A novel, one-pot reductive alkylation of amines by S-ethyl thioesters mediated by triethylsilane and sodium triacetoxyborohydride in the presence of palladium on carbon

The reductive alkylation of primary amines with aldehydes or ketones is an important tool in the synthesis of wide variety of amines, We described her e a novel, one-pot reductive alkylation method using multifunctional S-ethy l thioesters as a source for in situ generation of aldehydes to alkylate a range of multifunctional primary amines. The corresponding multifunctional secondary amines were obtained in good to excellent yields (mostly >90%). T his one-pot reductive alkylation included the treatment of a mixture of pro tected S-ethyl thioester, primary amine, 10% Pd/C, and sodium triacetoxybor ohydride in N,N-dimethylformamide with triethylsilane for 30 min at tempera ture lower than 20 degrees C. This method has special merit when the aldehy de is not stable enough to allow isolation and therefore does not lend itse lf to a stepwise strategy of reductive alkylation. This was the case with t ert-butyl 1(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-oxobutyrate (10) which could not be obtained from the alpha-tert-butyl gamma-S-ethyl (S)-N-(9-flu orenylmethoxycarbonyl) thioglutamate (9). However, by our one-pot reductive alkylating method, treatment of 9-fluorenemethyl phenylalaninate (6a) with 9 afforded tert-butyl 2(S)-[(9-fluorenylmethoxycarbonyl)amino]-4-[[3-pheny l-1(S)-(9-fluorenylmethoxycarbonyl)propyl]amino]butyrate (11) in 76% yield. Furthermore, the acid labile tert-butyloxycarbonyl, and the hydogenation l abile benzyloxycarbonyl and benzyl protecting groups, were stable in the on e-pot reductive alkylation reaction. While the conjugated double bond is st able in these reaction conditions, the monosubstituted C-C double bond, as in the allyl protecting group in alpha-allyl beta-cyclohexyl aspartate, was reduced to the corresponding propyl ester.