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2.5 C—C Bond Formation by Double C—H Activation

DOI: 10.1055/sos-SD-218-00066

Xia, J.-B.; You, S.-L.Science of Synthesis: Catalytic Transformations via C—H Activation, (20152115.

General Introduction

This chapter focuses on transition-metal-catalyzed aryl—aryl bond-forming reactions via double C—H activation. Biaryl scaffolds have received much attention as a privileged structure broadly found in biologically active natural products, pharmaceuticals, agrochemicals, and functional molecules in material sciences, etc.[‌1‌,‌2‌] Several general methods have been developed to synthesize biaryls. Traditional methods such as the Ullmann reaction,[‌3‌] the Scholl reaction,[‌4‌] and the Gomberg–Bachmann reaction[‌5‌] are very useful but the substrate scope is limited. Recently developed transition-metal-catalyzed cross-coupling reactions have proved to be efficient for the synthesis of biaryls, generally in high yields and with excellent selectivity and broad substrate scope.[‌6‌]

In general, for biaryl synthesis via transition-metal-catalyzed cross-coupling reactions, both coupling partners need to be preactivated when compared with simple arenes. Typically, one partner is an organometallic compound and the other is an aryl halide or pseudohalide (Scheme 1). These reactions are widely used in both academia and industry but still have many fundamental drawbacks. Preparation of both coupling partners often requires additional synthetic operations starting from simple arenes, thus generating waste from reagents, solvents, and purifications. Moreover, a stoichiometric amount of metal waste is produced from the arene-activating groups upon completion of the cross-coupling reaction. Over the past decade, significant advances have been made in transition-metal-catalyzed biaryl synthesis through C—H activation (Scheme 2).[‌7‌‌12‌] In this reaction, one of the preactivated coupling partners is replaced by a simple arene. Therefore, the cost of the reaction will be reduced by using the inexpensive starting material, and the waste generated by the reaction can also be greatly reduced to benefit our environment.

Scheme 1 Biaryl Synthesis via Transition-Metal-Catalyzed Cross-Coupling Reaction[‌6‌]

Scheme 2 Biaryl Synthesis via Transition-Metal-Catalyzed C—H Activation[‌7‌‌12‌]

Given the success of transition-metal-catalyzed biaryl synthesis through C—H activation of one of the coupling partners, a more economic and attractive alternative is obviously the coupling reaction via double C—H activation of two arenes (Scheme 3). In 1965, the first transition-metal-promoted coupling of benzene to give biphenyl was reported by van Helden and Verberg.[‌13‌] A stoichiometric amount of palladium(II) chloride was used in this reaction. Over the last 10 years, there have been great advances in transition-metal-catalyzed biaryl synthesis through double C—H activation, in particular with palladium(II) salts as the catalyst.[‌14‌‌16‌] However, the development of a practical process is still challenging because many difficulties remain to be overcome. Firstly, control of selectivity is a big challenge when the two coupling partners have more than one type of aromatic C—H bond.[‌17‌‌19‌] Secondly, replacement of the stoichiometric heavy-metal oxidants with environmentally benign oxidants is another issue in the synthesis of biaryls by oxidative coupling. Thirdly, oxidative cross-coupling reactions usually need a large amount of simple arenes as the solvent. How to decrease the amount of the arenes used is an important subject in this area.

Scheme 3 Biaryl Synthesis via Transition-Metal-Catalyzed Double C—H Activation[‌14‌‌16‌]