Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles

Francis Gosselin; Paul D. O’Shea; Robert A. Webster; Robert A. Reamer; Richard D. Tillyer; Edward J. J. Grabowski

doi:10.1055/s-2006-956487

LETTER

Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles

Francis Gosselin*^a, Paul D. O’Shea*^a, Robert A. Webster^a, Robert A. Reamer^b, Richard D. Tillyer^b, Edward J. J. Grabowski^b
^a Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 route transcanadienne, Kirkland, Québec, H9H 3L1, Canada
Fax: +1(514)4284936; e-Mail: francis_gosselin@merck.com;
^b Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA

Abstract

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Abstract

A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines is described. The reaction proceeds at room temperature in N,N-dimethylacetamide and furnishes pyrazoles in 59-98% yields.

Key words

1,3-diketones - arylhydrazines - cyclocondensation - regioselectivity - amide solvents

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References and Notes

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Representative Procedure: To a solution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1b; 1.47 g, 5 mmol) in N,N-dimethylacetamide (20 mL) at r.t. was added phenylhydrazine hydrochloride (723 mg, 5 mmol), followed by 10 N HCl (250 µL, 50 mol%). The mixture was let to stir for 24 h at r.t., cooled to 0 °C and H₂O (20 mL) was slowly added. After diluting with toluene (30 mL), the organic layer was washed with H₂O (3 × 20 mL) and concentrated to a brown oil that crystallized. The crystals were washed with cold heptane (3 × 5 mL) to give phenyl-3-(trifluoromethyl)-5-(4-bromophenyl)-1H-pyrazole(2j) as colorless crystals; yield: 1.36 g (74%); mp 103.7-105.4 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.44 (d, J = 7.4 Hz, 2 H), 7.36 (m, 3 H), 7.28 (m, 2 H), 7.07 (d, J = 7.4 Hz, 2 H), 6.74 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 143.4, 143.3 (q, J = 39 Hz), 138.9, 131.9, 130.2, 129.2, 128.7, 128.0, 125.4, 123.4, 121.1 (q, J = 269 Hz), 105.6. LRMS: m/z calcd for C₁₆H₁₀BrF₃N₂: 367.16; found [M - 1]: 366.8. Pyrazoles could also be readily purified by column chromatography using 5-20% EtOAc-hexanes as eluent.