Organocatalytic <i>meta</i>-C–H Hydroxylation of Azaarene <i>N</i>-Oxides

Abstract

The chemoselective and site-selective molecular editing of azaarenes presents significant potential, as it allows for the precise construction of complex molecules with diverse applications in pharmaceuticals and materials science. Nevertheless, the most substantial challenge lies in the meticulous control of reaction selectivity, primarily due to the complex electronic properties and multiple reactive sites inherent in azaarenes. In this regard, the development of efficient and practical catalysts, especially organocatalysts for these selective transformations, is of the utmost significance and represents a formidable challenge. Against this backdrop, we report an organocatalytic thermodynamically driven cyclizative rearrangement that enables highly site-specific meta -hydroxylation of azaarenes with excellent chemoselectivities. Specifically, a structurally specific nitrilium ion, formed in situ from the reaction of N -methylacetamide with oxalyl chloride, serves as a highly efficient catalyst, enabling a diverse range of azaarene 1-oxides to undergo a unique stepwise 1,3-oxygen transfer. This process ultimately leads to the formation of their corresponding 3-hydroxylated derivatives. Remarkably, this transformation features column-free operation, scalability, a broad scope, high yields, and an inexpensive catalyst system. Applications in the late-stage meta -hydroxylation of pharmaceutically relevant compounds are also demonstrated.

Topics & Concepts