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E. Moine et al. / European Journal of Medicinal Chemistry 89 (2015) 386e400
under reduced pressure. The crude product was finally chromato-
graphed on silica gel eluting with dichloromethane/petroleum
ether (20/80 v/v) to give 46% of 4b as colorless oil.
bromophenyl)-3,3-dimethylbutan-2-one 5b as starting materials.
The crude residue was chromatographed on neutral alumina
eluting with CH2Cl2 to give 7c in 50% yield.
1H NMR (200 MHz, CDCl3)
d
7.40 (d,1H, J ¼ 7.6 Hz, Ph-4), 7.36 (m,
Mp 193 ꢁC. 1H NMR (300 MHz, CDCl3)
d 7.67e7.62 (m, 3H), 7.58
1H, Ph-2), 7.21 (t, 1H, J ¼ 7.6 Hz, Ph-5), 7.13 (d, 1H, J ¼ 7.6 Hz, Ph-6),
(t, 1H, J ¼ 1.5 Hz, Br-Ph-2), 7.42e7.33 (m, 4H), 7.31 (dd, 1H, J ¼ 3.0,
3.80 (s, 2H, CH2), 1.24 (s, 9H, 3 ꢂ CH3). 13C NMR (50 MHz, CDCl3)
1.5 Hz, Th-2), 7.17 (dd, 1H, J ¼ 5.1, 1.5 Hz, Th-4), 1.32 (s, 9H, 3 ꢂ CH3).
d
211.8,137.2,132.5,129.7,129.6,128.3,122.1, 44.5, 42.5, 26.2 (3 ꢂ C).
13C NMR (75 MHz, CDCl3)
d 153.1, 142.4, 138.3, 135.0, 133.5, 132.4,
130.8,130.6,126.9,125.9,124.6, 123.0,121.7, 120.7, 119.7,118.6,116.9,
5.2.10. 2-(3-Bromophenyl)-1-(2-methoxyphenyl)ethanone (4c)
Compound 4c was synthesized following the general method D,
using N,2-dimethoxy-N-methylbenzamide 3b as starting material.
The crude residue was chromatographed on silica gel eluting with
petroleum ether/ethyl acetate (gradient from 100/0 to 70/30 v/v) to
give 71% of 4c as yellow oil.
33.7, 31.3 (3 ꢂ C).
5.2.14. 3-(3-Bromophenyl)-2-(2-methoxyphenyl)-6-(thien-3-yl)
imidazo[1,2-a]pyridine (7e)
Compound 7e was synthesized following the general method E,
using 5-(thien-3-yl)pyridin-2-amine 6b and 2-bromo-2-(3-
bromophenyl)-1-(2-methoxyphenyl)ethanone 5c as starting ma-
terials. The crude residue was chromatographed on neutral
alumina eluting with CH2Cl2 to give 7e in 16% yield.
1H NMR (300 MHz, CDCl3)
d
7.70 (dd, 1H, J ¼ 7.8, 1.8 Hz, CH3OPh-
6), 7.46 (ddd, 1H, J ¼ 9.0, 7.2, 1.8 Hz, CH3OPh-4), 7.40e7.33 (m, 2H,
Br-Ph-2,5), 7.16 (m, 2H, Br-Ph-4,6), 7.02e6.94 (m, 2H, CH3OPh-3,5),
4.27 (s, 2H, CH2), 3.90 (s, 3H, OCH3).
Mp 241 ꢁC. 1H NMR (300 MHz, CDCl3)
d 8.34 (br s, 1H, H-5), 7.72
(dd, 1H, J ¼ 9.3, 0.6 Hz, H-8), 7.62 (dd, 1H, J ¼ 7.5, 1.8 Hz, CH3OPh-6),
7.59 (br s, 1H, Br-Ph-2), 7.53e28 (m, 8H), 7.03 (td, 1H, J ¼ 7.5, 0.9 Hz,
CH3OPh-5), 6.84 (d, 1H, J ¼ 7.8 Hz, CH3OPh-3), 3.40 (s, 3H, OCH3).
5.2.11. 5-(Fur-3-yl)pyridin-2-amine (6c)
A mixture of 5-iodopyridin-2-amine (200 mg, 0.91 mmol), fur-
3-ylboronic acid (203 mg, 1.82 mmol), Na2CO3 (204 mg, 1.93 mmol)
and tetrakis(triphenylphosphine)palladium (52 mg, 0.045 mmol) in
1,2-dimethoxyethane (4 mL) and water (2 mL) was stirred
magnetically at 120 ꢁC for 30 min in a CEM Discover microwave
apparatus. After cooling, the suspension was taken up in water,
extracted three times with CH2Cl2. The organic layer was dried with
MgSO4, and evaporated to dryness. The residue was chromato-
graphed on silica gel eluting with CH2Cl2/CH3OH (100/1 v/v) to give
68% of 6c.
13C NMR (75 MHz, CDCl3)
d 156.5, 143.7, 140.8, 138.1, 132.5, 131.9
(2 ꢂ C), 131.2, 130.5, 129.9, 127.9, 127.2, 125.9, 125.5, 122.9, 122.6,
122.2, 121.5, 121.1, 120.8, 119.5, 117.6, 111.0, 54.8.
5.2.15. 3-(3-Bromophenyl)-6-(fur-3-yl)-2-(2-methoxyphenyl)
imidazo[1,2-a]pyridine (7f)
Compound 7f was synthesized following the general method E,
using 5-(fur-3-yl)pyridin-2-amine 6c and 2-bromo-2-(3-
bromophenyl)-1-(2-methoxyphenyl)ethanone 5c as starting ma-
terials. The crude residue was chromatographed on neutral
alumina eluting with CH2Cl2 to give 7f in 18% yield.
Mp 139e141 ꢁC. 1H NMR (300 MHz, CDCl3)
d 8.19 (d, 1H,
J ¼ 2.4 Hz, Pyr-6), 7.60 (br s, 1H, Fur-2), 7.47 (dd, 1H, J ¼ 8.4, 2.4 Hz,
Pyr-4), 7.43 (dd, 1H, J ¼ 1.8, 1.5 Hz, Fur-5), 6.58 (dd, 1H, J ¼ 1.8,
Mp 99e100 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.23 (dd, 1H, J ¼ 1.5,
0.9 Hz, Fur-4), 6.48 (d, 1H, J ¼ 8.4 Hz, Pyr-3), 4.69 (br s, 2H, NH2). 13
C
0.9 Hz, H-5), 7.76e7.72 (m, 2H), 7.63e7.50 (m, 4H), 7.40e7.30 (m,
4H), 7.03 (td, 1H, J ¼ 7.5, 1.2 Hz, CH3OPh-5), 6.84 (d, 1H, J ¼ 8.4 Hz,
NMR (75 MHz, CDCl3)
108.8, 108.5.
d 157.7, 145.1, 143.7, 137.4, 135.6, 123.6, 118.7,
CH3OPh-3), 6.62 (dd, 1H, J ¼ 1.8, 0.9, Fur-4), 3.41 (s, 3H, OCH3). 13
C
NMR (75 MHz, CDCl3) d 156.5, 144.2, 143.5, 138.9, 132.3, 131.9, 131.9,
5.2.12. 3-(3-Bromophenyl)-2-(4-fluorophenyl)-6-(thien-3-yl)
imidazo[1,2-b]pyridazine (7a)
131.3, 130.6,130.0,129.2,127.9,127.1, 125.1,122.9,122.8,121.4, 120.8,
119.2, 118.8, 117.6, 111.0, 108.5, 54.8.
Method E: a mixture of 6-(thien-3-yl)pyridazin-3-amine 6a
(21 mg, 0.12 mmol), 2-bromo-2-(3-bromophenyl)-1-(4-
fluorophenyl)ethanone 5a (53 mg, 0.14 mmol), and 1,2-
dimethoxyethane (330 L) was stirred overnight at room temper-
ature. The solvent was removed under reduced pressure, the
resulting residue was then dissolved in ethanol (330 L) and
5.2.16. 3-(3-Bromophenyl)-2-(2-methoxyphenyl)-6-phenylimidazo
[1,2-a]pyridine (7g)
m
Compound 7g was synthesized following the general method E,
using
5-phenylpyridin-2-amine
6d
and
2-bromo-2-(3-
m
bromophenyl)-1-(2-methoxyphenyl)ethanone 5c as starting ma-
terials. The crude residue was chromatographed on neutral
alumina eluting with CH2Cl2 to give 7g in 47% yield.
refluxed overnight. After cooling and concentration, the residue
was suspended in water, made alkaline with Na2CO3 and extracted
three times with CH2Cl2. After drying with MgSO4, the organic
layers were evaporated to dryness. The residue was chromato-
graphed on silica gel eluting with CH2Cl2 to give 7a in quantitative
yield.
Mp 255e256 ꢁC. 1H NMR (300 MHz, CDCl3)
d 8.32 (dd, 1H,
J ¼ 1.8, 0.9 Hz, H-5), 7.77 (dd, 1H, J ¼ 9.3, 0.9 Hz, H-8), 7.64 (dd, 1H,
J ¼ 7.5, 1.8 Hz, CH3OPh-6), 7.61e7.29 (m, 11H), 7.04 (td, 1H, J ¼ 7.5,
1.2 Hz, CH3OPh-5), 6.84 (d, 1H, J ¼ 7.5 Hz, CH3OPh-3), 3.41 (s, 3H,
Mp 161e164 ꢁC. 1H NMR (300 MHz, CDCl3)
d
8.01 (d, 1H,
OCH3). 13C NMR (75 MHz, CDCl3)
d 156.5, 144.1, 141.5, 137.5, 132.8,
J ¼ 9.6 Hz, H-8), 7.94 (dd, 1H, J ¼ 1.8 Hz, Br-Ph-2), 7.86 (dd, 1H,
J ¼ 3.0, 1.5 Hz, Th-2), 7.72e7.64 (m, 3H, Th-4, F-Ph-2,6), 7.60e7.52
(m, 2H, Br-Ph-4,6), 7.50 (d, 1H, J ¼ 9.6 Hz, H-7), 7.44 (dd, 1H, J ¼ 5.1,
3.0 Hz, Th-5), 7.35 (dd, 1H, J ¼ 8.1 Hz, Br-Ph-5), 7.07 (m, 2H, F-Ph-
132.0,131.9,131.0,130.5,129.7,129.1 (2 ꢂ C),127.9,127.9,127.3,127.1
(2 ꢂ C), 125.6, 122.9, 122.8, 121.6, 120.8, 120.2, 117.7, 111.0, 54.7.
5.2.17. 2-(4-Fluorophenyl)-3-(20-hydroxybiphen-3-yl)-6-(thien-3-
yl)imidazo[1,2-b]pyridazine (8a)
3,5). 13C NMR (75 MHz, CDCl3)
d
162.8 (J ¼ 247 Hz), 147.6, 143.1,
138.2, 137.9, 133.2, 131.4, 130.8, 130.2 (2 ꢂ C, J ¼ 8 Hz), 130.1, 129.9
(J ¼ 3 Hz), 129.0, 127.1, 126.0, 125.4, 124.8, 123.4, 122.4, 116.7, 115.6
(2 ꢂ C, J ¼ 21 Hz).
Compound 8a was synthesized following the general method A,
using imidazo[1,2-b]pyridazine 7a and (2-hydroxyphenyl)boronic
acid as starting materials (100% yield).
Mp 233e235 ꢁC. 1H NMR (300 MHz, CDCl3)
d 8.06 (d, 1H,
5.2.13. 3-(3-Bromophenyl)-2-tert-butyl-6-(thien-3-yl)imidazo[1,2-
a]pyridine (7c)
Compound 7c was synthesized following the general method E,
using 5-(thien-3-yl)pyridin-2-amine 6b and 1-bromo-1-(3-
J ¼ 9.3 Hz, H-8), 7.87 (dd, 1H, J ¼ 2.7, 1.2 Hz, Th-2), 7.82 (br s, 1H,
BiPh-2), 7.76e7.40 (m, 10H), 7.29e7.22 (m, 1H), 7.09e6.96 (m, 4H).
13C NMR (75 MHz, CDCl3)
d
163.0 (J ¼ 248 Hz), 152.8, 148.4, 138.1,
137.4 (2 ꢂ C), 132.2, 132.0 (3 ꢂ C), 131.1, 130.4, 130.3 (J ¼ 3 Hz), 129.7,