DOI: 10.3109/14756366.2013.815177
(5-amino-1, 2, 4-triazin-6-yl)(2-(benzo[d]isoxazol-3-yl) pyrrolidin-1-yl)methanone derivatives
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ꢀ: 8.60 (dd, 2H, J ¼ 8.2 Hz, Ph-H), 7.88 (dd, 1H, J ¼ 8.0 Hz, General procedure for synthesis of (5-amino-3-substi-
benzisoxazole-H), 7.65–7.50 (m, 3H, Ph-H), 7.35 (d, 1H, tuted-1, 2, 4-triazin-6-yl) (2-(6-chlorobenzo[d]isoxazol-
J ¼ 7.7 Hz, benzisoxazole-H), 7.10–6.90 (m, 1H, benzisoxazole- 3-yl) pyrrolidin-1-yl) methanone [5g–5l]
H), 6.65 (br s, 2H, NH2, D2O exchangeable), 4.05 (t, 1H,
A mixture of triazine ester 3a–3f (3a–3b/0.20 mL, 3c–3f/0.25 mL,
1.0 mmol), 6-chloro-3-(pyrrolidin-2-yl)benzo[d]isoxazole 4b
(2.22 gm, 10.0 mmol) and DBU (0.07 gm, 0.5 mmol) was stirred
at room temperature for 48 h. Ethyl acetate was added (15 mL)
and the organic phase was washed with saturated aqueous NH4Cl
solution (4 ꢃ 15 mL), dried on Na2SO4 and concentrated to give
white crystalline solids 5g–5l.
J ¼ 6.2 Hz, pyrrolidine-H), 3.25–1.99 (m, 6H, pyrrolidine-H); 13C
NMR (CDCl3, ppm) ꢀ: 166.6 (C), 165.0 (C¼O), 162.2 (C-F),
155.5 (C), 149.9 (C), 148.4 (C), 140.6 (C), 134.3 (CH), 132.2
(2 ꢃ CH), 130.0 (2 ꢃ CH), 129.2 (CH), 120.5 (C), 111.5 (CH),
102.2 (CH), 59.6 (C), 46.5 (CH2), 32.6 (CH2), 25.1 (CH2); ESI-
MS: 405.50 (C21H17FN6O2 (Mþ þ 1)); Anal. calcd. for
C21H17FN6O2 (404.40) C: 62.37, H: 4.24, N: 20.78, Found C:
62.35, H: 4.20, N: 20.75.
(5-Amino-3-methyl-1, 2, 4-triazin-6-yl)(2-(6-chlorobenzo[d]isox-
azol-3-yl) pyrrolidin-1-yl) methanone [5g]
(5-Amino-3-(pyridin-2-yl)-1, 2, 4-triazin-6-yl)(2-(6-fluorobenzo[-
d]isoxazol-3-yl) pyrrolidin-1-yl) methanone [5d]
Yield: 62%; mp 108–111 ꢁC; IR (umax/cmꢂ1): 3320, 3127, 2960,
2925, 1655, 1520, 1475, 840, 570; 1H NMR (CDCl3, ppm) ꢀ: 7.85
(m, 1H, benzisoxazole-H), 7.70 (d, 1H, J ¼ 8.2 Hz, benzisoxazole-
H), 7.02 (t, 1H, J ¼ 7.5 Hz, benzisoxazole-H), 6.52 (br s, 2H, NH2,
D2O exchangeable), 4.05 (t, 1H, J ¼ 4.8 Hz, pyrrolidine-H), 3.10–
1.95 (m, 6H, pyrrolidine-H), 2.80 (s, 3H, CH3); 13C NMR
(CDCl3, ppm) ꢀ: 165.5 (C), 165.1 (C), 163.7 (C¼O), 155.5 (C),
148.8 (C), 139.8 (C), 133.2 (C-Cl), 129.3 (CH), 124.0 (CH), 120.5
(C), 119.4 (CH), 57.7 (C), 45.5 (CH2), 34.2 (CH2), 24.8 (CH2),
21.7 (CH3); ESI-MS: 361.05, 359.80 (C16H15ClN6O2 (Mþ þ 2),
(Mþ þ 1)); Anal. calcd. for C16H15ClN6O2 (358.78) C: 53.56, H:
4.21, N: 23.42, Found C: 53.50, H: 4.25, N: 23.40.
Yield: 74%; mp 130–132 ꢁC; IR (umax/cmꢂ1): 3412, 3105, 2955,
2911, 1670, 1510, 1470, 870, 790, 740, 615; H NMR (CDCl3,
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ppm) ꢀ: 8.95 (d, 1H, J ¼ 5.5 Hz, Py-H), 8.72 (d, 1H, J ¼ 8.2 Hz,
Py-H), 7.90–7.60 (m, 3H, 1 ꢃ benzisoxazole-H and 2 ꢃ Py-H),
7.30 (d, 1H, J ¼ 8.5 Hz, benzisoxazole-H), 7.15 (m, 1H,
benzisoxazole-H), 6.65 (br s, 2H, NH2, D2O exchangeable),
4.11 (t, 1H, J ¼ 6.7 Hz, pyrrolidine-H), 3.00–2.05 (m, 6H,
pyrrolidine-H); 13C NMR (CDCl3, ppm) ꢀ: 168.2 (C), 164.4
(C¼O), 161.4 (C-F), 158.3 (C), 156.6 (C), 155.2 (C), 149.8 (C),
145.5 (CH), 140.2 (C), 137.2 (CH), 130.2 (CH), 129.2 (CH),
126.8 (CH), 120.2 (C), 112.6 (CH), 104.2 (CH), 57.8 (C), 46.6
(CH2), 34.6 (CH2), 24.1 (CH2); ESI-MS: 406.60 (C20H16FN7O2
(Mþ þ 1)); Anal. calcd. for C20H16FN7O2 (405.39) C: 59.26, H:
3.98, N: 24.19, Found C: 59.25, H: 3.95, N: 24.22.
(2-(6-Chlorobenzo[d]isoxazol-3-yl) pyrrolidin-1-yl)(3, 5-diamino-
1, 2, 4-triazin-6-yl) methanone [5h]
Yield: 60%; mp 115–117 ꢁC; IR (umax/cmꢂ1): 3443, 3310, 3097,
2965, 2915, 1665, 1525, 1470, 844, 570; H NMR (CDCl3, ppm)
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(5-Amino-3-(pyrimidin-2-yl)-)-1, 2, 4-triazin-6-yl)(2-(6-fluoro-
benzo[d]isoxazol-3-yl) pyrrolidin-1-yl)methanone [5e]
ꢀ: 7.88 (dd, 1H, J ¼ 8.5 Hz, benzisoxazole-H), 7.65 (d, 1H,
J ¼ 7.5 Hz, benzisoxazole-H), 7.10–7.00 (m, 1H, benzisoxazole-
H), 6.80 (br s, 2H, NH2, D2O exchangeable), 6.45 (br s, 2H, NH2,
D2O exchangeable), 4.20 (t, 1H, J ¼ 6.5 Hz, pyrrolidine-H), 3.00–
1.90 (m, 6H, pyrrolidine-H); 13C NMR (CDCl3, ppm) ꢀ: 166.2
(C), 163.4 (C¼O), 157.2 (C), 154.8 (C), 150.0 (C), 139.8 (C),
132.1 (C-Cl), 130.4 (CH), 125.5 (CH), 121.3 (C), 119.2 (CH),
60.6 (C), 45.6 (CH2), 34.4 (CH2), 24.4 (CH2); ESI-MS: 361.01,
360.60 (C15H14ClN7O2 (Mþ þ 2), (Mþ þ 1)); Anal. calcd. for
C15H14ClN7O2 (359.77) C: 50.08, H: 3.92, N: 27.25, Found C:
50.10, H: 3.90, N: 27.22.
Yield: 68%; mp 140–141 ꢁC; IR (umax/cmꢂ1): 3420, 3110, 2945,
2925, 1660, 1510, 1468, 1032, 870, 620; H NMR (CDCl3, ppm)
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ꢀ: 8.80 (d, 2H, J ¼ 4.5 Hz, Pm-H), 7.85 (dd, 1H, J ¼ 8.5 Hz,
benzisoxazole-H), 7.33 (d, 1H, J ¼ 8.5 Hz, benzisoxazole-H), 7.20
(t, 1H, J ¼ 7.2 Hz, J ¼ 1.8 Hz, Pm-H), 7.10–6.80 (m, 1H,
benzisoxazole-H), 6.61 (br s, 2H, NH2, D2O exchangeable),
4.11 (t, 1H, J ¼ 6.2 Hz, pyrrolidine-H), 3.30–2.00 (m, 6H,
pyrrolidine-H); 13C NMR (CDCl3, ppm) ꢀ: 165.5 (C), 164.4
(C¼O), 162.2 (C-F), 160.0 (C), 158.2 (C), 156.4 (C), 155.5
(2 ꢃ CH), 149.8 (C), 140.5 (C), 129.5 (CH), 120.8(CH), 120.0
(C), 109.2 (CH), 102.5 (CH), 60.2 (C), 45.7 (CH2), 34.5 (CH2),
24.4 (CH2); ESI-MS: 407.45 (C19H15FN8O2 (Mþ þ 1)); Anal.
calcd. for C19H15FN8O2 (406.37) C: 56.16, H: 3.72, N: 27.57,
Found C: 56.15, H: 3.69, N: 27.55.
(5-Amino-3-phenyl-1, 2, 4-triazin-6-yl)(2-(6-chlorobenzo[d]isox-
azol-3-yl) pyrrolidin-1-yl) methanone [5i]
Yield: 81%; mp 130–133 ꢁC; IR (umax/cmꢂ1): 3430, 3107, 3100,
2959, 2915, 1665, 1520, 1466, 845, 565; H NMR (CDCl3, ppm)
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ꢀ: 8.66 (dd, 2H, J ¼ 8.0 Hz, Ph-H), 7.78 (dd, 1H, J ¼ 8.0 Hz,
benzisoxazole-H), 7.66 (d, 1H, J ¼ 7.7 Hz, benzisoxazole-H),
7.60–7.45 (m, 3H, Ph-H), 7.00–6.90 (m, 1H, benzisoxazole-H),
6.66 (br s, 2H, NH2, D2O exchangeable), 4.08 (t, 1H, J ¼ 4.2 Hz,
pyrrolidine-H), 2.99–1.95 (m, 6H, pyrrolidine-H); 13C NMR
(CDCl3, ppm) ꢀ: 166.2 (C), 165.4 (C¼O), 155.5 (C), 149.5 (C),
148.8 (C), 140.4 (C), 134.2 (C-Cl), 134.0 (CH), 132.6 (2 ꢃ CH),
130.1 (2 ꢃ CH), 129.9 (CH), 124.2 (CH), 121.5 (CH), 120.2 (C),
59.9 (C), 47.2 (CH2), 32.9 (CH2), 23.8 (CH2); ESI-MS: 422.95,
421.50 (C21H17ClN6O2 (Mþ þ 2), (Mþ þ 1)); Anal. calcd. for
C21H17ClN6O2 (420.85) C: 59.93, H: 4.07, N: 19.97, Found C:
59.90, H: 4.05, N: 19.90.
(5-Amino-3-(pyrazin-2-yl)-1, 2, 4-triazin-6-yl)(2-(6-fluorobenzo[-
d]isoxazol-3-yl) pyrrolidin-1-yl) methanone [5f]
Yield: 66%; mp 145–148 ꢁC; IR (umax/cmꢂ1): 3390, 3090, 2960,
2930, 1675, 1572, 1515, 1473, 875, 615; H NMR (CDCl3, ppm)
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ꢀ: 9.25 (d, 2H, J ¼ 5.5 Hz, Pz-H), 8.85 (m, 1H, J ¼ 4.5 Hz, Pz-H),
7.88–7.65 (m, 1H, benzisoxazole-H), 7.30 (d, 1H, J ¼ 8.0 Hz,
benzisoxazole-H), 7.15–6.90 (m, 1H, benzisoxazole-H), 6.51 (br
s, 2H, NH2, D2O exchangeable), 4.10 (t, 1H, J ¼ 6.2 Hz,
pyrrolidine-H), 3.10–1.90 (m, 6H, pyrrolidine-H); 13C NMR
(CDCl3, ppm) ꢀ: 165.0 (C), 163.8 (C¼O), 162.6 (C-F), 158.5
(C), 156.4 (C), 150.4 (C), 145.5 (2 ꢃ CH), 144.4 (CH), 142.2
(C), 140.5 (C), 129.2 (CH), 120.6 (C), 108.6 (CH), 103.3
(CH), 60.5 (C), 45.6 (CH2), 35.4 (CH2), 24.3 (CH2); ESI-MS:
407.35 (C19H15FN8O2 (Mþ þ 1)); Anal. calcd. for C19H15FN8O2
(5-Amino-3-(pyridin-2-yl)-1, 2, 4-triazin-6-yl)(2-(6-chlorobenzo[-
d]isoxazol-3-yl) pyrrolidin-1-yl) methanone [5j]
(406.37) C: 56.16, H: 3.72, N: 27.57, Found C: 56.10, H: 3.70, Yield: 72%; mp 136–137 ꢁC; IR (umax/cmꢂ1): 3330, 3130, 2955,
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N: 27.60.