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One-Pot Synthesis of 1-Aryl-3-trifluoromethylpyrazoles Using Nitrile Imines and Mercaptoacetaldehyde As a Surrogate of Acetylene

Kamil Świątek, Greta Utecht-Jarzyńska, Marcin Palusiak, Jun-An Ma* and Marcin Jasiński*

*Tianjin University, Tianjin 300072, P. R. of China; University of Lodz, Tamka 12, 91403 Łódź, Poland, Email: majun_an68tju.edu.cn, mjasinskiuni.lodz.pl

K. Świątek, G. Utecht-Jarzyńska, M. Palusiak, J.-A. Ma, M. Jasiński, Org. Lett., 2023, 25, 4462-4467.

DOI: 10.1021/acs.orglett.3c01437


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Abstract

A (3 + 3)-annulation of in situ generated nitrile imines and mercaptoacetaldehyde as a surrogate of acetylene provides 5,6-dihydro-5-hydroxy-4H-1,3,4-thiadiazines. A subsequent dehydration/ring contraction reaction with p-TsCl enables a one-pot preparation of 1-aryl-3-trifluoromethylpyrazoles. In addition, nonfluorinated analogues functionalized with Ph, Ac, and CO2Et groups were also prepared.

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proposed mechanism



General one-pot procedure for synthesis of pyrazoles

To a solution of the respective hydrazonoyl halide (1.0 mmol) and 2,5-dihydroxy-1,4-dithiane-2,5-diol (0.55 mmol, 84 mg) in dry solvent (10 mL; DCM or DCE for electron-deficient nitrile imines) was added dropwise excess triethylamine (10 mmol, 1.4 mL) and the resulting mixture was stirred at room temperature until the nitrile imine precursor was fully consumed (TLC monitoring, typically 2-4 h). Then, a solution of p-toluenesulfonic chloride (2.5 mmol, 477 mg) in appropriate solvent (5 mL; DCM or DCE, respectively) was added dropwise and stirring was continued for 16 h. For intermediates bearing electron-deficient aryl groups, the resulting mixture was additionally refluxed (oil bath) for 2 h prior aqueous workup. Water (15 mL) was added, the mixture was extracted with DCM (3 × 10 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvents were roved under reduced pressure. The crude product was purified by column chromatography (CC) using silica gel as the stationary phase and hexanes/DCM or hexanes/EtOAc mixtures as an eluent.


Key Words

pyrazoles


ID: J54-Y2023