A Convenient Synthesis of Tetrasubstituted Pyrazoles from Nitrile Imines and 2-(Thioxothiazolidin-5-ylidene)acetates

Abstract

Alkyl 2-(3-alkyl-4-oxo-2-thioxothiazolidin-5-ylidene)acetates react with hydrazonoyl chlorides in the presence of triethylamine to ­afford tetrasubstituted pyrazole derivatives. Formally, this transformation is regarded as a 1,3-dipolar cycloaddition of the exocyclic carbon–carbon double bond of the thioxothiazolidine derivatives with nitrile imines generated in situ. This efficient method provides fast access to a range of structurally diverse pyrazoles. The structure of a typical product is confirmed by X-ray crystallography.

Key words

nitrile imines - 1,3-dipolar cycloaddition - regioselective - tetrasubstituted pyrazoles - X-ray crystallography

• References and Notes

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• 23 Tetrasubstituted Pyrazoles 3; General Procedure A mixture of hydrazonoyl chloride derivative 1 (1 mmol) and Et₃N (0.101 g, 1 mmol) in MeCN (5 mL) was stirred at r.t. for 15 min. Next, the rhodanine derivative 2 (1 mmol) was added and the mixture was stirred at r.t. for 3 h. After completion of the reaction (the reaction progress was followed by TLC), the solvent was removed under reduced pressure. The crude residue was purified by flash column chromatography (silica gel, n-hexane–EtOAc, 3:1) to give the pyrazole 3. Methyl 5-(Isobutylcarbamoyl)-1,3-diphenyl-1H-pyrazole-4-carboxylate (3a) Yield: 0.34 g (90%); colorless powder; mp 181–183 °C; IR (KBr): 3300, 3057, 2954, 2871, 1720, 1650, 1552, 1269, 761, 692 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ = 0.93 (d, ³ J = 6.0 Hz, 6 H, Me), 1.86 (m, 1 H, CH), 3.22 (t, ³ J = 5.0 Hz, 2 H, CH₂), 3.77 (s, 3 H, Me), 7.42–7.48 (m, 5 H, ArH), 7.49 (t, ³ J = 5.0 Hz, 1 H, NH), 7.55–7.58 (m, 3 H, ArH), 7.64 (t, ³ J = 7.8 Hz, 2 H, ArH); ¹³C NMR (125.7 MHz, CDCl₃): δ = 20.0 (2 Me), 28.2 (CH), 47.4 (CH₂), 51.9 (Me), 111.4 (C), 124.8 (2 CH), 127.9 (2 CH), 128.6 (CH), 128.7 (CH), 128.9 (2 CH), 129.1 (2 CH), 132.2 (C), 139.9 (C), 140.4 (C), 153.0 (C=N), 159.3 (C=O), 164.7 (C=O); MS (EI): m/z (%) = 377 (1) [M⁺], 318 (8), 305 (10), 274 (22), 218 (25), 100 (23), 72 (100), 59 (23); Anal. Calcd for C₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 70.38; H, 6.17; N, 11.15. Methyl 5-(Benzylcarbamoyl)-1-phenyl-3-(p-tolyl)-1H-pyrazole-4-carboxylate (3f) Yield: 0.35 g (83%); colorless powder; mp 146–148 °C; IR (KBr): 3438, 3208, 2950, 1727, 1646, 1576, 693 cm^–1; ¹H NMR (500 MHz, CDCl₃): δ = 2.42 (s, 3 H, Me), 3.71 (s, 3 H, Me), 4.57 (d, ³ J = 5.0 Hz, 2 H, CH₂), 7.23 (d, ³ J = 7.9 Hz, 2 H, ArH), 7.26 (d, ³ J = 8.1 Hz, 2 H, ArH), 7.29–7.36 (m, 3 H, ArH), 7.45–7.49 (m, 3 H, ArH), 7.53 (d, ³ J = 8.1 Hz, 2 H, ArH), 7.56 (t, ³ J = 8.5 Hz, 2 H, ArH), 7.66 (t, ³ J = 5.0 Hz, 1 H, NH); ¹³C NMR (125.7 MHz, CDCl₃): δ = 21.5 (Me), 44.0 (CH₂), 52.1 (Me), 111.3 (C), 124.7 (2 CH), 127.7 (CH), 128.0 (2 CH), 128.8 (4 CH), 128.9 (CH), 129.1 (2 CH), 129.2 (2 CH), 134.7(C), 137.4 (C), 138.7 (C), 139.7 (C), 140.2 (C), 153.3 (C=N), 159.5 (C=O), 164.6 (C=O); MS (EI): m/z (%) = 425 (1) [M⁺], 394 (9), 334 (50), 319 (8), 232 (70), 106 (100), 91 (25), 77 (10), 59 (4); Anal. Calcd for C₂₆H₂₃N₃O₃: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.71; H, 5.43; N, 9.94.
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• 25 X-Ray Crystal-Structure Determination of 3f X-ray diffraction was carried out on a STOE IPDS 2T diffractometer with graphite monochromated MoKα radiation. A single crystal suitable for X-ray analysis was obtained from DMF solution and mounted on a glass fiber for data collection. Compound 3f crystallized in the monoclinic crystal system and P21/n (14) space group. For the unit cell, a = 16.063(3) Å, b = 7.7382(15) Å, c = 17.916(4) Å, β = 93.49(3)°, Z = 4, cell volume = 2222.8(8) ų, and orientation matrixes for data collection were obtained by least-square refinement of the diffraction data from 3914 reflections for compound 3f. Diffraction data were collected in a series of ω scans in 1° oscillations and integrated using the STOE X-AREA software package (see Ref. 27). Numerical absorption correction was applied using X-Red32 software. The structure was solved by direct methods and subsequent difference Fourier maps, and then refined on F ² to final R1 = 0.0499 and wR2 (all data) = 0.0976 by a full-matrix least-squares procedure using anisotropic displacement parameters. Atomic factors are from the International Tables for X-ray Crystallography. All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters. All refinements were performed using the X-STEP32, SHELXL-2014 and WinGX-2013.3 programs (see Ref. 28).
• 26 CCDC 1584414 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 27 X-AREA: Program for the Acquisition and Analysis of Data, Version 1.30. STOE & Cie GmbH; Darmstadt: 2005

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