Diastereoselective acyclic aza-2,3 Wittig sigmatropicrearrangements

摘要

J. Chem. Soc. Perkin Trans. 1 1997 1517 Diastereoselective acyclic aza-2,3 Wittig sigmatropic rearrangements James C. Anderson,*,dagger;,a Stephen C. Smith b and Martin E. Swarbrick a a Department of Chemistry University of Sheffield Sheffield UK S3 7HF b Zeneca Agrochemicals Jealottrsquo;s Hill Research Station Bracknell Berkshire UK RG42 6EY The scope of anion-stabilising groups in promoting and controlling the diastereoselection of the aza-2,3 Wittig sigmatropic rearrangement has been assessed by the syntheses of allylic amines 1cndash;g that have incorporated SiPhMe2 Ph SPh SOPh and SO2Ph respectively at the C-2 position. The subsequent anionic 2,3-sigmatropic rearrangements are analysed with respect to the extent of diastereoselection of the product homoallylic amines 2 and 3. It appears that silicon not only is the most efficient at electronically facilitating this rearrangement but its steric bulk controls the diastereoselectivity of the process exclusively.Phenyl and phenylthio substituents also have a similar but decreased effect on diastereoselection that mirrors their lower steric bulk in comparison to the silicon derivative. Sulfoxide and sulfone substituents are incompatible with the reaction conditions required for rearrangement. Introduction Despite the numerous synthetic applications of the 2,3 Wittig sigmatropic rearrangement of allylic ethers (Scheme 1 X = O),1 the use of the aza congener (Scheme 1 X = N) has been limited by the reluctance of simple allyl amines to undergo this transformation. 2 The first unequivocal example of this rearrangement 3 which is driven by relief of ring strain has been extended by others to include vinyl aziridines.4 The 2,3- rearrangement of N-allyl nitrogen ylides has been shown to be potentially useful.2e We have concentrated our efforts on the acyclic variant of this rearrangement and want to develop the aza-2,3 Wittig sigmatropic process into a versatile method for the preparation of unnatural amino acids.To this end we have managed to markedly accelerate our preliminary reaction 5 and control the diastereoselectivity of the acyclic rearrangement by the incorporation of a trimethylsilyl group at the C-2 position of our substrate (Scheme 2).6 We believe the silicon atom due to its ability to stabilise adjacent negative charge,7 is stabilising the transition state,8 thus reducing the activation energy of the reaction.The inherent bulk of the silyl group is dictating the diastereoselection.6 This strategy has allowed the acyclic Scheme 1 X R1 R2 HX R1 R2 X = O NR3 anionic 2,3 shift Scheme 2 Reagents and conditions BuLi Et2Ondash;HMPA (4 1); a X = H 278 to 240 8C 14 h 82; b X = SiMe3 278 8C 10 min 88 N Me Ph Boc X HN Me Ph Boc HN Me Ph Boc X X a X = H ds ratio of 2:3 = 3:2 b X = SiMe3 ds ratio of 2:3 = 1:20 3 1a X = H 1b X = SiMe3 + 2 2 dagger;E-mail j.anderson@sheffield.ac.uk aza-2,3 Wittig rearrangement to become more applicable to a wider range of substrates.9 We report here the first examples of other anion-stabilising groups successfully incorporated into rearrangement precursors 1 that both facilitate and increase the synthetic scope of the aza-2,3 Wittig rearrangement.Our first concern was that we could not remove the trimethylsilyl group from 3 presumably because the accepted mechanism would require the formation of an incipient primary carbocation. 10 Although there is a rich chemistry associated with vinyl silanes 10 that could be applied to compounds such as 3 our methodology would be more versatile if the silyl group could also be removed at an early stage. An added incentive was that we could obtain unambiguous proof of diastereoselection from the desilylated product 3 (X = H).5 Following an isolated report that the phenyldimethylsilyl group could be removed from the C-2 position of a vinyl silane with tetrabutyl ammonium fluoride (TBAF),11 we sought to obtain 1c (X = SiPhMe2). We were also interested in the rearrangements of compounds analogous to 1 where X = Ph SPh S(O)Ph and SO2Ph (1dndash;g respectively); as all these groups are capable of stabilising an adjacent negative charge and could control diastereoselectivities in a manner similar to that found with SiMe3 (vide supra).Results and discussion Allylic alcohols 4cndash;e were prepared from the addition of the corresponding a-lithio-a-substituted vinyl precursors to acetaldehyde. In the case of the phenyldimethylsilane derivative 4c we had to develop a reliable synthesis of (1-bromovinyl)- phenyldimethylsilane based upon a description in the literature of the triphenyl congener.12 Addition of bromine to phenyldimethylvinylsilane and then elimination of hydrogen bromide with refluxing pyridine produced the desired halide in 62 yield. Allylic alcohols 4cndash;e were then transformed into the desired rearrangement precursors 1cndash;e via the established procedure for stereoselective conversion of secondary allylic alcohols to allyl amides 5cndash;e (Scheme 3).13 Compounds 1f and 1g were obtained from the controlled oxidation of 1e.Rearrangement of 1c was carried out by treatment with BuLi at 278 8C in tetrahydrofuran (THF) for 14 h to give the rearranged product 3c in 81 yield with complete diastereoselectivity (Scheme 4). This diastereoisomer exhibited characteristic chemical shifts in its NMR spectrum that we had used to assign the trimethylsilyl analogue (Table 1).6 Treatment with 1518 J. Chem. Soc. Perkin Trans. 1 1997 TBAF in DMSO under standard literature conditions 11 produced a single diastereoisomer of the desilylated product in 47 yield. This compound had an identical NMR spectrum to the minor diastereoisomer 3a (Scheme 3) obtained from our first rearrangement the structure of which had been proven by correlation to authentic isoleucine.5 Treatment of 1d with BuLi in THFndash;HMPA (4 1) at 278 8C and then at 240 8C for 14 h led to a mixture of 2d and 3d in 71 yield with a diastereoisomeric ratio of 1 7 (Scheme 5).Similarly treatment of 1e under identical conditions led to an inseparable mixture by chromatography of 2e N-tert-butoxycarbonylbenzylamine and 3e in 49 yield with a ratio of 1 2 4 (Scheme 5). Samples of pure diastereoisomers 3d and 3e could be obtained by trituration of the chromatographed mixed prod- Scheme 3 Reagents and conditions i ButLi Et2O 278 8C MeCHO; ii BuLi TMEDA THF 278 8C MeCHO; iii KH cat. Cl3CCN; iv xylenes 140 8C; v (Boc)2O then NaOH; vi KH BnBr; vii mCPBA; viii Oxone Br SiPhMe2 Br Ph SPh OH Me X NH Me Boc X N Me Ph Boc X 4c X = SiPhMe2 86 4d X = Ph 89 4e X = SPh 69 5c 40 5d 61 5e 41 1c 95 1d 94 1e 82 1f X = S(O)Ph 90 1g X = SO2Ph 95 i iii iv v vii i ii viii Scheme 4 Reagents and conditions i BuLi THF 278 8C 14 h; ii TBAF DMSO 100 8C 2 h N Me Ph Boc SiPhMe2 HN Me Ph Boc Me2PhSi HN Me Ph Boc 3c 1c 3a i ii Scheme 5 Reagents and conditions i BuLi THFndash;HMPA (4 1) 278 8C 1 h then 240 8C 14 h HN Me Ph Boc HN Me Ph Boc X X N Me Ph Boc X 1d X = Ph 1e X = SPh 2d,e 3d,e + i Table 1 Selected NMR data for 2 and 3 1b 1c 1d 1e X SiMe3 SiPhMe2 Ph SPh Diastereoselectivity a 2 3 1 20 3 only 1 7 1 4 d Me groups 2; 3 b 1.02; 0.66 0.53 0.80; 0.70 1.13; 0.76 J C-1Hndash;C-2H 3 10.4 9.6 9.5 9.8 a Ratios of unpurified products determined by 250 MHz NMR.b 2H6DMSO. ucts with cold light petroleum in 59 and 26 yield respectively. The diastereoselection could be ascertained from inspection of selected NMR characteristics (Table 1). As with the trimethylsilyl derivative the large C-1Hndash;C-2H coupling constant (Fig. 1) suggested conformations where the methyl substituents of the major diastereoisomer were shielded by the proximal phenyl ring.6 This analysis was supported by the conversion of 3c to 3a (vide supra). These results support the proposed transition state model6 (Scheme 6) for these rearrangements. The change in the extent of diastereoselection nicely mirrors the decrease in the steric bulk of the anion-stabilising vinyl substituents X in the order PhMe2Si Ph SPh.We expected the sulfoxide 1f and sulfone 1g analogues to behave similarly; 1f offering the potential of a chiral anionstabilising vinyl substituent that could control the enantioselection of this particular variant of the process. Unfortunately treatment of 1f with BuLi under standard conditions led only to the desulfurised starting material 1a (30) and N-tert-butoxycarbonylbenzylamine (48) (Scheme 7). Treatment of 1g and 1f under a range of similar conditions led to complex mixtures of products none of which could be identified. We can only conclude that the sulfoxide and sulfone substituents render the system incompatible towards the strong base necessary to facilitate the anionic sigmatropic rearrangement. Fig. 1 HN Ph Me Boc HN Ph Me Boc H HNBoc Ph H Me H Ph BocNH H Me X X X X 3 1 1 2 2 Scheme 6 Transition-state model for major diastereoisomer Me H N Ph Boc X Me H N Ph Boc X N Me Ph Boc X HN Me Ph Boc X d- d- 1 3 Scheme 7 Reagents and conditions i BuLi THFndash;HMPA (4 1) 278 8C 1 h then 240 8C 14 h N Me Ph Boc (O)SPh N Me Ph Boc Boc Ph HN + 1a 30 48 i 1f J.Chem. Soc. Perkin Trans. 1 1997 1519 The aza-2,3 Wittig rearrangement has been shown to be accelerated by the incorporation of certain anion-stabilising vinyl substituents at the central vinyl carbon atom. The diastereoselection ranges from 4 1 to 20 1 depending on the steric bulk of the substituents X in allyl amines 1 with silyl substituents emerging as the front runners. The phenyldimethylsilyl group after its removal has verified our structural assignments and increases the synthetic utility of the silicon-stabilised aza- 2,3 Wittig rearrangement.The phenyl and phenylthio substituents further expand the process. The use of the rearranged precursors as synthetic building blocks will be reported shortly and the investigation of other less obvious accelerating groups are underway. Experimental General details Our general experimental details have been reported elsewhere.6 (1-Bromovinyl)phenyldimethylsilane Bromine (1.84 ml 0.036 mol 1 equiv.) in carbon tetrachloride (20 ml 1 2 times; 5 ml wash) was added dropwise via a cannula to a stirred solution of phenyldimethylvinylsilane (5.78 g 0.036 mol) in carbon tetrachloride (30 ml) at 0 8C. The solution was stirred for 10 min at 0 8C washed sequentially with saturated aqueous sodium hydrogen carbonate containing some sodium hydrogen sulfite (3 times; 50 ml) and brine (50 ml) dried over magnesium sulfate and concentrated in vacuo to give the crude dibromide (12.62 g) as a pale yellow oil.This crude product was dissolved in pyridine (50 ml) and refluxed for 14 h. After cooling to room temperature the dark brown reaction mixture was diluted with diethyl ether (100 ml) and washed with water (70 ml). The aqueous layer was further extracted with diethyl ether (2 times; 70 ml) and the combined organics washed repeatedly with a saturated copper sulfate solution until all of the pyridine had been removed as indicated by the aqueous phase retaining a light blue colour. The organics were then washed with brine (70 ml) dried over magnesium sulfate and concentrated in vacuo to give a pale brown oil (5.63 g) which was purified by flash column chromatography (15 times; 5 cm silica light petroleum) to give the bromovinylsilane (5.32 g 62) as a colourless oil (Found C 50.2; H 5.8; Br 33.4.C10H13BrSi requires C 49.8; H 5.4; Br 33.1); nmax(thin film)/cm21 3071 2962 1592 1429 1397 1250 1114 1070 915; dH(250 MHz; CDCl3) 0.49 6H s (CH3)2Si 6.17 (1H d J 1.7 CHH ) 6.35 (1H d J 1.7 CHH ) 7.30ndash;7.70 (5H m ArH); dC(63 MHz; CDCl3) 23.4 128.0 129.8 131.5 134.1 135.2 136.7; m/z (EI1) 241.9940 (31 M1. C10H13 81BrSi requires M 241.9949) 239.9962 (32 M1. C10H13 79BrSi requires M 239.9970) 227 (51)/225 (50 M1 2 CH3) 201 (100)/199 (100) 161 (23 M1 2 Br) 145 (37) 135 (97) 105 (46). 3-Phenyldimethylsilylbut-3-en-2-ol 4c tert-Butyllithium (15.5 ml of a 1.7 M solution in pentane 26.4 mmol 2.1 equiv.) was added dropwise to a stirred solution of (1-bromovinyl)phenyldimethylsilane (3.03 g 12.6 mmol) in diethyl ether (40 ml) at 278 8C.After complete addition the reaction was stirred for 1 h at 278 8C. A solution of acetaldehyde (1.40 ml 25.1 mmol 2 equiv.) in diethyl ether (10 ml) was then added dropwise via a cannula. After stirring for a further hour at 278 8C the reaction was allowed to warm to room temperature. Water (50 ml) was added the mixture separated and the aqueous layer extracted with diethyl ether (3 times; 30 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil (3.24 g) which was purified by flash column chromatography (15 times; 5 cm silica 15 ethyl acetatendash;light petroleum) to give 4c (2.23 g 86) as a colourless oil (Found C 69.4; H 8.8.C12H18OSi requires C 69.8; H 8.8); nmax(thin film)/cm21 3358 1428 1250 1111 845; dH(250 MHz; CDCl3) 0.42 (3H s CH3Si) 0.44 (3H s CH3Si) 1.20 (3H d J 6.4 CH3CH) 1.39 (1H d J 4.3 OH by D2O exchange) 4.44 (1H qdt J 6.4 4.3 1.2 CH3CH) 5.45 (1H dd J 2.4 1.2 CHH ) 5.91 (1H dd J 2.4 1.2 CHH ) 7.30ndash;7.65 (5H m ArH); dC(63 MHz; CDCl3) 22.3 22.1 24.1 71.7 124.7 127.9 129.1 133.9 138.4 155.0; m/z (EI1) 191.0893 (25 M1 2 CH3. C11H15OSi requires M 2 CH3 191.0892) 137 (100) 135 (44) 105 (12) 75 (26). 3-Phenylbut-3-en-2-ol 4d a-Bromostyrene (3 ml 23.1 mmol) was converted to 4d in an identical fashion to that for 4c and was purified by flash column chromatography (15 times; 5 cm silica 15 ethyl acetatendash;light petroleum) to give a pale straw coloured oil (3.06 g 89);14 dH(250 MHz; CDCl3) 1.32 (3H d J 6.4 CH3) 1.79 (1H d J 4.0 OH by D2O exchange) 4.82 (1H qd J 6.4 4.0 CHOH) 5.28 (1H t J 0.9 CHH ) 5.36 (1H t J 1.2 CHH ) 7.25ndash;7.45 (5H m ArH).3-Phenylthiobut-3-en-2-ol 4e Phenyl vinyl sulfide (5 ml 0.038 mol) in tetrahydrofuran (40 ml 1 2 times; 10 ml wash) was added dropwise via a cannula to a stirred solution of butyllithium (16.1 ml of a 2.5 M solution in hexane 0.040 mol 1.05 equiv.) and TMEDA (6.1 ml 0.040 mol 1.05 equiv.) in tetrahydrofuran (120 ml) at 278 8C. After stirring at 278 8C for 2 h a solution of acetaldehyde (4.2 ml 0.077 mol 2 equiv.) in tetrahydrofuran (10 ml 1 2 times; 2 ml wash) was added dropwise via a cannula. Upon complete addition the reaction was stirred for a further hour at 278 8C before being warmed to room temperature. Saturated aqueous ammonium chloride (100 ml) was added the mixture separated and the aqueous layer further extracted with diethyl ether (3 times; 70 ml).The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a crude yellow oil (9.1 g) which was purified by flash column chromatography (15 times; 7 cm silica 20 ethyl acetatendash;light petroleum) to give the alcohol 4e (4.75 g 69) as a yellow oil;15 dH(250 MHz; CDCl3) 1.43 (3H d J 6.4 CH3) 1.93 (1H br s OH by D2O exchange) 4.37 (1H qt J 6.4 0.6 CHOH) 4.97 (1H d J 0.9 CHH ) 5.50 (1H d J 0.9 CHH ) 7.20ndash;7.50 (5H m ArH). Preparation of compounds 1 We have previously reported general methods for the preparation of 1 from 4 via 5.6 (Z)-N-tert-Butoxycarbonyl-2-(phenyldimethylsilyl)but-2-enylamine 5c. Compound 5c was prepared in 40 yield from 4c as a colourless oil; nmax(thin film)/cm21 3356 1703 1505 1366 1249 1171; dH(250 MHz; CDCl3) 0.41 6H s (CH3)2Si 1.42 9H s (CH3)3C 1.64 (3H dt J 7.0 1.2 CH3CH ) 3.77 (2H m NCH2CH ) 4.35 (1H br s NH by D2O exchange) 6.31 (1H qt J 7.0 1.2 CH3CH ) 7.30ndash;7.55 (5H m ArH); dC(63 MHz; CDCl3) 21.5 17.8 47.9 79.1 127.9 128.9 133.7 134.8 140.5 155.4; m/z (CI1) 306.1880 (13 MH1.C17H28NO2Si requires MH1 306.1889) 278 (17) 248 (13 M1 2 But) 234 (47) 172 (100) 135 (16) 57 (But). (E)-N-tert-Butoxycarbonyl-2-phenylbut-2-enylamine 5d. Compound 5d was prepared in 61 yield from 4d as a colourless oil; nmax(thin film)/cm21 3351 1704 1505 1366 1249 1172 702; dH(250 MHz; CDCl3) 1.40 9H s (CH3)3C 1.59 (3H dt J 7.0 1.2 CH3) 3.97 (2H m NCH2CH ) 4.55 (1H br s NH by D2O exchange) 5.71 (1H q J 7.0 CH ) 7.15ndash;7.40 (5H m ArH); dC(63 MHz; CDCl3) 14.5 28.4 47.4 79.1 123.0 127.0 128.2 128.7 138.3 139.6 155.8; m/z (EI1) 247.1575 (3.8 M1.C15H21NO2 requires M 247.1572) 191 100 MH1 2 (CH3)3C 176 (9) 146 (6) 130 (37) 115 (8). (E)-N-tert-Butoxycarbonyl-2-phenylthiobut-2-enylamine 5e. Compound 5e was prepared in 41 yield from 4e as a yellow solid mp 52ndash;54 8C (Found C 64.4; H 7.5; N 4.9; S 11.6. C15H21NO2S requires C 64.5; H 7.6; N 5.0; S 11.5); nmax(thin film)/cm21 3348 1702 1584 1507 1478 1366 1249 1170; dH(250 MHz; CDCl3) 1.41 9H s (CH3)3C 1.90 (3H dt J 6.7, 1520 J. Chem. Soc. Perkin Trans. 1 1997 1.2 CH3) 3.77 (2H d J 5.5 NCH2) 4.77 (1H br s NH by D2O exchange) 6.25 (1H q J 6.7 CH3CH ) 7.15ndash;7.30 (5H m ArH); dC(63 MHz; CDCl3) 15.5 28.4 46.4 79.3 126.1 128.9 129.0 130.8 133.6 134.6 155.6; m/z (EI1) 279.1291 (32 M1.C15H21NO2S requires M 279.1293) 223 MH1 2 (CH3)3C 74 162 (96) 149 (37) 129 (22) 114 (92) 57 (100). (Z)-N-tert-Butoxycarbonyl-N-2-(phenyldimethylsilyl)but-2- enylbenzylamine 1c. Compound 1c was prepared in 95 yield from 5c as a colourless oil; nmax(thin film)/cm21 1694 1454 1410 1365 1248 1168 1111; dH(250 MHz; CDCl3) 0.38 6H s (CH3)2Si 1.45 9H s (CH3)3C 1.67 (3H dt J 7.0 1.5 CH3CH ) 3.93 (2H br m NCH2) 4.31 (2H br m NCH2) 6.12 (1H q J 7.0 CH3CH ) 7.10ndash;7.55 (10H m ArH); dC(63 MHz; CDCl3) 21.5 17.7 28.4 48.7 51.9 79.6 126.7 127.1 127.6 127.8 128.4 128.8 133.6 138.4 139.0 155.9; m/z (EI1) 395.2279 (9 M1. C24H33NO2Si requires M 395.2281) 338 17 M1 2 (CH3)3C 324 (60) 262 (100) 135 (51) 91 (65). (E)-N-tert-Butoxycarbonyl-N-(2-phenylbut-2-enyl)benzylamine 1d.Compound 1d was prepared in 94 yield from 5d as a pale yellow oil (Found C 78.1; H 8.0; N 3.95. C22H27NO2 requires C 78.3; H 8.1; N 4.15); nmax(thin film)/cm21 1694 1454 1416 1365 1243 1167 1124 879 700; dH(250 MHz; CDCl3) 1.30 9H s (CH3)3C 1.55 (3H m CH3) 3.87ndash;4.40 (4H m CH2NCH2) 5.50 (1H m CH ) 7.00ndash;7.30 (10H m ArH); dC(63 MHz; CDCl3) 14.4 28.3 48.3 52.6 79.5 123.5 124.0 126.9 127.1 127.4 128.1 128.4 128.8 137.3 138.3 155.7; m/z (EI1) 337.2037 (7 M1. C22H27NO2 requires M 337.2042) 281 74 MH1 2 (CH3)3C 132 (27) 91 (100) 57 (46). (E)-N-tert-Butoxycarbonyl-N-(2-phenylthiobut-2-enyl)benzylamine 1e. Compound 1e was prepared in 82 yield from 5e as a yellow oil; nmax(thin film)/cm21 1695 1584 1477 1453 1410 1365 1244 1167 1117 878; dH(250 MHz; CDCl3) 1.40 9H s (CH3)3C 1.94 (3H dt J 6.7 1.5 CH3) 3.87 (2H m NCH2) 4.38 (2H m NCH2) 6.03ndash;6.17 (1H m CH3CH ) 7.05ndash;7.35 (10H m ArH); dC(63 MHz; CDCl3) 15.4 28.3 49.1 51.1 79.8 125.8 127.1 127.3 127.9 128.3 128.9 133.4 135.2 138.0 155.9; m/z (EI1) 369.1770 (0.8 M1.C22H27NO2S requires M 369.1763) 313 1.2 MH1 2 (CH3)3C 296 (4) 204 (100) 91 (58) 57 (25). (E)-N-tert-Butoxycarbonyl-N-(2-phenylsulfinylbut-2-enyl)- benzylamine 1f m-Chloroperbenzoic acid (0.56 g 1 equiv.) was added portionwise to a stirred solution of (E)-N-tert-butoxycarbonyl-N- (2-phenylthiobut-2-enyl)benzylamine 1e (1.20 g) in dichloromethane (30 ml) at room temperature. After 1 h further dichloromethane (20 ml) was added and the reaction mixture washed with saturated aqueous sodium hydrogen carbonate (3 times; 50 ml) dried over magnesium sulfate and concentrated in vacuo to give a yellow oil (1.60 g).This was purified by flash column chromatography (15 times; 3 cm silica 30 ethyl acetatendash; light petroleum) to give the sulfoxide 1f (1.13 g 90) as a viscous pale yellow oil; nmax(thin film)/cm21 1694 1454 1415 1366 1247 1166 1044 749 697; dH(250 MHz; CDCl3) 1.37 9H m (CH3)3C 2.18 (3H dt J 7.3 1.6 CH3) 3.60ndash;4.30 (4H m CH2NCH2) 5.90ndash;6.30 (1H m CH3CH ) 7.00ndash;7.55 (10H m ArH); dC(63 MHz; CDCl3) 14.9 28.3 42.2 50.1 80.1 123.9 127.2 127.7 128.4 129.1 131.7 134.6 138.1 140.6 142.6 155.8; m/z (EI1) 385.1709 (19 M1. C22H27NO3S requires M 385.1712) 329 16 MH1 2 (CH3)3C 312 25 M1 2 (CH3)3CO 284 15 M1 2 (CH3)3COCO 268 (47 M1 2 PhSO) 204 (100) 158 (35) 144 (40). (E)-N-tert-Butoxycarbonyl-N-(2-phenylsulfonylbut-2-enyl)- benzylamine 1g A suspension of Oxone (5.79 g 3 equiv.) and water (15 ml) was added portionwise to a stirred solution of 1e (1.16 g) in methanol (25 ml) at 0 8C.Upon complete addition the reaction was warmed to room temperature and stirred for 14 h. The methanol was removed in vacuo the residue partitioned between water (15 ml) and dichloromethane (15 ml) the organic layer was separated and the aqueous layer further extracted with dichloromethane (3 times; 15 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a crude yellow oil which was purified by flash column chromatography (15 times; 3 cm silica 20 ethyl acetatendash; light petroleum) to give the sulfoxide 1g (1.20 g 95) as a viscous pale yellowndash;green oil; nmax(thin film)/cm21 1694 1447 1410 1366 1305 1247 1159 1137 1083 729 690; dH(250 MHz; CDCl3) 1.40 9H m (CH3)3C 2.15 (3H dt J 7.6 1.5 CH3) 4.05 (2H br m NCH2) 4.33 (2H s NCH2) 6.00ndash;6.35 (1H br m CH3CH ) 7.05ndash;7.90 (10H m ArH); dC(63 MHz; CDCl3) 14.7 28.4 48.2 49.9 80.6 127.2 127.6 128.7 129.4 133.5 136.8 137.6 138.1 140.6 141.5 155.7; m/z (EI1) 401.1658 (0.3 M1.C22H27NO4S requires M 401.1661) 345 10 MH1 2 (CH3)3C 300 37 M1 2 (CH3)3COCO 204 (59) 150 (38) 144 (31) 106 (90) 91 (100) 77 (24) 57 (85). (1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1-phenyl-3-(phenyldimethylsilyl) but-3-enylamine 3c Butyllithium (0.66 ml of a 2.5 M solution in hexane 1.7 mmol 1.2 equiv.) was added dropwise to a stirred soution of (Z)- N-tert-butoxycarbonyl-N-2-(phenyldimethylsilyl)but-2-enyl- benzylamine 1c (0.55 g 1.4 mmol) in tetrahydrofuran (11 ml) at 278 8C.After stirring for 14 h at 278 8C the reaction was quenched by the addition of methanol (0.1 ml) and warmed to room temperature. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate (20 ml) and diethyl ether (15 ml) the organic layer was separated and the aqueous layer further extracted with diethyl ether (3 times; 15 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a viscous pale yellow oil (0.63 g) which was purified by flash column chromatography (12 times; 2.5 cm silica 7 ethyl acetatendash;light petroleum) to give the title compound 3c as a colourless oil (0.44 g 81) (Found C 72.4; H 8.6; N 3.8. C24H33NO2Si requires C 72.9; H 8.4; N 3.5); nmax(thin film)/cm21 3425 1702 1496 1366 1250 1171 817 734 701; dH250 MHz; (CD3)2SO 0.42 3H s (CH3)Si 0.47 3H s (CH3)Si 0.53 (3H d J 7.0 CCHCH3) 1.15 9H s (CH3)3C 2.59 (1H dq J 9.6 7.0 =CCHCH3) 4.47 (1H t J 9.6 NCHPh) 5.42 (1H d J 2.4 HHC ) 5.81 (1H d J 2.4 HHC ) 6.87 (1H d J 9.6 NH by D2O exchange) 6.95ndash;7.45 (10H m ArH); dC(63 MHz; CDCl3) 22.6 19.7 28.4 42.2 59.3 79.0 127.0 127.1 127.5 128.0 128.2 129.3 134.1 137.9 142.8 152.9 154.9; m/z (EI1) 395.2274 (3.7 M1.C24H33NO2Si requires M 395.2281) 382 (2) 262 (7) 206 (49) 172 (9) 150 (100) 135 (48) 106 (79) 91 (7) 57 (94). (1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1,3-diphenylbut-3- enylamine 3d Butyllithium (1.64 ml of a 2.5 M solution in hexane 4.1 mmol 1.2 equiv.) was added dropwise to a stirred solution of (E)- N-tert-butoxycarbonyl-N-(2-phenylbut-2-enyl)benzylamine 1d (1.15 g 3.4 mmol) in tetrahydrofuranndash;HMPA (4 1 23 ml) at 278 8C.After stirring for 1 h at 278 8C the reaction was slowly warmed to 240 8C and stirred for 14 h before being quenched by the addition of methanol (0.2 ml). The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate (50 ml) and diethyl ether (30 ml) the organic layer was separated and the aqueous layer further extracted with diethyl ether (3 times; 30 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a viscous yellow gum (2.3 g) which was purified by flash column chromatography (12 times; 4 cm silica 10 ethyl acetatendash;light petroleum) to give a pale yellow solid (0.82 g 71 of a 7 1 mixture of the title compound 3d to the minor diastereoisomer 2d).Trituration with ice-cold light petroleum furnished the major diastereoisomer only as a white powder (0.68 g 59) mp 123ndash;124 8C (Found C 77.9; H 7.7; N 4.3. C22H27NO2 J. Chem. Soc. Perkin Trans. 1 1997 1521 requires C 78.3; H 8.1; N 4.2); nmax(thin film)/cm21 3274 1701 1495 1454 1390 1365 1248 1170 701; dH250 MHz; (CD3)2SO 0.70 (3H d J 6.7 CH3) 1.30 9H s (CH3)3C 3.02 (1H dq J 9.5 6.7 CH3CHC ) 4.53 (1H t J 9.5 NHCHPh) 5.11 (1H s CHH ) 5.21 (1H s CHH ) 7.20ndash;7.50 (11H m ArH and NH by D2O exchange); dC63 MHz; (CD3)2SO 18.7 28.7 43.8 58.3 78.0 113.2 127.2 127.7 127.9 128.4 128.7 142.6 142.9 151.9 155.2; m/z (EI1) 337.2039 (0.4 M1. C22H27NO2 requires M 337.2042) 281 3 MH1 2 (CH3)3C 236 10 M1 2 (CH3)3COCO 206 (38) 196 (24) 150 (87) 106 (83) 91 (47) 57 (100).(1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1-phenyl-3-phenylthiobut- 3-enylamine 3e (E)-N-tert-Butoxycarbonyl-N-(2-phenylthiobut-2-enyl)benzylamine 1e (0.72 g 2.0 mmol) was treated with BuLi under exactly the same conditions and work up as for 3d to give a viscous yellow oil (1.2 g) which was purified by flash column chromatography (15 times; 3 cm silica 10 ethyl acetatendash;light petroleum) to give a pale yellow solid (0.35 g 49 of a 1 2 4 mixture of the minor diastereoisomer 2e N-tert-butoxycarbonylbenzylamine and the title compound 3e respectively). Trituration with ice-cold light petroleum furnished the title compound only as a white powder (0.19 g 26) mp 121ndash; 122 8C; nmax(thin film)/cm21 3375 1679 1512 1368 1292 1250 1171 742 704; dH250 MHz; (CD3)2SO 0.76 (3H d J 7.0 CH3) 1.35 9H s (CH3)3C 2.76 (1H dq J 9.8 7.0 CH3CHC ) 4.60 (1H s CHH ) 4.70 (1H t J 9.5 NHCHPh) 5.30 (1H s CHH ) 7.20ndash;7.55 (11H m ArH and NH by D2O exchange); dC63 MHz; (CD3)2SO 17.7 28.8 46.9 58.2 78.1 113.2 127.4 127.9 128.6 128.7 129.9 133.0 134.1 142.7 149.4 155.1; m/z (EI1) 369.1767 (5 M1.C22H27NO2S requires M 369.1762) 296 5 M1 2 (CH3)3CO 268 3 M1 2 (CH3)3COCO 260 (2 M1 2 Ph) 206 (63) 150 (100) 106 (87) 57 (96). Attempted aza-2,3 Wittig sigmatropic rearrangement of (E)-Ntert- butoxycarbonyl-N-(2-phenylsulfinylbut-2-enyl)benzylamine 1f (E)-N-tert-Butoxycarbonyl-N-(2-phenylsulfinylbut-2-enyl)- benzylamine 1f (63 mg 0.16 mmol) was treated with butyllithium under exactly the same conditions and work up as for 3d to give a viscous yellow oil (70 mg) which was purified by flash column chromatography (15 times; 1 cm silica 20 ethyl acetatendash;light petroleum) to furnish (E)-N-tert-butoxycarbonyl- N-but-2-enylbenzylamine 1a 6 (13 mg 30) and N-tert-butoxycarbonylbenzylamine (16 mg 48).(1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1-phenylbut-3-enylamine 3a Tetrabutylammonium fluoride (1.1 ml of a 1 M solution in tetrahydrofuran 1.1 mmol 5 equiv.) was added to a stirred solution of (1S*,2R*)-N-tert-butoxycarbonyl-2-methyl-1-phenyl-3- (phenyldimethylsilyl)but-3-enylamine 3c (85 mg 0.2 mmol) in dimethyl sulfoxide. After stirring for 2 h at 100 8C (oil bath temperature) the reaction mixture was cooled diluted with ethyl acetate (10 ml) washed sequentially with water (4 times; 10 ml) and brine (10 ml) dried thoroughly over magnesium sulfate and concentrated in vacuo to give an off-white solid (34 mg).Purification by flash column chromatography (15 times; 1 cm silica 10 ethyl acetatendash;light petroleum) furnished the title compound 3a as a white solid (26 mg 47).6 Acknowledgements We dedicate this paper to the memory of Mr S. A. Johnson an able chemist who was called away from his life on this earth. This work was supported by Zeneca Agrochemicals and the University of Sheffield. We would also like to thank The Royal Society and Zeneca (Strategic Research Fund award) for additional financial support. References 1 For a recent review see T. Nakai and K. Mikami Org. React. 1994 46 105. 2 (a) M. A. Reetz and D. Schinzer Tetrahedron Lett. 1975 3485; (b) C. A. Broka and T. Shen J. Am. Chem. Soc. 1989 111 2981; (c) Y. Murata and T.Nakai Chem. Lett. 1990 2069; (d) I. Coldham J. Chem. Soc. Perkin Trans. 1 1993 1275; (e) R. E. Gawley Q. Zhang and S. Campagna J. Am. Chem. Soc. 1995 117 11 817; ( f ) M. Gulea-Purcarescu E. About-Jaudet N. Collignon M. Saquet and S. Masson Tetrahedron 1996 52 2075. 3 T. Durst R. V. D. Elzen and M. J. Le Belle J. Am. Chem. Soc. 1972 94 9261. 4 (a) J. Ahman and P. Somfai J. Am. Chem. Soc. 1994 116 9781; (b) I. Coldham A. J. Collis R. J. Mould and R. E. Rathmell J. Chem. Soc. Perkin Trans. 1 1995 2739. 5 J. C. Anderson D. C. Siddons S. C. Smith and M. E. Swarbrick J. Chem. Soc. Chem. Commun. 1995 1835. 6 J. C. Anderson D. C. Siddons S. C. Smith and M. E. Swarbrick J. Org. Chem. 1996 61 4820. 7 P. v. R. Schleyer T. Clark A. J. Kos G. W. Spitznagel C. Rohde D. Arad K. N. Houk and N.G. Rondan J. Am. Chem. Soc. 1984 106 6467. 8 Here we draw an analogy to the calculated transition state for the oxy-2,3 Wittig rearrangement. Y.-D. Wu K. N. Houk and J. A. Marshall J. Org. Chem. 1990 55 1421. See also K. Mikami T. Uchida T. Hirano Y.-D. Wu and K. N. Houk Tetrahedron 1994 50 5917. 9 J. C. Anderson M. E. Swarbrick and C. A. Roberts unpublished results. 10 I. Fleming J. Dunoduegrave;s and R. Smithers Org. React. 1989 37 57. 11 H. Oda M. Sato Y. Morizawa K. Oshima and H. Nozaki Tetrahedron 1985 41 3257. 12 A. G. Brook J. M. Duff and D. G. Anderson Can. J. Chem. 1970 48 561. 13 L. E. Overman J. Am. Chem. Soc. 1976 98 2901. 14 K. Burgess and L. D. Jennings J. Am. Chem. Soc. 1991 113 6129. 15 K. Takaki M. Okada M. Yamada and K. Negoro J. Org. Chem. 1982 47 1200. Paper 6/08226B Received 5th December 1996 Accepted 21st January 1997 J.Chem. Soc. Perkin Trans. 1 1997 1517 Diastereoselective acyclic aza-2,3 Wittig sigmatropic rearrangements James C. Anderson,*,dagger;,a Stephen C. Smith b and Martin E. Swarbrick a a Department of Chemistry University of Sheffield Sheffield UK S3 7HF b Zeneca Agrochemicals Jealottrsquo;s Hill Research Station Bracknell Berkshire UK RG42 6EY The scope of anion-stabilising groups in promoting and controlling the diastereoselection of the aza-2,3 Wittig sigmatropic rearrangement has been assessed by the syntheses of allylic amines 1cndash;g that have incorporated SiPhMe2 Ph SPh SOPh and SO2Ph respectively at the C-2 position. The subsequent anionic 2,3-sigmatropic rearrangements are analysed with respect to the extent of diastereoselection of the product homoallylic amines 2 and 3.It appears that silicon not only is the most efficient at electronically facilitating this rearrangement but its steric bulk controls the diastereoselectivity of the process exclusively. Phenyl and phenylthio substituents also have a similar but decreased effect on diastereoselection that mirrors their lower steric bulk in comparison to the silicon derivative. Sulfoxide and sulfone substituents are incompatible with the reaction conditions required for rearrangement. Introduction Despite the numerous synthetic applications of the 2,3 Wittig sigmatropic rearrangement of allylic ethers (Scheme 1 X = O),1 the use of the aza congener (Scheme 1 X = N) has been limited by the reluctance of simple allyl amines to undergo this transformation.2 The first unequivocal example of this rearrangement 3 which is driven by relief of ring strain has been extended by others to include vinyl aziridines.4 The 2,3- rearrangement of N-allyl nitrogen ylides has been shown to be potentially useful.2e We have concentrated our efforts on the acyclic variant of this rearrangement and want to develop the aza-2,3 Wittig sigmatropic process into a versatile method for the preparation of unnatural amino acids. To this end we have managed to markedly accelerate our preliminary reaction 5 and control the diastereoselectivity of the acyclic rearrangement by the incorporation of a trimethylsilyl group at the C-2 position of our substrate (Scheme 2).6 We believe the silicon atom due to its ability to stabilise adjacent negative charge,7 is stabilising the transition state,8 thus reducing the activation energy of the reaction.The inherent bulk of the silyl group is dictating the diastereoselection.6 This strategy has allowed the acyclic Scheme 1 X R1 R2 HX R1 R2 X = O NR3 anionic 2,3 shift Scheme 2 Reagents and conditions BuLi Et2Ondash;HMPA (4 1); a X = H 278 to 240 8C 14 h 82; b X = SiMe3 278 8C 10 min 88 N Me Ph Boc X HN Me Ph Boc HN Me Ph Boc X X a X = H ds ratio of 2:3 = 3:2 b X = SiMe3 ds ratio of 2:3 = 1:20 3 1a X = H 1b X = SiMe3 + 2 2 dagger;E-mail j.anderson@sheffield.ac.uk aza-2,3 Wittig rearrangement to become more applicable to a wider range of substrates.9 We report here the first examples of other anion-stabilising groups successfully incorporated into rearrangement precursors 1 that both facilitate and increase the synthetic scope of the aza-2,3 Wittig rearrangement.Our first concern was that we could not remove the trimethylsilyl group from 3 presumably because the accepted mechanism would require the formation of an incipient primary carbocation. 10 Although there is a rich chemistry associated with vinyl silanes 10 that could be applied to compounds such as 3 our methodology would be more versatile if the silyl group could also be removed at an early stage. An added incentive was that we could obtain unambiguous proof of diastereoselection from the desilylated product 3 (X = H).5 Following an isolated report that the phenyldimethylsilyl group could be removed from the C-2 position of a vinyl silane with tetrabutyl ammonium fluoride (TBAF),11 we sought to obtain 1c (X = SiPhMe2).We were also interested in the rearrangements of compounds analogous to 1 where X = Ph SPh S(O)Ph and SO2Ph (1dndash;g respectively); as all these groups are capable of stabilising an adjacent negative charge and could control diastereoselectivities in a manner similar to that found with SiMe3 (vide supra). Results and discussion Allylic alcohols 4cndash;e were prepared from the addition of the corresponding a-lithio-a-substituted vinyl precursors to acetaldehyde. In the case of the phenyldimethylsilane derivative 4c we had to develop a reliable synthesis of (1-bromovinyl)- phenyldimethylsilane based upon a description in the literature of the triphenyl congener.12 Addition of bromine to phenyldimethylvinylsilane and then elimination of hydrogen bromide with refluxing pyridine produced the desired halide in 62 yield.Allylic alcohols 4cndash;e were then transformed into the desired rearrangement precursors 1cndash;e via the established procedure for stereoselective conversion of secondary allylic alcohols to allyl amides 5cndash;e (Scheme 3).13 Compounds 1f and 1g were obtained from the controlled oxidation of 1e. Rearrangement of 1c was carried out by treatment with BuLi at 278 8C in tetrahydrofuran (THF) for 14 h to give the rearranged product 3c in 81 yield with complete diastereoselectivity (Scheme 4). This diastereoisomer exhibited characteristic chemical shifts in its NMR spectrum that we had used to assign the trimethylsilyl analogue (Table 1).6 Treatment with 1518 J. Chem. Soc. Perkin Trans. 1 1997 TBAF in DMSO under standard literature conditions 11 produced a single diastereoisomer of the desilylated product in 47 yield.This compound had an identical NMR spectrum to the minor diastereoisomer 3a (Scheme 3) obtained from our first rearrangement the structure of which had been proven by correlation to authentic isoleucine.5 Treatment of 1d with BuLi in THFndash;HMPA (4 1) at 278 8C and then at 240 8C for 14 h led to a mixture of 2d and 3d in 71 yield with a diastereoisomeric ratio of 1 7 (Scheme 5). Similarly treatment of 1e under identical conditions led to an inseparable mixture by chromatography of 2e N-tert-butoxycarbonylbenzylamine and 3e in 49 yield with a ratio of 1 2 4 (Scheme 5). Samples of pure diastereoisomers 3d and 3e could be obtained by trituration of the chromatographed mixed prod- Scheme 3 Reagents and conditions i ButLi Et2O 278 8C MeCHO; ii BuLi TMEDA THF 278 8C MeCHO; iii KH cat.Cl3CCN; iv xylenes 140 8C; v (Boc)2O then NaOH; vi KH BnBr; vii mCPBA; viii Oxone Br SiPhMe2 Br Ph SPh OH Me X NH Me Boc X N Me Ph Boc X 4c X = SiPhMe2 86 4d X = Ph 89 4e X = SPh 69 5c 40 5d 61 5e 41 1c 95 1d 94 1e 82 1f X = S(O)Ph 90 1g X = SO2Ph 95 i iii iv v vii i ii viii Scheme 4 Reagents and conditions i BuLi THF 278 8C 14 h; ii TBAF DMSO 100 8C 2 h N Me Ph Boc SiPhMe2 HN Me Ph Boc Me2PhSi HN Me Ph Boc 3c 1c 3a i ii Scheme 5 Reagents and conditions i BuLi THFndash;HMPA (4 1) 278 8C 1 h then 240 8C 14 h HN Me Ph Boc HN Me Ph Boc X X N Me Ph Boc X 1d X = Ph 1e X = SPh 2d,e 3d,e + i Table 1 Selected NMR data for 2 and 3 1b 1c 1d 1e X SiMe3 SiPhMe2 Ph SPh Diastereoselectivity a 2 3 1 20 3 only 1 7 1 4 d Me groups 2; 3 b 1.02; 0.66 0.53 0.80; 0.70 1.13; 0.76 J C-1Hndash;C-2H 3 10.4 9.6 9.5 9.8 a Ratios of unpurified products determined by 250 MHz NMR.b 2H6DMSO. ucts with cold light petroleum in 59 and 26 yield respectively. The diastereoselection could be ascertained from inspection of selected NMR characteristics (Table 1). As with the trimethylsilyl derivative the large C-1Hndash;C-2H coupling constant (Fig. 1) suggested conformations where the methyl substituents of the major diastereoisomer were shielded by the proximal phenyl ring.6 This analysis was supported by the conversion of 3c to 3a (vide supra). These results support the proposed transition state model6 (Scheme 6) for these rearrangements. The change in the extent of diastereoselection nicely mirrors the decrease in the steric bulk of the anion-stabilising vinyl substituents X in the order PhMe2Si Ph SPh.We expected the sulfoxide 1f and sulfone 1g analogues to behave similarly; 1f offering the potential of a chiral anionstabilising vinyl substituent that could control the enantioselection of this particular variant of the process. Unfortunately treatment of 1f with BuLi under standard conditions led only to the desulfurised starting material 1a (30) and N-tert-butoxycarbonylbenzylamine (48) (Scheme 7). Treatment of 1g and 1f under a range of similar conditions led to complex mixtures of products none of which could be identified. We can only conclude that the sulfoxide and sulfone substituents render the system incompatible towards the strong base necessary to facilitate the anionic sigmatropic rearrangement.Fig. 1 HN Ph Me Boc HN Ph Me Boc H HNBoc Ph H Me H Ph BocNH H Me X X X X 3 1 1 2 2 Scheme 6 Transition-state model for major diastereoisomer Me H N Ph Boc X Me H N Ph Boc X N Me Ph Boc X HN Me Ph Boc X d- d- 1 3 Scheme 7 Reagents and conditions i BuLi THFndash;HMPA (4 1) 278 8C 1 h then 240 8C 14 h N Me Ph Boc (O)SPh N Me Ph Boc Boc Ph HN + 1a 30 48 i 1f J. Chem. Soc. Perkin Trans. 1 1997 1519 The aza-2,3 Wittig rearrangement has been shown to be accelerated by the incorporation of certain anion-stabilising vinyl substituents at the central vinyl carbon atom. The diastereoselection ranges from 4 1 to 20 1 depending on the steric bulk of the substituents X in allyl amines 1 with silyl substituents emerging as the front runners. The phenyldimethylsilyl group after its removal has verified our structural assignments and increases the synthetic utility of the silicon-stabilised aza- 2,3 Wittig rearrangement.The phenyl and phenylthio substituents further expand the process. The use of the rearranged precursors as synthetic building blocks will be reported shortly and the investigation of other less obvious accelerating groups are underway. Experimental General details Our general experimental details have been reported elsewhere.6 (1-Bromovinyl)phenyldimethylsilane Bromine (1.84 ml 0.036 mol 1 equiv.) in carbon tetrachloride (20 ml 1 2 times; 5 ml wash) was added dropwise via a cannula to a stirred solution of phenyldimethylvinylsilane (5.78 g 0.036 mol) in carbon tetrachloride (30 ml) at 0 8C. The solution was stirred for 10 min at 0 8C washed sequentially with saturated aqueous sodium hydrogen carbonate containing some sodium hydrogen sulfite (3 times; 50 ml) and brine (50 ml) dried over magnesium sulfate and concentrated in vacuo to give the crude dibromide (12.62 g) as a pale yellow oil.This crude product was dissolved in pyridine (50 ml) and refluxed for 14 h. After cooling to room temperature the dark brown reaction mixture was diluted with diethyl ether (100 ml) and washed with water (70 ml). The aqueous layer was further extracted with diethyl ether (2 times; 70 ml) and the combined organics washed repeatedly with a saturated copper sulfate solution until all of the pyridine had been removed as indicated by the aqueous phase retaining a light blue colour. The organics were then washed with brine (70 ml) dried over magnesium sulfate and concentrated in vacuo to give a pale brown oil (5.63 g) which was purified by flash column chromatography (15 times; 5 cm silica light petroleum) to give the bromovinylsilane (5.32 g 62) as a colourless oil (Found C 50.2; H 5.8; Br 33.4.C10H13BrSi requires C 49.8; H 5.4; Br 33.1); nmax(thin film)/cm21 3071 2962 1592 1429 1397 1250 1114 1070 915; dH(250 MHz; CDCl3) 0.49 6H s (CH3)2Si 6.17 (1H d J 1.7 CHH ) 6.35 (1H d J 1.7 CHH ) 7.30ndash;7.70 (5H m ArH); dC(63 MHz; CDCl3) 23.4 128.0 129.8 131.5 134.1 135.2 136.7; m/z (EI1) 241.9940 (31 M1. C10H13 81BrSi requires M 241.9949) 239.9962 (32 M1. C10H13 79BrSi requires M 239.9970) 227 (51)/225 (50 M1 2 CH3) 201 (100)/199 (100) 161 (23 M1 2 Br) 145 (37) 135 (97) 105 (46). 3-Phenyldimethylsilylbut-3-en-2-ol 4c tert-Butyllithium (15.5 ml of a 1.7 M solution in pentane 26.4 mmol 2.1 equiv.) was added dropwise to a stirred solution of (1-bromovinyl)phenyldimethylsilane (3.03 g 12.6 mmol) in diethyl ether (40 ml) at 278 8C.After complete addition the reaction was stirred for 1 h at 278 8C. A solution of acetaldehyde (1.40 ml 25.1 mmol 2 equiv.) in diethyl ether (10 ml) was then added dropwise via a cannula. After stirring for a further hour at 278 8C the reaction was allowed to warm to room temperature. Water (50 ml) was added the mixture separated and the aqueous layer extracted with diethyl ether (3 times; 30 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil (3.24 g) which was purified by flash column chromatography (15 times; 5 cm silica 15 ethyl acetatendash;light petroleum) to give 4c (2.23 g 86) as a colourless oil (Found C 69.4; H 8.8.C12H18OSi requires C 69.8; H 8.8); nmax(thin film)/cm21 3358 1428 1250 1111 845; dH(250 MHz; CDCl3) 0.42 (3H s CH3Si) 0.44 (3H s CH3Si) 1.20 (3H d J 6.4 CH3CH) 1.39 (1H d J 4.3 OH by D2O exchange) 4.44 (1H qdt J 6.4 4.3 1.2 CH3CH) 5.45 (1H dd J 2.4 1.2 CHH ) 5.91 (1H dd J 2.4 1.2 CHH ) 7.30ndash;7.65 (5H m ArH); dC(63 MHz; CDCl3) 22.3 22.1 24.1 71.7 124.7 127.9 129.1 133.9 138.4 155.0; m/z (EI1) 191.0893 (25 M1 2 CH3. C11H15OSi requires M 2 CH3 191.0892) 137 (100) 135 (44) 105 (12) 75 (26). 3-Phenylbut-3-en-2-ol 4d a-Bromostyrene (3 ml 23.1 mmol) was converted to 4d in an identical fashion to that for 4c and was purified by flash column chromatography (15 times; 5 cm silica 15 ethyl acetatendash;light petroleum) to give a pale straw coloured oil (3.06 g 89);14 dH(250 MHz; CDCl3) 1.32 (3H d J 6.4 CH3) 1.79 (1H d J 4.0 OH by D2O exchange) 4.82 (1H qd J 6.4 4.0 CHOH) 5.28 (1H t J 0.9 CHH ) 5.36 (1H t J 1.2 CHH ) 7.25ndash;7.45 (5H m ArH).3-Phenylthiobut-3-en-2-ol 4e Phenyl vinyl sulfide (5 ml 0.038 mol) in tetrahydrofuran (40 ml 1 2 times; 10 ml wash) was added dropwise via a cannula to a stirred solution of butyllithium (16.1 ml of a 2.5 M solution in hexane 0.040 mol 1.05 equiv.) and TMEDA (6.1 ml 0.040 mol 1.05 equiv.) in tetrahydrofuran (120 ml) at 278 8C. After stirring at 278 8C for 2 h a solution of acetaldehyde (4.2 ml 0.077 mol 2 equiv.) in tetrahydrofuran (10 ml 1 2 times; 2 ml wash) was added dropwise via a cannula. Upon complete addition the reaction was stirred for a further hour at 278 8C before being warmed to room temperature.Saturated aqueous ammonium chloride (100 ml) was added the mixture separated and the aqueous layer further extracted with diethyl ether (3 times; 70 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a crude yellow oil (9.1 g) which was purified by flash column chromatography (15 times; 7 cm silica 20 ethyl acetatendash;light petroleum) to give the alcohol 4e (4.75 g 69) as a yellow oil;15 dH(250 MHz; CDCl3) 1.43 (3H d J 6.4 CH3) 1.93 (1H br s OH by D2O exchange) 4.37 (1H qt J 6.4 0.6 CHOH) 4.97 (1H d J 0.9 CHH ) 5.50 (1H d J 0.9 CHH ) 7.20ndash;7.50 (5H m ArH). Preparation of compounds 1 We have previously reported general methods for the preparation of 1 from 4 via 5.6 (Z)-N-tert-Butoxycarbonyl-2-(phenyldimethylsilyl)but-2-enylamine 5c.Compound 5c was prepared in 40 yield from 4c as a colourless oil; nmax(thin film)/cm21 3356 1703 1505 1366 1249 1171; dH(250 MHz; CDCl3) 0.41 6H s (CH3)2Si 1.42 9H s (CH3)3C 1.64 (3H dt J 7.0 1.2 CH3CH ) 3.77 (2H m NCH2CH ) 4.35 (1H br s NH by D2O exchange) 6.31 (1H qt J 7.0 1.2 CH3CH ) 7.30ndash;7.55 (5H m ArH); dC(63 MHz; CDCl3) 21.5 17.8 47.9 79.1 127.9 128.9 133.7 134.8 140.5 155.4; m/z (CI1) 306.1880 (13 MH1. C17H28NO2Si requires MH1 306.1889) 278 (17) 248 (13 M1 2 But) 234 (47) 172 (100) 135 (16) 57 (But). (E)-N-tert-Butoxycarbonyl-2-phenylbut-2-enylamine 5d. Compound 5d was prepared in 61 yield from 4d as a colourless oil; nmax(thin film)/cm21 3351 1704 1505 1366 1249 1172 702; dH(250 MHz; CDCl3) 1.40 9H s (CH3)3C 1.59 (3H dt J 7.0 1.2 CH3) 3.97 (2H m NCH2CH ) 4.55 (1H br s NH by D2O exchange) 5.71 (1H q J 7.0 CH ) 7.15ndash;7.40 (5H m ArH); dC(63 MHz; CDCl3) 14.5 28.4 47.4 79.1 123.0 127.0 128.2 128.7 138.3 139.6 155.8; m/z (EI1) 247.1575 (3.8 M1.C15H21NO2 requires M 247.1572) 191 100 MH1 2 (CH3)3C 176 (9) 146 (6) 130 (37) 115 (8). (E)-N-tert-Butoxycarbonyl-2-phenylthiobut-2-enylamine 5e. Compound 5e was prepared in 41 yield from 4e as a yellow solid mp 52ndash;54 8C (Found C 64.4; H 7.5; N 4.9; S 11.6. C15H21NO2S requires C 64.5; H 7.6; N 5.0; S 11.5); nmax(thin film)/cm21 3348 1702 1584 1507 1478 1366 1249 1170; dH(250 MHz; CDCl3) 1.41 9H s (CH3)3C 1.90 (3H dt J 6.7, 1520 J. Chem. Soc. Perkin Trans. 1 1997 1.2 CH3) 3.77 (2H d J 5.5 NCH2) 4.77 (1H br s NH by D2O exchange) 6.25 (1H q J 6.7 CH3CH ) 7.15ndash;7.30 (5H m ArH); dC(63 MHz; CDCl3) 15.5 28.4 46.4 79.3 126.1 128.9 129.0 130.8 133.6 134.6 155.6; m/z (EI1) 279.1291 (32 M1.C15H21NO2S requires M 279.1293) 223 MH1 2 (CH3)3C 74 162 (96) 149 (37) 129 (22) 114 (92) 57 (100). (Z)-N-tert-Butoxycarbonyl-N-2-(phenyldimethylsilyl)but-2- enylbenzylamine 1c. Compound 1c was prepared in 95 yield from 5c as a colourless oil; nmax(thin film)/cm21 1694 1454 1410 1365 1248 1168 1111; dH(250 MHz; CDCl3) 0.38 6H s (CH3)2Si 1.45 9H s (CH3)3C 1.67 (3H dt J 7.0 1.5 CH3CH ) 3.93 (2H br m NCH2) 4.31 (2H br m NCH2) 6.12 (1H q J 7.0 CH3CH ) 7.10ndash;7.55 (10H m ArH); dC(63 MHz; CDCl3) 21.5 17.7 28.4 48.7 51.9 79.6 126.7 127.1 127.6 127.8 128.4 128.8 133.6 138.4 139.0 155.9; m/z (EI1) 395.2279 (9 M1. C24H33NO2Si requires M 395.2281) 338 17 M1 2 (CH3)3C 324 (60) 262 (100) 135 (51) 91 (65).(E)-N-tert-Butoxycarbonyl-N-(2-phenylbut-2-enyl)benzylamine 1d. Compound 1d was prepared in 94 yield from 5d as a pale yellow oil (Found C 78.1; H 8.0; N 3.95. C22H27NO2 requires C 78.3; H 8.1; N 4.15); nmax(thin film)/cm21 1694 1454 1416 1365 1243 1167 1124 879 700; dH(250 MHz; CDCl3) 1.30 9H s (CH3)3C 1.55 (3H m CH3) 3.87ndash;4.40 (4H m CH2NCH2) 5.50 (1H m CH ) 7.00ndash;7.30 (10H m ArH); dC(63 MHz; CDCl3) 14.4 28.3 48.3 52.6 79.5 123.5 124.0 126.9 127.1 127.4 128.1 128.4 128.8 137.3 138.3 155.7; m/z (EI1) 337.2037 (7 M1. C22H27NO2 requires M 337.2042) 281 74 MH1 2 (CH3)3C 132 (27) 91 (100) 57 (46). (E)-N-tert-Butoxycarbonyl-N-(2-phenylthiobut-2-enyl)benzylamine 1e. Compound 1e was prepared in 82 yield from 5e as a yellow oil; nmax(thin film)/cm21 1695 1584 1477 1453 1410 1365 1244 1167 1117 878; dH(250 MHz; CDCl3) 1.40 9H s (CH3)3C 1.94 (3H dt J 6.7 1.5 CH3) 3.87 (2H m NCH2) 4.38 (2H m NCH2) 6.03ndash;6.17 (1H m CH3CH ) 7.05ndash;7.35 (10H m ArH); dC(63 MHz; CDCl3) 15.4 28.3 49.1 51.1 79.8 125.8 127.1 127.3 127.9 128.3 128.9 133.4 135.2 138.0 155.9; m/z (EI1) 369.1770 (0.8 M1.C22H27NO2S requires M 369.1763) 313 1.2 MH1 2 (CH3)3C 296 (4) 204 (100) 91 (58) 57 (25). (E)-N-tert-Butoxycarbonyl-N-(2-phenylsulfinylbut-2-enyl)- benzylamine 1f m-Chloroperbenzoic acid (0.56 g 1 equiv.) was added portionwise to a stirred solution of (E)-N-tert-butoxycarbonyl-N- (2-phenylthiobut-2-enyl)benzylamine 1e (1.20 g) in dichloromethane (30 ml) at room temperature. After 1 h further dichloromethane (20 ml) was added and the reaction mixture washed with saturated aqueous sodium hydrogen carbonate (3 times; 50 ml) dried over magnesium sulfate and concentrated in vacuo to give a yellow oil (1.60 g).This was purified by flash column chromatography (15 times; 3 cm silica 30 ethyl acetatendash; light petroleum) to give the sulfoxide 1f (1.13 g 90) as a viscous pale yellow oil; nmax(thin film)/cm21 1694 1454 1415 1366 1247 1166 1044 749 697; dH(250 MHz; CDCl3) 1.37 9H m (CH3)3C 2.18 (3H dt J 7.3 1.6 CH3) 3.60ndash;4.30 (4H m CH2NCH2) 5.90ndash;6.30 (1H m CH3CH ) 7.00ndash;7.55 (10H m ArH); dC(63 MHz; CDCl3) 14.9 28.3 42.2 50.1 80.1 123.9 127.2 127.7 128.4 129.1 131.7 134.6 138.1 140.6 142.6 155.8; m/z (EI1) 385.1709 (19 M1. C22H27NO3S requires M 385.1712) 329 16 MH1 2 (CH3)3C 312 25 M1 2 (CH3)3CO 284 15 M1 2 (CH3)3COCO 268 (47 M1 2 PhSO) 204 (100) 158 (35) 144 (40).(E)-N-tert-Butoxycarbonyl-N-(2-phenylsulfonylbut-2-enyl)- benzylamine 1g A suspension of Oxone (5.79 g 3 equiv.) and water (15 ml) was added portionwise to a stirred solution of 1e (1.16 g) in methanol (25 ml) at 0 8C. Upon complete addition the reaction was warmed to room temperature and stirred for 14 h. The methanol was removed in vacuo the residue partitioned between water (15 ml) and dichloromethane (15 ml) the organic layer was separated and the aqueous layer further extracted with dichloromethane (3 times; 15 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a crude yellow oil which was purified by flash column chromatography (15 times; 3 cm silica 20 ethyl acetatendash; light petroleum) to give the sulfoxide 1g (1.20 g 95) as a viscous pale yellowndash;green oil; nmax(thin film)/cm21 1694 1447 1410 1366 1305 1247 1159 1137 1083 729 690; dH(250 MHz; CDCl3) 1.40 9H m (CH3)3C 2.15 (3H dt J 7.6 1.5 CH3) 4.05 (2H br m NCH2) 4.33 (2H s NCH2) 6.00ndash;6.35 (1H br m CH3CH ) 7.05ndash;7.90 (10H m ArH); dC(63 MHz; CDCl3) 14.7 28.4 48.2 49.9 80.6 127.2 127.6 128.7 129.4 133.5 136.8 137.6 138.1 140.6 141.5 155.7; m/z (EI1) 401.1658 (0.3 M1.C22H27NO4S requires M 401.1661) 345 10 MH1 2 (CH3)3C 300 37 M1 2 (CH3)3COCO 204 (59) 150 (38) 144 (31) 106 (90) 91 (100) 77 (24) 57 (85). (1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1-phenyl-3-(phenyldimethylsilyl) but-3-enylamine 3c Butyllithium (0.66 ml of a 2.5 M solution in hexane 1.7 mmol 1.2 equiv.) was added dropwise to a stirred soution of (Z)- N-tert-butoxycarbonyl-N-2-(phenyldimethylsilyl)but-2-enyl- benzylamine 1c (0.55 g 1.4 mmol) in tetrahydrofuran (11 ml) at 278 8C.After stirring for 14 h at 278 8C the reaction was quenched by the addition of methanol (0.1 ml) and warmed to room temperature. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate (20 ml) and diethyl ether (15 ml) the organic layer was separated and the aqueous layer further extracted with diethyl ether (3 times; 15 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a viscous pale yellow oil (0.63 g) which was purified by flash column chromatography (12 times; 2.5 cm silica 7 ethyl acetatendash;light petroleum) to give the title compound 3c as a colourless oil (0.44 g 81) (Found C 72.4; H 8.6; N 3.8.C24H33NO2Si requires C 72.9; H 8.4; N 3.5); nmax(thin film)/cm21 3425 1702 1496 1366 1250 1171 817 734 701; dH250 MHz; (CD3)2SO 0.42 3H s (CH3)Si 0.47 3H s (CH3)Si 0.53 (3H d J 7.0 CCHCH3) 1.15 9H s (CH3)3C 2.59 (1H dq J 9.6 7.0 =CCHCH3) 4.47 (1H t J 9.6 NCHPh) 5.42 (1H d J 2.4 HHC ) 5.81 (1H d J 2.4 HHC ) 6.87 (1H d J 9.6 NH by D2O exchange) 6.95ndash;7.45 (10H m ArH); dC(63 MHz; CDCl3) 22.6 19.7 28.4 42.2 59.3 79.0 127.0 127.1 127.5 128.0 128.2 129.3 134.1 137.9 142.8 152.9 154.9; m/z (EI1) 395.2274 (3.7 M1. C24H33NO2Si requires M 395.2281) 382 (2) 262 (7) 206 (49) 172 (9) 150 (100) 135 (48) 106 (79) 91 (7) 57 (94). (1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1,3-diphenylbut-3- enylamine 3d Butyllithium (1.64 ml of a 2.5 M solution in hexane 4.1 mmol 1.2 equiv.) was added dropwise to a stirred solution of (E)- N-tert-butoxycarbonyl-N-(2-phenylbut-2-enyl)benzylamine 1d (1.15 g 3.4 mmol) in tetrahydrofuranndash;HMPA (4 1 23 ml) at 278 8C.After stirring for 1 h at 278 8C the reaction was slowly warmed to 240 8C and stirred for 14 h before being quenched by the addition of methanol (0.2 ml). The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate (50 ml) and diethyl ether (30 ml) the organic layer was separated and the aqueous layer further extracted with diethyl ether (3 times; 30 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo to give a viscous yellow gum (2.3 g) which was purified by flash column chromatography (12 times; 4 cm silica 10 ethyl acetatendash;light petroleum) to give a pale yellow solid (0.82 g 71 of a 7 1 mixture of the title compound 3d to the minor diastereoisomer 2d).Trituration with ice-cold light petroleum furnished the major diastereoisomer only as a white powder (0.68 g 59) mp 123ndash;124 8C (Found C 77.9; H 7.7; N 4.3. C22H27NO2 J. Chem. Soc. Perkin Trans. 1 1997 1521 requires C 78.3; H 8.1; N 4.2); nmax(thin film)/cm21 3274 1701 1495 1454 1390 1365 1248 1170 701; dH250 MHz; (CD3)2SO 0.70 (3H d J 6.7 CH3) 1.30 9H s (CH3)3C 3.02 (1H dq J 9.5 6.7 CH3CHC ) 4.53 (1H t J 9.5 NHCHPh) 5.11 (1H s CHH ) 5.21 (1H s CHH ) 7.20ndash;7.50 (11H m ArH and NH by D2O exchange); dC63 MHz; (CD3)2SO 18.7 28.7 43.8 58.3 78.0 113.2 127.2 127.7 127.9 128.4 128.7 142.6 142.9 151.9 155.2; m/z (EI1) 337.2039 (0.4 M1. C22H27NO2 requires M 337.2042) 281 3 MH1 2 (CH3)3C 236 10 M1 2 (CH3)3COCO 206 (38) 196 (24) 150 (87) 106 (83) 91 (47) 57 (100).(1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1-phenyl-3-phenylthiobut- 3-enylamine 3e (E)-N-tert-Butoxycarbonyl-N-(2-phenylthiobut-2-enyl)benzylamine 1e (0.72 g 2.0 mmol) was treated with BuLi under exactly the same conditions and work up as for 3d to give a viscous yellow oil (1.2 g) which was purified by flash column chromatography (15 times; 3 cm silica 10 ethyl acetatendash;light petroleum) to give a pale yellow solid (0.35 g 49 of a 1 2 4 mixture of the minor diastereoisomer 2e N-tert-butoxycarbonylbenzylamine and the title compound 3e respectively). Trituration with ice-cold light petroleum furnished the title compound only as a white powder (0.19 g 26) mp 121ndash; 122 8C; nmax(thin film)/cm21 3375 1679 1512 1368 1292 1250 1171 742 704; dH250 MHz; (CD3)2SO 0.76 (3H d J 7.0 CH3) 1.35 9H s (CH3)3C 2.76 (1H dq J 9.8 7.0 CH3CHC ) 4.60 (1H s CHH ) 4.70 (1H t J 9.5 NHCHPh) 5.30 (1H s CHH ) 7.20ndash;7.55 (11H m ArH and NH by D2O exchange); dC63 MHz; (CD3)2SO 17.7 28.8 46.9 58.2 78.1 113.2 127.4 127.9 128.6 128.7 129.9 133.0 134.1 142.7 149.4 155.1; m/z (EI1) 369.1767 (5 M1.C22H27NO2S requires M 369.1762) 296 5 M1 2 (CH3)3CO 268 3 M1 2 (CH3)3COCO 260 (2 M1 2 Ph) 206 (63) 150 (100) 106 (87) 57 (96). Attempted aza-2,3 Wittig sigmatropic rearrangement of (E)-Ntert- butoxycarbonyl-N-(2-phenylsulfinylbut-2-enyl)benzylamine 1f (E)-N-tert-Butoxycarbonyl-N-(2-phenylsulfinylbut-2-enyl)- benzylamine 1f (63 mg 0.16 mmol) was treated with butyllithium under exactly the same conditions and work up as for 3d to give a viscous yellow oil (70 mg) which was purified by flash column chromatography (15 times; 1 cm silica 20 ethyl acetatendash;light petroleum) to furnish (E)-N-tert-butoxycarbonyl- N-but-2-enylbenzylamine 1a 6 (13 mg 30) and N-tert-butoxycarbonylbenzylamine (16 mg 48).(1S*,2R*)-N-tert-Butoxycarbonyl-2-methyl-1-phenylbut-3-enylamine 3a Tetrabutylammonium fluoride (1.1 ml of a 1 M solution in tetrahydrofuran 1.1 mmol 5 equiv.) was added to a stirred solution of (1S*,2R*)-N-tert-butoxycarbonyl-2-methyl-1-phenyl-3- (phenyldimethylsilyl)but-3-enylamine 3c (85 mg 0.2 mmol) in dimethyl sulfoxide. After stirring for 2 h at 100 8C (oil bath temperature) the reaction mixture was cooled diluted with ethyl acetate (10 ml) washed sequentially with water (4 times; 10 ml) and brine (10 ml) dried thoroughly over magnesium sulfate and concentrated in vacuo to give an off-white solid (34 mg).Purification by flash column chromatography (15 times; 1 cm silica 10 ethyl acetatendash;light petroleum) furnished the title compound 3a as a white solid (26 mg 47).6 Acknowledgements We dedicate this paper to the memory of Mr S. A. Johnson an able chemist who was called away from his life on this earth. This work was supported by Zeneca Agrochemicals and the University of Sheffield. We would also like to thank The Royal Society and Zeneca (Strategic Research Fund award) for additional financial support. References 1 For a recent review see T. Nakai and K. Mikami Org. React. 1994 46 105. 2 (a) M. A. Reetz and D. Schinzer Tetrahedron Lett. 1975 3485; (b) C.A. Broka and T. Shen J. Am. Chem. Soc. 1989 111 2981; (c) Y. Murata and T. Nakai Chem. Lett. 1990 2069; (d) I. Coldham J. Chem. Soc. Perkin Trans. 1 1993 1275; (e) R. E. Gawley Q. Zhang and S. Campagna J. Am. Chem. Soc. 1995 117 11 817; ( f ) M. Gulea-Purcarescu E. About-Jaudet N. Collignon M. Saquet and S. Masson Tetrahedron 1996 52 2075. 3 T. Durst R. V. D. Elzen and M. J. Le Belle J. Am. Chem. Soc. 1972 94 9261. 4 (a) J. Ahman and P. Somfai J. Am. Chem. Soc. 1994 116 9781; (b) I. Coldham A. J. Collis R. J. Mould and R. E. Rathmell J. Chem. Soc. Perkin Trans. 1 1995 2739. 5 J. C. Anderson D. C. Siddons S. C. Smith and M. E. Swarbrick J. Chem. Soc. Chem. Commun. 1995 1835. 6 J. C. Anderson D. C. Siddons S. C. Smith and M. E. Swarbrick J. Org. Chem. 1996 61 4820. 7 P. v. R. Schleyer T.Clark A. J. Kos G. W. Spitznagel C. Rohde D. Arad K. N. Houk and N. G. Rondan J. Am. Chem. Soc. 1984 106 6467. 8 Here we draw an analogy to the calculated transition state for the oxy-2,3 Wittig rearrangement. Y.-D. Wu K. N. Houk and J. A. Marshall J. Org. Chem. 1990 55 1421. See also K. Mikami T. Uchida T. Hirano Y.-D. Wu and K. N. Houk Tetrahedron 1994 50 5917. 9 J. C. Anderson M. E. Swarbrick and C. A. Roberts unpublished results. 10 I. Fleming J. Dunoduegrave;s and R. Smithers Org. React. 1989 37 57. 11 H. Oda M. Sato Y. Morizawa K. Oshima and H. Nozaki Tetrahedron 1985 41 3257. 12 A. G. Brook J. M. Duff and D. G. Anderson Can. J. Chem. 1970 48 561. 13 L. E. Overman J. Am. Chem. Soc. 1976 98 2901. 14 K. Burgess and L. D. Jennings J. Am. Chem. Soc. 1991 113 6129. 15 K. Takaki M.Okada M. Yamada and K. Negoro J. Org. Chem. 1982 47 1200. Paper 6/08226B Received 5th December 1996 Accepted 21st January 1997 J. Chem. Soc. Perkin Trans. 1 1997 1517 Diastereoselective acyclic aza-2,3 Wittig sigmatropic rearrangements James C. Anderson,*,dagger;,a Stephen C. Smith b and Martin E. Swarbrick a a Department of Chemistry University of Sheffield Sheffield UK S3 7HF b Zeneca Agrochemicals Jealottrsquo;s Hill Research Station Bracknell Berkshire UK RG42 6EY The scope of anion-stabilising groups in promoting and controlling the diastereoselection of the aza-2,3 Wittig sigmatropic rearrangement has been assessed by the syntheses of allylic amines 1cndash;g that have incorporated SiPhMe2 Ph SPh SOPh and SO2Ph respectively at the C-2 position. The subsequent anionic 2,3-sigmatropic rearrangements are analysed with respect to the extent of diastereoselection of the product homoallylic amines 2 and 3.It appears that silicon not only is the most efficient at electronically facilitating this rearrangement but its steric bulk controls the diastereoselectivity of the process exclusively. Phenyl and phenylthio substituents also have a similar but decreased effect on diastereoselection that mirrors their lower steric bulk in comparison to the silicon derivative. Sulfoxide and sulfone substituents are incompatible with the reaction conditions required for rearrangement. Introduction Despite the numerous synthetic applications of the 2,3 Wittig sigmatropic rearrangement of allylic ethers (Scheme 1 X = O),1 the use of the aza congener (Scheme 1 X = N) has been limited by the reluctance of simple allyl amines to undergo this transformation.2 The first unequivocal example of this rearrangement 3 which is driven by relief of ring strain has been extended by others to include vinyl aziridines.4 The 2,3- rearrangement of N-allyl nitrogen ylides has been shown to be potentially useful.2e We have concentrated our efforts on the acyclic variant of this rearrangement and want to develop the aza-2,3 Wittig sigmatropic process into a versatile method for the preparation of unnatural amino acids. To this end we have managed to markedly accelerate our preliminary reaction 5 and control the diastereoselectivity of the acyclic rearrangement by the incorporation of a trimethylsilyl group at the C-2 position of our substrate (Scheme 2).6 We believe the silicon atom due to its ability to stabilise adjacent negative charge,7 is stabilising the transition state,8 thus reducing the activation energy of the reaction.The inherent bulk of the silyl group is dictating the diastereoselection.6 This strategy has allowed the acyclic Scheme 1 X R1 R2 HX R1 R2 X = O NR3 anionic 2,3 shift Scheme 2 Reagents and conditions BuLi Et2Ondash;HMPA (4 1); a X = H 278 to 240 8C 14 h 82; b X = SiMe3 278 8C 10 min 88 N Me Ph Boc X HN Me Ph Boc HN Me Ph Boc X X a X = H ds ratio of 2:3 = 3:2 b X = SiMe3 ds ratio of 2:3 = 1:20 3 1a X = H 1b X = SiMe3 + 2 2 dagger;E-mail j.anderson@sheffield.ac.uk aza-2,3 Wittig rearrangement to become more applicable to a wider range of substrates.9 We report here the first examples of other anion-stabilising groups successfully incorporated into rearrangement precursors 1 that both facilitate and increase the synthetic scope of the aza-2,3 Wittig rearrangement.Our first concern was that we could not remove the trimethylsilyl group from 3 presumably because the accepted mechanism would require the formation of an incipient primary carbocation. 10 Although there is a rich chemistry associated with vinyl silanes 10 that could be applied to compounds such as 3 our methodology would be more versatile if the silyl group could also be removed at an early stage. An added incentive was that we could obtain unambiguous proof of diastereoselection from the desilylated product 3 (X = H).5 Following an isolated report that the phenyldimethylsilyl group could be removed from the C-2 position of a vinyl silane with tetrabutyl ammonium fluoride (TBAF),11 we sought to obtain 1c (X = SiPhMe2).We were also interested in the rearrangements of compounds analogous to 1 where X = Ph SPh S(O)Ph and SO2Ph (1dndash;g respectively); as all these groups are capable of stabilising an adjacent negative charge and could control diastereoselectivities in a manner similar to that found with SiMe3 (vide supra). Results and discussion Allylic alcohols 4cndash;e were prepared from the addition of the corresponding a-lithio-a-substituted vinyl precursors to acetaldehyde. In the case of the phenyldimethylsilane derivative 4c we had to develop a reliable synthesis of (1-bromovinyl)- phenyldimethylsilane based upon a description in the literature of the triphenyl congener.12 Addition of bromine to phenyldimethylvinylsilane and then elimination of hydrogen bromide with refluxing pyridine produced the desired halide in 62 yield.Allylic alcohols 4cndash;e were then transformed into the desired rearrangement precursors 1cndash;e via the established procedure for stereoselective conversion of secondary allylic alcohols to allyl amides 5cndash;e (Scheme 3).13 Compounds 1f and 1g were obtained from the controlled oxidation of 1e. Rearrangement of 1c was carried out by treatment with BuLi at 278 8C in tetrahydrofuran (THF) for 14 h to give the rearranged product 3c in 81 yield with complete diastereoselectivity (Scheme 4). This diastereoisomer exhibited characteristic chemical shifts in its NMR spectrum that we had used to assign the trimethylsilyl analogue (Table 1).6 Treatment with 1518 J. Chem. Soc. Perkin Trans.1 1997 TBAF in DMSO under standard literature conditions 11 produced a single diastereoisomer of the desilylated product in 47 yield. This compound had an identical NMR spectrum to the minor diastereoisomer 3a (Scheme 3) obtained from our first rearrangement the structure of which had been proven by correlation to authentic isoleucine.5 Treatment of 1d with BuLi in THFndash;HMPA (4 1) at 278 8C and then at 240 8C for 14 h led to a mixture of 2d and 3d in 71 yield with a di