Diaryl ether scaffolds are important structural motifs in the field of organic synthesis due to the prevalence of C(sp2)–O bonds in intermediates of natural products and in several prominent pharmaceuticals. Previous research focused on the transition-metal mediated phenol etherification with prefunctionalized arenes (aryl halides or pseudohalides), which not only generate a stoichiometric amount of halide salt waste but also require elevated temperatures. Although a number of pioneering processes were developed in the synthesis of diaryl ethers, some limitations still remain, such as the requirement of pre-functionalized arenes, transition metals and often cost-intensive ligands, while cheaper, unmodified arenes remain elusive reactants. The direct electrochemical functionalization of phenolic reactants is a promising alternative, which could result in an optimal step- and atom economy for the formation of diaryl ethers. Only H2 gas is formed as only by-product. Although performant protocols were developed over the past decades for the selective formation of carbon-carbon bonds, the selective formation of C-O bonds is problematic as both the C-H bonds of the aromatic ring as well as well as the O-H bond are susceptible to oxidation. Under autoxidative conditions, such a dual reactivity can lead to uncontrolled polymerization and oxidation side-reactions. Despite the tremendous progress of the past decade in the selective activation of C-H bonds of the aromatic ring, robust protocols which selectively address O-H bonds remain elusive. We here demonstrate a performant electrocatalytic method for diaryl ether formation from simple phenols and non-prefunctionalized tertiary anilines. Unprecedented levels of chemoselectivity for the O-H bond functionalization can be reached by a rational choice of the coupling partners. A key advance was the selective oxidation of the aniline coupling partner, which was experimentally verified by means of EPR and CV measurements. Our results demonstrate an unprecedented performance in the selective O-H functionalization of phenolics under electrocatalytic conditions. Such a direct pathway is of high interest for the rapidly developing field of oxidative coupling reactions, which can be used as alternative to traditional coupling reactions. On the other hand, we show that the nucleophilic character of phenol can be harnessed even under oxidative conditions.

Electro-oxidative C(sp2)–H/O–H cross-dehydrogenative coupling of phenols and tertiary anilines for diaryl ether formation

ACS Spring 2022

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