A. Shaabani et al. / Tetrahedron Letters 50 (2009) 6355–6357
6357
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Tashima, M.; Kajikawa, F.; Sato, Y.; Kashimoto, S.; Chiba, K.; Hino, K. J. Med.
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9. (a) Coussens, L. M.; Werb, Z. Nature 2002, 420, 860–867; (b) Grossi, G.; Di
Braccio, M.; Roma, G.; Ballabeni, V.; Tognolini, M.; Barocelli, E. Eur. J. Med. Chem.
2005, 40, 155–165; (c) Dianzani, C.; Collino, M.; Gallicchio, M.; Di Braccio, M.;
Roma, G.; Fantozzi, R. J. Inflamm. 2006, 3, 4.
13C NMR (75.47 MHz, DMSO-d6) d 17.4, 21.2 (CH3), 42.2 (CH2), 90.1 (CH),
114.6, 122.7, 125.9, 126.7, 127.3, 128.3, 129.2, 129.9, 130.7, 134.0, 136.8,
138.4, 138.9, 144.5, 145.6 (C-Ar and C@C), 148.9, 166.8 (CO). MS m/z: 297 (M+-
106, 6), 271 (10), 229 (14), 172 (15), 106 (100), 91 (80), 65 (42). Anal. Calcd for
C24H22ClN3O: C, 71.37; H, 5.49; N, 10.40. Found: C, 71.25; H, 5.43; N, 10.35.
N-Benzyl-6-bromo-4-(4-chlorophenyl)-2-methyl-1,4-dihydro-1,8-naphthyridine-
3-carboxamide 5c: White powder (0.33 g, 71%): mp 170–171 °C. IR (KBr) cmÀ1
:
3342, 3177, 3108, 2924, 1675, 1652, 1566, 1490, 1374. 1H NMR (300.13 MHz,
DMSO-d6) d 2.28 (3H, s, CH3), 4.34–4.39 (2H, m, CH2), 6.41 (1H, s, CH), 7.08–
8.20 (11H, m, H-Ar), 9.01 (1H, br s, NH), 9.97 (1H, br s, NH). 13C NMR
(75.47 MHz, DMSO-d6) d 21.2 (CH3), 42.8 (CH2), 103.2 (CH), 111.2, 115.3,
125.9, 128.6, 128.9, 129.1, 129.8, 131.9, 132.8, 134.4, 135.2, 138.4, 138.8,
145.7, 146.0 (C-Ar and C@C), 156.0, 167.0 (CO). MS m/z: 361 (M+-106, 6), 333
(12), 295 (35), 202 (8), 174 (30), 157 (50), 106 (100), 91 (84), 65 (34). Anal.
Calcd for C23H19BrClN3O: C, 58.93; H, 4.09; N, 8.96. Found: C, 58.97; H, 4.16; N,
8.89.
2-Methyl-N-(4-methylbenzyl)-4-p-tolyl-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide 5d: White powder (0.26 g, 67%): mp 159–161 °C. IR (KBr) cmÀ1: 3416,
3328, 3113, 2916, 1678, 1653, 1574, 1439, 1379. 1H NMR (300.13 MHz, DMSO-
d6) d 2.23 (3H, s, CH3), 2.28 (3H, s, CH3), 2.37 (3H, s, CH3), 4.22–4.34 (2H, m,
3
CH2), 5.01 (1H, br s, CH), 6.57 (2H, d, JHH = 7.7 Hz, H-Ar), 6.90 (2H, d,
3JHH = 7.6 Hz, H-Ar), 6.96–7.48 (5H, m, H-Ar), 7.83–7.91 (1H, m, H-Ar), 8.26–
8.36 (2H, m, H-Ar and NH), 8.43 (1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6)
d 21.1 (CH3), 21.3 (CH3), 25.0 (CH3), 53.2 (CH2), 90.3 (CH), 113.3, 114.9, 125.9,
126.9, 128.6, 128.9, 129.8, 132.2, 135.9, 138.3, 138.8, 145.9 (C-Ar and C@C),
150.4, 166.8 (CO). MS m/z: 263 (M+-120, 14), 223 (6), 195 (30), 172 (18), 145
(16), 120 (100), 105 (32), 91 (60), 79 (82), 65 (30). Anal. Calcd for C25H25N3O: C,
78.30; H, 6.57; N, 10.96. Found: C, 78.38; H, 6.53; N, 10.91.
10. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005; (b) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210; (c)
Ganem, B. Acc. Chem. Res. 2009, 42, 463–472.
11. (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem. 2007, 72, 6309–6311;
(b) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J. J. Org. Chem. 2008,
73, 3925–3927; (c) Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.; Rezazadeh, F.;
Behnam, M. J. Comb. Chem. 2009, 11, 375–377; (d) Shaabani, A.; Seyyedhamzeh,
M.; Maleki, A.; Behnam, M.; Rezazadeh, F. Tetrahedron Lett. 2009, 50, 2911–
2913.
6-Bromo-4-(4-fluorophenyl)-2-methyl-N-(4-methylbenzyl)-1,4-dihydro-1,8-naph-
thyridine-3-carboxamide 5e: White powder (0.33 g, 71%): mp 157–159 °C. IR
(KBr) cmÀ1: 3344, 3178, 3008, 2925, 1675, 1569, 1508, 1437, 1375. 1H NMR
(300.13 MHz, DMSO-d6) d 2.23 (3H, s, CH3), 2.29 (3H, s, CH3), 4.20–4.34 (2H, m,
CH2), 5.07 (1H, br s, CH), 6.55 (2H, d, 3JHH = 7.5 Hz, H-Ar), 6.90–7.64 (8H, m, H-
Ar), 8.38 (1H, br s, NH), 9.95 (1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6) d
21.2 (CH3), 21.6 (CH3), 42.6 (CH2), 92.8 (CH), 111.5, 117.4, 123.9, 126.9, 127.4,
128.9, 129.7, 129.9, 133.2, 134.8, 136.3, 137.5, 138.8, 143.4, 146.5 (C-Ar and
C@C), 152.7, 168.7 (CO). MS m/z: 345 (M+-120, 4), 317 (14), 280 (6), 238 (8),
212 (12), 172 (48), 120 (100), 105 (30), 91 (55), 65 (28). Anal. Calcd for
C24H21BrFN3O: C, 61.81; H, 4.54; N, 9.01. Found: C, 61.86; H, 4.59; N, 9.08.
2-Methyl-N-(4-methylbenzyl)-4-(3-nitrophenyl)-1,4-dihydro-1,8-naphthyridine-
12. Typical procedure for the synthesis of N-benzyl-4-(4-chlorophenyl)-2-methyl-1,4-
dihydro-1,8-naphthyridine-3-carboxamide (5a):
A solution of benzylamine
(0.107 g, 1.0 mmol) and diketene (0.084 g, 1.0 mmol) was magnetically
stirred in 5 mL of dry CH2Cl2 for 2 h. Then, 4-chlorobenzaldehyde (0.140 g,
1.0 mmol), 2-aminopyridine (0.094 g, 1.0 mmol), and p-TsOHÁH2O (0.019 g,
0.1 mmol) were added simultaneously. The reaction mixture was allowed to
stir for 8 h until a precipitate appeared. After completion of the reaction, as
indicated by TLC (EtOAc:n-hexane, 1:2), the reaction mixture was filtered and
the residue was washed with water and then with ethanol and dried in vacuo
to give 5a.
3-carboxamide 5f: White powder (0.32 g, 77%): mp 147–149 °C. IR (KBr) cmÀ1
:
3391, 3267, 3083, 2924, 1715, 1642, 1603, 1554, 1519, 1480, 1419. 1H NMR
(300.13 MHz, DMSO-d6) d 2.21 (3H, s, CH3), 2.23 (3H, s, CH3), 4.07–4.29 (2H, m,
CH2), 5.81–5.90 (1H, m, CH), 6.43–8.09 (11H, m, H-Ar), 8.29 (1H, br s, NH), 8.73
(1H, br s, NH). 13C NMR (75.47 MHz, DMSO-d6) d 21.1 (CH3), 28.7 (CH3), 42.5
(CH2), 109.3 (CH), 113.1, 122.2, 122.5, 122.6, 127.0, 127.3, 128.0, 128.9, 129.2,
129.9, 135.4, 136.1, 144.6, 148.0 (C-Ar and C@C), 157.9, 165.6 (CO). MS m/z:
323 (M+-91,10), 226 (6), 202 (12), 176 (20), 160 (12), 120 (100), 105 (18), 91
(12), 79 (22), 65 (25). Anal. Calcd for C24H22N4O3: C, 69.55; H, 5.35; N, 13.52.
Found: C, 69.51; H, 5.33; N, 13.57.
N-Benzyl-4-(4-chlorophenyl)-2-methyl-1,4-dihydro-1,8-naphthyridine-3-carbox-
amide 5a: White powder (0.28 g, 73%): mp 167–169 °C. IR (KBr) cmÀ1: 3463,
3335, 3069, 2916, 1654, 1565, 1491, 1448, 1388. 1H NMR (300.13 MHz,
DMSO-d6) d 2.28 (3H, s, CH3), 4.32–4.42 (2H, m, CH2), 5.44 (1H, s, CH), 6.60–
6.65 (2H, m, H-Ar), 7.00–7.16 (3H, m, H-Ar), 7.41–7.48 (3H, m, H-Ar), 7.84–
7.93 (2H, m, H-Ar), 8.26–8.51 (3H, m, H-Ar and NH), 9.74 (1H, br s, NH). 13C
NMR (75.47 MHz, DMSO-d6) d 21.3 (CH3), 42.2 (CH2), 90.3 (CH), 113.5, 114.9,
125.9, 126.7, 128.4, 128.7, 129.2, 129.9, 132.2, 134.0, 136.6, 138.5, 138.9,
142.4, 145.5 (C-Ar and C@C), 150.4, 166.7 (CO). MS m/z: 389 (M+, 2), 302 (15),
283 (25), 255 (45), 218 (30), 172 (32), 107 (50), 91 (100), 65 (46). Anal. Calcd
for C23H20ClN3O: C, 70.85; H, 5.17; N, 10.78. Found: C, 70.73; H, 5.23; N, 10.75.
N-Benzyl-4-(4-chlorophenyl)-2,6-dimethyl-1,4-dihydro-1,8-naphthyridine-3-car-
6-Bromo-4-(4-bromophenyl)-2-methyl-N-propyl-1,4-dihydro-1,8-naphthyridine-
3-carboxamide 5g: White powder (0.35 g, 76%): mp 164–166 °C. IR (KBr) cmÀ1
:
3374, 3335, 3066, 2963, 1711, 1659, 1592, 1548, 1479, 1408, 1366. 1H NMR
(300.13 MHz, DMSO-d6) d 0.48–0.74 (3H, m, CH3), 1.23–1.33 (2H, m, CH2), 2.09
(3H, s, CH3), 2.90–3.01 (2H, m, CH2), 5.60 (1H, br s, CH), 6.43–6.57 (1H, m, H-
Ar), 7.25–7.52 (5H, m, H-Ar), 7.92–8.00 (1H, m, NH), 8.06–8.14 (1H, m, NH). 13C
NMR (75.47 MHz, DMSO-d6) d 11.6, 22.2, 22.5, 28.3, 29.2 (CH3, CH2), 106.4
(CH), 111.2, 120.4, 120.6, 129.9, 130.2, 131.4, 132.1, 139.6, 141.2, 141.4, 148.1
(C-Ar and C@C), 156.7, 167.2 (CO). MS m/z: 377 (M+-86, 14), 339 (18), 157
(100), 102 (10), 78 (32), 57 (25). Anal. Calcd for C19H19Br2N3O: C, 49.06; H,
4.12; N, 9.03. Found: C, 49.01; H, 4.19; N, 9.09.
boxamide 5b: White powder (0.28 g, 69%): mp 178–179 °C. IR (KBr) cmÀ1
:
3332, 3117, 2928, 1678, 1588, 1565, 1491, 1450, 1379. 1H NMR (300.13 MHz,
DMSO-d6) d 2.23 (3H, s, CH3), 2.28 (3H, s, CH3), 4.33–4.45 (2H, m, CH2), 5.06
(1H, br s, CH), 6.63 (2H, d, 3JHH = 6.2 Hz, H-Ar), 6.98 (1H, d, 3JHH = 8.9 Hz, H-Ar),
7.07–7.16 (2H, m, H-Ar), 7.41–7.51 (3H, m, H-Ar), 7.76 (1H, d, 3JHH = 8.8 Hz, H-
Ar), 8.13 (1H, br s, H-Ar), 8.40–8.46 (2H, m, H-Ar and NH), 9.58 (1H, br s, NH).