Oxidative phenolic couplings, wherein two or more molecules of a phenol become linked together, are an important class of reactions, constituting frequent key transformations during the synthesis of many natural products. In particular, one product of the oxidative coupling of <i>para</i>-substituted phenols is Pummerer’s ketone, being a common pharmacophoric motif. In this context, we set out to evaluate the usefulness of hypervalent iodine reagents, which have been utilized for various oxidation of arenols, for the synthesis of this important moiety.<br/><br/>We have developed an iodosobenzene-promoted oxidative phenolic coupling affording Pummerer’s ketone and its analogs. The reaction allows for the preparation of products derived from both phenols and naphthols, bearing various substitution patterns, in excellent diasteroselectivity. The compounds are formed in 20-40% yield, which is synthetically useful considering the large increase of the molecular complexity during this one-step process, and surpasses the other existing protocols for the intermolecular oxidative phenolic coupling. Importantly, the Pummerer’s ketone analogs are selectively formed under the developed conditions, adding to the practical synthetic usefulness of the method.

Synthesis of Pummerer’s ketone and its analogs by iodosobenzene-promoted oxidative phenolic coupling

ACS Spring 2022

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