Research Projects

The regioselective functionalization of pyridines, particularly at the C4-position, remains a formidable synthetic challenge despite their ubiquity in pharmaceutically active molecules. Traditional approaches, often reliant on transition metal catalysis or prefunctionalized substrates, are limited by issues of regioselectivity, toxicity, and poor functional group tolerance. This proposal aims to develop a novel electrochemical strategy for C4-selective alkylation of pyridines using pyridyl phosphonium salts under reductive conditions, enabling late-stage diversification of bioactive scaffolds. The rationale stems from the growing recognition of organic electrosynthesis as a sustainable, redox-economical platform for C–C bond formation, wherein radical intermediates can be generated under mild and green conditions. The central hypothesis is that pyridyl phosphonium salts can undergo single-electron reduction to form persistent radical anions that selectively react at the C4-position with alkyl radicals generated via hydrogen atom transfer (HAT) from unactivated or activated hydrocarbons. The key scientific objectives include: (1) establishing a dual-electrode electrochemical system that enables in situ generation of both pyridyl radical anions and carbon-centered radicals from inert hydrocarbons via HAT; (2) expanding the scope to activated C–H partners and examining the reactivity of tetrahydrofuran, pyrrolidine, benzylic, and allylic substrates; and (3) exploring a cascade strategy involving radical cyclization and subsequent alkylation to furnish structurally complex pyridine derivatives. The experiments will involve optimizing electrochemical parameters, electrode materials, solvents, electrolytes, and HAT mediators to maximize selectivity and efficiency. Substrate scope will be validated using various pyridyl salts and hydrocarbon partners, including late-stage functionalization of drug-like molecules. If successful, the project will establish a broadly applicable, metal-free, and sustainable approach to pyridine alkylation, advancing both the fundamental understanding of electrochemical radical cross-coupling and its application to medicinal chemistry, agrochemicals, and material science. The proposed strategy has the potential to transform current synthetic paradigms by replacing stoichiometric reagents with electricity as a clean reagent and enabling novel retrosynthetic disconnections for complex heterocycles.