Transition metal catalyzed cross-coupling of aryl Grignard reagents with aryl fluorides via Pd- or Ni-activation of the C–F bond: an efficient synthesis of unsymmetrical biaryls – application of microwave technology in ligand and catalyst screening

Abstract

Biaryl compounds are prevalent in both nature and in active pharmaceutical ingredients. The palladium and nickel catalyzed cross-coupling of aryl Grignard reagents with aryl fluorides reported herein affords moderate to excellent yields of the corresponding unsymmetrical biaryls. In addition, the first example of a biaryl cross-coupling utilizing unactivated aryl fluorides under phosphine free palladium conditions is reported. Microwave technology allowed rapid optimization of catalyst systems, which identified several ligands for this cross-coupling reaction.

Introduction

Unsymmetrical biaryls represent an important class of compounds in drug discovery [1] natural product [2], and material science [3]. These biaryls have been typically prepared via cross-coupling of aryl metal compounds with aryl halides (aryl iodides, bromides, and chlorides) mediated by transition metal catalysts [4]. Efforts have been made to expand the synthetic scope of these coupling reactions to include aryl electrophiles such as benzonitriles [5], anisoles [6], and aryl carbamates [7], which were previously regarded as unreactive in these transition-metal cross-coupling procedures. Within the aryl halide series of compounds, aryl fluorides have been known to be the least reactive toward standard cross-coupling protocols [9], [10], [11], [12], [13]. Indeed, activation of a C–F bond is an extremely challenging process due to the inherent strength of this bond [8]. Kumada and co-workers [9] demonstrated for the first time a C–F activation process involving the reaction of fluorobenzene and i-PrMgCl mediated by NiCl₂(dmpe)₂. In a significant extension of this initial report, Herrmann and co-workers [10] expanded the use of aryl fluorides as synthetically useful substrates in these couplings by the application of N-heterocyclic carbenes as ligands in a nickel catalyzed cross-coupling with aryl Grignard reagents. Most recently, Mongin et al. [11]. has reported the C–F activation chemistry of fluoroazine and diazine compounds using NiCl₂L₂ (L = dppe, dppp, and dppf) as the catalyst precursor. In the palladium catalysis arena, there have been several reports describing both the Suzuki and Stille biaryl cross-coupling protocols of highly activated substrates such as substituted fluoronitrobenzene derivatives and (fluoroarene) tricarbonylchromium(0) complexes [13]. However, mechanistically these cross-coupling reactions utilizing activated substrates probably proceed via an S_NAr type oxidative addition process.

Herein, our results concerning the application of both nickel and palladium mediated Kumada–Corriu coupling reactions of unactivated aryl fluorides is reported.