Selective α-Monomethylation by an Amine-Borane/N,N-Dimethylformamide System as the Methyl Source

Abstract

A new and practical α-monomethylation strategy using an amine-borane/N,N-dimethylformamide (R₃ N-BH₃ /DMF) system as the methyl source was developed. This protocol has been found to be effective in the α-monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R₃ N-BH₃ donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH₂ -, CD₂ H-, and CD₃ - units using Me₂ NH-BH₃ /d₇ -DMF, Me₃ N-BD₃ /DMF and Me₃ N-BD₃ /d₇ -DMF systems, respectively. Further application of this method to the facile synthesis of anti-inflammatory flurbiprofen and its varied deuterium-labeled derivatives was demonstrated.

Keywords: alkylation; deuterated methyl groups; deuterium labeling; methylation; synthetic methods.