Microwave Assisted Cu-Mediated Trifluoromethylation of Pyrimidine Nucleosides.

Abstract

Trifluoromethylated nucleosides, such as trifluridine, have widespread applications in pharmaceuticals as anticancer and antiviral agents. However, site-selective addition of a trifluoromethyl group onto a nucleobase typically requires either inconvenient multi-step synthesis or expensive trifluoromethylation reagents, or results in low yield. This article describes a simple, scalable, and high-yielding protocol for late-stage direct trifluoromethylation of pyrimidine nucleosides via a microwave-irradiated pathway. First, 5-iodo pyrimidine nucleosides undergo complete benzoylation to obtain N3 -benzoyl-3',5'-di-O-benzoyl-5-iodo-pyrimidine nucleosides as key precursors. Next, trifluoromethylation is carried out under both conventional and microwave heating using an inexpensive and commercially accessible Chen's reagent, i.e., methyl fluorosulfonyldifluoroacetate, to produce N3 -benzoyl-3',5'-di-Obenzoyl-5-trifluoromethyl-pyrimidine nucleosides. The microwave-assisted transformation accentuates its simplicity, mild reaction conditions, and dominance, providing a facile route to access trifluoromethylation. Finally, the envisioned 5-trifluoromethyl pyrimidine nucleosides are obtained by a routine debenzoylation procedure. This concludes a convenient three-step synthesis to obtain trifluridine and its 2'-modified analogs on a gram scale with consistently high yields, starting from their respective iodo-precursors, and requires only one chromatographic purification at the trifluoromethylation step. Furthermore, this operationally simple protocol can be utilized as a definitive methodology to produce various other trifluoromethylated therapeutics. © 2021 Wiley Periodicals LLC. Basic Protocol: Synthesis of 5-trifluoromethyl pyrimidine nucleosides 4a-c Alternate Protocol: Conventional trifluoromethylation: Synthesis of N3-benzoyl-3',5'-di-O-benzoyl-5-trifluoromethyl pyrimidine nucleosides (3a-c).