Regioselective Microwave-Assisted Synthesis of Substituted Pyrazoles from Ethynyl Ketones

Mark C. Bagley; M. Caterina Lubinu; Christopher Mason

doi:10.1055/s-2007-970783

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Synlett 2007(5): 0704-0708
DOI: 10.1055/s-2007-970783

LETTER

Regioselective Microwave-Assisted Synthesis of Substituted Pyrazoles from Ethynyl Ketones

Mark C. Bagley*^a, M. Caterina Lubinu^a, Christopher Mason^b
^a School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Fax: +44(29)20874030; e-Mail: Bagleymc@cf.ac.uk;
^b CEM Microwave Technology Ltd, 2 Middle Slade, Buckingham, MK18 1WA, UK

Further Information

Publication History

Received 8 November 2006
Publication Date:
08 March 2007 (online)

Abstract
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Abstract

Reaction of α,β-ethynyl ketones and hydrazine derivatives gives 1,3- and 1,5-disubstituted pyrazoles in good yield. Microwave irradiation in concentrated hydrochloric acid-methanol (1.5% v/v), with concurrent cooling at sub-ambient temperatures or at 120 °C, for 30 or 2 minutes, respectively, facilitates rapid heterocyclization and preferentially gives the 1,3-disubstituted regioisomer.

Key words

ethynyl ketones - pyrazoles - heterocycles - microwave synthesis - concurrent heating and cooling

References and Notes

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31

All pyrazoles exhibited satisfactory characterization data, including ¹H NMR, ¹³C NMR, IR, MS and HRMS.

32

Qualitative NOESY effects were seen for 1,3-disubstituted pyrazoles (Table [4] , entries 1, 6 and 8) between the aryl ortho-methine resonances and the pyrazole methine signals, the latter of which were well separated (see ref. 3) in chemical shift in the ¹H NMR spectrum of both pyrazole regioisomers. The 5-ethyl-trisubstituted pyrazole (entry 4) showed NOESY effects between the aryl ortho-methine resonances and the methylene protons.

33

1,3-Diphenylpyrazole (3): mp 81-83 °C (lit.³⁵ mp 84-85 °C); R _f = 0.61 (CH₂Cl₂). HRMS: m/z [MH⁺] calcd for C₁₅H₁₃N₂: 221.1073; found: 221.1074 [MH⁺]. IR (nujol): ν_max = 1598, 1526, 1504, 1360, 1264, 1114, 1061, 1046, 954, 755, 686 cm^-1. UV (CH₂Cl₂): λ_max (ε) = 284 (17959), 224 (6189) nm. ¹H NMR (400 MHz, CDCl₃): δ = 7.89 (1 H, d, J = 2.5 Hz, 5-H), 7.85 (2 H, m, PhH), 7.71 (2 H, m, PhH), 7.38 (4 H, PhH), 7.24 (2 H, m, PhH), 6.71 (1 H, d, J = 2.5 Hz, 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 153.3 (C), 140.6 (C), 133.5 (C), 129.8 (CH), 129.1 (CH), 128.5 (CH), 128.4 (CH), 126.7 (CH), 126.2 (CH), 119.5 (CH), 105.4 (CH) ppm. MS (APCI): m/z (%) = 221 (100) [MH⁺], 194 (5), 118 (10).

34

1,5-Diphenylpyrazole (4): mp 52-55 °C (lit.³⁵ mp 55-56 °C); R _f = 0.18 (CH₂Cl₂). HRMS: m/z [MH⁺] calcd for C₁₅H₁₃N₂: 221.1073; found: 221.1072 [MH⁺]. IR (nujol): ν_max = 1596, 1541, 1502, 1450, 1385, 1224, 1158, 1130, 1068, 960, 761, 695 cm^-1. UV (CH₂Cl₂): λ_max (ε) = 252 (14493). ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (1 H, d, J = 1.5 Hz, 3-H), 7.28-7.22 (8 H, PhH), 7.19-7.15 (2 H, m, PhH), 6.45 (1 H, d, J = 1.5 Hz, 4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 143.0 (C), 140.3 (CH), 140.1 (C), 130.6 (CH), 128.9 (CH), 128.8 (CH), 128.5 (CH), 128.2 (CH), 127.4 (CH), 125.2 (CH), 107.9 (CH) ppm. MS (APCI): m/z (%) = 221 (100) [MH⁺], 194 (10), 152 (5), 103 (5).