Surfactant-Mediated Buchwald–Hartwig Coupling of Aliphatic Amines for the Synthesis of DNA-Encoded Libraries

Abstract

New and efficient chemical reactions with broad substrate applicability are needed to expand the diversity of DNA-encoded libraries (DELs), which are becoming established as a powerful technology for hit finding in medicinal chemistry. For reactions to be useful, they must be compatible with the DNA-tags and with the aqueous conditions used in DEL synthesis. One potential approach to address this requirement is the application of surfactant-mediated chemistry, which can lead to improved reaction efficiency. Our recent application of this technology to Buchwald–Hartwig aminations is very effective at coupling (hetero)aryl amines but performed less well for aliphatic substrates. This paper describes the development of an efficient, surfactant-promoted method of effecting on-DNA Buchwald–Hartwig aminations on DNA with aliphatic amines. This was developed through sequential optimization of the base, palladium ligand and the surfactant, for which Span 60 proved optimal. The applicability of the method is demonstrated across a broad substrate scope and its use in the synthesis of DELs is demonstrated by the synthesis of a prototype library.