Unusual C-2 selectivity of Grignard additions to N-Boc-protected isatin 3-imines

Abstract

A series of N-tert-butoxycarbonyl-protected isatin 3-imines underwent an unexpected C-2 selective addition reaction with Grignard reagents, affording 3-imino-2-phenethylindolin-2-ols. The protecting group plays a role in this observed chemoselectivity, with N-benzyl and N-p-methoxybenzyl-protected isatin 3-imines undergoing C-3 addition under Grignard reaction conditions, affording 3-amino-3-phenethylindolin-2-ones. Both C-2 and C-3 addition products were assessed for antiplasmodial activity in vitro, with four compounds displaying activity in the sub-micromolar range against both drug-sensitive and drug-resistant Plasmodium falciparum strains.