Isaline F.S.F. Castan; Andrew Madin; Garry Pairaudeau; Michael J. Waring
Bioorg. Med. Chem., 2022, 116688
https://doi.org/10.1016/j.bmc.2022.116688

Abstract

DNA-Encoded Libraries (DEL) represent a promising hit finding strategy for drug discovery. Nonetheless, the available DNA-compatible chemistry remains of limited scope. Nucleophilic aromatic substitution (SNAr) has been extensively used in DEL synthesis but has generally been restricted to highly activated (hetero)arenes. Herein, we report an optimised procedure for of the SNAr reaction through the use of factorial experimental design (FED) on-DNA using 15% THF as a co-solvent. This method gave conversions of > 95% for pyridine and pyrazine scaffolds for 36 secondary cyclic amines. This analysis provides a new DNA-compatible SNAr reaction to produce high yielding libraries. The scope of this reaction on other amines is described. This work identifies challenges for the further development for DNA-compatible SNAr reactions.