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Synthesis of Secondary Trifluoromethylated Alkyl Bromides Using 2-Bromo-3,3,3-trifluoropropene as a Radical Acceptor

Peng Guo, Maoling Tao, Wen-Wen Xu, An-Jun Wang, Weipiao Li, Qiuli Yao, Jie Tong and Chun-Yang He*

*Generic Drug Research Center of Guizhou Province, Zunyi Medical University, Zunyi, Guizhou 563000, P. R. China, Email: hechy2002163.com

P. Guo, M. Tao, W.-W. Xu, A.-J. Wang, W. Li, Q. Yao, J. Tong, C.-Y. He, Org. Lett., 2022, 24, 2145-2148.

DOI: 10.1021/acs.orglett.2c00425


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Abstract

The reaction of redox-active esters as radical precursors and the commercially available 2-bromo-3,3,3-trifluoropropene (BTP) as a radical acceptor provides a wide range of secondary trifluoromethylated alkyl bromides in good to excellent yields with broad functional group tolerance.

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proposed mechanism



General procedure for the synthesis of redox-active ester

The corresponding alkyl carboxylic acids or N-protected amino acids (2 mmol, 1.0 equiv.), N-hydroxyphthalimide (2 mmol, 1.0 equiv.), and 4-dimethylaminopyridine (0.2 mmol, 10 mol%) were mixed in a flask equipped with a magnetic stirring bar, and DCM (5 mL) was added. Then, a solution of N,N'-dicyclohexylcarbodiimide (454 mg, 2.2 mmol, 1.1 equiv.) in DCM (5 mL) was added slowly at room temperature. After complete conversion of N-hydroxyphthalimide traced by TLC, the white precipitate was filtered off and the solution was concentrated on a rotary evaporator. The residue was purified by silica gel chromatography to give corresponding redox active esters.

Method A for catalyst-free decarboxylative cross-coupling of redoxactive ester with 2-bromo-3,3,3-trifluoropropene:

A 25 mL oven-dried Schlenk tube equipped with a magnetic stirrer bar was charged with the redox active esters (0.2 mmol, 1.0 equiv.), Hantzsch ester (0.3 mmol, 1.5 equiv.). The tube was evacuated and backfilled with argon for three times, followed by the addition of dry MeOH (2.0 mL) and 2-bromo-3,3,3-trifluoropropene (0.4 mmol, 2.0 equiv.). The tube was screw capped and heated to 40C (heat produced by blue LEDs) under irradiation of 24W blue LEDs (430-490 nm, peak wavelength: 455.0 nm, with a distance of 1 cm between the reaction vessel and the light source). After stirring for 8 h, the reaction mixture was concentrated on a rotary evaporator. The product was purified with silica gel chromatography to give the corresponding pure product.


Key Words

trifluoromethylated alkanes, Hantzsch ester, photochemistry


ID: J54-Y2022