148
N. Masurier et al. / European Journal of Medicinal Chemistry 52 (2012) 137e150
M.p. 139e141 ꢁC; 1H NMR (400 MHz)
d
1.30 (t, 6H,
4.1.10.9. Diethyl N-(2-(30-methoxyphenyl)imidazo[1,2-a]pyridin-8-
J ¼ 7.0 Hz), 2.35 (s, 3H), 4.25 (q, 4H, J ¼ 7.0 Hz), 6.83 (d, 1H,
J ¼ 7.0 Hz), 7.10 (s, 1H), 7.25 (s, 1H), 7.95 (d, 1H, J ¼ 7.0 Hz), 8.45
(d, 1H, J ¼ 13.0 Hz), 10.95 (d, 1H, J ¼ 13.0 Hz); 13C NMR (100 MHz)
yl)aminomethylenemalonate (31j). From 30j; Reaction time: 27 h;
Yield: 58%; M.p. 165e170 ꢁC; 1H NMR (400 MHz)
d 1.47 (m, 6H),
3.88 (s, 3H), 4.33 (q, 2H, J ¼ 7.0 Hz), 4.41 (q, 2H, J ¼ 7.0 Hz), 6.78 (t,
1H, J ¼ 7.0 Hz), 6.86 (d, 1H, J ¼ 7.0 Hz), 6.91 (d, 1H, J ¼ 8.0 Hz); 7.36
(t,1H, J ¼ 8.0 Hz), 7.61 (m, 2H), 7.90 (m, 2H), 9.37 (d,1H, J ¼ 13.6 Hz),
d
13.6, 14.2, 14.4, 53.4, 60.3, 60.6, 95.1, 101.0, 104.4,
109.1, 126.3, 136.1, 144.6, 145.2, 150.7, 165.1, 168.9. ESI-MS:
[M þ H]þ ¼ 318.14; [M þ H]þ
¼ 318.14.
11.46 (d, 1H, J ¼ 13.6 Hz); 13C NMR (100 MHz)
d 14.4, 14.5, 55.3, 60.3,
60.6, 97.7, 106.3, 109.5, 111.7, 112.3, 113.6, 118.6, 120.8, 128.6, 129.7,
134.7, 138.8, 145.3, 151.2, 160.0, 165.7, 168.0.
req
found
4.1.10.3. Diethyl
methylenemalonate (27h). From 26h; Reaction time: 21 h; Yield:
81%; M.p. 116e118 ꢁC; 1H NMR (200 MHz)
1.41 (m, 6H), 2.52 (s,
N-(2-isopropylimidazo[1,2-a]pyridin-7-yl)amino-
d
4.1.11. General method for the synthesis of 2-substituted
6H), 4.38 (m, 6H), 6.70 (m, 6H), 7.37 (s, 2H), 8.11 (d, 2H, J ¼ 7.3 Hz),
7-aminooimidazo[1,2-a]pyridine derivatives 28(fej) and 32(gej)
Method A: An appropriate malonate derivative 27(fej) or
31(gej) (3.30 mmol) was added to dry 1,2-dichlorobenzene
(50 mL), and the solution was heated at 180 ꢁC for 4 h. After
cooled at room temperature, the solvent was removed in vacuo and
the residue was washed with methylene chloride. Method B: The
appropriate ethyl malonate derivative 27(fej) or 31(gej)
(0.49 mmol) was dissolved in 2.79 g of polyphosphoric acid (PPA).
Then, 27.75 mmol of POCl3 were added dropwise. The reaction
mixture was heated at 100 ꢁC (external temperature during the
appropriate period of time). After cooled to room temperature,
3 mL of ethanol were added and the solvent was evaporated under
reduce pressure. The crude product was dissolved in 5 mL of water
and basified with a saturated solution of Na2CO3 (pH ¼ 8). The
precipitate was filtered off and poured onto 20 mL of ethanol. The
mixture was evaporated to dryness.
8.58 (d, 2H, J ¼ 13.3 Hz), 11.13 (d, 1H, J ¼ 13.3 Hz); 13C NMR
(100 MHz)
d 14.3, 14.4, 60.3, 60.8, 95.1, 101.0, 104.5, 109.1, 126.3,
136.1, 144.6, 145.2, 150.7, 165.1, 168.9. ESI-MS: [M þ H]þ ¼ 346.17;
req
[M þ H]þ
¼ 346.17.
found
4.1.10.4. Diethyl
methylenemalonate (27i). From 26i; Reaction time: 21 h; Yield:
76%; M.p. 189e191 ꢁC; 1H NMR (200 MHz, DMSO-d6)
1.36 (m, 6H),
N-(2-phenylimidazo[1,2-a]pyridin-7-yl)amino-
d
4.31 (m, 4H), 6.62 (dd, 1H, J ¼ 7.2 Hz, J ¼ 1.8 Hz), 7.29e7.47 (m, 5H),
7.78 (s, 1H), 7.92 (d, 2H, J ¼ 7.9 Hz), 8.06 (d, 1H, J ¼ 7.3 Hz), 8.51 (d,
1H, J ¼ 13.3 Hz), 11.03 (d, 1H, J ¼ 13.3 Hz); 13C NMR (100 MHz)
d
14.3, 14.4, 60.4, 60.8, 95.6, 101.5, 105.6, 107.7, 126.0, 126.7, 128.2,
128.8, 133.3, 136.7, 145.9, 146.9, 150.4, 165.0, 168.9. ESI-MS:
[M þ H]þ ¼ 380.16; [M þ H]þ
¼ 380.16.
req
found
4.1.10.5. Diethyl N-(2-(30-methoxyphenyl)imidazo[1,2-a]pyridin-7-
yl)aminomethylenemalonate (27j). From 26j; Reaction time: 17 h;
4.1.11.1. Ethyl 10-oxo-7,10-dihydroimidazo[2,1-f]-1,6-naphthyridine-
Yield: 58%; M.p. 174e176; 1H NMR (400 MHz)
d
1.30 (m, 6H), 4.22
8-carboxylate (28f). From 27f; Method A; Reaction time: 21 h;
(m, 4H), 3.80 (s, 3H), 6.57 (dd,1H, J ¼ 7.0 Hz, J ¼ 1.0 Hz), 6.82 (dd,1H,
J ¼ 8.0 Hz, J ¼ 1.3 Hz), 7.26 (m, 1H), 7.28 (m, 1H), 7.40 (d, 1H,
J ¼ 6.8 Hz), 7.45 (m, 1H), 7.71 (s, 1H), 8.00 (d, 1H, J ¼ 7.0 Hz), 8.44 (d,
1H, J ¼ 13.2 Hz), 10.90 (d, 1H, J ¼ 13.2 Hz); 13C NMR (100 MHz)
Yield: 90%; M.p. 139e141 ꢁC; 1H MNR (400 MHz)
d 1.30 (t, 3H,
J ¼ 7.1 Hz); 4.26 (q, 2H, J ¼ 7.1 Hz); 7.78 (d, 1H, J ¼ 7.3 Hz); 8.01 (m,
1H); 8.45 (m,1H); 8.71 (s,1H); 8.98 (d, J ¼ 7.3 Hz); 14.3 (brs,1H); 13C
NMR (100 MHz) d 14.2; 60.4; 109.5; 110.4; 115.2; 116.1; 112.2; 132.0;
d
14.3, 14.4, 55.4, 60.8, 61.1, 100.9, 105.7, 108.0, 111.0, 114.4, 118.4,
136.8; 142.2; 144.8; 163.6; 171.3. ESI-MS: [M þ H]þ ¼ 258.09;
req
126.7, 129.8, 134.6, 136.8, 146.6, 148.4, 150.3, 160.1, 165.0, 168.9. ESI-
[M þ H]þ
¼ 258.07.
found
MS: [M þ H]þ ¼ 410.17; [M þ H]þ
¼ 410.17.
req
found
4.1.11.2. Ethyl
naphthyridine-8-carboxylate (28g). From 27g; Method B; Reaction
time: 6 h; Yield: 53%; M.p. 269e271 ꢁC; 1H NMR (400 MHz)
1.31
(t, 3H, J ¼ 7.0 Hz), 4.29 (q, 2H, J ¼ 7.0 Hz), 7.83 (s, 1H), 8.21 (s, 1H),
8.67 (s, 1H), 8.99 (s, 1H), 14.42 (s, 1H); 13C NMR (100 MHz)
10.4,
2-methyl-10-oxo-7,10-dihydroimidazo[2,1-f]-1,6-
4.1.10.6. Diethyl N-(2-methylimidazo[1,2-a]pyridin-8-yl)aminomethyle-
nemalonate (31g). From 30g; Reaction time: 24 h; Yield: 54%; M.p.
d
120e121 ꢁC; 1H NMR (400 MHz)
d 1.39 (m, 6H), 2.48 (s, 3H), 4.33 (m,
4H), 6.72 (m, 1H), 6.84 (d, 1H, J ¼ 7.0 Hz), 7.38 (s, 1H), 7.82 (d, 1H,
d
J ¼ 7.0 Hz), 9.04 (d, 1H, J ¼ 13.4 Hz), 11.47 (d, 1H, J ¼ 13.4 Hz); 13C NMR
14.1, 60.3, 109.0, 110.2, 112.7, 114.8, 131.5, 132.7, 136.5, 141.7, 144.6,
(100 MHz)
d
14.1, 14.3, 14.4, 60.2, 60.6, 95.6, 105.0, 111.0, 111.6, 120.5,
163.7, 171.3. ESI-MS: [M þ H]þ ¼ 272.10; [M þ H]þ
¼ 271.56.
req
found
128.1, 138.4, 143.4, 150.7, 165.7, 168.1.
4.1.11.3. Ethyl
naphthyridine-8-carboxylate (28h). From 27h; Method B; Reaction
time: 6 h; Yield: 59%; M.p. 264e266 ꢁC; 1H NMR (400 MHz)
1.31
2-isopropyl-10-oxo-7,10-dihydroimidazo[2,1-f]-1,6-
4.1.10.7. Diethyl
N-(2-isopropylimidazo[1,2-a]pyridin-8-yl)amino-
methylenemalonate (31h). From 30h; Reaction time: 5 h; Yield:
d
34%; M.p. 102e103 ꢁC; 1H NMR (400 MHz)
d
1.36 (t, 3H, J ¼ 7.0 Hz),
(m, 9H), 3.32 (m, 1H), 4.30 (q, 2H, J ¼ 7.1 Hz), 7.74 (d, 1H, J ¼ 7.3 Hz),
1.38 (d, 6H, J ¼ 7.0 Hz), 1.43 (t, 3H, J ¼ 7.0 Hz), 3.12 (sept, 1H,
J ¼ 7.0 Hz), 4.27 (q, 2H, J ¼ 7.0 Hz), 4.37 (q, 2H, J ¼ 7.0 Hz), 6.70 (t,1H,
J ¼ 6.8 Hz), 6.81 (dd, 1H, J ¼ 6.8 Hz, J ¼ 1.0 Hz), 7.36 (s, 1H), 7.82 (dd,
1H, J ¼ 6.8 Hz, J ¼ 1.0 Hz), 9.27 (d, 1H, J ¼ 13.0 Hz), 11.32 (d, 1H,
8.25 (s, 1H), 8.67 (s, 1H), 8.92 (d, 1H, J ¼ 7.3 Hz), 14.3 (brs, 1H); 13C
NMR (100 MHz)
d 14.2; 21.6; 25.0; 60.4; 109.2; 110.4; 111.0;
114.9; 131.6; 136.7; 141.9; 143.1; 144.8; 163.7; 171.3. ESI-MS:
[M þ H]þ ¼ 300.13; [M þ H]þ
¼ 300.02.
req
found
J ¼ 13.0 Hz); 13C NMR (100 MHz)
d 14.3, 14.4, 22.4, 28.4, 60.2, 60.5,
95.4, 105.6, 108.8, 111.5, 120.7, 128.2, 138.2, 151.2, 154.2, 165.8, 168.0.
4.1.11.4. Ethyl
naphthyridine-8-carboxylate (28i). From 27i; Method B; Reaction
time: 6 h; Yield: 53%; M.p. 263e265 ꢁC; 1H NMR (400 MHz)
1.20
2-phenyl-10-oxo-7,10-dihydroimidazo[2,1-f]-1,6-
4.1.10.8. Diethyl
methylenemalonate (31i). From 30i; Reaction time: 26 h; Yield:
81%; M.p. 149e150 ꢁC; 1H NMR (400 MHz)
1.45 (m, 6H), 4.33 (q,
N-(2-phenylimidazo[1,2-a]pyridin-8-yl)amino-
d
(t, 3H, J ¼ 7.0 Hz), 2.36 (s, 3H), 4.16 (q, 2H, J ¼ 7.0 Hz), 7.41 (m, 3H),
d
7.69 (d, 1H, J ¼ 7.0 Hz), 7.85 (m, 2H), 8.60 (s, 1H), 8.70 (s, 1H), 8.82 (d,
2H, J ¼ 7.0 Hz), 4.42 (q, 2H, J ¼ 7.0 Hz), 6.75 (t,1H, J ¼ 7.0 Hz), 6.81 (d,
1H, J ¼ 7.0 Hz), 7.36 (t,1H, J ¼ 7.0 Hz), 7.45 (t, 2H, J ¼ 7.0 Hz), 7.88 (m,
2H), 8.04 (d, 2H, J ¼ 7.0 Hz), 9.42 (d, 1H, J ¼ 13.6 Hz), 11.49 (d, 1H,
1H, J ¼ 7.0 Hz); 13C NMR (100 MHz)
d 14.2, 60.4, 109.8, 110.5, 112.6,
115.0, 126.1, 127.6, 128.9, 130.1, 131.8, 135.3, 137.9, 142.3, 144.9, 163.6,
171.3. ESI-MS: [M þ H]þ ¼ 334.12; [M þ H]þ
¼ 334.01.
req
found
J ¼ 13.6 Hz); 13C NMR (100 MHz)
d 14.4, 14.5, 60.2, 60.6, 95.6, 106.4,
109.2, 112.3, 120.8, 126.0, 128.2, 128.6, 128.7, 133.3, 138.8, 145.5,
151.4, 165.6, 168.2.
4.1.11.5. Ethyl
[2,1-f]-1,6-naphthyridine-8-carboxylate (28j). Method B; From 27j;
2-(30-methoxyphenyl)-10-oxo-7,10-dihydroimidazo