Synthesis of trifluoromethylated heterocycles using partially fluorinated epoxides

Reaction of 2-trifluoromethyl- (1) and 2,2-bis(trifluoromethyl)- (2) oxiranes with a variety of sulfur nucleophiles proceeds rapidly and under mild conditions. For example, epoxide 2 reacts with aqueous solution of Na2S, producing S[CH2C(CF3)2OH]2. Reaction of 2 with Na2S2O3 leads to the formation of the corresponding Bunte salt. Interaction of 2 with NaSCN in water proceeds exothermically and results in high-yield formation of cyclic imine 5. Although this material can be isolated, it has limited stability and undergoes cyclotrimerization at ambient temperature, giving the corresponding 1,3,5-triazine. A number of heterocyclic compounds containing pendant –CH2C(CF3)2OH group were prepared by the reaction of the corresponding thio-derivatives, such as pyridine-2-thiole with epoxide 2. It was found that fluoride anion catalyzes the reaction of epoxides 1 and 2 with isothiocyanates carrying electron withdrawing groups at nitrogen. The reaction results in nucleophilic cyclization and formation of the corresponding exocyclic imines containing a 1,3-oxothiolane moiety. Carbon disulfide was also found to be active in this process, reacting with epoxides 1 and 2 at ambient to give the corresponding trifluoromethylated 1,3-oxathiolane-2-thiones in 58–65% yield.

Graphical abstract.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights▶ Reaction of metal thiocyanate salts with 2,2-bis(trifluoromethyl)-oxirane. ▶ Reaction of 2,2-bis(trifluoromethyl)oxirane with metal thiocyanate salts. ▶ Reaction of isothiocyanates with 2-trifluoromethyloxirane. ▶ Reaction of isothiocyanates with 2,2-bis(trifluoromethyl)oxirane. ▶ Reaction of carbon disulfide with fluorinated epoxides.