134 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Meng et al.
General Procedure for N-Alkylation in K2CO3/
MeCOMe System: Ethyl 5-phenyl-1-(prop-2-ynyl)-1H-
pyrazole-3-carboxylate (6{1}) and ethyl 3-phenyl-1-(prop-
2-ynyl)-1H-pyrazole-5-carboxylate (7{1}). To a solution of
ethyl 3-phenyl-1H-pyrazole-5-carboxylate 3{1} (3.9 g, 18
mmol) in acetone (75 mL) was added K2CO3 (7.6 g, 54
mmol) and propargyl bromide solution (80 wt % in toluene)
(5.4 g, 36 mmol). The reaction mixture was heated to 70 °C
for 6.5 h. The reaction mixture was cooled, and the solvent
was removed to give a crude residue. The residue was taken
into EtOAc, and filtered to remove undissolved particles. The
filtrate was dried over anhydrous MgSO4, filtered, and
concentrated. The crude solid was purified by CombiFlash
on silica gel with eluent hexane/EtOAc, 2:1. The first eluted
is ethyl 3-phenyl-1-(prop-2-ynyl)-1H-pyrazole-5-carboxylate
(7{1}) (off-white solid, 3.7 g, 81% yield): mp 83-84 °C;
IR (neat) 3216, 3134, 3063, 2990, 2942, 2119, 1717, 1542,
1507, 1470, 1454, 1430, 1369, 1317, 1294, 1262, 1204, 1094,
959, 943, 773, 756, 695 cm-1; 1H NMR (600 MHz, CDCl3)
δ 7.79-7.80 (m, 2H), 7.34-7.37 (m, 2H), 7.26-7.28 (m,
1H), 7.11 (s, 1H), 5.35 (d, J ) 3.0 Hz, 2H), 4.30 (q, J ) 7.2
Hz, 2H), 2.42 (t, J ) 3.0 Hz, 1H), 1.32 (t, J ) 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 159.5, 150.8, 133.5, 132.4,
128.9, 128.5, 125.8, 108.7, 78.2, 73.6, 61.5, 41.8, 14.4;
ESIMS m/z 255.10 (M + H)+; Purity was determined to be
100% by HPLC analysis on the basis of absorption at 214
nm. The second eluted is ethyl 5-phenyl-1-(prop-2-ynyl)-
1H-pyrazole-3-carboxylate (6{1}) (off-white solid, 754 mg,
17% yield): mp 102-103 °C; IR (neat) 3227, 3149, 3069,
2984, 2941, 2119, 1711, 1475, 1449, 1419, 1372, 1341, 1312,
1256, 1218, 1167, 1109, 1026, 1000, 946, 838, 822, 781,
755, 721, 686 cm-1; 1H NMR (600 MHz, CDCl3) δ
7.24-7.34 (m, 5H), 6.65 (s, 1H), 4.76 (d, J ) 2.4 Hz, 2H),
4.19 (q, J ) 7.2 Hz, 2H), 2.34 (t, J ) 2.4 Hz, 1H), 1.19 (t,
J ) 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 162.1,
145.2, 143.6, 129.4, 129.1, 129.0, 128.8, 109.1, 77.6, 74.8,
61.1, 40.7, 14.5; ESIMS m/z 255.10 (M + H)+; Purity was
determined to be 94% by HPLC analysis on the basis of
absorption at 214 nm.
(m, 1H), 7.57 (t, J ) 7.8 Hz, 1H), 7.43-7.49 (m, 5H), 6.83
(s, 1H), 5.26-5.31 (m, 1H), 4.37 (q, J ) 7.2 Hz, 2H),
4.35-4.46 (m, 2H), 3.40-3.49 (m, 2H), 1.37 (t, J ) 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 162.4, 155.3, 148.6,
146.7, 143.9, 132.5, 131.0, 130.0, 129.7, 129.6, 129.4, 129.2,
125.0, 121.9, 109.5, 80.0, 61.4, 52.4, 38.1, 14.6; ESIMS m/z
421.18 (M + H)+; Purity was determined to be 100% by
HPLC analysis on the basis of absorption at 214 nm.
General Procedure for Isoxazol(in)e Synthesis (Strat-
egy 3): Ethyl 1-((3-methylisoxazol-5-yl)methyl)-3-phenyl-
1H-pyrazole-5-carboxylate (12{1,5}). 1,4-Phenylene diiso-
cyanate (1.92 g, 12 mmol) was added to 7{1} (1.02 g, 4
mmol) in dry THF (53 mL). Triethylamine (1.67 mL, 12
mmol) was added to the reaction mixture, and this was heated
to 45 °C. Nitroethane (862 µL, 12 mmol) was added in
syringe pump over a period of 6-8 h, and then the reaction
was heated an additional 2 h. The reaction was quenched
with water (24 mL) and allowed to stir at room temperature
for 1 h. 1,4-Phenylene diisocyanate was removed by filtration
over Celite (washing several times with ethyl acetate), and
the filtrate was then concentrated and subjected to flash
column chromatography (Combiflash, silica gel, hexane/
EtOAc in gradient) to afford 12{1,5} as white solid (1.02 g,
82% yield): mp 66-67 °C; IR (neat) 3124, 3058, 2900, 2937,
2901, 1711, 1610, 1544, 1509, 1471, 1454, 1432, 1385, 1360,
1324, 1269, 1205, 1094, 1018, 1004, 957, 886, 828, 797,
1
782, 760, 747, 689 cm-1; H NMR (600 MHz, CDCl3) δ
7.79-7.81 (m, 2H), 7.39-7.41 (m, 2H), 7.31-7.34 (m, 1H),
7.18 (s, 1H), 5.92 (s, 1H), 5.89 (s, 2H), 4.36 (q, J ) 7.2 Hz,
2H), 2.23 (s, 3H), 1.38 (t, J ) 7.2 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 167.5, 160.1, 159.6, 151.3, 134.0, 132.3,
128.9, 128.6, 125.9, 109.0, 103.7, 61.7, 47.4, 14.4, 11.6;
ESIMS m/z 312.12 (M + H)+; Purity was determined to be
98% by HPLC analysis on the basis of absorption at 214
nm.
General Procedure for Solution-Phase Synthesis of
Isoxazol(in)e-CH2-Pyrazole Amides: N-(Benzo[d][1,3]dioxol-
5-ylmethyl)-1-((3-(4-methoxyphenyl)-4,5-dihydro isoxazol-
5-yl)methyl)-5-phenyl-1H-pyrazole-3-carboxamide
(17{1,2,4}). To a solution of compound 9{1,2} (989 mg, 2.44
mmol) in THF/water (1:1, 20 mL) was added 5 M NaOH (1
mL). The reaction mixture was stirred at 50 °C for 6 h. The
reaction mixture was allowed to cool to room temperature.
The THF was removed in vacuo, and the remaining aqueous
layer was acidified by 2 M HCl to pH 2. The precipitate
formed was filtered, washed with water and pentane, and
dried in vacuum to give 13{1,2} as a white solid (918 mg,
99% yield): mp 196-197 °C; IR (neat) 2946, 2367, 1725,
1607, 1515, 1445, 1424, 1359, 1253, 1176, 1042, 1013, 826,
786, 766, 698 cm-1; 1H NMR (600 MHz, CD3OD) δ
7.52-7.55 (m, 4H), 7.41-7.47 (m, 3H), 6.92-6.94 (m, 2H),
6.74 (s, 1H), 5.14-5.18 (m, 1H), 4.35 (dd, J ) 14.4, 7.2
Hz, 1H), 4.25 (dd, J ) 14.4, 5.4 Hz, 1H), 3.82 (s, 3H), 3.47
(dd, J ) 16.8, 10.2 Hz, 1H), 3.35 (dd, J ) 16.8, 5.4 Hz,
1H); 13C NMR (150 MHz, (CD3)2SO) δ 164.2, 161.4, 157.1,
145.7, 130.2, 129.8, 129.5, 129.4, 128.9, 122.1, 114.9, 108.9,
105.0, 79.3, 56.0, 52.9, 38.6; ESIMS m/z 378.20 (M + H)+;
Purity was determined to be 100% by HPLC analysis on
the basis of absorption at 214 nm.
General Procedure for Isoxazoline Synthesis (Strategy
2B): Ethyl 1-((3-(3-nitrophenyl)-4,5-dihydroisoxazol-5-
yl)methyl)-5-phenyl-1H-pyrazole-3-carboxylate (9{1,3}).
Compound 4{1} (317 mg, 1.24 mmol) and N-hydroxy-3-
nitrobenzimidoyl chloride (purified via flash column chro-
matography on silica gel with 20% EtOAc in hexane, 372
mg, 1.85 mmol) were dissolved in DCM (5 mL) in 25 mL
round-bottom flask, and the reaction mixture was cooled to
0 °C and placed under nitrogen. Triethylamine (513 µL, 3.72
mmol) was added to the reaction mixture via syringe. The
reaction mixture was allowed to warm to room temperature
and vigorously stirred overnight. After washing with water,
the organic layer was dried over anhydrous MgSO4, filtered,
and concentrated. The residue was purified by CombiFlash
on silica gel with eluent hexane/EtOAc in gradient to give
the product 9{1,3} as pale-yellow solid (461 mg, 89% yield):
mp 108-109 °C; IR (neat) 3073, 2995, 2938, 2162, 1733,
1526, 1479, 1458, 1443, 1391, 1350, 1246, 1205, 1112, 1034,
1
923, 889, 760, 739 cm-1; H NMR (600 MHz, CDCl3) δ
8.36 (t, J ) 1.8 Hz, 1H), 8.24- 8.26 (m, 1H), 7.96-7.98