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 chemistry1,2. Hindered alkyl ethers are especially desirable given their prevalence in bioactive natural products and their favourable physicochemical properties3. Classically, dialkyl ether synthesis relies on nucleophilic substitution strategies; however, SN2 reactions are fundamentally limited by steric congestion at the transition state, whereas SN1 pathways proceed through promiscuous carbocation intermediates that are prone to elimination, rearrangement and loss of stereogenic information4-6. Here we report a radical-based paradigm for general dialkyl ether synthesis enabled by an underutilized heteroatom homolytic substitution (het-SH2) mechanism. This mechanistic paradigm overcomes the intrinsic limitations of classical polar substitution chemistry by leveraging carbon-centred radicals generated under mild conditions that are insensitive to steric congestion in the bond-forming transition state. Using a titanium-based catalytic platform in combination with visible-light photoredox catalysis, we demonstrate 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 a dialkyl ether chemical space that is largely inaccessible through conventional approaches, including sterically demanding bicyclo[1.1.1]propane 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.