Clark Ch1 001-113 FINAL 27/5/02 10:35 Am Page 1

Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 1

Nitrogen, oxygen and sulfur ylides: an overview J. STEPHEN CLARK

1. Introduction Over the past three decades, there has been a rapid increase in the use of oxygen, nitrogen and sulfur ylides in organic synthesis. This is due in large part to the discovery of mild, efﬁcient and general methods for the generation of these unstable and highly reactive intermediates. Much of the impetus for the exploitation of oxygen, nitrogen and sulfur ylides in organic synthesis has resulted from the discovery that these intermediates have a rich chemistry that can be used for the rapid preparation of highly functionalized compounds from relatively simple components. The development of mild catalytic methods for the preparation of a wide range of oxygen, nitrogen and sulfur ylides has generated further interest in these intermediates. Oxygen, nitrogen and sulfur ylide chemistry now covers a very large area of research and embodies a broad range of synthetic and mechanistic work concerning both the generation and reaction of ylides. This introductory chapter is intended to provide the reader with an insight into the evolution of oxygen, nitrogen and sulfur ylide chemistry and its application to synthesis, and will focus on important synthetic landmarks and recent innovations. It is not intended to provide a fully comprehensive review of this vast area of organic chemistry.

2. Ammonium ylides1 2.1 Deprotonation of ammonium salts The deprotonation of ammonium salts was the ﬁrst method for ammonium ylide generation to be discovered; the ﬁrst example of base-promoted ammonium ylide generation and rearrangement was published by Stevens in 1928.2 In this study, Stevens generated the ammonium ylide 2 by deprotonation of phenacylbenzyldimethylammonium bromide (1) with aqueous sodium hydroxide (Scheme 1). Immediate thermal [1,2] rearrangement of the ylide then provided the amino ketone 3 in very high yield. Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 2

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O Me O Me O 10% NaOH aq., [1,2]-shift N N NMe2 Ph Me heat Ph Me Ph Br Ph Ph Ph 1 2 3 90%

Scheme 1

In subsequent mechanistic studies, Stevens demonstrated that there is no cross-over during the rearrangement of a mixture of ammonium ylides generated from ammonium salts of similar reactivity.3 Stevens also showed that the reaction is unimolecular and that it occurs under basic conditions. From these results, he concluded that the reaction proceeds by intramolecular [1,2] rearrangement of an ammonium ylide intermediate and speculated that the process involves an ion pair.3 Further mechanistic insights were gained when reactions of enantiomerically pure ammonium salts bearing chiral migrating groups were studied.4 Treatment of the ammonium salt 4, prepared from enantiomerically pure - methylbenzylamine, with aqueous sodium hydroxide afforded the ammonium ylide 5, which then rearranged to give a mixture of two diastereoisomeric amino ketones 6 of high enantiomeric purity (Scheme 2). This result ruled out any possible mechanism involving dissociated ions as intermediates, but at this stage it was not clear whether the reaction had proceeded with retention or inversion of configuration of the migrating group. Brewster and Kline later showed that the reaction proceeds with retention of configuration of the migrating group,5 a finding which rules out a bimolecular process requiring inversion of configuration. Further work of Stevens6 and Ollis7 confirmed that there is almost complete retention of configuration upon [1,2] rearrangement of ammonium ylides possessing chiral migrating groups.

O Me O Me O 10% NaOH aq., [1,2]-shift H N N NMe2 Ph Me heat Ph Me Ph Me Ph Me Ph H H Me Ph H 4 5 6 >99% e.e. Scheme 2

The results of cross-over experiments and the fact that there is retention of conﬁguration at the carbon centre of migrating group during [1,2] rearrangement of chiral ammonium ylides have led to the conclusion that the reaction proceeds by a radical pair mechanism in which the radicals recombine within a solvent cage.7,8 Ollis studied the rearrangement of ammonium ylides in which competing [1,2], [1,3] and [1,4] rearrangements were possible, and found that 2 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 3

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chiral migrating groups underwent rearrangement to give products with high enantiomeric excess and retention of conﬁguration.7 In the case of benzylically substituted ammonium ylides, Sommelet–Hauser [2,3] rearrangement can proceed through the aromatic system.9 In the simplest case, equilibration (89) of the benzylic ammonium ylide 8 formed by deprotonation of the salt 7 allows [2,3] rearrangement to occur (Scheme 3).10 Aromatization of the initially formed amine 10 leads to the ortho- substituted toluene 11. The reaction was originally discovered by Sommelet,9 and the mechanism was elucidated later by Hauser.11 Hauser also demonstrated that it is possible to perform the Sommelet–Hauser reaction in an iterative manner to give 2,3,4,5,6-pentamethylbenzyldimethylamine (12) (Scheme 3).

Br Me NaNH2, NH3 Me CH2 N N N Me Me Me Me Me Me 798

Me H Me Me NMe2 NMe2

Me Me Me 12 11 96% 10 Me2N

Scheme 3

Stevens [1,2] rearrangement frequently competes with Sommelet–Hauser [2,3] rearrangement, and the distribution of products is dependent on the reaction conditions. Several other factors can also limit the synthetic utility of the Sommelet–Hauser rearrangement reaction. Equilibration of the stable benzylic ammonium ylide to give a less stable ylide is required unless an additional activating group is present,11 and the presence of electron-withdrawing substituents on the aromatic ring can retard this equilibration process. In addition, -elimination of the ammonium ylide is often a competing process with substrates bearing substituents other than methyl on the ammonium nitrogen atom.12 Furthermore, problems involving regioselectivity arise in cases where the alkyl groups on nitrogen are non-equivalent. For example, deprotonation of the salt 13 with a strong base leads to a mixture of the expected benzylic ammonium ylide which then equilibrates to give a mixture of the ylides 14 and 15. Sommelet–Hauser rearrangement then produces both amines 16 and 17 (Scheme 4). 3 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 4

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Br Me Me base CH2 N N N Me Me Me Et Et Et 13 14 15

Me Et N NMe2 Me Me Me 16 17

Scheme 4

Competitive [1,4] rearrangement of some ammonium ylides during Som- melet–Hauser rearrangement has been reported (Scheme 5).13 For example, deprotonation of the ammonium ion 18 affords the ylides 19 and 20. The ylide 19 undergoes conventional Sommelet–Hauser [2,3] rearrangement to give the amine 24 after aromatization of the triene 21. In contrast, the ylide 20 undergoes either [1,2] rearrangement to give the amine 22 or [1,4] rearrangement to give the intermediate 23, which then undergoes aromatization to give the amine 24, i.e. the product obtained by conventional Sommelet–Hauser rearrangement of the ylide 19. Appropriate 13C labelling studies have con- ﬁrmed that [1,4] rearrangement can compete during the Sommelet–Hauser rearrangement of certain base-generated ammonium ylides and that the [1,4] rearrangement can be the dominant pathway under certain reaction conditions.14

CN CN CN Me NaOH aq., Me NaOH aq., Me N Me C6H6 N Me C6H6 N Me

CN or CN or CN 19 18 20 K2CO3, DMF K2CO3, DMF

[2,3] [1,4] [1,2]

CN CN CN CN

NMe2 NMe2 NMe2 NMe2 CN H H CN CN CN 21 24 23 22

Scheme 5

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The synthetic potential of the symmetry-allowed [2,3] rearrangement of ammonium ylides generated by deprotonation of allylic ammonium salts has been recognized for many years.6,15 The original method of ylide generation involved alkylation of a tertiary allylic amine with an alkyl halide, and subsequent base-promoted deprotonation of the resulting quaternary ammonium salt sometimes leads to poor yields. However, Coldham has recently developed an improved one-pot procedure for the generation of ammonium ylides by N-alkylation of the N-allylic -amino ester 25 and in situ deprotonation (Scheme 6).16 Spontaneous [2,3] rearrangement of the intermediate ammonium ylide delivers the N,N-dialkylated allyl glycine ester 26 in reasonable yield (48–65%), and problems associated with the isolation and handling of the sensitive ammonium salt are avoided when using this method.16

R2 R3 N 2 3 R R X, K2CO3, R1 NCOMe CO Me 2 DBU, DMF, 40 °C 2 ~60:40 R1 25 26 R1 = H, Me R3X = MeI, BnBr R2, R3 = Me, Bn

Scheme 6

It has been shown that with certain base-generated allylic ammonium ylides, [1,2] and [1,4] rearrangement reactions may compete effectively with the expected [2,3] rearrangement process.17 Competing [1,2] and [1,4] rearrangement reactions are especially prevalent in cases where the allylic ammonium salt possesses two electron-withdrawing groups adjacent to nitrogen and hence has two possible sites for deprotonation. In these cases, interconversion between two allylic ammonium ylides is possible and the product distribution is highly dependent on the substrate structure, the type of base used and the reaction conditions employed.17 One of the most interesting synthetic uses of ammonium ylides generated by deprotonation of allylic amine salts is for the ring contraction or ring expansion of cyclic amines. As part of a study concerning ring contraction by [2,3] rearrangement of ammonium ylides, Ollis demonstrated that a vinyl pyrrolidine could be prepared by rearrangement of an ylide derived from a tetrahydropyridine (Scheme 7).18 In this example, treatment of the ammonium salts 27 with aqueous sodium hydroxide afforded the unusually stable ammonium ylides 28, which were isolated and characterized. When the ylides were heated in benzene at reﬂux, [2,3] rearrangement occurred through the endo transition state to afford the ring-contracted pyrrolidines 29 with high levels of diastereocontrol.

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R1 R1 O 1 R2 R2 R NaOH aq. C H , reflux Ph 2 6 6 1 R R O 2 N Br N N R N Me Me Me endo Ph O Ph O Ph Me 27 28 29 >24:1

R1 = H, Me R2 = H, Me, Et, t-Bu Scheme 7

The same one-carbon ring contraction sequence can be accomplished with larger cyclic allylic amines, and the reaction has been used to prepare vinyl- substituted piperidines from tetrahydroazepines.19 However, in contrast to the cases above, a homologous allylic ammonium ylide derived from a 2,5- dihydropyrrole underwent one-carbon ring expansion by a [1,2] Stevens-type rearrangement to give a tetrahydropyridine instead of [2,3] rearrangement to afford a vinyl azetidine.18 The same type of ring contraction sequence has been explored by Sweeney and co-workers.20 They found that the choice of the base had a profound inﬂuence on the course of the rearrangement reaction of cyclic ammonium ylides. Treatment of the ammonium salt of the tetrahydropyridine 30 with sodium methoxide at ambient temperature led exclusively to the diene 32, resulting from ring opening by elimination, instead of the vinyl pyrrolidine 31 arising from ylide formation and rearrangement. However, when either sodium hydride or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was employed as the base at elevated temperatures, the ring-contracted vinyl pyrrolidine 31 was obtained in good yield, with only a small amount of the elimination product.20

O + OMe N Br N N Me Me OMe Me O O OMe 30 31 32

NaOMe, MeOH, rt 0% 63% NaH, DHE, reflux 58% 5%

Scheme 8

The [2,3] rearrangement of ammonium ylides generated from -vinyl- substituted cyclic amines can be used to accomplish ring expansion. The reaction has been employed most commonly for the ring expansion of pyrrolidines 6 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 7

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and piperidines. In the case of the vinyl pyrrolidine 33, treatment of either of the diastereoisomeric salts 34a or 34b with potassium carbonate or potassium t-butoxide results in a mixture of alkene isomers with a preference for the Z-azacyclooctene 35a from the salt 34a and a modest preference for the E-azacyclooctene 35b from the salt 34b (Scheme 9).21 The mixture of isomeric products 35a and 35b apparently arises by competing interconversion of the diastereoisomeric ammonium ylides prior to rearrangement. Unfortunately, the E-azacyclooctene 35b is too unstable to be isolated from the reaction mixture.

CF3SO3CH2CO2Et N N + N → MeCN, 0°C rt Ph Ph Ph EtO2C OTfEtO2C OTf 33 34a 34b

t-BuOK, or K2CO3, THF, rt MeCN, rt

+ N CO2Et N CO2Et Ph Ph 48% 35a (3:2→2:3) 35b

Scheme 9

The analogous [2,3] rearrangement reactions of ylides derived from vinyl piperidines have also been investigated. Deprotonation of the ammonium tri- ﬂate salt 36, in which the piperidine system is conformationally locked, with DBU results in ylide formation and rearrangement to give the ring-expanded cyclic amine 38 as a single geometric isomer in high yield (Scheme 10).22 The high yield and selectivity are ascribed to rearrangement through the cis-oid conformation of the intermediate ammonium ylide 37.22 t-Bu t-Bu t-Bu DBU N Ph [2,3] N Ph 90% CO2Et N EtO2C OTf CO2Et 36 37 Ph 38

Scheme 10

Ring expansion of cyclic amines can also be accomplished during Sommelet– Hauser rearrangement (Scheme 11). For example, treatment of the quaternary 7 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 8

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ammonium salt 39 with sodamide in liquid ammonia gives the ammonium ylide 40 which then undergoes sequential Sommelet–Hauser rearrangement and aromatization to provide the benzo-fused azonane 41 in high yield.23

NaNH2, [2,3] N N N NH (l) Me Me I 3 CH Me Me 2 83% 39 40 41

Scheme 11

The base-promoted generation and subsequent rearrangement of ammonium ylides has proved to be a useful procedure for the manipulation of acyclic systems. For example, Mander has developed a powerful method for the synthesis of ,-unsaturated aldehydes by [2,3] rearrangement of allylic ammonium ylides (Scheme 12).24 The required ammonium ylides are generated from N-cyanomethylpyrrolidinium salts (43), which can be prepared in situ by treatment of N-cyanomethylpyrrolidine with an allylic halide or by reaction of an N-allylpyrrolidine (42) with chloroacetonitrile. Treatment of these salts with potassium t-butoxide at low temperature results in formation of the ammonium ylides 44 which immediately undergo [2,3] rearrangement to provide the nitriles 45. Upon acidic work-up, loss of the nitrile group occurs and hydrolysis of the resulting iminium ion affords the ,-unsaturated aldehyde 46 in excellent yield (usually 90% from the allylic halide).24

N R3 Cl N CN N CN ClCH2CN, t-BuOK, 2 3 3 R DMSO R THF, –33°C R R1 R1 R1 R2 R2 42 43 44

[2,3]

+ O H3O N

HR1 NC R1 R3 R2 R3 R2 46 45

Scheme 12

The stereochemical outcome of [2,3] rearrangement reactions of base- generated acyclic ammonium ylides has received much attention.25 Ollis 8 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 9

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studied the rearrangement of the cinnamyl-substituted ammonium ylides 48 generated by treatment of the ammonium salts 47 with aqueous sodium hydroxide (Scheme 13).18 He found that the ammonium ylides 48 bearing an E-cinnamyl group prefer to undergo rearrangement via an exo transition state, giving mainly the homoallylic amines 49a, whereas the ylides bearing the Z-cinnamyl group exhibit a modest preference for rearrangement through the endo transition state to afford a mixture of the amines 49a and 49b, with the former predominating. Ollis also observed that the endo selectivity during [2,3] rearrangement of E-cinnamyl-substituted ammonium ylides can be improved by increasing the steric bulk of the substituent (R3) adjacent to the carbonyl group of the ylides 48. These results demonstrate that the strong preference for the endo transition state during [2,3] rearrangement reactions of ammonium ylides derived from cyclic allylic amines does not extend to acyclic systems.

R1 R2

R3 Me N 2 H exo R1 R1 O 49a NaOH aq. [2,3] Me NR2 Me NR2 + Me Me 2 R 1 O R3 O R3 R Br 47 48 R3 Me N 2 H O endo R1 R2 R3 49a:49b 49b

Ph H Ph 5:1

H Ph Ph 2:1

Ph H t-Bu 9:1

Scheme 13

The presence of proximal oxygen-bearing substituents can have a profound inﬂuence on the stereochemical outcome of [2,3] rearrangement reactions of certain base-generated ammonium ylides.26 For example, it has been found that the trisubstituted alkenes 52 are produced upon deprotonation of the allylic ammonium salts 50 and that the isomer ratio is dependent on the nature of the substituent R1 and the activating group Y (Scheme 14).26 In most cases, there is a clear preference for the formation of the E-isomer. However, in the case of the nitrile-stabilized ylide 51b, there is a modest preference for the Z-isomer upon rearrangement. In this case, the stereoselect- ivity can be reversed by removal of the benzyl protecting group, and 9 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 10

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rearrangement of the ammonium ylide 51c gives predominantly the E-isomer of the trisubstituted alkene 52c.

R2 R2 R2 base 1 [2,3] Me2N R1 R 1 YNMe YNMe Y R Me Me Br 50 51 52

R1 R2 Y reaction conditions yield E:Z

a OBn H CO2Et LHMDS, DMF, –50°C 68% 96:4

b OBn H CN t-BuOK, THF, –70°C 67% 34:66

c OHH CN t-BuOK, DMF, –50°C 29% 95:5

Scheme 14

The presence of substituents adjacent to the site of allylic ammonium ylide generation can dictate the stereochemical course of the rearrangement reaction. Efﬁcient transfer of stereochemical information has been observed upon rearrangement of non-racemic base-generated ammonium ylides possessing a stereogenic centre adjacent to nitrogen. For example, Hill observed a high degree of ‘chirality transfer’ upon rearrangement of the ylide generated from the enantiomerically pure chiral allylic ammonium ion 53 (Scheme 15).27 The ketone 55 resulting from deamination of the [2,3] rearrangement product 54 was found to have an enantiomeric excess of 88%.

O Ph O Ph O Ph Me NaOH Me [2,3] H Me N Me N Me N Me 2 H H Me H Me Me Me 53 54 Me

Zn, AcOH

H Ph Me O

88% e.e. 55 Me Scheme 15

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There have been several elegant applications of the base-promoted generation and [2,3] rearrangement of allylic ammonium ylides in target-directed synthesis. For example, Kaiser employed the reaction to prepare penicillin analogues substituted at the C-6 position (Scheme 16).28 Sequential treatment of the methyl ester of N,N-dimethylaminopenicillanic acid (56) with allyl bromide and sodium hydride resulted in ammonium ylide formation, and subsequent [2,3] ylide rearrangement proceeded in a highly diastereoselective manner to afford the C-6 allylated product 57 in good yield. This example is particularly noteworthy because of the sensitivity of the substrate and remarkable level of diastereocontrol.

Me Me H H H Me2N S N S Me 1. CH2CHCH2Br Me

N Me 2. NaH, DMF, C6H6 N Me O O H CO2Me H CO2Me 56

[2,3]

H Me2N S Me N Me O H CO2Me 57 75%

Scheme 16

Ammonium ylides generated from propargylic ammonium salts bearing a suitable activating group for deprotonation usually undergo [2,3] rearrangement in an analogous fashion to ylides derived from allylic amines. Ollis performed a detailed study concerning the rearrangement of propargylic ammonium ylides derived from the simple ammonium salts 58 and found that they generally undergo [2,3] rearrangement to give the allenic products 59 (Scheme 17).29 However, with certain substrates (e.g. 58, R1, R2, R3 Ph),

R3 R3 3 1 R NaOH aq. [2,3] R Me2N Me NR1 Br Me NR1 Me Me O R2 O R2 O R2 1 2 3 58 R = H, Ph R = Me, Ph, CMe3, OMe R = H, Ph 59

Scheme 17

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Stevens [1,2] rearrangement of the ylide competes effectively with the symmetry-allowed [2,3] rearrangement process, and in other cases (e.g. 58, R1 H, R2, R3 Ph) signiﬁcant amounts of new cyclic ammonium ylide products are obtained. In cases where an activating group is not present, deprotonation of the salt will normally occur at the propargylic position and ammonium ylide rearrangement will proceed by the Stevens [1,2] pathway.30 Ollis also explored the thermal rearrangement of ammonium ylides derived from pentadienyl ammonium salts and obtained mixtures of products arising from [2,3], [1,2] and [2,5] rearrangement of the diene systems.31 Although the products from the symmetry-allowed [2,3] rearrangement process predominated, the relative amount of [1,2] and [2,5] rearrangement products could be appreciable; in some cases, they were the major compounds isolated. The formation of the [1,2] and [2,5] rearrangement products was found to be highly dependent on both the substituents and the reaction conditions employed.

2.2 Desilylation of α-silyl ammonium salts Although deprotonation of an ammonium salt with a strong base is often a satisfactory method for ammonium ylide generation, complications can arise in cases where the ammonium salt has more than one possible site for deprotonation or where the ylide is particularly unstable. Regiochemical problems are frequently encountered when competing kinetic deprotonation at two or more sites is possible, or when the kinetically favoured ylide can reorganize to give a thermodynamically more stable ylide. In addition, the deprotonation method is not viable when generation of the required ammonium ylide is dis- favoured on both kinetic and thermodynamic grounds. The generation of ammonium ylides by desilylation of -silyl ammonium ylides (see Chapter 2.2) was developed by Vedejs to circumvent the problems identiﬁed above, and the method has proved to be a useful alternative to base- promoted methods in certain circumstances (Scheme 18).32 In some cases, the course of the rearrangement reaction may differ from that of the corresponding base-generated ammonium ylide.

F R RCH2 N SiR'3 N R R X R R

Scheme 18

In early work, Vedejs investigated the rearrangement of ammonium ylides generated from cinnamyl amines (Scheme 19).33 Generation of the ammo- 12 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 13

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nium salt 61 was accomplished by treatment of the cinnamyl-substituted piperidine 60 with (trimethylsilyl)methyl triﬂate. Exposure of the salt to caesium ﬂuoride resulted in formation of the homoallylic amine 63 by presumed [2,3] rearrangement of the putative ammonium ylide 62.34

N N Me3SiCH2OTf, CsF [2,3] N Me3Si H2C N CH2Cl2, 20°C diglyme TfO Ph Ph Ph Ph 54% 60 61 62 63

Scheme 19

In another early example of ammonium ylide generation from -silyl ammonium salts, Vedejs investigated the rearrangement of the simple ammonium salt 64 (Scheme 20).33 Exposure of the salt to caesium ﬂuoride resulted in Hofmann elimination of the ammonium ylide to give E-cyclododecene rather than [1,2] Stevens rearrangement.

CsF diglyme

Me3Si N Me OTf 70% Me 64

Scheme 20

The Sommelet–Hauser rearrangement of ammonium ylides generated from -silyl ammonium salts has received particular attention. Sato discovered that treatment of -triphenylsilyl ammonium salts with lithium aluminium hydride resulted in ammonium ylide formation by cleavage of the Si–C bond (Scheme 21).35 Thus, treatment of the ammonium salt 65 with lithium aluminium hydride affords the ylide 66, which undergoes either [1,2] or [2,3] rearrangement to give the amines 67 and 68, or ejects methylene carbene to afford the minor product 69. It transpired that the ratio of [1,2] or [2,3] rearrangement products is dependent on the nature of the substituent (R) present on the aromatic ring.

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R R Me Me LiAlH4, Me Me + Ph3SiH Ph3Si N THF, reflux N X H2C 65 6–10 h 66

[2,3] [1,2]

RR R Me2N Me2N Me N Me 2 67 68 69

R = H X = Br 31% 8% 4%

R = OMe X = I 2% 18% 5%

Scheme 21

Subsequent studies concerning the generation of ammonium ylides by treatment of -silyl ammonium salts with lithium aluminium hydride revealed that good yields are only obtained from triphenylsilyl-containing substrates.36 Reaction of other trialkylsilyl substrates results in simple cleavage of the ammonium salt rather than ylide generation. The Sommelet–Hauser rearrangement of ammonium ylides generated by fluoride-mediated desilylation of -silyl ammonium salts has been studied in detail (see Chapter 2.2). Sato found that use of fluoride ion rather than lithium aluminium hydride results in much higher yields of Sommelet–Hauser rearrangement products (Scheme 22).37 The rearrangement of ylides generated from a variety of aryl-substituted benzylamine salts 70 was explored. Sato found that caesium fluoride is generally superior to tetrabutylammonium fluoride (TBAF) as a fluoride source and also discovered that bromide salts generally react faster than the corresponding chloride salts. In general, Sato found that Sommelet–Hauser products 71 predominate upon reaction of substrates bearing electron-donating or weakly electron-withdrawing sub-

R1 R1 R1 CsF, 2 2 2 R SiMe3 R Me + R HMPA or N NMe2 Me DMF or 70Me Br 71 NMe2 72 DMSO 58–88% R1 or R2 = H, Me, OAc, Cl, >94:6 (R1 or R2 = H, Me, OAc, Cl) COMe, CN, NO2

Scheme 22

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stituents (R1 or R2). However, competitive [1,2] Stevens rearrangement becomes significant when strongly electron-withdrawing substituents are 1 2 present. In extreme cases (e.g. 70, R NO2, R H), almost exclusive formation of the Stevens rearrangement product 72 can be achieved. Interest- ingly, Sato isolated a significant amount of the para-substituted Stevens rearrangement product in the case where R1 CN and R2 H, providing evidence of rearrangement via a dissociated radical or ion pair. Additives or UV irradiation can have a profound influence on the Som- melet–Hauser rearrangement of ylides generated from -silyl benzylammonium salts bearing substituents on the aromatic ring.38 Sato discovered that the addition of DBU promotes a [1,3] antarafacial H-shift of the intermediate 5-methylene-1,3-cyclohexadiene, formed by Sommelet–Hauser rearrangement of the ammonium ylide, to provide the expected product in good yield.38 In contrast, exposure of the reaction mixture to UV light in the absence of DBU delivers the formal [1,2] shift product, produced by a radical pathway or suprafacial [1,3] migration of the aminoalkyl group of the 5-methylene-1,3- cyclohexadiene, along with the product resulting from homolytic cleavage of the intermediate followed by radical abstraction. The difference in behaviour of base-generated ammonium ylides and those generated by desilylation of -silyl ammonium salts has also been explored by Sato (Scheme 23).39 He found that treatment of the -silyl- or -stannyl- substituted benzylammonium iodides 73 with caesium fluoride afforded only the ammonium salt arising from desilylation or destannylation, without evidence of competing Stevens or Sommelet–Hauser rearrangement. In the presence of benzaldehyde, the intermediate ylide was trapped to afford the ammonium salt 74. However, when the ylide was generated by treatment of the stannane 73b with n-butyllithium and then warmed to room temperature, a mixture of the Stevens rearrangement product 75 and the Sommelet– Hauser rearrangement product 11 was obtained; the ratio of products was

MR 3 H OH CsF, NMe3 NMe3 I HMPA, (PhCHO), rt NMe I I H 3 73 74

a MR3 = SiMe3 92% b MR3 = SnBu3 91%

a MR3 = SiMe3 + PhCHO 15% 61%

b MR3 = SnBu3 + PhCHO 29% 51%

Scheme 23

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dependent on the solvent used (Scheme 24). Base-promoted ylide generation at –78°C and subsequent quench at that temperature afforded only the salt 8. High temperatures are required for Stevens rearrangement or ylide equilibration and Sommelet–Hauser rearrangement.39

SnBu3 Me n Me NMe3 -BuLi NMe3 NMe2 NMe2 I I 73b 75 11

Et2O, –78°C→rt 67% 4% THF, –78°C→rt 28% 32%

THF, –78°C 75%

Scheme 24

Sato has found that benzylammonium N-methylides bearing N-cyano- methyl or N-carboxymethyl groups usually rearrange to give complex mixtures of products (Scheme 25).40 For example, a mixture of the ylides 77 and 79 is obtained by treatment of the benzylammonium salts 76 with ﬂuoride ion, and the ylides 77 can rearrange to give the thermodynamically favoured ylides 78. Each of the ylides can then undergo Sommelet–Hauser or Stevens rearrangement to produce complex mixtures of products. The relative amounts of each ammonium ylide, and hence the ratio of rearranged products, is dependent on the reaction temperature and the nature of the activating group R.40

Me Me N R N R

CH2 Me R 77 78 Me CsF, N DMF, rt

Br SiMe3 76 Me R = CN, CO2Et N R

SiMe3 79

Scheme 25

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2.3 From carbenes or catalytically generated metal carbenoids41 The intermolecular or intramolecular generation of ammonium ylides by reaction of tertiary amines with thermally or photochemically generated carbenes has been known for many years. However, in most cases, low yields and multiple products are obtained which precludes the use of this approach in synthesis.42 In early studies, simple tertiary amines were reacted with dichlorocarbene, generated by treatment of chloroform with base. Very low yields (usually 10%) of products arising from [1,2] rearrangement of the corresponding ammonium ylides were obtained, even in cases where [2,3] rearrangement would have been possible.43,44 In the case of allylic amines, cyclopropanation usually was the predominant pathway.44 Stevens investigated the thermal reaction of aryl-substituted diazo compounds with bulky tertiary amines (e.g. ﬂuorenyl-substituted amines) and did observe signiﬁcant amounts of the products expected from [1,2] rearrangement of a formal ammonium ylide intermediate.45 In certain circumstances, photochemically generated carbenes react with tertiary amines to give reasonable yields of ammonium ylide rearrangement products. Tomioka and co-workers have shown that irradiation of the diazo ester 80 in the presence of a tertiary amine can provide the formal C–H insertion product 83 (Scheme 26).46 However, in the case of amines bearing an electron- withdrawing group (e.g. Y CO2Et), the apparent C–H insertion product arises by [1,2] rearrangement of the ammonium ylide 82 produced by a [1,3] shift of the initially formed ylide 81. Tomioka obtained the product arising from [2,3] rearrangement of the ammonium ylide 81 when an allylic amine 46 (Y CHCH2) was used as a partner in these reactions.

O O ν Ph h , –N2 Ph OMe OMe R2NY N2 42–81% R2NY 80 R = Me, Et 83

Y = Me, CO2Me, COMe, CN [1,2]

O O Ph Ph OMe [1,3] OMe NY NY R R R R 81 82

Scheme 26

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Intramolecular reactions of photochemically generated carbenes have also been investigated by Tomioka (Scheme 27).47 Exposure of the diazo amines 84 to UV light results in carbene generation and subsequent formation of the ammonium ylides 85. In the case where n 1, treatment of the ylide 85 with chloroform affords the ammonium salt 86. With the higher homologue (n 2), the indane 87 is isolated along with a substantial amount of the alkene 88 resulting from Hofmann-type elimination of the intermediate ammonium ylide 85. Although the major product 87 can be produced by [1,2] rearrangement of the ammonium ylide 85, trapping experiments have demonstrated that this product is formed by direct C–H insertion of the carbene intermediate. Me Me N CHCl3 Ph n = 1 NMe Me Cl N ( ) 2 Me 86 2 n N hν, –N2 ( )n Ph Ph

Me2N 84 85 Me2N Ph + Ph n = 2

62% 8736% 88

Scheme 27 The production of ammonium ylides by reaction of catalytically generated metal carbenoids with amines has proved to be superior to those methods involving free carbenes (see Chapters 2.1 and 2.3). In an early example of this approach, Hata and Watanabe studied the reactions of a copper carbenoid generated from ethyl diazoacetate with a variety of cyclic amines (Scheme 28).48 The outcome of these reactions was found to be dependent on the ring size of the cyclic amine 89. Only the ammonium ylide 90 derived from an azetidine (89, n 2, m 0) underwent [1,2] rearrangement with ring expansion to give the cyclic amine 91. The corresponding ammonium ylide derived from an aziridine (89, n 1, m 1) underwent decomposition with loss of ethene to afford an imine. O O OEt O N N 2 ( )n OEt [1,2] ( )mPh NOEt N Cu(acac) , ( )n ( ) 2 ( )m n ( ) Ph ° m 70–80 C Ph n = 1, 2 m = 0, 1 n = 2, m = 0 96% 89 90 91

Scheme 28

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The [1,2] rearrangement of ammonium ylides generated from rhodium or copper carbenoids has been used as a very effective synthetic transformation by West (see Chapter 2.1). For example, tertiary -amino esters and ketones have been prepared by the reaction of simple amines with -diazo ketones, -diazo esters and -diazo -keto esters (see Chapter 2.1).49 In general, copper catalysts are superior to rhodium catalysts, as a consequence of competitive coordination of the amine to the vacant site required for catalysis in the case of rhodium catalysts. The benzyl group and substituted analogues were found to have the highest [1,2] migratory aptitude of those groups explored. Recently, the reaction has been exploited by Burger for the preparation of triﬂuoromethyl-substituted -amino acid esters.50 West has also investigated the intramolecular variant of the reaction as a method for the preparation of piperidines and tetrahydroisoquinolines (see Chapter 2.1).51 Products arising from coupling of radical products were isolated from some reactions, providing evidence for [1,2] rearrangement arising by a radical dissociation–recombination pathway.51 Initially, intramolecular ammonium ylide formation was accomplished using rhodium(II) acetate as the catalyst for carbenoid generation. However, later studies revealed that copper carbenoids are more suitable for the formation of cyclic amines with ring sizes greater than six, because the problem of competitive C–H insertion encountered with rhodium carbenoids is suppressed when copper carbenoids are used.52 Catalytic ammonium ylide generation and subsequent [1,2] or [2,3] rearrangement has also been applied to the synthesis of morpholin-2-ones (see Chapter 2.1).53 Good yields of morpholin-2-ones are usually obtained by exposure of tethered amino-substituted -diazo esters or -diazo -keto esters to either copper powder or copper(II) acetylacetonate in toluene at reﬂux. The yields obtained are dependent on the substituent pattern, with benzylic or allylic amines affording the highest yields.53 The Stevens rearrangement of catalytically generated ammonium ylides has found two particularly elegant applications in natural product synthesis. West has used the reaction to prepare a quinolizidine system from a diazo-tethered enantiomerically pure pyrrolidine (see Chapter 2.1).54 The [1,2] rearrangement reaction proceeded with preservation of stereochemical information at the chiral migrating group, and the quinolizidine product was then elaborated to the natural product (–)-epilupinine in three steps (see Chapter 2.1). Padwa has also applied the reaction to natural product synthesis.55 In this case, the tandem ammonium ylide generation and [1,2] rearrangement was used to construct the cephalotaxine skeleton. Treatment of the -diazo -keto esters 92 with copper(II) acetylacetonate afforded the tricyclic amino ketones 93 resulting from ylide rearrangement with one-carbon ring expansion (Scheme 29). In all cases, the only products isolated were those resulting from migration of the benzylic carbon atom. It is noteworthy that in one case (92, n 1 R H), the intermediate ammonium ylide was isolable as a crystalline 19 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 20

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solid. When the ylide was heated in the absence of the catalyst, [1,2] rearrangement proceeded in high yield to give the expected product 93.

( )n ( )n ( )n N N O Cu(acac)2, N [1,2]

R O PhMe, reflux R R EtO N2 O EtO2C O O 92 OEt 93 n = 0, 1 68–77% R = H, Me, CHCHMe Scheme 29

The [2,3] rearrangement of ammonium ylides derived from metal carbenoids has also received considerable attention (see Chapters 2.1 and 2.3). Doyle has shown that rhodium carbenoids derived from ethyl diazoacetate react with simple allylic amines to give the homoallylic -amino acid esters 94 expected from ylide formation and subsequent [2,3] rearrangement (Scheme 30).56 In many cases, the yields are good and the reaction proceeds without formation of the cyclopropane products usually encountered upon reaction of allylic amines with thermally or photochemically generated carbenes. In those cases where two stereogenic centres are created upon rearrangement (i.e. R1 R2), Doyle obtained only a modest level of diastereocontrol.56

O 2 N R 2 1 1 OEt R R NMe2 Rh (OAc) or Rh (CO) R2 2 4 6 16 EtO2C NMe2 R1, R2 = H, Me, Ph ~75:25 (R1 - R2) 32–82% 94

Scheme 30

We have explored the catalytic intramolecular generation and [2,3] rearrangement of allylic ammonium ylides and found that this is a useful method for the preparation of simple cyclic amines with ring sizes 5–8 (see Chapter 2.1).57 In addition, we have applied this chemistry to the synthesis of simple pyrrolizidine, indolizidine and quinolizidine systems from simple cyclic amines.57,58 We have found that copper(II) acetylacetonate is the catalyst of choice for carbenoid generation (see Chapter 2.1). We have also applied the reaction to substrates in which the allylic amine forms part of a ring (see Chapter 2.1). For example, we used the reaction to prepare a simple model (96) for the CE ring system found in some members of the manzamine family of alkaloids.59 Upon treatment of the enantiomeric- 20 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 21

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ally pure pyrrolidine-tethered -diazo ketone 95 with copper(II) acetylacetonate, the bicyclic amine 96 was obtained as a single product with high enantiomeric excess (Scheme 31). The high enantiomeric excess indicates that efﬁcient ‘transfer of chirality’ occurs during the rearrangement reaction.

N Cu(acac)2 N 2 N C6H6, reflux O H O 95 96 56% Scheme 31

The reaction of related substrates has been investigated by McMills and co- workers. The cyclization of diazo ester-tethered 2-vinyl pyrrolidines or 2-vinyl piperidines was explored (Scheme 32).60 In the case of the vinyl pyrrolidine 97 (n 1), ammonium ylide generation and rearrangement resulted in a mixture of the [2,3] and [1,2] rearrangement products 98 and 99. Efﬁcient ‘transfer of chirality’ was accomplished during the [2,3] rearrangement reaction, and the product 98 was obtained as a single geometric isomer with high enantiomeric excess. In contrast, reaction of the vinyl piperidine 97 (n 2) resulted in exclusive formation of the [2,3] rearrangement product as a 5:1 mixture of Z and E isomers, without competitive Stevens rearrangement of the intermediate ylide (Scheme 32).60

( )n ( )n Cu(hfacac)2 N ( )n N N2 N + O O Me O PhMe, reflux O O O O OMe O Me 97 98 99

n = 170% 2.5:1 (98 Z only, >97% e.e.)

n = 2 65% 98 only (98 Z:E, 5:1)

Scheme 32

The generation of ammonium ylides from metal carbenoids is not restricted to electron-rich tertiary amines. Padwa has demonstrated that some amides will react with carbenoids in an intramolecular fashion to afford ammonium ylides.61 For example, reaction of the -diazo -keto ester 100 with rhodium(II) perﬂuorobutyrate produced the lactam 101 resulting from ammonium ylide formation and subsequent [1,2] shift of the benzyl group (Scheme 33). Interestingly, when dimethyl acetylenedicarboxylate (DMAD) was added to the reaction, the major product (57% yield) was that resulting from trapping of the 1,3-dipole produced by reaction of carbenoid with the amide 21 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 22

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carbonyl group (see Section 6.4), and the lactam 101 was obtained as a minor product (23% yield). This suggests that formation of either or both of the ylide intermediates is reversible.

O O O N EtO Bn EtO Me 2 Me O OEt Rh2(pfb)4 N [1,2] Bn N Bn N O O O O O Me 62% 100 101

Scheme 33

3. Oxonium ylides Until recently, the chemistry of oxonium ylides had received scant attention compared with that of ammonium or sulfonium ylides. Oxonium ylides are characterized by their instability and high reactivity and, unlike some ammonium ylides and many sulfonium ylides, they are not isolable and are difﬁcult to characterize spectroscopically. Circumstantial evidence for the existence of oxonium ylides has been provided by the isolation of products expected from the rearrangement of these putative reactive intermediates. In the past decade, the efﬁcient generation of free oxonium ylides or their metal-bound equivalents by the reaction of ethers with electrophilic metal carbenoids has resulted in the rapid expansion of their synthetic reper- toire.41,62

3.1 Deprotonation of oxonium salts or desilylation of -silyl oxonium salts Oxonium ylides have been implicated as intermediates during the conversion of methanol or methyl ethers into ethene and other hydrocarbons promoted by heterogeneous transition metal oxide or oxyhalide catalysts at 300–350°C. In order to explore mechanistic aspects of the process and conﬁrm the intermediacy of oxonium ylides, Olah has studied the product distribution obtained upon deprotonation of oxonium ions or desilylation of -silyl oxonium ions.63 In these studies, 13C- or D-labelled substrates were used to reveal the reaction pathway. The generation of oxonium ylides by direct deprotonation of oxonium ions is generally problematic because oxonium ions are powerful alkylating agents and will alkylate most bases instead of undergoing deprotonation. However, Olah found that it was possible to deprotonate simple oxonium salts such as trimethyloxonium tetraﬂuoroborate by using sodium hydride as the base (Scheme 34). Although simple hydride alkylation to afford dimethyl ether 22 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 23

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and methane is the dominant process, deprotonation of the oxonium ion does occur to give signiﬁcant amounts of methylenedimethyloxonium ylide. The ylide can then undergo Stevens rearrangement or methylation to afford the dimethylethyloxonium ion. Subsequent elimination of the new oxonium ion or reaction with hydride occurs, and dimethyl ether, methane, ethene, ethane and methanol are isolated as the ﬁnal products from the reaction (Scheme 34).63

CH4 Me2O MeOMe CH2CH2 Me Me NaH O –H Me BF4 Me Me Me O BF Me Me NaH O 3 4 O CH3CH3 Me O CH2 –Me2O 2 Me BF4

[1,2] shift NaH

EtOMe MeOH EtOMe

CH2CH2 CH4

Scheme 34

Olah found that ﬂuoride-induced desilylation of -silyl oxonium ions could be used as a convenient alternative method for oxonium ylide generation.63 The required -silyl oxonium salts can be prepared by direct alkylation of simple dialkyl ethers with (trimethylsilyl)methyl halides.64 Treatment of an -silyl oxonium salt with a ﬂuoride source results in loss of the silyl group to afford an oxonium ylide that can then undergo alkylation to afford a homologue of the dialkyl ether used to prepare the original -silyl oxonium salt (Scheme 35). Results from studies involving isotopically labelled substrates rule out Stevens rearrangement of the intermediate oxonium ylide as a mechanistic possibility in this case.

Me Et Me Et Me Me O CsFO Et O F EtF

CH EtCH2OMe Me Si BF 2 Et 3 4 0.02%

Scheme 35

Although the methods described above do yield the products expected from oxonium ylide intermediates, competitive alkylation results in low yields of ylide-derived products, and the high reactivity of the putative oxonium ylides leads to uncontrolled reactions. Consequently, these reactions are of mechanistic interest but of limited synthetic scope. 23 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 24

J. S. Clark 3.2 From carbenes generated thermally or photochemically The generation of oxonium ylides from free carbenes has been the subject of many studies. Although free carbenes can react in a rather indiscriminate manner, satisfactory ylide formation has been accomplished in some cases. In one of the earliest examples of the direct generation and rearrangement of oxonium ylides from free carbenes, Nozaki and co-workers investigated the thermal and photochemical reactions of ethyl diazoacetate with 2-phenyl- oxirane and 2-phenyloxetane.65 Although several products were isolated in each case, some of the compounds appeared to be derived from an oxonium ylide. Compelling evidence for the intermediacy of free oxonium ylides was provided by the isolation of ring-expanded Stevens rearrangement products from these reactions. Ando explored the analogous reactions of allylic ethers with the carbenes generated photochemically from dimethyldiazomalonate (Scheme 36).66 In general, mixtures of the ylide rearrangement product 102 and the cyclopropane 103 were obtained from each reaction, with a modest preference for the former. When the size of the alkyl group (R1) was increased, the major product was the cyclopropane 103. Addition of benzophenone or another photosensitizer to the reactions resulted in almost exclusive formation of the cyclopropane 103 at the expense of the ylide rearrangement product 102. Thus, it is apparent that the triplet carbene generated in the photosensitized reaction undergoes alkene cyclopropanation in preference to oxonium ylide formation, whereas the singlet carbene generated in the absence of a photosensitizer shows relatively little selectivity.66

MeO2CCO2Me R2 MeO C CO2Me N2 2 1 2 MeO2C + MeO2C R OR ν h R1O R1O R 2 102 103 R1 = Me R2 = H 31% 20%

R1 = Me R2 = Me 37% 17%

R1 = Et R2 = Me 15% 38% Scheme 36

Olah studied the reaction of simple dialkyl ethers with methylene carbene generated photochemically from diazomethane.67 Earlier studies had indicated that C–H insertion adjacent to the ether oxygen is the major reaction pathway in most cases,68 and this was conﬁrmed by Olah. However, products arising from oxonium ylide intermediates were also isolated from these reactions. Experiments with deuterium-labelled substrates revealed that the oxonium ylide intermediates usually undergo elimination or reaction with proton sources to afford oxonium ions rather than undergo Stevens rearrangement.67 24 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 25

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The generation of oxonium ylides by the intermolecular or intramolecular reaction of ethers with carbenes generated from diazo compounds has been studied extensively by Kirmse. Reactions of oxetane with carbenes generated by photolysis of diazomethane, phenyl diazomethane or ethyl diazoacetate give mainly tetrahydrofuran products, resulting from sequential oxonium ylide formation and Stevens rearrangement (Scheme 37).69 The other major products are those produced by C–H insertion adjacent to the ether oxygen and those obtained by elimination of the ylide. When the reactions are performed in the presence of methanol, protonation competes effectively with ylide rearrangement, and signiﬁcant amounts of the 1,3-dialkoxypropanes produced by ring opening of the oxonium ion are obtained.

elimination O

R R O [1,2] O hν (MeOH) R N2 O R OMe MeOH MeOH R = H, Ph, CO2Et O O

R R Scheme 37

Kirmse also found that treatment of (S)-methyloxetane [67% enantiomeric excess (e.e.)] with methylene carbene, generated by irradiation of diazomethane, affords a 1:3.2 mixture of 2- and 3-methyltetrahydrofuran. The latter compound was found to have an e.e. of 14% with net retention of configuration, which corresponds to an e.e. of 21% when corrected to account for the e.e. of the oxetane.70 The intramolecular generation of oxonium ylides from photochemically generated carbenes has also been explored.71 Kirmse found that carbenes generated by flash photolysis of the tosylhydrazone salts 104 undergo intramolecular cyclization to afford the ylide-derived cyclic ethers 106 and the C–H insertion products 105 and 107 (Scheme 38). The C–H insertion pathway dominates when higher homologues (n 1) are used. Interestingly, benzyl- substituted oxonium ylide intermediates do not undergo Sommelet–Hauser rearrangement, and this behaviour contrasts with that of analogous ammonium ylides. Oku has studied the generation of oxonium ylides by the reaction of simple cyclic ethers with carbenes generated photochemically from diazo compounds.72 When Oku’s reaction conditions are employed, C–H insertion is not a significant competing reaction. In the presence of a suitable protic nucleophile, such as an alcohol, amine, sulfide, carboxylic acid or amide, the inter- 25 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 26

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N M Ph NTs Ph hν Ph H DMF or O + O + O Ph ( ) ( ) O ( )n diglyme n–1 n ( )n 104 105 106 107

M = Li n = 1 0% 80% 17%

M = Na n = 2 36% 33% 5%

Scheme 38

mediate ylide undergoes protonation to give an oxonium ion which then suffers nucleophilic attack (Scheme 39). The complete process constitutes a three-component coupling procedure. Oku discovered that the yield of the coupled product is highly dependent on the nature of the diazo compound and the acidity of the nucleophile. For example, irradiation of a mixture of methyl diazophenylacetate and tetrahydrofuran in methanol affords little of the coupled ether 108 and gives mainly the elimination product 109, resulting from apparent proton transfer (Scheme 39). However, when acetic acid is used instead of methanol, the expected product 108 is isolated in reasonable yield.72

OR3 1 2 R R O O R1 + R1 3 N2 hν, R OH R1 R2 R2 O R2 O 108 109

R1 = Ph R2 = H R3 = Me 50%

1 2 3 R = CO2Et R = H R = Ph(CH2)2 61%

1 2 3 R = CO2Me R = Ph R = Me 37–44%

1 2 3 R = CO2Me R = Ph R = Ac 57%

Scheme 39

3.3 From catalytically generated metal carbenoids There has been a dramatic increase in the study and synthetic exploitation of oxonium ylides in recent years. This has been due largely to the advent of mild catalytic methods for their preparation involving intermolecular or intramolecular reaction of ethers with metal carbenoids generated from diazo compounds (see Chapter 2.3). Although the exact identity of the intermediates produced upon reaction of ethers with metal carbenoids is still the subject of some debate, current evidence suggests that metal-bound intermediates 26 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 27

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rather than free oxonium ylides are the product-forming species in some of these reactions. In most cases, however, the intermediates exhibit reactivity proﬁles similar to those expected of free oxonium ylides, and so they can be regarded as direct equivalents of free oxonium ylides. In early studies, Nozaki and co-workers found that copper-catalysed reaction of ethyl diazoacetate with 2-phenyloxetane afforded 2-carboethoxy- 3-phenyltetrahydrofuran as a mixture of isomers in 80% yield.65b The isolation of the tetrahydrofuran product was consistent with the generation and subsequent [1,2] rearrangement of an oxonium ylide. Shortly thereafter, Kirmse and Kapps explored the reaction of simple allylic ethers with carbenoids generated by treatment of diazomethane with various copper salts.73 In each case, they obtained mainly the cyclopropane and a small amount of the product expected from [2,3] rearrangement of an intermediate oxonium ylide. Interest in the tandem catalytic generation and rearrangement of oxonium ylides as a general synthetic transformation was ﬁrmly established after Pirrung and Werner,74 and Roskamp and Johnson75 published results of their studies on the reaction. In these studies, the intramolecular generation of oxonium ylides from metal carbenoids and their subsequent formal [2,3] rearrangement were explored. Treatment of the simple allylic ethers 110 bearing a pendant -diazo ketone or -diazo -keto ester with rhodium(II) acetate afforded the simple cyclic ethers 111 arising from formal [2,3] rearrangement of the putative free oxonium ylide (Scheme 40). The yields of furanone products (111, n 1) were generally good, whereas the yields of pyranone products (111, n 2) were generally modest (usually 60%).

O O O R1 ( )n ( )n ( )n Rh2(OAc)4, N 1 O 2 O R O C6H6 or 33–95% 1 R 2 CH Cl , rt R R2 2 2 R2 110 111 n = 1, 2 1 R = H, CO2Me R2 = H, Me Scheme 40

Johnson also brieﬂy explored the [1,2] rearrangement of intramolecularly generated oxonium ylides.75 For example, treatment of the -diazo ketone 112 with a sub-stoichiometric amount of rhodium(II) acetate in benzene afforded a mixture of the cyclobutanones 113a and 113b arising from [1,2] ylide rearrangement with concomitant ring contraction (Scheme 41).75 In this example, the rearrangement process positioned the oxygen substituent out- side the ring, and so a carbocycle was produced instead of a cyclic ether. 27 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 28

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OMe O O O Rh2(OAc)4, Me + C6H6, rt Me Me Ph OMe OMe N2 Ph Ph 11257%113a 17% 113b

Scheme 41

Pirrung explored the utilization of the reaction to accomplish ring expansion of a cyclic ether.74 Conversion of the vinyl-substituted tetrahydrofurans 114 into the corresponding rhodium carbenoids resulted in oxonium ylide formation and formal [2,3] rearrangement. In this case, location of the allylic ether as part of the existing ring meant that three-carbon ring expansion occured upon rearrangement and the oxygen-bridged bicyclic compound 115 was obtained.74 Me O

R Me Rh2(OAc)4, O O R CH2Cl2, rt N2 H O 114R = H 81% 115

R = CO2Me 67%

Scheme 42

The [2,3] rearrangement of oxonium ylides is not restricted to those generated from the reaction of allylic ethers with metal carbenoids. Although oxonium ylides generated from benzylic ethers normally undergo a [1,2] shift in preference to Sommelet–Hauser rearrangement, the corresponding ylides generated from propargylic ethers do undergo apparent [2,3] rearrangement, even though it is more difﬁcult for the oxonium ylide to adopt the correct transition state geometry. Pirrung established the viability of the reaction by demonstrating that treatment of the -diazo -keto ester 116 (R CO2Me) with rhodium(II) acetate results in formation of the allene 117 (Scheme 43).74 The success of the reaction is dependent on the substrate structure, and the corresponding -diazo ketone (R H) failed to undergo the same reaction.

O O R R Rh2(OAc)4, N O 2 CH2Cl2, rt O

116 R = H 0% R = CO2Me 91% 117

Scheme 43

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The intermolecular catalytic generation and rearrangement of allylic oxonium ylides has also received considerable attention. One obvious disadvan- tage of this reaction is that it is necessary to use a large excess of the allylic ether relative to the diazo compound in order to minimize the formation of products arising from dimerization of the diazo compound or further reaction of the diazo compound with the product. Another problem, which is usually avoided in intramolecular reactions, is competitive alkene cyclopropanation. The degree to which cyclopropanation occurs is highly dependent on the steric environment around the ether oxygen, the alkene substituent pattern and the catalyst employed for ylide generation. Unfortunately, in many cases, cyclopropanation is the dominant reaction pathway. In spite of the problems described above, Doyle has explored the synthetic potential of the intermolecular oxonium ylide generation and rearrangement sequence using simple allylic ethers (see Chapter 2.3).76 Treatment of an allylic methyl ether such as 118 with a simple -diazo ketone or ester in the presence of rhodium(II) acetate affords a mixture of the diastereoisomeric rearrangement products 120a and 120b in good yield (Scheme 44). The alkene geometry dictates the stereochemical course of the reaction, and Doyle has proposed that rearrangement of the putative oxonium ylide intermediate 119 proceeds through the ‘envelope’ transition state in which steric interactions between the methyl substituent and the carbonyl group are minimized.

2 3 O O R R 2 3 Rh2(OAc)4, R R + R1 R1 CH2Cl2, rt O N Me 2 MeO 118 119 1 R = MeO, EtO, Ph, p-MeOC6H4 2 3 [2,3] R = H, R = Me, Ph, Me3Si or R2 = Ph, n-Bu, R3 = H H

O R3 R2 O R2 R3 H R3 R2 1 1 O R + R Me MeO MeO O H 120a 120b R1

R1 = Ph R2 = H R3 = Ph 91:9 81%

R1 = Ph R2 = Ph R2 = H 19:81 64%

Scheme 44 Doyle has also examined the analogous intermolecular reactions of propargylic ethers with diazo carbonyl compounds and has found that allenes are produced along with signiﬁcant amounts of cyclopropene products.77 When 29 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 30

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Doyle employed rhodium(II) acetate as the catalyst, the cyclopropene was the predominant product in each case. However, a dramatic reversal in selectivity was observed when rhodium(II) perﬂuorobutyrate was employed as the catalyst; the highly oxophilic carbenoids generated using this catalyst exhibited a marked preference for oxonium ylide formation instead of cyclo- propenation. The synthesis of cyclic ethers by [1,2] rearrangement of oxonium ylides generated in an intramolecular fashion has been explored extensively by West and co-workers. In preliminary studies, they explored the conversion of the simple diazo ketones 121 into the cyclic ethers 122 and discovered that oxonium ylides generated from benzylic ethers generally undergo [1,2] rearrangement with migration of the benzyl group (Scheme 45).78 The tether has an important inﬂuence on the success of the reaction, and West found that increasing the tether length usually results in a lower yield of the ylide rearrangement product as a consequence of competitive C–H insertion adjacent to the ether oxygen. In the case of substrates bearing a substituent adjacent to the ether oxygen in the tether, a diastereoisomeric mixture of products is obtained upon cyclization.

2 2 R O R O R1 O R2 R2 Rh2(OAc)4, [1,2] N2 BnO CH Cl , rt 1 1 2 2 R O R O Bn R2 R2 121 Bn 122

R1 = H, R2 = H 64%

R1 = H, R2 = Me 65% R1 = Me, R2 = H 52% (1.5:1)

Scheme 45

In some cases, yields of the cyclic ether are depressed and homodimeric products such as dibenzyl are obtained. The homodimeric products are thought to arise by homolysis of the oxonium ylides to give a radical pair, escape of the radicals from the solvent cage and subsequent recombination. The isolation of homodimeric products provides strong evidence to support the radical pair mechanism proposed for Stevens rearrangement of oxonium ylides.78 In contemporaneous studies, we investigated the intramolecular generation and [2,3] rearrangement of oxonium ylides as a method for the diastereoselective synthesis of 2,5-dialkyltetrahydrofuran-3-ones.79 Treatment of the -diazo ketones 123 with either rhodium(II) acetate or copper(II) acetylacetonate afforded a mixture of the diastereoisomeric furanones 124a and 124b in which the trans isomer 124a predominated. In general, copper(II) 30 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 31

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acetylacetonate is superior to rhodium(II) acetate or other rhodium complexes as the catalyst for the reaction, affording higher yields and excellent levels of diastereocontrol.79

O O O OO MLn [2,3] + R R O R O R O N2 123 124a 124b

R = CHMe2 Cu(acac)2, THF, reflux 83–85% (>97:3)

R = CHMe2 Rh2(OAc)4 51–68% (<81:19)

R = (CH2)2Me Cu(acac)2, THF, reflux 83% (>97:3)

Scheme 46

In order to broaden the scope of the reaction, we explored the preparation of larger cyclic ethers by tandem oxonium ylide formation and rearrangement. We discovered that copper(II) hexaﬂuoroacetylacetonate is an excep- tional catalyst for ylide generation and that the cyclic ethers 126 can be prepared in good yield from the diazo ketones 125 (Scheme 47).80 The use of copper(II) acetylacetonate generally gives lower yields of the ylide rearrangement products, and competitive C–H insertion is encountered when carbenoid generation is performed using rhodium(II) acetate. Copper(II) tri- ﬂuoroacetylacetonate-mediated cyclization of the substituted precursor 125 (R Me) affords the tetrahydropyranone product 126 with a reasonable level of diastereocontrol. The major isomer (126a) has been transformed into the natural product ()-decarestrictine L.81

O O O ( )n ( )n ( )n CuL n + R O N2 R O R O CH2Cl2, reflux

125 126a 126b

n = 1 R = H Cu(hfacac)2 83%

n = 2 R = H Cu(hfacac)2 76%

n = 3 R = H Cu(hfacac)2 40%

n = 1 R = Me Cu(tfacac)2 65% (91:9)

Scheme 47

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Diastereoselective [2,3] rearrangement of catalytically generated oxonium ylides can be accomplished using allylic ethers bearing a substituent at the allylic position. Pirrung has used this reaction to introduce two stereogenic centres during a total synthesis of the anti-fungal agent ()-griseofulvin (Scheme 48).82 Treatment of the enantiomerically pure diazo ketone 127 with rhodium(II) pivalate in benzene at reﬂux afforded the rearrangement product 128 in good yield. Although the original stereogenic centre was destroyed upon rearrangement, there was efﬁcient ‘chirality transfer’ during the reaction and the product was isolated as a single diastereoisomer with high enantiomeric purity. The benzofuranone 128 was then elaborated to give the natural product in three steps.

MeO OO MeO O t O OMe Rh2(O2C -Bu)4,

N2 MeO O C6H6, reflux, 1 h MeO O OMe Me Cl Cl Me Me Me 127 [2,3]

MeO O OMe MeO O O steps OMe O MeO O MeO O Me Cl Me Cl Me (+)-griseofulvin 128

Scheme 48

The marked differences in the behaviour of rhodium and copper carbenoids with regard to ylide formation and C–H insertion reported by us have also been observed by West in contemporaneous studies.83 He found that cyclization of a rhodium carbenoid generated from the diazo ketone 129 (R Me, n 0) afforded the [1,2] shift product 130 in reasonable yield, and that generation of the analogous carbenoid using copper(II) hexafluoroacetylacetonate resulted in a lower yield of the cyclic ether 130 along with the enol ether 131. However, when the tether length was increased (R H, n 1), the rhodium(II) acetate-promoted reaction furnished mainly the C–H insertion product 132, and copper(II) hexafluoroacetylacetonate proved to be a superior catalyst in this case. When copper(II) hexafluoroacetylacetonate was employed as the catalyst, a significant amount of the formal [1,4]-shift product 131 was isolated in addition to the expected cyclic ether 130.83 32 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 33

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R R R R R R O O O OBn ( ) MLn, ( ) ( ) ( ) n n + n + n N CH2Cl2 O 2 OBn O OBn Bn 129 130 131 132

R = Me n = 0 Rh2(OAc)4 rt 65%

R = Me n = 0 Cu(hfacac)2 reflux 24% 6%

R = H n = 1 Rh2(OAc)4 rt 16% 47%

R = H n = 1 Cu(hfacac)2 reflux 35%24% 6%

Scheme 49

West has also exploited the catalytic generation and [1,2] rearrangement process to prepare oxygen-bridged medium-ring systems, and showed that cyclization of the -diazo ketones 133 affords the bridged bicyclic ethers 134a and 134b (Scheme 50).84 Complete selectivity for migration of the benzylic group was observed and the stereochemical outcome of the reaction was highly dependent on the relative stereochemistry in the -diazo ketone 133 and the ring size formed. For example, cyclization of the substrate with the shorter tether (133, n 1) proceeded with predominant retention of configuration at the migrating centre, whereas complete retention of configuration was observed when the tether length was increased by one carbon (133, n 2). In some cases (133, n 2), significant amounts of the elimination product 135 were also isolated.

( ) ( )n ( )n n Ph ( )n 2 O Rh2(OAc)4, R O + O + 1 O R CH Cl , rt R2 R1 2 2 O O O R1 R2 N2 O 133134a 134b 135

R1 = Ph, R2 = H n = 1 60% (a+b) (15–19:1)

R1 = Ph, R2 = H n = 2 12% 0% 27%

R1 = H, R2 = Ph n = 1 90% (a+b) (2:1)

R1 = H, R2 = Ph n = 2 51% 0% 4%

Scheme 50

We have also explored the rearrangement of catalytically generated bicyclic oxonium ylides to produce ring-expanded bridged ethers.85 Treatment of the diazo ketone 136 with copper(II) hexaﬂuoroacetylacetonate in dichloromethane at reﬂux afforded the bicyclic ether 137b, possessing E-alkene geo- 33 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 34

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metry, in 51% yield (Scheme 51). In contrast, generation of the ylide from a rhodium carbenoid at a lower temperature gave a 1:1 mixture of the E and Z products in poor yield. Further studies showed that the E product 137b is probably the preferred product irrespective of the catalyst use for ylide generation, and that isomerization to the Z product occurs in the presence of rhodium(II) acetate.85

AcO Me Me Me MLn O AcO O + AcO O CH2Cl2 N O O O 2 136 137a 137b

Rh2(OAc)4 0°C 15% 15%

Cu(hfacac)2 reflux 0% 51%

Scheme 51

Tandem catalytic oxonium ylide generation and rearrangement has also been applied to the synthesis of macrocycles (ring size ≥10). For example, Doyle has found that treatment of -diazo esters such as 138 with a suitable rhodium or copper complex produces a 13-membered cyclic oxonium ylide that undergoes [2,3] rearrangement with three-atom ring contraction to afford the lactone 139 (Scheme 52).86 Doyle observed competitive cyclopropanation to afford the lactone 140, but was able to suppress this side reaction by generating the carbenoid using a copper catalyst.

HH O MLn O O + O O CH2Cl2, reflux OR H OR O OOR O O 138139 140 N2 Cu(MeCN)4PF6 62% (74:26)

Rh2(OAc)4 80% (33:67)

Cu(MeCN)4PF6 70% (85:15)

Scheme 52

An unusual example of indirect oxonium ylide formation from a metal carbenoid has been reported by Padwa and co-workers.87 The rhodium carbenoid generated from the diazo ketone 141 undergoes alkyne metathesis to provide the vinylic carbenoid 142 which then delivers the tetrahydrofuran 34 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 35

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143 by tandem oxonium ylide formation and [2,3] rearrangement (Scheme 53). Products arising from rearrangement of the oxonium ylide formed directly from the initial rhodium carbenoid are not observed.

O O O rhodium(II) N2 mandelate O CH2Cl2, 81% RhLn O 25°C O 141 142 143

Scheme 53

The generation of oxonium ylides by reaction of carbenoids with acetals has received considerable attention in recent years. In some cases, the ylides exhibit substantially different rearrangement proﬁles from those of ylides derived from simple ethers. The difference in reaction pathways is particularly marked when ylide generation is performed in an intramolecular fashion. The rearrangement of oxonium ylides generated by the intermolecular reaction of metal carbenoids with simple allylic acetals has been explored by Doyle (Scheme 54).88 Reaction of the acrolein dimethyl acetal with the rhodium carbenoid, generated by treatment of ethyl diazoacetate with rhodium(II) acetate, affords a stereoisomeric mixture of the enol ether 144, arising from [2,3] rearrangement of an oxonium ylide, along with a signiﬁcant amount of the cyclopropane 145.

O O OEt OEt MeO O N2 OEt + OMe MeO OMe Rh2(OAc)4 144 OMe 145 OMe

(E:Z, 5.7:1) 75% (3.3:1)

Scheme 54

Roskamp and Johnson originally reported two examples of oxonium ylide generation by intramolecular reaction of an acetal with a rhodium carbenoid (Scheme 55).75 Treatment of the acetal 146 with rhodium(II) acetate afforded a mixture of the [1,2] shift product 147 and the elimination product 148, with the former predominating. None of the elimination product was obtained upon reaction of the substrate bearing a methyl substituent (R Me) on the 35 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 36

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tether connecting the diazo ketone to the acetal. In this case, the yield of the [1,2] rearrangement product was reduced, but the reaction was highly dia- stereoeselective.75

R O O O O Rh2(OAc)4 O OO O + O R + O Me H Me O OO AcO R Me R Me O Me O R N2 146 147 148 149

R = H C6H6, rt 68% 16%

R = Me C6H6, rt 54% (97:3)

R = H CH2Cl2, AcOH, rt 0% 46% 41% Scheme 55 The elimination process is promoted when a suitable proton donor is present during the reaction of an acetal with a metal carbenoid. Oku and co- workers found that acetic acid facilitates oxonium ion formation by protonation of the putative oxonium ylide intermediate (Scheme 55).89 Thus, the major products obtained for the rhodium(II) acetate-mediated reaction of the diazo ketone 146 (R H) in the presence of acetic acid are the elimination product 148 and the acetal 149 produced by reaction of the enol ether with acetic acid (Scheme 55). The success of the reaction is heavily dependent on the pKa of the acid employed; with weak acids such as alcohols, the carbenoid tends to undergo O–H insertion. The rearrangement of oxonium ylides derived from the reaction of metal carbenoids with acetals can be used to prepare some very unusual cyclic systems. For example, Zercher and co-workers have employed the reaction to prepare the dioxabicyclic core of the zaragozic acids.90 Early studies revealed that carbenoids derived from copper(II) hexaﬂuoroacetylacetonate are generally superior to those derived from rhodium(II) acetate.90a Treatment of the simple -diazo -keto ester substrates 150 with copper(II) hexaﬂuoroacetyl- acetonate was found to afford the bridged bicyclic compound 151 in good yield (Scheme 56). Interestingly, in the unsubstituted case (R H), none of

R R MeO O O R Cu(hfacac) , 2 O [1,2] O R OO O O Me R C6H6, reflux O Me N2 MeO O R OMe Me

150 OO 151

R = CH2CH 64% R = Ph 65% Scheme 56

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the required product was obtained from the reaction and a -elimination product was obtained as the major product along with a small amount of the alternative [1,2] rearrangement product.90c West has also explored the synthesis of the dioxabicyclic systems 153 by rearrangement of ylides generated from acetals in an intramolecular fashion (Scheme 57).91 In general, the reactions of the diazo ketones 152 were cleaner and higher yielding when the metal carbenoid was generated using copper(II) hexaﬂuoroacetylacetonate rather than rhodium(II) acetate. The presence of an acetal substituent was crucial to the success of the reaction, and none of the expected [1,2] rearrangement products were isolated when unsubstituted acetals (i.e. R1 and R2 H) were employed as substrates.

R1 R1 R2 R2 R2 R1 O O Cu(hfacac)2, O O O + O O ( ) O O n CH2Cl2, reflux H ( )n ( )n N2 152 153a 153b

n = 1 R1 = Ph, R2 =H 94% 14:1

n = 1 R1 = H, R2 = Ph 90% 1:1.2

n = 2 R1 = Ph, R2 =H 96% 1.5:1

Scheme 57

Although the level of diastereocontrol is usually modest, the relative conﬁguration of the acetal 152 dictates the stereochemical outcome of the reaction when copper carbenoids are involved. In contrast, the stereochemistry of the major product 153 appears to be independent of the substrate stereochemistry when a rhodium catalyst is used. West’s results suggest that the reaction involves a stepwise mechanism in which rearrangement occurs through a biradical or ion pair. One of the advantages of generating oxonium ylides from carbenoids is that it is possible to render the reaction enantioselective by using a chiral metal catalyst. The potential of this asymmetric reaction was ﬁrst recognized by Nozaki who showed that it was possible to prepare non-racemic tetrahydrofurans from racemic oxetanes (Scheme 58).92 Treatment of ()-2-phenyloxetane (154, R1 Ph) with the chiral carbenoid generated from reaction of methyl diazoacetate and the chiral copper complex 155 afforded a mixture of the diastereoisomeric tetrahydrofurans 157a and 157b resulting from formal [1,2] benzylic rearrangement. Although the products were obtained in good yield, the level of asymmetric induction was very low (Scheme 58). 37 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 38

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O 1 1 R1 R R CuL*n + OR2 O + O O (CH2Cl2) N2 O O (±) OR2 OR2 154 157a 157b

NPh R1 = Ph R2 = Me 87% ~5% e.e. Cu O 155 2

R1 = Ph R2 = t-Bu 36% (59:41) 75%e.e. 81% e.e. N N R1 = CCPh R2 = t-Bu 88% (1:1) 75% e.e. 71% e.e. CuOTf Me Me Me Me OTBS TBSO 156

Scheme 58 Katsuki later explored reaction of racemic 2-substituted oxetanes catalysed by the chiral copper complex 156 and obtained an ~1:1 mixture of the dia- stereoisomers 157a and 157b, each of which had high enantiomeric purity (Scheme 58).93 These results suggest that one of the diastereotopic lone pairs undergoes selective ylide formation and stereospeciﬁc rearrangement occurs prior to inversion at the oxonium centre, or that the metal complex partici- pates in the rearrangement process and the C–C bond-forming step does not involve a free oxonium ylide. McKervey later demonstrated that it is possible to perform asymmetric tandem intramolecular ylide formation and rearrangement using an achiral substrate and a chiral catalyst (Scheme 59).94 For example, treatment of the diazo ketone 158 with a chiral rhodium(II) complex, prepared from t-butyl glycine, afforded the benzofuranone 159 in excellent yield and with reasonable enantiomeric purity. Lower levels of asymmetric induction were obtained when other substrates or chiral rhodium complexes were employed.

OO O O * OMe Rh2L 4, * OMe L* = O O N ° N O 2 C6H14, 20 C O O 96% 60% e.e. t-Bu 158 159 O

Scheme 59 We have also found that it is possible to prepare non-racemic cyclic ethers by intramolecular asymmetric tandem oxonium ylide formation and [2,3] 38 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 39

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rearrangement (Scheme 60).95 Treatment of the achiral -diazo ketones 160 with 2 mol% of a chiral copper bis-imine complex afforded the non-racemic cyclic ethers 161 with up to 57% e.e. The level of asymmetric induction was found to be variable and highly dependent on both the tether length and the substituent pattern of the substrate. The reactions of benzo-substituted diazo ketones were also investigated, but the levels of asymmetric induction were modest.

Cl NN Cl

O Cl Cl 1 R1 R O R1 R3 R1 (3 mol%) 2 R2 R N2 Cu(MeCN) (2 mol%) O 4 2 O R2 R * CH2Cl2, reflux 54–92% 6–57% e.e. 160R3 R1, R2, R3 = H, Me 161

Scheme 60

The asymmetric generation and rearrangement of oxonium ylides by intramolecular reaction of metal carbenoids with acetals has been explored by Doyle and co-workers.96 They found that treatment of 1,3-dioxan-5-yl diazo acetates with chiral rhodium(II) carboxamidates resulted in asymmetric oxonium ylide formation and rearrangement. For example, exposure of the diazo ester 162 to the chiral catalyst Rh2(MPPIM)4 resulted in stereoselective oxonium ylide formation by reaction of the intermediate rhodium carbenoid with one of the two enantiotopic axial lone pairs (Scheme 61). Subsequent Stevens rearrangement afforded the bridged bicyclic lactone 163 in good yield and with high e.e. In cases where the substrate conformation did not allow the diazo ester group to be positioned in an axial position on the cyclic acetal, the level of asymmetric induction was reduced and C–H insertion was the dominant reaction.

O O O Ph O Me Me N Rh2MPPIM4, O MPPIM = O O N2 Me O Me CH2Cl2, reflux O O N Me CO2Me Me 86% 81% e.e. 162 163

Scheme 61

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J. S. Clark 4. Sulfonium and oxosulfonium ylides Many of the methods commonly used for ammonium and oxonium ylide generation can also be used to prepare sulfur ylides. However, sulfonium ylides are usually easier to prepare than the corresponding ammonium or oxonium ylides because of their enhanced stability resulting from additional d-orbital participation.97 In many cases, sulfonium ylides are stable enough to be isolated and characterized, and rearrangement only occurs at elevated reaction temperatures. Consequently, it is often possible to prepare sulfur ylides in high yield and perform the subsequent addition or rearrangement as a separate reaction.

4.1 Deprotonation of sulfonium and sulfoxonium salts The generation of sulfonium and sulfoxonium ylides by deprotonation of the corresponding salts is a widely used method, and is especially useful when the ylide is stabilized by adjacent functional groups. In one of the earliest examples of base-promoted ylide generation, Ingold and Jessop demonstrated that it was possible to isolate the stabilized sulfonium ylide 165 generated by deprotonation of the salt 164 using an aqueous base (Scheme 62).98 This ylide has also been generated from the perchlorate salt under aprotic conditions and then analysed by low temperature nuclear magnetic resonance (NMR).99

base

S S Me Me X Me Me 164 165

X = Br NH4OH aq. or Ba(OH)2 aq. or NaOH aq., heat

X = ClO4 LiHMDS, THF, –78°C

Scheme 62

The generation of the simple sulfur ylides dimethylsulfoxonium methylide (166) and dimethylsulfonium methylide (167) by direct deprotonation of the corresponding chloride or iodide salt was ﬁrst reported by Corey and Chaykovsky in 1962 (Schemes 63 and 64).100 Dimethylsulfoxonium methylide (166) is a relatively stable ylide, and has a reasonable shelf life when stored at 0°C. In contrast, dimethylsulfonium methylide (167) decomposes readily at room temperature and is usually prepared in situ. Both ylides are efﬁcient methylene transfer agents; dimethylsulfonium methylide (167) is the more powerful of the two. Both ylides are useful reagents for the conversion of aldehydes and ketones into epoxides. 40 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 41

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O NaH, DMSO, rt Me3SOX Me2SCH2 or THF, reflux X = Cl, I 166 Scheme 63

n-BuLi, Me3SMeI 2SCH2 THF, 0°C 167

Scheme 64

Highly functionalized dialkylsulfonium alkylides bearing a variety of substituents (e.g. trialkylsilyl, alkenyl, alkynyl) have been prepared from sulfonium salts in an analogous manner to dimethylsulfonium methylide (167),101 and strong bases are generally required to facilitate deprotonation. Ylides generated in this fashion have been used to prepare epoxides from ketones and aziridines from imines.101b The deprotonation of sulfonium salts bearing a chiral group attached to sulfur has received considerable attention in recent years. The resulting sulfonium ylides have signiﬁcant potential as stoichiometric reagents for the asymmetric synthesis of epoxides and aziridines. For example, Huang and co-workers have introduced a simple procedure for the asymmetric synthesis of epoxides from carbonyl compounds in which preparation of the salt, ylide generation and epoxide formation are accomplished in a single reaction (Scheme 65).102 In this one-pot procedure, the enantiomerically pure chiral sulﬁde 168 is mixed with methyl iodide, potassium hydroxide and a suitable aldehyde. The intermediate ylide 169 reacts with the aldehyde (e.g. benzaldehyde) to afford an epoxide with good e.e.

Me Me Me Me Ph Ph MeI, KOH Me PhCHO S S O OH PhCHO, OH Me Ph MeCN, rt Me Ph 74% e.e. 168 169 87%

Scheme 65

The generation and [2,3] rearrangement reactions of allylic sulfonium ylides have been explored extensively. Alkylation of simple allylic sulﬁdes using Meerwein’s salt affords the corresponding sulfonium tetraﬂuoroborate salts 170 (Scheme 66). In cases where the salt possesses a moderately stabilizing substituent R1 (e.g. aryl or alkenyl), deprotonation can be effected using 41 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 42

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bases such as potassium carbonate, sodium hydride or metal alkoxides.103 In general, [2,3] rearrangement of the sulfonium ylide 171 occurs without the complication of competitive [1,2] rearrangement. Ollis and co-workers and Baldwin and co-workers have explored rearrangement reactions of simple allylic sulfonium ylides generated in this manner as models for the bio- synthetic pathway of squalene.104a,b Kocienski has employed a related reaction to prepare -silyl-substituted sulﬁdes in good yield.104c

R2 [2,3] R3 R2 R2 R2 R1 SEt Et3OBF4 base, rt R3 R3 R3 S S S R2 1 1 1 R R Et BF4 R Et R3 170 171 [1,2] R1 SEt

1 R = Ph, p-ClC6H4, p-O2NC6H4, PhCO base = NaOEt, EtOH 2 R = H, Me, Ph K2CO3, EtOH R3 = H, Me

Scheme 66

It is also possible to prepare allylic sulfonium ylides at low temperature by deprotonation of sulfonium salts generated by the reaction of allylic sulfides with diazonium salts.105 The diazonium salts are prepared by treatment of simple -diazocarbonyl compounds such as ethyl diazoacetate with tetra- fluoroboric acid at –25°C. One of the most widely explored applications of allylic sulfonium ylide rearrangement is for the ring expansion of cyclic sulfides to medium- or large- ring cyclic sulfides. Vedejs and Hagen demonstrated that it is possible to convert 2-vinyl tetrahydrothiophene (172) into the 8-membered cyclic sulfide 174 by alkylation of the sulfide and deprotonation of the resulting sulfonium salt (Scheme 67).106 Upon [2,3] ylide rearrangement, the ring-expanded product 174 was obtained as a mixture of the Z and E isomers, with the former predominating.

O N2 1. Ph HClO4, MeCN 75% S [2,3] S Ph S 2. DBU, ° Ph PhMe, 90 C O O 172 173 174 67% Z 7% E

Scheme 67

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The ring expansion sequence can be repeated several times when allyl- substituted sulfonium salts are employed as substrates (Scheme 68).107 For example, treatment of the cyclic sulfonium salts 175 with an appropriate base results in deprotonation to afford the kinetic ylides 176. Rearrangement with three-carbon ring expansion delivers the cyclic sulfides 178, which possess a suitable vinyl handle for further iterations of the allylation, ylide generation and rearrangement sequence. This ‘ring-growing’ strategy allows sequential conversion of 5- to 8- to 11-, or 6- to 9- to 12-membered cyclic sulfides (e.g. 178180), and has been used to prepare large rings.107a It is necessary to use non-nucleophilic strong bases to deprotonate the salts because conversion of the kinetic ylides 176 into the isomeric ylides 177 can occur when bases such as DBU or potassium hydroxide are used. The ylides 177 undergo [2,3] rearrangement to afford the sulfide products 179 instead of the ring-expanded cyclic sulfides 178.

( )n ( )n ( )n ( )n base [2,3] S S

S S X 175 176 178 180

( )n ( )n [2,3] S S

177 179

X = Br n = 1 KOH, H2O, C5H12, rt 46% 178 (10:1 Z:E, crude) 10% 179

X = OTf n = 2 DBU, MeCN, –20°C 2:1 (178:179) 178 E only

X = OTf n = 2 LDA, THF, –70→65°C 75% 24:1 (178:179) 178 E only

Scheme 68

The stereochemical outcome of the ring expansion reactions of vinyl- substituted cyclic sulfonium salts has been studied extensively. In general, ylides derived from 2-vinyl tetrahydrothiophenes rearrange to provide ring-expanded cyclic sulﬁdes with Z alkene geometry as the major or exclusive products, probably as a result of interconversion between the cis and trans isomers of the salt or ylide.21,108 In the case of ylides derived from 2-vinyl tetrahydro- thiopyrans, such as 181, [2,3] rearrangement occurs to give the E isomer (182-E) exclusively because the orientation of the vinyl group required to give the 43 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 44

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Z isomer (182-Z) would result in poor orbital overlap in the transition state (Scheme 69).22,109 Mixtures of isomers, with the E isomer predominating, are often obtained from the ring-expanding [2,3] rearrangement reactions of larger systems.109

S OEt OEt O S 181 182–E O

S OEt S O

O OEt 182–Z

Scheme 69

Fava and co-workers have explored the preparation and rearrangement of 2-vinyl-substituted cyclic sulfonium ylides in which interconversion between cis and trans isomers is not possible.110 The results of these studies suggest that trans ylides can only react through a transoid transition state, whereas cis ylides can attain both transoid and cisoid transition states. The relative transition state energies of the cis ylides can be assessed by analysis of the ground state energies (implying the involvement of an early reactant-like transition state), and the stereochemical outcome of the reaction is determined by the substituents on the ring or vinyl group. In cases where ylide equilibration is possible (e.g. when a weak base is used to generate the ylide), the ring- expanded product arises largely from the cis ylide. In cases where equilibration is not possible, the product distribution merely reflects the relative proportion of the cis and trans ylides generated initially, and the trans ylide and hence the E product usually predominates. Vedejs and co-workers have applied the ring-expanding [2,3] rearrangement of vinyl-substituted cyclic sulfonium ylides to solve a variety of problems in natural product synthesis.111 The reaction has been used to prepare the 111a C1–C9 fragment of erythronolide A, the core structure of the cycto- chalasans111b and zygosporin A.111c Perhaps the most elegant application of this methodology has been the synthesis of ()-methynolide (Scheme 70).112 In this case, the macrocyclic sulfide 184 was prepared in good yield and with high selectivity for the E isomer by concurrent alkylation of the cyclic sulfide 183, in situ ylide generation and [2,3] rearrangement. Either diastereoisomer of the sulfide 183, or a mixture of both, could be used to generate the sulfonium ylide without markedly altering the product alkene isomer ratio. The resulting macrocycle 184 was then elaborated to the natural product in an efficient manner.112 44 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 45

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Me Me Me O O OTf Me OBn Et OBn OH Me Me Me 2,6-lutidine S Me O S H Me Me Et HO Et O O 183 (1:1) 76% 16:1 184 methynolide

Scheme 70

The rearrangement of sulfonium ylides can be used to perform ring contraction rather than ring expansion. Ollis and co-workers demonstrated the potential of the ring contraction reaction by using it to prepare 2,3-disubstituted tetrahydrothiophenes from dihydrothiopyrans (Scheme 71).18 Treat- ment of the sulfonium salt 185 with a two-phase mixture of aqueous sodium hydroxide and dichloromethane afforded the ylide 186, which then rearranged to give the tetrahydrothiophenes 187a and 187b in a 25:1 ratio, with the thermodynamically less favourable isomer (187a) predominating.18 A two-phase system was used in order to prevent equilibration of the isomeric cyclic sulﬁde products.

NaOH aq., [2,3] S S O + O Ph CH2Cl2, Ph 86% 25:1 S S Ph Ph H2O, 0°C O Br O NaOMe, 185 186 187a 187b MeOH, rt 1:19 Scheme 71

Propargylic sulfonium ylides also undergo [2,3] rearrangement in a manner similar to allylic sulfonium ylides. The resulting allenic products can be isolated in some cases, but further rearrangement to give dienes or alkynes is frequently observed. Baldwin and co-workers demonstrated that the sulfonium salt 189, generated by treatment of the sulﬁde 188 with Meerwein’s salt, undergoes low temperature deprotonation to afford an ylide which then rearranges to give the allene 190 (Scheme 72).113 Others have found that the products arising from isomerization of the allenic product are obtained and that the degree of isomerization is dependent on the substituents present.114 Isomerization of the allenic product to give a diene is particularly favourable in cases where sulfonium ylide rearrangement results in the generation of an allene within a medium-sized ring.115 45 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 46

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Ph Ph n Ph Et3OBF4 -BuLi, S S Et ° Ph Ph –70 C, THF SEt BF4 188189 190

Scheme 72

There are many examples of Sommelet–Hauser rearrangement of base- generated sulfonium ylides. Competitive [1,2] rearrangement of benzylic sulfonium ylides is sometimes problematic, and the product distribution is frequently dependent on factors such as the type of the base used and the concentration of reagents.116 Substituents on the aromatic ring can have a significant influence on the fate of the sulfonium ylide, and electron-donating substituents generally reduce the amount of the Sommelet–Hauser rearrangement product.116 Julia and co-workers have developed a convenient one-pot procedure for sulfonium ylide generation and Sommelet–Hauser rearrangement (Scheme 73).117 For example, generation of the simple sulfonium ylide 191 and Sommelet–Hauser rearrangement was accomplished in one pot by alkylation of benzyl phenyl sulfide with chloromethyl phenyl sulfide in the presence of potassium tert-butoxide. The thioacetal 192 produced by Sommelet–Hauser rearrangement was obtained in good yield using this procedure.

Ph Me SPhPhSCH2Cl, S [2,3] t-BuOK, SPh SPh ° THF, –10 C 70% SPh 191 192

Scheme 73

Examples of related Sommelet–Hauser reactions have been reported by others, and sequential Sommelet–Hauser reactions of benzylic sulfonium ylides have been used to prepare polysubstituted aromatic systems.118 The Sommelet–Hauser reactions of sulfonium ylides derived from furans have also been explored in detail.118 Chirality transfer from sulfur to carbon during the rearrangement of base- generated sulfonium ylides that are chiral at sulfur is possible. In an early study concerning chirality transfer from sulfur to carbon during ylide rearrangement, Trost explored the [2,3] rearrangement of the sulfonium ylide prepared by deprotonation of the enantiomerically pure sulfonium salt 193 (Scheme 74).119 The enantiomeric purity of the rearrangement product 46 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 47

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194 was judged to be 94% e.e., which conﬁrmed that there was substantial preservation of stereochemical integrity during the [2,3] rearrangement reaction.

Me Me t-BuOK, t-BuOH, S BF4 S + SEt * C6H6, –33°C ~100% e.e. 74% 94% e.e. 17% 193 194

Scheme 74

Chirality transfer from sulfur to carbon during the Sommelet–Hauser rearrangement of chiral benzylic sulfonium ylides has also been investigated (Scheme 75).120 Significant erosion of stereochemical integrity was encountered upon [2,3] rearrangement of the sulfonium ylides generated by deprotonation of the chiral sulfonium salts 195. The sulfides 197 were obtained with low enantiomeric excesses, and significant amounts of the achiral sulfides 196 were also obtained by [2,3] rearrangement of the regioisomeric ylides.

X X

base + Me Me ClO4 S * * Me Me Me SEt SMe 195 196 197

X = NO2 OH (ion exchange resin) 12% 33% 18–20% e.e.

X = Cl NaOMe, MeOH, 70°C 94% (1:4.2) 21–24% e.e.

Scheme 75

4.2 Desilylation of -silyl sulfonium salts The generation of sulfonium ylides by desilylation of -silyl sulfonium salts can be accomplished in an analogous fashion to the generation of ammonium ylides (see Chapter 2.4).32 Treatment of simple disulfides with (trimethylsilyl)- methyl triflate affords the isolable sulfonium triflate salts 198 which can be converted into the corresponding ylides by treatment with caesium fluoride (Scheme 76).121 The sulfonium ylides can be trapped with various aldehydes to provide the epoxides 199 in variable yield. Although the yields of the epoxides are often slightly lower than those obtained using the base-generated method, ylide generation by desilylation of -silyl sulfonium salts has the advantage that base-sensitive substrates can be employed in the reaction. 47 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 48

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SiMe3 2 3 O Me3SiCH2OTf, CsF, R R CHO S S 3 30–94% R1 R1 R1 R1 OTf R Et2O, rt DMSO, rt R2 198 199 R1 = Me, Ph R1 = Me 100% R2, R3 = H, aryl, cycloalkyl

R1 = Ph 73%

Scheme 76

Desilylation of allylic -silyl sulfonium salts usually results in ylide generation followed by immediate [2,3] rearrangement. For example, conversion of the allylic sulfide 200 into the sulfonium triflate 201 and subsequent treatment of the salt with caesium fluoride results in ylide formation and immediate [2,3] rearrangement to give the sulfide 202 (Scheme 77).122 A significant amount of the minor product 203 is also produced by [2,3] rearrangement of the alternative sulfonium ylide formed by equilibration of the initially formed ylide.

OEt S OEt Me SiCH OTf, OEt S 3 2 S CsF 81% O 202 O MeCN, 20°C O Ph Ph Ph SiMe3 OTf 200 201 OEt MeS 9% O 203 Scheme 77

The [2,3] rearrangement of allylic sulfonium ylides generated by desilylation of -silyl sulfonium salts has been exploited in natural product synthesis. For example, Cohen and co-workers used the reaction to convert the simple allylic sulﬁde 204 into the -methylene cyclopentanone 205, and this compound was then transformed in the anti-tumour agent sarkomycin (Scheme 78).123

O (i) Me3SiCH2OTf, O O MeCN, rt SPh (ii) CsF, PhCHO, rt one pot SPh OH O 204 205 sarkomycin

Scheme 78

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Sulfonium ylides generated by desilylation of benzylic -silyl sulfonium salts undergo Sommelet–Hauser rearrangement in an analogous fashion to the corresponding ammonium ylides (see Chapter 2.4).124 The reaction has been used to good effect in order to accomplish ring expansion of cyclic sulfides. Padwa and co-workers found that treatment of the cyclic sulfides 206 with (trimethylsilyl)methyl triflate affords the salts 207 with trans arrangement of the ring substituents in a highly diastereoselective manner (Scheme 79).125 Subsequent exposure of the triflates 207 to caesium fluoride resulted in Sommelet–Hauser rearrangement to provide the ring-expanded cyclic sulfides 208 as the major products. The product yields were found to be sensitive to the reaction conditions and dependent on the substituent (R) attached to the aryl ring participating in the Sommelet–Hauser reaction. The highest yields were obtained from substrates possessing an electron-withdrawing substituent.

OTf S S S Me3SiCH2OTf, CsF, DMSO, rt

Et2O, rt SiMe3

R R R = H, MeO, Cl, CF3 R 96:4→100:0 15–90% 206 207 208

Scheme 79

4.3 From carbenes generated thermally or photochemically The generation of sulfonium ylides from free carbenes is plagued by the same problems of multiple by-product formation and low yields that are encountered when attempting to prepare ammonium and oxonium ylides in this manner. However, although other methods for sulfonium ylide generation are generally superior, there have been several notable cases in which free carbenes have been used to prepare sulfonium ylides in respectable yield (see Chapter 2.6). Evans and Andrews demonstrated that it was possible to construct a quaternary centre in a diastereoselective manner by [2,3] rearrangement of an exocyclic allylic sulfonium ylide generated from a free carbene (Scheme 80).126 Treatment of the allylic sulﬁde 209 with dichlorocarbene, generated by reaction of chloroform with aqueous base, afforded the sulfonium ylide 210. Rearrangement of the ylide proceeded in a highly diastereoselective manner to provide the thioesters 211a and 211b in a 97:3 ratio after exposure of the initially formed dichlorides to silica gel.

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SPh Ph S

CCl2 CHCl3, NaOH aq., Triton B cat. t-Bu t-Bu 209 210

[2,3]

OO Cl Cl Cl Cl SPh SPh SPh SPh SiO + 2 +

t-Bu t-Bu t-Bu t-Bu 211a53% 97:3 211b

Scheme 80

The intermolecular and intramolecular generation of sulfonium and oxosulfonium ylides by photolysis of diazo compounds in the presence of sulfides has been studied extensively by Ando and co-workers (see Chapters 2.6 and 2.7).127 Sulfonium ylides generated from cyclic allylic sulfides usually undergo [2,3] rearrangement with one-carbon ring contraction. For example, photolysis of dimethyl diazomalonate in the presence of 5,6-dihydrothiapyran provides the stable sulfonium ylide 212 and thermolysis of this ylide results in efficient rearrangement to give the vinyl-substituted tetrahydrothiophene 213 (Scheme 81).127a In cases where [2,3] rearrangement is not possible, it is usually possible to isolate the sulfonium ylides derived from carbenes generated from diazo compounds.127b Stable sulfonium ylides generated in this manner generally will undergo Stevens rearrangement or Hofmann elimination at elevated temperatures.

MeO CCOMe hν [2,3] + 2 2 S ° CO2Me S 180 C S N2 CO2Me MeO2CCO2Me 46% 83% 212 213

Scheme 81

Sulfonium ylide generation can be accomplished by intramolecular trapping of a sulﬁde with a carbene produced by photolysis of the sodium salt of an N-tosylhydrazone (Scheme 82).128 For example, photolysis of the N-tosyl- 50 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 51

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hydrazone salt 214 produces the strained cyclic ylide 215 which undergoes direct [2,3] rearrangement to give an isomeric mixture of the thietanes 216 or equilibration to give the sulfonium ylide 217. Subsequent [2,3] rearrangement of the ylide 217 produces the tetrahydrothiophene 218 as a mixture of dia- stereoisomers.

Me Me Me Me S monoglyme, Me [2,3] S Me Me S hν, 10°C Me N Ph Ph MePh Na NTs 215 216 25% (56:44) 214

Ph Me Me [2,3] Me S Me Me S Ph Me 217 218 33% (60:40)

Scheme 82

4.4 From catalytically generated metal carbenoids The reaction of a sulfide with a metal carbenoid is one of the most general methods for sulfonium ylide generation (see Chapters 2.5 and 2.6). The reaction has received considerable attention in recent years, and has the advantage that the mild conditions enable stable sulfonium ylides to be isolated. In an early example of allylic sulfonium ylide generation from a metal carbenoid, Grieco and co-workers explored the reaction of a copper carbenoid with allylic sulfides (Scheme 83).129 Reaction of methyl diazomalonate with simple allylic sulfides such as 219 in the presence of copper(II) sulfate afforded the sulfonium ylides 220, which then underwent immediate [2,3] rearrangement at the elevated reaction temperature employed. The resulting alkenes 221 were produced as mixtures of isomers, with the E-isomer predominating.

Scheme 83

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Doyle and co-workers showed that allylic sulfonium ylides can be prepared in high yield at lower temperatures by treatment of simple allylic sulfides with carbenoids generated by treatment of ethyl diazoacetate with rhodium(II) acetate or a rhodium carbonyl complex.130 The reaction has proven to be very useful for the preparation of trifluoromethyl-substituted compounds; treatment of a simple allylic sulfide with ethyl trifluorodiazopropionate in the presence rhodium(II) acetate at 65°C results in sulfonium ylide for-mation and immediate [2,3] rearrangement to give an -trifluoromethyl sulfide.131 Sulfonium ylides generated from metal carbenoids have found numerous uses in target-directed synthesis. The reaction has been used to introduce further functionality into -lactams. For example, Thomas and co-workers were able to functionalize the -lactam nucleus by treatment of the diazo penicillin 222 with copper(II) acetate in the presence of a variety of simple allylic sulfides (Scheme 84).132 The resulting penicillins 223 were produced with reasonable levels of diastereocontrol and possessed a sulfide group and allylic side chain suitable for further elaboration to give a variety of penicillin analogues.

2 N H R S H 2 2 S Me R S S Me

N Me Cu(acac)2, N Me O O 1 CH Cl , reflux 1 222CO2R 2 2 223 CO2R

1 2 R = CH2CCl3, CH2Ph R = Me, Ph 60–65% 80:20→87:13 Scheme 84

The reaction has also been used in an ingenious manner for the conversion of cephalosporins into penicillins (Scheme 85).133 Treatment of the cephalosporins 224 with the copper carbenoid generated by reaction of ethyl diazoacetate with copper powder delivered the novel penicillins 225 by one-carbon ring contraction upon rearrangement of the intermediate cyclic sulfonium ylides. Although yields are modest and an excess of the cephalosporin is required, the reaction offers rapid access to a novel class of penicillins.

O O O Ph Ph H H OEt H H N S N S H N2 H H

N Cu powder, N CO2Et O Me O xylene, 130°C CO2R 224CO R 225 2 Me R = Me, Bn, CH2Cl3 R = Me 53% (50% consumption) Scheme 85

The catalytic generation of sulfonium ylides by treatment of chiral sulﬁdes with copper carbenoids has been used by Aggarwal as the basis of a powerful 52 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 53

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catalytic method for the asymmetric synthesis of epoxides (Scheme 86).134 Reaction of the camphor-derived sulfide 226 with phenyldiazomethane in the presence of copper(II) acetylacetonate affords the sulfonium ylide 227. The ylide then reacts with a suitable aldehyde such as benzaldehyde to provide the epoxide in an enantioselective manner. The sulfide 226 is regenerated after epoxidation and so only substoichiometric amounts of both the sulfide and copper catalyst are required.

Me Me Me Me O PhCHN2, PhCHO Ph S O Cu(acac) S O Ph Me 2 Me Ph 71% 93% e.e. 226 227 226

Scheme 86

In many cases, it is possible to generate a stable sulfonium ylide from a metal carbenoid and perform rearrangement in a subsequent reaction (see Chapter 2.5). Davies135 and Moody136 have shown that stable cyclic sulfonium ylides 229 can be prepared by intramolecular reaction of rhodium carbenoids generated from the diazocarbonyl-tethered sulfides 228 (Scheme 87). In cases where [2,3] rearrangement is not possible, the sulfonium ylides are isolable and [1,2] rearrangement can be accomplished by heating them at 160°C in xylene.135 Allylic sulfonium ylides usually undergo immediate [2,3] rearrangement to give the cyclic sulfides 230 when generated in benzene at reflux.136

OO O O O O OEt ( )n OEt Rh2(OAc)4, [2,3] or [1,2] ( )n ( )n OEt R N2 CH Cl or C H , xylene, reflux SR 2 2 6 6 S S reflux R 228 229 230

n = 0–3 [1,2] 24–69% R = Et, Ph, PhCH2, CH2CHCH2, CH2CHCMe2, [2,3] 59–78% E-CH2CHCHPh, Z-CH2CHCHPh

Scheme 87

The generation of sulfonium ylides by the reaction of dithioacetals with metal carbenoids has also been explored by Doyle and co-workers and by Nickon and co-workers.137,138 Vinyl-substituted 1,3-dithianes and 1,3-dithio- lanes react with rhodium137 or copper138 carbenoids generated from diazo- acetates and diazomalonates to give ring-expanded products, arising from [2,3] rearrangement of the intermediate sulfonium ylide, and elimination products. 53 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 54

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Products arising from [1,2] rearrangement are not usually isolated from these reactions. Kido and co-workers have studied the generation of cyclic allylic sulfonium ylides which can undergo [2,3] rearrangement with either ring expansion or contraction to provide lactones or cyclic ketones.139,140 For example, treatment of the diazomalonates 231 with rhodium(II) acetate affords the sulfonium ylides 232 by intramolecular reaction of the sulﬁde with the intermediate rhodium carbenoid (Scheme 88).139b The ylides 232 then undergo [2,3] rearrangement with one-atom ring expansion to provide the lactones 233.

3 PhS R1 EtO O R SPh R2 O OEt R2 CO2Et ( )n Rh2(OAc)4, Ph O [2,3] S O 3 O C6H6, reflux 1 R N2 O R ( )nO R3 ( )n O R1 R2 231 232 233

n = 1,2 n = 1 49–63% R1 = H, Bn R1, R2, R3 = H n = 2 19% 2 3 R , R = H, Me, –(CH2)3–, –(CH2)4–

Scheme 88

Allylic diazomalonates 234 bearing an allylic sulﬁde appendage with the sulfur substituent at the terminal position, react with rhodium(II) acetate to give the medium-ring cyclic sulfonium ylides 235 (Scheme 89). Subsequent [2,3] rearrangement with three-atom ring contraction delivers the vinyl- substituted lactones 236 in good yield.139a,c

Ph SPh S SPh N2 Rh2(OAc)4, [2,3] CO2Et ( )n CO2Et ( )n O OEt ( )n O C6H6, reflux R OO R O O R O 234 235 236

n = 0,1 n = 0 52–68% R = H, n-Pr, i-Pr, n-Bu, Bn n = 1 65–74% ~3:1 (–R)

Scheme 89

An analogous reaction can be used to prepare carbocycles rather than lactones,140 and Kido and co-workers have applied this procedure to the synthesis of the spirocyclic natural product acorenone B (Scheme 90).141 Treatment of the diazo substrate 237 with rhodium(II) acetate in benzene at reﬂux 54 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 55

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afforded the spirocyclic sulﬁde 238 as a single diastereoisomer by formation of a medium-ring cyclic sulfonium ylide from the intermediate carbenoid and immediate [2,3] rearrangement with ring contraction. The sulﬁde 238 was then converted into the natural product.141 Ph S Me SPh O CO2Et O O N Rh2(OAc)4, 2 OEt C6H6, reflux Me Me Me Me Me O 72% Me Me 237 238 (+)-acorenone B Scheme 90

4.5 Miscellaneous methods There are a variety of synthetically useful but less widely employed methods for sulfonium ylide generation. In most cases, they are less generally applicable than those described previously but have specific applicability. Ollis and co-workers have explored the preparation of sulfonium ylides by the reaction of sulfides with benzyne. In order to establish the possible intermediacy of sulfonium ylides in the biosynthesis of squalene, these workers investigated the rearrangement of the ylide generated by reaction of the doubly allylic sulfide 239 with benzyne generated from o-fluorophenylmagnesium bromide (Scheme 91).142 The resulting sulfonium ylide 240 underwent immediate [2,3] rearrangement through the pendant vinyl group to afford the sulfide 241. The sulfide product was then converted into squalene by reduction with sodium in liquid ammonia.

Me Me Me Me Me Me

Me S Me 239

Me Me Me Me Me Me

Me S Me

240

[2,3]

Me Me Me SPh Me Me 241 Me Me Me

Scheme 91

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Several procedures are available for the preparation of sulfur ylides directly from alkynes. For example, Julia and co-workers have shown that it is possible to produce allenic sulfonium ylides by reaction of allylic sulfides with carbenoids generated from -chloro lithium acetylides.143 Stable allenic sulfides are obtained upon [2,3] rearrangement of the sulfonium ylides generated in this manner. The sequence has been used by Julia to prepare the natural product artemisia ketone.143 Hoye144 and Padwa87b have shown that it is possible to prepare sulfonium ylides by intermolecular or intramolecular reaction of sulfides with vinyl carbenoids generated by intramolecular addition of metal carbenoids to alkynes. Subsequent [2,3] sigmatropic rearrangement occurs when allylic sulfides are used as ylide precursors. Stable sulfonium ylides are accessible by the addition of simple sulfoxides to activated alkynes such as DMAD.145 Chow and co-workers prepared a variety of stabilized sulfur ylides 243 in his manner (Scheme 92).145 In this reaction, the presumed intermediate (242) underwent immediate rearrangement and was not isolated.

O R MeO2C R S R S O R R R SO

C6H6, reflux 10–65% MeO C CO Me MeO C CO Me 2 2 MeO2C 2 2 R = Me, Bn, n-Bu, Ph 242 243

Scheme 92

Ide and Kishida have shown that it is possible to prepare stable sulfoxonium ylides 245 by addition of a simple sulfoxonium ylides such as dimethylsulfoxonium methylide to the conjugated alkynes 244 (Scheme 93).146 The sulfoxonium ylides 245 were isolated in good yield, and the nature of the aromatic group had little inﬂuence on the outcome of the reaction. However, other alkynes either failed to react with sulfoxonium ylides or underwent reaction to give unstable ylides that could not be isolated. Thus, the route is not an entirely general one and seems to be restricted to a limited number of activated alkyne substrates. O

S Ar H Me CH Me 2 XC6H4 CO2Et CO2Et DMSO S O X = H, p-Me, p-MeO, o-Cl, m-Cl, p-ClMe Me 62–100% 244 245

Scheme 93

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1: Nitrogen, oxygen and sulfur ylides: an overview 5. Azomethine ylides The generation and reaction of azomethine ylides has received considerable attention and continues to be a very active area of research. The synthetic importance of azomethine ylides stems mainly from their use for the preparation of 5-membered nitrogen heterocycles, which are ubiquitous in nature and often found as subunits of bioactive natural products. Cycloaddition of an azomethine ylide to a suitable dipolarophile (usually an electron-deﬁcient alkene) results in formation of a 5-membered nitrogen-containing heterocycle (Scheme 94). Cycloaddition reactions of azomethine ylides are often highly stereoselective and consequently allow efﬁcient access to single diastereo- isomers of highly functionalized pyrrolidines and related heterocycles.

N N

X X X = CR2, O, NR etc.

Scheme 94

There are many methods for the preparation of stabilized azomethine ylides, in which an adjacent electron-withdrawing group is present, and non- stabilized azomethine ylides. The following discussion will focus on the most general and reliable methods commonly used for the generation of azomethine ylides.

5.1 Deprotonation of iminium salts One of the most obvious methods for the preparation of an azomethine ylide involves the direct deprotonation of an iminium salt with a suitable base. In general, an electron-withdrawing substituent is required to facilitate deprotonation, and so the method is usually restricted to the preparation of stabilized azomethine ylides. A typical example of the generation of a stabilized azomethine ylide by deprotonation of an iminium salt is that shown in Scheme 95.147 In this case, deprotonation of the dihydroisoquinolinium salt 246, in the presence of 2-phenylazirine, afforded the ylide 247 which underwent immediate cycloaddition with the azirine dipolarophile to give a mixture of the exo product 248a and endo isomer 248b in modest yield. The product distribution indicates that the cycloaddition reaction proceeds via the azomethine ylide 247b rather than the isomeric ylide 247a. Iminium salts derived from other partially reduced aromatic nitrogen heterocycles can be converted to stabilized azomethine in an analogous manner.148, 149 57 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 58

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N MeO MeO Ph

N Br CaCO , CH Cl , rt N CO2Et MeO 3 2 2 MeO

246CO2Et 247a

MeO

N MeO CO Et H 2 N N Ph MeO 248a Ph + N MeO 41% 1:1.9 MeO 247b N CO2Et MeO CO Et H 2 N 248b Ph Scheme 95

Vedejs and co-workers have studied the generation of related stabilized azomethine ylides from simple acyclic imines and obtained direct spectroscopic evidence of dipole formation (Scheme 96).150 Treatment of the imine 249 with the triflate derived from ethyl glycolate afforded the iminium triflate 250. The ylide 251, which was identified by UV spectroscopy, was generated by deprotonation of the iminium salt using potassium t-butoxide. In the presence of the reactive dipolarophile DMAD, the stabilized azomethine ylide was trapped to give the dihydropyrrole 252. Upon slow addition of a cold solution of the ylide to toluene at 100°C in the absence of a dipolarophile, electrocyclic ring-closure occurred and the aziridine 253 was obtained in good yield (Scheme 96).

DMAD, –70°C EtO2C CO2Et

Ph CO Et CO Et CO2Et 2 2 Ph N TfO CO2Et t-BuOK, THF Ph N Ph N Ph N Me 87% Me >90% Me –78°C Me 252 Ph Ph TfO Ph 249 250 251 Ph H

PhMe, pyridine, PhN CO2Et 100°C Me 78% 253

Scheme 96

Cycloaddition reactions of azomethine ylides generated by deprotonation of iminium salts have been exploited in natural product synthesis. Williams 58 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 59

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and Flanagan were able to gain rapid access to the core structure of quino- carcin by reaction of methyl acrylate with the azomethine ylide 256 (Scheme 97).151 The ylide was formed by deprotonation of the cyclic iminium salt 255, which was generated from the amine 254 in situ. The cycloaddition reaction was regioselective and diastereoselective, affording the major adduct 257a and the minor adduct 257b in reasonable yield.

Me Me N NBS, CHCl3, reflux N N N Br

MeO O MeO O 254OH 255 OH

CO2Me CO2Me Me Et N, CHCl , 0°C N 3 3 N Me MeO O N 257a OH CO Me 2 N + CO2Me 55%, ~5:1 MeO O Me 256 N OH N

MeO O 257b OH

Scheme 97

The deprotonation of iminium salts is a particularly attractive method for the preparation of azomethine ylides derived from aromatic nitrogen heterocycles. Azomethine ylides derived from pyridines,152 isoquinolines,152 phenan- thridines,153 benzothiazoles154 and pyrrolodiazines155 have been prepared by N-alkylation of the parent heterocycle with an -halo carbonyl compound and deprotonation of the resulting aromatic iminium salt.

5.2 1,2 Prototropic shifts of imines One of the simplest methods of generating a stabilized azomethine ylide is by the 1,2 prototropic shift of an imine generated upon condensation of an aldehyde or ketone with a primary -amino carbonyl compound. The sim- plicity of the method makes it an attractive one for the preparation of simple stabilized azomethine ylides, and there have been many examples of its use. For example, Grigg and co-workers showed that it was possible to generate a viable amount of the azomethine ylide tautomer 259 by heating the simple imine 258 at reﬂux in toluene (Scheme 98).156 In the presence of the reactive dipolarophile N-phenylmaleimide, the azomethine ylide 259 underwent cycloaddition to give the cycloaddition products 260. 59 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 60

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H O O N N CO2Me R1 H O R2 1 PhMe, reflux 1 Ph R NCO2Me R N H H 1,2 shift OMe R2 R2 O N O Ph 258 259 260

Scheme 98

Many imines have been used as precursors for this reaction, and the azomethine ylides produced by 1,2 prototropy react with a wide range of reactive dipolarophiles. The process is particularly favourable when the substrate possesses additional groups capable of stabilizing the ylide by hydrogen bond- ing.157 The 1,2 prototropic shift reaction has also been used to prepare azomethine ylides from solid-supported aldimines.158 Cyclic azomethine ylides can be prepared by 1,2 prototropic shifts of cyclic imines, and they undergo cycloaddition to afford bridged bicyclic systems.159 For example, the dihydroisoquinolines 260 tautomerize to give the stabilized azomethine ylides 261 when heated in toluene (Scheme 99).159a The ylides 261 undergo cycloaddition with dimethylfumarate to afford the bridged bicyclic compounds 262 in reasonable yield.

MeO CO Me MeO CO Me 2 PhMe, reflux 2 N 1,2 shift N MeO MeO H 260R 261 R

R = H, Me, Ph CO2Me

MeO2C H N MeO2C CO2Me

R CO2Me 262 49–70%

Scheme 99

The generation of an azomethine ylide by a 1,2 prototropic hydrogen shift is not restricted to imines. Bazureau and co-workers have shown that imidates derived from -amino esters also undergo thermal rearrangement.160 The resulting azomethine ylides undergo cycloaddition with a variety of dipolarophiles to give heterocyclic products. 60 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 61

1: Nitrogen, oxygen and sulfur ylides: an overview 5.3 Condensation of aldehydes and ketones with secondary -amino carbonyl compounds The direct generation of stabilized azomethine ylides by the condensation of carbonyl compounds with secondary -amino carbonyl compounds has become a popular method, and is closely related to the foregoing methods of azomethine ylide generation (see Chapter 3.3). Tsuge and co-workers have investigated the generation and reaction of ester-stabilized azomethine ylides by condensation of aldehydes with simple secondary -amino esters such as sarcosine ethyl ester (Scheme 100).161 In this case, the azomethine ylide 264, generated from the presumed intermediate iminium ion 263, undergoes efﬁcient cycloaddition with N-phenylmaleimide to give two of the four possible cycloaddition products 265a–d.161c It transpired that the major products (265a and 265b) were those arising from exo or endo cycloaddition of the anti form of ylide 264, which is favoured due to stabiliza- tion of the 1,5-dipolar interaction between the ester carbonyl group and the carbon atom of the ylide.

O N O H Ph RNCOEt RNCOEt NCO2Et 2 2 Me RCHO, PhMe, Me Me R = H, Me, Et, Ph reflux (–H O) syn/anti 2 263 264

Me Me Me Me N N N N R CO2Et R CO2Et R CO2Et R CO2Et H H ++H H H H H H

O N O O N O O N O O N O 66–93% Ph Ph Ph Ph endo:exo ~3:1 anti, endo anti, exosyn, endo syn, exo anti:syn >95:5 265a 265b 265c 265d

Scheme 100

Joucla and co-workers162 and others163 have shown that the method can be used to prepare a variety of substituted N-substituted pyrrolidines. They found that the pyrrolidine 267 could be prepared stereoselectively and in good yield by the condensation of N-benzylglycine methyl ester with benzaldehyde in the presence dimethylmaleate (Scheme 101).162 The stereochemistry of the cycloaddition adduct 267 was elucidated by X-ray crystallography, and this proved that the reaction proceeded by endo cycloaddition of the dienophile to the anti ylide 266, a ﬁnding which is consistent with the results of Tsuge.161c 61 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 62

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MeO2C CO2Me CO2Me H MeO2CCO2Me NCO2Me Ph N Ph CO Me PhCHO, PhMe, N 2 Ph reflux (–H2O) Ph Ph 75% 266 267

Scheme 101

The preparation of bicyclic and polycyclic systems has been accomplished by condensation of secondary amines bearing a stabilizing group with aldehydes that are tethered to a suitable dipolarophile. In these cases, intermolecular azomethine ylide formation is followed immediately by intramolecular cycloaddition, and two rings are constructed concurrently.164 Another approach to the preparation of polycyclic systems involves the use of cyclic amines bearing an electron-withdrawing group at one of the sites adjacent to nitrogen. The most commonly used substrates are esters of the simple cyclic amino acids proline and pipecolinic acid,162,165 or tetrahydro- isoquinoline carboxylic acid esters.166 In these cyclic cases, the number of possible azomethine ylide isomers is reduced from four to two. The groups of Harwood,167 Williams168 and Laude169 have used cyclic azomethine ylides derived from the condensation of aldehydes with enantiomerically pure morpholinones in order to prepare highly functionalized pyrrolidines. Treatment of the amino acid-derived morpholinones 268 with formaldehyde affords the azomethine ylides 269 which undergo cycloaddition with N-phenylmaleimide to give the tricyclic products 270a and 270b, with the former (endo) isomer predominating (Scheme 102).167a A wide variety of other reactive dipolarophiles can be used, and the endo isomer is favoured in each case. Many other aldehydes can be employed to generate azomethine ylides from morpholinones, and the generation of analogous ylides from

O H Ph N Ph N H O O H O N R Ph N R Ph N R Ph O O 270a endo + O (HCHO)n, O O O O H Ph 268 C6H6, reflux 269 N endo exo Ph N H O R = H 45% 13% R R = i-Pr 34% 7% O O 270b exo

Scheme 102

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imidazolidinones has also been explored.170 Harwood and co-workers have also explored the intramolecular trapping of azomethine ylides generated by the reaction of morpholinones with aldehydes which are tethered to dipolarophiles.167b

5.4 Desilylation reactions Desilylation of an -silyl imine/iminium compound or an -silyl amine bearing a good leaving group is one of the most popular methods for the generation of non-stabilized azomethine ylides. There are several simple protocols starting from both imines and amines. The desilylation of an -silyl amine bearing an appropriate leaving group (usually CN or OMe) can be readily accomplished and the resulting non- stabilized ylide can be trapped with a variety of dipolarophiles to produce highly functionalized pyrrolidines. For example, Padwa and co-workers have demonstrated that the simple azomethine ylide 272 can be generated by treatment of the -silyl amines 271a171a or 271b171b with ﬂuoride ion (Scheme 103). Trapping of the ylide with N-phenylmaleimide delivers the adduct 273, and a variety of other dipolarophiles can also be used.172 The procedure has also been adapted for the generation of several other simple non-stabilized azomethine ylides.173

Ph O O N O N O Ph XNSiMe3 N H H

Ph Ph N

271 272 273 Ph a X = CN AgF, MeCN, rt 84% b X = OMeLiF, MeCN, ultrasound, rt 75%

Scheme 103

Pandey and co-workers have shown that cyclic non-stabilized azomethine ylides can be generated and trapped in a highly efﬁcient manner by treatment of cyclic ,-bis(trimethylsilylmethyl)amines with silver(I) ﬂuoride in the presence of a dipolarophile.174 The reaction has been used to prepare alkaloids such as ()-epibatidine,174a ()-retronecine,174b ()-trachelantha- mine,174c ()-isoretronecol174c and ()-tashiromine.174c The same group of workers has also explored a complementary method of non-stabilized azomethine ylide generation in which sequential two-electron oxidative double desilylation of ,-bis(trimethylsilylmethyl)alkylamines is performed under photochemical conditions using a sensitizer (see Chapter 3.2). Non-stabilized azomethine ylides can also be generated by acid-mediated desilylation of -silyl amines bearing an appropriate leaving group (Scheme 63 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 64

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104). Triﬂuoroacetic acid is a strong enough acid to initiate the reaction, and is usually the reagent of choice. Studies involving the speciﬁcally 13C-labelled (*) precursor 274 have demonstrated that the free non-stabilized ylide 275 is generated during the reaction because a 1:1 mixture of the two possible labelled cycloaddition products 276a/b is produced (Scheme 104).175

O O O O SiMe3 * O O * CF3CO2H, MeO N N H H + H H CH Cl , rt 2 2 * * * = 13C Ph Ph N N

274 275 276a Ph 276b Ph

Scheme 104

Simple non-stabilized azomethine ylides generated by the acid-mediated reaction of -silyl amines bearing an appropriate leaving group have been used to prepare a variety of enantiomerically pure pyrrolidines from various chiral dipolarophiles.176 The acid-mediated reaction is particularly useful for the preparation of triﬂuoromethyl-substituted pyrrolidines from highly reactive triﬂuoromethyl alkenes.177 Desilylation of N-(silylmethyl)imines can be used to generate reactive intermediates which function as azomethine ylide equivalents. Tsuge and co- workers have shown that it is possible to generate non-stabilized ylides by exposure of simple N-(silylmethyl)imines such as 277 to water (Scheme 105).178 In this case, the diastereoisomeric bicyclic compounds 278a and 278b were obtained when N-methylmaleimide was employed as the dipolarophile.178

H H O O N N Ph N Ph Me Ph N SiMe3 H HH+ H HMPA, H2O, rt, 24 h O N O O N O Me Me 277 100% (2:1) 278a 278b

Scheme 105

Although azomethine ylide equivalents can be generated by desilylation of N-(silylmethyl)imines, the more reactive iminium compounds are generally employed. The most common method used for the preparation of the iminium intermediates involves alkylation of an imine with (trimethylsilyl)methyl triﬂate. Subsequent treatment with ﬂuoride ion then delivers the reactive non-stabilized azomethine ylide which can be trapped with an appropriate 64 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 65

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dipolarophile.179,180 This is a particularly useful method for generating azomethine ylides from aromatic heterocycles such as pyridines, quinolines, isoquinolines and -carbolines,179 or their partially reduced derivatives. For example, Fishwick and co-workers prepared the isolable iminium salt 280 by treatment of the imine 279 with (trimethylsilyl)methyl triﬂate (Scheme 106). Treatment of the salt with ﬂuoride ion in the presence of DMAD afforded the tricyclic amine 281 in good yield.180a A variety of other dipolarophiles were also used to trap the azomethine ylide in situ.

Me Me Me Me Me Me Me SiCH OTf CsF, DMAD, 3 2 Me CH Cl , rt MeCN, 60°C N Me 2 2 N Me N CO2Me

Me3Si OTf 75% CO Me 279 280 281 2

Scheme 106

Several alternative methods for the preparation of N-(silylmethyl)iminium systems are available. One of the most convenient approaches involves direct O-alkylation of an N-(silylmethyl)amide, S-alkylation of an N-(silylmethyl) thioamide or N-alkylation of an N-(silylmethyl)amidine using a reagent such as methyl triﬂate, trimethylsilyl triﬂate or Meerwein’s salt.181

5.5 Ring opening of aziridines The inherent ring strain of aziridines means that they can be converted into azomethine ylides under appropriate conditions. Aziridines can be ring opened using photochemical methods or by thermolysis, and the resulting azomethine ylides can be trapped in an intermolecular or intramolecular fashion. In general, the method is best used for the generation of stabilized azomethine ylides from aziridines bearing one or more carbonyl substituents. In 1965, Heine and Peavy discovered that 1,2,3-triphenylaziridine undergoes ring opening to give an azomethine ylide when heated in p-xylene at reﬂux.182 They were able to trap the dipole with a variety of simple dipolarophiles. Huisgen and co-workers then demonstrated that an equilibrium is established between aziridines and azomethine ylides at high temperature and that the geometry of the azomethine ylide is dependent on the relative conﬁg- uration of stereogenic centres in the aziridine as a consequence of conrotatory ring opening (Scheme 107).183 They demonstrated that the trans-disubstituted aziridine 282a opens to give the azomethine ylide 283a, whereas the cis isomer 282b affords the isomeric ylide 283b. Huisgen and co-workers also discovered that interconversion between isomeric azomethine ylides is possible but that each azomethine ylide can be intercepted before equilibration when a highly reactive dipolarophile such as DMAD is present (Scheme 107). In these cases, the distribution of isomeric cycloaddition products such as 284a and 284b is 65 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 66

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dependent on the relative conﬁguration and stereochemical integrity of the aziridine.183

Ar Ar N N H CO2Me H H MeO C H MeO C CO Me 2 282a 2 282b 2

>100°C >100°C

Ar Ar

MeO2C N CO2Me MeO2C N H

HH HCO2Me 283a 283b

DMAD DMAD

Ar Ar N N MeO2C CO2Me MeO2C CO2Me

MeO2CCO2Me MeO2CCO2Me 284a 284b

Scheme 107

The generation of stabilized azomethine ylides from aziridines and the intramolecular trapping of these intermediates with dipolarophiles has been widely explored.184 In early studies, Padwa and Hamilton established that an acyl substituent enhances the formation of an azomethine ylide.185 The intramolecular trapping of stabilized azomethine ylides generated thermally from aziridines has received considerable attention as a method for the construction of polycyclic systems.186–188 For example, the construction of the core of the marine natural product sarain A has been accomplished by intramolecular cycloaddition of stabilized azomethine ylides generated from acyl aziridines.186,187 Weinreb and co-workers were able to prepare the bicyclic intermediate 287 by intramolecular cycloaddition of the stabilized azomethine ylide 286 generated from the aziridine 285 at 325°C (Scheme 108).186c Heathcock and co-workers also constructed the core of sarain A using an analogous azomethine ylide generated at lower temperature. The stereoselective intermolecular cycloaddition of azomethine ylides generated by thermal rearrangement of acyl aziridines bearing chiral auxiliaries has been investigated in detail. For example, Garner and Dogan demonstrated that good levels of diastereocontrol [70% diastereomeric excess (d.e.)] could be achieved using camphor-derived sultam auxiliaries but the 66 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 67

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Ph Ph Ph O Ph O N o -Cl2C6H4, N N OMe N OMe 325°C, OMe sealed tube OMe 285 286

Ph O Ph H N N 78%

H OMe

287 OMe Scheme 108

endo:exo ratios were modest and mixtures of regioisomers were obtained when unsymmetrical dipolarophiles were used.189 The photochemical generation of azomethine ylides from aziridines has also received considerable attention,190,191 and the ylides have been trapped by dipolarophiles in an intermolecular190 and intramolecular191 fashion. The use of photoinduced electron transfer to generate non-stabilized azomethine ylides has also been explored.192 When an aziridine is photolysed in the presence of the sensitizer 9,10-dicyanoanthracene, it is oxidized to give a radical cation which either behaves as an azomethine ylide equivalent or is converted to the ylide prior to reaction with a dipolarophile.192

5.6 From carbenes and catalytically generated metal carbenoids Azomethine ylides can be generated by the reaction of carbenes or carbenoids with imines (see Chapter 3.1). The reaction is usually performed using -diazocarbonyl compounds and so stabilized ylides often result. The reaction is complicated by competitive aziridine formation, but the azomethine ylides can be trapped when reactive dipolarophiles are present. Padwa and co- workers have explored a variety of intermolecular and intramolecular reactions of this type.193 For example, rhodium(II) acetate-catalysed reaction of dimethyl diazomalonate (288) in the presence of the imine 289 and N-methylmaleimide afforded the bicyclic imide 290 in good yield with a modest preference for the exo isomer (Scheme 109).193c Metal-catalysed intramolecular azomethine ylide generation followed by intermolecular capture with a dipolarophile can be used to prepare N-bridged bicyclic systems. Padwa and co-workers have used such a reaction to prepare the core structure (293) of the phencyclidine receptor ligand MK-801 67 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 68

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MeO C O N O 2 O Me MeO2C H MeO2CCO2Me N Me + Me N NMe N2 Ph H Rh2(OAc)4, ° PhMe, 110 C Ph H O 50% exo 34% endo 288 289 290

Scheme 109

OMe O O OMe N N

Rh2(Oct)4 N2 O O 291

AcO O

Ac O, pyridine N 2 N MeO MeO OAc O

O O 293 67% (2 steps) 292

Scheme 110

(Scheme 110).193a Treatment of the diazo compound 291 with rhodium octanoate in the presence of quinone afforded the cycloaddition product 292 as a mixture of endo and exo isomers. Subsequent aromatization was accomplished by treatment of the product 292 with acetic anhydride and pyridine to deliver ketone 293 in 67% yield over two steps. Padwa and co-workers have also explored the generation of azomethine ylides from carbonyl ylides.194 In this reaction, a carbonyl ylide is generated by intramolecular reaction of a diazo ketone with an amide carbonyl group. Proton exchange with solvent then allows conversion of the carbonyl ylide into the thermodynamically more stable azomethine ylide. In some cases, the nature of the dipolarophile dictates whether the carbonyl ylide or the stabilized azomethine ylide is trapped.

5.7 Decarboxylation of imines derived from -amino acids Imines generated from -amino acids readily undergo decarboxylation through their zwitterionic forms to generate azomethine ylide intermediates. The reaction has been studied extensively by Grigg and co-workers195 and by 68 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 69

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others,196 and is especially useful for the generation of non-stabilized ylides from naturally occurring amino acids or N-alkylated amino acids (see Chapter 3.4). For example, Grigg and co-workers studied the generation of azomethine ylides by the reaction of simple amino acids with pyruvate derivatives in the presence of N-methylmaleimide (Scheme 111).195h When the amino acid and the pyruvate derivative are heated together, the zwitterion 294 is produced which undergoes stereoselective decarboxylation to give the ener- getically favoured azomethine ylide 296. The ylide is then immediately trapped with dipolarophile N-methylmaleimide to give the bicyclic product 297 resulting from reaction through an endo transition state. Although direct azomethine ylide generation by decarboxylation of the zwitterion 294 is possible, Grigg and co-workers have postulated that the oxazolidin-5-one 295 is an intermediate and the ylide is produced by loss of carbon dioxide from this heterocycle.

O X O Me O O O R O Me O O R H2NCO2H DMF, N R X Me N 80–100°C X H H 294 295

Me O N O O N O Me H Me X O H H N R R 53–88% OH X Me N H 297 296 X = OH, OEt, NH2 R = Me, Ph, CH Ph, CH CMe , 2 2 2 N CH2OH, CH2CO2H, (CH2)2SMe, N

Scheme 111

Grigg and co-workers have also shown that it is possible to generate azomethine ylides by decarboxylation and then trap them in an intramolecular manner.195e In this case, an amino acid is condensed with a carbonyl compound containing a suitable dipolarophile and immediate cycloaddition of the intermediate azomethine ylide delivers the polycyclic amine product(s).

5.8 From oxazolines, oxazolidines and oxazolidinones Oxazolium salts and reduced oxazoles are convenient and stable precursors for the generation of stabilized azomethine ylides. Vedejs and co-workers 69 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 70

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have performed detailed studies concerning the reduction of oxazolium salts to give 4-oxazolines which then undergo C–O bond cleavage to deliver stabilized azomethine ylides.197,198 The ylides have been trapped with external dipolarophiles197 and in an intramolecular manner198 to give bicyclic systems. For example, Vedejs and Grissom showed that conversion of the oxazole 298 into the corresponding N-methylated oxazolium salt 299 followed by treatment with a silane and caesium fluoride in the presence of methyl acrylate results in reduction to give the oxazoline 300 which then undergoes ring opening to give the azomethine ylide 301.197a,c Cycloaddition affords a mixture of the regioisomeric products 302a and 302b, reflecting the geometry of the intermediate azomethine ylide 301. The combination of phenylsilane and caesium fluoride allows ylide generation to be performed under neutral aprotic conditions and without over-reduction.197a

Me Me N MeOTf, N OTf CO2Me N 1 2 1 2 1 2 R O R MeCN, rt R O R PhSiH3, R O R 298 299CsF, rt 300 R1 = H, Me, Ph R2 = Me, Ph, OEt

Me O Me O Me 1 R1 N R1 N R N R2 + R2 O R2 MeO2C CO2Me 302a 47–87% 302b 301

Scheme 112

Intramolecular variants of the reaction, in which substrates possessing an internal dipolarophile are used, have been explored and generally provide bicyclic systems in high yield.198,199 In addition, Vedejs and Piotrowski have shown that it is possible to perform both oxazolium salt generation and azomethine ylide cycloaddition in an intramolecular manner.198b Oxazolidines can also be used as precursors for azomethine ylide generation. The most common procedure for ylide generation involves treatment of the oxazolidine with trimethylsilyl triﬂate in the presence of a reactive dipolarophile. Husson and co-workers have explored the reactions of a variety of chiral substrates such as the oxazolidine 303 (Scheme 113).200 On treatment of the oxazolidine 303 with trimethylsilyl triﬂate and Hünig’s base, the stabilized azomethine ylide 304 is produced which can be trapped in good yield using dipolarophiles such as N-phenylmaleimide.200a Mixtures of the bicyclic products 305a and 305b are usually produced, with varying levels of endo:exo selectivity. The levels of diastereocontrol exerted by the substituent(s) are frequently modest but can be high in some cases. The levels of 70 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 71

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diastereocontrol and the endo:exo selectivity can be improved by judicious choice of ring substituents and the incorporation of auxiliary groups into the 200b ylide-stabilizing acyl substituent (R CO2R*).

O Ph O N Ph Ph O O Ph NO R N TMS R N TMS TMSOTf, R 303i-Pr2NEt, OTf 304 CH2Cl2, –78°C

Ph Ph OTMS OTMS R N R N HH+ HH

O N O O N O Ph Ph 305a 305b

Scheme 113

Oxazolidinones usually undergo thermal decomposition to give azomethine ylides with loss of carbon dioxide by an analogous process to that by which imines produced from -amino acids undergo decarboxylation. However, Gallagher and co-workers have shown that it is possible to generate azomethine ylides from -lactam-bearing oxazolidinones without loss of carbon dioxide (Scheme 114).201 Thus, thermolysis of -lactam 306 in the presence of N-phenylmaleimide in acetonitrile results in C–O bond cleavage to give the zwitterion 308 which does not lose carbon dioxide to give the ylide 307 but instead tautomerizes to produce the intermediate azomethine ylide 309.201b The stabilized azomethine ylide 309 reacts with N-phenylmaleimide to give the cycloaddition product 310, and decarboxylation occurs thereafter to give the tricyclic product 311. The mechanism of the reaction has been studied extensively and there is substantial evidence that cycloaddition occurs prior to decarboxylation.201c,d

5.9 From N-oxides of tertiary amines An important though under-utilized method for the generation of non- stabilized azomethine ylides is the formal dehydration of tertiary amine N- oxides with non-nucleophilic strong bases such as lithium diisopropylamide (LDA).202–204 Roussi and co-workers have been instrumental in developing this method for the generation of non-stabilized azomethine ylides, and have demonstrated that even the simple substrate trimethylamine N-oxide can be converted into the reactive azomethine ylide 312 by treatment with LDA 71 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 72

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H O OH O LiBr, N N O O O N MeCN, O O O ° CO2PNB CO2PNB CO2PNB 80 C 306 308 309 O

NPh –CO2 PNB = 4-nitrobenzyl

O O O H Ph H Ph H N H N –CO N 2 O O O N H N H CO PNB O O 2 CO2PNB 42% CO2PNB HO2C 307 311 310

Scheme 114

1. LDA, THF, Li Me O O CH –78°C –"LiOH" 2 N N N N Me Me 2. styrene Me CH2 Me CH2 Me Me Ph 312 313 57%

Scheme 115

(Scheme 115).202a In the presence of styrene, cycloaddition occurs to give the simple pyrrolidine 313. Other simple unactivated acyclic or cyclic alkenes can be employed as dipolarophiles in this reaction. Roussi and co-workers have also shown that a variety both simple cyclic and acyclic amine N-oxides can be used for ylide generation.202d They also investigated the possibility of controlling the stereochemical outcome of the cycloaddition reaction by generating ylides from N-oxides possessing an adjacent stereogenic centre or a chiral auxiliary such as a carbohydrate group.203 In general, only moderate levels of diastereocontrol were obtained using these chiral substrates. The intramolecular capture of reactive azomethine ylides generated from tertiary amine N-oxides bearing a simple alkene tether has also been explored. These reactions proceed well at low temperature (usually –78°C) and com- pletely unactivated alkenes will undergo intramolecular cycloaddition with the reactive azomethine ylide generated from the N-oxide. The only signiﬁ- cant limitation of the method appears to be the compatibility of sensitive functionality in the substrate with the conditions used for ylide generation. 72 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 73

1: Nitrogen, oxygen and sulfur ylides: an overview 5.10 Generation of N-metallated azomethine ylides In recent years, N-metallated azomethine ylides have become widely used as equivalents of stabilized azomethine ylides. In early studies, Tsuge and co- workers demonstrated that it is possible to generate N-lithiated stabilized azomethine ylides by deprotonation of N-(cyanoalkyl)imines with LDA (Scheme 116).205 Treatment of the imine 314 with LDA at low temperature generates the N-lithiated azomethine ylide 315 which then undergoes cycloaddition with dipolarophiles such as dimethylmaleate. The initially formed cycloaddition product 316 suffers elimination to provide the imine 317 which rapidly isomerizes to give the thermodynamically preferred dihydropyrrole 318. Tsuge and co-workers explored the reaction of other N-metallated azomethine ylides with a range of dipolarophiles and concluded that the ratio of products and the yield were inﬂuenced by identity of the metal and by additives.

CO2Me Li N CN LDA, THF, CO Me Ph CN Ph N CN 2 ° ° Ph N –78 C Li –78 C, 6 h MeO2C CO2Me 314 315 316

–LiCN

H Ph N Ph N 71%

MeO2C CO2Me MeO2C CO2Me 318 317

Scheme 116

Subsequent studies have shown that other N-metallated azomethine ylides can be generated from imines under mild conditions at room temperature using simple lithium or silver salts in the presence of a base such as triethylamine or DBU.206–208 The stereochemical outcome of the cycloaddition reaction usually depends on whether a lithium or silver salt is employed to generate the azomethine ylide, and widely differing yields and ratios of products are sometimes observed.206 When imines of -amino esters are used as ylide precursors, the geometry of the N-metallated azomethine ylide is usually well deﬁned as a result of coordination of the ester carbonyl oxygen to the Lewis acidic metal centre. This can lead to exceptionally high levels of endo:exo selectivity and diastereoselectivity, especially when chiral ,-unsaturated esters/ketones207 and acrylates/acrylamides208 bearing chiral auxiliaries are used as dipolarophiles. 73 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 74

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Although lithium and silver N-metallated azomethine ylides are used most frequently, it is possible to prepare ylides bearing other metals. Grigg and co- workers and Kanemasa and co-workers have shown that it is possible to generate titanium ylides by transmetallation from the N-lithiated complex or by direct treatment of an imine with a suitable titanium complex and an amine.209 The ratios of products from these reactions are highly dependent on the reaction temperature and the nature of the dipolarophile. Grigg and co-workers have also shown that it is possible to prepare N-metallated azomethine ylides from cobalt and manganese salts and that highly enantioselective addition of achiral ylides to achiral dipolarophiles is possible when a chiral non-racemic amino alcohol is present.210 For example, treatment of the imines 319 with cobalt(II) chloride and the chiral ephedrine-derived amino alcohol 320 in the presence of methyl acrylate afforded the cycloaddition product 321 as a single diastereoisomer in good yield and with high e.e. (Scheme 117). MeO C CO Me 2 2 CH CHCO Me 2 2 CO2Me Ar N R Ph Me Ar N R 319 321 H 320 HO N Ar = 2-naphthyl 45–96% 4-BrC6H4 CoCl2, 80–96% e.e. 4-MeOC6H4 MeCN, 25°C

Scheme 117

Samarium(III)-substituted azomethine ylides can also be generated by a rather unusual route.211 Alvarez-Ibarra and co-workers have shown that the samarium(III) azomethine ylides 323 are produced by treatment of the imino- dithiocarbonates 322 with samarium(II) iodide (Scheme 118). Reaction of the ylides with various ,-unsaturated esters affords the pyrrolines 324a and 324b with modest to good levels of diastereocontrol.

3 MeO2C R 1 CO2R 3 MeS R2 O MeS MeS R N R2 SMe 324a 1 MeS N SmLn R O N SmI2, CO2Me O + THF, rt 2 Me O R 3 MeO2C R –[MeCO]• OR1 1 322 323 CO2R R1 = Me, Et 2 MeS N R 2 R = Me, Ph, Bn 55–90% 324b R3 = Me, i-Bu, Bn 3:2→20:1

Scheme 118

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1: Nitrogen, oxygen and sulfur ylides: an overview 5.11 Other methods for azomethine ylide generation There are a several less general but useful methods for the generation of azomethine ylides. One of the simplest involves dehydrogenation of tertiary amino esters in the presence of a catalyst and an excess of the dipolarophile which also acts as a sink for hydrogen. Grigg and Heaney have demonstrated that heating the amino ester 325 with palladium on carbon in the presence of excess N-methylmaleimide produces the diastereoisomeric cycloaddition products 326a and 326b, resulting from trapping of the anti dipole under kinetic conditions, in good yield along with N-methylsuccinimide produced by hydro- genation of the dipolarophile (Scheme 119).212 The reaction appears to be restricted to cyclic amines possessing a benzylic methylene group adjacent to nitrogen and so the method is unlikely to be applicable to many systems other than partially reduced isoquinolines and -carbolines.212

NMe N N N CO2Me CO2Me O H H HH+ H H MeO O Pd-C, DMF, 110°C O N O O N O 325 326a Me 65% (1:1) 326b Me

Scheme 119

Yoon and co-workers and Mariano and co-workers have shown that it is possible to generate azomethine ylides by photochemical rearrangement of N-(trimethylsilyl)phthalimides.213 In its simplest form, the reaction involves irradiation of the substrate 327 in the presence of a suitable dipolarophile (Scheme 120). When acrylonitrile is used as the dipolarophile, the azomethine ylide 328 undergoes highly regio- and diastereoselective cycloaddition to deliver the endo product 329 in 81% yield. Other dipolarophiles have been used to trap the azomethine ylide, and mixtures of endo and exo isomers have been obtained in some cases. The method is of limited scope because azomethine ylide generation is apparently restricted to phthalimides and related systems.

NC O OTMS TMSO SiMe3 N NCH2 N hν, MeCN, O CH2CHCN O 81% O 327 328 329

Scheme 120

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A ﬁnal specialist method for azomethine ylide generation involves the generation of relatively stable zwitterionic oxidopyraziniums from pyrazin-2-ones by treatment with a reactive alkyl halide and deprotonation of the resulting quaternary ammonium salt with basic Amberlite IRA-400 resin.214 The oxido- pyrazinium compound behaves as an azomethine ylide equivalent and undergoes cycloaddition with standard dipolarophiles. Joule and co-workers have used this reaction to prepare the bicyclic core of the natural product quino- carcin.214c

6. Carbonyl ylides 6.1 Thermal or photochemical ring opening of epoxides It has been known for many years that it is possible to generate carbonyl ylides by thermal or photochemical ring opening of epoxides.215 The thermal process usually requires relatively high temperatures, and in situ intermolecular trapping of the intermediate carbonyl ylide often furnishes only a modest yield of the cycloaddition product. Photochemical ring opening and trapping also frequently provides a rather low yield of the cycloaddition products. Thermal generation of a carbonyl ylide is usually accomplished by heating an epoxide in a high boiling solvent in the presence of a suitable trap. For example, Mloston and co-workers were able to generate the stabilized carbonyl ylide 332 by heating the epoxide 331 in p-xylene (Scheme 121).216 When the reaction was performed in the presence of the xanthenethione 330, the carbonyl ylide 332 was trapped to give the spiro-fused compound 333 in high yield.

H CN H O CN Ph CN O Ph CN S O 331 Ph OCN 81% p HCN S -xylene, S 330 140–150°C 332 333

Scheme 121

It is also possible to generate vinyl-stabilized carbonyl ylides from epoxides. Substrates such as the epoxide 334 undergo ring opening to give carbonyl ylides which can be trapped with a variety of dipolarophiles (Scheme 122).217 In this case, when the reaction is performed in the presence of DMAD, the expected dihydrofuran 335 is obtained in modest yield along with a small amount of the oxepane 336 produced by cyclization through the pendant vinylic groups (Scheme 122).217 Carbonyl ylides generated from epoxides are readily trapped by tethered dipolarophiles in an intramolecular fashion to produce cyclic ethers.218–220 Eberbach and co-workers have explored this reaction and have used it to 76 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 77

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CO2Et Me Si CO Et 3 2 O O H O DMAD, 30% + 9% ° H CCl4, 145 C MeO2CCO2Me Me3Si CO2Me Me3Si 334 335 336 Scheme 122

prepare polycyclic ethers in good yield.218 For example, thermolysis of the epoxide 337 in a high boiling hydrocarbon solvent affords a diastereoisomeric mixture (3:1) of the angularly fused compounds 338a and 338b in reasonable yield (Scheme 123).218c Intramolecular reaction of the carbonyl ylide is favoured and it is not possible to intercept it with an external trap when substrates bearing a suitable tethered dipolarophile are employed.218a In fact, the intramolecular reaction is so favourable that macrocyclic fused systems can be prepared using substrates in which the epoxide is connected to the dipolarophile by an extended tether.218b

H H O CN iso-octane, O O H Ph + H Ph O 145°C O O H Ph CN CN H H H H 337 338a43% (3:1) 338b

Scheme 123

Good yields of intramolecular cycloaddition products can be obtained when the carbonyl ylide is generated by ﬂash vacuum pyrolysis (FVP) of an epoxide. Sharp and O’Shea have used FVP (625°C) to generate carbonyl ylides which can then be trapped in an intramolecular fashion with heterocyclic groups, such as thiophenes and pyridines, to give polycyclic products.220 The method (thermal or photochemical) used to generate a carbonyl ylide from an epoxide can have a profound inﬂuence on both the yield and stereochemical outcome of the subsequent cycloaddition reaction.221–223 The thermal reaction involves conrotatory opening, whereas the photochemical reaction is a disrotatory process, and this has direct stereochemical implications for the resulting carbonyl ylide. Whiting and co-workers have shown that the aryl- substituted epoxide 339 undergoes thermal ring opening, and intermolecular addition of the resulting carbonyl ylide to dimethyl fumarate gives a low yield of the isomeric cycloaddition products 340a and 340b.223 In contrast, the corresponding photochemical reaction delivers a mixture of the three cycloaddition products 340a–c in good yield.223 77 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 78

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CO2Et

1 O 2 1 O 2 H O Ar2 EtO C Ar Ar Ar Ar 2 + ∆ ν Ar1 H or h MeO2CCO2Me MeO2CCO2Me 339 340a + 340b 1 1 O 2 Ar = p-NO2C6H4 Ar Ar 2 Ar = p-MeOC6H4

PhNEt2, 217°C – 340a,b low yield MeO2CCO2Me photolysis – 340a–b 62% 340c

Scheme 124

Carbocyclic epoxides can be ring opened under photochemical conditions to deliver cyclic carbonyl ylides. Cycloaddition with a suitable dipolarophile then delivers an ether-bridged compound. The photochemical reaction of epoxides such as 341 has been studied extensively by Ishii and co-workers (Scheme 125).224 They found that the carbonyl ylide 342 could be generated by photolysis of the epoxide 341 using a low pressure mercury lamp, and then trapped with ethyl vinyl ether to give a diastereoisomeric mixture of the exo and endo products 343a and 343b, with the former predominating.224a,d Other enol ethers such as dihydrofuran proved to be effective dipolarophiles, but non-activated or electron-deﬁcient alkenes proved to be unsuitable as dipolarophiles.224e The success of the reaction is also dependent on the structure of the epoxide, and a conjugated alkene bearing two nitrile substituents is required for efﬁcient carbonyl ylide generation.224a Ishii and co-workers also demonstrated that it is possible to trap the carbonyl ylide with internal nucleophiles. Spirocyclic acetals are produced from substrates possessing a chain containing a suitably positioned hydroxyl substituent.224b,c

NC CN NC CN NC CN

OEt R2 O hν (λ 254 nm), O O 1 Et N, CH Cl , rt R 341 3 2 2 342 343a R1 = OEt, R2 = H 36% 343b R1 = H, R2 = OEt 8% Scheme 125

6.2 From fragmentation of oxadiazolines Carbonyl ylides can be generated by thermally induced fragmentation of 3-1,3,4-oxadiazolines.225 The reaction was originally discovered by Rajago- palan and Advani226 and has been studied extensively by Warkentin and co-workers225,227 and by other research groups.228 This method of carbonyl 78 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 79

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ylide generation has the advantage that 3-1,3,4-oxadiazolines are readily accessible by the cyclization of suitably functionalized ketone hydrazones with oxidants such as lead(IV) acetate and iodobenzene diacetate.225,229 How- ever, the reaction is rather restricted in its synthetic scope because a fairly narrow range of substituents are tolerated and variable yields of cycloaddition products are obtained when the ylides are trapped with dipolarophiles. The thermal generation of carbonyl ylides from of 3-1,3,4-oxadiazolines and in situ trapping with dipolarophiles delivers cycloaddition product(s), but fragmentation of the ylide is frequently a competing process.227d,h,j Warkentin and co-workers have explored substituent effects, especially in spiro-fused -lactam-containing 3-1,3,4-oxadiazolines.227c,e,f,g When the reactive carbonyl ylide possesses appropriate substituents, it can be trapped efﬁciently with standard dipolarophiles.227a,i For example, Chiba and Okimoto used DMAD to trap the carbonyl ylide 345 generated by thermolysis of the 3-1,3,4-oxa- diazoline 344, and the resulting dihydrofuran 346 was obtained in good yield (Scheme 126).229

MeO2C CO2Me N N Me Ph DMAD, Me Ph Me Ph Me O OMe Me O OMe C6H6, reflux 83% Me O OMe 344 345 346

Scheme 126

6.3 Non-stabilized carbonyl ylides from -haloethers Non-stabilized carbonyl ylides can be prepared from -halo ethers using a variety of precursors and reagents. In the case of -halo -silyl ethers, treatment with ﬂuoride ion results in carbonyl ylide generation by desilylation with concomitant loss of halogen.230 For example, treatment of the ether 347 with ﬂuoride ion in the presence of dimethyl fumarate produces a diastereoisomeric mixture of the tetrahydrofurans 349 (Scheme 127).230 The non-stabilized carbonyl ylide 348 is presumed to be an intermediate in this reaction.

MeO2C MeO C CO Me Ph Cl 2 2 CO2Me Me3Si O CsF, MeCN, rt Ph O 81% (52:48) Ph O 347 348 349

Scheme 127

It is also possible to generate non-stabilized carbonyl ylides from ,-dihalo ethers by treatment with a samarium reagent or a manganese– lead reducing system (see Chapter 3.8).231,232 Hosomi and co-workers have 79 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 80

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shown that treatment of the ,-dichloro ether 350 with samarium metal in the presence of iodine and a suitable dipolarophile affords the diastereoisomeric tetrahydrofurans 352a and 352b (Scheme 128).231b Although the yields are exceptionally high for this and related reactions, the level of diastereocontrol is generally low.

OMe MeO OMe

Me O Et Cl Cl Et 352a OMe + Me O Et Me O 96% (55:45) Sm, I2,THF, MeO OMe 350 0°C→rt 351

Me O Et 352b

Scheme 128

Hosomi and co-workers have also shown that it is possible to generate related non-stabilized carbonyl ylides by intermolecular reaction of -iodo silyl ethers mediated by samarium metal in the presence of mercury(II) chloride.231a For example, samarium-mediated reaction of the iodoether 353 with 1-decene affords the tetrahydrofuran 355 resulting from cycloaddition of the putative intermediate carbonyl ylide 354 (Scheme 129).231a In most of the cases studied by Hosomi and co-workers, the levels of diastereocontrol were reasonable or very good.

(i) Sm, HgCl2, C8H17 PhMe, rt Et OSiEt3 C8H17 Et O Et Et Et I (ii) addition 89% (87:13) O 353–78°C→rt 354 355

Scheme 129

Takai and co-workers have shown that it is possible to perform analogous ylide-forming reactions by treating -iodo silyl ethers with manganese and lead(II) chloride in the presence of chlorotrimethylsilane.232 In this case, manganese(0) acts as the electron donor to generate the carbonyl ylide intermediate.231c

6.4 From carbenes or catalytically generated metal carbenoids The most general and widely used method for the synthesis of stabilized carbonyl ylides involves the reaction of a carbonyl compound with a catalytically 80 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 81

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generated metal carbenoid (see Chapter 3.6) or a free carbene (see Chapter 3.5) generated from a diazocarbonyl compound. In general, metal carbenoids have a more satisfactory reaction proﬁle and are more widely employed than free carbenes.41,233 However, there have been some notable examples of carbonyl ylide generation using free carbenes. For example, de March and Huisgen have demonstrated that it is possible to prepare carbonyl ylides by thermolysis of diazocarbonyl compounds in the presence of aldehydes, and that dioxolanes are produced in reasonable yield by reaction of the ylide with a second equivalent of the aldehyde.234 Janulis and Arduengo have published a remarkable example of photochemical generation of a stable carbonyl ylide from a diazo compound (Scheme 130).235 In this case, photolysis of the diazo cyclopentadiene 356 in the presence of tetramethylurea afforded the stable crystalline ylide 357, the structure of which was conﬁrmed by X-ray crystallography.

O CF3 CF3 F3C F3C Me2N NMe2 N2 O hν NMe2 F3C F3C CF3 CF3 NMe2 356 357

Scheme 130

Although carbonyl ylides can be generated by intermolecular reaction of a metal carbenoid with a ketone or aldehyde,236 the most common approach to carbonyl ylide generation involves intramolecular reaction of a metal carbenoid with a ketone, ester or amide followed by either intermolecular or intramolecular trapping with a dipolarophile such as an alkene (see Chapter 3.6). In cases where both the carbonyl group and dipolarophile are tethered to the diazocarbonyl unit, competitive cyclopropanation of the alkene by the intermediate metal carbenoid can be problematic and is dependent on the tether length and the catalyst employed.237 Carbonyl ylides generated by intramolecular reaction of metal carbenoids with ketones can be trapped in an intermolecular fashion by added dipolarophiles.238 For example, Padwa and co-workers have shown that the carbonyl ylide 359, produced by cyclization of the rhodium carbenoid derived from the diazoketone 358, undergoes cycloaddition with DMAD to give the O-bridged compound 360 in 97% yield (Scheme 131).239a The same workers have employed the reaction to synthesize members of the illudin, pterosin and ptaquilosin families of sesquiterpene natural products,239b–d and Kinder and Bair have prepared ()-illudin M in an analogous fashion.239e It is also possible to generate carbonyl ylides by intramolecular reaction of metal carbenoids with esters and then trap them with added dipolarophiles. Ibata and co-workers have investigated the generation of benzopyrylium-4- 81 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 82

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MeO2CCO2Me OO Rh2(OAc)4, O Me O Me DMAD, Me O 97% ° N2 CDCl3, 25 C O 358 359 360

Scheme 131

olates by the intramolecular reaction of esters with copper carbenoids and have shown that they react with a variety of electron-deﬁcient alkenes, aldehydes, isocyanates and isothiocyanates to give bridged bicyclic compounds (see Chapter 3.7).240 Padwa and Stull have performed analogous reactions using rhodium carbenoids and lactone-containing substrates.241 Carbonyl ylides generated from ketones which also possess a suitable dipolarophile usually undergo intramolecular cycloaddition to deliver O- bridged bicyclic products. However, it is sometimes possible to intercept the ylide with a highly reactive external dipolarophile if the internal trap is non- activated or is not well disposed to react due to geometric constraints.242 In contrast, carbonyl ylides derived from esters possessing a suitable internal dipolarophile often fail to undergo intramolecular cycloaddition due to conformational factors.243 The contrast between ester- and ketone-derived carbonyl ylides in this regard is illustrated by the contrasting reactions of the diazo ketones 361a and 361b (Scheme 132).243a Upon exposure to rhodium(II) acetate, both substrates react to give the carbonyl ylide 362. The ketone- derived ylide 362a then undergoes intramolecular cycloaddition to give the bridged tricyclic ether 363, whereas the ester-derived ylide 362b does not cyclize and reacts with water to give the acyclic alcohol 364. It should be appreciated that intramolecular trapping of ester-derived carbonyl ylides does proceed in high yield in some cases.244 O O

N2 a O O 363 O Rh2(OAc)4, O

X C6H6 X OH 361 362 b O O a X = CH2 b X = O O 364 Scheme 132

The intramolecular generation of carbonyl ylides by reaction of metal carbenoids with ketones and esters has been used extensively in natural product synthesis. For example, Dauben and co-workers have assembled the core 82 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 83

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structure found in tigliane diterpenes by intramolecular cycloaddition of a carbonyl ylide generated by reaction of a ketone with a rhodium carbenoid,245a and McMills and co-workers have used the same approach to prepare an analogous system (see Chapter 3.6).245b The acetal core found in the zaragozic acids has also been assembled in a highly efﬁcient manner by Hashimoto and co-workers (Scheme 133).246b In this case, treatment of the diazo ester 365 with rhodium(II) acetate resulted in metal carbenoid formation. Interception of the carbenoid by the ester carbonyl group afforded a cyclic carbonyl ylide which then underwent intermolecular cycloaddition with the enedione 366 to give the highly functionalized bicyclic core structure 367 found in the zaragozic acids as a single diastereoisomer. Simpler zaragozic acid model compounds have been prepared by other groups using similar carbonyl ylide cycloaddition strategies,246a,c but in these cases ketones rather than esters have been used as carbonyl ylide precursors.

Me O O O EtO C N2O Me Me 2 O OMOM 366 Me O OMOM EtO2C MeO2C O TMSO Rh2(OAc)4, MeO2C O OTBDPS OTBDPS C6H6, reflux TMSO 365 367 47% Scheme 133

It is possible to generate carbonyl ylides indirectly from metal carbenoids using alkynyl diazo ketones.87b,247 Padwa and co-workers have studied the reaction in detail and have shown that it can be highly efﬁcient in certain circumstances. For example, treatment of the diazo ketone 368 with rhodium(II) acetate in the presence of DMAD delivers the cycloaddition product 371 in excellent yield (Scheme 134). The reaction is presumed to occur by interception of the initially formed metal carbenoid by the alkyne. A new metal alkylidene 369 is produced and the carbonyl ylide 370 is formed by subsequent trapping of this reactive intermediate by the ketone. In some cases, competitive reaction of the intermediate metal alkylidene with the dipolarophile reduces the yield of the carbonyl ylide cycloaddition product.247a Carbonyl ylide generation by the intramolecular reaction of a metal carbenoid with an amide is a more complex process than the corresponding reactions of ketones or esters. The fate of the carbonyl ylide is dictated by the relative position of the amide carbonyl group with respect to carbenoid and is dependent on whether the amide nitrogen is exocyclic or endocylic in the intermediate cyclic carbonyl ylide. Amides of -amino diazo ketones undergo cyclization to give carbonyl ylides which then isomerize to produce the corresponding azomethine ylides.248 The reaction of the proline-derived diazoketone 372 is a good example of this type of dipole cascade process (Scheme 135). Treatment of the diazoketone 372 83 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 84

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O O Me O Me Rh2(OAc)4, Me N2 Me DMAD, CH2Cl2 L Rh O 368n 369

O O

Me Me

CO2Me O O CO Me 2 Me 371 Me 97% 370

Scheme 134

O O O N Rh2(OAc)4 N 1,3 H-shift N

Me O N2 Me O Me O 372 373 374

Scheme 135

with rhodium(II) acetate delivers the carbonyl ylide 373 but this undergoes an immediate 1,3 H-shift to give the azomethine ylide 374 which is trapped by the dipolarophile present.248 When the amide nitrogen lies exocyclic to the cyclic carbonyl ylide generated from a metal carbenoid, an N,O-acetal is usually formed by a 1,4 H-shift even if a suitable internal or external dipolarophile is present.249 For example, the carbenoid generated from the diazo -keto ester 375 cyclizes to give the transient carbonyl ylide 376 which is not trapped by the pendant alkene but instead isomerizes to give the N,O-acetal 377 (Scheme 136).249b

O O O

N N N

Rh2(OAc)4 1,4 H-shift O O O O O O N2 O EtO O EtO O 375 EtO 376 377

Scheme 136

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Isomerization of the carbonyl ylide is not a problem when the position adjacent to the amide carbonyl group does not possess a hydrogen atom because isomerization by hydrogen migration is not possible in these cases. In substrates of this type, carbonyl ylide formation proceeds as usual and trapping with an internal or external dipolarophile is possible. Padwa and Dean have demonstrated the synthetic utility of systems of this type by preparing the skeleton found in the aspidosperma family of alkaloids (Scheme 137).250 In this example, treatment of the diazocarbonyl compound 378 with rhodium(II) acetate resulted in formation of the carbonyl ylide 379 which underwent intramolecular cycloaddition with the indole to give the complex polycyclic system 380 which was then converted into the aspidosperma core system 381.250

Et Et O N O O N Me Me O Rh2(OAc)4 N O OMe N O N2 C H , 6 6 OMe O 50°C O 378 379

O N N

H Et O Et 95% N OAc N O H H Me HO CO2Me Me CO Me 381 380 2 Scheme 137

Carbenoids derived from -diazo imides undergo cyclization to give iso- münchnones (see Chapters 3.9 and 3.10). These mesoionic dipoles represent a distinct class of carbonyl ylide and are best described as a hybrid of the several possible resonance forms.251 Maier and co-workers have demonstrated that it is possible to generate isomünchnones from diazo imides and trap them with internal dipolarophiles to give bridged bicyclic systems (see Chapter 3.9).252 For example, exposure of the diazo substrate 382 to rhodium(II) acetate resulted in formation of the mesoionic dipole 383 which underwent intramolecular trapping to give the bridged system 384 (Scheme 138).252a Padwa and co-workers and Moody and co-workers have surveyed other rhodium complexes as catalysts for the generation and subsequent intramolecular trapping of related isomünchnones.253 Padwa and co-workers have also used tethered indoles to trap intramolecularly the isomünchnones generated from carbenoids and applied this reaction to the synthesis of polycyclic units found in complex alkaloids.254 85 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 86

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O O O O O Me Me Rh2(OAc)4 O O N Me etc. PhMe, O O N2 N N Ph reflux 382 Ph383 Ph

Me O 91% N O Ph O 384

Scheme 138

It is possible to use external dipolarophiles to trap the isomünchnones generated from rhodium- or copper-catalysed reactions of diazo imides.255 High yields are usually obtained using a variety of dipolarophiles such as maleimides and vinyl ethers, but the nature of the catalyst used to generate the carbenoid can have a profound inﬂuence on the course of the reaction.255c In the preceding discussion of the reaction of carbonyl compounds with metal carbenoids, it has been assumed that a free carbonyl ylide is involved and that this intermediate undergoes cycloaddition. However, in many cases, the catalyst used to generate the carbonyl ylide also inﬂuences the cycloaddition process to an extent which suggests that the reaction takes place through a metal-bound carbonyl ylide equivalent. The involvement of the metal is most evident when chiral catalysts are used to generate metal carbenoids from achiral substrates. If a free carbonyl ylide is generated by reaction of the carbenoid with an achiral carbonyl compound, subsequent cycloaddition reactions should deliver racemic products because a new stereogenic centre is not created upon formation of the carbonyl ylide. However, there are several examples in which carbenoids generated from achiral substrates using chiral catalysts have delivered non-racemic cycloaddition products with high e.e.256,257 One of the most impressive examples of this type of asymmetric reaction has been published by Hodgson and co-workers (Scheme 139).256b In this example, treatment of the achiral diazo substrate 385 with the chiral rhodium complex Rh2(R-DDBNP)4 in hexane at 0°C afforded the formal carbonyl ylide cycloaddition product 387 in good yield and with high e.e. Direct reaction of the metal-bound carbonyl ylide 386 is presumed to have occurred in this case. Diazo compounds are not the only precursors which can be used for carbene or carbenoid generation prior to carbonyl ylide formation. Ibata and co-workers have shown that it is possible to generate carbonyl ylides by ther- 86 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 87

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O Rh2L4* N O 2 hexane, O O t-BuO 0°C t O -BuO Rh2Ln* O t-BuO O O 81% 88% e.e. 385 386 387

C12H25

O ORh Rh2L4* = P Rh2(R-DDBNP)4 O O Rh

C12H25 4

Scheme 139

molysis of diazirines in the presence of carbonyl compounds.258 In addition, Padwa and co-workers have shown that iodonium ylides are useful altern- atives to diazocarbonyl compounds for the generation of copper carbenoids which can be trapped to give carbonyl ylides.259

6.5 Other methods for carbonyl ylide generation There are some less general methods for carbonyl ylide generation which offer convenient access to carbonyl ylides in certain circumstances. For example, Dittami and co-workers prepared the carbonyl ylide 389 from the enol ether 388 by photochemically induced ring closure (Scheme 140).260,261 The pendant ,-unsaturated ester then participated in an intramolecular cycloaddition reaction to afford the unusual bridged system 390.261 In the absence of a suitable internal dipolarophile, carbonyl ylides generated in this manner typically rearrange by an H-shift to give the corresponding dihydrofuran.260

EtO O H H H O hν O O O H

O O OOEt 85% OOEt388 389 390

Scheme 140

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Another interesting but non-general method for the generation of carbonyl ylides involves the reaction of azomethine ylides with cyclopropenones. Matsumoto and co-workers have reported that the azomethine ylide 391, generated by photolytic cleavage of an aziridine, reacts with diphenylcyclo- propenone to give the carbonyl ylide 393 which is then trapped by the imine produced by fragmentation of the intermediate 392 to give bridged bicyclic products (Scheme 141).262 This method is clearly of rather limited synthetic use but represents an interesting type of dipole cascade process.

O C6H11O Ph N Ph Ph C6H11O Ph Ph Ph Ph –PhCHNC6H11 Ph N O Ph Ph O Ph O 391 392 393

Scheme 141

7. Thiocarbonyl ylides In general, thiocarbonyl ylides have received less attention than their oxygen- containing counterparts. However, there is a substantial body of literature describing a variety of approaches to thiocarbonyl ylide generation. In most cases, these methods parallel those employed for carbonyl ylide formation and so a relatively brief survey of approaches to thiocarbonyl ylide generation follows.

7.1 Ring opening of thiiranes Thiiranes can be ring opened in an analogous fashion to oxiranes and aziridines, but desulfurization frequently is a competing process. Kamata and Miyashi were the ﬁrst to report that thiiranes can be converted into thiocarbonyl ylides under photochemical conditions.263a For example, photolysis of the aryl-substituted thiirane 394 in the presence of tetracycanoethene (TCNE) results in electron transfer to generate the radical cation 395 (Scheme 142). Conrotatory ring opening and subsequent electron transfer from the TCNE radical anion delivers the thiocarbonyl ylide 396.263b The ylide in then trapped by TCNE and the tetrahydrothiophene 397 is produced in high yield.263a The reaction is stereospeciﬁc when performed at –90°C but isomerization of the ylide occurs prior to cycloaddition at higher reaction temperatures.263b

7.2 From fragmentation of thiadiazolines In the same way that the fragmentation of 3-1,3,4-oxadiazolines provides carbonyl ylides, the fragmentation of 3-1,3,4-thiadiazolines can be used to prepare thiocarbonyl ylides (see Chapter 3.12).264 In fact, this is one of the 88 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 89

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NC CN

S S Ar1 Ar3 NC CN Ar1 Ar3 TCNE ν Ar2Ar4 h Ar2Ar4 394 395

1 2 3 4 Ar , Ar , Ar , Ar = Ph, p-MeOC6H4, p-MeC6H4,

Ar1 S Ar3 1 3 Ar2 Ar4 Ar SAr NC CN Ar2 Ar4 NC CN 397 396

Scheme 142

most widely exploited methods for the generation of thiocarbonyl ylides because the heterocyclic starting materials are readily available and the reaction can be performed under mild conditions. An early example of this method of thiocarbonyl ylide generation was published by Huisgen and Mloston´ (Scheme 143).265 They demonstrated that it was possible to prepare the 3-1,3,4-thiadiazoline 398a along with a small amount of the isomeric 2-1,2,3-thiadiazoline 398b by treatment of adamantanethione with diazomethane in pentane at –20°C. Generation of the carbonyl ylide 399 was accomplished by heating the 3-1,3,4-thiadiazoline 398a in xylene at 80°C. In the absence of a suitable dipolarophile, the thiirane 400 was obtained in 94% yield. The addition of a reactive dipolarophile such as DMAD afforded high yields of the corresponding cycloaddition product(s) (e.g. the dihydrothiophene 401).

N N N S CH N , N 2 2 S + S –20°C, pentane 398a (91:9) 398b 80°C, xylene

MeO C CO2Me S 2 S DMAD S

94% 400 399 87% 401

Scheme 143

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Generation of the requisite 3-1,3,4-thiadiazolines by addition of diazo alkanes to thioketones is a general process, and the fragmentation and cycloaddition sequence has been applied in a variety of situations. For example, Heimgartner, Mloston´ and co-workers have investigated the reaction of 1,3-thiazole-5(4H)-thiones with diazo alkanes and thermal generation of thiocarbonyl ylides from the resulting thiadiazolines.266 The generation of thiadiazolines by the reaction of diazo alkanes with simple thioketones followed by thiocarbonyl ylide generation and trapping with a variety of electron- deﬁcient alkenes, carbonyl or thiocarbonyl compounds has been studied extensively.267 In the absence of a suitable trapping agent, a thiirane is usually produced from the thiocarbonyl ylide. The reaction has been used to good effect to construct a tetrahydrothiophene during a synthesis of biotin.268 In this case, the thiadiazoline was generated at low temperature by reaction of diazomethane with an activated thiocarbonyl compound and the resulting thiocarbonyl ylide was trapped with fumaryl chloride.268 -Diazocarbonyl compounds will also undergo direct uncatalysed addition to thiocarbonyl compounds.269 However, elevated reaction temperatures are usually employed which result in immediate thiocarbonyl ylide generation and so the intermediate thiadiazoline is not usually isolated. Oxathiolenes, produced by a ring closure reaction in which the carbonyl group attacks the thiocarbonyl ylide, are often the ﬁnal products of these reactions.269b,d

7.3 Desilylation reactions -Silyl thioethers are important precursors for the production of non- stabilized thiocarbonyl ylides. Ylide generation can be accomplished using a variety of mild reaction conditions. For example, Achiwa and co-workers have shown that it is possible to generate thiocarbonyl ylides from -bromo- silylthioethers (Scheme 144).270 The starting bromide 402 is generated conveniently by treatment of bis(trimethylsilylmethyl)sulﬁde with N-bromo- succinimide. The non-stabilized thiocarbonyl ylide 403 is then produced by elimination of bromotrimethylsilane upon thermolysis of this compound in dimethylformamide (DMF). When the reaction is performed in the presence maleic anhydride, the tetrahydrothiophene 404 is produced in excellent yield. This cycloaddition product has been converted into a key intermediate used in the synthesis of the natural product biotin.270c A variety of other dipolarophiles will also add to the thiocarbonyl ylide 403, and the yields of the

O Me Si Br O O 3 O O O H H S SiMe3 DMF, 130°C S SiMe3 SiMe S 3 402 403 404 91%

Scheme 144

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cycloaddition products are generally high. However, mixtures of regioisomers are produced when the ylide is trapped using unsymmetrical dipolarophiles.270b A similar reaction can be used to generate non-stabilized thiocarbonyl ylides from -chloro--silylthioethers at room temperature.271 Treatment of the simple thioether 405 with ﬂuoride ion in the presence of a suitable dipolarophile results in generation of the highly reactive ylide 406 (Scheme 145).271a When dimethylmaleate is used to trap the ylide, the tetrahydrothiophene 407 is produced in good yield. Reasonable levels of diastereocontrol have been achieved when ,-unsaturated carbonyl compounds bearing a chiral auxiliary have been employed as dipolarophiles.271c Aldehydes can also be used to trap the thiocarbonyl ylide 406 in high yield.271b

CO2Me MeO2C CO2Me Me Si HH 3 CO2Me S SClCsF, MeCN, rt S 405 406 407 84%

Scheme 145

An even more straightforward method of preparing simple non-stabilized thiocarbonyl ylides involves treating thioketones with (trimethylsilyl)methyl trifluoromethanesufonate.272 For example, treatment of thiobenzophenone with (trimethylsilyl)methyl trifluoromethanesulfonate gives the salt 408 which then undergoes desilylation to give the ylide 409, and trimethylsilyl trifluoromethanesulfonate as a by-product (Scheme 146).272

Ph Ph OTf Ph TfO SiMe3 –Me3SiOTf S S S DME, rt Ph Ph SiMe3 Ph 408 409

Scheme 146

Thiocarbonyl ylides can also be generated from silylmethyl sulfoxides by a reaction which is analogous to the sila-Pummerer rearrangement. Achiwa and co-workers have demonstrated that the simple ylide 406 can be prepared from bis[(trimethylsilyl)methyl] sulfoxide (410) by heating it in hexamethyl- phosphoramide (HMPA) (Scheme 147).273 During the reaction, the sulfonium ion 411 produced initially is attacked by the trimethylsilanolate ion to give the thiocarbonyl ylide 406, and hexamethyldisiloxane as the by-product. In the presence of diethyl fumarate, the ylide 406 undergoes cycloaddition to give the tetrahydrothiophene 412 in good yield, and a variety of other reactive dipolarophiles can also be used to trap the ylide. It is also possible to use the 91 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 92

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reaction to generate ylides of thioketenes by employing vinylic sulfoxides as starting materials.273b,c

CO2Et

OSiMe3 EtO2C Me3Si S SiMe3 Me3Si S O HMPA, 100°C 410 411

–(Me3Si)2O

EtO2C CO2Et HH S S 412 80% 406

Scheme 147

7.4 From carbenes generated thermally or photochemically In common with most other ylides, thiocarbonyl ylides can be produced from free carbenes generated under thermal or photochemical conditions. McGimpsey and Scaiano investigated the reaction of triplet carbenes such as diphenyl carbene with simple thioketones such as adamantanethione.274 In this case, laser photolysis of diazo compounds in Freon-113 afforded carbenes which then reacted with the thioketones to give thiocarbonyl ylides with suf- ﬁcient lifetimes (18.5–100 s) for spectroscopic identiﬁcation. It is also possible to generate simple thiocarbonyl ylides by reaction of thioketones with dichlorocarbene generated by the reaction of chloroform with sodium hydroxide.275 In the absence of trapping agents, thiiranes can be isolated in excellent yield.

7.5 From catalytically generated metal carbenoids Metal carbenoids have proved to be useful reactive intermediates for the generation of thiocarbonyl ylides from the corresponding thiocarbonyl compounds (see Chapter 3.11). Treatment of an appropriate carbonyl-stabilized diazo compound with rhodium(II) acetate at an elevated temperature in the presence of a thiocarbonyl compound usually delivers either the thiirane resulting from cyclization of the intermediate ylide or the alkene resulting from extrusion of sulfur from the thiirane.276b,c It is also possible to generate the required metal carbenoid by treatment of an iodonium ylide with a copper catalyst.277 The generation of thiocarbonyl ylides from metal carbenoids allows the preparation of some rather unusual ylides. For example, it is possible to prepare ylides by the reaction of rhodium carbenoids with thioketenes or thio- isocyanates.278 In the latter case, thiocarbonyl ylide formation is favoured over azomethine ylide formation.278a 92 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 93

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The generation of thiocarbonyl ylides from metal carbenoids is an especially efﬁcient process when it is performed in an intramolecular manner. For example, Padwa and co-workers have explored the generation of thiocarbonyl ylides by intramolecular reaction of thioamides with rhodium carbenoids (Scheme 148).279 Treatment of the thioamide 413 with rhodium(II) acetate in the presence of N-phenylmaleimide afforded the bridged system 415 resulting from cycloaddition of the intermediate mesoionic thiocarbonyl ylide 414. Padwa found that it was sometimes not possible to trap the ylide efﬁciently with an added dipolarophile in situations where the thiocarbonyl ylide was not mesoionic. In those cases, a thiirane was produced which underwent immediate desulfurization to give the corresponding alkene.279

Ph O O N O N S NS N S N Ph N2 O O Rh2(OAc)4, O OMe O C6H6, reflux O OMe O O OMe 413 414 415 75%

Scheme 148

7.6 Other methods for thiocarbonyl ylide generation There are some less general methods of thiocarbonyl ylide formation that are worthy of note. Aryl vinyl sulﬁdes will undergo photochemical ring closure to give thiocarbonyl ylides in the same way as aryl vinyl ethers give carbonyl ylides. The ylides will usually undergo an H-shift to give stable reduced thiophenes as the ﬁnal products.280 It is possible to prepare mesoionic thiocarbonyl ylides directly by the reaction of -halo acid chlorides with thioamides. Potts and co-workers have shown that thioamides such as 416 react with 2-bromophenylacetyl chloride to afford the ylides 417 which undergo intramolecular cycloaddition to give diastereoisomeric mixtures of the bridged polycyclic compounds 418a and 418b in good yield (Scheme 149).281 The ease of reaction, yield and level of diastereocontrol are dependent on the group (X CH2 or O) in the alkene tether.

8. Nitrile ylides Nitrile ylides are a synthetically important class of 1,3-dipoles and have been used extensively for the synthesis of pyrroles and reduced pyrroles.282 There are several well established methods for their formation, and the choice of method is largely dictated by the substituents required on the nitrile ylide, the nature of the dipolarophile and the mode of addition (endocyclic or exocyclic).283 93 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 94

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X H S O N X Ph X Ph Ph Cl 418a O NHPh Br S + Et N, C H Ph S 3 6 6 N X Ph H 416 417 O S N X = CH2 rt 82% (6:1) Ph Ph X = O reflux 65% (34:1) 418b O

Scheme 149

8.1 From imidoyl halides Treatment of an imidoyl halide with a base is one of the best established and most reliable methods for nitrile ylide formation. This approach to nitrile ylide generation was pioneered by the Huisgen284 group in the 1960s and has been widely adopted by others.285 Simple imidoyl chlorides can be prepared by the reaction of amides with thionyl chloride, and subsequent ylide generation can be accomplished by treatment with a tertiary amine. For example, Huisgen and co-workers were able to prepare the imidoyl chloride 420 by heating the amide 419 with thionyl chloride (Scheme 150). Treatment of this substrate with triethylamine afforded the nitrile ylide 421, which was trapped with a wide variety of dipolarophiles to give either pyrroles or pyrrolines.284b,c Reaction with acrylonitrile afforded a diastereoisomeric mixture of the pyrrolines 422a and 422b in high yield (Scheme 150).

NO NO H 2 2 SOCl2 Ph N Ph N

O 419 Cl 420 70%

Et3N, C6H6, 0°C

H NO2 H NO2 N N NO Ph Ph CN Ph 2 + N CN 86% CN 422a422b 421

Scheme 150

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An analogous reaction has been used to prepare sulfur-substituted nitrile ylides from imino chlorosulﬁdes.286 In this case, the precursors are prepared by the addition of sulfenyl chlorides to isonitriles. Trapping of the nitrile ylides with dipolarophiles such as DMAD affords thio-substituted pyrroles. Nitrile ylides generated from imidoyl chlorides can be trapped in an intramolecular fashion. However, the success of an intramolecular reaction is highly dependent on the length of the tether connecting the imidoyl chloride to the dipolarophile, and in some cases intermolecular interception of the nitrile ylide is favoured even when the substrate possesses a suitable dipole trap.287 Sharp and co-workers have exploited the intramolecular reaction of nitrile ylides generated from imidoyl chlorides to prepare a wide variety of benza- zepines.288 In this work, nitrile ylide generation was accomplished by treating the substrate with potassium tert-butoxide rather than a tertiary amine base. For example, treatment of the biaryl substrates 423 with potassium tert-butoxide resulted in nitrile ylide formation. Intramolecular trapping of the ylide gave the tricyclic compounds 424 which then underwent immediate rearoma- tization to give the isolated products 425 (Scheme 151).288a In subsequent work, Sharp and co-workers trapped the base-generated nitrile ylides in an intramolecular manner using aromatic heterocycles and dienes.288c,f,g

R R R

t-BuOK THF, 0°C Ar Ar NAr N N

423Cl 424 425 R = H, Cl 65–78%

Ar = Ph, 2-ClC6H4, 2-FC6H4, 3,4-(MeO)2C6H4,

Scheme 151

8.2 Fragmentation of heterocycles Thermal or photochemical fragmentation of heterocyclic compounds is a convenient although under-utilized method for the generation of nitrile ylides. In most cases, the heterocycle is comparatively unstable and a very strong bond is formed in the departing fragment. Burger and co-workers have exploited the thermal and photochemical reactivity of 1,4,2-oxazaphospholines to generate nitrile ylides (see Chapter 4.2).289 In a typical example of this approach to ylide generation, the heterocycles 426 were heated in xylene or irradiated at room temperature to give the nitrile ylides 427 which were then trapped with DMAD and other dipolarophiles to 95 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 96

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give products such as the heterocycle 428 (Scheme 152).289 Heimgartner and co-workers have adopted a similar approach to nitrile ylide generation by thermally extruding carbon dioxide from 1,3-oxazol-5(2H)-ones.290 The resulting nitrile ylides can be trapped by reactive alkenes and ketones to give oxazolines, pyrroles or dihydropyrroles.290 High temperature (300°C) thermolysis of 1,2,4-triazoles has also been used to generate nitrile ylides in an analogous manner.291

R2 F3C N 2 N F3C R F C DMAD, 3 O NR2 F3C F3C P hν, rt or R1O OR1 F3C ° MeO2C CO2Me OR1 xylene, 140 C 1 426 – OP(OR )3 427 428 R1 = Me, Et 2 R = Ph, 4-MeC6H4, t-Bu

Scheme 152

There are also some rather unusual methods of preparing nitrile ylides which involve heterocyclic rearrangement rather than fragmentation. For example, the stable nitrile ylides 430 can be prepared by heating the 7- azidolumazines 429 in xylene (Scheme 153).292 The nitrile ylides 430 produced by pyrazine ring contraction are stable enough to be characterized using spectroscopic methods.

O O 1 1 R N ∆, R N N xylene, –N2 N NCH N O NNN3 O N R2 R2 1 2 429 R , R = Me, i-Pr, C8H17 430

Scheme 153

8.3 Photochemical heterolytic cleavage of azirines The photochemical generation of nitrile ylides from 2H-azirines and their cycloaddition reactions were ﬁrst reported by Padwa and co-workers in 1971.293 The reaction has been studied extensively by several groups over the past 30 years and a considerable amount of spectroscopic evidence conﬁrming the intermediacy of nitrile ylides has been obtained.294,295 In general, azirines with one or more aryl substituents are used as substrates and laser photolysis is usually employed. The nitrile ylides produced react with a wide variety of dipolarophiles including carbonyl compounds, conjugated alkenes and alkynes.296 96 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 97

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Nitrile ylides generated from 2H-azirines have been trapped in an intramolecular manner. Padwa and co-workers have shown that photolysis of the azirine 431 delivers the bicyclic compound 432 resulting from intramolecular cycloaddition of the intermediate ylide (Scheme 154).297 However, when the photolysis reaction is performed in the presence of DMAD, the ylide is intercepted by the more reactive external dipolarophile to give the heterocycle 433.

Me N Me N Me N Ph DMAD hν, C6H6 Ph Ph hν, C6H6 MeO2C CO2Me 433 78% 431 432 80%

Scheme 154

It is also possible to generate nitrile ylides by direct photolysis of azido cinnamates.298 Phenyl 2H-azirines, produced by cyclization of the initially generated nitrenes, are presumed to be transient intermediates but are not isolated from these reactions.

8.4 Reaction of carbenes and metal carbenoids with nitriles Free carbenes, generated by photolysis of diazo compounds or diazines, react with nitriles to give nitrile ylides.299 Evidence for the formation of nitrile ylides has been obtained using IR spectroscopy when these reactions are performed in an argon matrix at 10 K.299c In some cases, it is possible to identify ylides at higher temperatures;300 Arduengo and co-workers have prepared and isolated the stable nitrile ylide 436 by photolysis of the diazo cyclopentadiene 435 in the presence of the adamantyl nitrile 434 (Scheme 155).301

F3C CF3

F3C CF3 F3C CF3 N2 435 CN CN hν CF 434 436 3 F3C

Scheme 155

The reaction of metal carbenoids with nitriles offers a mild catalytic method for the generation of stabilized nitrile ylides. Extensive studies on this reaction have been performed by Ibata and co-workers (see Chapter 4.1).302 The most reliable general procedure involves reaction of a nitrile with a rhodium carbenoid generated by treatment of a diazo carbonyl compound with 97 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 98

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rhodium(II) acetate. In cases where diazo ketone precursors are employed, intramolecular reaction of the carbonyl group with the ylide results in oxazole formation even when a reactive external dipolarophile is present. For example, Ibata and co-workers have shown that the rhodium carbenoid derived from diazo ketone 437 reacts with benzonitrile in the presence of DMAD to give mainly the oxazole 438 instead of the pyrrole 439 resulting from intermolecular cycloaddition of the ylide with DMAD (Scheme 156).302a,c When rhodium carbenoids derived from diazo esters are used, the combined yields are lower but the proportion of the pyrrole product is increased.

Ph O Ph O O Ph 438 61% Rh (OAc) , C 2 4 N Ph Ph + PhCN, DMAD N2 MeO2C CO2Me 437 60°C Ph N Ph O H 439 18% Scheme 156

8.5 Desilylation of -silyl thioimidates Treatment of -silyl thioimidates with fluoride ion delivers nitrile ylides which can be trapped with various dipolarophiles.299a,b The precursors are prepared in a single step by treatment of a nitrile with (trimethylsilyl)methyl triflate in the presence of a thiol such as thiophenol. Treatment of the thioimidate 440 with silver(I) fluoride in the presence of DMAD gives the ylide 441 which has been identified by visible UV spectroscopy (Scheme 157).299a,b Reaction of the ylide 441 with DMAD delivers the pyrrole 442 in reasonable yield, and the ylide can be trapped with a variety of other dipolarophiles.

MeO2C CO2Me Me AgF, DMAD N Me CNCH2 Me MeCN, rt N PhS SiMe3 H 440 441 442 60%

Scheme 157

References 1. For a review of the generation of ammonium and sulfonium ylides, see Markó, I. E. In Comprehensive Organic Synthesis, Pergamon: Oxford, 1991, vol. 3, Ch. 3.10, pp. 913–974.

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2. Stevens, T. S.; Creighton, E. M.; Gordon, A. B.; MacNicol, M. J. Chem. Soc. 1928, 3193. 3. Stevens T. S. J. Chem. Soc. 1930, 2107. 4. Campbell, A.; Houston, A. H. J.; Kenyon, J. J. Chem. Soc. 1947, 93. 5. Brewster, J. H.; Kline, M. W. J. Am. Chem. Soc. 1952, 74, 5179. 6. Millard, B. J.; Stevens, T. S. J. Chem. Soc. 1963, 3397. 7. Chantrapromma, K.; Ollis, W. D.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1 1983, 1049. 8. Schöllkopf, U.; Ludwig, U.; Ostermann G.; Patsch, M. Tetrahedron Lett. 1969, 3415. 9. Sommelet, M. C. R. Hebd. Sceances. Acad. Sci. 1937, 205, 56. 10. (a) Beard, W. Q., Jr; Hauser, C. R. J. Org. Chem. 1960, 25, 334. (b) Beard, W. Q., Jr; Hauser, C. R. J. Org. Chem. 1961, 26, 371. (c) Jones, G. C.; Beard, W. Q.; Hauser, C. R. J. Org. Chem. 1963, 28, 199. 11. Kantor, S. W.; Hauser, C. R. J. Am. Chem. Soc. 1951, 73, 4122. 12. Bumgardner, C. L.; Hsu, H.-B.; Afghahi, F.; Roberts, W. L.; Purrington, S. T. J. Org. Chem. 1979, 44, 2348. 13. Jonćzyk, A.; Lipiak, D.; Sienkiewicz, K. Synlett 1991, 493. 14. Zdrojewski, T.; Jonćzyk, A. Tetrahedron Lett. 1995, 36, 1355. 15. Jemison, R. W.; Ollis, W. D. Chem. Commun. 1969, 294. 16. Coldham, I.; Middleton, M. L.; Taylor, P. L. J. Chem. Soc., Perkin Trans. 1 1997, 2951. 17. Jonćzyk, A.; Zdrojewski, T.; Grzywacz, P.; Balcerzak, P. J. Chem. Soc., Perkin Trans. 1 1996, 2919. 18. Mageswaran, S.; Ollis, W. D.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1 1981, 1953. 19. Neeson S. J.; Stevenson, P. J. Tetrahedron Lett. 1988, 29, 3993. 20. Hyett, D. J.; Sweeney, J. B.; Tavassoli, A.; Hayes, J. F. Tetrahedron Lett. 1997, 38, 8283. 21. Vedejs, E.; Hagen, J. P.; Roach, B. L.; Spear, K. L. J. Org. Chem. 1978, 43, 1185. 22. Vedejs, E.; Arco, M. J.; Renga, J. M. Tetrahedron Lett. 1978, 523. 23. Lednicer, D.; Hauser, C. R. J. Am. Chem. Soc. 1957, 79, 4449. 24. Mander, L. N.; Turner, J. V. J. Org. Chem. 1973, 38, 2915. 25. Heffe, W. Helv. Chim. Acta 1964, 47, 1289. 26. Honda, K.; Igarashi, D.; Asami, M.; Inoue, S. Synlett 1998, 685. 27. Hill, R. K. In Asymmetric Synthesis; Morrison, J. D., ed.; Academic Press: London, 1984, vol. 3, Ch. 8, pp. 503–572. 28. Kaiser, G. V.; Ashbrook, C. W.; Baldwin, J. E. J. Am. Chem. Soc. 1971, 93, 2342. 29. Mageswaran, S.; Ollis, W. D.; Southam, D. A.; Sutherland, I. O.; Thebtaranonth, Y. J. Chem. Soc., Perkin Trans. 1 1981, 1969. 30. Iwai, I.; Hiraoka, T. Chem. Pharm. Bull. 1963, 11, 1556. 31. Chantrapromma, K.; Ollis, W. D.; Sutherland, I. O. J. Chem. Soc., Chem. Com- mun. 1978, 673. 32. Vedejs, E.; West, F. G. Chem. Rev. 1986, 86, 941. 33. Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1979, 101, 6452. 34. Zhang, C.; Maeda, Y.; Sato, Y. Chem. Pharm. Bull. 1998, 46, 572. 35. Sato, Y.; Sakakibara, H. J. Organomet. Chem. 1979, 166, 303. 36. Sato, Y.; Yagi, Y.; Koto, M. J. Org. Chem. 1980, 45, 613. 99 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 100

J. S. Clark

37. Nakano, M.; Sato, Y. J. Org. Chem. 1987, 52, 1844. 38. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034. 39. Maeda, Y.; Sato, Y. J. Chem. Soc., Perkin Trans. 1 1997, 1491. 40. Zhang, C.; Maeda, Y.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin Trans. 1 1997, 25. 41. Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263. 42. Franzen, V.; Kuntze, H. Liebigs Ann. Chem. 1959, 627, 15. 43. Saunders, M.; Murray, R. W. Tetrahedron, 1960, 11, 1. 44. Parham, W. E.; Potoski, J. R. J. Org. Chem. 1967, 32, 275. 45. Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4675. 46. Tomioka, H.; Suzuki, K. Tetrahedron Lett. 1989, 30, 6353. 47. Tomioka, H.; Yamada, S.; Hirai, K. J. Org. Chem. 1995, 60, 1298. 48. Hata, Y.; Watanabe, M. Tetrahedron Lett. 1972, 4659. 49. West, F. G.; Glaeske, K. W.; Naidu, B. N. Synthesis 1993, 977. 50. Osipov, S. N.; Sewald, N.; Kolomiets, A. F.; Fokin, A. V.; Burger, K. Tetrahedron Lett. 1996, 37, 615. 51. West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 115, 1177. 52. West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59, 6892. 53. West, F. G.; Naidu, B. N. J. Org. Chem. 1994, 59, 6051. 54. (a) West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1994, 116, 8420. (b) Naidu, B. N.; West, F. G. Tetrahedron 1997, 53, 16565. 55. Beall, L. S.; Padwa, A. Tetrahedron Lett. 1998, 39, 4159. 56. Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org. Chem. 1981, 46, 5094. 57. Clark, J. S.; Hodgson, P. B. J. Chem. Soc., Chem. Commun. 1994, 2701. 58. Clark, J. S.; Hodgson, P. B. Goldsmith, M. D.; Blake, A. J.; Cooke, P. A.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 2001, 3325. 59. Clark, J. S.; Hodgson, P. B. Tetrahedron Lett. 1995, 36, 2519. 60. Wright, D. L.; Weekly, R. M.; Groff, R.; McMills, M. C. Tetrahedron Lett. 1996, 2165. 61. Curtis, E. A.; Worsencroft, K. J.; Padwa, A. Tetrahedron Lett. 1997, 38, 3319. 62. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds; John Wiley and Sons: New York, 1998. 63. (a) Olah, G. A.; Doggweiler, H.; Felberg, J. D. J. Org. Chem. 1984, 49, 2112. (b) Olah, G. A.; Doggweiler, H.; Felberg, J. D.; Frohlich, S.; Grdina, M. J.; Karpeles, R.; Keumi, T.; Inaba, S.; Ip, W. M.; Lammertsma, K.; Salem, G.; Tabor, D. C. J. Am. Chem. Soc. 1984, 106, 2143. 64. Olah, G. A.; Doggweiler, H.; Felberg, J. D.; Frohlich, S. J. Org. Chem. 1985, 50, 4847. 65. (a) Nozaki, H.; Takaya, H.; Noyori, R. Tetrahedron Lett. 1965, 2563. (b) Nozaki, H.; Takaya, H.; Noyori, R. Tetrahedron 1966, 22, 3393. 66. Ando, W.; Kondo, S.; Nakayama, K.; Ichibori, K.; Kohoda, H.; Yamato, H.; Imai, I.; Nakaido, S.; Migita, T. J. Am. Chem. Soc. 1972, 94, 3870. 67. Olah, G. A.; Doggweiler, H.; Felberg, J. D. J. Org. Chem. 1984, 49, 2116. 68. Voisey, M. A. Trans. Faraday Soc. 1968, 64, 3058. 69. (a) Friedrich, K.; Jansen, U.; Kirmse, W. Tetrahedron Lett. 1985, 26, 193. (b) Kirmse, W.; Lelgemann, R.; Friedrich, K. Chem. Ber. 1991, 124, 1853. 70. Kirmse, W.; Chiem, P. V.; Schurig, V. Tetrahedron Lett. 1985, 26, 197. 71. Kirmse, W.; Kund, K. J. Am. Chem. Soc. 1989, 111, 1465. 72. Oku, A.; Kimura, K.; Ohwaki, S. Acta Chem. Scand. 1993, 47, 391. 100 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 101

1: Nitrogen, oxygen and sulfur ylides: an overview

73. Kirmse, W.; Kapps, M. Chem. Ber. 1968, 101, 994. 74. Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060. 75. Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108, 6062. 76. Doyle, M. P.; Bagheri, V.; Harn, N. K. Tetrahedron Lett. 1988, 29, 5119. 77. Doyle, M. P.; Bagheri, V.; Claxton, E. E. J. Chem. Soc., Chem. Commun. 1990, 46. 78. Eberlein, T. H.; West, F. G.; Tester, R. W. J. Org. Chem. 1992, 57, 3479. 79. Clark, J. S. Tetrahedron Lett. 1992, 33, 6193. 80. Clark, J. S.; Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385. 81. Clark, J. S.; Whitlock, G. A. Tetrahedron Lett. 1994, 35, 6381. 82. Pirrung, M. C.; Brown, W. L.; Rege, S.; Laughton, P. J. Am. Chem. Soc. 1991, 113, 8561. 83. West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59, 6892. 84. West, F. G.; Eberlein, T. H.; Tester, R. W. J. Chem. Soc., Perkin Trans. 1 1993, 2857. 85. Clark, J. S.; Dossetter, A. G.; Whittingham, W. G. Tetrahedron Lett. 1996, 37, 5605. 86. Doyle, M. P.; Peterson, C. S. Tetrahedron Lett. 1997, 38, 5265. 87. (a) Padwa A.; Krumpe, K. E.; Kassir, J. M. J. Org. Chem. 1992, 57, 4940. (b) Padwa A.; Kassir, J. M.; Semones, M. A.; Weingarten, M. D. J. Org. Chem. 1995, 60, 53. 88. Doyle, M. P.; Grifﬁn, J. H.; Chinn, M. S.; van Leusen, D. J. Org. Chem. 1984, 49, 1917. 89. Oku, A.; Murai, N.; Baird, J. J. Org. Chem. 1997, 62, 2123. 90. (a) Brogan, J. B.; Bauer, C. B.; Rogers, R. D.; Zercher, C. K. Tetrahedron Lett. 1996, 37, 5053. (b) Brogan, J. B.; Zercher, C. K.; Bauer, C. B.; Rogers, R. D. J. Org. Chem. 1997, 62, 3902. (c) Brogan, J. B.; Zercher, C. K. Tetrahedron Lett. 1998, 39, 1691. 91. Tester, R. W.; West, F. G. Tetrahedron Lett. 1998, 39, 4631. 92. (a) Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Tetrahedron 1968, 24, 3655. (b) Nozaki, H.; Takaya, H.; Noyori, R. Tetrahedron 1996, 22, 3393. 93. (a) Ito, K.; Katsuki, T. Chem. Lett. 1994, 1857. (b) Ito, K.; Yoshitake, M.; Katsuki, T. Chem. Lett. 1995, 1027. (c) Ito, K.; Yoshitake, M.; Katsuki, T. Heterocycles 1996, 42, 305. 94. (a) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy, E.; Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983. (b) Pierson, N.; Fernández-García, C.; McKervey, M. A. Tetrahedron Lett. 1997, 38, 4705. 95. Clark, J. S.; Fretwell, M.; Whitlock, G. A.; Burns, C. J.; Fox, D. N. A. Tetrahedron Lett. 1998, 39, 97. 96. Doyle, M. P.; Ene, D. G.; Forbes, D. C.; Tedrow, J. S. Tetrahedron Lett. 1997, 38, 4367. 97. Johnson, A. W. In Ylide Chemistry; Academic Press: New York, 1966, p. 306. 98. Ingold, C. K.; Jessop, J. A. J. Chem. Soc. 1930, 713. 99. Aggarwal, V. K.; Schade, S.; Taylor, B. J. Chem. Soc., Perkin Trans. 1 1997, 2811. 100. (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782. (c) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. 101 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 102

J. S. Clark

101. (a) Fleischmann, C.; Zbiral, E. Tetrahedron 1978, 34, 317. (b) Wang, D.-K.; Dai, L.-X.; Hou, X.-L. Chem. Commun. 1997, 1231. 102. Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Huang, Y.-Z.; Li, F.-W. J. Org. Chem. 1996, 61, 489. 103. Cose, R. W. C.; Davies, A. M.; Ollis, W. D.; Smith, C.; Sutherland, I. O. Chem. Commun. 1969, 293. 104. (a) Blackburn, G. M.; Ollis, W. D.; Plackett, J. D.; Smith, C.; Sutherland, I. O. Chem. Commun. 1968, 186. (b) Baldwin, J. E.; Hackler, R. E.; Kelly, D. P. Chem. Commun. 1968, 537. (c) Kocienski, P. J. Chem. Commun. 1980, 1096. 105. (a) Hartley R. C.; Warren, S.; Richards, I. C. J. Chem. Soc., Perkin Trans. 1 1994, 507. (b) Hartley R. C.; Richards, I. C.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1996, 359. 106. Vedejs, E.; Hagen, J. P. J. Am. Chem. Soc. 1975, 97, 6878. 107. (a) Schmid, R.; Schmid, H. Helv. Chim. Acta 1977, 60, 1361. (b) Vedejs, E.; Mullins, M. J.; Renga, J. M.; Singer, S. P. Tetrahedron Lett. 1978, 519. (c) Vedejs, E. Acc. Chem. Res. 1984, 17, 358. 108. Ceré, V.; Paolucci, C.; Pollicino, S.; Sandri, E.; Fava, A. J. Org. Chem. 1978, 43, 4826. 109. Vedejs, E.; Arco, M. J.; Powell, D. W.; Renga, J. M.; Singer, S. P. J. Org. Chem. 1978, 43, 4831. 110. (a) Ceré, V.; Paolucci, C.; Pollicino, S.; Sandri, E.; Fava, A. J. Org. Chem. 1979, 44, 4128. (b) Ceré, V.; Paolucci, C.; Pollicino, S.; Sandri, E.; Fava, A. J. Org. Chem. 1981, 46, 3315. 111. (a) Vedejs, E.; Dolphin, J. M.; Mastalerz, H. J. Am. Chem. Soc. 1983, 105, 127. (b) Vedejs, E.; Reid, J. G.; J. Am. Chem. Soc. 1984, 106, 4617. (c) Vedejs, E.; Rodgers, J. D.; Wittenberger, S. J. J. Am. Chem. Soc. 1988, 110, 4822. 112. Vedejs, E.; Buchanan, R. A.; Conrad, P.; Meier, G. P.; Mullins, M. J.; Watanabe, Y. J. Am. Chem. Soc. 1987, 109, 5878. 113. Baldwin, J. E.; Hackler, R. E.; Kelly, D. P. Chem. Commun. 1968, 1083. 114. (a) Pourcelot, G.; Veniard, L.; Cadiot, P. Bull. Chim. Soc. Fr. 1975, 1275. (b) Ratovelomanana, V.; Julia, S. Synth. Commun. 1978, 8, 87. 115. Sashida, H.; Tsuchiya, T. Chem. Pharm. Bull. 1986, 34, 3644. 116. Hayashi, Y.; Oda, R. Tetrahedron Lett. 1968, 5381. 117. Julia, S.; Huynh, C.; Michelot, D. Tetrahedron Lett. 1972, 3587. 118. Ishibashi, H.; Tabata, T.; Kobayashi, T.; Takamuro, I.; Ikeda, M. Chem. Pharm. Bull. 1991, 39, 2878. 119. Trost, B. M.; Hammen, R. F. J. Am. Chem. Soc. 1973, 95, 962. 120. Campbell, S. J.; Darwish, D. Can. J. Chem. 1976, 54, 193. 121. Hioki, K.; Tani, S.; Sato, Y. Synthesis 1995, 649. 122. Vedejs, E.; Martinez, G. R. J. Am. Chem. Soc. 1979, 101, 6452. 123. Cohen, T.; Kosarych, Z.; Suzuki, K.; Yu, L.-C. J. Org. Chem. 1985, 50, 2965. 124. (a) Padwa, A.; Gasdaska, J. R. J. Org. Chem. 1986, 51, 2857. (b) Padwa, A.; Gas- daska, J. R. Tetrahedron 1988, 44, 4147. 125. Tanzawa, T.; Shirai, N.; Sato, Y.; Hatano, K.; Kurono, Y. J. Chem. Soc., Perkin Trans. 1, 1995, 2845. 126. Andrews, G.; Evans, D. A. Tetrahedron Lett. 1972, 5121. 127. (a) Ando, W.; Kondo, S.; Nakayama, K.; Ichibori, K.; Kohoda, H.; Yamato, H.; Imai, I.; Nakaido, S.; Migita, T. J. Am. Chem. Soc. 1972, 94, 3870. (b) Ando, W.; 102 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 103

1: Nitrogen, oxygen and sulfur ylides: an overview

Yagihara, T.; Tozune, S.; Imai, I.; Suzuki, J.; Toyama, T.; Nakaido, S.; Migita, T. J. Org. Chem. 1972, 37, 1721. 128. (a) Kondo, K.; Ojima, I. J. Chem. Soc., Chem. Commun. 1972, 63. (b) Kondo, K.; Ojima, I. J. Chem. Soc., Chem. Commun. 1972, 860. 129. Grieco, P. A.; Boxler, D.; Hiroi, K. J. Org. Chem. 1973, 38, 2572. 130. Doyle, M. P.; Tamblyn, W. H.; Bagheri, V. J. Org. Chem. 1981, 46, 5094. 131. Shi, G.; Xu, Y.; Xu, M. Tetrahedron 1991, 47, 1629. 132. Giddings, P. J.; John, D. I.; Thomas, E. J. Tetrahedron Lett. 1980, 21, 395. 133. Yoshimoto, M.; Ishihara, S.; Nakayama, E.; Soma, N. Tetrahedron Lett. 1972, 2923. 134. (a) Aggarwal, V. K.; Ford, J. G.; Thompson, A.; Jones, R. V. H.; Standen, M. C. H. J. Am. Chem. Soc. 1996, 118, 7004. (b) Aggarwal, V. K.; Ford, J. G.; Jones, R. V. H.; Fieldhouse, R. Tetrahedron: Asymmetry 1998, 9, 1801. 135. Davies, H. M. L.; Crisco, L. V. T. Tetrahedron Lett. 1987, 28, 371. 136. Moody, C. J.; Taylor, R. J. Tetrahedron 1990, 46, 6501. 137. Doyle, M. P.; Grifﬁn, J. H.; Chinn, M. S.; van Leusen, D. J. Org. Chem. 1984, 49, 1917. 138. Nickon, A.; Rodriguez, A.; Shirhatti, V.; Ganguly, R. Tetrahedron Lett. 1984, 25, 3555. 139. (a) Kido, F.; Sinha, S. C.; Abiko, T.; Yoshikoshi, A. Tetrahedron Lett. 1989, 30, 1575. (b) Kido, F.; Kazi, A. B.; Yoshikoshi, A. Chem. Lett. 1990, 613. (c) Kido, F.; Sinha, S. C.; Abiko, T.; Watanabe, M.; Yoshikoshi, A. Tetrahedron 1990, 46, 4887. 140. (a) Kido, F.; Yamaji, K.; Sinha, S. C.; Abiko, T.; Kato, M. Tetrahedron 1995, 51, 7697. (b) Kido, F.; Yamaji, K.; Sinha, S. C.; Yoshikoshi, A.; Kato, M. Chem. Com- mun. 1994, 789. (c) Kido, F.; Abiko, T.; Kato, M. J. Chem. Soc., Perkin. Trans. 1 1995, 2989. 141. Kido, F.; Abiko, T.; Kato, M. J. Chem. Soc., Perkin. Trans. 1 1992, 229. 142. Blackburn, G. M.; Ollis, W. D.; Smith, C.; Sutherland, I. O. Chem. Commun. 1969, 99. 143. Michelot, D.; Linstrumelle, G.; Julia, S. Chem. Commun. 1974, 10. 144. Hoye, T. R.; Dinsmore, C. J. Tetrahedron Lett. 1992, 33, 169. 145. Chow, T. J.; Tan, U.-K.; Peng, S.-M. Synth. Commun. 1988, 18, 519. 146. Ide, J.; Kishida, Y. Tetrahedron Lett. 1966, 1787. 147. Bende, Z.; Bitter, I.; To˝ke, L.; Weber, L.; Tóth, G.; Janke, F. Liebigs Ann. Chem. 1982, 2146. 148. Minguez, J. M.; Castellote, I.; Vaquero, J. J.; Garcia Navio, J. L.; Alvarez-Builla, J.; Castaño, O.; Andrés, J. L. Tetrahedron 1997, 53, 9341. 149. Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Lett. 1996, 37, 1707. 150. Vedejs, E.; Dax, S.; Martinez, G. R.; McClure, C. K. J. Org. Chem. 1987, 52, 3470. 151. Flanagan, M. E.; Williams, R. M. J. Org. Chem. 1995, 60, 6791. 152. Kanemasa, S.; Takenaka, S.; Watanabe, H.; Tsuge, O. J. Org. Chem. 1989, 54, 420. 153. (a) Dostál, J.; Potácˇek, M.; Humpa, O.; Marek, J. Bull. Soc. Chim. Belg. 1994, 103, 343. (b) Potácˇek, M.; Topinka, T.; Dostál, J.; Marek, J. Collect. Czech. Chem. Commun. 1994, 59, 2641. 154. Padwa, A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W. Tetrahedron 1985, 41, 3529. 155. Mínguez, J. M.; Castellote, M. I.; Vaquero, J. J.; García-Navio, J. L.; Alvarez- Builla, J.; Castaño, O.; Andrés, J. L. J. Org. Chem. 1996, 61, 4655. 103 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 104

J. S. Clark

156. (a) Grigg, R.; Kemp, J.; Sheldrick, G.; Trotter, J. J. Chem. Soc., Chem. Commun. 1978, 109. (b) Grigg, R.; Sridharan, V.; Suganthan, S.; Bridge, A. W. Tetrahedron 1995, 51, 295. (c) Grigg, R. Bull. Soc. Chim. Belg. 1984, 93, 593. 157. (a) Dondas, H. A.; Grigg, R.; Thornton-Pett, M. Tetrahedron 1996, 52, 13455. (b) Metwally, S. A. M.; Aly, M. F.; Abd-Alla, M. A.; Atta, F. M.; Abd-El-Monem, M. E. Liebigs Ann. Chem. 1991, 387. 158. Hamper, B. C.; Dukesherer, D. R.; South, M. S. Tetrahedron Lett. 1996, 37, 3671. 159. (a) Lakhliﬁ, T.; Sedqui, A.; Laude, B.; An, N. D.; Vebrel, J. Can. J. Chem. 1991, 69, 1156. (b) Lakhliﬁ, T.; Sedqui, A.; Fathi, T.; Laude, B.; Robert, J.-F. Can. J. Chem. 1994, 72, 1417. 160. (a) Lerestif, J. M.; Bazureau, J. P.; Hamelin, J. Synlett 1995, 647. (b) Lerestif, J. M.; Perrocheau, J.; Tonnard, F.; Bazureau, J. P.; Hamelin, J. Tetrahedron 1995, 51, 6757. 161. (a) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Chem. Lett. 1986, 973. (b) Tsuge, O.; Kanemasa, S.; Ohe, M.; Yorozu, K.; Takenaka, S.; Ueno, K. Chem. Lett. 1986, 1271. (c) Tsuge, O.; Kanemasa, S.; Ohe, M.; Yorozu, K.; Takenaka, S.; Ueno, K. Bull. Chem. Soc. Jpn. 1987, 60, 4067. 162. Joucla, M.; Mortier, J.; Hamelin, J.; Toupet, L. Bull. Soc. Chim. Fr. 1988, 143. 163. (a) Ardill, H.; Dorrity, M. J. R.; Grigg, R.; Leon-Ling, M.-S.; Malone, J. F.; Srid- haran, V.; Thianpatanagul, S. Tetrahedron 1990, 46, 6433. (b) Ardill, H.; Fontaine, X. L. R.; Grigg, R.; Henderson, D., Montgomery, J.; Sridharan, V.; Surendrakumar, S. Tetrahedron 1990, 46, 6449. (c) Grigg, R.; Coulter, T. Tetrahe- dron Lett. 1991, 1359. (d) Keller, E.; de Lange, B.; Rispens, M. T.; Feringa, B. L. Tetrahedron 1993, 49, 8899. (e) Nyerges, M.; Bitter, I.; Kádas, I.; Tóth, G.; To˝ke, L. Tetrahedron 1995, 51, 11489. (f) Lubineau, A.; Bouchain, G.; Queneau, Y. J. Chem. Soc., Perkin Trans. 1 1995, 2433. (g) Wittland, C.; Flörke, U.; Risch, N. Synthesis 1997, 1291. 164. (a) Martin, S. F.; Cheavens, T. H. Tetrahedron Lett. 1989, 30, 7017. (b) Kanemasa, S.; Doi, K.; Wada, E. Bull. Chem. Soc. Jpn. 1990, 63, 2866. 165. Felluga, F.; Pitacco, G.; Visintin, C.; Valentin, E. Helv. Chim. Acta 1997, 80, 1457. 166. Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Somasunderam, A. Tetrahedron 1993, 49, 8679. 167. (a) Anslow, A. S.; Harwood, L. M.; Phillips, H.; Watkin, D.; Wong, L. F. Tetrahe- dron: Asymmetry 1991, 2, 1343. (b) Harwood, L. M.; Kitchen, L. C. Tetrahedron Lett. 1993, 34, 6603. 168. Williams, R. M.; Zhai, W.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1992, 57, 6527. 169. Monnier, K.; Schmitt, G.; Laude, B.; Mercier, M.-F.; Kubicki, M. M.; Jannin, M. Can. J. Chem. 1995, 73, 181. 170. Peyronel, J.-F.; Grisoni, S.; Carboni, B.; Courgeon, T.; Carrié, R. Tetrahedron 1994, 50, 189. 171. (a) Padwa, A.; Chen, Y.-Y. Tetrahedron Lett. 1983, 24, 3447. (b) Padwa, A.; Dent, W. Org. Synth. 1989, 67, 133. 172. (a) Padwa, A.; Chen, Y.-Y.; Dent, W.; Nimmesgern, H. J. Org. Chem. 1985, 50, 4006. (b) Padwa, A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W. Tetrahedron 1985, 41, 3529. (c) Rispens, M. T.; Keller, E.; de Lange, B.; Zijlstra, R. W. J.; Feringa, B. L. Tetrahedron: Asymmetry 1994, 5, 607. 104 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 105

1: Nitrogen, oxygen and sulfur ylides: an overview

173. (a) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235. (b) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117. 174. (a) Pandey, G.; Bagul, T. D.; Lakshmaiah, G. Tetrahedron Lett. 1994, 35, 7439. (b) Pandey, G.; Lakshmaiah, G. Synlett 1994, 277. (c) Pandey, G.; Lakshmaiah, G. Tetrahedron Lett. 1993, 34, 4861. (d) Pandey, G.; Lakshmaiah, G.; Ghatak, A. Tetrahedron Lett. 1993, 34, 7301. 175. Bentley, J. M.; Smith, D. M.; Wadsworth, H. J.; Willis, C. L. J. Chem. Res. (S), 1993, 240. 176. (a) Ma, Z.; Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J. K.; Plagge, F.; Chu, D. T. W. Tetrahedron: Asymmetry 1997, 8, 883. (b) Kopach, M. E.; Fray, A. H.; Meyers, A. I. J. Am. Chem. Soc. 1996, 118, 9876. (c) Fray, A. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 3362. (d) Fray, A. H.; Meyers, A. I. Tetrahedron Lett. 1992, 33, 3575. (e) Wee, A. G. H. J. Chem. Soc., Perkin Trans. 1 1989, 1363. 177. (a) Bégué, J.-P.; Bonnet-Delpon, D.; Lequeux, T. Tetrahedron Lett. 1993, 34, 3279. (b) Bonnet-Delpon, D.; Bégué, J.-P.; Lequeux, T.; Ourevitch, M. Tetrahe- dron 1996, 52, 59. 178. (a) Tsuge, O.; Kanemasa, S.; Hatada, A.; Matsuda, K. Chem. Lett. 1984, 801. (b) Tsuge, O.; Kanemasa, S.; Hatada, A.; Matsuda, K. Bull. Chem. Soc. Jpn. 1986, 59, 2537. 179. (a) Poissonnet, G.; Potier, P.; Dodd, R. H. Tetrahedron Lett. 1989, 30, 3423. (b) Poissonnet, G.; Théret, M.-H.; Dodd, R. H. Heterocycles 1993, 36, 435. (c) Pois- sonnet, G.; Théret-Bettiol, M.-H.; Dodd, R. H. J. Org. Chem. 1996, 61, 2273. 180. (a) Fishwick, C. W. G.; Jones, A. D.; Mitchell, M. B.; Szantay, C. Jr. Tetrahedron Lett. 1988, 29, 5325. (b) Fishwick, C. W. G.; Foster, R. J.; Carr, R. E. Tetrahedron Lett. 1996, 37, 5163. (c) Fishwick, C. W. G.; Foster, R. J.; Carr, R. E. Tetrahedron Lett. 1996, 37, 3915. 181. (a) Padwa, A.; Haffmanns, G.; Tomas, M. J. Org. Chem. 1984, 49, 3314. (b) Tsuge, O.; Kanemasa, S.; Matsuda, K. J. Org. Chem. 1986, 51, 1997. (c) Tsuge, O.; Kanemasa, S.; Matsuda, K. Chem. Lett. 1985, 1411. 182. Heine, H. W.; Peavy, R. Tetrahedron Lett. 1965, 3123. 183. (a) Huisgen, R.; Scheer, W.; Szeimies, G.; Huber, H. Tetrahedron Lett. 1966, 397. (b) Huisgen, R.; Scheer, W.; Huber, H. J. Am. Chem. Soc. 1967, 89, 1753. (c) Huisgen, R.; Scheer, W.; Mäder, H. Angew. Chem., Int. Ed. Engl. 1969, 8, 602. (d) Huisgen, R.; Scheer, W.; Mäder, H.; Brunn, E. Angew. Chem., Int. Ed. Engl. 1969, 8, 604. (e) Huisgen, R.; Martin-Ramos, V.; Scheer, W. Tetrahedron Lett. 1971, 477. (f) Huisgen, R.; Scheer, W. Tetrahedron Lett. 1971, 481. 184. (a) Vedejs, E.; Grissom, J. W. J. Org. Chem. 1988, 53, 1882. (b) Mloston, G.; Skrzypek, Z. Bull. Soc. Chim. Belg. 1990, 99, 167. (c) Perrocheau, J.; Carrié, R. Bull. Soc. Chim. Belg. 1994, 103, 9. (d) Tanaka, K.; Nagatani, S.; Ohsuga, M.; Mit- suhashi, K. Bull. Chem. Soc. Jpn. 1994, 67, 589. (e) Coldham, I.; Collis, A. J.; Mould, R. J.; Robinson, D. E. Synthesis 1995, 1147. 185. Padwa, A.; Hamilton, L. Tetrahedron Lett. 1965, 4363. 186. (a) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1991, 56, 3210. (b) Sisko, J.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4945. (c) Irie, O.; Samizu, K.; Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1999, 64, 587. 187. (a) Henke, B. R.; Kouklis, A. J.; Heathcock, C. H. J. Org. Chem. 1992, 57, 7056. (b) Grifﬁth, D. A.; Heathcock, C. H. Tetrahedron Lett. 1995, 36, 2381. (c) Heath- cock, C. H.; Clasby, M.; Grifﬁth, D. A.; Henke, B. R.; Sharp, M. J. Synlett 1995, 105 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 106

J. S. Clark

467. (d) Denhart, D. J.; Grifﬁth, D. A.; Heathcock, C. H. J. Org. Chem. 1998, 63, 9616. 188. (a) DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309. (b) Toy- ota, M.; Nishikawa, Y.; Fukumoto, K. Heterocycles 1994, 39, 39. 189. Garner, P.; Dogan, O. J. Org. Chem. 1994, 59, 4. 190. Ramaiah, D.; Muneer, M.; Gopidas, K. R.; Das, P. K.; Rath, N. P.; George, M. V. J. Org. Chem. 1996, 61, 4240. 191. (a) Garner, P.; Sunitha, K.; Shanthilal, T. Tetrahedron Lett. 1988, 29, 3525. (b) Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J.; Kennedy, V. O. J. Org. Chem. 1991, 56, 5893. (c) Garner, P. P.; Cox, P. B.; Klippenstein, S. J.; Youngs, W. J.; McConville, D. B. J. Org. Chem. 1994, 59, 6510. (d) Garner, P.; Cox, P. B.; Anderson, J. T.; Protasiewicz, J.; Zaniewski, R. J. Org. Chem. 1997, 62, 493. 192. (a) Brigaud, T.; Laurent, E.; Tardivel, R.; Cebulska, Z.; Bartnik, R. J. Chem. Res. (S) 1994, 330. (b) Gaebert, C.; Mattay, J. Tetrahedron 1997, 53, 14297. 193. (a) Padwa, A.; Dean, D. C. J. Org. Chem. 1990, 55, 405. (b) Padwa, A.; Austin, D. J.; Precedo, L.; Zhi, L. J. Org. Chem. 1993, 58, 1144. (c) Padwa, A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A. J. Org. Chem. 1994, 59, 5347. 194. (a) Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1989, 111, 6451. (b) Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1992, 114, 593. (c) Padwa, A.; Dean, D. C.; Hertzog, D. L.; Nadler, W. R.; Zhi, L. Tetrahedron 1992, 48, 7565. 195. (a) Grigg, R.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 180. (b) Grigg, R.; Aly, M. F.; Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 182. (c) Grigg, R.; Surendrakumar, S.; Thianpatanagul, S.; Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 47. (d) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc., Chem. Commun. 1987, 49. (e) Aly, M. F.; Ardill, H.; Grigg, R.; Leong-Ling, S.; Rajviroongit, S.; Surendrakumar, S. Tetrahedron Lett. 1987, 28, 6077. (e) Ardill, H.; Grigg, R.; Sridharan, V.; Suren- drakumar, S. Tetrahedron 1988, 44, 4953. (f) Grigg, R.; Surendrakumar, S.; Thian- patanagul, S.; Vipond, D. J. Chem. Soc., Perkin Trans. 1 1988, 2693. (g) Grigg, R.; Idle, J.; McMeekin, P.; Surendrakumar, S.; Vipond, D. J. Chem. Soc., Perkin Trans. 1 1988, 2703. (h) Grigg, R.; Henderson, D.; Hudson, A. J. Tetrahedron Lett. 1989, 30, 2841. (i) Grigg, R.; Kennewell, P.; Savic, V.; Sridharan, V. Tetrahe- dron 1992, 48, 10423. (j) Ardill, H.; Grigg, R.; Malone, J. F.; Sridharan, V.; Thomas, W. A. Tetrahedron 1994, 50, 5067. 196. (a) Joucla, M.; Mortier, J. J. Chem. Soc., Chem. Commun. 1985, 1566. (b) Joucla, M.; Mortier, J. Bull. Soc. Chim. Fr. 1988, 579. (c) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron 1988, 44, 519. (d) Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti, M.; Merati, F.; Gariboldi, P. J. Heterocycl. Chem. 1988, 25, 1665. (e) Tsuge, O.; Kanemasa, S.; Ohe, M.; Yorozu, K.; Takenaka, S.; Ueno, K. Bull. Chem. Soc. Jpn. 1987, 60, 4067. (f) Kanemasa, S.; Sakamoto, K., Tsuge, O. Bull. Chem. Soc. Jpn. 1989, 62, 1960. (g) Casaschi, A.; Desimoni, G.; Faita, G.; Invernizzi, A. G.; Grünanger, P. Heterocycles 1994, 37, 1673. (h) Nyerges, M.; Balázs, L.; Kádas, I.; Bitter, I.; Kövesdi, I.; To˝ke, L. Tetrahedron 1995, 51, 6783. 197. (a) Vedejs, E.; Grissom, J. W. J. Am. Chem. Soc. 1986, 108, 6433. (b) Vedejs, E.; Grissom, J. W. J. Org. Chem. 1988, 53, 1876. (c) Vedejs, E.; Grissom, J. W. J. Am. Chem. Soc. 1988, 110, 3238. 106 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 107

1: Nitrogen, oxygen and sulfur ylides: an overview

198. (a) Vedejs, E.; Dax, S. L. Tetrahedron Lett. 1989, 30, 2627. (b) Vedejs, E.; Piotrowski, D. W. J. Org. Chem. 1993, 58, 1341. (c) Vedejs, E.; Monahan, S. D. J. Org. Chem. 1997, 62, 4763. 199. Hassner, A.; Fischer, B. J. Org. Chem. 1992, 57, 3070. 200. (a) Rouden, J.; Royer, J.; Husson, H.-P. Tetrahedron Lett. 1989, 30, 5133. (b) Deprez, P.; Royer, J.; Husson, H.-P. Tetrahedron: Asymmetry 1991, 2, 1189. (c) Deprez, P.; Rouden, J.; Chiaroni, A.; Riche, C.; Royer, J.; Husson, H.-P. Tetrahe- dron Lett. 1991, 32, 7531. 201. (a) Martel, S. R.; Wisedale, R.; Gallagher, T.; Hall, L. D.; Mahon, M. F.; Brad- bury, R. H.; Hales, N. J. J. Am. Chem. Soc. 1997, 119, 2309. (b) Martel, S. R.; Planchenault, D.; Wisedale, R.; Gallagher, T.; Hales, N. J. Chem. Commun. 1997, 1897. (c) Brown, D.; Brown, G. A.; Martel, S. R.; Planchenault, D.; Turmes, E.; Walsh, K. E.; Wisedale, R.; Hales, N. J.; Fishwick, C. W. G.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 2001, 1270. (d) Brown, G. A.; Martel, S. R.; Wisedale, R.; Charmant, J. P. H.; Hales, N. J.; Fishwick, C. W. G.; Gallagher, T. J. Chem. Soc., Perkin Trans. 1 2001, 1281. 202. (a) Beugelmans, R.; Negron, G.; Roussi, G. J. Chem. Soc., Chem. Commun. 1983, 31. (b) Beugelmans, R.; Benadjila-Iguertsira, L.; Chastanet, J.; Negron, G.; Roussi, G. Can. J. Chem. 1985, 63, 725. (c) Chastanet, J.; Roussi, G. J. Org. Chem. 1985, 50, 2910. (d) Chastanet, J.; Roussi, G. J. Org. Chem. 1988, 53, 3808. 203. (a) Roussi, G.; Zhang, J. Tetrahedron Lett. 1988, 29, 3481. (b) Roussi, G.; Zhang, J. Tetrahedron 1991, 47, 5161. (c) Negron, G.; Roussi, G.; Zhang, J. D. Hetero- cycles 1992, 34, 293. (d) Chastanet, J.; Fathallah, H.; Negron, G.; Roussi, G. Heterocycles 1992, 34, 1565. 204. (a) Roussi, G. Heterocycles 1990, 31, 1445. (b) Takano, S.; Sugihara, Y.; Oga- sawara, K. Heterocycles 1992, 34, 1519. 205. Tsuge, O.; Kanemasa, S.; Yorozu, K.; Ueno, K. Bull. Chem. Soc. Jpn. 1987, 60, 3359. 206. (a) Grigg, R.; Montgomery, J.; Somasunderam, A. Tetrahedron, 1992, 48, 10431. (b) Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell, P.; Redpath, J. Tetra- hedron 1995, 51, 7791. (c) Pyne, S. G.; Safaei-G., J.; Koller, F. Tetrahedron Lett. 1995, 36, 2511. (d) Bonnet-Delpon, D.; Chennouﬁ, A.; Rock, M. H. Bull. Soc. Chim. Fr. 1995, 132, 402. (e) Nyerges, M.; Rudas, M.; Tóth, G.; Herényi, B.; Kádas, I.; Bitter, I.; To˝ke, L. Tetrahedron 1995, 51, 13321. (f) Nyerges, M.; Rudas, M.; Bitter, I.; To˝ke, L.; Szántay, C. Tetrahedron 1997, 53, 3269. (g) Javidan, A.; Schafer, K.; Pyne, S. G. Synlett 1997, 100. 207. (a) Kanemasa, S.; Yamamoto, H.; Wada, E.; Sakurai, T.; Urushido, K. Bull. Chem. Soc. Jpn. 1990, 63, 2857. (b) Kanemasa, S.; Hayashi, T.; Tanaka, J.; Yamamoto, H.; Sakurai, T. J. Org. Chem. 1991, 56. 4473. (c) Pätzel, M.; Galley, G.; Jones, P. G.; Chrapkowsky, A. Tetrahedron Lett. 1993, 34, 5707. (d) Galley, G.; Liebscher, J.; Pätzel, M. J. Org. Chem. 1995, 60, 5005. 208. (a) Waldmann, H.; Bläser, E.; Jansen, M.; Letschert, H.-P. Angew. Chem., Int. Ed. Engl. 1994, 33, 683. (b) Waldmann, H.; Bläser, E.; Jansen, M.; Letschert, H.-P. Chem.–Eur. J. 1995, 1, 150. (c) Barr, D. A.; Dorrity, M. J.; Grigg, R.; Har- greaves, S.; Malone, J. F.; Montgomery, J.; Redpath, J.; Stevenson, P.; Thornton- Pett, M. Tetrahedron 1995, 51, 273. 209. (a) Barr, D. A.; Dorrity, M. J.; Grigg, R.; Malone, J. F.; Montgomery, J.; Raj- viroongit, S.; Stevenson, P. Tetrahedron Lett. 1990, 31, 6569. (b) Kanemasa, S.; Uchida, O.; Wada, E.; Yamamoto, H. Chem. Lett. 1990, 105. 107 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 108

J. S. Clark

210. Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817. 211. Alvarez-Ibarra, C.; Csákÿ, A. G.; Martínez, M.; Quiroga, M. L. Tetrahedron Lett. 1996, 37, 6573. 212. (a) Grigg, R.; Heaney, F. J. Chem. Soc., Perkin Trans. 1 1989, 198. 213. (a) Yoon, U. C.; Kim, D. U.; Kim, J. C.; Lee, J. G.; Mariano, P. S.; Lee, Y. J.; Ammon, H. L. Tetrahedron Lett. 1993, 34, 5859. (b) Yoon, U. C.; Kim, D. U.; Lee, C. W.; Choi, Y. S.; Lee, Y.-J.; Ammon, H. L.; Mariano, P. S. J. Am. Chem. Soc. 1995, 117, 2698. (c) Yoon, U. C.; Cho, S. J.; Lee, Y.-J.; Mancheno, M. J.; Mariano, P. S. J. Org. Chem. 1995, 60, 2353. 214. (a) Allway, P. A.; Sutherland, J. K.; Joule, J. A. Tetrahedron Lett. 1990, 31, 4781. (b) Yates, N. D.; Peters, D. A.; Allway, P. A.; Beddoes, R. L.; Scopes, D. I. C.; Joule, J. A. Heterocycles 1995, 40. 331. (c) Peters, D. A.; Yates, N. D.; Scopes, D. I. C.; Joule, J. A. Heterocycles 1995, 40. 983. 215. Huisgen, R. Angew. Chem., Int. Ed. Engl. 1977, 16, 572. 216. Meier, K.-R.; Linden, A.; Mloston´, G.; Heimgartner, H. Helv. Chim. Acta 1997, 80, 1190. 217. Chou, W.-N.; White, J. B. Tetrahedron Lett. 1991, 32, 7637. 218. (a) Brokatzky, J.; Eberbach, W. Chem. Ber. 1981, 114, 384. (b) Brokatzky-Geiger, J.; Eberbach, W. Tetrahedron Lett. 1982, 23, 4665. (c) Brokatzky-Geiger, J.; Eber- bach, W. Chem. Ber. 1983, 116, 2383. 219. Bernaus, C.; Font, J.; de March, P. Tetrahedron 1991, 47, 7713. 220. O’Shea, D. F.; Sharp, J. T. J. Chem. Soc., Perkin Trans. 1 1996, 515. 221. Wong, J. P. K.; Fahmi, A. A.; Grifﬁn, G. W.; Bhacca, N. S. Tetrahedron 1981, 37, 3345. 222. (a) Brokatzky-Geiger, J.; Eberbach, W. Heterocycles 1983, 20, 1519. (b) Brokatzky-Geiger, J.; Eberbach, W. Tetrahedron Lett. 1984, 25, 1137. (c) Brokatzky-Geiger, J.; Eberbach, W. Chem. Ber. 1984, 117, 2157. 223. (a) Clawson, P.; Lunn, P. M.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1990, 153. (b) Clawson, P.; Lunn, P. M.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1990, 159. (c) Clawson, P.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1990, 1193. 224. (a) Kotera, M.; Ishii, K.; Tamura, O.; Sakamoto, M. J. Chem. Soc., Perkin Trans. 1 1994, 2353. (b) Ishii, K.; Kotera, M.; Nakano, T.; Zenko, T.; Sakamoto, M.; Iida, I.; Nishio, T. Leibigs Ann. Chem. 1995, 19. (c) Kotera, M.; Ishii, K.; Sakamoto, M. Chem. Pharm. Bull. 1995, 43, 1621. (d) Kotera, M.; Ishii, K.; Tamura, O.; Sakamoto, M. J. Chem. Soc., Perkin Trans. 1 1998, 313. (e) Kotera, M.; Ishii, K.; Hiraga, M.; Sakamoto, M. Heterocycles 1999, 51, 2147. 225. Warkentin, J. J. Chem. Soc., Perkin Trans. 1 2000, 2161. 226. Rajagopalan, P.; Advani, B. G. Tetrahedron Lett. 1967, 2689. 227. (a) Bekhazi, M.; Warkentin, J. J. Am. Chem. Soc. 1981, 103, 2473. (b) Békhazi, M.; Warkentin, J. Can. J. Chem. 1983, 61, 619. (c) Zoghbi, M.; Warkentin, J. J. Org. Chem. 1991, 56, 3214. (d) El-Saidi, M.; Kassam, K.; Pole, D. L.; Tadey, T.; Warkentin, J. J. Am. Chem. Soc. 1992, 114, 8751. (e) Zoghbi, M.; Warkentin, J. Can. J. Chem. 1992, 70, 2967. (f) Zoghbi, M.; Warkentin, J. Can. J. Chem. 1993, 71, 907. (g) Zoghbi, M.; Warkentin, J. Can. J. Chem. 1993, 71, 912. (h) Kassam, K.; Warkentin, J. J. Org. Chem. 1994, 59, 5071. (i) Sharma, P. K.; Warkentin, J. Tetrahedron Lett. 1995, 36, 7591. (j) Couture, P.; El-Saidi, M.; Warkentin, J. Can. J. Chem. 1997, 75, 326. 108 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 109

1: Nitrogen, oxygen and sulfur ylides: an overview

228. Yang, R.-Y.; Dai, L.-X. J. Org. Chem. 1993, 58, 3381. 229. Chiba, T.; Okimoto, M. J. Org. Chem. 1992, 57, 1375. 230. Hojo, M.; Ohkuma, M.; Ishibashi, N.; Hosomi, A. Tetrahedron Lett. 1993, 34, 5943. 231. (a) Hojo, M.; Aihara, H.; Hosomi, A. J. Am. Chem. Soc. 1996, 118, 3533. (b) Hojo, M.; Aihara, H.; Ito, H.; Hosomi, A. Tetrahedron Lett. 1996, 37, 9241. (c) Hojo, M.; Aihara, H.; Suginohara, Y.; Sakata, K.; Nakamura, S.; Murakami, C.; Hosomi, A. J. Org. Chem. 1997, 62, 8610. 232. Takai, K.; Kaihara, H.; Higashiura, K.; Ikeda, N. J. Org. Chem. 1997, 62, 8612. 233. Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765. 234. de March, P.; Huisgen, R. J. Am. Chem. Soc. 1982, 104, 4952. 235. Janulis, E. P., Jr; Arduengo, A. J., III. J. Am. Chem. Soc. 1983, 105, 5929. 236. (a) Alt, M.; Maas, G. Tetrahedron 1994, 50, 7435. (b) Alt, M.; Maas, G. Chem. Ber. 1994, 127, 1537. (c) Doyle, M. P.; Forbes, D. C.; Protopopova, M. N.; Stanley, S. A.; Vasbinder, M. M.; Xavier, K. R. J. Org. Chem. 1997, 62, 7210. (d) Hama- guchi, M.; Matsubara, H.; Nagai, T. Tetrahedron Lett. 2000, 41, 1457. 237. (a) Gillon, A.; Ovadia, D.; Kapon, M.; Bien, S. Tetrahedron 1982, 38, 1477. (b) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Price, A. T. Tetrahedron Lett. 1992, 33, 6427. (c) Cox, G. G.; Moody, C. J.; Austin, D. J.; Padwa, A. Tetrahedron 1993, 49, 5109. (d) Padwa, A.; Austin, D. J.; Hornbuckle, S. F. J. Org. Chem. 1996, 61, 63. 238. (a) Dean, D. C.; Krumpe, K. E.; Padwa, A. J. Chem. Soc., Chem. Commun. 1989, 921. (b) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z. J. J. Org. Chem. 1991, 56, 3271. (c) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1996, 61, 73. (d) Muthusamy, S.; Babu, S. A.; Gunanathan, C.; Suresh, E.; Dasti- dar, P.; Jasra, R. V. Tetrahedron 2000, 56, 6307. (e) Padwa, A.; Zhang, Z. J.; Zhi, L. J. Org. Chem. 2000, 65, 5223. 239. (a) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhi, L. Tetrahedron Lett. 1989, 30, 301. (b) Padwa, A.; Sandanayaka, V. P.; Curtis, E. A. J. Am. Chem. Soc. 1994, 116, 2667. (c) Curtis, E. A.; Sandanayaka, V. P.; Padwa, A. Tetrahedron Lett. 1995, 36, 1989. (d) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1997, 62, 1317. (e) Kinder, F. R., Jr; Bair, K. W. J. Org. Chem. 1994, 59, 6965. 240. (a) Ibata, T.; Toyoda, J. Chem. Lett. 1983, 1453. (b) Ibata, T.; Toyoda, J. Bull. Chem. Soc. Jpn. 1985, 58, 1787. (c) Ibata, T.; Toyoda, J. Bull. Chem. Soc. Jpn. 1986, 59, 2489. (d) Ibata, T.; Toyoda, J.; Sawada, M.; Tanaka, T. J. Chem. Soc., Chem. Commun. 1986, 1266. (e) Ibata, T.; Nakano, H.; Tamura, H. Bull. Chem. Soc. Jpn. 1992, 65, 1362. (f) Suga, H.; Ishida, H.; Ibata, T. Tetrahedron Lett. 1998, 39, 3165. 241. Padwa, A.; Stull, P. D. Tetrahedron Lett. 1987, 28, 5407. 242. Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Zhang, Z. J. J. Org. Chem. 1992, 57, 5747. 243. (a) Padwa, A. Acc. Chem. Res. 1991, 24, 22. (b) Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. J. Org. Chem. 1993, 58, 4646. 244. (a) Curtis, E. A.; Worsencroft, K. J.; Padwa, A. Tetrahedron Lett. 1997, 38, 3319. (b) Baldwin, J. E.; Mayweg, A. V. W.; Neumann, K.; Pritchard, G. J. Org. Lett. 1999, 1, 1933. (c) Padwa, A.; Precedo, L.; Semones, M. A. J. Org. Chem. 1999, 64, 4079. 109 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 110

J. S. Clark

245. (a) Dauben, W. G.; Dinges, J.; Smith. T. C. J. Org. Chem. 1993, 58, 7635. (b) McMills, M. C.; Zhuang, L.; Wright, D. L.; Watt, W. Tetrahedron Lett. 1994, 35, 8311. 246. (a) Koyama, H.; Ball, R. G.; Berger, G. D. Tetrahedron Lett. 1994, 35, 9185. (b) Kataoka, O.; Kitagaki, S.; Watanabe, N.; Kobayashi, J.; Nakamura, S.; Shiro, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 2371. (c) Hodgson, D. M.; Bailey, J. M.; Villalonga-Barber, C.; Drew, M. G. B.; Harrison, T. J. Chem. Soc., Perkin Trans. 1 2000, 3432. 247. (a) Padwa, A.; Krumpe, K. E.; Gareau, Y.; Chiacchio, U. J. Org. Chem. 1991, 56, 2523. (b) Padwa, A. J. Organomet. Chem. 2000, 610, 88. 248. (a) Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1992, 114, 593. (b) Padwa, A.; Dean, D. C.; Hertzog, D. L.; Nadler, W. R.; Zhi, L. Tetrahedron 1992, 48, 7565. 249. (a) Padwa, A.; Price, A. T.; Zhi, L. J. Org. Chem. 1996, 61, 2283. (b) Kissel, W. S.; Padwa, A. Tetrahedron Lett. 1999, 40, 4003. 250. Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556. 251. (a) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123. (b) Padwa, A.; Coats, S. J.; Hadjiarapoglou, L. Heterocycles 1995, 41, 1631. 252. (a) Maier, M. E.; Evertz, K. Tetrahedron Lett. 1988, 29, 1677. (b) Maier, M. E.; Schöfﬂing, B. Chem. Ber. 1989, 122, 1081. 253. (a) Padwa, A.; Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J. Org. Chem. 1994, 59, 1418. (b) Miah, S.; Slawin, A. M. Z.; Moody, C. J.; Sheehan, S. M.; Marino, J. P., Jr; Semones, M. A.; Padwa, A.; Richards, I. C. Tetrahedron 1996, 52, 2489. 254. Padwa, A.; Hertzog, D. L.; Nadler, W. R. J. Org. Chem. 1994, 59, 7072. 255. (a) Hamaguchi, M.; Ibata, T. Tetrahedron Lett. 1974, 4475. (b) Doyle, M. P.; Pieters, R. J.; Taunton, J.; Pho, H. Q.; Padwa, A.; Hertzog, D. L.; Precedo, L. J. Org. Chem. 1991, 56, 820. (c) Prein, M.; Padwa, A. Tetrahedron Lett. 1996, 37, 6981. (d) Padwa, A. Top. Curr. Chem. 1997, 189, 121. (e) Savinov, S. N.; Austin, D. J. Chem. Commun. 1999, 1813. 256. (a) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett. 1997, 38, 6471. (b) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem. Commun. 1999, 2185. 257. (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.; Watanabe, N.; Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417. (b) Kitagaki, S.; Yasugahira, M.; Anada, M.; Nakajima, M.; Hashimoto, S. Tetrahedron Lett. 2000, 41, 5931. 258. (a) Ibata, T.; Liu, M. T. H.; Toyoda, J. Tetrahedron Lett. 1986, 27, 4383. (b) Ibata, T.; Toyoda, J.; Liu, M. T. H. Chem. Lett. 1987, 2135. 259. Fairfax, D. J.; Austin, D. J.; Xu, S. L.; Padwa, A. J. Chem. Soc., Perkin Trans. 1 1992, 2837. 260. Schultz, A. G. Acc. Chem. Res. 1983, 16, 210. 261. Dittami, J. P.; Nie, X. Y.; Nie, H.; Ramanathan, H.; Breining, S.; Bordner, J.; Decosta, D. L.; Kiplinger, J.; Reiche, P.; Ware, R. J. Org. Chem. 1991, 56, 5572. 262. Matsumoto, K.; Ikemi, Y.; Toda, M.; Kakehi, A.; Uchida, T.; Lown, J. W. Tetra- hedron Lett. 1995, 36, 3011. 263. (a) Kamata, M.; Miyashi T. J. Chem. Soc., Chem. Commun. 1989, 557. (b) Glass, R. S.; Jung, W. J. Am. Chem. Soc. 1994, 116, 1137. 110 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 111

1: Nitrogen, oxygen and sulfur ylides: an overview

264. (a) Huisgen, R.; Fulka, C.; Kalwinsch, I.; Xingya, L.; Mloston, G.; Moran, J. R.; Pröbstl, A. Bull. Soc. Chim. Belg. 1984, 93, 511. (b) Huisgen, R. Chem. Pharm. Bull. 2000, 48, 757. 265. (a) Huisgen, R.; Mloston, G. Tetrahedron Lett. 1985, 26, 1049. (b) Mloston, G.; Huisgen, R. Tetrahedron Lett. 1985, 26, 1053. 266. (a) Mloston´, G.; Heimgartner, H. Helv. Chim. Acta 1992, 75, 1825. (b) Kägi, M.; Linden, A.; Heimgartner, H.; Mloston´, G. Helv. Chim. Acta 1993, 76, 1715. (c) Mloston´, G.; Petit, M.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1994, 77, 435. (d) Kägi, M.; Mloston´, G.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1994, 77, 1299. 267. (a) Huisgen, R.; Langhals, E.; Nöth, H. Tetrahedron Lett. 1986, 27, 5475. (b) Huis- gen, R.; Langhals, E.; Mloston, G.; Oshima, T. Heterocycles 1989, 29, 2069. (c) Mloston´, G. Bull. Soc. Chim. Belg. 1990, 99, 265. (d) Huisgen, R.; Mloston, G. Heterocycles 1990, 30, 737. (e) Mloston´, G.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1991, 74, 1386. (f) Zoghbi, M.; Warkentin, J. Tetrahedron 1993, 49, 10229. (g) Mloston´, G.; Gendek, T.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1998, 81, 66. (h) Mloston´, G.; Gendek, T.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1999, 82, 290. 268. Alcázar, V.; Tapia, I.; Morán, J. R. Tetrahedron 1990, 46, 1057. 269. (a) Villalgordo, J. M.; Enderli, A.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 1995, 78, 1983. (b) Kägi, M.; Linden, A.; Mloston´, G.; Heimgartner, H. Helv. Chim. Acta 1996, 79, 855. (c) Mloston´, G.; Roman´ski, J.; Linden, A.; Heimgart- ner, H. Helv. Chim. Acta 1997, 80, 1992. (d) Kägi, M.; Linden, A.; Mloston´, G.; Heimgartner, H. Helv. Chim. Acta 1998, 81, 285. 270. (a) Terao, Y.; Tanaka, M.; Imai, N.; Achiwa, K. Tetrahedron Lett. 1985, 26, 3011. (b) Terao, Y.; Aono, M.; Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 1734. (c) Yamano, T.; Tanaka, M.; Takanohashi, K. Heterocycles 1993, 36, 2397. 271. (a) Hosomi, A.; Matsuyama, Y.; Sakurai, H. J. Chem. Soc., Chem. Commun. 1986, 1073. (b) Hosomi, A.; Hayashi, S.; Hoashi, K.; Kohra, S.; Tominaga, Y. J. Chem. Soc., Chem. Commun. 1987, 1442. (c) Karlsson, S.; Högberg, H.-E. Org. Lett. 1999, 1, 1667. 272. (a) Aono, M.; Terao, Y.; Achiwa, K. Chem. Lett. 1987, 1851. (b) Aono, M.; Terao, Y.; Achiwa, K. J. Pharm. Sci. 1987, 76, S138. 273. (a) Aono, M.; Hyodo, C.; Terao, Y.; Achiwa, K. Tetrahedron Lett. 1986, 27, 4039. (b) Terao, Y.; Aono, M.; Takahashi, I.; Achiwa, K. Chem. Lett. 1986, 2089. (c) Aono, M.; Terao, Y.; Achiwa, K. Heterocycles 1995, 40, 249. 274. McGimpsey, W. G.; Scaiano, J. C. Tetrahedron Lett. 1986, 27, 547. 275. Mloston´, G.; Romanski, J.; Swia˛tek, A.; Heimgartner, H. Helv. Chim. Acta 1999, 82, 946. 276. (a) Mloston´, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta 1996, 79, 1537. (b) Mloston´, G.; Heimgartner, H. Helv. Chim. Acta 1996, 79, 1785. (c) Ham- aguchi, M.; Funakoshi, N.; Oshima, T. Tetrahedron Lett. 1999, 40, 8117. 277. Saito, T.; Kikuchi, H.; Kondo, A. Synthesis 1995, 87. 278. (a) Ibata, T.; Nakano, H. Bull. Chem. Soc. Jpn. 1992, 65, 3088. (b) Nakano, H.; Ibata, T. Bull. Chem. Soc. Jpn. 1995, 68, 1393. 279. (a) Padwa, A.; Kinder, F. R.; Zhi, L. Synlett 1991, 287. (b) Padwa, A.; Kinder, F. R.; Nadler, W. R.; Zhi, L. Heterocycles 1993, 35, 367. 111 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 112

J. S. Clark

280. (a) Dittami, J. P.; Nie, X. Y.; Nie, H.; Ramanathan, H.; Buntel, C.; Rigatti, S.; Bordner, J.; Decosta, D. L.; Williard, P. J. Org. Chem. 1992, 57, 1151. (b) Dittami, J. P.; Luo, Y.; Moss, D.; McGimpsey, W. G. J. Org. Chem. 1996, 61, 6256. 281. (a) Potts, K. T.; Dery, M. O. J. Chem. Soc., Chem. Commun. 1986, 561. (b) Potts, K. T.; Dery, M. O.; Juzukonis, W. A. J. Org. Chem. 1989, 54, 1077. 282. Bird, C. W.; Cheeseman, G. W. H. In Comprehensive Heterocyclic Chemistry; Bird, C. W.; Cheeseman, G. W. H., eds; Pergamon Press: Oxford, 1984, vol. 4, Ch. 3.03, pp. 89–153. 283. Hansen, H.-J.; Heimgartner, H. In 1,3-Dipolar Cycloaddition Chemistry, Padwa, A.; ed.; John Wiley & Sons, New York, 1984, pp. 177–290. 284. (a) Huisgen, R.; Stangl, H.; Sturm, H. J.; Wagenhofer, H. Angew. Chem., Int. Ed. Engl. 1962, 1, 50. (b) Huisgen, R.; Stangl, H.; Sturm, H. J.; Raab, R.; Bunge, K. Chem. Ber. 1972, 105, 1258. (c) Bunge, K.; Huisgen, R.; Raab, R.; Sturm, H. J. Chem. Ber. 1972, 105, 1307. 285. (a) Ried, W.; Fulde, M. Helv. Chim. Acta 1988, 71, 1681. (b) Perrocheau, J.; Dan- ion, D.; Carrié, R. Bull. Soc. Chim. Belg. 1995, 104, 39. 286. (a) Bossio, R.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 1986, 27, 4643. (b) Berrée, F.; Marchand, E.; Morel, G. Tetrahedron Lett. 1992, 33, 6155. 287. Padwa, A.; Ku, A. J. Am. Chem. Soc. 1978, 100, 2181. 288. (a) Groundwater, P. W.; Struthers-Semple C.; Sharp, J. T. J. Chem. Soc., Chem. Commun. 1987, 1367. (b) Cullen, K. E.; Sharp, J. T. J. Chem. Soc., Chem. Com- mun. 1991, 658. (c) Motion, K. R.; Robertson, I. R.; Sharp, J. T.; Walkinshaw, M. D. J. Chem. Soc., Perkin Trans. 1 1992, 1709. (d) Groundwater, P. W.; Sharp, J. T. Tetrahedron 1992, 48, 7951. (e) Cullen, K. E.; Sharp, J. T. J. Chem. Soc., Perkin Trans. 1 1993, 2961. (f) Finch, H.; Reece, D. H.; Sharp, J. T. J. Chem. Soc., Perkin Trans. 1 1994, 1193. (g) Strachan, J.-P.; Sharp, J. T.; Parsons, S. Chem. Commun. 1996, 2739. 289. (a) Burger, K.; Fehn, J. Chem. Ber. 1972, 105, 3814. (b) Burger, K.; Tremmel, S.; Roth, W.-D.; Goth, H. J. Heterocycl. Chem. 1981, 18, 247. 290. (a) Wipf, P.; Prewo, R.; Bieri, J. H.; Germain, G.; Heimgartner, H. Helv. Chim. Acta 1988, 71, 1177. (b) Bozhkova, N.; Heimgartner, H. Helv. Chim. Acta 1989, 72, 825. 291. Carlsen, P. H. J.; Jørgensen, K. B. J. Heterocycl. Chem. 1997, 34, 797. 292. Pﬂeiderer, W. Heterocycles 1989, 28, 203. 293. (a) Padwa, A.; Smolanoff, J. J. Am. Chem. Soc. 1971, 93, 548. (b) Padwa, A.; Dha- ran, M.; Smolanoff, J.; Wetmore, S. I., Jr. J. Am. Chem. Soc. 1973, 95, 1954. (c) Padwa, A.; Dharan, M.; Smolanoff, J.; Wetmore, S. I., Jr. Pure Appl. Chem. 1973, 33, 269. (d) Padwa, A. Acc. Chem. Res. 1976, 9, 371. 294. (a) Naito, I.; Morihara, H.; Ishida, A.; Takamuku, S.; Isomura, K.; Taniguchi, H. Bull. Chem. Soc. Jpn. 1991, 64, 2757. (b) Naito, I.; Fujiwara, Y.; Tanimoto, Y.; Ishida, A.; Takamuku, S. Bull. Chem. Soc. Jpn. 1995, 68, 2905. 295. Albrecht, E.; Mattay, J.; Steenken, S. J. Am. Chem. Soc. 1997, 119, 11605. 296. (a) Giezendanner, H.; Märky, M.; Jackson, B.; Hansen, H.-J.; Schmid, H. Helv. Chim. Acta 1972, 55, 745. (b) Gilgen, P.; Jackson, B.; Hansen, H.-J.; Heimgartner, H.; Schmid, H. Helv. Chim. Acta 1974, 57, 2634. 297. Padwa A.; Kamigata, N. J. Am. Chem. Soc. 1977, 99, 1871. 298. Hickey, D. M. B.; Moody, C. J.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1986, 1119. 112 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 113

1: Nitrogen, oxygen and sulfur ylides: an overview

299. (a) Turro, N. J.; Cha, Y.; Gould, I. R.; Padwa, A.; Gasdaska, J. R.; Tomas, M. J. Org. Chem. 1985, 50, 4415. (b) Padwa, A.; Gasdaska, J. R.; Tomas, M. Turro, N. J.; Cha, Y.; Gould, I. R. J. Am. Chem. Soc. 1986, 108, 6739. (c) Naito, I.; Naka- mura, K.; Kumagai, T.; Oku, A.; Hori, K.; Matsuda, K.; Iwamura, H. J. Phys. Chem. A 1999, 103, 8187. 300. Scaiano, J. C.; McGimpsey, W. G.; Casal, H. L. J. Am. Chem. Soc. 1985, 107, 7204. 301. (a) Janulis, E. P., Jr; Arduengo, A. J., III. J. Am. Chem. Soc. 1983, 105, 3563. (b) Janulis, E. P., Jr; Wilson, S. R.; Arduengo, A. J., III. Tetrahedron Lett. 1984, 25, 405. 302. (a) Ibata, T.; Fukushima, K. Chem. Lett. 1992, 2197. (b) Fukushima, K.; Ibata, T. Heterocycles 1995, 40, 149. (c) Fukushima, K.; Ibata, T. Bull. Chem. Soc. Jpn. 1995, 68, 3469. (d) Fukushima, K.; Lu, Y.-Q.; Ibata, T. Bull. Chem. Soc. Jpn. 1996, 69, 3289.

113 Clark Ch1 001-113 FINAL 27/5/02 10:36 am Page 114