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Synlett 2008(19): 3058-3062  
DOI: 10.1055/s-0028-1087348
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Synthesis of Trifluoromethyl-Containing Pyrazoles via Sequential Yb(PFO)3-Catalyzed Three-Component Reaction and IBX-Mediated Oxidation

Li Shena, Jian Zhanga, Song Cao*a,b, Jinlong Yua, Nianjin Liua, Jingjing Wua, Xuhong Qian*a
a Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. of China
b Key Laboratory of Organofluorine Chemistry, Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. of China
Fax: +86(21)64252603; e-Mail: scao@ecust.edu.cn; e-Mail: xhqian@ecust.edu.cn;
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Publication History

Received 15 July 2008
Publication Date:
12 November 2008 (online)

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Abstract

Fourteen trifluoromethyl-containing fully substituted pyrazoles were synthesized via Yb(PFO)3-catalyzed three-component condensations of aromatic hydrazines, aldehydes, and ethyl trifluoroacetoacetate, followed by IBX-mediated oxidation of pyrazolines. A possible mechanism is suggested.

Key words

trifluoromethyl-containing pyrazole - IBX - Yb(PFO)3 - three-component synthesis

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Experimental
All chemicals were purchased commercially and used without further purification. Melting points were measured in open capillary using Büchi melting point B540 apparatus and were uncorrected. The ¹H NMR and ¹³C NMR spectra were recorded on a Bruker AM-400 spectrometer (400 MHz and 100 MHz, respectively) using TMS as internal standard. The ¹9F NMR and HMQC spectra were obtained using a Bruker Avance-500 spectrometer (470 MHz), and the ¹9F NMR spectra were measured with external CF3CO2H as the standard. High-resolution mass spectra (HRMS) were recorded under electron-impact conditions using a MicroMass GCT CA 055 instrument.

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General Procedure for the One-Pot Synthesis of Trifluoromethyl-Substituted Pyrazolines
Aldehydes 1 (1 mmol) and aromatic hydrazines 2 (1 mmol) were stirred for 20 min before ethyl trifluoroacetoacetate (2.5 mmol) and Yb(PFO)3 (0.05 mmol) were added. The mixture was heated at 120 ˚C for 0.5 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to r.t. Dichloromethane (3 mL) was added and then filtered. The filtrate was washed with sat. aq NaCl solution and dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure to leave the crude product which was recrystallized by EtOH to give the pure compound. If necessary, the product was purified by chromatography over SiO2.

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Typical Data for Representative Compound: Ethyl 1,3-Diphenyl-5-trifluoromethyl-Δ ² -pyrazolin-4-carboxylate (4a) Yield 70.4%; white solid; mp 82.2-82.8 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 7.89-7.86 (2 H, m, Ph), 7.45-7.40 (3 H, m, Ph), 7.38-7.29 (4 H, m, Ph), 7.03-6.98 (1 H, m, Ph), 5.05 (1 H, qd, ³ J HF = 6.8 Hz, J HH = 3.6 Hz, CHCF3), 4.50 (1 H, d, J = 3.6 Hz, 4-H), 4.20-4.09 (2 H, m, CO2CH 2CH3, nonequivalent geminal hydrogens), 1.12 (3 H, t, J = 7.2 Hz, CO2CH2CH 3). ¹³C NMR (100 MHz, CDCl3): δ = 167.9, 145.9, 144.7, 130.4, 129.6, 129.1, 128.5, 126.9, 124.4 (q, ¹ J CF = 281 Hz), 121.5, 114.9, 65.6 (q, ² J CF = 31 Hz), 62.5, 53.1 (d, ³ J CF = 1.5 Hz), 13.8. ¹9F NMR (470 MHz, CDCl3):
δ = -76.33 (d, ³ J HF = 6.6 Hz). HRMS: m/z calcd for C19H17N2O2F3 [M+]: 362.1242; found: 362.1242.

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General Procedure for the One-Pot Synthesis of Trifluoromethyl-Substituted Pyrazoles
Aldehydes 1 (1 mmol) and aromatic hydrazines 2 (1 mmol) were stirred for 20 min before ethyl trifluoroacetoacetate (2.5 mmol) and Yb(PFO)3 (0.05 mmol) were added. The mixture was heated at 120 ˚C for 0.5 h and stirred for another 10 min after IBX (1.5 mmol) was added. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to r.t. Dichloromethane (3 mL) was added, and the mixture was passed through a Celite pad, which was successively washed with PE and EtOAc. The filtrate was washed with sat. aq NaCl solution and dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure to leave the crude product which was recrystallized by EtOH to give the pure compound. If necessary, the product was purified by chromatography over SiO2.

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Typical Data for Representative Compound: Ethyl 1,3-Diphenyl-5-trifluoromethyl-1 H -pyrazole-4-carboxylate (5a)
Yield 54.5%; white solid; mp 83.1-83.6 ˚C; ¹H NMR (400 MHz, CDCl3): δ = 7.73-7.71 (2 H, m, Ph), 7.53 (5 H, s, Ph), 7.44-7.42 (3 H, m, Ph), 4.36 (2 H, q, J = 7.2 Hz, CO2CH 2CH3), 1.31 (3 H, t, J = 7.2 Hz, CO2CH2CH 3). ¹³C NMR (100 MHz, CDCl3): δ = 162.8, 151.5, 139.0, 132.5 (q, ² J CF = 39 Hz), 131.9, 130.9, 129.8, 129.2, 129.0, 128.4, 125.9, 119.1 (q, ¹ J CF = 270 Hz), 115.1, 61.9, 13.8. ¹9F NMR (470 MHz, CDCl3): δ = -56.87. HRMS: m/z calcd for C19H15N2O2F3 [M+]: 360.1086; found: 360.1086.