Addition-Migration Cascade for Ortho-Selective Carbon Functionalization of Phenols.

Abstract

Ortho- and para-carbon-disubstituted phenols are prevalent in natural products and pharmaceuticals, yet their selective synthesis remains challenging. The strong resonance-donating effect of the hydroxyl group renders phenols electron-rich, activates both ortho and para positions, and limits their direct functionalization with external nucleophiles. Herein, we report an addition-migration-rearomatization strategy for the ortho-selective carbon functionalization of phenols using readily accessible para-quinol carbonates and diverse organometallic nucleophiles. The transformation proceeds through nucleophilic 1,2-addition to the dienone carbonyl, followed by C1-to-C2 group migration and rearomatization, thereby enabling the formal installation of carbon nucleophilic substituents at the enone α-position. A broad range of sp3-, sp2-, and sp-hybridized nucleophiles, including alkyl, vinyl, aryl, heteroaryl, polyaromatic, and alkynyl reagents, participate efficiently under mild conditions. DFT calculations identify syn-methyl facial attack as kinetically preferred over syn-Boc facial attack by 24.72 kcal mol- 1, establish that both SN2' manifolds are noncompetitive, and show that aromatization proceeds via a Mg-assisted decarboxylation/deprotonation pathway rather than an unassisted route. Synthetic utility is demonstrated through a concise five step synthesis of the bioactive natural product honokiol from commercially available allyl anisole.

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