Gaonan Wang, Xiaona Zhang, Zhuo Wen, Xiaodong Shi, Weiren Cui, Alexander L. Satz, Wenji Su, Qi Zhang

Organic Letters

DOI: 10.1021/acs.orglett.6c03765

Abstract

The Doebner reaction is a classical method for the synthesis of quinoline-4-carboxylic acids via the condensation of anilines, aldehydes, and pyruvic acid. However, its application in DNA-encoded library (DEL) technology has been limited due to harsh reaction conditions that degrade the DNA. Herein, we report a DNA-compatible Doebner reaction that proceeds under mild and catalyst-free conditions. This methodology enables the efficient construction of desirable quinoline scaffolds on-DNA with a broad substrate scope for electron-rich and electron-neutral aromatic amines, although electron-deficient aromatic amines generally afford lower conversions. The qPCR and NGS results demonstrate that the reaction conditions preserve DNA amplifiability and sequence fidelity.