TBS-Directed 1,3-Dipolar Cycloaddition to 5-Trifluoromethyl-1,2,3-triazoles

Significance

In 1994, Hlasta and co-workers ­reported the use of the TMS group as a regiocontrolling group in the regioselective synthesis of 1,5-disubstituted 4-TMS-1,2,3-triazoles (J. Org. Chem. 1994, 59, 6184). Based on these observations, the first regioselective synthesis of 5-trifluoromethyl-1,2,3-triazole nucleoside analogues via tert-butyldimethylsilyl (TBS)-directed 1,3-dipolar cycloaddition is presented. Using crude 3,3,3-tri­fluoro-1-TBS-propyne 1 (synthesized in one step from 2-bromo-3,3,3-trifluoropropene), the 1,3-­cycloaddition of O-protected glycosyl azides 2 proceeds smoothly in toluene at moderate temperatures to afford exclusively 5-CF₃-1,4,5-tri-substituted 1,2,3-triazoles 3 in moderate yields and with retention of configuration at the anomeric carbon. Glycopyranosyl azides proved to be more reactive than glycofuranozyl azides. The structure of 3 was confirmed by X-ray diffraction analysis. The cycloaddition may be directed by the TBS group by a combination of steric and electronic ­effects as proposed previously by Hlasta and co-workers (see reference above).