Y.-Y. Xing et al.: Substituted imidazo[4,5-b]pyridinesꢀꢂꢁꢁꢁꢀ329
+
1
19.9, 31.2, 29.3; HRMS (ESI) m/z calcd for C H N O (M+H) : 240.1137, Anal. Calcd for C H N ‧2C HF O : C, 46.36; H, 3.46; N, 12.01. Found:
14 14 3 14 14 4 2 3 2
found: 240.1139.
C, 46.23; H, 3.50; N, 12.18.
2
-Benzyl-7-chloro-1-methyl-1H-imidazo
N-(2-Benzyl-1-methyl-1H-imidazo[4,5-b]
pyridine-7-yl)-3,3-dimethylbutanamide, a
salt with trifluoroacetic acid (9)
[
4,5-b]pyridine (6)
Compound 5 (9.0 g, 37.6 mmol) was dissolved in POCl (160 mL) and
the solution stirred under reflux overnight. Af er cooling, the mix-
ture was concentrated and the residue dissolved in ethyl acetate
3
To a solution of 6 (200 mg, 0.78 mmol), 3,3-dimethylbutanamide
(
104 mg, 0.9 mmol) and Pd (dba) (13 mg, 0.01 mmol) in 1,4-dioxane
2 3
(
(
600 mL). The solution was washed with saturated aqueous NaHCO3
200 mL ꢀ× ꢀ 2) and brine (200 mL ꢀ× ꢀ 2), dried over Na SO , filtered,
and concentrated. The residue was purified by silica gel chroma-
(7 mL) was added Cs CO (507 mg, 1.56 mmol) and xantphos (9 mg,
2
3
2
4
0.01 mmol) under nitrogen atmosphere. The resulting mixture was
stirred at 110°C for 16 h. Af er cooling, the mixture was concentrated
and the residue was dissolved in ethyl acetate (150 mL), and the solu-
tion washed with brine (30 mL ꢀ× ꢀ 3), dried over anhydrous Na SO , fil-
tography with petroleum ether/ethyl acetate (1:2) as eluent to afford
1
5
.2 g (54%) of compound 6 as a yellow solid, mp 168–170°C; H NMR
2
4
(
300 MHz, DMSO-d ): δ 3.96 (s, 3H), 4.37 (s, 2H), 7.24–7.36 (m, 6H),
6
tered, and then concentrated. The residue was purified by preparative
HPLC with 0.1% trifluoroacetic acid as additive to afford 61 mg (23%)
of 9 as an off-white salt with trifluoroacetic acid, mp 192–194°C (dec);
1
3
8
.27 (d, J ꢀ= ꢀ 5 Hz, 1H); C NMR (75 MHz, DMSO-d ): δ 154.1, 149.8, 144.7,
6
1
39.5, 133.6, 129.3, 128.8, 126.2, 124.7, 120.3, 32.2, 31.5; HRMS (ESI) m/z
+
calcd for C H ClN (M+H) : 258.0798, found: 258.0793.
1
14
13
3
H NMR (300 MHz, CDCl ) δ 1.09 (s, 9H), 2.49 (s, 2H), 3.91 (s, 3H), 4.23
3
(
s, 2H), 7.14–7.33 (m, 5H), 7.59–7.71 (m, 2H), 8.62 (br, 1H), 10.53 (s, 1H);
1
3
C NMR (75 MHz, CDCl ): δ 174.1, 149.7, 145.4, 138.6, 137.0, 127.5, 127.1,
3
1
(
26.7, 126.1, 117.9, 115.2, 52.5, 33.1, 31.8, 31.3, 29.2; LC-MS: m/z 336.5
2
-Benzyl-7-benzylamino-1-methyl-
+
+
M) ; HRMS (ESI) m/z calcd for C H N O (M+H) : 337.2028, found:
20 25 4
1
H-imidazo[4,5-b]pyridine (7)
3
37.2022. Anal. Calcd for C H N O‧C HF O : C, 58.66; H, 5.59; N, 12.44.
20 24 4 2 3 2
Found: C, 58.78; H, 5.71; N, 12.52.
To a solution of 6 (1.0 g, 3.9 mmol), benzylamine (0.46 g, 4.3 mmol)
and Pd (dba) (0.36 g, 0.39 mmol) in 1,4-dioxane (25 mL) was added
2
3
Cs CO (1.9 g, 0.59 mmol) and xantphos (0.67 g, 1.16 mmol) under
2
3
nitrogen atmosphere. The mixture was stirred at 90–100°C for 16 h.
Af er cooling, the mixture was concentrated and the residue was puri-
fied by flash column chromatography with dichloromethane/metha-
N-(2-Benzyl-1-methyl-1H-imidazo[4,5-b]
pyridine-7-yl)-3-cyclohexylpropanamide, a
nol (10:1) as eluent to afford 1.2 g (94%) of compound 7 as a yellow salt with trifluoroacetic acid (10)
1
solid, mp 203–205°C; H NMR (400 MHz, DMSO-d ): δ 3.98 (s, 3H), 4.27
6
(
s, 2H), 4.44 (d, J ꢀ= ꢀ 6 Hz, 2H), 6.17 (d, J ꢀ= ꢀ 6 Hz, 1H), 6.75 (t, J ꢀ= ꢀ 5 Hz, 1H), To a solution of 6 (200 mg, 0.76 mmol), 3-cyclohexylpropanamide
13
(118 mg, 0.76 mmol) and Pd (dba) (14 mg, 0.01 mmol) in 1,4-dioxane
7
.20–7.42 (m, 10H), 7.83 (d, J ꢀ= ꢀ 6 Hz, 1H); C NMR (100 MHz, DMSO-d ):
2 3
6
δ 158.3, 152.2, 146.4, 140.2, 137.2, 128.6, 127.6, 127.3, 127.1, 126.8, 126.1, (5 mL) was added Cs
CO (493 mg, 1.52 mmol) and xantphos (9 mg,
3
2
+
0.01 mmol) under nitrogen atmosphere. The mixture was stirred
at 110°C for 16 h. Af er cooling, the mixture was concentrated and
the residue was dissolved in ethyl acetate (150 mL). The solution
was washed with brine (30 mL ꢀ× ꢀ 3), dried over anhydrous Na SO ,
1
(
25.8, 118.9, 116.2, 58.2, 33.0, 31.8; LC-MS: m/z 329.2 (M+1) ; HRMS
+
ESI) m/z calcd for C H N (M+H) : 329.1766, found: 329.1762.
21 21 4
2
4
filtered, and then concentrated under reduced pressure. The resi-
due was purified by preparative HPLC with 0.1% trifluoroacetic
acid as additive to afford 81 mg (28%) of 10 as a yellow salt with
2
-Benzyl-1-methyl-1H-imidazo[4,5-b]
pyridine-7-amine, a salt with trifluoroacetic
acid (8)
1
trifluoroacetic acid, mp 197–199°C (dec); H NMR (400 MHz, CDCl ) δ
3
0.78–0.86 (m, 2H), 1.03–1.18 (m, 5H), 1.50–1.63 (m, 6H), 2.51 (m, 2H),
3
.85 (s, 3H), 4.22 (s, 2H), 7.06–7.22 (m, 5H), 7.65 (s, 1H), 7.92 (s, 1H),
1
3
To a solution of 7 (0.6 g, 1.8 mmol) in a mixture of MeCN (10 mL) 10.14 (br, 1H), 10.53 (br, 1H); C NMR (100 MHz, CDCl ): δ 176.3, 150.1,
3
and H O (2 mL) was added CAN (3.0 g, 5.5 mmol), and the mixture 146.3, 138.3, 137.2, 127.4, 127.1, 126.7, 125.9, 116.8, 115.4, 36.8, 34.6, 32.9,
2
+
was stirred at 8–14°C overnight. The mixture was concentrated and 32.7, 32.3, 31.6, 26.1. 25.7; LC-MS: m/z 376.9 (M+1) ; HRMS (ESI) m/z
+
the residue was treated with water (10 mL) and dichloromethane calcd for C H N O (M+H) : 377.2341, found: 377.2337. Anal. Calcd
2
3
29
4
(
(
10 mL). The resultant solid was filtered, suspended in methanol for C H N O‧C HF O : C, 61.21; H, 5.96; N, 11.42. Found: C, 61.35; H,
23 28 4 2 3 2
30 mL), and the mixture was stirred for 10 min. Af er filtration the 6.06; N, 11.53.
filtrate was collected and then concentrated. The residue was puri-
fied by preparative HPLC with 0.1% trifluoroacetic acid as additive
to afford 0.19 g (44%) of 8 as a yellow salt with trifluoroacetic acid, Acknowledgment: We are grateful for the financial sup-
1
mp 186–188°C (dec); H NMR (400 MHz, DMSO-d ): δ 4.01 (s, 3H), port from Shanghai Training Program Foundation for the
6
4
.35 (s, 2H), 6.61 (d, J ꢀ= ꢀ 7 Hz, 1H), 7.25–7.36 (m, 5H), 7.95–8.01 (m, 3H),
Talents (yyy11026).
1
3
1
4.03 (br, 1H); C NMR (100 MHz, DMSO-d ): δ 151.1, 149.4, 146.2, 137.3,
6
+
1
27.6, 127.3, 127.1, 126.2, 118.6, 115.3, 33.2, 31.4; LC-MS: m/z 239.2 (M+1) ;
+
HRMS (ESI) m/z calcd for C H N (M+H) : 239.1297. Found: 239.1299. Received April 10, 2013; accepted May 24, 2013
14
15
4
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