Pd-catalyzed sequential distal C–H alkenylation and π-allylic amination of arylacetic acids using MBH acetates: access to macrocyclic lactams

Abstract

Palladium(II)-catalyzed directed meta-selective C–H functionalization of arylacetic acids has been accomplished utilizing Morita–Baylis–Hillman (MBH) acetates as the coupling partner to furnish β-aryl MBH acetates that can be converted into 14-membered macrocyclic lactams employing water as the oxygen source via a π-allyl intermediate. The sequential meta/meta′ C–H difunctionalization can be accomplished with varied coupling partners. Mechanistic investigations underscore the roles of the nitrile-directing template, palladium(II)-catalysis and ligand in meta-selectivity. The macrocyclization pathway has been validated through an ¹⁸O-labeling experiment and the photophysical studies reveal distinct fluorescence in the selected macrocycles. In addition, the selected lactams exhibited biocompatibility with Vero cells and dose-dependent cytotoxicity against MCF-7 cells, highlighting their therapeutic potential. The substrate scope, functional group tolerance, selectivity, photophysical and biological properties, and the late-stage functionalization of drug molecules as well as natural product derivatives are important practical features.