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Synlett 2007(5): 0704-0708  
DOI: 10.1055/s-2007-970783
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Microwave-Assisted Synthesis of Substituted Pyrazoles from Ethynyl Ketones

Mark C. Bagley*a, M. Caterina Lubinua, Christopher Masonb
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
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Received 8 November 2006
Publikationsdatum:
08. März 2007 (online)

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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

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

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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.

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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): νmax = 1598, 1526, 1504, 1360, 1264, 1114, 1061, 1046, 954, 755, 686 cm-1. UV (CH2Cl2): λmax (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).

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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): νmax = 1596, 1541, 1502, 1450, 1385, 1224, 1158, 1130, 1068, 960, 761, 695 cm-1. UV (CH2Cl2): λmax (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).