Regioselective one-step C2–H methylation of free (N–H) indoles enabled by Pd(ii)/norbornene cooperative catalysis

Abstract

The C2-methylated indole scaffolds are prevalent and crucial components of numerous pharmaceutical molecules and biologically active entities. However, their synthesis traditionally requires a laborious three-step sequence involving the installation of suitable directing groups, C2-functionalization, and deprotection. Herein, we report a one-step, regioselective C2–H methylation of free (N–H) indoles via Pd(II)/norbornene(NBE) catalysis using trimethyl phosphate as a practical methyl source. This modular methodology uniquely circumvents previous multi-step strategies, demonstrating broad applicability with excellent functional group tolerance, high to quantitative yields, robust scalability, successful trideuteromethylation, and operational simplicity due to its air and moisture insensitivity. This step-economical strategy significantly streamlines access to valuable C2-methylated indole derivatives, offering a more direct and efficient pathway for late-stage methylation of drug-like indoles compared to previous methods.