Efficient Copper-Catalyzed Synthesis of Substituted Pyrazoles at Room Temperature

Abstract

An efficient method for the synthesis of pyrazoles through a copper-catalyzed condensation reaction has been developed. The new catalytic system not only maintained a broad substrate scope but was also active under acid-free reaction conditions, overcoming the conventional requirement for an acid-catalyzed system. Furthermore, the copper catalyst enabled this reaction to be performed at room temperature and in a short reaction time.

Key words

pyrazoles - condensation reaction - copper catalysis - arylhydrazines - sulfonyl hydrazides

• References and Notes

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• 10 3,5-Dimethyl-1-phenyl-1H-pyrazole (3a); Typical ProcedureCu(NO₃)₂·3 H₂O (10 mol%) was added to a stirred solution of PhNHNH₂ (1a; 0.5 mmol) and pentane-2,4-dione (2; 0.6 mmol) in CH₃CN (2 mL) at r.t., and the resulting solution was stirred at r.t. for 1 h. When the reaction was complete, the mixture was concentrated to remove MeCN, and the residue was dissolved in CH₂Cl₂ (30 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (Na₂SO₄), filtered, concentrated, and purified by column chromatography [silica gel, PE–EtOAc (20:1)] to give a colorless oil; yield: 75 mg (87%). ¹H NMR (400 MHz, CDCl₃): δ = 7.46–7.40 (m, 4 H), 7.36–7.32 (m, 1 H), 6.01 (s, 1 H), 2.32 (s, 3 H), 2.31 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 148.94, 139.99, 139.35, 128.98, 127.21, 124.75, 106.94, 13.53, 12.37. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₃N₂: 173.1073; found: 173.1074.
• 11 3,5-Dimethyl-1-tosyl-1H-pyrazole (5a); Typical ProcedurePentane-2,4-dione (2; 0.6 mmol) and Cu(NO₃)₂·3H₂O (10 mol%) were added to a round-bottomed flask containing a solution of TsNHNH₂ (4a, 0.5 mmol) in CH₃CN (2 mL), and the mixture was stirred for 15 min. The mixture was then concentrated to remove MeCN, and the residue was dissolved in CH₂Cl₂ (30 mL). The organic layer was washed with H₂O (3 × 10 mL), dried (Na₂SO₄), filtered, concentrated, and purified by column chromatography [silica gel, PE–EtOAc (20:1)] to give a white solid; yield 101 mg (81%); mp 97–98 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.83 (d, J = 8.3 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H), 5.90 (s, 1 H), 2.49 (s, 3 H), 2.41 (s, 3 H), 2.20 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.46, 145.22, 144.15, 135.48, 129.96, 127.63, 110.81, 21.71, 13.90, 13.16. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₅N₂O₂S: 251.0849; found: 251.0846.