Late-stage N-Me selective alkenylation and alkynylation of drugs and unactivated tertiary amines using photoredox catalysis.

Abstract

Late-stage functionalization (LSF) of marketed drugs facilitates novel chemical space around drug leads. Considering alkyl tertiary amines are present in a large number of life-saving drugs, the development of a LSF strategy to introduce functionalizable groups provides a toolbox for future drug discovery. The introduction of vinyl and alkyne groups into a marketed drug also offers numerous advantages and potential applications, including augmented structural diversity, bio-orthogonal labeling, click chemistry, pharmacological modulation, and drug conjugation strategies. Herein, we report a synthetic strategy for N-methyl selective alkenylation and alkynylation of aliphatic tertiary amines using organophotoredox catalysis and their application to the late-stage functionalization of marketed drugs. Molecular modeling followed by bioactivity studies of novel imipramine alkenylated and alkynylated analogues shows improved efficiency compared to imipramine in reducing the depressive state, justifying the importance of N-methyl selective alkenylation and alkynylation. A thorough investigation of the reaction mechanism has been conducted to understand the regioselective formation of the N-Me selective product. DFT calculations combined with experimental evidence indicate that the regioselective outcome is controlled by the radical addition step not the radical formation step, which mostly remains unknown.