Visible Light‐Mediated Late‐Stage Thioetherification of Mercaptopurine Derivatives

Abstract

AbstractWe disclose herein a novel and general radical approach to alkylthiopurines, encompassing 4 types of thiopurines, as well as their corresponding ribosides. This strategy is achieved through visible light‐mediated late‐stage functionalization of the sulfur atoms of mercaptopurines. The in situ‐generated disulfide was proposed as the pivotal neutral intermediate for this transformation. We present herein a novel photo‐mediated homolytic C−S bond formation for the preparation of alkylthiopurines and alkylthiopurine nucleosides. Despite the presence of reactive sites for the Minisci reaction, chemoselective S‐alkylation remained the predominant pathway. This method allows for the late‐stage introduction of a broad spectrum of alkyl groups onto the sulfur atom of unprotective mercaptopurine derivatives, encompassing 2‐, 6‐, and 8‐mercaptopurine rings. Organoborons serve as efficient and eco‐friendly alkylating reagents, providing advantages in terms of readily availability, stability, and reduced toxicity. Further derivatization of the thioetherified nucleosides, together with anti‐tumor assays, led to the discovery of potent anti‐tumor agents with an IC50 value reaching 6.1 μM (Comp. 31 for Jurkat).