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Gold-catalysed dehydrogenative cross-coupling of arenes

Final Report Summary - AU-DOUBLEC-H (Gold-catalysed dehydrogenative cross-coupling of arenes)

(for a version including schemes, see attached pdf)

1. Summary of results:
Cross-coupling methodologies proceeding via two-fold C-H activation have the potential to become a new generation of cross-coupling type reactions for the synthesis of biaryls. Such motifs are ubiquitous in natural products, pharmaceuticals and organic materials but today their synthesis mainly rely on the use of pre-functionalised starting materials such as arylhalides and aryl organometallic species (Figure 1a). By comparison, procedures in which two aryl C-H bonds are directly cross-coupled in the presence of an oxidant could offer more direct, more economic and significantly greener approaches than current methods as pre-functionlisation is avoided and waste is minimized. However, all C-H activation methodologies face the difficulty of breaking poorly reactive C-H bonds, and reactions proceeding via two-fold C-H activation must in addition overcome the challenge of favoring the formation of cross-coupled products over homo-coupled by-products (Figure 1b). Thus, the main objective of the Au-doubleC-H proposal was to develop the first example of a Au-catalysed oxidative biaryl cross-coupling via two-fold C-H activation, and to take advantage of the specific properties of Au in order to achieve high selectivity for cross- over homo-coupled biaryls.

Our interest in using Au as the catalyst for this transformation was prompted by intrinsic differences in reactivities of the Au(I) and (III)oxidation states towards electron-deficient and electron-rich arenes, respectively, which in our view held great promise for developing selective cross-couplings and minimizing homocoupling side-products. We recently reported a stoichiometric cross-coupling of Aryl-Au(I) complexes with electron-rich arenes in the presence of an iodine(III) oxidant.2b However, a catalytic version had not been realized, likely due to the significant challenge of combining in one pot the elementary steps of this reaction in the presence of a strong oxidant required for overcoming the high oxidation potential of the Au(I/III) redox couple, in order to achieve turnover under catalytic conditions. We have now reported a novel catalytic procedure that addresses the challenge of cross-coupling polyfluoroarenes with electron-rich hetero- and carbocyclic arenes in an efficient manner (Figure 2a). The developed cross-coupling is the first of its kind with respect to using Au-complexes as catalyst in double C-H functionalization biaryl cross-coupling reactions. A new iodine(III) oxidant was synthesized which showed the desirable compatibility with reagents while at the same time efficiently oxidizing Au(I) to Au(III). The reaction showed a large substrate scope, and tolerated substrates containing halogens as well as oxidation sensitive functional groups such as aldehydes, benzylic alcohols and thioethers. Indoles reacted selectively at the C3-position thus avoiding formation of regioisomeric products which are difficult to separate. Furthermore, not only indoles, but other heterocyclic arenes such as pyrroles, furans, thiophenes and electron-rich carbocyclic arenes were also reactive (Figure 2b). Importantly, high cross- vs homocoupling selectivity was retained even at close to stoichiometric ratio of the two arenes. Thus, under the standard reaction conditions, a 5-fold to 10-fold excess of polyfluoroarene was used, however in examples we showed that this could be reduced to a 1.5-fold excess while maintaining high yields and selectivity, which is a promising result for approaching greener and more efficient couplings of this type.

We hope that the developed methodology described herein will encourage further exploration of the use of gold in cross-coupling reactions, in trying to address future greener methodologies for the preparation of biaryl scaffolds, and inspire research both in academic and industrial settings within the EU economic area.