Synthesis
Example A: Synthesis of 1-phenyl-1H-pyrazole-5-carbaldehyde
Experimental Steps:
A heptane solution of n-butyllithium (2.61 M, 5.3 mL, 13.9 mmol) was slowly added dropwise to a solution of 1-phenyl-1H-pyrazole (2.0 g, 13.9 mmol) in anhydrous THF (60 mL) cooled to -78 °C under nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 2 hours. Subsequently, a solution of anhydrous N,N-dimethylformamide (1.1 mL, 13.9 mmol) in anhydrous THF (8 mL) was slowly added. The mixture was continued to be stirred at -78 °C for 1 hour, then slowly warmed to room temperature and stirred for 18 hours. Upon completion of the reaction, the reaction was quenched with water (10 mL) and subsequently extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by fast chromatography (column size: diameter 6 cm, height 12 cm; eluent: n-hexane/ethyl acetate=8:2, 30 mL; Rf=0.24) to give a yellow oil, which crystallized as a yellow solid after cooling, melting point: 31 °C, yield: 2.15 g (90%).
Product Characterization:
Molecular formula: C10H8N2O (172.2)
Mass Spectrum (EI): m/z (relative intensity) = 172 [M+, 100], 144 [M-CO, 69]
IR spectrum (pure): ν (cm-1) = 3063 (aromatic CH), 2923 (fatty CH), 2854 (CH), 1683 (C=O), 1596, 1517, 1499 (C=C), 763, 694 (CH)
1H-NMR (CDCl3): δ (ppm) = 7.11 (d, J=2.1 Hz, 1H, pyrazole-4-CH), 7.46-7.56 (m, 5H, phenyl-CH), 7.76 (d, J=2.0 Hz, 1H, pyrazole-3-CH), 9.88 (s, 1H, CHO)
13C-NMR (CDCl3): δ (ppm) = 112.5 (1C, pyrazole-4-CH), 125.8 (2C, phenyl-CH, neighboring), 129.4 (1C, phenyl-CH, para), 129.6 (2C, phenyl-CH, interstitial), 139.0 (1C, phenyl-C, tetralin), 140.3 (1C, pyrazole-5- C), 140.7 (1C, pyrazole-3-CH), 180.2 (1C, CHO)
References
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 2992 - 3001
[2] Patent: EP1982987, 2008, A1. Location in patent: Page/Page column 13-14; 18-19
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6704 - 6713
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 10, p. 2749 - 2750
