Modified McFadyen–Stevens reaction for a versatile synthesis of aliphatic/aromatic aldehydes: design, optimization, and mechanistic investigations

Abstract

The traditional McFadyen–Stevens reaction requires harsh alkaline reaction conditions, thus precluding application to the synthesis of aliphatic aldehydes. Our modified McFadyen–Stevens reaction enables the transformation from the N,N-acylsulfonyl hydrazine to the corresponding aldehyde upon treatment with an imidazole–TMS imidazole combination without relying on oxidative or reductive reagents. The reduced basicity and in situ protection of the resulting aldehyde widens the substrate scope to include aliphatic aldehydes, even ones bearing an α-hydrogen atom. Close examination of the side reactions for particular substrates in combination with theoretical considerations via DFT calculations led to a mechanistic understanding of the McFadyen–Stevens reaction involving an acyl diazene and a hydroxy carbene as reasonable intermediates.