Unleashing Selective Reduction and Reductive Methylation of N‑Heterocycles Using Methanol via Strategic Reaction Condition Modulation

Saturated N-heterocycles and the N-methylated or alkylated derivatives are vital in different areas of science due to their diverse biological and pharmacological activities. Thus, achieving their selective formations is highly essential yet demands innovative approaches. We here reported an Ir(III)-catalyzed selective reduction and N-methylation of N-heterocycles using methanol as a dual H2 and methylating source. The selectivity was precisely governed through strategic modulation of reaction parameters, where AgOTf was essential for the reduction, and 2,2,2-trifluoroethanol (TFE) facilitated the reductive methylation. The methodology was also successfully extended to other alcohols for the reductive alkylation reaction as well as the synthesis of several molecules of various biological importance. Control experiments, kinetic studies, and density functional theory (DFT) calculations further revealed an Ir(III)-catalyzed outer-sphere pathway for the synthesis of tetrahydroquinolines (THQ) and N-methyltetrahydroquinoline (N-MTHQ).