Cu-Mediated trifluoromethylation of benzyl, allyl and propargyl methanesulfonates with TMSCF3

A Cu-mediated trifluoromethylation of benzyl, allyl and propargyl methanesulfonates with TMSCF3 was developed for the first time. This method offers a convenient and economical approach to various trifluoroethyl-containing compounds.


Results and Discussion
We initiated our investigation by reacting benzyl methanesulfonate 1a with TMSCF 3 (2.0 equiv) in the presence of KF (2.0 equiv) and CuI (0.2 equiv) in DMF (2.0 mL) at 60 °C under Ar atmosphere. However, only 17% yield of the desired product 2a was observed in this case ( Table 1, entry 1). The yield was improved to 31% when the reaction was carried out in With the optimal conditions in hand, we next examined the substrate scope of the Cu-mediated trifluoromethylation of benzyl methanesulfonates with TMSCF 3 (Scheme 2). This method tolerates various functional groups. A wide range of benzyl methanesulfonates bearing electron-withdrawing groups, such as nitro (1f), cyano (1g), trifluoromethyl (1h) and ester (1i), as well as electron-donating groups such as phenyl (1b), smoothly underwent the transformation, affording the desired products in moderate to good yield. Importantly, both chloro (1d) and bromo (1e) substituents are also compatible with this method. It is particularly noteworthy that the reaction can be scaled up efficiently. 2a and 2c were successfully prepared on 10 mmol scale, indicating the good reliability of the process.
The present reaction could also be expanded to the trifluoromethylation of allylic methanesulfonates (Scheme 3). Treatment of the substrate 1k under the standard reaction conditions afforded the linear trifluoromethylated product 2k in 78% yield with a trace amount of Z isomer. Interesting, the reactions with the allylic methanesulfonates 1l and 1m gave the same regioselectivity and stereoselectivity with good yields. These observations indicate that a π-allyl/Cu ш complex might be involved in the C sp3 -CF 3 bond formation, but the detailed mechanism remains to be elucidated. We were next interested in the trifluoromethylation of propargyl methanesulfonate derivates. Both aliphatic and aryl-substituted linear propargyl methanesulfonates under standard reaction conditions afforded the corresponding trifluoromethylated propargylic products in moderate yields (Scheme 4a). However, the reaction of the branched substrates under identical conditions gave the trifluoromethylated allenylic products in good to excellent yields, without any trifluoromethylated propargylic products (Scheme 4b). Thus, this reaction provides an efficient protocol for the synthesis of allenylic-CF 3 derivatives, which are useful building blocks for pharmaceuticals [28,29].

Conclusion
In summary, we have developed an efficient copper-mediated trifluoromethylation of benzyl methanesulfonates at the benzylic position under mild conditions. The reaction can be easily scaled up and allows for the efficient synthesis of a series of (trifluoroethyl)arenes with excellent functional group compatibility. Furthermore, the method could also be extended to the trifluoromethylation of allyl and progargyl methanesulfonates, affording the corresponding allylic-, progargylic-and allenylic-CF 3 derivatives.

Experimental
General procedure for the Cu-mediated trifluoromethylation of benzyl methanesulfonates: CuI (2.2 mmol) and KF (4.0 mmol) were added into a Schlenk tube equipped with a magnetic stirring bar under Ar atmosphere. DMF (5.0 mL) and Me 3 SiCF 3 (2.0 equiv) were added. After stirring for 20 minutes, the mixture was heated to 60 °C and then benzyl methanesulfonate (2.0 mmol) was added under N 2 atmosphere. The reaction mixture was kept at 60 °C for 4 hours and then cooled to room temperature. The resulting mixture was diluted with diethyl ether, washed with water and brine, dried over sodium sulfate, and concentrated. The crude products were purified by column chromatography on silica gel to give the products.

Supporting Information
Supporting Information File 1 Experimental details, characterization data of all products and copies of NMR spectra.