A facile 2,2,2-trifluoroethyl fatty acid ester synthesis with phenyl(2,2,2-trifluoroethyl)iodonium triflate at room temperature

ABSTRACT A series of complex 2,2,2-trifluoroethyl fatty acid esters were synthesized by the reaction of fatty acids and phenyl(2,2,2-trifluoroethyl)iodonium triflate in the presence of Cs2CO3. The reaction at room temperature without any other additive provided the corresponding 2,2,2-trifluoroethyl esters in up to quantitative yield. The conjugated carbon–carbon double bonds, the unprotected hydroxyl group, and the amido functionalities in the substrates are all tolerated in the reaction. Compared to the known synthetic methods, advantages of this reaction include mild conditions, good functional group tolerance, and without using harsh and toxic condensation agents, which allows for a green, facile, and efficient way to 2,2,2-trifluoroethyl fatty acid esters. GRAPHICAL ABSTRACT

At last, several traditional approaches were employed to synthesize 2,2,2-trifluoroethyl esters (Table 3) (14). Fatty acids such as 1a, 1k (with conjugated carboncarbon double bonds), 1q (with N-Boc protection group), and 1s (with free hydroxyl group) were chosen as the model substrates to compare the efficiency of these methods. At the beginning, reaction of 1a with 2,2,2-trifluoroethanol in CH 2 Cl 2 in the presence of 0.2 or 2 equiv. of concentrated H 2 SO 4 at reflux for 24 h (Method A) provided 2a in 52% or 79% yield, respectively. When 1k, 1q, and 1s were treated with CF 3 CH 2 OH under the same conditions (Method A), however, no desired products were obtained. Another approach using DCC/DMAP as the condensation agents (Method B) was applied to esterification of 2,2,2-trifluoroethanol with 1a, 1k, 1q, and 1s, which afforded 2a in 82% yield, 2k in 75% yield, and 2q in 82% yield, and none of 2s was formed in the conversion. Reactions of 1a and 1k with (COCl) 2 provided carboxylic chlorides, which without isolation reacted with CF 3 CH 2 OH (2 equiv.) in CH 2 Cl 2 in the presence of NEt 3 (3 equiv.) at room temperature for 2-3 h (Method C) to form 2a in 46% yield and 2k in 32% yield (over two steps). Nevertheless, substrates 1q and 1s failed to give 2q and 2s in the reaction by Method C. All these results combined indicated that the reaction described in Table  2 is simpler, milder, more efficient, and showed better functional group tolerance, compared to the known ones.

Conclusions
In conclusion, we have developed a facile method to the construction of 2,2,2-trifluoroethyl esters from complex fatty acids and aryl(2,2,2-trifluoroethyl)iodonium triflate in the presence of Cs 2 CO 3 at room temperature under mild conditions. The reaction provided a series of fatty acid 2,2,2-trifluoroethyl esters in high yields, which are promising building blocks in the preparation of functional materials and potentially bioactive molecules.
The conjugated carbon-carbon double bonds, the free hydroxyl group, and the amido groups in the substrates were all tolerated in the reaction. This protocol supplies an efficient and green access to 2,2,2-trifluoroethyl fatty acid esters without using harsh, toxic, and moisture-sensitive condensation agents that are indispensable in the previous methods.

Experimental section
General All reactions were carried out under ambient atmosphere. Unless otherwise specified, NMR spectra were recorded in CDCl 3 on a 500 or 400 MHz (for 1 H), 471 or 376 MHz (for 19 F), or 126 or 100 MHz (for 13 C) spectrometer. All chemical shifts were reported in ppm relative to TMS (0 ppm) for 1 H NMR or PhCF 3 (-63.5 ppm) for 19 F NMR as an internal or external standard. Melting points of new compounds were measured and uncorrected. Phenyl-and mesityl(2,2,2-trifluoroethyl)iodonium triflates were synthesized according to the literature (13). Boc-L-Phenylalanine (1q) was synthesized from L-phenylalanine according to the literature (15a). Tos-L-Proline (1r) was synthesized from L-proline according to the literature (15b). Other fatty acids and reagents were all purchased from commercial sources and used without further purification.

Disclosure statement
No potential conflict of interest was reported by the authors.

Funding
We thank Wuhan University of Technology, the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China [grant number 21602165], the "Chutian Scholar" Program from Department of Education of Hubei Province (China), the "Hundred Talent" Program of Hubei Province, and the Wuhan Youth Chen-Guang Project [grant number 2016070204010113] for financial support.

Notes on contributors
Qiu-Yan Han is a senior undergraduate in Wuhan University of Technology. Her research interests are the synthesis of aryl (2,2,2-trifluoroethyl)iodonium triflates and their applications in trifluoroethylation reactions.
Cheng-Long Zhao is a first-year master student in the research group of Prof. Cheng-Pan Zhang at Wuhan University of Technology. He obtained his B.S. degree in pharmaceutical engineering from Wuhan University of Technology. His research interests focus on the transitionmetal-free trifluoroethylation reactions.
Jing Yang is a second-year master student in the research group of Prof. Cheng-Pan Zhang at Wuhan University of Technology. She obtained her B.S. degree in pharmaceutical engineering from Wuhan University of Technology. Her research interests include the transition-metal catalyzed trifluoroethylation and the synthesis of 1,1-difluorocyclopropane derivatives.