Difluorocarbene-enabled N-deuteroformylation of amines and sulfonamides: access to formamide-1-d and N-CH2D motifs

Abstract

Labelled compounds bearing deuterium are cornerstone tools across many fields, underpinning a multi-billion-dollar global market that spans pharmaceuticals, advanced smart materials, and analytical research. Herein, we present a straightforward protocol for introducing a deuteroformyl group (C(O)D) onto complex amines and sulfonamides. The transformation employs potassium 2-bromo-2,2-difluoroacetate (BrCF₂CO₂K) as a C₁ synthon and D₂O as an inexpensive deuterium source, in the presence of K₂CO₃ at room temperature. This method provides access to N-deuteroformamides (N–C(O)D) and N-deuteroformyl sulfonamides (SO₂N–C(O)D) in good to excellent yields, with deuterium degree reaching up to 92%. The reaction proceeds via in situ generation of difluorocarbene at room temperature from BrCF₂CO₂K, which is trapped by amines or sulfonamides in the presence of D₂O to form N-deuterodifluoromethylated intermediates. Subsequent deuterolysis furnishes valuable formamide-1-d building blocks. Furthermore, we showcase N-deuteroformamides as versatile precursors for the synthesis of unique monodeuteromethylated amines (N-CH₂D), which belong to a challenging compound class, and hence they are usually difficult to produce. These N-CH₂D compounds are mainly used in drug discovery, particularly for tracking metabolic pathways in biomedical research.