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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 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 con- cerning 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 ammo- nium 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 J. S. Clark 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 gen- erated 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 enantiomeri- cally 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] rearrange- ment 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 1: Nitrogen, oxygen and sulfur ylides: an overview 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 (8Ǟ9) 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 demon- strated 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 addi- tional 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 J. S. Clark 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 under- goes 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 4 Clark Ch1 001-113 FINAL 27/5/02 10:35 am Page 5 1: Nitrogen, oxygen and sulfur ylides: an overview 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 sub- sequent base-promoted deprotonation of the resulting quaternary ammonium salt sometimes leads to poor yields. However, Coldham has recently de- veloped an improved one-pot procedure for the generation of ammonium ylides by N-alkylation of the N-allylic ␣-amino ester 25 and in situ deproton- ation (Scheme 6).16 Spontaneous [2,3] rearrangement of the intermediate ammonium ylide delivers the N,N-dialkylated allyl glycine ester 26 in reason- able 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] rearrange- ment 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.
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