Deoxygenative alcohol–nucleophile coupling via carbocations

The direct employment of widely available alcohol feedstocks as synthons in nucleophilic couplings is a long-standing objective within the synthetic community. Traditional methods utilizing alcohols require the preactivation of one coupling partner due to the inherent mismatched electronics for C–O bond formation. Here, free alcohols are leveraged as carbocation precursors via in situ activation, reversing their traditional nucleophilic behavior and avoiding the need for prefunctionalization. The direct catalytic deoxygenative coupling of alcohols toward selective C–O heterocoupling is described. Mechanistic studies support the intermediacy of a discrete carbocation, which can be intercepted by a diverse array of simple nucleophiles. Application of this protocol toward natural products and complex active pharmaceutical ingredients is also demonstrated. The compatibility toward a large breadth of nucleophiles enables the construction of C–O, C–S, C–C, and C–N bonds in a single step, showcasing the broad applicability of this alcohol activation platform.