Dialkyl ether synthesis through heteroatom homolytic substitution

The modular and selective synthesis of dialkyl ethers, particularly sterically congested variants, remains a longstanding challenge in drug discovery and medicinal chemistry. 1,2 Hindered alkyl ethers are especially desirable given their prevalence in bioactive natural products and favorable physicochemical properties. 3 Classically, dialkyl ether synthesis relies on nucleophilic substitution strategies; however, S N 2 reactions are fundamentally limited by steric congestion at the transition state, while S N 1 pathways proceed through promiscuous carbocation intermediates prone to elimination, rearrangement, and loss of stereogenic information. 4–6 Herein, we report a radical-based paradigm for general dialkyl ether synthesis enabled by an underutilized heteroatom homolytic substitution (het-S H 2) mechanism. This mechanistic paradigm overcomes the intrinsic limitations of classical polar substitution chemistry by leveraging carbon-centered radicals generated under mild conditions that are insensitive to steric congestion in the bond-forming transition state. Utilizing a titanium-based catalytic platform in combination with visible-light photoredox catalysis, we demonstrate the efficient coupling of carboxylic acid-derived redox-active esters with alcohols across a broad range of substitution patterns, including 3°–2°, 3°–1°, 2°–2°, and 2°–1° architectures. This strategy grants access to dialkyl ether chemical space largely inaccessible through conventional approaches, including sterically demanding BCP ether bioisosteres, and enables late-stage diversification of complex pharmaceutical scaffolds. This platform is expected to serve as a broadly applicable blueprint for radical-mediated heteroatom bond formation.