DNA-Compatible One-Pot Stahl Oxidation–Alkylation Enables Broader Use of Primary Alcohols in DEL Synthesis

Aldehydes are central synthons for DNA-encoded library (DEL) diversification, yet their limited commercial availability and stability restrict the accessible chemical space. Alcohols, a much more abundant pool of potential building blocks, have far fewer reported avenues to use in DNA-compatible chemistry. We report a DNA-compatible one-pot method that converts primary alcohols into aldehydes off-DNA via Cu(I)/ABNO-mediated Stahl oxidation followed directly by on-DNA reductive alkylation. Systematic optimization of the ligand, reaction time, and solvent composition enabled efficient oxidation under microplate conditions, while a premixed catalyst solution significantly improved reproducibility. A plate screen established broad applicability across substrate classes such as benzylic, heterobenzylic, and aliphatic alcohols. Benchmarking against reactions using isolated aldehydes confirmed that in situ -generated aldehydes perform comparably in reductive alkylation. The workflow also supports additional DNA-compatible transformations, including the Cushman reaction and imidazolidinone formation. qPCR analysis verified excellent DNA amplifiability throughout the sequence. Together, this platform provides a practical route to leverage abundant alcohol building blocks for expanded DEL diversification.