Issue in Honor of Prof. Rainer Beckert ARKIVOC 2012 (iii) 49-65
General procedure for the reduction of amides (24a) and (25b,c) to amines (15a,b) and (26c)
Under argon, LiAlH4 (1 M in THF, 10 mL, 10 mmol) was added to a cooled (0 °C) solution of amide 24 or 25 (5 mmol) in anhydrous THF (10 mL) and the resulting reaction mixture was stirred at 0 °C for 20 min. and then at 60°C for 5 h. The reaction mixture was cooled to 0 °C and quenched subsequently with aq. sat. NaHCO3 (5 mL) and MeOH (10 mL). The resulting mixture was stirred at room temperature for 10 min. followed by filtration through a short plug of Celite® and washing with EtOAc (200 mL). The filtrate was evaporated in vacuo and the residue was purified by CC. Fractions containing the product were collected and volatile components evaporated in vacuo to give 15a,b and 26c. Compound 15b was isolated as dihydrochloride in the following way. The partially purified free amine obtained by CC was dissolved in CH2Cl2 (5 mL) and, while vigorous stirring at r.t., 2 M HCl–EtOAc (2 mL, 4 mmol) was added. The precipitate was collected by filtration, washed with EtOAc, dried in vacuo to give the dihydrochloride of 15b. 3-(2-(Benzyl(methyl)amino)ethyl)-5-hydroxy-1-phenyl-1H-pyrazole (15a). Prepared from 24a (1.605 g, 5 mmol), CC (MeOH/EtOAc, 1:7). Yellowish-brown semi-solid, yield 50%, 771 mg, IR (•max, cm–1): 3030, 2951, 2790, 1598, 1564, 1498, 1454, 1362, 1153, 1069, 1023, 907, 757, 698. 1H NMR (300 MHz, CDCl3), •H 2.26 (3H, s, NMe), 2.68 (4H, s, 2•CH2), 3.38 (2H, s, CH2), 3.52 (2H, s, CH2), 7.14–7.43 (8H, m, 8H of Ph), 7.86 (2H, d, 3JHH = 8.0 Hz, 2H of Ph). MS, m/z = 308 (MH+), HRMS (ESI), m/z = 308.1759 (MH+), C19H22N3O requires 308.1763. Anal. Calcd for C19H21N3O3 (307.39): C, 74.24; H, 6.89; N, 13.67%, Found: C, 73.19; H, 6.88; N, 13.31%.
5-Hydroxy-1-(4-methoxyphenyl)-3-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazole dihydrochloride (15b). Prepared from 25b (1.506 g, 5 mmol), CC (neutral Al2O3, MeOH/CH2Cl2, 1:9). White solid, yield 54%, 981 mg, mp 199–201 °C, IR (•max, cm–1): 3424, 2958, 2841, 2702, 2605, 2514, 2359, 2331, 1592, 1580, 1559, 1535, 1508, 1448, 1420, 1400, 1362, 1303, 1257, 1184, 1172, 1109, 1065, 1034, 1018, 850, 799. 1H NMR (300 MHz, DMSO-d6), •H 1.80–2.09 (4H, m, 3''CH2, 4''-CH2), 2.88–2.98 and 2.99–3.10 (4H, 2m, 1:1, CH2CH2), 3.35–3.46 and 3.47–3.60 (4H, 2m, 1:1, 2''-CH2, 5''-CH2), 3.78 (3H, s, OMe), 5.52 (1H, s, 4-H of pyrazole), 5.93 (2H, br s, NH2+), 6.96–7.04 and 7.52–7.61 (4H, 2m, 1:1, C6H4), 10.75 (1H, br s, OH). 13C NMR (126 MHz, DMSO-d6), •C 22.8, 24.2, 52.3, 52.8, 55.5, 88.1, 114.2, 124.0, 129.9, 146.8, 154.0, 157.9. MS, m/z = 288 (MH+), HRMS (ESI), m/z = 288.1720 (MH+), C16H22N3O2 requires 288.1712. Anal. Calcd for C16H23Cl2N3O2 (360.28): C, 53.34; H, 6.43; N, 11.66%, Found: C, 52.76; H, 6.41; N, 11.60%. 3-(2-(Dibenzylamino)ethyl)-1-phenyl-1H-pyrazol-5(4H)-one (26c). Prepared from 25c (1.985 g, 5 mmol), CC (EtOAc/hexanes, 1:1). Brownish oil, yield 50%, 966 mg, IR (•max, cm–1): 3060, 3027, 2928, 2800, 2359, 2341, 1714 (C=O), 1597, 1558, 1497, 1453, 1409, 1365, 1337, 1248, 1154, 1128, 1071, 1027, 977, 906, 749, 697. 1H NMR (300 MHz, CDCl3), •H 2.61–2.67 and 2.69–2.76 (4H, 2m, 1:1, CH2CH2), 2.99 (2H, s, 4-CH2 of pyrazole), 3.57 (4H, s, 2•CH2Ph), 7.14–7.43 (13H, m, 13H of Ph), 7.84–7.91 (2H, m, 2H of Ph). 1H NMR (500 MHz, DMSO-d6),
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