Heterogeneously catalyzed Suzuki–Miyaura conversion of broad scope

Abstract

The reaction tolerates a broad range of functional groups in the coupling partners and is usually performed in solution under homogeneous conditions at T ¢ 60 uC using 2–3 mol% catalytic amounts. The catalyst is often a Pd(0) complex with triarylphosphane ligands. 2 The catalytic cycle (Scheme 2) begins with the oxidative addition of an aryl halide to a Pd(0) species formed in situ to form an arylpalladium(II) halide intermediate. 3 Chloroarenes, especially nonactivated aryl chlorides, are notoriously less reactive due to the stability of the C–Cl bond (the relative reactivity of Ar–X is correlated to the respective bond dissociation energy: Ph–Cl: 96 kcal mol 21 ,P h–Br: 81 kcal mol 21 ,P h–I: 65 kcal mol 21 ). This, from a practical viewpoint adds cost to the products of traditional Suzuki–Miyaura reactions, because aryl chlorides are considerably less costly than iodo and bromoarenes. Another significant problem preventing widespread utilization of palladium homogeneous catalysis lies in the Pd impurities left in the reaction product since the upper limit for residual Pd levels in active pharmaceutical ingredients is typically very low (less than 5 ppb). 4 Removing residual palladium in a pharmaceutical substance to reduce its content to the maximum acceptable concentration limit requires rigorous product–catalyst separation processing (a purification process that often makes use of silica-based Pd scavengers). Intense research activities have therefore being devoted in the last decade to finding heterogeneous Pd catalysts of broad scope, capable of affording the recovery and reuse of the valued palladium while avoiding time-consuming catalyst separation and product purification steps which impact cost and worsen the environmental footprint of the reaction. 5