Waste-Minimized Continuous-Flow Synthesis of Oxindoles Exploiting a Polymer-Supported N Heterocyclic Palladium Carbene Complex in a CPME/Water Azeotrope

Abstract

Herein, we report the development of an effective synthetic protocol for the synthesis of oxindoles in flow based on a C(sp3)-H activation process promoted by a supported N-heterocyclic carbene palladium heterogeneous catalytic system using cyclopentyl methyl ether (CPME) as the reaction medium. The design of the catalyst, the selection of the solvent medium, and the definition of a tailored continuous flow reactor have been all designed to establish an efficient waste-minimized process for the intramolecular cyclization of N-methyl-2-halo-acetanilides. The use of CPME in its aqueous azeotropic mixture has allowed us to reach high yields of products with a simplified precipitation workup that includes the downstream process separation and recycling of the solvent. An assessment of the environmental and safety hazard features has also been made in order to better clarify the implications in terms of sustainability of the newly developed process.