Simple, versatile, and chemoselective reduction of secondary amides and lactams to amines with the Tf2O–NaBH4 or Cp2ZrHCl–NaBH4 system

Abstract

The reduction of secondary amides to amines is an important transformation for the total synthesis of alkaloids and pharmaceuticals. General and chemoselective direct methods for this transformation are scarce. We report in this paper a simple method for the direct reduction of secondary amides, which uses only two reagents, triflic anhydride for amide activation, and NaBH₄ for reduction. Running under mild conditions (0 °C to r.t.), the reaction works well with several types of secondary amides including aromatic amides, aliphatic amides, and α,β-unsaturated amides. The reaction displays a good functional group tolerance for a series of reducible functional groups. The method is applicable to the direct reduction of C–H lithiation-functionalization products, and C–H activation-functionalization products. Moreover, chemoselective reduction of secondary lactams has been achieved using Cp₂ZrHCl–NaBH₄ combination.