Pd(NHC)(μ-Cl)Cl]2: Versatile and Highly Reactive Complexes for Cross-Coupling Reactions that Avoid Formation of Inactive Pd(I) Off-Cycle Products.

Tongliang Zhou,Albert Poater,Fady Nahra,Steven P. Nolan,Catherine S.J. Cazin,Alan M.C. Obled,Luigi Cavallo,Michal Szostak,Siyue Ma

doi:10.1016/j.isci.2020.101377

Abstract

SummaryThe development of more reactive, general, easily accessible, and readily available Pd(II)–NHC precatalysts remains a key challenge in homogeneous catalysis. In this study, we establish air-stable NHC–Pd(II) chloro-dimers, [Pd(NHC)(μ-Cl)Cl]2, as the most reactive Pd(II)–NHC catalysts developed to date. Most crucially, compared with [Pd(NHC)(allyl)Cl] complexes, replacement of the allyl throw-away ligand with chloride allows for a more facile activation step, while effectively preventing the formation of off-cycle [Pd2(μ-allyl)(μ-Cl)(NHC)2] products. The utility is demonstrated via broad compatibility with amide cross-coupling, Suzuki cross-coupling, and the direct, late-stage functionalization of pharmaceuticals. Computational studies provide key insight into the NHC–Pd(II) chloro-dimer activation pathway. A facile synthesis of NHC–Pd(II) chloro-dimers in one-pot from NHC salts is reported. Considering the tremendous utility of Pd-catalyzed cross-coupling reactions and the overwhelming success of [Pd(NHC)(allyl)Cl] precatalysts, we believe that NHC–Pd(II) chloro-dimers, [Pd(NHC)(μ-Cl)Cl]2, should be considered as go-to precatalysts of choice in cross-coupling processes.

Highlights

Palladium-catalyzed cross-coupling reactions are among the most powerful molecular assembly tools in chemistry by enabling facile construction of C–C and C–heteroatom bonds (Molander et al, 2013; Colacot, 2015; Diez-Gonzalez et al, 2009)
We establish air-stable Nheterocyclic carbene (NHC)–Pd(II) chloro-dimers, [Pd(NHC)(m-Cl) Cl]2, as the most reactive Pd(II)–NHC catalysts developed to date
We establish air-stable NHC–Pd(II) chloro dimers, [Pd(NHC)(m-Cl)Cl]2, as the most reactive Pd(II)–NHC catalysts developed to date

Summary

Introduction

Palladium-catalyzed cross-coupling reactions are among the most powerful molecular assembly tools in chemistry by enabling facile construction of C–C and C–heteroatom bonds (Molander et al, 2013; Colacot, 2015; Diez-Gonzalez et al, 2009). The development of well-defined Pd(0) and Pd(II) precatalysts, wherein Pd and ligand are in a 1:1 ratio, represents a major direction in catalyst design (Molander et al, 2013; Colacot, 2015; Diez-Gonzalez et al, 2009; Fortman and Nolan, 2011; Martin and Buchwald, 2008) In this context, commercially available [Pd(NHC)(allyl) Cl] (NHC = N-heterocyclic carbene) complexes developed by one of us (S.P.N.) are among the most powerful and widely used Pd catalysts for various cross-coupling reactions worldwide (Marion et al, 2006; Hopkinson et al, 2014; Nolan and Cazin, 2017); their reactivity is limited by the formation of off-cycle Pd(I) allyl products (Figures 1A and 1B) (Hruszkewycz et al, 2014; Melvin et al, 2015; Johansson Seechurn et al, 2017)

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Conclusion