Optimization of Reaction Conditions for On‐DNA Synthesis of Ureas, Thioureas, and Sulfonamides

Isocyanates, isothiocyanates, and sulfonyl chlorides can be found in valuable building blocks for the construction of DNA‐Encoded Chemical Libraries (DELs), leading to the generation of ureas, thioureas, and sulfonamides. We present the development of reaction conditions for the addition of isocyanates, isothiocyanates, and sulfonyl chlorides to single‐stranded oligonucleotides, with a focus on maximizing on‐DNA conversion while preserving DNA integrity. We explored and optimized reaction parameters to achieve efficient coupling and minimize DNA degradation and by‐product formation. The protocols reported in this paper broaden the scope of DNA‐compatible reactions and may be applicable to the construction of novel DELs.