LETTER 2191 Sulfur Ylide Mediated Three-Component Aziridination and Epoxidation Reactions Using Vinyl Sulfonium Salts Three-ComponentChristoforos Aziridination and Epoxidation Reactions G. Kokotos, Eoghan M. McGarrigle, Varinder K. Aggarwal* School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK Fax +44(117)9298611; E-mail: [email protected] Received 18 July 2008 This paper is dedicated with deep respect to Prof. Sir Jack Baldwin on the occasion of his 70th birthday. Although vinyl sulfonium salts such as 2 have been em- Abstract: Coupling of diphenylvinyl sulfonium triflate with nu- cleophiles and either aldehydes or imines gives epoxides and aziri- ployed in two-component reactions (nucleophiles with dines, respectively, in a three-component reaction. cis-Aziridines tethered electrophiles) generating 5-, 6-, and 7-membered could be formed in good diastereomeric ratio, and the selectivity ring epoxides and aziridines and subsequently applied to was correlated to the reactivity of the imine. This represents the first the synthesis of mitomycins3 and balanol,2b,c their use in study of cis/trans selectivity in the reactions of imines with non- three-component coupling reactions has not been investi- stabilized sulfur ylides. gated.4 Key words: sulfur ylides, epoxidations, aziridinations, multicom- However, initial experiments with N-methyl tosylamide ponent reactions, vinyl sulfonium salts (1a), diphenylvinylsulfonium salt 2, and benzaldehyde in the presence of NaH were not promising – a large number of products were obtained, some of which were highly po- Three-component coupling reactions have not only been lar. We believed that the ylide intermediate 3 was prefer- employed to enhance efficiency in organic synthesis but entially reacting with the vinyl sulfonium salt instead of have also played a central role in diversity-oriented syn- 1 the aldehyde. To minimize this side reaction we needed to thesis. The key to success in the development of such re- increase the concentration of the aldehyde and reduce the actions is controlled reactivity. Nucleophile A (e.g., a concentration of the vinyl sulfonium salt. Indeed, carrying cuprate) should react selectively with electrophile B (e.g., out a slow addition of the vinyl sulfonium salt to a solu- an enone) generating an intermediate nucleophile AB tion of the tosyl amide 1a, NaH and five equivalents of which should then react selectively with electrophile C benzaldehyde furnished the epoxide in good yield (e.g., an aldehyde), all other permutations (e.g. A+C or (Table 1, entry 1). Brief optimization of the reaction con- AB+C) should be slow or unproductive (Scheme 1). Our t 2 ditions showed that KO -Bu in CH2Cl2 was optimal (entry interest in vinyl sulfonium salts led us to consider their 2). The reaction could be extended to a range of alterna- potential use in these types of processes. In particular, the tive nucleophiles including malonate 1b (entry 3), an al- trapping of an intermediate ylide 3 with an aldehyde 4 or cohol 1c (entry 4), a thiol 1d (entry 5), and an amine 1e imine 5 would furnish an epoxide 6 or aziridine 7, which (entry 6). In all cases, the epoxides 6 were obtained in are very useful products for further elaboration good yields but with poor diastereoselectivity. The low (Scheme 2). diastereoselectivities are typical of reactions of non- stabilized ylides with aldehydes,5 but the moderate-to- high yields are not (they usually give low yields). We be- C AB A AB C B lieve the high yields are a consequence of rapid (in situ) Scheme 1 General scheme for three-component reaction trapping of the ylide. The reaction, however, is limited to nucleophiles with only one acidic proton. A different pathway is followed in reactions of nucleophiles bearing X Ph two acidic protons (Scheme 3). Thus, in the case of dieth- – OTf X + base S R yl malonate 8a, following ylide formation 1,3-proton Ph + – NuH Ph + S X = O 4 transfer occurred instead, followed by ring closure to give Nu R 5 X = NTs Ph Nu 12 3 6 X = O SPh 7 X = NTs 2 Scheme 2 Proposed three-component epoxidation and aziridination OTf 2 R n HX reactions using vinyl sulfonium salt 2 R n R XH X R X n 2 n SPh 2 SPh 2 9 8 a: R = CO Et, n = 2 2 b: R = Ts, n = 1 SYNLETT 2008, No. 14, pp 2191–2195 22.08.2008 Advanced online publication: 05.08.2008 Scheme 3 Reaction of vinyl sulfonium salt 2 with nucleophiles 8 DOI: 10.1055/s-2008-1078252; Art ID: D27108ST bearing two acidic protons © Georg Thieme Verlag Stuttgart · New York 2192 C. G. Kokotos et al. LETTER a cyclopropane 9a. In the case of tosylamide 8b, an aziri- with moderate trans selectivity whilst stabilized ylides dine 9b was formed by the same process.6 gave moderate cis selectivity. In the event, application of our standard conditions with Table 1 Three-Component Epoxidation Reaction Using Vinyl Sul- fonium Salt 2 and Benzaldehyde N-methyl tosylamide and 2 but replacing benzaldehyde for the corresponding N-Ts imine furnished aziridine 7a in base – OTf O O (1.2 equiv) high yield as a 4:1 mixture of cis/trans-isomers (Table 3, Ph + + NuH + S entry l). Further improvement in yield and diastereoselec- 0 °C to r.t. Nu Ph Ph 18 h Ph tivity was observed when using NaH in THF (entry 2, 12 4a 6 Table 3). The reaction could be extended to malonate de- 1 equiv 5 equiv 1.5 equiv rivatives (entries 3, 4), an alcohol (entry 5), and a thiol Entry NuH Conditions Yield (%)a cis/transb (entry 6) as before, but not amines (pyrrolidine was inef- fective). Surprisingly, the major diastereomers derived 1 MeNHTs NaH, THF 74 1.8:1 from the alcohol and thiol reactions were now the trans- aziridines. 2MeNHTs t-BuOK, CH2Cl2 87 1.5:1 Table 3 Three-Component Aziridination Using Vinyl Sulfonium O O Salt 2 and N-Tosylbenzaldimine 3 t-BuOK, CH2Cl2 86 1.1:1 EtO OEt Ts base – Ts OTf Me (1.2 equiv) N N Ph + + NuH + S 4PhCH2OH t-BuOK, CH2Cl2 77 1:1.4 0 °C to r.t. Ph Nu 18 h Ph Ph 5PhSH t-BuOK, CH2Cl2 59 1:1.3 7 12 5 quiv 1.5 equiv 5 equiv 6 Pyrrolidine t-BuOK, CH2Cl2 57 1:1 1 e a b a Isolated yield after purification. Entry NuH Conditions Yield (%) cis/trans b Determined from 1H NMR of the crude reaction mixture. 1MeNHTs t-BuOK, CH2Cl2 91 4:1 The reaction (demonstrated for N-methyl tosylamide) was 2MeNHTsNaH, THF955:1 O easily extended to other aromatic and aliphatic aldehydes O (Table 2), giving moderate-to-good yields but low diaste- 3NaH, THF893:1 OEt reoselectivities. EtO Me O Table 2 Three-Component Epoxidation of Various Aldehydes O 4NaH, THF913:1 OEt t-BuOK EtO –OTf (1.2 equiv) O O NHAc Ph MeNHTs + + + S CH2Cl2 NMe 5 PhCH OH NaH, THF 57 1:5 R 0 °C to r.t. R 2 Ts Ph 18 h 2 1a 46a6 PhSH NaH, THF 33 1:5 1 equiv 1.5 equiv 5 equiv a Isolated yield after purification. a b Entry R Yield (%) cis/trans b Determined from 1H NMR of the crude reaction mixture. 1 Ph 87 1.5:1 24-ONC H 97 1.1:1 The aziridination reaction was extended to a range of imi- 2 6 4 nes (Table 4) with moderate-to-good yields being ob- 34-MeOC6H4 71 1.3:1 tained in all cases. The diastereoselectivity was also found to be highly sensitive to the electronic nature of the imine: 4 Bu 45 1.6:1 electron-rich imines gave very high cis selectivity whilst 5 Cy 61 1.0:1 electron-poor imines gave low selectivity. In fact, the dia- s+ a Isolated yield after purification. stereoselectivities correlated well with (Hammer sub- b Determined from 1H NMR of the crude reaction mixture. stituent constant) (Figure 1). This observation is consistent with the development of positive charge in the transition states (TS) and a larger dependence on the Related three-component coupling reactions with imines imine’s electronic properties in one of the two TS. More as electrophiles were also considered. Of particular inter- reactive imines show low selectivity while less reactive est were the diastereoselectivities of these processes as the imines give better selectivity in line with the Hammond reactions of imines with non-stabilized sulfur ylides had postulate. In the case of less reactive imines the later TS 7,8 not been reported (except those of methylides). Semi- should lead to closer contacts between the imine and ylide stabilized ylides were known to react with N-Ts imines Synlett 2008, No. 14, 2191–2195 © Thieme Stuttgart · New York LETTER Three-Component Aziridination and Epoxidation Reactions 2193 Table 4 Three-Component Aziridination of Various Imines favourable charge–charge Ts interaction NaH – OTf Ts (1.2 equiv) N N Ts Ts Ph Ts + + NuH Ts N N + + S 0 °C to r.t Ph S H H R 2 N N R Nu THF, 18 h Ph R Ph H H Ph R SPh 2 Ph R 12 57 Ph R + 1 equiv 1.5 equiv 5 equiv - - TS 1 TS 2 trans-aziridines cis-aziridines sterically favoured by favoured Entry NuH R Yield (%)a cis/transb Coulombic interaction 1 MeNHTs 4-O2NC6H4 99 1.5:1 Scheme 4 Transition states proposed to lead to the betaine interme- diates that give cis- and trans-aziridines 2 MeNHTs 4-ClC6H4 94 3:1 3 MeNHTs Ph 95 5:1 group which dictates that the only substituent ‘allowed’ in 4 MeNHTs 4-MeC H 89 6:1 its vicinity is an H.