Benchtop factory for cross-coupling reactions by circulatory catalyst flow using low-viscosity ionic liquid as reaction medium and catalyst support

Abstract

This article describes the development of a circulatory catalyst flow system for Pd-catalyzed cross-coupling reactions, such as the Mizoroki-Heck reaction and the Sonogashira reaction, in which low-viscosity ionic liquids such as [bmim]NTf2 and [emim]NTf2 were used as a recyclable reaction medium and a catalyst support. A benchtop production system consisting of a flow reactor (micromixer plus residence time unit), a dual extraction unit with two T-shaped micromixers, and a catalyst/solvent pumping back system has been designed and tested for a 100 g scale synthesis using the Mizoroki-Heck reaction, which indeed worked well. Using a similar continuous-flow equipment, 103 g of the key intermediate of the matrix metalloproteinase inhibitor was synthesized by Cu-free Sonogashira reaction with [emim]NTf2 as a solvent, in which the system was run for 5.5 h. The attributes of facile separation and recycling of both the catalyst and the ionic liquid reaction medium impart certain characteristics of heterogeneous catalysis to this continuous-flow system.