Iridium‐Catalyzed Reductive Strecker Reaction for Late‐Stage Amide and Lactam Cyanation

A new iridium‐catalyzed reductive Strecker reaction for the direct and efficient formation of α‐amino nitrile products from a broad range of (hetero)aromatic and aliphatic tertiary amides, and N‐alkyl lactams is reported. The protocol exploits the mild and highly chemoselective reduction of the amide and lactam functionalities using IrCl(CO)[P(C6H5)3]2 (Vaska's complex) in the presence of tetramethyldisiloxane, as a reductant, to directly generate hemiaminal species able to undergo substitution by cyanide upon treatment with TMSCN (TMS=trimethylsilyl). The protocol is simple to perform, broad in scope, efficient (up to 99 % yield), and has been successfully applied to the late‐stage functionalization of amide‐ and lactam‐containing drugs, and naturally occurring alkaloids, as well as for the selective cyanation of the carbonyl carbon atom linked to the N atom of proline residues within di‐ and tripeptides. Magic nitrile! A highly chemoselective iridium‐catalyzed reductive Strecker reaction of tertiary amides and lactams has been developed. The protocol is simple to perform, broad in scope, highly efficient, and has been successfully applied to the late‐stage functionalization of tertiary amides in drugs, naturally occurring alkaloids and peptides. TMDS=tetramethyldisiloxane, TMS=trimethylsilyl, Vaska's complex=IrCl(CO)[P(C6H5)3]2.