Novel β‐amino Amide Organocatalysts for the Synthesis of Pharmaceutically Relevant Oxindoles

Abstract

AbstractIn this work, a series of novel organocatalysts derived from unique unnatural β‐amino acid scaffold were synthesized and further developed to enhance the desired catalytic properties. Their evaluation was carried out in the asymmetric crossed‐aldol condensation of isatin and enolizable ketone donors. Following a systematic study of the reaction parameters including variations of additive, solvent, temperature, catalyst loading and substrate scope, (1R,2R)‐2‐amino‐N‐((R)‐1‐phenylethyl)cyclohexane carboxamide 9 proved particularly successful, affording the corresponding 3‐hydroxy‐3‐alkyl‐2‐oxindole in excellent yield (>99%) and distereoselectivity (>99% dr) with good enantioselective control (up to 52% ee) in the presence of p‐nitrophenol and EtOH in <24 h. An added benefit of this catalyst was its catalytic activity and selectivity at room temperature eliminating the requirement of reduced reaction temperatures. This scaffold, comprising of β‐amino amide, has not yet been applied in organocatalysis, thus, this is the first reported in this growing area. In mechanistic studies, direct infusion ESI‐MS proved a valuable tool forproposal of the catalytic cycle, confirming the formation of 2 key reaction intermediates.