Electrochemically Driven Site-Selective N-Hydroxymethylation of Indoles and Derivatives

Abstract

Described herein is a facile electrochemical strategy for the generation of formaldehyde from N,N-dimethylacetamide (DMA) and water (H2O) toward a direct and site-selective N-hydroxymethylation of indoles and derivatives. Mechanistic studies suggested that N-(hydroxymethyl)-N-methylacetamide generated in situ from DMA/H2O under electrochemical conditions serves as a formaldehyde surrogate. The developed methodology features mild, base- and metal catalyst-free conditions. The reaction can accommodate a broad range of substrate scopes and offers an alternative route to access a series of N-hydroxymethylated indole, bis-indole, carbazole, and indazole derivatives. A gram-scale synthesis was demonstrated to show the scaled-up applicability of this transformation.