Highly Regioselective Synthesis of Pyrazole Derivatives Using a 1,3-Dipolar Cycloaddition Approach

Abstract

We report a simple and regioselective procedure for the synthesis of 1H-pyrazol-5-yl (2-hydroxyphenyl)methanone derivatives. This process includes the 1,3-dipolar cycloaddition reaction of nitrile imines generated in situ from hydrazonoyl chloride and triethylamine with 3-formylchromones.

Key words

3-formylchromone - pyrazole - hydrazonoyl chloride - nitrile imine - 1,3-dipolar cycloaddition

• References and Notes

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• 22 General Procedure A mixture of hydrazonoyl chloride derivative 1 (1 mmol) and Et₃N (1 mmol) in EtOH (3 mL) was stirred at r.t. for 10 min. Then 3-formylchromone 2 (1 mmol) was added to the above mixture, and the reaction was stirred at r.t. for 4 h. After completion of the reaction, the precipitate washed with EtOH to afford the pure product 3 in high yield. Representative Analytical Data (1,3-Diphenyl-1H-pyrazol-5-yl)(2-hydroxyphenyl)methanone (3a) White powder; yield 0.29 g (88%); mp 106–107 °C. IR (KBr): 3430 (OH), 1617 (CO), 1527 and 1487 (Ar), 1210 (CO) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.97 (1 H, t, ³ J _HH = 6.8 Hz, CH of Ar), 6.98 (1 H, d, ³ J _HH = 6.8 Hz, CH of Ar), 7.37 (1 H, s, CH of pyrazole), 7.39–7.53 (9 H, m, 9 × CH of Ar), 7.70 (1 H, d, ³ J _HH = 8.0 Hz, CH of Ar), 7.95 (2 H, d, ³ J _HH = 7.2 Hz, 2 × CH _ortho of Ph), 10.71 (1 H, s, OH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 109.8 (CH of pyrazole), 117.1 (CH of Ar), 119.3. (CH of Ar), 122.9 (C _ipso CO), 124.5 (2 × CH _ortho of Ph), 125.5 (2 × CH _ortho of Ph), 127.9 (CH _para of Ph), 128.4 (CH _para of Ph), 128.8 (2 × CH _meta of Ph), 128.9 (2 × CH _meta of Ph), 131.4 (CH of Ar), 131.7 (C _ipso C³), 135.4 (CH of Ar), 139.6 (C⁵ of pyrazole), 141.5 (C _ipso N), 150.7 (C³ of pyrazole), 158.7 (COH), 187.5 (CO). MS (EI, 70 eV): m/z = 340 [M⁺], 295, 220, 121, 77, 65. Anal. Calcd (%) for C₂₂H₁₆N₂O₂ (340.38): C, 77.63; H, 4.74; N, 8.23. Found: C, 77.70; H, 4.70; N, 8.31. Crystal Data for 3a C₂₂H₁₆N₂O₂ (CCDC 1058597): MW = 340.37, orthorhombic, P-1, a = 12.3063(6) Å, b = 13.4269(6) Å, c = 21.6550(13) Å, α = 90.00, β = 90.00, γ = 90.00, V = 3578.2(3) ų, Z = 8, D _c = 1.264 mg m^–3, F(000) = 1424, crystal dimension 0.43 × 0.4×0.38 mm, radiation, Mo Kα (λ = 0.71073 Å), 2.93 ≤ 2θ ≤ 25.09, intensity data were collected at 293(2) K with a Bruker APEX area-detector diffractometer, and employing ω/2θ scanning technique, in the range of –14 ≤ h ≤ 14, –15 ≤ k ≤ 16, –25 ≤ l ≤ 20; the structure was solved by a direct method, all nonhydrogen atoms were positioned and anisotropic thermal parameters refined from 2331 observed reflections with R(into) = 0.0659 by a full-matrix least-squares technique converged to R = 0.0452 and R _aw = 0.1728 [I > 2σ(I)]. (5-Chloro-2-hydroxyphenyl)(1,3-diphenyl-1H-pyrazol-5-yl)-methanone (3b) Yellow powder; yield 0.32 g (85%); mp 122 °C. IR (KBr): 3422 (OH), 1619 (CO), 1533 and 1492 (Ar), 1199 (CO) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.94 (1 H, d, ³ J _HH = 8.8 Hz, CH of Ar), 7.40 (1 H, s, CH of pyrazole), 7.42–7.52 (9 H, m, 9 × CH of Ar), 7.56 (1 H, d, ³ J _HH = 2.8 Hz, CH of Ar), 7.94 (2H, d, ³ J _HH = 7.2 Hz, 2 × CH _ortho of Ph), 10.62 (1 H, s, OH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 110.2 (CH of pyrazole), 118.7 (CH of Ar), 122.7 (C _ipso CO), 124.8 (2 × CH _ortho of Ph), 125.5 (2 × CH _ortho of ph), 125.9 (C _ipso Cl), 128.1 (CH _para of Ph), 128.4 (CH _para of Ph), 128.8 (4 × CH _meta of 2 × Ph), 129.5 (CH of Ar), 131.7 (C _ipso C³), 133.6 (CH of Ar), 139.6 (C⁵ of pyrazole), 141.7 (C _ipso N), 150.7 (C³ of pyrazole), 155.9 (COH), 184.8 (CO). MS (EI, 70 eV): m/z = 376 [M⁺ + 2], 374 [M⁺], 329, 220, 116, 89, 77. Anal. Calcd (%) for C₂₂H₁₅ClN₂O₂ (374.82): C, 70.50; H, 4.03; N, 7.47. Found: C, 70.56; H, 4.08; N, 7.40. [3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-5-yl](2-hydroxyphenyl)methanone (3c) Yellow powder; yield 0.31 g (85%); mp 175 °C. IR (KBr): 3390 (OH), 1615 (CO), 1521 and 1489 (Ar), 1211 (CO) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.95–6.97 (2 H, m, 2 × CH of Ar), 7.42–7.50 (9 H, m, 9 × CH of Ph), 7.68 (1 H, d, ³ J _HH = 7.9 Hz, CH of Ar), 7.98 (2 H, d, ³ J _HH = 6.4 Hz, 2 × CH of Ar), 10.64 (1 H, s, OH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 109.9 (CH of pyrazole), 117.1 (CH of Ar), 119.3 (CH of Ar), 123.1 (C _ipso CO), 124.5 (2 × CH _ortho of Ph), 127.3 (2 × CH of Ar), 128.1 (CH _para of Ph), 128.8 (2 × CH of Ar), 128.9 (2 × CH _meta of Ph), 130.7 (C _ipso Cl), 131.4 (CH of Ar), 132.9 (C _ipso C³), 135.4 (CH of Ar), 139.6 (C⁵ of pyrazole), 141.9 (C _ipso N), 149.6 (C³ of pyrazole), 156.1 (COH), 184.7 (CO). MS (EI, 70 eV): m/z = 376 [M⁺ + 2], 374 [M⁺], 329, 254, 121, 77, 65. Anal. Calcd (%) for C₂₂H₁₅ClN₂O₂ (374.82): C, 70.50; H, 4.03; N, 7.47. Found: C, 70.42; H, 3.95; N, 7.40. (5-Chloro-2-hydroxyphenyl)(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-5-yl)methanone (3d) Yellow powder; yield 0.36 g (88%); mp 152–154 °C. IR (KBr): 3433 (OH), 1622 (CO), 1535 and 1487 (Ar), 1200 (CO) cm^–1. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 6.89 (1 H, d, ³ J _HH = 8.8 Hz, CH of Ar), 7.39–7.50 (9 H, m, 9 × CH), 7.53 (1 H, d, ⁴ J _HH = 2.5 Hz, CH of Ar), 7.95 (2 H, d, ³ J _HH = 8.5 Hz, 2 × CH _ortho of Ar), 10.56 (1 H, s, OH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 110.3 (CH of pyrazole), 118.8 (CH of Ar), 122.6 (C _ipso CO), 124.8 (2 × CH _ortho of Ph), 126.0 (C _ipso Cl), 127.3 (2 × CH of Ar), 128.2 (CH _para of Ph), 128.82 (2 × CH of Ar), 128.86 (2 × CH _meta of Ph), 129.5 (C _ipso C³), 130.6 (CH of Ar), 132.9 (CH of Ar), 133.6 (C _ipso Cl), 139.6 (C⁵ of pyrazole), 141.9 (C _ipso N), 149.6 (C³ of pyrazole), 156.1 (COH), 184.7 (CO). MS (EI, 70 eV): m/z = 412 [M⁺ + 4], 410 [M⁺ + 2], 408 [M⁺], 365, 254, 155, 99, 77. Anal. Calcd (%) for C₂₂H₁₄Cl₂N₂O₂ (409.27): C, 64.56; H, 3.45; N, 6.84. Found: C, 64.51; H, 3.51; N, 6.78.