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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 here a novel, one-pot reductive alkylation method using multifunctional S-ethyl 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%). This one-pot reductive alkylation included the treatment of a mixture of protected S-ethyl thioester, primary amine, 10% Pd/C, and sodium triacetoxyborohydride in N,N-dimethylformamide with triethylsilane for 30 min at temperature lower than 20 degrees C. This method has special merit when the aldehyde is not stable enough to allow isolation and therefore does not lend itself to a stepwise strategy of reductive alkylation. This was the case with tert-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-fluorenylmethoxycarbonyl) 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-phenyl-1(S)-(9-fluorenylmethoxycarbonyl)propyl]amino]butyrate (11) in 76% yield. Furthermore, the acid labile tert-butyloxycarbonyl, and the hydogenation labile benzyloxycarbonyl and benzyl protecting groups, were stable in the one-pot reductive alkylation reaction. While the conjugated double bond is stable 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.