Amination of Optically Active Azaallylic Anions$% Stefania Fioravanti, Lauso Olivieri, Lucio Pellacani* and Paolo A. Tardella* Dipartimento di Chimica, Universita¢® `La Sapienza', P.le Aldo Moro 2, I-00185 Roma, Italy The reaction of azaallylic anions with ethyl N-[4-nitrobenzenesulfonyl)oxy]carbamate in the presence of a base gives a mixture of an -amino ketone derivative with a slight preference for the (S) enantiomer and of an -hydrazino ketone derivative as by-product; the same azaenolates react with bis(tert-butoxycarbonyl)diazene giving the analogous -hydrazino ketone derivative, with a slight preference for the (R) enantiomer.Chiral enamines, imines and hydrazones allow good enantio- and diastereo-selectivity in carbon¡¾carbon bond- forming reactions.1 We have recently been exploring the for- mation of carbon¡¾nitrogen bonds starting from enamines.2 Our attention was then directed towards the amination reaction of azaallylic anions derived from imines.In this paper we describe results concerning the reactions of two aminating agents, namely ethyl N-[(4-nitrobenzene- sulfonyl)oxy]carbamate (NsONHCO2Et) and bis(tert- butoxycarbonyl)diazene [N2(CO2But)2, TBD] with azaallylic anions. The reaction of NsONHCO2Et in the presence of LiOH was ¢çrst carried out with the N-cyclohexylidene- benzylamine lithium salt 1 in order to optimise the yields of 2-[(ethoxycarbonyl)amino]cyclohexanone 2 (Scheme 1). The best results were obtained using a mixture of THF or DME and CH2Cl2.As a base we ¢çrst chose LiOH in order to have a common cation in the reaction mixture. The best conditions are those of entry 5 (Table 1). We note that this is the ¢çrst successful amination by NsONHCO2Et at low temperatures, although electrophilic amination by TBD of ester enolates3 and chiral amide cuprates4 has been reported. The reaction was then extended to chiral substrates 3 and 4 (Scheme 2). The chiral metallated hydrazone 5, usually employed in alkylation reactions,5 was unreactive.In Table 2 the results of reactions run using NsONHCO2Et are collected. Entries 1, 7 and 9 refer to the best conditions of Table 1. The major enantiomer of 2 showed an S con¢çguration6 as expected on the basis of an attack from the less hindered side and as previously noted in the amination of (S)-(¢§)-1- (1-cyclohexenyl)-2-(methoxymethyl)pyrrolidine in the presence of calcium oxide.2b When the anion was generated by the use of KH (entries 4, 6 and 8) the e.e.rose slightly, according to data reported for the alkylation of N,N-disubstituted amides.7 The large excess of LiOH required for the NsONHCO2Et deprotonation, might be responsible for the low e.e. observed in the aminations of 4, probably interfering with the formation of a rigid ¢çve membered chelate.8 J. Chem. Research (S), 1998, 338¡¾339$ Scheme 1 Scheme 2 Table 1 Amination of compound 1 with NsONHCO2Et and LiOH Molar ratio Reaction Yield of Entry Solvent T (8C) 1: NsONHCO2Et: LiOH time (h) 2 (%) 1 THF 0 1:3:10 20 2 2 THF ¢§50 1:3:10 24 5 3 DME ¢§70 1:3:10 3 16 4 THF/CH2Cl2 ¢§70 1:3:10 2 10 5 DME/CH2Cl2 ¢§70 1:3:10 3 32 6 DME/CH2Cl2 ¢§70 1:5:10 3 31 TBD gives a slow amination reaction only in the presence of HMPA, showing a lower reactivity towards this kind of azaenolates than that observed towards enolates.9 The reaction conditions and the yield of 2-[N,N'-bis(tert- butoxycarbonyl)hydrazino]cyclohexanone 7 (Scheme 3) are reported in Table 3.The R con¢çguration of the major enan- $This is a Short Paper as de¢çned in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S)1998, Issue 1]: there is there- fore no corresponding material in J. Chem. Research (M). %Presented in part at the XXIII Convegno Nazionale della Divisione di Chimica Organica della SocietaA Chimica Italiana, Monopoli, Italy, September 22¡¾27, 1996, P99. *To receive any correspondence (e-mail: pellacani@uniroma1.it). 338 J. CHEM. RESEARCH (S), 1998tiomer and the e.e. values were established on the basis ofthe [a]D values (see Experimental section). In this case theobserved reversal of facial selectivity might be rationalised ifone assumes a role of HMPA, as suggested in alkylation ofhydrazone lithio anions.10Free bases of the salts 1, 3 and 5, were treated directlywith TBD in toluene at reux, under conditions reported forMichael additions to the same substrates.11 After 2¡Ó5 h ofheating and subsequent hydrolytic work-up, the rst twobases gave the same product 7 in 45 and 30% yield, respect-ively.In the last case only 5% e.e. was found.ExperimentalGeneral Procedure for the Reactions of 1 with NsONHCO2Et.Asolution of BunLi in hexane (Fluka, 25 mmol, 1.6 M) was addeddropwise to a solution of diisopropylamine (25 mmol) in 20 ml ofTHF or DME, under nitrogen at 0 8C, and stirred for 30 minto obtain LDA. Then N-cyclohexylidenebenzylamine (20 mmol) in150 ml of anhydrous THF or DME or CH2Cl2 (Table 1, entries4¡Ó6) was added slowly and the mixture stirred for 1.5 h.AnhydrousLiOH (Carlo Erba) was added batchwise and NsONHCO2Et addedportionwise in 30 min. The mixture was allowed to warm to roomtemperature, poured into water¡ÓTHF, acidied to pH13 with 1 Moxalic acid and extracted with diethyl ether. Compound 212 wascollected by ash chromatography on silica gel (hexane¡Ódiethylether, 1:1) in the yields reported in Table 1.Reaction of 3, 4 and 5 with NsONHCO2Et.The general pro-cedure was followed, changing the cation (entries 4¡Ó6, 8 and 10 ofTable 2), the bases (entries 2, 3, 5 and 6) and the molar ratios(entries 2 and 3).After work-up, the products 2 and/or 613 wereseparated by ash chromatography on silica gel. The e.e. wasevaluated upon conversion into diastereomeric ketals with (2R,3R)-2,3-butanediol.6 6: C 14.20, 24.14 (CH3) 26.56, 29.52, 30.58, 41.18(CH2), 61.84 (NCH), 62.19, 62.75 (OCH2), 156.65 (CO2) and 207.67(CO).Reaction of 3, 4 and 5 with TBD.A solution of BunLi inhexane (50 mmol, 1.6 M) was added dropwise to a solution ofdiisopropylamine (50 mmol) in 200 ml of THF, under nitrogen at0 8C, and stirred to obtain LDA.After 30 min HMPA (50 ml) and3, 4 or 5 (20 mmol) in 100 ml of anhydrous THF were added slowlyand the mixture was stirred for 1.5 h. TBD (Fluka) in 100 ml ofTHF was added in the molar ratios reported in Table 3. After 1 h,the mixure was allowed to warm to room temperature and stirred(3¡Ó8 d) in the dark.After work-up with water¡ÓTHF and 1 M oxalicacid, the mixture was extracted with diethyl ether and the organiclayer washed with a saturated solution of NaCl. Compound 72b wascollected by ash chromatography on silica gel (hexane¡Óethylacetate, 8 : 2) in the yields and e.e. reported in Table 3. The e.e. wasobtained by comparison between the []D values (25 8C, c 0.12 inCH2Cl2) for 7 and that previously measured for a dierent enantio-meric mixture of the same -hydrazino ketone derivative (£¾12,CH2Cl2).2bReaction of free bases of 1, 3 and 5 with TBD.A solution ofsubstrate (10 mmol) and TBD (12 mmol) and 50 ml of toluenewas reuxed for 2¡Ó9 h.The mixture was poured into water¡ÓEtOH,acidied with 1 M oxalic acid and extracted with diethyl ether. Afterwork-up, starting from the rst two bases the product 7 wasobtained by ash chromatography on silica gel (hexane¡Óethylacetate, 8 : 2).Starting from the free base of 5, only the substratewas recovered by ash chomatography.This work was supported by the Ministero dell'Universitae della Ricerca Scientica e Tecnologica (MURST) and theConsiglio Nazionale delle Ricerche (CNR, Roma).Received, 24th December 1997; Accepted, 23rd February 1998Paper E/7/09277FReferences1 P. W. Hickmott, Tetrahedron, 1982, 38, 3363.2 (a) S. Fioravanti, L. Pellacani, D. Ricci and P. A. Tardella,Tetrahedron: Asymmetry, 1997, 8, 2261; (b) S.Fioravanti,L. Pellacani and P. A. Tardella, Gazz. Chim. Ital., 1997, 127, 41.3 J. P. Genet, S. Mallart, C. Greck and E. Piveteau, TetrahedronLett., 1991, 32, 2359.4 N. Zheng, J. D. Armstrong III, J. C. McWilliams and R. P.Volante, Tetrahedron Lett., 1997, 38, 2817.5 (a) D. Enders, H. Eichenauer, U. Baus, H. Schubert andK. A. M. Kremer, Tetrahedron, 1984, 40, 1345; (b) D. Enders,W. Gatzweiler and E. Dederichs, Tetrahedron, 1990, 46, 4757.6 S. Fioravanti, M. A. Loreto, L. Pellacani and P.A. Tardella,J. Chem. Res. (S), 1987, 310.7 M. Larcheveque, E. Ignatova and T. Cuvigny, TetrahedronLett., 1978, 3961.8 A. I. Meyers, D. R. Williams, G. W. Erickson, S. White andM. Druelinger, J. Am. Chem. Soc., 1981, 103, 3081.9 G. Guanti, L. Ban and E. Narisano, Tetrahedron, 1988, 44,5553; D. E. Evans, T. C. Britton, R. L. Dorow and J. F.Dellaria, Jr., Tetrahedron, 1988, 44, 5525.10 K. G. Davenport, H. Eichenauer, D. Enders, M. Newcomb andD. E. Bergbreiter, J. Am. Chem. Soc., 1979, 101, 5654.11 J. D'Angelo, D. Desmae le, F. Dumas and A. Guingant,Tetrahedron: Asymmetry, 1992, 3, 459.12 T. Hiyama, H. Taguchi, S. Fujita and H. Nozaki, Bull. Chem.Soc. Jpn., 1972, 45, 1863.13 R. M. Moriarty and I. Prakash, Synth. Commun., 1985, 15, 649.Table 2 Amination of compounds 3, 4 and 5 with NsONHCO2EtAdded Molar ratio Yield of 2 Yield of 6Entry Substrate M base substrate:NsONHCO2Et base (e.e., %) (e.e., %)1 3 Li LiOH 1:3:10 23% (28) ¡Ó2 3 Li Et3N 1:3:3.5 ¡Ó 22% (¡Ó)3 3 Li ¡Ó 2:1:¡Ó ¡Ó 13% (¡Ó)4 3 K LiOH 1:3:10 25% (34) 10% (8)5 3 K K2CO3 1:3:10 ¡Ó ¡Ó6 3 K CaO 1:3:10 13% (30) 10% (8)7 4 Li LiOH 1:3:10 12% (24) ¡Ó8 4 K LiOH 1:3:10 10% (36) 5% (9)9 5 Li LiOH 1:3:10 ¡Ó ¡Ó10 5 K LiOH 1:3:10 ¡Ó ¡ÓTable 3 Amination of compounds 3, 4 and 5 with TBDSubstrateMolar ratioHMPA: substrate:TBDTime(d)Yield of 7(e.e., %)[a]Dof 73 7:1:2.5 3 23% (¡Ó) ¡Ó4 6:1:1.25 4 19% (29) 9.05 6:1:1.25 8 28% (33) 11.2Scheme 3J. CHEM. RESEARCH (S), 1998 339