Biaryl synthesis reductive coupling, aryl halides

The synthesis of unsymmetrical biaryls 8 from two monoaryl species involves the coupling of a metallated aromatic molecule 6 with an aryl halide or triflate 4 under the action of palladium(O) catalysis. The reaction involves a catalytic cycle in which palladium(O) inserts into the C-halogen bond via an oxidative addition to generate an arylpalladium(II) species 5 (Scheme 10.18). This undergoes a trans-metallation with the metallated component, producing a biarylpalladi-um(II) complex 7. The biaryl product is formed by reductive elimination. In the process, Pd(0) is regenerated and this can then react with a second molecule of aryl halide. Pd(0) is therefore a catalyst for the reaction. 

As early as 1901, Ullmann discovered the copper promoted coupling of aryl halides to biaryls, one of the first uses of transition metals in synthesis. The mechanism is still not entirely clear, but a binuclear reductive elimination of Ar—Ar from CuAr is possible. 

In 2009, a one-step protocol for the synthesis of xanthones via Pd-catalyzed coupling between 1,2-dibromoarenes and salicylaldehydes was developed. The success of the reaction relies heavily on the careful selection of a proper palladium catalyst, solvent and base moderate yields of the desired products were formed (Scheme 3.2). In this communication, a reaction mechanism was proposed by the authors. The Pd(0) catalyst first underwent oxidative insertion into one of the carbon-halide bonds to generate the aryl-Pd(ii) intermediate, which reacted with the phenolate to displace the halide, then underwent C-H activation of the C-H bond of the aldehyde to form intermediate A. After abstraction of the hydrogen atom by the base and reductive elimination to exclude the Pd(0) catalyst, the biaryl ketone intermediate was... 

In another publication, the Miyaura group described the cross-coupling of aryl triflates to arylboronic esters as well as the synthesis of unsymmetrical biaryls using a modified protocol. In both cases, the authors used KOAc as base since stronger bases such as K2CO3 afforded symmetrical biaryls (see also 4.18) as by-products. The proposed mechanism of this reaction is depicted in Scheme 5-166. Oxidative addition of the catalyst to haloarene followed by displacement of the halide leads to the corresponding pentacoordinated palladium(II) species. Transmetalation with bis(pinacolato)diboron followed by reductive elimination yields the arylboronic ester. 

In Suzuki reaction, cross-coupling of aryl- or vinyl-boronic acid with an aryl or vinyl halide catalyzed by a palladium complex, is one of the most versatile reactions for the construction of carbon-carbon bonds, in particular for the formation of biaryls. Recent developments have expanded the possible applications of this reaction enormously. Microwave-assisted Suzuki reactions can now be performed in many different ways and have been incorporated into a variety of challenging synthesis. Under microwave-heated condition, the Suzuki coupling of aryl chlorides with bo-ronic acids was performed in an aqueous media using the air and moisture-stable palladium catalyst. A drastic reduction of the reaction time to 15 min and the formation of products in good yields were achieved (Miao et al, 2005). 

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