagent prepared from 9-BBN and a glucofuranoside acetonide. 142 An alternative way to exploit the steric screening principle in the elaboration of chiral a-hydroxy-esters is by asymmetric alkylations of the dioxolanones (140) and (141) [R=H] derived in a ratio of 1.3:1 from 8-phenylmenthone and a silylated glycolic acid.

3: Carboxylic Acidr and Derivatives

117

S i M e Ph .I, II .’

&

N

iii, i v

R

so2 Reagents:

i, RCU, BF . 0 E t 2 ;

3

it,

~

~

R

S i PhMe,

L

OH

xc,,,e

~

L i O H then CH N

2 2

;

iii, H B F ; iv, MCPBA

Scheme 13

H Scheme 1L

4

c

o

,

M

t

118

General and Synthetic Methodr

After chromatographic separation, (the major drawback of the method) both isomers can be alkylated (LDA, RX) to give the derivatives shown with very high or complete asymmetric inductions. 143 Subsequent alcoholysis returns the chiral auxiliary and optically pure a-hydroxy-esters. Complimentary diastereoselectivities have been observed in condensations of methyl pyruvates with various organometallic nucleophiles, the allylborane (142) giving largely the threo- adducts (143) whereas the silyl allene (144) affords predominantly the erythro-isomers (145) Bulky ester groups favour product (143) while the reverse is found with esters (145). A simple method for preparing a-hydroxy-esters related to esters (143) is by lead-promoted attack of allylic bromides onto ethyl pyruvate.145 Vinyl phosphonates (146), obtained from the corresponding ketones (R'R'CO) by a Peterson reaction, can be oxidised using O s 0 4 to give a-hydroxy-esters (147) following elimination of diethyl phosphite (Scheme 12). Overall the process represents a one-carbon homologation of ketones to a-hydroxyesters effectively by attack of an acyl anion equivalent.146 Methods for obtaining chiral a-hydroxy-esters by Walden inversion of chiral a-sulphonyloxy-esters using a variety of oxygen nucleophiles have been described in detail. 147 Reformatsky reactions can be carried out using a zinc/silvergraphite, prepared from C8K, ZnC12 and AgOAc, at temperatures as low a s -78°C under which conditions much higher levels of stereoselection can be achieved.148 Many other developments have taken place in

aldol-based approaches to p-hydroxy-esters. The use of a complex formed between TiC14 and Ph3P greatly improves the &-selectivity in condensations between acetals (148) and aldehydes to give almost pure isomers (149) In principle, chiral induction in such reactions could be achieved using a chiral Lewis acid; some examples of such a catalyst have been given.lS0 The chiral thiazolidine-2thione derivatives ( 1 5 0 ) are also very effective at controlling Lewis-acid catalysed aldol condensations with a,@-unsaturated aldehydes, using tin (11) triflate and N-ethylpiperidine as reagents, which give rise to aldols (151) with > 9 0 % ee and in 70-80% chemical ~ie1d. l~' Similarly, boron enolates derived from the Evans-type amides (152) condense with aldehydes to give the --esters (153) The enantiomers of esters after hydrolysis and esterif ication.152 (153) can be obtained by using an analogue of amide (152) derived from ephedrine.

3: CarboxyIic Acidr and Derivatives

119

H

OH

Bu'O&

H

OH

C

O

R'O A

(161) R'

C0,Et

, R

= H or Me

( 163 1

(162 1

(164) n = 1 o r 2

(165)

Scheme 15

(166)

S c h e m e 16

(167)

GeneraI and Synthetic Methoa3

120

The useful silyl- and stannyl-esters (154) and (155) can be readily obtained from crotonate esters with good to excellent stereocontrol either by combined Michael addition (of R 2 X e ) and aldol 3

condensation [ (154)l or by quenching the intermediate enolate, re-enolisation and condensation to give esters (155) A combination of the principle of steric screening and Fleming's observation that PhMe2Si-substituents can be converted into hydroxy groups with retention of configuration has been used by Oppolzer in the development of another highly enantioselective approach to B-hydroxy-esters (Scheme 13) The same type of product can also be accessed using aldol condensations of related sterically screened enolates. Highly stereoselective aldol condensations occur between the 6-hydroxy-ester (156) and symmetrical ketones leading to the z - a d d u c t s (157) ( G . 9 0 % ) when enolisation of the ester is carried out at -100°C using lithium diethylamide and lithium triflate as an enolisation promoter. 155 In condensations with aldehydes, control of stereochemistry at the newly-formed secondary alcohol centre is only moderate. A different type of steric shielding method can be used to obtain substituted 0-hydroxy-esters from a dioxanone derived from ( R ) -3-hydroxybutyric acid and pivalaldehyde (Scheme 14) 156 The initial products can be converted into the opposite enantiomer by re-enolisation and protonation while the derived enol acetal (158) undergoes highly selective Michael additions leading to esters (159) via the self-reproduction of chirality principle. A number of reports have further advanced the utility of yeast reduction of 6-keto-esters as an enantioselective route to 8-hydroxy-esters. The use of methanol as carbon source rather than glucose can lead to higher e n a n t i o s e l e ~ t i v i t i e s as ~ ~ ~can reductions of keto-amides, derived formally from NH2CH2C02Et, rather than the usual methyl or n-octyl keto-esters. Specific examples of yeast the reduction products include the 4-t-butoxy derivative (160), and the branched derivative (162)16', one-carbon homologues (161) +

.

obtained by reduction of the corresponding chiral B-keto-ester; these examples clearly indicate some general trend regarding the relationship between substituent hydrophilicity and product stereochemistry. Yeast reduction of 2-methyl-3-oxobutanoate gives largely the =-isomer [ (163): R1=H] especially when the n-octyl ester is used.162 This complements a popular chemical approach to this type of ester using alkylations of 3-hydroxybutyrates, as these

121


. ' HgX Y OR 2

R 1 Y q M e R3

(171 1

R:q

C02Et

C02Me

OH Ph

OH (1 7 3 )

OH

OH a

C

0

n 2

R

o

L

R'

E

t

R'R~CO

,

R2

R+Co2Et OH

C1,TiJ' (176)

(1 78)

(177)

TU

CO2BU'

S

(179)

(1 81 1

(1801

(182)


122

lead to the corresponding anti-isomers. An alternative method which provides both enantiomers of esters [ (163), R1=heteroaryl, styryl] consists of enantioselective hydrolyses of the corresponding racemic acetates using various lipases.1 6 3 A variety of micro-organisms are capable of producing cyclic B-hydroxy-esters ( 1 6 4 ) from the corresponding keto-esters usually with the (15)-stereochemistry shown but as cis-trans mixtures, while the useful hydroxy-ester (165) can be obtained by kinetic resolution using fermenting Baker's yeast in 0.1M phosphate buffer in order to preserve the acetal function.165 The remaining keto-ester can be isolated with 94% ee using a different yeast strain (2.bailli) and mild epimerisation (NaOH, EtOH) provides the trans-isomer of ester (165). A highly stereoselective route to B-hydroxy-esters, based on a [1.3l-dipolar cycloaddition pathway is outlined in Scheme 15.166 Overall yields are generally high although problems of regioselectivity will arise with many unsymmetrical olefins; the presence of other olefins is also precluded. An enantioselective alternative to the aldol-based homologation method discussed above for the conversion of aldehydes into 6-hydroxy-esters consists of two-carbon extension using standard phosphonate chemistry, reduction, Sharpless epoxidation, followed by Ru04 oxidation and esterification to give glycidic esters (166). These undergo regioselective attack at C-2 by (167) mixed cuprates, R2CuCNLi2 to provide the &-hydroxy-esters 2 (Scheme 16) Despite the obvious limitations of the method in terms of the functionality which can be present in groups R1 and R2, the selective formation of the anti-isomers is significant as many aldol routes lead to the *-isomers.

Cuprates derived from Grignard

reagents in ether-THF react with epoxy-ester (168) specifically at C-4

when the reactions are carried out at -60°C (at higher

temperatures, enolisation and rapid 6-elimination occurs) to give B-hydroxy-esters (169) in good to excellent yields, thus providing yet another possible "disconnection" for B-hydroxy-ester synthesis. The availability of chiral epoxides ( 1 6 8 1 , for example from yeast reductions, would extend the method to the production of chiral hydroxy-esters. Hydroxy- and alkoxy-mercurals ( 1 7 0 ) ,

readily available by

oxymercuration of the corresponding a,B-unsaturated esters, can be converted into the erythro isomers ( 1 7 1 ) by demercuration using thiols but into the threo-isomers (172) using hydride reduction. a,B-Dihydroxy-esters can also be prepared by yeast reductions;


123

0

0 Me0

I1 )--CO,R Me0 (184)

-CCO,R

R-E-SiMe,

(185)

(186)

O o 4H MS eO

+

RAC02Me

(1 87)

& He3sin R'

H30+

C0,Et

R'

R*

H

C0,Et

uo RoH

H L C 0 2 R R2

(1921


124

thus racemic hydroxy-esters (173) are converted largely into the (2SI3S)-anti-esters (174) with > 9 7 % ee.170 Up to 20% of the corresponding (2Rr3g)-syn-esters are also formed. Dihydroxy-esters (1751, in racemic form, can be obtained by crossed pinacol coupling between a range of ketones and methyl phenylglyoxalate using aqueous acidic (HOAc) titanium trichloride as reagent. 17' Yields are variable, up to 85%. High selectivities in favour of the *-isomers (176) have been achieved in reduction of 6-hydroxy-B-keto-esters using a variety of methods.172 The products are useful precursors to 8-hydroxy-valerolactones. A full report has appeared173 on the preparation of the isolable homo-enolate equivalents (177) which react readily with aldehydes to provide a simple route to y -hydroxy-esters [ ( 1 7 8 ) , R2=Hl : 3 condensations with ketones require the more reactive alkoxytitanium species, easily prepared by adding a titanium tetraalkoxide to carbanion ( 1 7 7 ) . Yet another use of a yeast reduction is in the preparation of the useful 6-hydroxy-ester (179) from the corresponding ketone, with 9 7 % ee.174 Attempted reduction of the analogous methyl ester resulted only in hydrolysis of the latter function. Alkylations of the 6-hydroxy-ester (156) mentioned above155 lead to the (180) with > 90% selectivity using LiNEt2-THF-HMPA as the =-adducts base-solvent combination. 175 The lithiated sulphone (181) can be regarded as the synthetic equivalent of the propanol carbanion (182) and is useful in, for example,the preparation of 6-hydroxy-hexanoates (183) by Michael additions to u , O-unsaturated esters. 176 A variety of hydroxy-esters can be prepared from the corresponding amino-esters by diazotization using sodium Despite the mildly basic conditions, this reagent nitropr~sside.'~' is especially effective with substrates prone to elimination. Zinc borohydride is especially useful for the reduction of phenylthio esters to the corresponding alcohols and therefore can be used to prepare hydroxy-esters from mixed sulphur and oxygen esters of diacids 78

.

Keto-esters.

-

Enolates derived from the acetals (184) can be

alkylated, especially by heteroaromatic chlorides such as 2-chlorobenzoxazole, and thus represent another synthetic equivalent of the acyl anion (185). Another source of a-keto-esters (187) are silylacetylenes (186) Os04 oxidations using t-butyl hydroperoxide as the re-oxidant for the osmium reagent.l8O Yields on the models

3: CarboxyIic Acirls and Derivatives

OAc

&

C0,Et

C0,Et

ac04

OC0,Et (200)

(201)

Scheme 17

AI-Hg

C02Me7

Me 0

Me0

A

C

0

2

M

e

PPh3

(202)

(203) Scheme 1 8

COzMe

N2

(206)

126

General and Synthetic Methadr

studied are generally around 6 0 % and, with the exception of substrates which contain other unsaturated C-C bonds, should be obtainable from a wide variety of acetylenes. The oxazines (1881, available by [4+2l-cycloadditions of vinyl nitroso compounds, upon treatment with an aqueous acid [4M HC1 or 70% HC104] undergo sequential imine hydrolysis and Peterson olefination leading to the unsaturated a-keto-esters in essentially quantitative yields from the simple oxazines studied. 18' The simplest members of the 8-keto-esters, 8-formyl-esters (191) can be prepared simply by heating formyl Meldrum's acid (190) in benzene containing an alcohol (ROH).182 It is not clear whether the transformation proceeds an alcoholysis-based pathway or by thermal decomposition of precursor (190) into formylketene. Crossed Claisen condensations can be carried out between 2,4,4trimethyloxazoline and symmetrical anhydrides in the presence of A1Cl3 and Et3N to give masked B-keto-esters (192) in 50-70% yield. 183 A perhaps more generally useful method is the crossed condensation between methyl esters and methoxymethyl esters using titanium (IV) bistriflate [TiC12(0Tf)2] and a tertiary amine. Strong chelation by the methoxymethyl group favours enolisation of the latter esters and hence predominant formation of keto-esters (193).184 The method is also particularly effective in Dieckmann cyclisations, e.g. (194)-+(195). Acylation of the bis-enamines (196) by acid chlorides followed by acidic alcoholysis leads to a wide variety of yields (highest in the absence of an a-H in the chloride) of O-keto-esters (197) in an alternative to the direct Claisen method. The intermediate acylated enamines can also be converted into B-keto-amides and methyl ketones185 (See also ref.31). Enantiomeric enrichments of up to 95% have been achieved in low temperature Michael additions of the chiral enamine (198) to di-t-butyl methylenemalonate. 132 Either enantiomer of the product (199) can be obtained by variations in the solvents used; slightly lower eels are obtained from similar additions using the corresponding ethyl 2-methylacetoacetate derivative186 (See also ref. 201) Michael additions of soft nucleophiles such as B-keto-esters to 2-cyclo-

.

hexenones can be accelerated by adding various iron- or copper-acac complexes.187 The allylic carbonates (200) can be readily prepared by an overall addition of acetic acid to the corresponding acetylenic carbonate using a ruthenium catalyst, and react in the presence of Pd(0) with 6-dicarbonyls including 6-keto-esters and malonates to

3: Carboxylic Acid and Derivatives

127

062 (207)

(208)

(209)

( 2 1 0)

H (211)

(212)

H30+

SPh

fiR COzMc SPh

Scheme 19


128

give homologues Ie.9. (201)I . Hydrolysis gives the corresponding diketo-ester; with a-unsubstituted B-dicarbonyis, double addition products only are isolated, as the second addition of carbonate (200) occurs faster than the first.188 A seemingly general and efficient procedure for the a-alkynylation of B-dicarbonyls is illustrated in Scheme 1 7 . l ~ ' An alkynyl-lead triacetate species is the presumed key intermediate. Alkoxy B-keto-esters (203) can be obtained in high yields from acid chlorides (202) by sequential acylation of a suitable phosphorane followed by reduction (Scheme 18) .Ig0 The products are useful as "protected" forms of the corresponding, rather reactive, vinyl ketones. The salt (204) derived from the neutral phosphorane using sodium hydride, "activated" by adding a small amount of water, condenses efficiently with aldehydes to give largely the (Z)-olefins (205). I g 1 The neutral phosphorane is unreactive with aldehydes in refluxing THF while the corresponding phosphonates tend to lead to

( E )-isomers

.

of keto-esters (205) Mesyl azide is reported to be superior to the commonly used tosyl azide for diazo transfer reactions such as in the preparation of a-diazo-acetoacetates (206). Aldol condensation of the bis-silyl enol ether (207) of methyl acetoacetate and (S)-2-benzyloxyhexanal using TiC14 as promoter leads almost exclusively to the z - a l d o l (208). I g 3 In contrast, anion-based aldols give a preponderance of the %-adduct. The homologous tris-silyl enol ether (209) has also been prepared;lg4

in

the presence of TiC14 , or TiC12 (OiPr)2, reactions with electrophiles (e.g. R'R~CO, RICOC1) occurs regioselectively at the terminal C-6 position.

Although the initial adducts [e.g. ( 2 1 O ) l from ketones are

isolable, a more useful pathway is acylation followed by cyclisation to dihydroxybenzoates. Chiral aldehydo-esters (212) are available in high optical purities, typically E. 9 0 % , by Michael additions of lithium dialkylcuprates to the oxazolidines (211) derived from the Hydrolysis of the corresponding aldehyde and E-Z-norephedrine. intermediate adducts is achieved in two steps by BF3-catalysed exchange with ethanedithiol followed by heating with MeI-CaC03 in wet acetone, apparently with little or no racemisation. An alternative route to racemic esters (212) is by Michael addition in the opposite sense using (methy1thio)methyl p-tolylsulphone as a formyl carbanion equivalent and 2-alkenoates as acceptors .Ig6 Y -Keto-esters in general

-

3: Carboxylic A c i d and Derivatives

129

0

OY

C0,E t

(2151

H

CO,E t

(216)

(217)

(218) OTMS I

Ph

L + +,

+/

OSi,

TrC104

T O SPh S i '

&

COSPh

Ph

\

!

Scheme 20

R-C02Et

(224)

-

R

R m C O z E t

HS d C 0 2 M e

(225)

(226)

130


can be prepared in the same way but using trityl or t-butylhydrazones derived from aldehydes as Michael nucleophiles.l g 7 Thermal ene reactions between the hydrazones and methyl acrylate also lead to 6-keto-esters. Another formyl carbanion equivalent (214) is a key element in an approach to substituted y-keto-esters starting from 3-alkoxycycloalkenones (213) (Scheme 19) .lg8 The a-substituents (RCH2) are derived either from an allylic iodide or methyl acrylate; no mono-alkylated derivatives were prepared. Full accounts have been given of further preparations of 6-keto-esters by ring openings of 2-si 1yloxycyc lopropane carboxylates Highly substituted 6-keto-esters [e.g. (215)l having vicinal quaternary centres can be prepared by Michael additions of ketone enolates to highly active acceptors containing two electron withdrawing groups. 2oo Substituted 6-keto-esters (218) have been obtained with good to excellent enanti0meri.c enrichments by Michael additions of the lithioenamide (216) to alkylidenemalonates (217), followed by hydrolysis and decarboxylation201 (See also ref. 186) Kinetic enrichment of the initial products can be achieved by treatment with aqueous NH4C1 in THF, which causes a selective retroMichael reaction of the minor isomer. An approach to 6-keto esters which is related to the Michael reaction involves additions of

.

.

silyl enol ethers to the isolable dithiolanylium salt (219), derived from the corresponding ketene dithioacetal by hydride abstraction using trityl tetrafluoroborate202 (See also ref .110). Largely the anti-isomers (220) are obtained, especially from cyclic silyl enolates. Trityl cations are also crucial to the success of an alternative Michael-type approach to 6-keto-esters with features additions of silyl enolates of thio-esters to enones, and which gives predominantly the anti-isomers (Scheme 20) .203 Finally, two useful preparations have been described i n reliable detail, those of methyl 6-oxohexanoate (221) and the corresponding ~ * of diformyl acetate acetal (222) by ozonolysis of c y c l ~ h e x e n e ~and (223) from monomethyl malonate and the Vilsmeier reagent.205 Unsaturated Esters. - An efficient, single step procedure for two carbon homologation of esters (224) into a,B-unsaturated esters (225) consists of reduction using diisobutylaluminum hydride at low temperature in the presence of a lithiated phosphonoacetate. 206 Yields of largely (E)-isomers are usually above 70% and the method works equally well with lactones to give o-hydroxy unsaturated esters. Both phosphoranes and phosphonates derived from long-chain

131


C0,Et

6""z

CO,E t

A

(228)

(227)

R2

Cp CO-Fe

I

I

C02Et

-111

PPh,

I

R2 R3%c02Me

co

-R3

______)

t

R'

R'

R'

(233) R 3 = Ph o r m a l o n a t e S c h e m e 21

Scheme 22

(234)

BrY

(2351

C02Me

_______)

C02Me

S i Me3

Br

132


a-halo-esters condense efficiently with long-chain aldehydes in Wittig-type reactions but the former phosphoranes give greater can be achieved trans-selectivity.207 Reasonable *-selectivity using the Still-Gennari method with bis(trifluoroethy1)phosphonates. Some specfic examples of useful Wittig products are the thiolsubstituted esters (226) available from the corresponding a-phosphoranylj-dene acetate or propionate and the commercially available dimer of 2-mercaptoacetaldehyde1208 esters (227) or (228) from aqueous glutaraldehyde and triethyl phosphonoacetate, (the actual product depends on the rate and order of addition) ,209 and the retinoic acid synthon (229) from pyruvaldehyde dimethylacetal.210 An alternative strategy for this type of olefination is the Reformatsky reaction, which, when mediated by tri-n-butyl stibine, directly gives excellent yields of (El-a,B-unsaturated esters with or without a solvent when aldehydes, both enolisable and non-enolisable, are the substrates.2 1 1 A lower temperature (-20°C rather than +8OoC) is required with Reformatsky reactions using sodium telluride, Na2Te.212 However, these are only effective with non-enolisable aldehydes;

one use of this method may be that (non-enolisable)

ketones are not attacked. Reformatsky or related carbanion chemistry of 4-bromocrotonates or crotonates themselves can be directed largely to the y-position to give, for example, the hydroxy-esters ( 2 3 0 ) . 213 A novel and useful version of the Favorskii rearrangement is in the conversion of dibromo-ketones (231) into essentially isomerically pure (2)-cinnamates (232), using two equivalent of methoxide at -20°C 2-14 (See also ref.270). Full details for preparations of (5)-crotonates and higher homologues using Lindlar reductions as a key step have been given.215 The method is reported to be an improvement on a previous 0rg.Synth. recipe for the preparation of (2)-crotonate. Some 6-heteroaryl acrylates have been successfully isomerised to the corresponding (?)-isomers [ie - (232); 2-fury1 or 2-imidazoyl in place of phenyll using photolysis in the presence of BF3 .0Et2.216

Alkenyliron complexes (233) are available from the corresponding T-alkynyliron complexes and a suitable nucleophile, R3 , and can be carbonylated in the presence of an alcohol to provide a route to highly substituted a , 6-unsaturated esters (Scheme 21) 217

.

Unsaturation can be introduced into an aliphatic ester by conversion to the p s i l y l enolate followed by treatment with an ally1 carbonate and a Pd(0) catalyst (Scheme 2 2 ) ;

a full account of this

3: Carboxytic Acids and Derivatives

133

F

R

F

Me3’3n% F

F

(238)

SnMe3

(240)

(239)

cop

+

+

COzMe

c 1,c

CO,

O + A02I

+

CHCl3

S c h e m e 23 R

\COP.

CSA

HoxYcoz R

+ s - - - p - t 01

-0’

N BS

Et3N

’

Me0 R

C02Me

R

OMe


134

method has now been given218 which suggests that it could prove to be at least as good as the now standard alternative based on a-phenylselenation, oxidation and elimination. The a-silyl ester (234) behaves as a typical allylsilane in TiC14-catalysed reactions with a variety of electrophiles (a-halo-ethers, aldehydes, Michael acceptors) to give generally good yields of the trimethyl esters (235).219 a-Bromo-esters (237) can be obtained in fai'r yields by Peterson olefinations using a-silyl ester (236),220 while a variety of 0-fluoro- and BIB-difluoro-a,O-unsaturated esters have been prepared from a-trif luoromethylacrylic acid.221 The a , 4-difluoro isomers (239) can, by contrast, be obtained by carboxylation of the vinylzinc species (238).222 Palladium ( 0 ) catalysis also plays a crucial role in the preparation of the (2)-bis-stannyl esters (240) by addition of hexamethylditin to the corresponding acetylenic esters. 223 Isomerisation of the corresponding (E)-isomers is easily effected by heating the isomers (240) at 75-95°C. A "salt-free'' method for obtaining enol ethers from O-keto-esters consists of heating the latter with the readily prepared silyl ester (241) at 120°C (Scheme 23) .224

Yields are essentially quantitative;

the trimethylsilyl analogue of ester (241) is known to behave similarly. 2-Phenyl analogues of such enol ethers can be obtained directly from 4-keto-esters using a triphenylbismuth diacetate in the presence of elemental copper.225 Full details for the preparation of ethyl 4-hydroxycrotonate [ (243); R=H] from monoethyl fumarate have been given.226 The homologues [(243); R=n-alkyl] can be obtained with 64-72% optical purities by acid-catalysed rearrangement of the chi.ra1 sulphoxides (242).227 The mechanism involves a prototropic shift to give the O,y-analogue followed by a [2.3]-sigmatropic rearrangement. Palladium-catalysed transfer hydrogenolysis, using HC02H-Et3N as hydrogen source, of the epoxides (244) leads to alcohols (245) with inversion of stereochemistry at the methyl substituent.228 The availability of epoxides (244) in optically active form further enhances the potential of this highly selective reaction. Keto-esters (247) can be readily obtained from the dihydrofurans (246) by sequential treatment with NBS and potassium carbonate in wet acetone followed by elimination of HBr using Et3N from the intermediate bromo-ketone formed by collapse of the initially formed bromo-hydrin.229 The furans (246) are derived in three steps from


135

1252)

Li

BF,OEt

,

RY OEt

(254)

(255)

R’

PhS

(256)

(257)

SEt -c

R

Br-, EtOH

(258)

SnBu, (260)

(261 1

136

Genera! and Synthetic Methodr

Scheme 24

C0,Et

RZ

OH (263)

(266)

(2651

C0,Et

(266)

Br d C0,Et

R

(269)

M e2 C u (CNILi,

C0,Me

R2f&

BF30Et

,

I

OMS

(2711

(270)

s

C 0,Me

R

+

CO,

R M gBr

CuBr

Et (273)

(272 1

kR COzE t

137

3: Carboxylic Acids and Derivatives 2,2-dichlorocyclopropanecarboxylic acid.

Protected forms (248) of the

keto-esters (247) can be prepared by electrolysis of a 2-substituted furan under appropriate conditions.230 The sulphoxide (249) can be regarded as a synthetic equivalent of the cation (250) and as such can be used to trap enolates formed by [1.4l-additions to enones to give for example cyclohexanone (251), starting from 3-methyl-2-cyclohexenone. The a-silylmethyl esters (252), potentially Useful as precursors to a-methylene esters can be prepared by additions of l-ethoxy-3trimethylsilyl-1-propyne to a wide variety of both saturated and unsaturated acetals.232 A Pummerer rearrangement is the key step in a route to the a-thio-esters (253) from the corresponding, saturated a-sulphinyl esters233 whereas the lithiated acrylate (254) can be used to prepare a variety of 6-thio-esters such as derivatives (255) following BF3-catalysed condensation with an oxetane and A ~full account has been given of the route to e~terification.~ ~ y-thio-esters (257) by acid-catalysed [1.2l-PhS shifts involving the lactones (256) for example.235 6-Thio-esters (258) can be converted into unsaturated esters (259) using electro-oxidation.236 A s the Michael adducts (258) can be considered as partly protected forms of unsaturated esters (259), the fact that this "deprotection" method occurs under neutral conditions could contribute to the usefulness of this method. A mild method for the elaboration of B-methylene esters (261) is by radical-mediated alkylations of the allylstannane (260) which produce 70% isolated yields. 237 Extrapolation of this method will not be possible in many cases because of competing [1.3l-rearrangements of allylstannanes, prior to coupling. (Rearrangement of stannane (260) is degenerate). A more common method for the introduction of an a-methylene function is by one carbon homologation

of an a-unsubstituted ester.

Useful in this respect are the bromomethyl benzyl sulphides and selenides (262) 238 The classical method for such homologations is to use a Mannich reaction (using HCHO

.

and Me2NH) although the requirement of a strong acid catalyst can preclude its application to many substrates. Such acidic conditions can be avoided using enolate alkylations by Eschenmoser's salt or by a more recently reported combination of enaminone formation and [1.4]reduction using LiA1H4, followed by quaternisation and elimination. (Scheme 24) .239 The elaboration of hydroxy-acrylates (263) from aldehydes or

General and Synthetic MetltorLr

138

K

(276)

(275)

(277)

OMc

(278) R R Et3N HMPA 160

‘C

EtO

(281) S c h e m e 25

(282)

Thpo-l+

(Prcferred1

(283)

- LpZH OThP

R l(o 0 (284)

(285)


139

ketones and methyl acrylate, using Dabco to form the ester enolate by Michael addition, is greatly accelerated by the application of high pressure :240 an alternative route to acrylates (263) is by aldol condensations using B-dimethylamino propionates. Elimination of the elements of dimethylamine to form esters (263) is effected using mCPBA and alumina. 241 Alkenylboranes (264), obtained from the corresponding terminal acetylene and g-BBN, couple smoothly with ethyl bromoacetate and related a-halo carbonyls in the presence of potassium t-butoxide to give the (E) - -6,y-unsaturated esters (265) in 60-65% yield. 242 Photodeconjugation has been developed as a viable approach to esters (265) in general; a synthesis of a San Jose scale pheromone features the elaboration of ester (266) by this process, using pyridine as an additive to control the regioselectivity.243 The methodology can also be used to obtain ( E , z ) - d i e n ~ a t e sand ~ ~ ~ can be conducted asymmetrically using a chiral base, although as yet, optical yields are poor.245 Vinyl epoxides (267) undergo rapid rearrangement when treated with samarium iodide at -9O"C, using ethanol as the proton source, resulting in formation of the deconjugated esters (268) in high yield.246 The availability of chiral epoxides (267) via the Sharpless method will further enhance the utility of this method. a-Bromo unsaturated esters (269), together with similar lactones, are reductively deconjugated when treated with diethyl phosphonate. 247 Yields of esters (265) are generally above 60%. Attempts to intercept intermediate enolates in the conversion (267).+ (268) have not yet proven successful as a route to a-alkyl homologues of the products.246 However, this type of compound (271) can be obtained by a Michael process applied to the mesylates (270) and using a mixed cuprate species.248 [ l . 3 I -Chirality transfer is essentially complete. Simple a-alkyl esters (274) can be obtained regioselectively in related Michael additions to the benzothiazoleesters (2721, perhaps directed via the intermediate complex (273).249 The high ( > 80%) yields obtained using fully substituted substrates are a highlight of this procedure. Chiral esters (276) result from a stereospecific l1.21-alkenyl shift when acetals (275) are heated with calcium carbonate in aqueous methanol. 250 Deconjugative alkylations of the corresponding a-thio-a,B-unsaturated esters have been used to prepare esters (2771, which upon treatment with thiophenol and AIBN are converted into y-thio-a,B-unsaturated esters by [1.3l-thiol

140

General and Synthetic Methoh

+ (2961 R

(297)

(299) Scheme 27

(300)

141


A full account has been given of an improved method migration.251 for Birch-type reductive alkylations of methoxy benzoates leading to 252 1,4-cyclohexadienes [e.g.(278)1. A rather different approach to B,y-unsaturated esters (280) features successive Cope rearrangements of cyanohydrins (279) followed by methanolysis; prolonged heating at 180°C is required which may preclude the use of some substrates although the method should be applicable to more highly substituted compounds than the example shown. 253 Claisen methodology for the elaboration of y,&-unsaturated acids and esters continues to be developed. The readily available dibromo-ether (281) is useful in the preparation of vinyl ether functions required for such rearrangements: the a-bromine is displaced by an alkoxide derived from an allylic alcohol to give a mixed acetal which undergoes both elimination and rearrangement in HMPA-Et3N at 160°C (Scheme 25).254 It remains to be seen whether substituted vinyl ethers can be prepared in this way. Incorporation of a substituent at the 2-position of an (E)-allylic alcohol (282) gives a preponderance of the --isomers (283) following Johnson ortho-ester Claisen rearrangement. 255 A reasonable rationale has been given, which is in line with some useful observations on substituent effects in Ireland-type Claisen rearrangements. 256 A similar effect of a 2-substituent is probably responsible for the largely regio- and stereo-selective enolate Claisen rearrangement of dienyl ester (284) into acid (285) 257 Sequential enolate Claisen rearrangement of allylic glycolates have been used to prepare esters (2861, the relative stereochemistries being controlled by changes in the allylic alcohol geometry; these initial products are then converted into the tocopherol side chain and a pine sawfly pheromone. 258 Asymmetric

.

rearrangements of allylic glycolates can be effected using an external chiral ligand derived from ( R ) -1-phenylethanol. 259 The major products are isomers (287) accompanied only by the enantiomeric =-isomer; ratios of these two are unfortunately only 3:l. Higher selectivities are observed in aza-Claisen rearrangements (288)+ (289); a full account of this work has been presented.260 Once again, the ally1 group geometry is a crucial controlling feature. An alternative general approach to y,&-unsaturated esters (291) is by palladium induced coupling of the zinc homoenolate (290) with vinyl or aryl halides.261 Yields are generally in excess of 75% for

z.

the relatively simple examples quoted, and elimination from the


142

Scheme 28 Ph

( 3 02 )

(301)

0

GY

PdCI?, MeOH

OTf

R

COzMc

co

______)

R.

( 305 )

(3041

co

________)

C o z C 0 8 , hv, MeO-

(3061

(307)

R’T C02Et

OMe

OMc

(308)

(309) COzMc

Li

-

Nu

i , Nu-

R/\yN02

SPh

R ACOSPh

OMc

(310)

(312)

143


homoenolate to give acrylate is not a problem (See also ref. 265). A palladium catalyst can also be used to couple Reformatsky reagents to allylic acetates to give substituted homologues of esters (291), although only in moderate yield.262 A molybdenum analogue of Tebbe's reagent has been discovered which can convert unsaturated ester (292) while isolated ketone inert; presumably the ester group assists in A systematic study has shown that one of

A-keto-pentanoate into groups are relatively the reaction.263 the best methods for

effecting Michael additions of allyl groups to unsaturated esters is to use a combination of allyltrimethylsilane and fluoride ion; both Lewis-acid catalysed methods and allyl cuprate reagents were found to be inferior.264 Along very similar lines to reactions of the homoenolate (290),261 3-carbethoxy propylzinc iodide (293) couples smoothly with vinyl triflates and iodides to give 6 , -unsaturated ~ esters (294) in generally good yields.265 An alternative approach proceeds by addition of allylzinc bromide to an alkenyl-lithium to give the doubly metallated species (295) which, among many.other uses, ~ these methods seem can be carboxylated to give 5 - a l k e n 0 a t e s . ~ ~All to have limitations in terms of the number and type of substituents that could easily be incorporated. All-trans dienoates (296) can be readily obtained in excellent yields by condensations between sulphones and 4-oxobutanoates followed by base-induced double elimination (Scheme 26) .267 Pyrolysis of the

z.

thiophen dioxides (297) also gives dienoates (296) in 6 0 % yield with excellent stereochemical purity. 268 Another pericyclic process, the Claisen rearrangement, in tandem with a Peterson olefination can also be used to prepare esters (296) and the corresponding (2?,4E)isomers (300).269 Thus rearrangement258r259 of glycolates (298) gives almost exclusively the syn-isomers (299) and thence dienoates (296) or (3001, depending on the method of elimination (Scheme 27). An unusual route to ( E , Z ) -dienoates (300) features a Favorskii rearrangement of tribromoketones derived from 3-alken-2-ones (Scheme 28) . 270 Overall yields for this simple two-step procedure are usually around 6 0 % (See

.

also ref.214) Allenic esters (302) can be obtained in one flask from propargylic carbonates (301) by a palladium-catalysed decarboxylationcarbonyla tion process. 271 The conversion requires 10-30 atmos. of carbon monoxide at 40-50°C for several hours and generally gives upwards of 70% yield. Pentatetraenecarboxylic esters Ie.9. (303)l have been obtained for the first time using Wittig-based methodology.272


144

Aromatic Esters. - Aromatic methyl groups can be ~ x i d i s e d ’ to ~ the -~~ carboxylic acid level electrochemically using tris(2,4-dibromophenyl) amine as redox catalyst.273 Under slightly basic conditions, the corresponding ortho-esters are formed. Methyl benzoates can also be formed from aromatic ketone hydrazones by oxidative degradation using Co(sa1en) in In view of related couplings of enol triflates, it is perhaps not surprising that triflates (304) derived from phenols undergo smooth carbonylation in the presence of palladium acetate and methanol to give good yields of the corresponding methyl benzoates (305). 2 7 5 The method can also be applied to heteroaromatic systems as well as to other esters and amides.

A related system, CO-PdC12-ROH-Hg(OAc)2-

Cu(OAc)2-LiBr, can be used to directly carboxylate unsubstituted heteroaromatics a- to the heteroatom in moderate yields. 276 Poly-halobenzenes can be converted into the corresponding polybenzoates [e.g. (306) (30711 by carbonylation using a cobalt carbonyl catalyst and irradiation at 350 nm.277 Yields are generally excellent -f

and amino, methyl, and methoxy groups are not affected. The useful carbanions (308), obtained from the parent o-toluate using LDA, can be efficiently acylated using N-methoxy-N-methylamides to give the isocoumarin precursors (309): many other more obvious acylating reagents failed to give reasonable yields 27a (See also ref. 194). Nucleoside analogues can be prepared using the vinyl anion (310) derived using LDA.279 Thioesters, selenoesters and related compounds. - Cobalt (11) chloride is an efficient catalyst for the coupling of thiols with acid chlorides or anhydrides giving thioesters in generally excellent yields.2 8 0 In studies of radical-mediated-11.21 thioester migrations,281 it has been indicated that trif luoroacetic anhydride is an excellent dehydrating reagent for the direct coupling of carboxylic acids and thiols.282 A variety of Lewis acids have been found suitable for effecting the alternative coupling of thioacids and alcohols: in general, very high yields of thioesters can be obtained with the appropriate catalyst.283 The nitro-alkenes (311) are readily available using aldol condensations and are good Michael acceptors: direct ozonolysis of the intermediate nitronates gives a-substituted thioesters (312) in good overall yields.284 A range of nucleophiles can be accommodated including alkoxides and amides as well as soft and hard carbon

145


R

Ph

N'

-Ic"

COSBu'

0

'COSBu' 'COSBu' (315)

(313)

I

R\ r C O S B u ' ~

OH

(316) ONa I

(319) RS MeO%oMe

hS

-

S

(3221

Scheme 2 9

i325)

(326) R3

RmSMc 0

SMe

(327)

(328)


146

SMe

20 -100 “ C

&SMe

R2

S

H

1 H PhSe

Scheme 3 0

0

0

PhTeSiMe

3 RATePh

(331)

R&==O ( 3 3 L ) R = R ’ S ( O ) , , , PPh,, o r Ck

(3321

(333)

CL

0

( 3 3 5 ) R = C l or CCl,

147


nucleophiles. The a-cyanoacetate (313) has proven to be a good Michael nucleophile, one useful aspect being the relative ease of reduction of the thioester group using sodium borohydride, giving an additional degree of flexibility in further manipulations of the

ad duct^.^^'

initial Michael Thioester functions have again featured in some highly selective aldol condensations. The oxazoline (314), derived from (&)-aspartic acid, gives very largely isomers (315) upon enolisation, aldol condensation and trapping, presumably controlled by chelation effects involving the nitrogen of the heterocycle.286 The latent symmetry and the availability of the optical isomer of oxazoline (314) further contribute to the utility of this protocol. Silyl enolates of thiopropionate esters similarly give largely the @-isomers (316) in Lewis acid catalysed condensations with aldehydes. 287 The =-isomers of esters (316) can be obtained using the corresponding boron or tin288 enolates, and three contiguous chiral centres can be set up by using a chiral a-substituted aldehyde as electrophile. The boron enolate (317) condenses with aldehydes to give thioesters (318) with ca. 90% enantiomeric enrichments. 289 Hopefully, more complex substrates will also be available using this excellent method. 6-Keto-thionoesters (320) are obtainable by acylation of ketone enolates using a trithiodicarbonate (319) in generally excellent yields.290 Unsaturated a-keto-thionoesters (322) have been prepared from dithiono-oxalate (321) by sequential thiophilic Grignard attack, S-allylation and thio-Claisen rearrangement (Scheme 29) 291 Dithioesters (323) can be doubly deprotonated and subsequently regioselectively alkylated at the 8-position to give reasonable yields of homologues (324).292 The intermediate dianion can thus be

.

regarded as an ester homoenolate [cf. structures (99), (1771, (290) and (293) above]. a-Keto dithioesters (326) are available from a-diazoketones (325) by treatment with elemental sulphur and an alkyl iodide; yields are moderate to good.293 The chemistry of 3-oxoketen dithioacetals (327),precursors to 8-keto dithioesters and many other species, has been reviewed.294 Enolates of dithioesters are good Michael nucleophiles and with acyclic enones give largely the anti-isomers (328) 2 the kinetic (E)-enolate. 295 ?-ally1 dienolates (329), prepared by 5-allylation of the corresponding enolates, can be equilibrated to unsaturated dithioesters (330); the latter is usually by far the major component.296


148

The equivalent of a selenolactonisation has been used to obtain thiolactones from appropriate unsaturated 2-acylselenosulphides, by a -- radical pathway (Scheme 30) .297 Subsequent selective oxidation and elimination provides unsaturated analogues with variable regioselectivities. Selenocarboxylate salts are not generally available due to the instability of the corresponding seleno-acids. An indiret method to obtain examples of these species (331) is by aminolysis of bis (acyl)diselenides using ~ i p e r i d i n e . ~ ’ The ~ salts can be alkylated at selenium by reactive halides such as a-bromoketones. Tellurol esters (333) can be prepared from acid chlorides (332) using a t e l l u r o ~ i l a n e . ~These ~~ could prove to be useful intermediates as coupling reactions with lithium dialkylcuprates lead to high yields of the corresponding ketones. Two new procedures for the conversion of thiocarbonyl groups into the corresponding carbonyls (C=S to C = O ) consist of sodium hydroxide under phase transfer conditions300 or cuprous chloride in aqueous sodium hydroxide.301 3.

Lactones

-

B-Lactones. Full details have been given302 for the preparation, on reasonably large scale, of the potentially useful 8-lactone synthons [ (334) and (335)I from diketene.303 Butyrolactones. - A variety of ruthenium304 and rhodium hydride305 complexes have been tested for their suitability as dehydrogenation catalysts for the oxidation of l,4-diols into butyrolactones. With 2-substituted and 2,2-disubstituted diols, the regioselectivity can be almost complete and the accompanying excellent yields make the overall transformation [(336) * (33711 a genuinely viable proposition. lI5-Pentanediols can similarly be transformed into valerolactones. An alternative approach to lactones (337) is by oxidation of the corresponding tetrahydrofurans; this can be achieved using mixtures of sodium bromate, NaBr02, and 47% hydrobromic acid.306 No regioselectivity studies have yet been reported with this method. A degradative approach to butyrolactones (339) consists of oxidations of of y-hydroxyalkenes (338) using cetyltrimethylammonium permanganate. 307 A key feature of this reagent is its inability to oxidise primary and secondary alcohols, which allows the preparation of mono- and bicyclic

149


6r

Br 1342)

-

0 (343)

R'

CO, E t

(3441 Ph I I

'2 MeCN

0 Scheme 3 1

o-.)

r-. "OF

(

346

)

O--

CO, H

RS/Y\I OH

CN

Rs

RS

CN

(349)

R e a g e n t s : i , M ~ ( O A C )R~S,S R , T F A , C H 2 C I Z ; i i , B a s i c h y d r o l y s i s ; iii, CoCI2, H20

Scheme 32


150

Scheme 33

O

w

NHAc

N3

HLdQ 0 Scheme 3 4

R3

I

X

= PhSe

or I

S c h e m e 35


151

lactones by this method, as well as of spiro-lactones from tertiary y-hydroxy alkenes. Some new carbonylation procedures have been reported in this area. A variety of 1-alkynes (340) are regiospecifically carbonylated upon treatment with bromopentacarbonylmanganese, carbon monoxide, and methyl iodide under phase transfer conditions.308 Yields are moderate to good, the conditions mild (35"C, 1 atmos.) but as yet the approach is restricted to the 4-methyl derivatives (341). Nickel tetracarbonyl is useful as a catalyst for the reductive carbonylation of gem-dibromocyclopropanes (342) leading to bicyclic lactones (343).3 0 9 (In the absence of the hydroxymethyl substituent, this represents a good route to cyclopropanecarboxylic acids, esters and amides). One drawback is the requirement of large excesses (up to 7 equivalents) of toxic Ni(COI4. A route to the related derivatives (345) is by regioselective attack by allylzinc organometallics onto the corresponding keto-esters (344).310 Yields are generally excellent for the simple alkyl- and phenyl-substituted examples reported. Full details have been reported of the thermodynamic and kinetic iodolactonisation conditions developed by Bartlett, in which sodium bicarbonate can be added to remove HI and thus prevent the reverse reaction and hence equilibration to the thermodynamically preferred trans-isomer (Scheme 31) .311 Reagent (346) is capable of effecting analogous "tosyloxylactonisations" in good yie1ds3l2 and is especially useful for the bis-lactonisation of unsaturated diacids by specific *-addition to the alkene [e.g. (347)* (348)I .313 The equivalent of sulphenolactonisation can be carried out in two steps, starting with an unsaturated nitrile which is first treated with a disulphide using manganic acetate as oxidant in CH2C12-TFA (Scheme 32) .314 This results in mixtures of both possible acetoxysulphides which are transformed, without separation, into the ~ a m elactone using aqueous cobalt(I1) chloride, nitrile hydrolysis and the necessary thiol migration. Overall yields are good and the method is also applicable to valerolactone synthesis and to butyrolactones (349), a class of isomer not normally available from related lactonisation procedures. Bromolactonisation of the protected a-amino-acids ( 3 5 0 ) leads largely to the cis-butyrolactones (3511, the controlling feature probably being complexation between the nitrogen and the bromonium Similar control in reactions of (E)-(350) also results in the

152


HQH

1359)

Ph

,CO2Me

R'--k (363)

Scheme 3 6

(365)

0


153

formation of the *-isomers, but epimeric, relative to lactones (351), at the secondary bromide position. The products are useful as precursors to highly substituted prolines such as (-1-Bulgecinine. Another route to a-amino-lactones involves Lewis acid induced rearrangements of oxazolones (Scheme 33) .316 A broad generality has not been established for this sequence. An interesting approach to diamino-butyrolactones proceeds formal intramolecular addition of a keto-nitrene to a butenolide (Scheme 34) .317 The somewhat strained intermediates in this sequence should have a number of other uses. A variety of reagents have been shown to be suitable for effecting cyclisations of 4-alkynoic acids (352) to give ylidenebutyrolactones (353), including sulphenyl and selenenyl halides (X=SPh or SePh) ,318 N-iodosuccinimide (X=I)3 1 9 and palladium (11) salts (X=PdY). 3 2 0 The iodolactones [ ( 3 5 3 ) , X=I; R1=Hl can be coupled with 1-alkynes using a palladium catalyst to give the homologues (354)319 and the corresponding vinylpalladium species [ (353), X=PdYl alkylated by allylic chlorides to give lactones ( 3 5 5 ) .320 In addition, the (?)-isomers of iodolactones (353) are available from mercury-induced cyclisations of iodo-alkynoic acids [ (352) ; R1=I] .319 Radical-type ring closure is now established as a generally useful entry into both butyrolactones and valerolactones. Some useful generalisations have been made regarding the radical based ring closure outlined in Scheme 35.321 In general, the method is more suited to butyrolactone formation unless the double bond is activated by a carbonyl ( g radical Michael addition) and tetra-substituted double bonds are often poor radical acceptors. Simple reductive removal of the 'X' group is often predominant. A full report has been published on the related, highly regioselective, cyclisation of acetals (356) to give butyrolactones ( 3 5 7 ) following dealkylation and oxidati Jn.322 One disadvantage of these approaches is that two functionalities, the radical precursor [ X in Scheme 351 and the alkene group are lost. By initiating cyclisations of substrates [cf. (356)l using a cobalt(1) species, the initial cyclisation product is a cobalt complex which then loses the elements of cobalt(1) hydride to provide an unsaturated product [e.g. (358)1, thereby considerably enhancing the overall utility of this methodology.323 An intermolecular approach to butyrolactones (360) by reductive couplings between carbonyls (359) and acrylates may also involve radicals or perhaps a homo-enolate species generated by Michael addition of the samarium iodide to the a ~ r y l a t e . ~ Yields ~~ are variable but can be

154


SnClq

(366)

q Cl

R

+

_____)

CO,H phs+ C0,Me

(369)

(

370)

1371)

Scheme 37

QoH

4 0

(3721

3: carboxylic Acids and Derivatives

155

as high as 82%, and are further improved by the addition of HMPA to the original THF-alcohol solvent system.325 Sm12 also mediates in the addition of iodomethyl groups to ketones in another process which could be either radical- or ~ a r b a n i o n - b a s e d .The ~ ~ ~products are isolable iodohydrins but in the case of reaction with a y-keto-ester (361), the initial product cyclises to butyrolactone (362) (overall yield: 9 3 % ) . The potential of this method as a completely different approach, relative to iodolactonisation routes, to this type of lactone thus seems to be considerable. Recent results from studies of additions of electrophiles to ester enolates suggest that an electron-donating substituent directs additions to the opposite face. This is nicely demonstrated in alkylations of the enolates derived from lactones (363) which give exclusively the homologues ( 3 6 4 ) .327 Condensations with aldehydes are similarly selective. Intermolecular Diels-Alder reactions between 5-substituted butenolides and 1,3-butadiene at 210°C are stereospecific, giving only bicyclic lactones (365) generally in good yields.328 Therefore, when applied to a chiral butenolide, two new and potentially distinguishable asymmetric centres are formed in optically pure form, while retaining the original asymmetric feature. A remarkably efficient intramolecular Diels-Alder sequence can be used to prepare a variety of bi- and tricyclic lactones (Scheme 36) .329 The mildness of this procedure angurs well for its application elsewhere. An alternative type of intramolecular Diels-Alder reaction leading to butyrolactones (368) features the use of a nitroalkene function as the diene (366); these Lewis acid catalysed processes result in higher stereoselectivities with more substituted substrates.330 Hydrolysis of the initial products (367) is achieved by sequential treatment with potassium t-butoxide and HC1-formaldehyde via a nitrile oxide intermediate. The selective production of trans-fused isomers is of significance with respect to the overall synthetic utility of this scheme. Other useful cyclisation procedures include rutheniumcatalysed transformations of dichloro-acids (369) into lactones ( 3 7 0 ) in high yield331 and Lewis catalysed additions of a-chlorosulphides (371) to p-substituted phenols leading to aromatic butyrolactones ( 3 7 2 ) .332The remarkable Michael-Michael-aldol ring closure sequence has been applied to spiro-lactone synthesis by using a-methylenebutyrolactone as the second Michael acceptor (Scheme 3 7 ) .333 The


156

5.1. R h - A 1 2 0 3 H 2 ( 7 o t m ) , E t O A c , 13h

* OMOM

I

VN" (383) N u : O R , N,

o r SR

(387)

(3881

157


overall yield for this example is 37%. Other versions of this idea can be devised and one such has been used in the construction of the tricyclic system (373) (Scheme 37)3 3 4 although in this particular case, at least two separate synthetic operations are required. An unusual reaction which could have other applications is a single flask conversion of unsaturated aldehyde (374) into (2)-Aeginetolide (375), together with some of the corresponding butenolide (Dihydroactinidiolide) 3 3 5 This latter compound together

.

with the tetrahydro-derivative (376) have been obtained optically pure by a classical resolution procedure employing a trans-fused lactone prepared by malonate attack onto a cyclohexane e p ~ x i d e . ~ ~ ~ One of the obvious alternatives to butyrolactone synthesis from ester enolates and epoxides is to use nucleophilic attack by ester homo-enolates (vide supra) onto aldehydes and ketones. Two further versions of this latter method are condensations between ketones and methyl 3-bromopropionate using a-lanthanum metal to provide the presumed homo-enolate species337 or chiral dianion (377).338 In the latter examples, separation of diastereoisomers and desulphurisation gives both enantiomers of the products (3781, or the corresponding butenolides, following elimination of the sulphoxide function. Various simple chiral 5-substituted butyrolactones [ (378); R2=H] have been obtained from B-keto-sulphones by sequential asymmetric yeast reduction and alkylation. 3 3 9 Butyrolactone (379) can be prepared by a highly enantioselective Claisen rearrangement starting with (S)-3-methylbutyrolactone; the usefulness of this reaction has been enhanced by the development of a relatively straightforward method to transpose this initial product into lactone (380) and hence higher homologues, by substitutions at the a-p~sition.~~'An impressive demonstration of the utility of ylidenetetronic acids as precursors of highly substituted butyrolactones is to be found in a recent synthesis of the steroid Brassinolide, in which four contiguous chiral centres are established ~~ in one step [ (381) +(382)] (92%) by h y d r ~ g e n a t i o n . ~Highly substituted a-substituted butyrolactones (383) can be readily obtained by regio- and stereocontrolled nucleophilic ring opening of 1 ,2-epoxy carbamates. 342 A somewhat simpler a-hydroxybutyrolactone, (g)-pantolactone (384) is in demand as a precursor to the B vitamin (+)-D-Pantothenic acid; further methods for obtaining this enantiomer include a practical classical resolution procedure343 and asymmetric hydrogenation of the corresponding keto-lactone. 344

In general,


158

s n Bu,

SnBu3

9 C0,Et

R'

(3891

gr :$ ,R1w

R'

RZ R 3 NMe,

COzMe

CO, R Z

R3

(3921

0 C0,Me

(393)

(39C1

(3951

- Rn -----

P ~ ~ SPrI S

Reagents

(3901 t

SPr'

Pr'S

13961

. )

(3971

I,

Bun2 C U L I ,

v, 5'1.

11,

H2S04,

VO(acoc),, VI,

(396)

ButOOH,

III,

PhCH2Br, N a H ,

MnO,

Scheme 3 8

0

OH

SEMO&O

H

SEMO \

S c h e m e 39

J CzO H

iv,

LI NEt,,

3: Carboxyiic Acidr and Derivatives

159

-cis/trans mixtures

of disubstituted lactones (385) can be converted into largely the cis-(E)-isomers (386) by sequential enolisation and protonation. 3 4 5

Once again, Eldanolide (387) has proven to be a popular target; two asymmetric syntheses have been reported, one based on boronic acid ester chemistry,346 the second starting with ( Q ) - r i b o n ~ l a c t o n e ~ ~ ~ while routes to racemic material have utilised a stereoselective condensation between 2-propenyl-1,3-dithiane and an aldehyde,348 B-lithioacrylate equivalents349 and an unusual dioxepin rearrange70% ment.350 A further synthesis of (-)-Blastmycinone (388) with ee involves an asymmetric [2+21 cycloaddition between an 2-2-menthyl ketene and a vinyl ether followed by Baeyer-Villiger oxidation of the resulting cyclobutanone.351

=.

a-Methylenebutyrolactones. - Recent advances in this area have been reviewed.352 Ally1 stannane species are featured in a number of attractive new approaches to the a-methylenebutyrolactone function. B-Stannyl propenamides (389) condense smoothly with aldehydes in the presence of a Lewis acid typically BF3 or TiC14, to give high yields of lactones (390) following acidic hydrolysis (10% HC1, reflux) .353 Significantly, products with 75-80% enantiomeric excesses are obtained R ’ = ( R ) - or ( 5 ) from reactions using a chiral amide “389); Bz(MeOCH2)CHl, making this one of the few brief methods available for the preparation of such enantiomers. However, one drawback with this method is the final rather harsh acidic hydrolysis step which would certainly remove a wide variety of protecting groups, for example. A solution to this is to use the corresponding esters (391) which condense equally well with aldehydes using BF3 as catalyst; subsequent hydrolysis to the lactones (390) is effected using one equivalent of TFA in methylene chloride at ambient temperature. 354 The possibilities for asymmetric synthesis with this system have yet to be examined. B,y-Disubstituted as well as monosubstituted lactones (390) can also be obtained related condensations of bromomethyl acrylates (392) with aldehydes using metallic tin in aqueous ether to provide the reactive intermediate. 3 5 5 Although perhaps somewhat more practical than the foregoing methods, overall yields are rather lower (50-75%). The most practical but not the mildest version of these methods is undoubtedly the direct condensation of bromomethacrylic acid [ (392), R1=R2=H] with aldehydes using stannous chloride in aqueous, acidic 2-methoxyethanol at 60-70°C; yields are usually

160


(399 1

(LOO)

(4021

(LO11

(LO31

co;

R-H Qo

( 40 7)

(LO61

OR’ (415)

(Ll01

(4091

(LO81

- kR co

co

“ P 4

H2S04

(ClCI(a1 R (b1 R

:H

= n-alkyl

R

W

(4171

o

3: Carboxylic Acia3 and Derivatives

161

above 80%. 356 A different approach to a-methylenebutyrolactones is a further development of the chemistry of 2-silyloxycyclopropane carboxylates ( 3 9 3 ) , which, when treated with the trifluoromethanesulphonate analogue of Eschenmoser's salt and a Lewis acid (TMSOTf), are converted into 8-amino-esters ( 3 9 4 ) and thence lactones ( 3 9 5 ) following borohydride reduction and elimination.357 Overall yields are reasonable for this multi-step approach. A carbanion based approach to monosubstituted lactones. ( 3 9 0 ) begins by metallation and regioselective condensation of ketene dithioacetal ( 3 9 6 ) with an aldehyde. The products ( 3 9 7 ) are subsequently sulphenated at the remaining methyl group and hydrolysed; yields are moderate to An efficient new method for the dehydration of a-hydroxymethyl butyrolactones ( 3 9 8 ) to give the corresponding a-methylene derivatives employs a water soluble carbodiimide in the presence of cuprous chloride as catalyst in hot acetonitrile.3 5 9 A procedure which could be useful in the construction of annulated butyrolactones is outlined in Scheme 3 8 .360 Vinyl lithium intermediates do not undergo cyclisation; it is a pity that the introduction of the lactone carbonyl group into the initial product requires so many steps! A rather neat application of the enolate Claisen rearrangement of glycolates is featured in a total synthesis of ( 2 )-Ethisolide (Scheme 3 9 ) .361 The key rearrangement presumably occurs via a chair-like transition state in which the side-chain is positioned over the opposite face to the ethyl group. The same methodology has also been used to prepared the homologous Avenaciolide and Isoavenaciolide.

Two new routes to a-alkylidenebutyrolactonesare worthy of note. Radical mediated cyclisations of selenocarbonates ( 3 9 9 ) afford lactones (400) in good yield, for the simple examples examined.362 Moderate yields (ca 40%) of lactones ( 4 0 2 ) have been obtained by tandem Michael addition-olefination reactions using the butenolide (401). 3 6 3 Nucleophiles used include t-butyl lithioacetate, and Bu2CuLi; annulations are possible by starting with a keto-malonate. Butenolides. - Disubstituted butenolides (404) can be easily obtained in 51-75% yields from the (?I-chloro-acrylate (403) by sequential treatment with a Grignard reagent [RMgBr, 2 eq.], lithium powder and carbon dioxide.364 Related vinyl lithium species can be obtained

162


(4221

(4231

.L R

,+'%fcozH R

(4241

14251

T CO, H

CO, H

EoR3

R2

M R' e0

(OH 1

(431)


163

directly by deprotonation of maleate or fumarate derivatives and condensed with aldehydes to give butenolides (405) in variable yields. 365 Another straightforward route to monosubstituted butenolides (407) is by condensations between dianion ( 4 0 6 ) and epoxides followed by ring closure (carbodiimide-DMAP) and a facile oxidative elimination. Overall yields are 70-75% but the most significant feature is the ease with which chiral butenolides can be prepared because of the availability of so many chiral e p ~ x i d e s . ~ ~ ~ Michael additions of malonate to allenic sulphoxides (408) proceed efficiently to give homologues (409) which, after [2.3]-sigmatropic rearrangement, lactonisation and finally isomerisation, are converted into a-carboxy-butenolides (410).367 Some new ways to convert furans into butenolides have been reported. Low temperature photo-oxygenation of 2-substituted furans followed by reduction using dimethyl sulphide leads to cis-enediones (411) which are converted into cyano-butenolides ( 4 1 2 ) by sequential treatment with TMSCN and PCC. 368 a-Seleno-furans (413) can be directly converted to butenolides (414) using hydrogen peroxide. 369 The ease of introduction of an a-seleno group into a suitable furan should make this a valuable method in complex butenolide synthesis. A very simple if somewhat limited approach to butenolides (416a) consists of carbonylation of allylic alcohols or derivatives (415) thereof in concentrated sulphuric acid.370 Similarly butenolides (416b) can be obtained from aldehydes (417) and the method can be extended to more unsymmetrical products by using preformed a,@-unsaturated aldehydes, the presumed first intermediates in the sequence.371 Yet another development of the Heck reaction is the PdC12-catalysed coupling of aryl iodides with unsaturated ester (418) under solid-liquid PT conditions.372 After acid hydrolysis, the B-aryl butenolides (419) are isolated in 48-71% yields. The olefin geometry presumably changes during the coupling step; applications of this method to more highly substituted substrates have not yet been examined. The chiral hydroxy-sulphoxides (420) and the epimeric alcohols can both be obtained from the same B-keto-sulphoxide by a judicious choice of reducing agent; oxidation to the sulphone, double deprotonation, alkylation by sodium iodoacetate and elimination then affords chiral butenolides (421).373 Overall yields are not spectacular but the optical purities of the final products are high (>

90%).


164

Ar

Ar

(434)

(4321

R -oR

o

d

o

At

(4351

(4331

SEt

( 4 5 1 ) R ’ r H or Me

I5521

(4431

3: Curboxylic Acidr und Derivutives

165

High yields of simple f3-ethynyl butenolides (423) may be prepared by gas-phase thermolysis ( 5 5 0 ° C ) of the propargylic esters (422); the likely mechanism is a tandem ene and [l.S]-hydride shift.374 Readily available hydroxy-esters (424) are easily converted into butenolides [ (425); R3=H] by sequential Michael addition of thiophenol and base-catalysed elimination. 375 If the intermediate 6-thio butyrolactones are converted into the corresponding butenolides [ (425); R3=SPhl using sulphuryl chloride then homologues [ (425); R3=n-alkyll are accessible by an addition-elimination sequence using an n-alkylcopper, in examples where R2=H. From an investigation of various Michael acceptors, it has emerged that ethoxymethylidene malonates are suitable for additionelimination reactions with acetylides to give diacids (426) after hydrolysis and elimination. Upon heating in a -dichlorobenzene, these acids cyclise to give ylidenebutenolides (427) 376 Chromium carbonyl complexes of acetylenes have been used to prepare 2-methoxyfurans and hence ylidenebutenolides; a specific example is a synthesis of bovolide (4281, a component of butter flavour.377

.

-

Tetronic Acids. An improved route to (E)- (and (Z)-) pulvinic acids (430) is by condensations between methoxymaleic anhydrides (429) and 378 zinc enolates of arylacetates followed by dehydration (MsC1; DBN). A further advance is the finding that trimethylsilyl iodide efficiently demethylates the initial condensation products to provide the naturally occurring acids (430). Related intramolecular condensations have been used to prepare tetronic acids [(431); bond indicated] required for various natural product syntheses. 379 A related structure (Ircinianin) has been obtained using an intramolecular Diels-Alder reaction with an ylidenebutenolide --double bond as the dien~phile.~~' Phthalides. - Complimentary procedures for the synthesis of aryl lignans have been developed; hydrogenation [Rh(I) cat., H2, 160°C] of anhydrides (432) leads almost exclusively to lignan (433) whereas dehydrogenation of diols (434) gives very largely the isomeric products (435).381 3-Hydroxyphthalides (437) can be prepared from the known carbanions (436) by carboxylation, followed by reduction and hydrolysis of the oxazoline function,382 and converted into via the 3-cyanophthalides (438) using KCN followed by DCC, corresponding cyanohydrin.383

166


(447)

0

n- C5H,,C HO

Scheme 4 0

3: Carboxylic Acia3 and Derivatives

1 4 5 11

"C9H19

Q> *

167

(4521

"-C9H19

no HO'

168

General and Synthetic Methoak

A full account has been given of the preparation of phthalides from 0 -iodobenzyl alcohols by Pd-catalysed carbonylation.384 A related procedure starting with iodophenyl ketones [e.g. (439)l leads to ylidenephthalides (440)-385

Valerolactones. - Dianions (441), derived from the parent acrylic acids using t-butyl lithium, condense smoothly with epoxides in the presence of BF3.0Et2 to give generally excellent yields of the unsaturated lactones (442), useful as precursors to a wide range of valerolactones and other derivatives. 386 Clearly condensations with chiral epoxides will lead to chiral valerolactones as, for example, in a synthesis of the pheromone (443), using a Sharpless-derived epoxide. 387 An alternative asymmetric synthesis of lactone (443) features a further example of the utility of the chiral 1,3-oxathianes developed by Eliel and c o - ~ o r k e r swhereas ~~~ a brief diastereoselective syntheses of both erythro and threo (443) rely on reactions between modified n-decylmagnesium bromide and the acrolein dimer. 389 A relatively rare example of the creation of chiral quaternary carbons has been uncovered in Michael addition-elimination reactions between lactone enolates [e.g. (44411 and a chiral nitro-alkene (445); in this example, the product (446) is obtained with 88% enantiomeric enrichment. 390 Intramolecular Michael additions are also useful for the elaboration of chiral valerolactones. In an extension of previous work, the allylic epoxide (447) has been found to cyclise to give the Vitamin D3 precursor (448) upon treatment with 2.4 mol% Pd2(tba)3.CHC13, without the need for a base.391 Based on observations made during work on Quassinoid synthesis, simpler model substrates [e.g. (44911 have been shown to cyclise to lactones [e.g. (450)] upon exposure to trimethylsilyl iodide.392 A tandem Michael-aldol sequence forms the basis of a stereoselective approach to highly substituted valerolactones (Scheme 40) . 393 Yields for this particular example are 83 and 70% respectively. Carbon radicals are usually noted for their ability to behave as Michael nucleophiles; an example of this is the radical mediated coupling of chiral iodide (451) to acrylate, leading to lactone (452).394 Other applications of this principle will doubtless be forthcoming. Two research groups have reported on the utility of facile intramolecular Diels-Alder reactions between enamine or vinyl One application of sulphide functions and enones [ (453) (454)I .395 +

this methodology is in a synthesis of (+)-Nepetalactone (455). A

169


(6661

(6631

HO,C

C02Mc

OAc

(4651

(6661

H

(467)

H

?-

OMe

-SiO

0 Me

\

SPh

(666)

(Et 012P 1670)

(669 1

H

Y

(471)

170


somewhat more conventional intermolecular Diels Alder cyclisation forms the basis of a total synthesis of (+)-Actinobolin (456).396 An oxidative electrolytic fragmentation of carboxylic acids, developed some years ago by Corey and co-workers, has been applied to a synthesis of malyngolide (459) by cleavage of acid (457),leading to ester (4581, using carbon plate electrodes followed by methylation and bis-hyd r~xylation?~~ A total synthesis of ( - ) - (459) from (+)-tartaric acid has been reported with full details.398 Careful acid-catalysed cyclisation of ketene dithioacetals (460) can take place with > 90% selectivity in favour of isomers (461) containing the substitution pattern present in the Prelog-Djerassi lactone (462).399 Further routes to (~)-(462)are based on an improved Diels-Alder cyclisation between benzyl propenyl ether and methacr~lein~ ~ ~ ref. 395) and on the stereoselective elaboration (cf. of a trisubstituted cycloheptenone.401 Iodo-valerolactones (464) can be easily obtained in one step from the corresponding vinyl ether (463) using the iodonium salt I(col1idine) BF4 in dimethyl 2 s u l p h ~ x i d e . ~Iodobutyrolactones ~~ can be similarly prepared. Selenoand sulpheno-lactonisation of 5,7-dienoic acids generally leads to the formal [1.4]-addition products (465); derivatives (466) of the alternative products are best obtained from lactones [(465), XR1=SePh] by sequential oxidation and [ 2.3 ] -sigmatropic 403 rearrangement. Details of some optimised conditions €or PLE-catalysed asymmetric hydrolyses of 3-substituted glutarates have been reported. 404 Reductions of the initial products (467) can then be used to obtain either enantiomer of the related 3-substituted valerolactones. The ability of Mevinolin and Compactin to block HMGCo reductase and hence cholesterol biosynthesis continues to stimulate the development of synthetic methodology in this area, past work in which has been comprehensively reviewed.*05 Two total syntheses of (+)-Compactin rely on a Diels-Alder strategy. An intermolecular version has diene (468) as the key synthon and suffers from a poor yield in the final demethylation step406 whereas an intramolecular approach using the aldehyde (469), derived from tri-~-acetyl-D-glucal, as the lactone synthon suffers from no such drawback at the deprotection stage. 407 A total synthesis of ( + ) -Dihydromevinolin features the use of keto-phosphonate ( 4 7 0 ) for construction of the valerolactone portion of the molecule.4o8 Yet another generally useful chiral synthon is the iodo-lactol ( 4 7 1 ) obtainable in twelve


171

. . H

R'-

R'

( 480)

(479)

H

(4841

(4851a; R b; R

= =

(Z1-n-C5H,, I€)-CHPh

H

(4861

172


OH

OH

0 ________)

DBU

S c h e m e 41

(p0-

173


steps from a-Q-glucopyranose. 409

Epimerimisation at C-6 in such

lactones (472) may be accomplished by conversion to the open-chain mesylates 8473) which re-close to epimers (474) upon work-up and chromatography. 410 @-Hydroxy-ketones (475) undergo stereospecific attack by the allenylboronic acid (476) to give diols (477) and thence hydroxylactones (478) following ruthenium tetroxide oxidation.4 1 1 BY using chiral derivatives obtained from acid (476) and bulky tartrate esters, the whole sequence can be carried out asymmetrically. Additions of amines and thiols to unsaturated mevinates (479) are stereospecific, 412 giving only the 4- ( R )-derivatives (480) The bulk of the tri-isopropylsilyloxy group in chiral 1,3-oxathianes (481) appears to prevent undesired chelation between the incoming reagent and the @-oxygen so that methylmagnesium bromide (especially) or L-selectride give very largely epimers (482) 413 Subsequent hydrolysis and homologation of product [(482); R=Me] leads to ( S ) -mevalonolactone (483) Both ( 2 )- and (R) -Mevalonolactone have been obtained in excellent optical purities by stereospecific Grignard reactions of keto-acetals derived from (2S,3~)-1,4-dimethoxy-2,3butanediol ,414 and various chiral deuterated mevalonolactones have been prepared using a Sharpless epoxidation to introduce asymmetry.415 Finally, the aldehyde (484) has been used to obtain lactones (485) by sequential Wittig homologation and hydrolysis.416 As well as an

.

.

.

obvious relationship to the foregoing mevinic acids, dehydration of lactones (495) gives the natural lactones (-)-Argentilactone (486a) and

( + ) -Goniothalamin

(48613).

Macrolides. - Although many notable total syntheses of naturally occurring macrolides have been reported this year, most have used previously reported methods to effect the ring closure step. One of the oldest ways to form macrolides is by lactonisation of w-halo-acids; tetra-alkylammonium salts of 2-pyrrolidinone in DMP have been found to be good bases for the promotion of such a l k y l a t i ~ n s . w-Hydroxy~~~ acids can be cyclised using a distannoxane simply by heating in decane with 20 mol% of the latter.418 Both methods give good to excellent yields of 13-17 membered lactones (no examples of the more difficult medium-sized rings are reported) and both require reasonably high dilutions I250ml mmol-1 respectively] A full account of the preparation of 10-membered lactones by fragmentation of hydroperoxides [ e.g. (487) (48811 using +

General and Synthetic Merhoa3

174

Scheme L 2

n = 3; 76 'I. n = 4 ; 9 2 '1. n

( 4 9 5 ) R z H or Me

(496)

1

Ph

H N R 2 R 3 , H20

R'CN

1505)

R u H Z ( P P h 3 ) & , 160

= 5 ; 0 2 *I8

*C'

R ' C O N R ZR 3 (506)

OAr

0

PhANHBu + ArOH

RyCoNH OH

(5071

175

3: Corboxyiic Acids and Derivatives

Cu (OAc)2-FeS04 has been given.419 A precursor to hydroperoxides ( 4 8 7 ) can be the corresponding lactol (489)l; these can be directly cleaved to saturated lactones (490) by photolysis with iodosobenzene diacetate. 420 The alternative and penultimate precursors to

[e

hydroperoxides ( 4 8 7 ) are vinyl ethers [e.g. (49111. Such compounds can be oxidatively cleaved directly using MCPBA to give a keto-lactone [e.g. (492)1, in this example a precursor of (2)-Dihydrorecifeiolide. 421 Keto-macrolides related to the foregoing example (492) are also available from a-nitrocycloalkenones by ring expansion, again by cleavage of an intermediate lactol ,422 Five-atom expansions are particularly favoured because of the relative stability of the intermediate lactol and in such compounds, the ketone group is best removed, if desired, by reduction of the corresponding tosylhydrazone using (Ph3P)2CuBH4. Benzomacrolides can be obtained using a similar fragmentation, but with a Michael addition to a benzoquinone as a first step (Scheme 41) .423 Yields for medium-sized rings are rather low but the simplicity and brevity of the sequence compensates for this. Ring expansion based on a Claisen rearrangement [(493) (494)l can be used to obtain unsaturated eight-membered lactones which are 424 amongst the most difficult to prepare from acyclic precursors. The starting materials (493) are readily obtained by selenoxide elimination from an acetal formed using phenylseleno-acetaldehyde diethyl acetal and the corresponding 1,3-diol. The difficulty in obtaining 8-10 membered lactones is also reflected in the development of an acetylenic oxy-Cope procedured for the synthesis of (5)-Phoracantholide I (Scheme 42).425 Presumably, more complex targets could +

be obtained by this procedure, rather than removing most of the useful functionality! In a preliminary report, it has been claimed that samarium iodide is an excellent reagent for performing intramolecular Reformatsky reactions [(495) (496)] even when the products are 8-10 membered.426 If generally applicable, this will be a significant -f

breakthrough, even though high dilution conditions are required Very large macrolides, such as a (typically 500 ml mmol-'). 26-membered model for the polyene Tetrin A, can be prepared by Pd-catalysed C-C bond formation between a allylic bis-sulphone and a vinyloxirane function; yields as high as 92% have been obtained.427 4

Carboxylic Acid Amides Uncatalysed aminolysis of esters by primary amines usually

requires temperatures of 200°C or more:

such reactions can however be

176


performed even with secondary amines at ambient temperature by using high pressure ( 8 kbar) .428 Although yields are essentially quantitative in most cases, the limitations of scale and apparatus availability are drawbacks. A severe test of any aminolysis procedure is the direct conversion of a-chloro-esters (497) into amides ( 4 9 8 ) ; this can be achieved in excellent yield using Et2NH and AlC13 in toluene at 20"C.429 Phenolic benzoates (499) can be readily cleaved by treatment with n-butylamine in benzene at room temperature to give the butylamide ( 5 0 0 ) and phenol (501).430 Although a good deprotection method for phenols, this could also be a useful and selective amide preparation as aliphatic esters are unreactive under these conditions (vide supra). Anilines can be directly acylated by carboxylic acids using polyphosphoric acid trimethylsilyl ester in at higher temperatures the corresponding amidines pyridine at 1 0 0 ° C ; are formed.431 Yet another amide and peptide coupling reagent is the phosphate (502), which appears to rank on equal terms with the best of the rest. It is an easily prepared crystalline solid, stable at O"C, and couples equimolar amounts of acids and amides in CH2Cl2 or DMF containing Et3N at 20°C in 0.5 h. Yields are excellent and minimal racemisation occurs. The known but little used reaction between carboxylic acids and isocyanates has been recommended as a viable route to a wide range of amides. 4 3 3 Ultrasonication of bromobenzene or 0 -bromotoluene in THF with metallic sodium and t-butylisocyanate leads rapidly to the anions [ ( 5 0 3 ) and (504),X=H] which can then be further metallated using n-butyl lithium to give the useful intermediates [ ( S O 3 1 and (5041, X=Li]. Subsequent condensations with aldehydes and ketones generally give reasonable yields.434 Simple aqueous work-up after the first step provides an easy one-carbon homologation method from bromobenzenes to amides. Many phenols can be directly ortho-acylated to give salicylamides by rections with an isocyanate and boron trichloride in ref luxing methylene chloride.4 3 5 Aminolyses of nitriles (505) are catalysed by many ruthenium species, most notably R U H ~ ( P P ~ ~to ) ~give , amides (506) in excellent yields but only with thermally robust substrates as temperatures of ca. 1 6 0 ° C are required.436 a-Hydroxyamides (507) can be readily obtained from the corresponding carboxylic acids and N-sulphinylaniline.437 The functional group combination is crucial as the latter

reagent does

not react with alcohols or carboxylic acids in isolation.


177

ax

CO, HNEt2)

NHAc

(510)

Pd (cat.)

CONEt2 NHAc

(512)

(511)

OH

0

R V N M c ,

RCHO *TIC I&

CONMc,

(518)

(517)

(5191

CONEt, ____)

OL i


178

Ph

ARp C02Mc \N C02Me (526 1

(525 ) H

R

xC02Mc

(527)

R = (CH2),P(0)(OEt),, (CH21ZON=CMe2, o r (CH,),N B z z

(5281

H (529)

(530)

(531)

179

3: Carboxylic Acidr and Derivatives a - H y d r o x y w a m i d e s are available from 2-TBDMS cyanohydrins by hydrolysis of the nitrile function to C(S)NH2 using diphenylphosphinodithioic acid (Ph2PS2H) [lPrOH, 60°C, 8 h] :

the

silyl group is not removed under these conditions.438 Double carbonylations of o-halo-acetanilides (508) can be used to prepare the amides (509), useful as isatin and quinoline precursors, 439 in up to 80% yields. Unsaturated amides (510) are selectively deprotonated at the

(z)

-y-position (arrowed) and give the deconjugated products (511) on m e t h y l a t i ~ n ~ ~or ' the keten aminal (512) with TMSC1.441 The latter intermediate undergoes a thermal [1.5]-shift leading to allylsilane (513) and thence to the syn-aldols (514) following TiC14-catalysed condensations with aldehydes. Contrary to a previous report in the literature, tertiary benzamides (515) can be reductively alkylated [+(516)1 successfully under Birch conditions;

the presence of a

suitable proton source such as t-butanol is crucial. 442 Double deprotonation of a-keto-amides (517) gives rise to the novel dianionic species (518) which react with alkylating reagents generally at the a-position to give hydroxyamides Use of an Evan's-type keto-amide derived from (S)-2-methoxymethylpyrrolidine, results in asymmetric inductions of up to 75% ee. Dienolates (520) derived from unsaturated amides using LDA in 4:l THF-HMPA react in a Michael fashion with unsaturated esters to give largely the threo-isomers (521); in the absence of HMPA, formation of the corresponding erythro-isomers begins to predominate. 444 additions

to

Michael

a,B-unsaturated amides by a range of carbon acids such as

ketones, nitriles, malonates, and nitro-alkanes are effectively catalysed by the system CsF-(MeO)4Si. 445 An electro-reductive method has been developed for the N-alkylation of secondary amides;

yields are 67-91% and perhaps the

salient feature of this method is the absence of strongly basic conditions.446 5

Amino-acids

a-Amino-acids.

-

Despite being first reported some ten years ago, the

Stork method for a-amino-acid synthesis by homologations of glycine Schiff bases continues to receive considerable attention. Many of the recent developments are extrapolations of methodology used elsewhere in carboxylic acid synthesis.

For example, the pyrrolidine derivative

(522) can be alkylated (LDA, RX) and subsequently hydrolysed (1MHC1)


180

to give a-amino-acids (523) in excellent yields and with > 95% enantiomeric enrichments.447 Somewhat lower optical yields

(z.

60% ee) are obtained in alkylations of related Schiff's bases derived

from polyacrylic crosslinked resins containing pendant (S)-methoxymethylpyrrolidine groups. 448

Imines (524) derived from camphor also

undergo asymmetric alkylations using similar methodology, the best results being obtained in reactions with allylic halides when enantiomeric enrichments are between 75 and Similarly, excellent selectivities can be achieved at both new centres from alkylations of carbanions of imine (524) by secondary allylic or benzylic halides.450 Achiral Schiff's bases prepared from amino-acids other than glycine can be resolved with ee's of up to 63% by asymmetric protonation of the derived enolates using a chiral amine ligand for the lithium counter cation and a chiral acid to provide the protons.451 A particularly mild method for the alkylation of glycinate Schiff's bases is by Pd(0)-catalysed reactions with allylic acetates or carbonates: in the latter cases, no base is required452 and moderate levels of asymmetric induction can be achieved by using a chiral diphosphine l i c ~ a n d . Asymmetric ~~~ Michael reactions of this type of glycinate with acylates can be effected using a nickel complex: a full account of this work has been given.454 Complete chiral induction at the a-position only is observed. Michael additions of simple glycinate Schiff's bases can conveniently be conducted under phase-transfer conditions 455 However , under these a

conditions, or using LDA-THF-HMPA, y-bromo butenoates react exclusively at the bromine to give amino-diester derivatives (525). On the other hand, enolates generated using LDA-THF do add in a Michael. fashion to give cyclopropylamino-acids (526) by an addition-el imination mechanism. 56 Cyclic a-amino-acid derivatives [ ( 5 2 7 ) , n=1-41 can be similarly prepared by alkylations using a,ud i h a l i d e ~while ~ ~ ~ reactions with w -halo-esters occur preferentially by displacement of the halogen. 458 Subsequent cyclisation of the resulting amino-diesters leads to various types of lactams. The Sch8llkopf bis-lactim ether method can be used to prepare

*

( p )-glutamic acid and a number of substituted homologues with excellent stereoselectivity at C-2 ( > 98% d.e.1 by Michael additions to a,B-unsaturated esters,459 as well as a range of other non-natural (D) - -amino-esters (528).460 By treatment of the usual bis-lactim ether carbanion with tosyl azide followed by further deprotonation and subsequent elimination of dilithium tosylamide, the diazo derivative

181


R' R ~ C O

OTMS

TMSOTf

ISL2 1

Br ( 5 4 51

Scheme L 3


182

(529) is formed which adds smoothly to simple alkenes,presumably via a

-

carbenoid intermediate, to give cyclopropyl derivatives (530) after hydrolysis.461 An entirely different approach to this class of a-amino-acids involves condensations between enolates of isocyanoacetates and epoxides;

the result-ing alcohols [e.g. (531)

from cyclohexene oxide] are then mesylated and cyclised using

K O ~ B 462 ~ . An alternative to the bis-lactim ether approach is based on condensations of saturated five-membered heterocycles such as imidazolidinone (532) which can now be obtained in an optically pure state by a straightforward classical resolution.463 The related oxazolidinone (533) has been obtained from methionine and used to prepare (R)-amino-acids [cf.(528) I as well as the vinyl substituted derivatives (534) by oxidation and elimination of the sulphur group.464 Yet more general routes to chiral amino-acids have been reported using a variety of asymmetrically substituted ester enolate equivalents (535) in combination with the electrophilic nitrogen source di-t-butyl azodicarboxylate (536).

These include the sterically screened camphor

derivatives developed by Oppolzer and co-workers,465 N-methylephedrine derivatives, 466

and Evans-type oxazolidine derivatives.467

All give excellent enantiorneric enrichments in the final products

“523)

or (528)l and generally, but not always, excellent chemical

yields: for many targets there seems to be little to choose between the individual sequences. Similarly excellent asymmetric inductions have been achieved in condensations between imines l e . 9 .

(53711 and

ally1 boranes [e.g. (538)l which give initially the N-benzyl amino-esters (539):

related organometallics such as Grignard

reagents display a much lower level of regioselectivity towards the three electrophilic sites in substrates (537).468

With t.he exception

of this last approach, an advantageous feature of all of the foregoing is that the chiral auxiliary can be recovered. A non-stereoselective route to 6-hydroxy-a-amino-acids (541) proceeds via condensations between aldehydes or ketones and the ketene ~

acetal (540) in the presence of TMS trif late.469 The significance of this procedure is that, in contrast to many of the foregoing methods,

a strong base is not involved.

A wide range of masked a-amino-acids

(543) are available, again non-stereoselectively, by direct addition of a range of organometallic species to the acyl imines (5421, prepared by photo-oxidation of the corresponding N-methoxy


183

Ph

Ph

(5501

(5511

OH

NH2

(553)

(552)

OH

R'do2Me

C02Me

'

0, N

NH2

(5551

(55L)

HNBoc

ZHN A C 0 2 (558)

R'HN

k 3

1559)

(5611

(560)

CO2Et

+

TsNHCHzTs

TsNHCHz

(562)

(5631

T s NH

3 97%, although one disadvantage is the requirement of a final hydrogenolytic step, which generally will preclude the presence of unsaturation or sulphur functionality in the side chain. 472 Effenberger and co-workers have given full details of their method for preparing amino esters (547) from a-hydroxy ester derivatives (546) by direct Walden inversion.473 The triflate derivatives turn out to be most suitable (milder conditions and hence less racemisation and elimination) and as esters (546) can be prepared from a-amino-acids by diazotisation with retention of configuration, this is a good method for obtaining the rarer (D)-isomers of a-amino-acids. A related approach relies upon asymmetric halogenation of sterically screened esters of the type prepared by Oppolzer and co-workers from camphor derivatives. Subsequent S 2 displacement by azide, trans-esterification and hydrogenation completes this versatile approach, which is ~~~ applicable to the elaboration of both ( & ) - and ( g ) - f ~ r m s . The anti-isomers (548) are the major products from reactions between (R)-2,3-isopropylideneglyceraldehyde derived from (D)-mannitol and organometallic reagents (RM); Mitsunobu inversion using phthalimide, hydrolysis and oxidation then completes yet another approach to (g)-a-amino-acids (549) (Scheme 4 3 ) . 475 An alternative route from (p)-mannitol to either (&)-a-amino-acids proceeds via diaziridine intermediates. 476 An example of an asymmetric Strecker synthesis is the reaction between (5)-1-phenylethylamine, benzylmethyl ketone and NaCN to give amino-nitrile (550) and thence the corresponding (El-amino-acid (551) after acid hydrolysis and hydrogenolysis.477 2-Oxazolines feature as intermediates in two diastereoselective approaches to hydroxy a-amino acids. Cycloaddition of ethoxycarbonyl nitrile oxide to 2-propenylpyridine affords the heterocycle (5521, a precursor of the N-terminal acid (553) found in some Nikkomycin n u c l e ~ s i d e swhereas ~~~ asymmetric aldol condensations between aldehydes and methyl

185


isocyanoacetate, catalysed by a chiral ferrocenylphosphine-gold(1) complex, afford mainly the trans-oxazolines ( 5 5 4 ) and subsequently esters (555).479 An alternative and potentially general route to esters (555) has regioselective attack by ammonia at the a-position of a glycidic acid as the key step.480 Diamino acids (557) with different N-protecting groups are available in racemic form by Michael addition of amines to the dehydroalamine derivative ( 5 5 6 ) ;481 differentially protected N-Alkyl a-amino glycines [e.g. ( 5 5 8 ) ] have also been prepared.482 glycines have been obtained from a-azidomalonates by a photolytic procedure which presumably proceeds via a nitrene-type insertion reaction. 483 a-Amino-acids in general are available from a-nitro esters using ammonium formate as a hydrogen transfer reagent.484 Fermenting Bakers yeast has been found capable of selectively hydrolysing lipophilic (&)-a-amino-esters in racemic mixtures; a simple extractive work-up of the brew gives (D)-amino-esters (559) with often excellent recoveries E. 45%1 and enantiomeric enrichments ( > 92%) .4g5 Similar specificities have been reported using alkaline protease.486

[x

8-Amino-acids. - A classical route to 6-amino-acids is by Michael additions of amines to a,@-unsaturated esters. Such reactions can be accelerated by the application of high pressure and performed asymmetrically by using chiral esters such as 8-naphthylmenthyl Almost complete asymmetric induction ha5 been observed in some cases. Another well established route is, by analogy with B-hydroxy-ester synthesis, an aldol condensation between an imine and an ester enolate. Further improvements to this approach include highly diastereoselective condensations between imines and tin(I1) thioester enolates, in the presence of tin(I1) triflate, leading to largely the &-isomers ( 5 6 0 ) 4 8 8 and a related, normal, aldol method which allows the creation of three contiguous chiral centres ( > 95%

derivative^.^"

de) in the thienamycin precursor ( 5 6 1 ) .489 Very similar products can be obtained by condensations of imines with (2)-c-vinyloxyboranes.490 The sulphone (562) can be regarded as a synthon of the cation ( 5 6 3 ) , and as such reacts with a variety of soft nucleophiles to give

B-amino [e.g. ( 5 6 4 ) I and a,B-diamino derivatives [e.g. (565)J in generally good yields. The likely mechanism involves an elimination to give N-methylene p-toluenesulphonamide followed by a Michael


186

NHAc

OH

%AoC0,B"'

R3R4NH

C0,Bu'

0-

ENCONE1

E1,NCONH

(570)

2C

0,H

(571)

(572)

R = H or Me

COzMe

""SM, (5751

(5731

NHAc

(5761

NHAc

(5771


. i R w M g B r

CI

I

THF, - 7 0 ° C

RHN"

C0,Mc

ZHN

Z H N*CO,Me (

187

578)

( 5 8 01

(5791

tco2Et 0

(581)

R'O

(5821

(583)

K

F

F

(5861

I5871 R' W N h C OH z R z

I

SES

(588)

Fe

(589)

188


addition; hence the requirement for soft nucleophiles.4 9 1 Aminolysis of glycidic esters with ammonia generally results in attack at the a-position;480 however Ritter-type ring opening of epoxy-esters (566) using acetonitrile in the presence of A1P04-A1203 selectively gives the 6-amino derivatives (567).492 Such cleavages can also be performed using trimethylsilyl azide with zinc chloride as promotor.493 It is of course unwise to assume that either of these methods will necessarily always provide such excellent regioselectivities when applied to new substrates. y-Amino-acids. - As mentioned above, a classical route to 6-amino-acids is by Michael addition of amines to a,6-unsaturated esters. A homologous version of this consists of ring opening of doubly activated cyclopropane diesters (568) by amines, in the presence of an equivalent of Et2A1C1.494 Yields of diesters (569) vary between 30% and 89% although these do include some rather sterically congested examples. Amidoethylation of carboxylic acid dianions (570) by aziridines provides a general route to a-aryl-GABA derivatives (571).495 The relatively poor yields in some cases are offset by the simplicity of the method. The related 6-hydroxy-y-amino-acids GABOB and carnitine (572) can be readily derived from (2g,4g)-4-hydroxyproline by electrochemical decarboxylation followed by oxidation and pyrrolidinone ring cleavage.496 The iodo-azide (573) plays the role of cation (574) in reactions with soft nucleophiles such as malonates and acetoacetates to give y-amino-acid precursors (575) in generally very good yields.497 The one carbon homologue behaves similarly leading to 6-amino acids. Unsaturated Amino-acids. - 2-Aminopropenoates (576) are converted into the corresponding butenoates (577) efficiently and stereospecifically by sequential reactions with diazomethane and pyrolysis of the resulting pyrazoline.4 9 8 An alternative route involving ring opening of an arylethylidene oxazolone by methoxide generally leads to both the ( g ) - and (E)-isomers of butenoates (577),499 as does a dehydrative route from the corresponding 0-silyloxy butanoates. The chloro-ester (578) behaves as a glycine cation equivalent in reations with vinyl Grignards leading to respectable yields (usually E. 60%) of 6,y-unsaturated amino-esters


189

(579) The amino-diacid (580) and the corresponding primary amide are obtainable by addition of amino-malonates to ethyl buta-2,3-dienoate or cyano-allene respectively.502 More highly

substituted examples are not reported. The Still-Genari phosphonate method has been applied to the elaboration of the (Z)-amino-diester (581) from phenylalanal; a variety of other phosphonates gave much lower stereoselectivities.

-

A review of recent advances in asymmetric Asymmetric Hydrogenation. synthesis includes a section on this topic.504 New chiral ligands for performing rhodium-catalysed hydrogenations of dehydroamino-acids include bis-l,2- (diphenylphosphinyl) c y c l ~ b u t a n eand ~ ~ ~the corresponding 3,4-disubstituted pyrrolidine derivatives. Both give very high enantiomeric enrichments and the latter has been shown to have an excellent turnover, with substrate/catalyst ratios as high as 50,OOO:l. 80% Aqueous formic acid is a useful source of hydrogen in conjunction with this type of catalyst and can sometimes result in better ee's than with molecular hydrogen.507 Dipamp is a particularly good ligand in Rh(1)-catalysed reductions of a dehydroamino-acid residue in an enkephalin pentapeptide, whereas reductions with achiral palladium catalysts of similar residues in cyclic peptides are often highly stereoselective being controlled, not surprisingly, by other chiral centres within the substrate. 509

Amino-acid Protection. - Carboxyamidomethyl (CAM) esters have been shown to be useful protecting groups in a-chymotrypsin and papain-catalysed peptide hydrolysis and synthesis. 1,3-Dioxans (582) can be obtained from Na-protected serine derivatives by acid-catalysed transacetalation and are sufficiently robust to survive both amino deprotection and peptide coupling reactions. (&)-Histidine benzyl ester can be prepared as the ditosylate salt by direct acid-catalysed esterification, contrary to claims in the literature that this is not possible. Both ally1 esters and Nu-allyloxy carbonyl (Alloc) groups can be cleaved using palladium-catalysed hydrostannolysis by tri-n-butyltin hydride without affecting benzyl- or t-butyl-based protecting groups.513 In contrast, all three N'-protecting groups [BOC, Z, and Alloc] are converted into the t-butyldimethylsiloxycarbonyl function upon treatment with t-butyldimethylsilane and palladium (11) acetate.514 Similarly, benzyl esters are exchanged to give the


190

corresponding silyl esters.

Both of these palladium-catalysed

processed should find many applications. The ease with which BOC anhydride (di-t-butyl dicarbonate) can be used to introduce Nu-BOC protecting groups has now led to the development of suitable methods for preparing the benzyl analogue, dibenzyl dicarbonate [Z20?]. It is to be hoped that the compound is sufficiently stable to become commercially available as it will be a welcome substituted for benzyl chloroformate.515 A realisation of the susceptibility of Nu-Fmoc groups to hydrogenolysis has led to an investigation of the homobenzyloxycarbonyl [homo-Z,hZ] function (583) for amino group protection.516 As with Nu-Z groups, the hZ moiety is best removed by transfer hydrogenolysis using freshly precipitated Pd-C and ammonium formate, but much more slowly than benzyl groups allowing the selective unmasking of the ester group in hZ-Gly-OBn. Chloroalkyl carbonates (584) are generally useful reagents for the introduction of a wide range of alkoxycarbonyl groups onto amino functions ( 5 8 5 ) .517 Yields are generally well in excess of 70% and little or no racemisation appears to occur. The carbonate (586) is useful for the introduction of Nu-Fmoc groups; the released phenol can be coupled to the carboxylic acid function prior to work-up by simply adding an equivalent of DCC to give a protected and activated derivative (587) in a single operation.518 Overall yields are generally high. The newly developed B-trimethylsilylethanesulphonyl (SES) function (588) is simply the sulphonamide analogue of the corresponding carbamate and as such will offer similar selectivity of removal and greater stability especially to acidic conditions: the group is unmoved by refluxing TFA or 6M HCl.519 The novel ferrocenylmethyl (Fem) group falls into a rather different category in that Fern derivatives (589) of a-amino-esters can be coupled with Nu-protected a-amino-acids using DCC, but the products are of course then masked at the peptide bond NH group. Features of the Fern group are its high lipophilicity and bright yellow colour making it easy to detect during chromatographic separations. The group is removed by TFA-thionaphthalene at the same rate as t-butyl-based functionalities.s 2 0 Amino groups in a-amino esters can be 5-arylated using triarylbismuth diacylates in good yield, although a minor by-product is the N,N-diarylated derivative.521 A useful review of the synthesis and reactions of Na-hydroxy-a-amino-acids

has been published. 522

3: Carboxylic A c i d and Derivatives

191

A mild reagent for the removal of 2,2,2-trichloro-t-butyloxycarbonyl (TCBOC) and 2,2,2-trichloroethoxycarbonyl groups is sodium 2-thiophenetellurolate.523 The reagent does not attack N-BOC groups. Immobilized penicillinacylase catalyses the removal of rather stable No-phenacetyl groups in aspartame and (&)-aspartic acid a-methyl ester.524 Other substrates have not yet been examined. Na-Protected tyrosines can be efficiently alkylated at the phenolic OH by treatment with an alcohol under typical Mitsunobu conditions;525 the dimethylphosphinyl (Dmp) has also been recommended for the protection of this function.526

The thiol group of cysteines 527 can be effectively blocked by a 9-fluorenylmethyl (Fm) group.

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41. 42. 43. 44. 45.

z,

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z,

3: Carboxylic Acids and Derivatives 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.

75. 76. 77. 78. 79. 80. 81. 82.

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A.


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83. 84. 85. 86. 87

-

88. 89. 90.

91. 92. 93. 94. 95. 96. 91. 98. 99. 100. 101 *

102. 103. 104. 105. 106. 107. 108. 109. , 110. 111. 112. 113. 114. 115.

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u.,

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~

137. 138. 139. 140. 141. 142.

143. 144. 145. 146. 147. 148. 149.

m.,


196

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4: Alcohols, Halogeno-compounds, and Ethers

503. 504. 505. 506. 507. 508. 509. 510. 511. 512. 513. 514. 515. 516. 517. 518. 519. 520. 521. 522. 523. 524. 525. 526. 527.

M.J. Hensel and P.L. Fuchs, Synth.Commun., 1986, 16, 1285. J.W. ApSimon and T.L. Collier, Tetrahedron, 1986, 42, 5157. T. Minami, Y. Okada, R. Nomura, S. Hirota, Y. Nagahara, and K. Fukuyama, Chem.Lett., 1986, 613. U. Nagel, E. Kinzel, J. Andrade, and G. Prescher, Chem.Ber., 1986, 119, 3326; U. Nagel and E . Kinzel, E., p . 1731. H. Brunner and M. Kunz, Chem-Ber., 1986, 119, 2868. J.M. Nuzillard, J.C. Poulin, and H.B. Kagan, Tetrahedron Lett., 1986, 27, 2993. H. Aoyagi, F. Horike, A. Nakaqawa, S. Yokote, N. Park, Y. Hashimoto, T. Kato, and N. Izumiya, Bull.Chem.Soc.Jpn., 1986, 59, 323. P. Kuhl, U. Zacharis, H. Burckhardt, and H-D. Jakubke, Monatsh fur Chimie, 1986, 117, 1195. Z.J. Kaminski and M.T. Leplawy, Synthesis, 1986, 649. J.H. Jones and M.E. Wood, Synth.Commun., 1986, 16, 1515. F. Guibe, 0. Dangles, and G. Balavoine, Tetrahedron Lett., 1986, 27, 2365. M. Sakaitani, N. Kurokawa, and Y. Ohfune, Tetrahedron Lett., 1986, 2 1 , 3753. E. W u n z h , W. Graf, 0. Keller, W. Keller, and G. Wersin. Synthesis, 1986, 958; G. Sennyey, G. Barcelo, and J-P. Senet, Tetrahedron Lett., 1986, 2,5375. L . A . Carpino and A. Tunga, J.Org.Chem., 1986, 51, 1930. G. Barcelo, J-P. Senet, G. Sennyey, J. BensoamTand A. Loffett, Synthesis, 1986, 627. I. Schon and L. Kisfaludy, Synthesis, 1986, 303. S.M. Weinreb, D.M. Demko, T.A. Lessen, and J.P. Demers, Tetrahedron Lett., 1986, 27, 2099. H. Eckert and C. Seidel, Angew.Chem.Int.Ed.Engl., 1986, 25, 159. D.H.R. Barton, J-P Finet, and J. Khamsi, Tetrahedron Lett., 1986, 27, 3615. See also W.H. Pirkle and T.C. Pochapsky, J.Org.Chem., 1986, 51, 102. H.C.J. Ottenheijm and J.D.M. Herscheid, Chem.Rev., 1986, 86, 697. M.V. Lakshmikantham, Y.A. Jackson, R.J. Jones, G.J. O'Malley, K. Ravichandran, and M.P. Cava, Tetrahedron Lett., 1986, 27, 4687. C. Fuganti, P. Grasselli, and P. Casati, Tetrahedron Lett., 1986, 27, 3191. K. B a r x s , M. Lampropoulon, V. Marmaras, D. Papaioannou, Liebigs Ann.Chem., 1986, 1407. M. Ueki, Y. Sano, I. Sori, K. Shinozaki, H. Oyamada, and S. Ikeda, Tetrahedron Lett., 1986, 27, 4181. M. Ruiz-Gayo, F. Albericio, E. Pedroso, and E. Giralt, J.Chem.Soc., Chem.Commun., 1986, 1501. ~~

Alcohols, Halogeno-compounds, and Ethers BY L.M. HARWOOD

Wherever possible, reactions are listed according to the type of compound prepared.

For example, ROH

R C 2 reactions are classified

as halide preparations and not alcohol reactions.

Exceptions are

those reactions which are considered to be protection or deprotection procedures. Within each functional group class, preparations are discussed before reactions and it has been attempted to list the references in any one section in increasing order of reaction selectivity.

Cross referencing to earlier reports

follows the established style. 1 Alcohols ______ Preparation. - By Addition to Alkenes. Triethylborane and phenylborinic acid have been found to catalyse hydroalumination of alkenes, and reaction of the intermediate alane with atmospheric oxygen efficiently furnished alcohols resulting from

&-

Markovnikov hydration. Procedures for the preparation of methylborane and dimethylborane and their use in the synthesis of tertiary alcohols containing a methyl group have been described (Scheme 1) .2 Preparation of 1,3-diols by hydroboration of allylic alcohols with thexylborane has been shown to proceed with high stereoselectivity when the substrates are 1-(1-hydroxyalky1)cyclohexenes.’ Stereocontrol in the hydrosilation of allylic and homoallylic alcohols has been studied jointly by the groups of Tamao and Ito. With certain substrates, notably 3-hydroxycyclohexene and

3-(hydroxymethyl)cyclohexene, high stereoselectivitites were observed for the formation of 1,3-diols (Scheme 2).Moderate success in the asymmetric generation of 1,2-diols by osmylation of alkenes in the presence of chiral amine auxiliaries such as ( 1 ) 5 and ( 2 1 6 has been achieved, enantiomeric excesses in the region of 90% being recorded with certain substrates. Osmium tetroxide catalysed hydroxylation has also been applied to chiral allylic 6-hydroxysulphoxide substrates to obtain vicinal triols with

209


i -iii _____)

Reagents

I,

(MeBH2I2 o r ( M e 2 B H ) Z .

- + 11,

C E O . I I I , H ~ O ~-QH ,

Scheme 1

I-

c;.

iii

-1OO:l d iastereomer ratio i n each c a s e

i -iii

Reagents

I , ( H M ~ ~ S I ) ~ N 1H 1 , , H2PtC16,

111,

MeOH, THF,

Scheme 2

,NMe2

OC,,,

aq. N a H C 0 3 , 6 0 ° C


210

?I P --

0I

OH I

OH

OH

I

&R

____)

major

1

OH Reagent:

i, OsOL(cot

+

1, Me3N-O-(2

e q u i v ) , oq THF, r.t

Scheme 3

Reagent:

I,

302,Ph3P, hv, T i ( O P r ' I 4 cat., C H Z C I Z , 0 'C

Scheme 4

2 KBPh3H THF, -78

*c

KBPh3H

*

~

THF, - 7 8 ° C

A

6 '1.

&6 98.5

Scheme 5

94 '1.

:

1.5

4: Alcohols. Halogeno-compounds, and Ethers

diastereoselectivities of 7 0

21 1

-

95% in favour of the material

.'

possessing a C-l/C-2 erythro relationship (Scheme 3) Studies by Vedejs have indicated that hyperconjugative 6 - l r interactions of allylic substituents with the double bond may not be as important as previously suggested in directing the stereochemistry of osmylation of alkenes.8 A one-pot procedure for the synthesis of B,y-epoxyalcohols via photo-oxygenation of alkesles in the presence of a titanium(1V) catalyst has been described (Scheme 4 )

.'

By Reduction of Carbonyl Compounds. Use of high (10 kbar) pressures has been shown to effect trialkylstannane reductions of ketones in the absence of radical initiators or Lewis acids." Zinc borohydride has been demonstrated to be a mild reducing agent for the conversion of benzenethiol esters into alcohols in good yield.'' Use of mixed solvents containing methanol has been found to confer some chemoselectivity upon reductions with lithium borohydride and permits enhanced rates of reduction of esters, lactones, and epoxides in the presence of carboxylic acids, amides, chlorides, and nitro-compounds. l2 In addition, use of lithium borohydride in methanol-tetrahydrofuran or methanol-diglyme is claimed to permit reduction of primary and tertiary amides in the presence of secondary amides. The chemo- and stereo-selective reduction of carbonyl compounds may be carried out using the highly hindered reagent potassium triphenylborohydride in THF at low temperatures. l 3 Methyl ketones are selectively reduced in the presence of higher alkyl ketones and a-substituted cyclic ketones are converted into the reduction products with high stereocontrol (Scheme 5). Regioselective 1,2-reduction of a,B-unsaturated ketones has been achieved by hydroiridium phosphine catalysed hydr~genationl~ or by using lithium aluminium hydride in the presence of lanthanoid salts,15 and the selective reduction of cyclic enones has been shown to occur with a combination of sodium borohydride and B-cyclodextrin. !-protected y-amino-a,$-unsaturated esters derived from naturally occurring amino acids may be reduced selectively to the allylic alcohols using di-isobutylaluminium hydride-BFj etherate at low temperatures without racemization of the chiral centre." The suggestion that chemoselective coversion of B-keto-esters into $-keto-alcohols might be feasible via reduction of the enolates has now been demonstrated by Japanese workers. After initial treatment of the B-keto-ester with potassium hydride or lithium di-isopropylamide at 0 OC, the

General and Synthetic Methorls

212

Reagent :

I,

Me4NHB(OAc)3, CH3CN, AcOH, or P r I 2 S i H C l

anti -selective

s y n - s e l e c t i v e . B I J I ~ A I HTHF, , - 7 8 "C Scheme 6

X

-

Y '

OH

X

I

B

0

n

O

~

C

OH X

> 99

= SiMef

X = H

1

8

OH

H

1

7~

v ~

OH

o

OH

(1

99

Reagent . L i B E t 3 H , THF, - 7 8 'C

Scheme 7

&k H

K+

(3)

m


213

intermediate enolate can be reduced with aluminium hydride. Several research groups have published work on the diastereoselective reduction of aldols to 1,3-diols. Formation of the anti-lI3-diols has been demonstrated using trimethylammonium triacetoxyborohydride” (cf.8, 205) or di-isopropylchlorosilane20 with 20 : 1

z.

diastereoselection, and the alternative reduction products may be obtained in better than 12 : 1 diastereoselectivity using an excess of di-isobutylaluminium hydride at -78 ‘C2’ (Scheme 6). Aldols possessing a 2-(l-trimethylsilyl)vinyl substituent give high yields of the corresponding 1,2-= reduction product with lithium triethylborohydride regardless of the substitution pattern at C-3. 22 The same workers have demonstrated that removal of the silyl group from the C - 2 vinylic substituent cleanly inverts the stereochemistry of the reduction, and have applied this procedure to the synthesis of avenaciolide and its epimer (Scheme 7) .23 Reports of chiral reducing agents continued to appear at an undiminished rate during 1986 and extremely high enantiomeric excesses can now be expected with many of these reagents. Amongst the borane-derived reagents are di-isopinocamphenylborane, which reduces a-tertiary alkyl ketones with e.e ! s consistently greater than (cf.2, 115; 2, 156; 9 , 236) and chiral borohydrides (3) derived from reaction of 9-BBN with chiral alcohols25 or sugar derivatives followed by treatment with potassium hydride. 26 Both optical antipodes of 2,5-dimethylborolane ( 4 ) have been found by Masamune and co-workers to result in high, complementary, enantioselective reduction of dialkyl ketones, u,sually with e.e.’s in the region of 99%, and the mechanism of this reaction has been the subject of study by this group.27 Asymmetric reductions have been attempted with 6-branched alkyl derivatives of beryllium and aluminium but the enantioselectivity of these reagents is disappointing, usually being in the range 25 - 35%.28 Reports on the use of hydride reagents modified with chiral amino-alcohols have been noticeably fewer than in previous years which probably reflects the generally low efficiency of such systems, (cf.8, 208). Indeed, in an example which appeared during 1986, in which (arylmethylamino)butanols were used in conjunction with lithium aluminium hydride, the optical yields were in the range 1 Likewise, lithium aluminium hydride in the presence of quinine forms alcohols from aryl ketones in only about 50% optical yield.30 A rhodium catalyst containing a chiral sulphoxide ligand derived from methionine has been found to promote enantioselective transfer

214


sYn

anti

:

2.8 4 1 8 . 3 Scheme 8

OH Tf Reagent :

I,

= CF,SO,-

R2C HO, CrC12(4equiv.), NiCl2(c at.), DMF

Scheme 9

RZ

Lx

I

X = CI, Br or 1 Reagent : i , R’CHO, BiC13-Zn or BiC13-Fe, THF, r . t .

Scheme 10

RCHO I

* I

P

h

Ph

v CL

> R e a g e n t : i, S n C I 2 - A I , aq. THF, 45-5O ’C

Scheme 11

90% t h r e o

1 .O

215


31 hydrogenation of ketones with optical yields of up to 75%. Interest in microbial transformations of ketones continues to flourish and a wide range of substrates may now be reduced with impressive optical yields and frequently high chemical yields (cf.8,210; 2 239). Baker's yeast appears to be the most popular choice for ketone reduction and substrates reduced with this system include simple ketones,3 2 1 ,3-diketonesI3 3 protected derivatives of a-keto-aldehydes,34 and a - 3 5 and f3-keto-este1-s.~~ In the case of acyclic methyl a-keto-esters it has been demonstrated that carrying out the reduction in a medium containing methanol furnishes largely the D-hydroxy-ester reduction products, whereas in the absence of methanol,L-hydroxy-esters are obtained. 37 Various strains of yeast and moulds have been assessed for their efficiency in the reduction of a-a1ky 1-0-keto-esters 38 Reduction of 2-3-chloroa1ken-3-ones

.

with Baker's yeast has been developed to produce either the saturated ketones or the totally reduced alcohols (Scheme 8 ) .39 The e.els in the initial lI4-reduction step vary from 44 to 84%, giving the (S)-configuration at the asymmetric centre, whilst the reduction of the carbonyl group occurs with very high optical yield to give a anti-products in which the syn-(2SI3S)-isomer mixture of syn- and predominates.

Some work has been reported using cell-free systems to

carry out the asymmetric reductions and these systems appear to be equal or superior to the microbial reductions. Alcohol dehydrogenase derived from the thermophilic bacterium Thermoanaerobium brockii, immobilized upon a solid support, reduces ketones with optical yields usually in excess of 97% and these conversions compare favourably with whole-cell fermentations.4 0 Glycerol dehydrogenase has also been used in the conversion of a-hydroxy-ketones into 1,2-diols in chemical and optical yields & fermentation with Baker's which are similar to those obtained y yeast.41 By Nucleophilic Alkylation. In situ generation of chromium(I1) by reduction of chromium(II1) chloride with either zinc dust or sodium amalgam in THF has led to an improved procedure for the generation of homoallylic alcohols from aldehydes and ally1 halides. 42 An excess of chromium(I1) chloride and catalytic quantity of nickel(I1) chloride have been shown to form a system capable of mediating the formation of allylic alcohols from enol

.

trif lates and aldehydes in moderately good yields (Scheme 9) 43 Similarly, the Cr(I1)-mediated coupling of vinyl iodides with

216


aldehydes to form allylic alcohols in which the original geometry of the vinylic component is retained has been found to benefit from the presence of Ni(I1) or Pd(II), and this has proven particularly useful in highly oxygenated substrates such as sugar derivatives.44 Lead mediates the coupling of ally1 bromide with ketones in the presence of a quaternary ammonium salt and chlorotrimethylsilane,45 and the chemoselective allylation of aldehydes with allylic halides using metallic zinc or iron in conjunction with boron trichloride has been described.46 In this latter procedure, the allylic alcohols produced result from three-carbon inversion of the allylic unit and the reaction is highly chemoselective, leaving nitriles, esters, and even carboxylic acid groups untouched (Scheme 10). In an electrochemical procedure using a tin cathode and a carbon anode, 8- and y-aryl ketones have been converted into didehydrodecalinols by a process which results in both cyclization and reduction of the substrate. 47 In another electrochemical procedure, it has been demonstrated for the first time that aldehydes may be carboxylated to form a-hydroxy-acids using a sacrificial aluminium anode in a diaphragmless cell.48 Di-isopropyl tartrate modified E-crotylboronates have been shown to act as highly enantioselective propionate E-enolate equivalents furnishing mainly threo-Cram adducts on reaction with a-chiral aldehydes in the molecular seives. 49 a-Heteroatom substituted presence of 4 allylboronates undergo a similar addition to aldehydes to furnish homoallylic alcohols in which the major geometric isomers, formed in good yield and with about 90% stereoselectivity, possess the Z-conf iguration. 50 A study of factors influencing the stereochemistry of reaction of substituted allylboronates with chiral aldehydes has been published. 5 1 Allyl- and crotyl-di-isopinocamphenylboranes have been used in the chiral synthesis of

x

homoallylic alcohols in high enantiomeric excess52 (cf. 3 , 144; 2, 164; 5 169; 2, 2451, and the practical application of chiral allenylboronate esters for the enantioselective preparation of homopropargylic alcohols has been demonstrated by the use of these reagents in a synthesis of ( - ) -ipsenol 53 The reductive generation of Sn(0) by the action of aluminium metal on tin(I1) chloride has permitted the highly diastereoselective reaction of cinnamyl chloride with various aldehydes under neutral conditions to furnish good yields of

.

.

threo-adducts (Scheme 1 1 ) 54

Samarium iodide in the presence of

Pd(0) results in the efficient reductive coupling of a ~ r y l a t e sor ~~


217

X X = Br o r I Reagents.

I,

CH212, S m I Z , THF, r t . , 3 m i n ,

11,

CHzIP Sm m e t o l p o w d e r , THF, 0 ‘C

Scheme 12

OH

0

OH

H

H

Fe I k i n -An h .

Chelat ion

R = ButMeZSi

>99

--.F%

C

56-

\\

IV,

II,

L

p

84 ‘1. e.e.

82

It.

Ill

99 '10 e.e.

99 *I. e.e.

99 'I. e.e.

0

0

II

II

?H

PhC,

mu I t istep

H bH

Cif+Hm

W C14H29

O NHZ

(6)

(7) 0

II

R e a g e n t s : i, Ph3P, Et02C - N=N-CO

2 Et, C6H/>NH,

ii

0

S c h e m e 13

THF

OH

269

5: Amines. Nitriles, and Other Nitrogen-containing Functional Groups

0

II (EtO),P-N-C02CMe3-

ROH

RhH3CI-

I

R

0

I1

R e a g e n t s : i , (Et0)2P-NHC02CMe3,

EtO CN=NCO

2

2

Et, P h P; 3

HCI

ii,

Scheme 14

phv* y0

111, I,lV,V,

I1,vI

HO C

0

VI

Ph&

I

NH2

1

H N C O ~ B ~

NH 2

(8) Reagents

I,

PhLi,

11,

CF CO H, HCL, Et20, 3 2

III,

Bu"LI,

IV,

CF3C02H, v, H2C204,Et20,

VI,

base

S c h e m e 15

H,N+

Reagents

m C H 2 0 H

HNTS

+

CI-

TsNH

TSNH

+NH3

HNTs

I,

u -CMS Msol Ill, I V

NTs

TsN

T s C I , NaOH aq ; I I , B H , T H F ,

2 6

III,

CI(CH2)30H, K2C03, D M F ,

CH2C12, E t 3 N , v, Cs2C03 ( 4 e q u i v 1, DMF, 8 0 ° C , MeOH ( 4 e q u i v )

S c h e m e 16

VI,

IV,

MsCL,

L I , NH3, THF,

270


hydrazones derived from ( R ) - or (z)-l-amino-2methoxymethylpyrrolidine is the basis for an enantioselective conversion of aldehydes into alkyl-substituted primary amines (Scheme 8). L 4 Primary amines, as their alkylammonium toluenesulphonates, were prepared by refluxing primary amides in acetonitrile containing A new route to primary amines [ hydroxy (tosyloxy)iodo]benzene. 2 5 involves the addition of organometallic reagents to

.

diarylidenesulphamides, followed by hydrolysis (Scheme 9) 2 6 Aminomethylphosphonic acid can be prepared by treating N-hydroxymethylbenzamide with a mixture of phosphorus trichloride and trimethyl phosphite, followed by hydrolysis of the intermediate ester. 2 7 Asymmetric reduction of chiral oxime ethers with lithium aluminium hydride or diborane-THF gives the optically active primary amines in modest optical yields: 28 the chiral portion was derived from B-pinene or a-amino acids.

2,2-Dialkylcyclopropylamines can be

prepared by the base-induced cyclization of a-chloroimines,followed by hydrolysis (Scheme 10); activating groups, which enhance 29 deprotonation of the a-chloroimine, are required. Allylic thermal rearrangement of cyanamides constitutes a method for the formal lI3-isomerization of allylamines (Scheme 1 1 ) . 3 0 Oxidative conversion of allylic selenides into allylic selenilimines and [3,2] sigmatropic rearrangements of the latter afford a route to allylamines."' Primary amines of essentially 100% optical purity have been conveniently obtained by the asymmetric hydroboration of a prochiral olefin, subsequent removal of the chiral auxiliary, and conversion of a boronic ester derivative into the primary amine with hydroxylamine-2-sulphonic acid (Scheme 12) .

A Mitsunobu reaction

also afforded an enantiomerically pure amino compound ( 6 1 , but with the expected clean inversion of configuration. Thus, in a synthesis of D-ribo-C-phytosphingosine (7), 3 3 the amino group was introduced by treating alcohol (5) with triphenylphosphine, diethyl azodicarboxylate, and phthalimide to give the phthalimido olefin (6) (Scheme 1 3 ) . Primary and secondary alkyl alcohols are converted in good yields into amine hydrochlorides, in a new version of the Mitsunobu reaction (Scheme 14). 3 4 An azaparacyclophane bearing an amino group on each of its eight hydrocarbon chains has been prepared and found to act as a cationic host for hydrophobic derivatives of vitamin B12 . 3 5

Chiral

27 1

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

0-J

A OHC

NO2

OHC

w

HOH,C

(9) Reagents.

I,

Me2NCH(OMe$, Me2NCH0,

11,

T i C L 3 a q (13equiv1, C5H5N, THF

Scheme 17

nitramine Reagents

I,

CH,=CHCN,

KOH, M e C N ,

11,

NaBH4,MeOH,

111,

ti2' P t 0 2 , E t O H .

IV,

L I A I H ~ T, H F

Scheme 18

R~CH,SO,NR,

I- Ill

------+

A~'NH

I

A r CH-

C H S O , N R,

I

R' Reagents

I,

LDA (1.1 e q u i v ) ,

11,

ArCHENArl,

i(i, H 3 0 +

S c h e m e 19

Reagent

I,

ally1 -9-BBN

Scheme 20

272


a-ferrocenylalkylamines have been prepared and tested as templates in peptide synthesis.36r37 Primary amines can be protected with the t-butyldiphenylsiiyi group which is smoothly cleaved with mild acid or with pyridine-HF. 3 8

A1 lyl and a1 lyloxycarbonyl amino acid derivatives

are deprotected by the action of tributyltin hydride, an acid, and a palladium catalysti3’ a considerable advantage of the method is the stability of benzyl and benzyloxycarbonyl groups under those conditions.

The naturally occurring amines cathinone (8) and

merucathinone have been prepared from Boc-L-alanine (Scheme 15) . 40 Secondary Amines. - Monoalkylation of primary amines continues to be an important route to secondary amines, despite the problem of overalkylation.

Irradiation of primary amines in alTohols

containing a suspension of titanium dioxide and platinum gives N-alkylated and N,N-dialkylated products .41

An optically active

spermine macrocycle has been synthesized from L-ornithine hydrochloride (Scheme 16) ; 4 2 macrocycle is formed with ATP.

a 1:1 complex of the protonated Ten kinds of linear pentaamines with

various combinations of three or four methylene chains have been prepared by successive alkylation of secondary amino derivatives of benzylamine with N-(3-bromopropyl)- or N-(4-bromobutyl)phthalimide. 43 Reduction of functionality containing nitrogen is a key method of obtaining secondary amines.

6-Indolemethanol was conveniently

prepared by reduction of the nitroenamine (9) with titanium(II1) chloride (Scheme 17) .44

The alkaloid nitramine was prepared

via

a

reductive cyclization of a y-cyano ester t o a spirolactam (Scheme 18) .45

Derivatives of 6-arylaminoethanesulphonic acids have been

prepared by the addition of sulphonamido carbanions to imines (Scheme 19) . 4 6

Phenyl azide reacts with toluene, cumene,

chlorobenzene, bromobenzene, and biphenyl in the presence of trifluoroacetic acid or trifluoromethanesulphonic acid to give mixtures of 2- and 4-substituted diarylamines, ions. 47

phenylnitrenium

Three bis (triptycyl)amines were prepared by thermolysis of

the corresponding lI3-bis(9-triptycyl)triazenes, which were obtained by the reaction of 9-triptycyllithiums with 9-triptycyl azides. 48 Unsymmetrical diarylamines have been obtained by reduction of t h e azo linkage in compounds derived by electrochemical reaction of 1arylazo-2-naphthols with anilines.49

273

5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups

n

:

l

n=2-19 Reagents,

p - T s O H , PhH,

I,

11,

H2, Pd-C

S c h e m e 21

CH=NPh

CH,NHPh

Q

I

R Reagent.

I,

R

B2H6, MeOH

S c h e m e 22

1-111

RLi

Reagents

I,

RN1Me)COPh

MeLi, M e N H O M e ,

11,

H20.

III,

PhCOCl

S c h e m e 23

RCSCSiMe3

+

Me3SiCN

A> NC

WMe3 N( SiMe3I2

H

Reagent

'

I,

PdCI2, A

Scheme

24


274

Imines have been reduced to secondary amines using a stoichiometric quantity of bis(dimethylg1yoximato)pyridine cobaltate(1) ;50

although in catalytic runs the maximum optical

yield reported using a cobaloxime quinine complex was 20%, that value is near the highest known for asymmetric hydrogenation of imines.

Secondary amines have also been prepared by the reaction of

allyl-9-borabicyclo [3.3.1]nonane with chiral imines;51

very high 1,2- and lI3-asymmetric induction was realized (Scheme 20). Amines containing two chiral centres directly attached to a nitrogen atom

were prepared in 33-90% diastereoselective excesses by catalytic hydrogenation of imines (Scheme 21) ; 52 hydrogenation occurred at the less hindered face of the imine.

Macrocycles Containing four

secondary amino groupings were obtained by condensing 4-methyl-2, 6-diformylphenol with a,w-diamines, followed by reduction of the imine complex so produced.53

Just as an aromatic nitro group can

be reduced by diborane-nickel(I1) choride to an amine,' imine derivatives afford secondary amines in excellent yields when reacted with diborane-methanol (Scheme 22) ; 54

the range of

p-substituents which are unaffected is wide in both cases, even a p-nitro group remaining unchanged upon reduction of the imino group.

Reductive amination is a versatile method of preparing secondary amines.

A general route to unsymmetrical triamines

involves formation of a secondary amine by reductive amination of an aldehyde, and subsequent incorporation of a guanidine moiety; 55 acarnidine was so prepared. 55

an

9-Hydroxy-14-azaprostanoic acids have

been prepared by conjugate addition of nitromethane to

2-(6-carbethoxyhexyl)cyclopent-2-en-l-one and

via subsequent steps

including ozonolysis of nitronate salts followed by reductive amination.56

N-Isopropyl p-haloamphetamines were prepared by

sequences involving boronic acid intermediates. 57

A water-soluble,

dimeric steroid with catalytic properties can be formed by reductive amination of terephthalaldehyde with a substituted 5a-androstane-36-amine using cyanoborohydride.58 Related to the Sheverdina-Kocheshkov amination of organolithium or Griqnard reagents with methoxyamine is an amination using N-methylmethoxyamine (Scheme 23) . 5 9

The method appears to be the

only one which allows direct conversion of an organolithium reagent into a secondary amine, usually isolated as the benzamide.

5-Amino-2-cyano-4-silylpyrroles can be prepared by the palladium or nickel catalysed condensation of silylacetylenes with trimethylsilyl cyanide (Scheme 24) . 6 0

215


R2 )C

=c

(11) R2, R 3 = H or

(10)

I,

I

____)

'OMe

R3

Reagent

/OSi M e 3

Me

CF3S03H ( c a t )

Scheme 2 5

TsNHCH2Ts

Reagents

I,

DBU,

A

THF,

ii,

lCH2=

NTsI

C - or N - n u c l e o p h i l e s ;

NuCH2NHTs

111,

H30t

S c h e m e 26

Ph

Ph Ph Ph

Ph

Ph

Reagents

I,

(E)-PhCH=CHSiMe3,

11,

Z n , HCL a q o r

v, ( z ) - P h C H = C H S l M e 3

Scheme 27

Ra-NI, H2,

111,

H+,

IV,

KH,


276

-%

R'-SePh

Reagents

I,

NCS, MeOH.

[Rid

11,

R'N-SePh

R2NH2,

III,

1-

R2NSePh

&5

[3,21

R1

R'

MeOH

Scheme 28

0

Me

I

Me

Reagent

I,

O=C=N

v

Ph

I

Me

S c h e m e 29

I

H

Me


211

Aminations which afford 8-aminocarboxylates are of interest in relation to monobactam antibiotics. A secondary aminomethyl group can be introduced at the a-position of carboxylic esters by reaction of hexahydro-1,3,5-triazines with ketene silyl acetals in the presence of a catalytic quantity of trifluoromethanesulphonic acid (Scheme 25). 61 The triazine (10) is considered to be converted into an y-silylated methyleneiminium salt which undergoes addition of the ketene silylacetal (11). An aminomethylation procedure involves addition of enamines or carbanions to the labile g-methylene-p-toluenesulphonamide (Scheme 26);62 the scope and limitations of this promising reaction are under investigation. a-Amino acids can be smoothly decarboxylated to the corresponding amino compounds by refluxing in mixtures of 2-cyclohexen-1-one and cyclohexanol.6 3 N-Phenylation of primary aliphatic amines and of variously substituted anilines was achieved in high yield by using a catalytic amount of copper added to triphenylbismuth diacetate.6 4 Allylic and homoallylic secondary amines were prepared by reductive cleavage of isoxazolidines formed by dipolar cycloaddition of nitrones with vinyl- and allyl-silanes, respectively (Scheme 27) . 6 5 The approach is useful because the geometry of the alkene can be controlled by choosing the conditions of elimination. Azaphospha macrocycles have been prepared from diethylenetriamine. 66 Rearrangement of selenilimines obtained by the oxidation of allylic selenides affords a route to allylic secondary amines.[31] Amines obtained by allylic rearrangement were prepared by treating a variety of aliphatic or aromatic primary amines with an allylic selenide activated by N-chlorosuccinimide (Scheme 28) .67 Chemical resolutions of (+)-mecamylamine (12) and of (+)l-noreseroline 2-methyl ether (15) have been reported which give the optically active amines in high yield and excellent optical purity (Scheme 29) .68 Thus, the diastereoisomers (13) and (14) of (a-methylbenzyllurea underwent thermal fragmentation in refluxing ethanolic sodium ethoxide, affording ( - ) - (12) and (+)-(12), respectively. A similar procedure was used to resolve the ether (15).

B-Trimethylsilylethanesulphonyl chloride is a useful reagent

for the protection of primary and secondary amines as their sulphonamides which can be cleaved using fluoride anion. 69


278

p- + vy

NHTs

Y

I, I1

___)

TsHN

Ts

1

Reagents

I,

Y = TsN

Y = TsN

Cs2C03, D M F , 8 0 " C ,

11,

33 "1. H B r , AcOH, P h O H

Scheme 30

Ts

( X = CH, Reagents

I,

BrCH2XBr,

11,

H2S04. HCL

S c h e m e 31

or p - C 6 H 4 C H z )

279

5: Amines, Nitriles. and Other Nitrogen-containing Functional Groups

Ar

k,

A

CI r k

7

+

NMe2 ClOi

N Me2

A

r

S

NMe,

R R e a g e n ts

I,

DMF, P0CL3

11,

MeOH, HCIOL a q ,

111,

NaBH3CN, MeOH,

IV,

R M g X , THF

S c h e me 3 2

+

ArSnR,

-

[R,N=CH,l+Cl-

ArCH2NR2

+

R3SnCI

S c h e m e 33

n =1,2or3 Reagent

I,

CF CO H ( 1 0 e q u i v ) , HCHO (1 2 equiv) , H 2 0 - THF ( 3 1 )

3

2

S c h e m e 34

R’

Reagent

I,

Lewis a c i d ,

+

11,

vNM R*

R3 C02Me

(16)

CH =NMe2

C1-, ( M e3Si0SO2CF3) , CH2CIZ

S c h e m e 35

280


Irradiation of N-tosylamines in aqueous ethanol in the presence of an aromatic electron donor such as 1,4-dimethoxybenzene, and a reductant such as sodium borohydride induced detosylation and liberation of the corresponding primary or secondary amine;70 selective deprotection of some NE- tosyl-lysine peptides was successful. Some macrobicyclic polyamines, isolated as their hexatosylate salts, have been prepared (Scheme 30) ; 7 1

in their hexaprotonated

forms they bind strongly a variety of anions, including nitrate, sulphate, and chloride. Tertiary Amines.

-

Alkylation under a variety of conditions

continues to be an important route to tertiary amines. Irradiation of secondary amines in alcohols containing a suspension of titanium dioxide and platinum gives tertiary amines, the incorporated alkyl chain being derived from the alcohol .41 Macrocycles containing two tertiary amino groups have been synthesized (Scheme 3 1 ) ; binuclear complexes with nickel (11) or copper(I1) ions.72

they form If the

length of the chain joining the tetra-aza units is sufficiently short, (e.g.X=CH2), two distinct one-electron redox processes can be observed, indicating that the two metal ions interact with each other. Tertiary allylamines have been prepared by several routes, including reductive methylation of imines, Mannich condensations involving acetophenones followed by reduction and dehydration, or by Mannich reactions employing alkynes, with subsequent h y d r ~ g e n a t i o n . ~The ~ scope of N-phenylation of aromatic secondary amines by condensation with cyclohexane-lI4-dione has been investigated;7 4 a variety of diphenylamines and certain other diarylamines may be used. N,N,N',N'-Tetraphenylbenzidine was prepared in good yield.74 (E)-l-Chloro-3-(~,~-dimethylamino)-l-arylprop-l-enes are conveniently prepared from aryl chloropropeniminium salts by Those iminium salts also

reduction with sodium cyanoborohydride.7 5

undergo 1 I 2-addition of Grignard reagents (Scheme 32) .76 N,N-Dialkylaminomethyl arenes can be obtained by the reaction of

aryl trialkylstannanes with dialkylmethyleneiminium salts (Scheme 33) .77 Cyclic tertiary amines can be prepared by intramolecular cyclization of iminium salts with allylsilanes (Scheme 3 4 ) ,78 a method particularly relevant to the synthesis of alkaloids; a similar procedure affords 3-vinylpyrrolidines. a-Amino-methylated

28 1


Reogent

I,

E t Z A I C L R 2 R 3 N H ( 2 equiv.)

Scheme 3 6

qNHC0,Et

I ii

I

NHC0,Et

N3

\

CI

N H CO, E t \

N3 Reagents

I,

CI,NC02Et,

11,

NaHS03,

III,

N o N 3 , iv, N O H , D M F ,

v, N a N j , NH4CL

Scheme 37

17

Reogent :

I,

n

0

NH, 3 0 "C

LJ

S c h e m e 38

282


-oxo-esters (16) can be obtained by the Lewis acid-promoted addition of cyclopropanes to iminium salts (Scheme 35) ; 7 9

these

y-0x0-esters can serve as precursors of a-methyleneY -butyrolactones.

The first examples of anodic amination of saturated aliphatic ethers have been reported: 2-aminotetrahydrofurans were prepared by the anodic oxidation of lithium amides and aminomagnesium bromides in

Tertiary amines have been prepared by the aminolysis of

activated cyclopropanes, amidation being minimized by choosing the di-t-butyl esters (Scheme 36) .81 New 'shell-shaped' macrobicyclic compounds containing a tertiary amino group have been prepared from monoaza-crown ether diols.82

Crown ethers consisting of a benzo-crown unit and a

monoaza-crown unit connected by an oxyethylene linkage have been reported;83 their complexation is closer to that of lariat monoazacrown ethers than to that of bisbenzo-crown ethers.

Macrocycles

characterized by a parent macrocyclic liqand and cation-ligating donor 'arms' have been prepared, 1,4,8,11-tetrabenzy1-1,4,8,11-

tetra-azacyclotetradecane being representative: 8 4

a furan-bearing

macrocycle of this category showed high catalytic activity in certain phase-transfer reactions. Amino ethers of trans-2-phenoxycyclohexanol have been prepared by coupling the anion of 2-phenoxycyclohexanol with halogenated tertiary amines under anhydrous conditions or those involving phase-transfer catalysis.85 Optimized conditions for the synthesis of bis(4-dialkylaminoary1)squaraines from di-n-butyl squarate and

_N,N-dialkylanilines _ have been reported;86 yields are comparable with routes based upon squaric acid. Diamines. - Traditional approaches to vicinal diamines involve the opening of epoxides or aziridines.

An alternative approach (Scheme

37) involves the addition of N,N-dichlorourethanes to olef ins;87 both the cis- and trans-azides underwent reduction to the corresponding diamines. Chiral ligands containinq 1,2-diamino groups have been prepared which afford useful enantioselectivities in the addition of cuprate reagents to 2-cycloalken-1-ones.88 Bicyclic diamines can be prepared in a one-pot reaction between alkane-lr2-diamines and triethyleneglycol ditosylate (or similar tosylamines) , without using conditions of high dilution.89 An improved resolution of (+)-lr2-diphenylethylenediamines using optically active mandelic acid has been reported.

283


Me

+

Me

1,

Me

I

I - 0 1

(17)m= n = 1 ;

m=2,

n = I ; or

m = n = 2 Reagents

I,

Et3N, P h H ,

11,

B2H6,THF,

111,

M ~ ( O A C ) ~ - A C O bHu f f e r ,

12, THF

Scheme 39

Reagents

0

I,

& , 11,

HCL, MeOH

I

III,

SOC12,

IV,

S c h e m e 40

KPPh2, d i o x a n e

284


Reagents

I,

T S O [ ( C H ~ ) ~ O C H N~ aI 2~C,0 3 , M e C N ,

11,

T s O [ ( C H 2 ) 2 0 C H 2 ] 2 , Cs2C03,MeCN

S c h e m e 41

+NHTS

+

I$

Ts

TsN

NHTs

Br Ts

( 1 9 ) n = 1 , 2 or 3

Ts R = H or M e Reog e n t .

I,

KZC03, DMF

Scheme 4 2

285


lJ3-Alkanediamines have been prepared by reduction of 4-amino-1-azabutadienes with sodium-isopropanol . Two amino functions have been introduced into a dibrominated steroid nucleus by the action of a large excess of either morpholine, or piperazine, or an N-substituted piperazine (Scheme 38) : the same regio- and

'*

stereo-selectivities are observed in the case of 1,8@-dibromo-10-methyl-A1 -octal-2-one. Disiloxanediyl diamines were prepared by the homocondensation of amino silanols such as (4-aminopheny1)methylphenylsilanol in the presence of tetrabutylammonium hydroxide. 9 3 A cyclophanediamine has been condensed with a crown ether diacid dichloride to give a new type of dissymmetric macrotricyc1 ic cryptand. The cryptahemispherands (17) are members of a new class of host which are half spherand and half cryptand. They were synthesized by condensing diacid chlorides with appropriate cyclic diamines (Scheme 39) ,9 5 followed by reduction and decomplexation. The cryptahemispherands are highly selective, binding strongly hosts for alkali metal ions J 9 6 and are in general more powerful complexing agents than the cryptands.

A

series of phosphine-functionalized diamine macrocycles has been prepared (Scheme 40) ;9 7 the 1 ,7-dithia-4,lO-diazacyclodecanes were prepared similarly. The combination of 2- and 0- (or 2-1 sites with P-sites provides ligands capable of bonding to dissimilar metals in proximity.9 7 Polyamines. - The macrotricyclic triamine (18) has been synthesized and reacted with palladium(I1) acetate and subsequently with sodium perchlorate to give a new kind of organometallic macrocycle, in which one carbon atom of the multidentate ligand is directly metallated.98 Bi- and tri-cyclic triamino azacrowns have been prepared from 1,4,7 10-tetra-azacyclodecane;9 9 using caesium carbonate, the reaction proceeds to a tricyclic product (Scheme 41) whose complex with sodium iodide involves only two rings; internal conversion via a symmetrical octacoordinate complex is proposed for this unsymmetrical complex. In a search for chemical congeners of coenzyme-B6, series of polyazapyridinophanes and polyazaparacyclophanes were synthesized in excellent yields (Scheme 42) , l o o the former by condensing ~

dichloropyridoxine derivatives with ethanamines (19). a:y-Diamino derivatives of steroids have been prepared by displacement reactions on a, v-dibromo-a,6-enone steroids. lo' Syntheses and coordination properties of twelve- and fourteen-

286


Ts

" MeOH or EtOH, C F 3 S 0 3 S i M e 3 , 111, PhSH, CCI,,

IV,

PhMgBr, E t 2 0

S c h e m e 98

(57)

(58)R

= N H -CHO

+

( 5 9 ) R = N=CR e a g e n t s i.PhMe, 80°C.

11,

Me3SICH2CH20H, iil,B14F, THF, IV, MeCO CH0,Et 0 , v, p - T s O H , C H N 2 2 5 5

S c h e m e 99

313

J: Amines, Nitriles, and Other Nitrogen-containing Functional Groups

Mono- and di-carbamate metabolites of felbamate (2-phenyl-lr3-propanedioldicarbamate) have been prepared by ammonolysis of mono- and bis-chloroformates.204 The carbamate ester

(55) which possesses the erythro stereochemistry of staurosporine has been synthesized from a 3,6-dihydrothiazine oxide, obtained by a hetero Diels-Alder reaction using N-sulphinyl benzyl carbamate (Scheme 93) .205 Alkylcarbamoylureas are readily obtained by hydrolysis of trichlorodiazapentadienes formed by the reaction of substituted ureas with trichloromethyl chloroformate (Scheme 94) . 206 6 Amides and Thioamides Relatively general routes to amides include the preparation of mixed anhydrides by the addition of a carboxylic acid to an isocyanate, and subsequent decarboxylation to give N-substituted amides;207

the reaction is applicable to both aliphatic and

aromatic carboxylic acids, and a range of isocyanates. the form R'C(0)NR2"

Amides of

are generated by the unimolecular

fragmentation of mixed anhydrides of the type (RO)(R "N)P(O)OC(O)R' derived from carboxylic and amidophosphoric acids.308 Amides are the principal products of the reaction of thiophenols or p-methylbenzyl mercaptan with aliphatic, benzylic or aromatic imines and carbon monoxide, in the presence of cobalt carbonyl.209 Those amides arise from cleavage of a reactant imine

R'CH=NR"

which occurs

via nucleophilic attack on an acyliminium

intermediate (Scheme 95).

A formal [3+21 cyclization of

(2-carbamoylallyl)lithium reagents with certain acrylamides gave 1 ,3-cyclopentanediamides (Scheme 96) , and also acyclic diamides. 2 1 0

A detailed study of the Favorskii rearrangement of a-chloro ketimines induced by base has been made;211 imidates or amides are produced by ring opening of the intermediate cyclopropylideneamines. The mechanism was found to be parallel with the Favorskii rearrangement of a-halo-ketones. N-Alkylformamides can be obtained by the N-formylation of phthalimides (Scheme 97);*12 the yields are good, and the reaction appears to be of wide scope. Reaction of N,N-bis(trimethylsily1) formamide with aldehydes gives 1-formamido-1-trimethylsilyloxyalkanes which are transformed by a variety of nucleophiles into a-substituted amides (Scheme 98) .213 The crystalline carbamate (57) has proved to be a convenient intermediate in the synthesis214 of the sesquiterpenoids axamide-1


314

111

-v

__3

Ac

H

H

(60)

(61 1

I,

A , CHZC$,,

11,

H:

R 4 = NHAc

R ' = H; R Z = N

xyfo

R3=

R' = N3; R 2 = H

lyxo

R 4 = NHAc, R 3 = H

3

Reagents

0

YN3, N a N , MeCN,

111,

H B r , AcOH,

IV,

H C I , v, A c Z 0 , C 5 H 5 N

S c h e m e 100

Reagents

I

B u " L 1 , THF, COz, - 7 8 " C ,

II>

(COCI)2, PhMe.

III,

R2R3NH

S c h e m e 101

I

R X = H or Me; R = p

X = H ; R = p-FC,H, Reagent

I ,

P h X , A \ C I 3 , C6H6

S c h e m e 102

-CIC6H4

X Y ~ O

lyxo


315

0

Reagents.

N a O M e , MeOH,

I,

11,

HBr

S c h e m e 103

@,",Me

CHO

q--+H

I

Boc

q +

Boc

+

Boc

CO, Et

+

KI c' o

OH

Boc

4

p

OH 1

' I ;

OH

I V

F-------

OH

(68)

(67)

Reagents.i,DIBAL, PhMe, -78°C. IV,

C 0, Et

C F3 C0,H.H

0

11,

LiCH2C02Et, THF, - 7 8 " C ,

K2C03 a q

S c h e m e 104

III,

CF3C02H,25"C,


316

(58) and axisonitrile-1 (59) (Scheme 99). Curtius rearrangement of the acyl azide (56) followed by treatment of the resultant isocyanate with 2-trimethylsilylethanol afforded the carbamate (57) which was deprotected. The resultant primary amine afforded axamide-1 (58) when treated with acetic formic anhydride, and axisonitrile-1 (59) when dehydrated. N-Alkylformamides can also be obtained by the 3-formylation of phthalimides (Scheme 97) ;212 yields are good, and the reaction appears to be of wide scope.

Rotamers

of several propionamides, acetamides, and formamides have been separated using high-performance liquid chromatography at low temperatures.215 Several routes to amides __ via heterocycles have been reported. A route to amino-sugar lactones (61) proceeds 2 nitrene addition to give an aziridine ring which is cleaved with azide ion to give heterocycle (60) (Scheme 100). Since stereoisomers were always found to be separable, both the xylo- and lyxo- products are available.216

Imidazoles available from methionine undergo diastereoselective alkylation, thus affording a route to a-branched vinylglycines (Scheme 70) and other amino acids.

(E,E)-Conjugated

dienamides (63) of high stereoisomeric purity can be prepared

via

extrusion of sulphur dioxide from the __ cis-disubstituted-2,5-dihydrothiophene-l,l-diox~~es(62),generated

by a retro Diels-Alder reaction (Scheme 101) .215

The naturally occurring insecticide pellitorine (63; R'=C5H11I R2=H, R3=Bui was so prepared. N-Substituted-2-benzoylamino-3-benzylthiopropenamides have been obtained by ring opening of 4-ethoxy-2-phenyl-2-oxazolin-5-one with

a mixture of benzylthiol and a primary amine.218 B-Amino-y-ketobutyric acid derivatives can be prepared by Friedel-Crafts reaction of benzene, toluene, or furan with the aspartic acid azalactones (64) (Scheme 102) .219 Substituted (a-arylethylidene)-5 (4E) -0xazo1ones (65) undergo stereospecific ring -amino-esters (66) (Scheme opening220 with methoxide to give the

(z)

103), which are related to 2,3-dehydroamino acid moieties present in some small peptides of antimalarial activity. The E-isomers were prepared by isomerization of the corresponding Z-isomers with HBr. A number of heterocyclic amines has been prepared. The lactam (68), which possesses the pyrrolizidine alkaloid skeleton,

2 conversion of an epimeric mixture of 3-protected hydroxy esters into a single crystalline

was synthesized from Boc-L-prolinal amine salt (67) (Scheme 104) .221

Protected pyrrole-2-carboxylic

5: Amines. Nitriles, and Other Nitrogen-containingFunctional Groups

317

L

R’

CON H, R4 Reagent.

I,

CF3S03H. CF3C02H ( 1

20)

S c h e m e 105

N

C

W

Me

NHMe ____)

0

Me

H*N-N

Reagent.

I,

KR 0

f---

H2, R h l C

S c h e m e 106

HO

R


318

(S-NHz

s.

Br

S-NH,

CO, H

COCl

Reagents

I,

HS(CH2),NH2,

KOH,

11,

SOC12,

111,

Et3N, P h M e

S c h e m e 107

S c h e m e 108

OAC


319

-

O -H

H NCOCC1-j

H NCOC C l3 \

ASePh CN /ylSePh

(CH-)

+

"I

I

I

H

n =1-4 Reagent

I,

CF3S0 H (Sequlv), IH20(5equiv)

S c h e m e 111

OH

.Jt

OH

I

0-C

- RY

o;

0,

7

cOz-+ ,NW,Ar

S

II

0 S c h e m e 112

I

ArNH2

-

N,N*

Ar,

IV, v

Ill

+ ArN=N-NHCH,CO,Et

---+ HO

0

II

ArNH-C-CHzOMe R e a g e n t s I , HNO , O T , VII,

11,

H,NCH

2

CO E t . H C t , 2

111,

NaOAc,

MeOH, A

Scheme 113

IV,

PN

1

v1

0

It

ArNH-C-CHN,

K O H , v, A c O H ,

VI,

A1203,CHC13,


320

acids and their derivatives have been coupled using DCC and subsequently transformed into analogues of distamycin A containing three 4-aminopyrrole-2-carboxylate residues.2 2 2 2-Methylbenzofuran3-carboxamides are formed by the acid-catalysed [ 3 , 3 ] sigmatropic rearrangement of 0-aryl-N-acetoacetylhydroxylamines (Scheme 105). 223 N-(Acylamino)alkylenediamines, required for the synthesis of some 2,4-quinazolinediamine derivatives of antihypertensive activity, can be prepared by catalytic hydrogenation of the 3-[ (N-acy~)methylaminolpropanenitriies (Scheme 106);

selective

ring opening of the putative hexahydro-l,3-pyrimidin-2-01~ was achieved using a catalyst of rhodium-on-carbon.224 A triazatrithiacyclophane has been prepared (Scheme 107) and shown to contain a central cavity towards which the three amide NH groups point.225

A synthesis of N-acetylneuraminic acid226 starts with a

Michael addition of the 1-nitro-D-mannopyranose (69) to t-butyl

2-(bromomethyl)prop-2-enoate, and subsequent hydrolytic removal of the nitro group to give the tautomeric 4-nonulosonate (70) (Scheme 108). A stereoselective synthesis of (2EI4E)-dienamides was achieved through a double elimination reaction of O-acetoxy-sulphones (Scheme 109) .227

Homogeneous hydration of unsaturated nitriles such as

acrylonitrile, methacrylonitrile, and crot-ononitrile to the corresponding unsaturated amides has been carried o u t in water at

80 " C by usinq

colloidal copper dispersions as catalysts.228

The

hydration of acrylonitrile and acetonitrile to the corresponding amides is catalysed by hydridobis(phosphine)platinum(II) complexes.229

The reaction of trichloroacetonitrile with dienic

alcohols, originally developed by Overman, has been used to prepare trichloroacetamides (Scheme 110) which were converted into daunosamine and

(2)-

( 2 )-vancosamine.230

Amides of acrylic and n-pentenoic acids have been prepared by a metal-catalysed condensation of ethylene with phenyl isocyanate. 2 3 1 6 , r-unsaturated-a-keto-amides can be prepared by a double

carbonylation of alkenes in a aminopalladation reaction. 232 Some previously reported limitations on the amidoselenation reaction have been overcome;

cyclic and acyclic 6-(acry1amido)alkyl

phenyl selenides free from side-products have been prepared using stoichoimetric quantities of nitriles (Scheme 111) ;233

the

reactions proceeded with retention of stereochemistry.

Amides have

been prepared by reacting a carboxylic acid with (trimethylsily1)ethoxyacetylene to give a 1-alkoxyvinyl ester which


X = Br or I

Scheme 114

Reagent

I,

Reagent:

NoOEt, EtOH

I,

Scheme 115

HN03, A c O H

S c h e m e 116

32 1

322


0 PhCH,O-C-N

11 0

=r H

0

0 Si Me,Bu'

II

SC,H4 N

P h CH, OCN H

+

____)

HO,C Reagent

0

'OSiMe2But

HO,C EtNPr',(O

I,

1 equiv)

Scheme 11 7 0 R1R2N-CH--COZH

I R3

+

I

0

II

NH-CH-C-R5

f + R 2 ~ - ~ ~ K ~ - ~ ~ - ~ - R 5

I

I

R3

Fern R L

Fern = C,H, Reagent

0

II

I

I

Fern R 4

FeC,H,CH2

DCC

I,

S c h e m e 118

+

H2N 0

Reagents

I,

DCC

S c h e m e 119

5: Amines, NitriIes, and Other Nitrogen-containing Functional Groups

323

is then reacted with an amine.234

2-Hydroxyarylcarboxamides are obtained in good yield by the reaction of phenols with isocyanates in the presence of one equivalent of boron trichloride.235 a-Hydroxyanilides have been prepared by the reaction of a-hydroxycarboxylic acids with N-sulphinylanilines; 2 3 6

the reaction appears to involve

intermolecular catalysis by the carboxylic acid moiety and intramolecular catalysis by the hydroxy group (Scheme 112). Moderate yields of the uncommon a-methoxyacetanilides were obtained by decomposition of a-diazoacetanilides (Scheme 113) . 237

Tertiary

amides containing at least one N-t-butoxycarbonyl moiety are conveniently prepared from a wide variety of secondary amides by the action of di-t-butyl dicarbonate in dry acetonitrile with 4-dimethylaminopyridine as catalyst;238 the yields are generally excellent.

Ceramide (29) can be prepared in good yield on a 135

multigram scale via an oxazolidine route (Scheme 5 6 ) . ~

a-Keto-amides, convertible into isatin and quinoline derivatives, were prepared by the palladium-catalysed double carbonylation of aryl halides (Scheme 114) .239

A preparatively

useful route to acenaphthylenone carboxamides by base-catalysed N-substituted homonaphthalimides has been reported rearrangement of (Scheme 115). 240 3,4-Diacylaminobutanetosylamines have been prepared

the Bamberger ring cleavage acylation of

N-p-toluenensulphonyl histamine.241

Nitration of certain

substituted indoles with a mixture of hot nitric and acetic acids affords 3,3-diaryloxindoles;

a pathway involving the rearrangement

of an indolenine intermediate has been tentatively proposed (Scheme 116) .242

Oxalic acid ethyl ester-N'-acyl amidrazones can be

prepared by acylation of suitable amidrazones. 243 An efficient peptide forming reaction employs 1-(trimethylsily1)imidazole as the agent for coupling an amino acid with a thiopyridyl ester;244 when an imino acid was used, only a catalytic quantity of a tertiary amine was required for the condensation (Scheme 117).

A derivative of 6-alaninamide has been

formed by cleavage of the cyclopropane ring of

N-(benzyloxycarbonyl)-l-aminocyclopropane-l-carboxamide with

-

[L,I-bis(trifluoroacetyl)iodolbenzene. 245 L-Serine stereospecifically labelled with deuterium at C-3 has been prepared __ via catalytic addition of deuterium to (Z)-2-acetamido-3methoxyacrylic acid.246

324


NH,

A z o t o m y c in

R = Ph C e l a b e n z i n e R = CH,CH,Ph

(71)

a , R = Me, R ' = Z b , R = CH,Ph, R ' = Z

(74)

( 7 2 ) c , R = Me, R ' = COCF3 ( 7 3 ) d ; R = a n i o n , R ' =H: Reagents

I,

CH2N2,

11,

( c o c ~ ) E~t 3,N ,

lII,

cIC02B~1

S c h e m e 120

> 9 8 'Ie e e Reagents

I

NaCN,

1 1

H 50,-5"C, 2 L

III,

HZ, P d l C ,

Scheme 121

Dihydrocelacinnine

I V

HBr aq.

325


The ferrocenylmethyl group, which can be introduced by catalytic reductive alkylation of amino acids or amino acid esters with ferrocenecarboxaldehyde and hydrogen, allows peptide synthesis to be effected without racemization (Scheme 118) ; 247 deprotection can be achieved with trifluoroacetic acid.

DCC acts as a coupling

agent in a reaction yielding tripeptides (Scheme 119) ;248 camphor-10-sulphonic acid catalyses the reaction and also suppresses troublesome side reactions.

A synthesis of (-)-azotomycin has been

achieved, in which the mixed carbonic anhydride method was used to form the peptide bonds; the azo groups were introduced by a modified Arndt-Eistert synthesis. 249 The thirteen-membered lactams celabenzine and dihydrocelacinnine have been synthesized by using a BOC protecting group.250 Syntheses of virginiamycins S1 and S4, using both cyclic and acyclic hexapeptides, have been described.251 A total synthesis of the cyclotetrapeptide chlamydocin has been reported,252 and methods of preparing cyclopeptides containing non-essential amino acids have been described. 252

A cyclotetradepsipeptide has been synthesized

by using the 2,4-bis(methylthio)phenoxycarbonyl group in a protection-activation sequence. 253 Phosphonic and phosphinic acids can be converted into their amides by activation with diphenyl phosphoryl azide and displacement with ammonia;254 in this way, a phosphinamide analogue of pepstatin has been prepared. Approaches to the syntheses of the Streptomyces anticancer antibiotics 6-diazo-5-0x0-L-norleucine (73 ; DON) and azotomycin using conversions of carboxylic acids into diazoketones have been described.255 The DON precursor (72) can be prepared from the v-carboxylic acid (74) by approaches involving either acyl chlorides (oxalyl chloride route) or mixed carbonic anhydrides (isobutyl chloroformate route) (Scheme 120). An alternative route to (73) involves selective attack at the Y-carbonyl of anhydride (71) with diazomethane; however the DON precursor (72) could not be prepared using this method. Two new carbamyl-substituted carbapenams (4) have Seen prepared by a route involving a hetero Diels-Alder reaction (Scheme 4) .14 Amides were prepared by the ruthenium-catalysed condensation of nitriles with amines in the presence of two equivalents of water; syntheses of polyamides were also effected.256 Tetraethylurea or diethylformamide can be obtained selectively from diethylamine, carbon dioxide, and a palladium catalyst. 2 5 7 Aromatic cyclic ureas have been prepared from 2-amino- or

326


N S0,C I

(75) Reagent

I,

CHZC12, 0°C

OCN-SO,CI,

S c h e m e 122

0 R’O -C

II

RL/ II

0

II

R3 N=C-CH-

I

Reagent

1,

1

C H-C O R ~

I

I

C O R ~

RZ CUCL~.ZH~O

Scheme 123

A

c0

RCO-N

O HN-CH,X 3

c,u

OJ

(76)X = C0,- o r CH,SO,-

Scheme 1 2 4

R5

R2

I

HNCO,R’

321

5: Amines, Nitriles, and Other Nitrogen-containing Functional Groups o-amino-alkyl substituted arylamines by reaction with carbon

monoxide and selenium. 2 5 8 Other syntheses of aromatic and heteroaromatic amides have appeared.

(g)-(+)-2-Methyl-3-phenylalanine has been synthesized by

a four-step asymmetric Strecker synthesis using (5)-(-)-1-phenylethylamine as the chiral auxiliary reagent (Scheme 121) . 2 5 9 A series of 5- (alkylsulphonyl)salicylanilides was prepared from a salicylic acid, thionyl chloride, and an aniline using a catalytic quantity of dimethylformamide;2 6 0 benzoic acids have been converted into substituted benzanilides by the same procedure. 261 New routes have been developed to y- (w-tosyloxyalkyl) phthalimides, from which polyamines have been prepared. 2 6 2 Triphenylantimony dicarboxylates react with amines to give the corresponding amides;263 amidation of a carboxylic acid with a primary amine is also catalysed by organoantimony compounds. react with chlorosulphonyl isocyanate to a,a,N-Triaryl-nitrones

form N,N-diaryl-arylamides (Scheme 122) , 264 an electron-rich aryl group migrating in preference to an electron-deficient aryl group. Whether the configuration of the nitrone is

S J J

or

anti was

found to

have no effect upon the migration of the aryl group; that is consistent with the postulation of the cycloadduct (75) as an intermediate. 1-Alkoxycarbonylamino-3-carbonylpyrroles can be prepared by the copper(I1) chloride-catalysed reaction of alkoxycarbonylazoalkenes with B-diketones (Scheme 123) . 2 6 5 If copper(I1) chloride is omitted, the reaction proceeds only to the lI4-adduct. 2-Pyridon-1-yl diphenyl phosphate is a useful coupling agent for the synthesis of amides and peptides; racemization of the latter is avoided. 2 6 6 The hydrolysis of a-aminophenylacetonitrile to phenylglycinamide is catalysed by various bifunctional compounds including ethane-1 2-diol, 2-mercaptoethanol and glutathione.267 Alkyl amphiphiles of the crown ether type (76) have been synthesized and shown to form membranous aggregates. 2 6 8 Aqueous cyanine dyes are adsorbed onto a monolayer of alkylammonium amphiphiles containing an amide group.2 6 9 _ N,N-Diethyl-2-chloropropionamide _ can be prepared by reacting methyl 2-chloropropionate with diethylamine and aluminium I

I

chloride.2 7 0 Ynamines and 1,3-thiazole-5(4H)-thiones undergo an addition reaction on heating in toluene, yielding mainly the thiazolylidene thioamides of type (77) (Scheme 124) .271

By analogy with other

328


HowHz X

EtOCH=CHC

II

s

II

II

"'d

0

+

0

Et OCH =CHCNHCNH

+

NCS

X Y (78) X=OH,Y=H X =H,Y=OH X =Y=OH

Y

Scheme 125

R2 R3 H,N

x

CO,H Z

= PhCH,OCO

(79)

R2

(80) S Reagents

I,

CICO2CH2Ph,

I I DCC, ~

HNMe,,

111,

M e O e ! / S ' P e O M e ,

's' IV,

HBr, MeCOZH,

v, R'COCl

I1

S

S c h e m e 126

(81)X

=O

(82)X = S OSi Me2But

I

I

RCHO

R-CHCN

-!!-+

OH I

O S i Me2But

I

111

R-CH-C-NH,

_j

R-CHCNH,

II

II

S Reagents

1,

NCSIMe2But, KCN, 1 8 - c r o w n - 6 ,

11,

THf

S c h e m e 127

PhZPSZH, P r ' O H ,

S III,

(NBun):F;


329

reactions of ynamines, a [2+2] cycloaddition to thiete intermediates, followed by electrocyclic ring opening is suggested as the mechanism of the reaction. Thiophenecarbothioamides are prepared by reacting thiophene or 2,5-dimethylthiophene with isothiocyanates in nitromethane, in the presence of aluminium chloride.272

A route to the carbocyclic analogues of 2-thiouracil nucleosides involves the condensation of 3-ethoxypropenoyl isothiocyanate with appropriate hydroxy derivatives of cis-3-aminocyclopentanemethanol to give the +hiocarbamoylpropenamides (78) (Scheme 125)273 which are cyclized in aqueous ammonia to give the 2-thiouracil nucleosides. Thioamides (79) can be conveniently prepared by thiation of the corresponding amides using Lawesson’s reagent (Scheme 126) .274 Thioamides ( 8 0 1 , preparable from thioamides (791, or by reaction of 3-amino-2s-azirines with thiocarboxylic acids, are readily converted into 1, 3-thiazole-5 (4H)-thiones (Scheme 126) ,274 a class of In searches

heterocycles hitherto available only with difficulty.

for an efficient route to thioamide analogues of peptides, Lawesson’s reagent was shown to distinguish between different amide groups; thus, tripeptide (81) can be selectively thiated to give the thioamide analogue (82) in excellent yield. 275 Various thioformamides were prepared by heating secondary amines with dimethylthioformamide.276

a-Hydroxy-thioamides were

prepared from aldehydes in a three-step route which appears to be general (Scheme 1 2 7 ) .277 Certain unsymmetrical N,”-dialkylthioureas can be prepared by heating a sodium N-alkyldithiocarbamate, an alkylamine, and a catalytic quantity of

sodium hydroxide in a two-phase system.2 7 8 The lithioketene-5,N-acetal derived from N,N-dimethylthioacetamide was reacted with aryl isocyanates to give

-

monodithioamides which were subsequently transformed into enaminonitriles.279

_ N,N-Dialkyl derivatives of thiopivalamide S-oxide have been prepared. 280 The cyclopeptide ulithiacyclamide has been synthesized, the ring-closure reactions to give amide groups being performed under

-

moderate dilution.281 Thioamides have been converted into amides with dinitrogen tetroxide. 2 8 2

330


Q

&CN

1

o//c--5+

(83) Reogent :

I,

NCCH2COSB~', D A B C O

S c h e m e 128

R

R = M e , E t , CH2Ph, o r P h Reagent

1,

( E t 0 ) 2 ~ ( o ) ~ LN ~, C N

S c h e m e 129

5: Amines, Nirriles, and Other Nitrogen-containing Functional Groups

33 1

RCONHZ

Reagent

I,

Cl3C0COCI

Scheme 130 R C =N S i Me,

[

RCONH,

Reagents

I,

bSiMe,

]

RCN

M e 3 S I C l , E i 3 N , Z n C I z 2 1 1 , FeCI3 o r ALC13, A

S c h e m e 131

coza

R Y c N ,

Reagents

I,

III

c o y

CN

R C H 2B r, K2C03,

CH =CHCHZOH, 2

11,

,

p-TsOH,

R

111,

W

C

N + COz

+ CH, ,

Pd( O) - PPh,,EtC N ,

A

S c h e m e 132

SEt

I

I

R-CHCH,CN

+RCH=CHCN

R e o g e n t : i , L i ar, E t O H , P t e l e c t r o d e ( 0 Z A )

S c h e m e 133

RHC=C=CH,

+

I

Me,SiCN

RHC=C

rCN ‘5iMc3

R e a g e n t : i, P d C I Z , C 5 H 5 N

Scheme 134

332


7

Nitriles and Isocyanides

Nitriles have been synthesized by a variety of methods.

The

formation of nitriles by the alkylation of potassium cyanide using solid-liquid phase-transfer catalysis without added solvent is optimized when a definite amount of water is present.283

Cyanation of aryl iodides has been achieved using trimethylsilyl cyanide and a palladium catalyst.284

Perf luoroalkyl nitriles were prepared from

perf luoroalkyl azides and triphenylphosphine.285

S-t-Butyl

-

cyanothiolacetate acts as a B-hydroxypropionitrile equivalent

in

Michael reactions with a,B-unsaturated ketones (Scheme 128) :286 addition to a carbonyl group is also possible, and afforded a synthesis of a-costal (83).287 The reagent diethyl

phosphorocyanidate-lithium cyanide can be used to prepare 2-cyano-3-indoleacetonitriles (Scheme 129) 288 which act as dienes in base-induced cycloaddition reactions which afford carbazole-fused ring systems.

The first direct observation of a thermally generated

nitirile ylide has been reported.289 Dehydration of nitrogen compounds is a well-known route to nitriles. Alkyl, aralkyl, aryl, and heteroaryl amides are readily converted into the corresponding nitriles using trichloromethyl chloroformate as the dehydrating agent (Scheme 130);

the work-up is

usually very simple owing to the gaseous nature of the side-products.290

Nitriles have also been prepared from amides

in a two-step procedure involving the catalysed elimination of hexamethyldisiloxane (Scheme 131) . 291 Oximes can be converted in good yields into nitriles using di-2-pyridyl sulphite in refluxing toluene;292

similarly, formamides are converted into isocyanides.

A variety of alkyl, aryl, and heteroaryl aldoximes have been converted into the corresponding nitriles using trichloromethyl carbonochloridate as dehydrating agent. 293 Recently reported methods of preparing a,B-unsaturated nitriles include the palladium-catalysed decarboxylation-dehydrogenation of ally1 a-cyano-carboxylates (Scheme 132) ,294 and electro-oxidative desulphenylation of Michael-type thiol adducts (Scheme 133) . 295 B,y-Unsaturated nitriles have been prepared from allenes and trimethylsilyl cyanide in the presence of a palladium or nickel E-isomer predominated. catalyst (Scheme 134) ; 2 9 6 the y

, 6-Unsaturated nitriles can be prepared297 by reduction of ,&-unsaturated nitronates using low-valent titanium;

the

nitronates are generated by the catalysed addition of allylic


Reagents

333

T I CI4, C H Z C 1 z , ii,Zn,THF

1,

S c h e m e 135

+

+ + 97 -98’1.)

Reagents:

\

Q

-

“XoH

HCO2NH4

4

,/p, I

PBu”,,

cot

= fluoroalkyl,

P d ( P P h 3 ) 2 C 1 2 , Bun3N,

R = CI, Me or HCOZH, D M F

Scheme 6

OM^

396


H R

R

117 o r

2=95%)

Me o r C H Z O M e ;

Rz

z

H, M e o r P h

S c h e m e 20

R

+ OAc

i

i I iii

-R

NH2

(59- 91

Reagents:

I,

cat

Pd(PPh3I4, NaN3,

11,

Scheme

PPh3;

21

111,

O/O)

NaOH/H20


404

0 0-

c a t Pd(PPh3)&, c a t PPh3

&A (Yield 47'1.; e e loo"/.)

-

Scheme 2 2

RD

R

O

H

R

= CH,CH ( N H A c ) C 0 2 M e or C H ( N H A c ) C 0 2 M e

+ M' n ( C 0 ) 3 Scheme 2 3

Cr (COI3

Reagents

I,

LiCMe2CN,

iiI

CF3C02H

Scheme 24

DOQ

405

6: Organometallics in Synthesis

prepared for the first time via - a route which involves regioselective addition of LiMeCuCN to an optically active dihydrodioxin-iron complex (Scheme 17) 30 Stabilization of a positive charge adjacent to cobalt alkyne complexes has been exploited in a synthesis of the guiane sesquiterpene cyclocolorenone,3 1 and in an approach to the

.

fusicoccin class of diterpenes. 3 2

The cyclocolorenone synthesis

involves addition of a silyl enol ether to a cationic cobalt complex followed by regiospecific hydration and cyclization (Scheme 18).

A

Lewis acid mediated intramolecular addition of an allylic silane to an allyloxy-acetal and an internal Pauson-Khand reaction are the key steps in the approach to the fusicoccins (Scheme 19). Palladium-catalysed allylation has again been the subject of numerous reports. O f note is the use of 9-ally1 5-alklyl dithiocarbonate substrates which results in the production of allyl alkyl sulphides (Scheme 2 0 ) .3 3 These substrates circumvent catalyst poisoning problems normally associated with catalytic allylation of sulphur nucleophiles by generating the nucleophile __ situ

at a concentration which is never higher than that of the T-ally1 intermediate. The azide anion has been used as the nucleophile in palladiumcatalysed allylations for the first time. The allyl azides produced are versatile synthetic intermediates; for example, they can be readily converted into allylamines (Scheme 21) . 3 4 An intramolecular palladium-catalysed allylation reaction has been used to produce 2-allylcyclohexanone in almost 100% optical yield (Scheme 2 2 ) . 3 5 Diary1 ethers have been prepared from tyrosine and 4-hydroxyphenylglycine by nucleophilic addition of their anions to a (ch1orobenzene)manganese cation (Scheme 23) .3 6

No detectable

racemization of the amino-acids occurred under the conditions used in this reaction which are mild in comparison to those employed in other methods available for the synthesis of diary1 ethers. It has been reported that addition of 2-lithioisobutyronitrile to p-chlorotoluenetricarbonylchromium followed by protonation leads to the production of m-2-cyanopropan-2-yltoluenetricarbonylchromium (Scheme 24) . 3 7 This represents the first example of cine-substituion of arenetricarbonylchromium complexes. Addition of carbanions to (alky1benzene)tricarbonylchromium

~

complexes occurs predominantly in the =-position. Introduction of an alcohol group into the alkyl side chain, however, leads to chelation-controlled nucleophilic addition of carbanions to the


406

woH, 2RLi

-pj

R-Li

-C r

W IO '

I

cr

Cr

(COl3

(CO),

R

& I 2Cr (COI3 17 - 4 8 "10

Scheme 2 5

Meo 0

Scheme 2 6

' I

11

Me

.\

, ph>>

TiH M ;2e< :

I

Me

I

-

H

OH

iii

R'

CH3

SO, R

S02R

(Yield 75-96%

e.e.79-90 1

Reagents:

I,

TiMe4,

11,

Me2CHOH,

ill,

R'CHO

S c h e m e 27

407

6: Organornetallies in Synthesis

I I

I

RMgBr

R'COR

(61-89"/0)

Reagents

VCI3,

I ,

R'COCI

11,

S c h e m e 28

M = L i or M g B r

Reagents:

I,

VCI3,

11,

R'CHO

Scheme

29

tLH R

( Y i e l d 7 3 - 90%; R

e.e. 85

= Et, B u n or B u ' O C H 2

I

I I

Reagent

I,

RLI,

Cur,

ph+~-'\

I

OH

1

S c h e m e 30

- 92 'lo l


408

+ ,

0@OCPh3 I

Wocph3 'r I

0

5

o2

R2

O y ! ,

( Y i e l d 60-98'1'

;

e.e. 81 - 95 '1' 1

Reagents

R'MgCI,

I

( Y i e l d 7 5 - 91 'I.;

e.e. 77 - 9 4 '1. 1

CuBr.SMe2, THF, - 2 3 ' ~ ; I I , c ~ n c HCI, MeOH,ili,

KOH

S c h e m e 31

xR\

1

Reagent

I,

ycu, BF3,

PBu3

Scheme

32

6: Organornetallics in Synthesis

409

R'

+

aNyS+c02R3 R4MgBr

' s

.-. C u B r , T H F

R2

Scheme 33

R

Reagents

OMe

OMe

OMe

OMe

= C 0 2 M e or S i M e 3

I,

B u L i , THF, - 7 8 " C , 1 h ,

11,

ClCO Me, - 7 8 " C ,

Scheme 34

2

111,

Me3SiCL, - 7 8 " C


410

ortho-position and subsequent formation of ortho-substituted

toluenetricarbonylchromium complexes (Scheme 25) .38

The structure

of the unusual ~6-5-methylene-cyclohexa-l, 3-diene intermediate was confirmed by X-ray crystal structure analysis. Rhodium carbenoid cyclizations have been used to synthesize seven-membered ring ethers in good yield (Scheme 26) . 3 9

The

substrates for this reaction were prepared in three steps from methyl acetoacetate. via Organometallic Nucleophiles - Addition of MeLi or MeMgCl to an ethereal solution of TiC14 at -78 " C followed by warming to -50 or -30 " C leads to the production of MeTiC13.

This reagent adds selectively to ketones in the presence of nitro, cyano, and ester

groups, a process which is inefficient or impossible using MeLi, MeMgC1, or MeTi(OCHMe2) .40

An optically active methyltitanium

reagent derived from TiMe4 and norephedrine has been used to deliver a methyl group stereoselectively to aromatic aldehydes (Scheme 27) . 41 Organovanadium reagents have been used to effect two useful transformations.

Alkylvanadium complexes, formed from Grignard

reagents and VC13, convert acid chlorides into ketones in high yield (Scheme 28) ,42 and vanadium acetylides, formed from acetylenic Grignard or lithium compounds and VC13, react with aldehydes to give a,B-acetylenic ketones via oxidative nucleophilic addition (Scheme 29).43 Enantioselective conjugate addition to a,B-unsaturated carbonyl compounds has been performed using two alternative strategies.

The possibility of achieving useful

enantioselectivies in the presence of a simple chiral controller ligand has been demonstrated for the first time (Scheme 30) .44 This reaction is strongly dependent, however, on the purity of the organolithium reagent used. ( ~ ) - v - T r i t y l o x y m e t h y l - u - b u t y r o l a c t a m serves as an efficient

chiral auxiliary in the conjugate addition reactions of the imides it forms with a , B-unsaturated carboxylic acids (Scheme 3 1 ) , 45 and conjugate addition of a 1-alkenylcopper reagent to the a , B-unsaturated ester of a chiral auxiliary alcohol has been employed in an enantioselective synthesis of California Red Scale pheromone (Scheme 32) .46 The reqioselectivity normally observed in the nucleophilic addition of organocopper reagents to a,B-unsaturated esters has been changed by the introduction of a leaving group in the y-position (Scheme 33) .47

a-Addition occurs cleanly leading to the

production of a-alkylated B,v-unsaturated esters.

41 1


Me

Cr KO),

Cr (CO),

\

Ph

( R 100% e.e.)

Cr (CO),

(R

R

>' 95 '1. e.e.)

= M e or E t

Reagents

1,

PhCHZNH2,

11,

LDA,

111,

R X ,

i v , H',hv

Scheme 35

Ph


412

11,

IV

OMe

OMe

OMe

OMe

S i Me,

Reagents

I,

Cr(COI6,

11,

SiMe,

Bu”L1,

III,

Me3SICI,

IV,

S c h e m e 36

Mel,

V,

Bun4NF3H20,

VI,

02

413


( Y i e l d s 81 - 9 4 ‘I.;

d.e.

Reagents.

I,

Bu”LI,

11,

R2X

Scheme

37

Me1 +

Scheme

38

> 98%)

414


r

1

I , I1

3 R , 4s

Reagents

I, P h C H Z N H L i ,

Me],

11,

111,

Br2

Scheme 39

- ***pJ3

I

I

I

ON

Re

I1

___._)

O N ,Rc, T P h 3

0 H--

Ph

Ph

H

Ph

(d.e. 9 6 *lo 1 Reagents

I, LI

N(SIMe3l2,

11,

Meoso2cF3

S c h e m e 40


415

Lithiation of tricarbonyl(fluoroanisole)chromium(O) complexes occurs exclusively ortho to the fluorine atom in contrast to lithiation of the uncomplexed arenes which occurs ortho to the oxygen atom (Scheme 3 4 ) . 4 8 This reactivity, in combination with nucleophilic displacement of the fluorine by amines, has been exploited in the totally regiocontrolled synthesis of a range of 1 ,2,3- , 1 ,2 ,4- , and 1,2,3 ,4 ,5-pol ysubs tituted arenes .4 9 Chiral benzylic amines have been synthesized from an optically y a stereoselective pure arene tricarbonyl chromium complex & 50 deprotonation/alkylation step (Scheme 3 5 ) . A stereoselective synthesis of (-)-(8R)-methylcanadine has been reported (Scheme 36) .51 This was achieved by regioselective complexation of the dimethoxyarene ring of (-)-canadine to tricarbonylchromium, protection of the C-11 position, stereoselective substitution at C-8, deprotection, and decomplexation. The high degree of stereochemical control afforded by the chiral auxiliary [ ( h5-C5H5)Fe (CO)(PPh3)3 has been studied further. It has been demonstrated that dienolates derived from [ q5-C H Fe (CO) (PPh3)COCH=CHCH2R'] can be regio- and stereo 5 5 selectively alkylated at the a-position to give a-substituted E-D, y-unsaturated acyl complexes (Scheme 37) .52

z-

A conformational analysis of the complex [ ( G-C5Hs)Fe (CO)(PPh3) COMel based on extended Hilckel and ab initio SCF MO calculations has been performeds3 and the results of this analysis have been used to improve the stereochemical control of the alkylation of enolates derived from [ R5-C5H5)Fe (CO)(PPh3)COCH2R] to 200 :1. 5 4 The enolate 5 [ ( R-C5H5) Fe (CO)(PPh3)C(CH2)0-1 has been trapped in its enol form using oxophilic [(45-C H ZrCl21, and in its keto form using carbophilic [Au (PPh3)C?l Addition of nucleophiles to a-alkyl-a, 0-unsaturated acyl ligands attached to [ ( q5-C5H5)Fe (CO)(PPh3)] has been shown to generate E-enolates which on alkylation produce quaternary carbon centres stereoselectively (Scheme 38) ,56 and stereocontrolled tandem Michael addition/alkylation reactions of a , 0-unsaturated acyl liqands bound to [ (q5-C5H5)Fe (CO) (PPh3)1 have been exploited in asymmetric syntheses of 8-lactams (Scheme 39) .57,58 Metal systems analogous to [ ( p

Ar3N+ SbCls

H

C0,Et

+

b

CH2CL2, 0 *C

:

€to&

Me

CH3

(2)

Ar = Br-@

0

MesYMe + CI

BUi

i, SnC14

b ii, Et3N

-

BU'

CuOTf

HO

0

hV

hv

Ar*

0

520


y---

yy-&

Me

0

H

a

HO (

Me

O

steps f---

Me0,C

- - Grandisol

Reagents:

i, C H 2 = C H 2 , h V ,

PhCOMe, - 7 8

'C;

Scheme 1

H

0

P

Me02C

Y

tie

+

O5

ii, H 2 S 0 4 , MeOH

Me

52 1

7: Saturated Carbocyclic Ring Synthesis

6Ph

SPh

Jr

+

4yPh 0

0(11 1

C02Bu'

J

7

+

-

Bun0

ZnBr2

- 78

C0,Bu'

BU'0,C

O C

7 2 '10

(12)

OH

I

FeSOq

b AcOH

(13)

fi

AlBN,

(1L)

ni

10% BujSnH

A,

dark

84 'lo

5 OIO


522

NC;l + Scheme

2

Me EtCOAf

i,LDA .____)

HO

ii,

BJO-

CONMe

(15 OH

-

PhSO, PriNOC4:-

Li'

4-

Pr; NOC'

(16)

0

I1 -

+

PhSO,

0

PriNoCC0,Me


523

but the latter is a shorter synthesis.

An alternative to using

s u c h chiral auxiliaries in photoadditions is to use a chiral

ketene such as (9), althouqh the diastereoselectivity in this reaction is only modest. l o Two new interesting polar cyclization routes to cyclobutanes have appeared. The first of these utilizes a new reaction of an enone with the thioenol ether (10) under the influence of Lewis acid, in a stepwise process presumably involving an intermediate such as (11) . I 1

The second new method also uses an

enol ether but in a reaction with t-butylmethylenemalonate ( 1 2 ) . I 2 Finally, a fully detailed account of a substitutive spiroannulation route to cyclobutanones will be useful .I3

3

Five-membered Rings

General Methods. - Cycloaddition strategies to cyclopentanes are potentially valuable, and a timely review on the use of trimethylenemethane to partially achieve this aim is of interest.l4 Radical ring closures continue to be widely studied with an intriguing new way of generating radicals, for use in subequent ring closure, being described and involving the 6-fragmentation of a tertiary cyclohexyl radical, generated from the hydroperoxide (13).15

A full account of the use of radical ring closure in

bi,tri- and poly-cycle formation will be of interest to anyone wishing to make use of these reactions,16 as will be a mechanistic study17 and a related report upon some of the factors influencing five versus six-membered ring formation in these cyclizations.'* Further work upon the radical cyclization of allenic ketones under dissolving metal conditions to give mainly cyclopentanes has been described,"

as has the cyclization of the iodo-alkyne (14),

initiated by tin hydride. This process has also been extended to triquinane synthesis.*' The use of an homoallylic radical in a Michael addition to an electron deficient alkene followed by cyclization results in an alternative synthesis of cyclopentanes (Scheme 2) . 2 1

A clever application of known chemistry has been used in a route to iridoids and involves Michael addition to the diester (15) followed by Dieckmann condensation.2 2 An anionic cyclization-elimination route to cyclopentenes is of interest, and involves the reaction of the anion (16) with a Michael acceptor, followed by cyclization and elimination to the cyclopentene (17). 2 3

A further research group has utilized the concept of preparing

524

Me RC02Et

+

1 BrMg(CH2),CHMgBr

-


R&,Me+ ,OH

Ho&Rs,Mc

Scheme 3

Reagents: i,

K, N H 3 (L), d O H , Me1 , ii, 03-Zn,

AcOH, Jones

Scheme 4

2,6 - Lutidine,

Me Me

(20)

HO (21

-20

1

'c 74 OIO


525

0 II 0 OCCF,

0

CH,CI,,

O'C

+ (22

1

78 'lo

- 0,C C F,

Me,Si 0,C

t

Si Me,

SiMe3

Me,Si

ii

I

OC0,Me

I

PdL,

Pd L,

(241

(23

1

iii

Hozc9 Me,Si 0,C

iv

R

EWG

I

Pd L,

Reagents: i. [ P d ( P P h 3 1 4 ] ; ii, MeJSiOCO,Me ( 2 5 1 ;

i i i , MeO-;

iv, R

-

Scheme 5

P

Reagents: i. MeCO2CH2CCH2SiMe3. Pd ( O A c 1 2 . ( P r ' 0 1 3 P - PhCH,,

Scheme 6

100 'C

~

~

~

526


vicinal ester dianions for annulations by reacting them with a ~ r y l a t e s ,and ~ ~ by using a relatively conventional ring closure of the ylid (18) some useful optically active cyclopentenones have been prepared. 25

Further uses of the bis-Grignard reagents

1,5-bis(bromomagnesio)pentane and 1,6-bis-(bromomagnesio)hexane in reactions with esters to form cyclic products have been described, as shown in Scheme 3.26 An interesting new route to cyclopentanes involves a ring contraction of a cyclohexadienol ether such as (19) upon treatment with p-bromobenzenesulphonyl azide. 27

The ready availability of

compounds like (191, a Birch reduction, plus the fact that dienol ethers bearing a chiral group react with a high degree of diastereoselectivity makes this a potentially powerful route to 5-membered rings.

Birch reduction, ozonolysis, and decarboxylation

of indanones also constitutes a new preparation of substituted cyclopentenones (Scheme 4) .28 The Claisen reaction mediated ring contraction of macrocyclic lactones is a well known route to cyclopentanes and other size rings, and full details of this approach have now a ~ p e a r e d . ~ ’ A combination of asymmetric 1,4-addition and the magnesium-ene cyclization has resulted in an excellent synthesis of 6-necrodol (20).3 0

The magnesium-ene

reaction has also been used in the preparation of chiral Q- and and 6-skytanthine31 and in the synthesis of racemic c h o k 0 1 - A ~ ~ racemic 6-protoilludene.33 A cationic cyclopentannulation, leading to a synthesis of methylenomycin B , is of interest and involves acid treatment of the allenic alcohol (21) .34 A comprehensive account of the chemistry of cyclopropene ketals, including their use as 1,3-dipoles in the preparation of cyclopentenones, is of interest.35 The trapping of Pummerer reaction intermediates formed from sulphoxides, such as (22), by alkenes is the basis for a new synthesis of ~ y c l o p e n t a n o n e s . ~ ~ I n a useful extension of the chemistry of the palladium ( 0 ) complexed trimethylenemethane moiety, Trost has described the formation of (24) from the bis-silyl compound (23). Even in the presence of an enone this complex is alkylated with the carbonate (25) produced in the first step, and then a second zwitterion is formed for reaction with an enone in a [3+2] cycloaddition (Scheme 5) . 3 7 The same research group has described an approach to brefeldin-A which uses the above [3+2] cycloaddition strategy to generate three contiguous stereocentres of correct absolute and relative stereochemistry as shown in Scheme 6.38 A previously

521


+

= - - CH,

Me-

I

CO,(

BF,

CO),

(26)

(27

COAr’

Ar’

1

OH T i CI4

Y

*

SiMe,

Me,Si

I

%

g*

BugSnH

(30 1

(p CO, E t

45% Scheme 7

15%

528


described donor-acceptor [3+21 annulation sequence has now been used in the preparation of racemic oplopanone.39 The useful rhodium catalysed intramolecular C-H insertion reaction of a-diazoketones to give cyclopentanes has now been described in

and rhodium chemistry has also been used in a

novel route to cyclopentenones which uses a rhodium carbonyl cluster catalysed hydrocarbonylation of enynes. 4 1 The cationic cobalt complex (26) serves as a precursor to lI4-diketones and so to cyclopentanones, by reaction with an enolate anion followed by decomplexation and alkyne hydration. 42

The application of this in

the synthesis of sesquiterpenes has also been described.43

A

mechanistic discussion of the cyclodimerization of enones such as n4-enone tricarbonyl iron complexes44 is valuable and (27) interesting as is the Lewis acid induced cyclization of the allylsilane (28) which provides a highly diastereoselective approach to cyclopentanes. 45

Finally in this section, the lithium-halide

exchanqe of the vinyl iodide (29) has been shown to result in ring closure to a cyclopentenone. 46 Fused Five-membered Rings. - As in the preparation of cyclopentanes, radical ring closures are playing an increasingly useful role in the synthesis of fused five-membered rings

for instance, a further

application of tandem radical cyclization in the synthesis of racemic silphiperfol-6-ene.47

A transannular radical cyclization

has been utilized in the preparation of linear triquinanes (Scheme

7), although the modest yields and lack of regiospecificity are currently limiting for this reaction.48

A combination of ester

enolate rearrangement-radical cyclization has been used to prepare fused cyclopentanes, albeit by use of a fairly lengthy sequence.49 1,3-Diyl trapping reactions have been shown to be of widespread use in the synthesis of cyclopentanes and a review of their use is most timely. 50 Three highly useful fused five-membered ring synthetic building blocks are bicyclo~3.3.0loct-l-ene-3-one, bicyclo[3.3.0loctane-3, 7-dione and bicyclo[3.3.0]oct-6-en-2-one and full details of convenient preparations of these molecules are genuinely useful. 5 1 r 5 2 t 5 3 Details of reactions involving the intramolecular addition of allylsilanes to Michael acceptors to give fused cyclopentanes have appeared,54 and a novel 'one-pot' annulating reagent (31) has been described, in which the two reactive centres are activated by one set of conditions.

Although currently lacking

529


BrMg100:1) and, given the range of substituents that could potentially be incorporated by this method, the scope of this reaction for the synthesis of optically pure B-lactams could be very wide indeed. Barrett et a1.144 have reported an alternative iron-mediated route to the 8-lactams (260) based upon addition of the cationic iron(I1) vinylidene (257) with the imines (258), followed by oxidative cleavage.

Yields are only

moderate at best and the products (259) are formed as inseparable


604

Ph-CEC-C

u

+

0

hP: $hp

0

II

P h C C H-N-A

lp

PY

r

r.t,

0 (261)

(262)

C02R‘ X-CHz-C

N-CH

II I

I

(263)

7 t-I RBr ( 2 6 5 ) . 2e-

€ t 4 N+ C lo4-

I

0 R3 R 2 ( 2 6 4 ) X = Br or CI

C0,R’ I B r C H Z i j Y-i-BrI

(267)

I

2e-

E t N+ C I04-

0 R3 R 2

(268)

R’OCH,COC[

(269)

+

(270)

M e s e Y - HR I O . E F e L NEt3)

N

\

H C02R

( 271 1

0

(2721 BU”

-b1 / 3

R 10

\C02R2 (273)

H

\

0

‘C02R2 (274)

Sn

8: Saturated Heterocyclic Ring Synthesis

(276)

10mM soln.of ( 2 7 5 ) . Bun3SnH, AIBN

H

H

-

(277) H

Triton B

0 (279)

(278)

K [ Pd I o(rP P Bu hjn),I4 N I

0

0>>I 1

CO2CHZP h

C02CH2Ph

( 2 8 0 ) X = 0 or CH,

(281 1

C0 2 CH2 Ph

(282)

R3

R3

hV MeCN (284) (283)

606


mixtures of diastereomers but the potential for a useful, perhaps asymmetric, route to substituted 3-lactams is clearly present. Treatment of the nitrones (262) with copper acetylide (261) affords the trans-N-arylazetidinones (263) in excellent yields145 and the 3-lactams (267) are formed, also in excellent yields by two related electrochemical methods involving formation of the C(3)-C(4) bond, from the halogenoacetamides ( 2 5 4 ) and (266)

In the former

route, the function of the bromide (265) is to provide a source of the base R- which can then abstract a proton from the precursor (264) and effect ring closure. S-acetyl cepham analogues (270) are formed in moderate The yields by low temperature photolysis of the N-acyl-2-thiotetrahydro-lf3-thiazines (268), followed by in situ

trapping of the intermediate thiols (269). 147

A useful extension to

the well known ketene-imine cycloaddition route to B-lactams has been reported by Nagao et al., which is based on the use of the methylseleno group as an activating and controlling element. 148 Thus, the reaction of the cyclic methylseleno imino compounds (272) with the alkoxyacetyl chlorides (2~71),in the presence of base, gives the 5-methylselenopenams (273) with high stereoselectivity and in generally good yields. Reductive demethylselenation is readily accomplished, to give the products (274). Knight et al. have reported a novel route to the carba-penam and -cepham analogues (276) and (277) respectively, which utilizes as the key step a radical cyclization of the vinyl bromide (275).14' The carbapenam (276) is formed with high diastereoselectivity and the regioselectivity of the cyclization can be controlled either by varying the initial concentration of the bromide (27s) or by varying the cyclization conditions (thermal or photochemical).

An

alternative approach to the carbapenam derivative (279) has been described by Dumas et al. which utilizes an efficient base-catalysed Interestingly, intramolecular N-alkylation of the iodide (278). attempted cyclization of the epimeric (at C - 3 )

iodide was

unsuccessful. Mori et al. have extended their palladium-catalysed ene-halogenocyclization methodology to provide a useful synthesis of the oxa- and carba-homocepham analogues (281) which can be closed readily with base to afford the corresponding cyclopropa-oxa- or -carba-cephams (282) The novel bis(B-lactams) (284) are formed in excellent yields by photochemical isomerization of the pyrimidinium-4-olates (283). The products (284) can be converted into monocylcic 6-lactams but


only in very poor yields. References 1.

2. 3. 4. 5. 6. 7. 8. 9. 10.

11 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34

-

35.

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2

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b

.

z,


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