256
S.D. Do gꢀ an et al. / Tetrahedron 71 (2015) 252e258
4
4
. Experimental
3287, 2979,1723,1592,1557,1413,1383,1329,1264,1179,1131,1077,
1
021. HRMS: m/z [MþNa]þ calcd for C20
20 4 6
H N O : 411.13101; found:
.1. General procedure
411.13273.
0
0
Melting points are uncorrected. Infrared (IR) spectra were
4.4. Diethyl 2,2 -(3,3 -(carbonylbis(azanediyl))bis(pyridine-
3,2-diyl))diacetate (16)
ꢁ1
1
recorded in the range 4000e600 cm via ATR diamond. The
H
13
and C NMR spectra were recorded on a 400 (100) MHz spec-
trometer. Apparent splitting is given in all cases. High resolution
mass spectra were recorded by LCeMS TOF electrospray ionization
technique. Chemicals and all solvents were commercially available
and used without further purification. Column chromatography
was performed on silica gel (60-mesh, Merck). TLC was carried out
on Merck 0.2 mm silica gel 60 F254 analytical aluminum plates.
Acyl azide (11) (640 mg, 2.56 mmol) was heated at reflux in
a mixture of benzene (20 mL) and water (2 mL) for 3 h. The solvent
was evaporated and the crude product was purified by crystalli-
zation from ethyl acetate/hexane at room temperature to give urea
ꢀ
1
16 as a white solid (390 mg, 84%), mp 147e148 C. H NMR
(400 MHz, CDCl
8.33 (dd, J¼4.7, 1.5 Hz, 2H), 8.30 (br s, 2H), 8.18
dd, J¼8.2, 1.5 Hz, 2H), 7.27 (dd, J¼8.2, 4.7 Hz, 2H), 4.19 (q, J¼7.1 Hz,
3
) d
(
13
4
.2. Ethyl 2-(3-(azidocarbonyl)pyridine-2-yl)acetate (11)
4H), 3.97 (s, 4H), 1.29 (t, J¼7.1 Hz, 6H). C NMR (100 MHz, CDCl
3
)
d
172.1, 153.2, 146.2, 145.1, 134.0, 131.9, 123.2, 61.9, 42.0, 14.01. n
max
To a solution of 2-(2-ethoxy-2-oxoethyl)nicotinic acid (10) (1.0 g,
.78 mmol) in 10 mLTHF at ꢁ5 C, triethylamine (0.7 mL, 4.78 mmol)
(ATR): 3279, 2953, 1722, 1630, 1589, 1557, 1437, 1328, 1252, 1218,
ꢀ
þ
4
1151, 1025. HRMS: m/z [MþNa] calcd for C19
22 4 5
H N O : 385.14935;
in THF (5 mL) was added dropwise and the resulting mixture was
stirred for 30 min. This was followed by slow addition of a cooled
solution of ethyl chloroformate (0.6 mL, 5.74 mmol) in THF (5 mL)
and the reaction mixture was stirred at the same temperature for
additional 30 min. A solution of sodium azide (0.62 g, 9.56 mmol) in
water (5 mL) was then added dropwise and the mixture was left to
stir at room temperature overnight. The mixture was extracted with
ethyl acetate (3ꢂ15 mL) and the organic phase was washed with
saturated sodium bicarbonate (3ꢂ30 mL) and with water (2ꢂ25 mL)
found: 385.15174.
2 3
4.5. Cyclization reaction of 16 with K CO
To a solution of urea derivative 16 (340 mg, 0.88 mmol) in
ꢀ
acetonitrile (20 mL) at 60 C was added excess K
2 3
CO (0.6 g,
4.3 mmol). After stirring for 3 h, excess K
2
CO
3
was filtered and
solvent was evaporated under reduced pressure. The formed
products were separated by column chromatography (silica gel,
EtOAc/hexane, 99:1). The fragmentation product 19 (43 mg, 36%)
was isolated as the first fraction. The major product 18 was eluted
as the second fraction (210 mg, 44%).
and dried over MgSO
1%) was obtained as pale yellow viscous liquid. H NMR (400 MHz,
CDCl
8.64 (dd, J¼4.8, 1.7 Hz, 1H), 8.20 (dd, J¼8.0, 1.7 Hz, 1H), 7.27
dd, J¼8.0, 4.8 Hz, 1H), 4.22 (s, 2H), 4.11 (q, J¼7.1 Hz, 2H), 1.19 (t,
4
. After removal of ethyl acetate azide 11 (0.91 g,
1
8
3
) d
(
1
3
21
J¼7.1 Hz, 3H). C NMR (100 MHz, CDCl
3
)
d
172.3, 170.4, 156.4, 153.1,
4.5.1. 1H-Pyrrolo[3,2-b]pyridin-2(3H)-one (19). Colorless viscous
1
1
1
38.6, 125.9, 122.4, 61.0, 43.7, 14.1. max (ATR) 2984, 2136, 1733, 1693,
n
liquid. H NMR (400 MHz, CDCl
3
)
d
9.15 (br s, 1H), 8.14 (dd, J¼2.4,
13
569, 1443, 1370, 1234, 1176, 1028.
4.4 Hz, 1H), 7.08 (br s, 1H), 7.07 (br s, 1H), 3.62 (s, 2H). C NMR
(100 MHz, CDCl
3
)
d
175.6, 148.0, 143.1, 137.6, 122.7, 115.9, 37.8.
4
.3. Thermolysis of 11 in benzene
0
0
4
.5.2. Diethyl 2,2 -(3,3 -((2-hydroxy-1H-pyrrolo[3,2-b]pyridine-1,3-
Ethyl 2-(3-(azidocarbonyl)pyridin-2-yl)acetate (11) (1.92 g,
.2 mmol) was heated at reflux in freshly distilled benzene (20 mL)
dicarbonyl)
bis
(azanediyl))
bis(pyridine-3,2-diyl))diacetate
ꢀ
1
8
(18). White crystals from EtOAc, mp 186e187 C.
H NMR
for 3 h. The precipitate formed was filtered off to give a mixture of
the products 12 and 13. The mixture was washed with hot chlo-
roform; 12 was soluble in hot chloroform and the other compound
(400 MHz, CDCl 12.52 (s, 1H), 11.28 (s, 1H), 9.71 (s, 1H), 8.43 (dd,
3
) d
J¼7.7, 0.9 Hz, 1H), 8.32 (dd, J¼4.6, 1.4 Hz, 1H), 8.30 (dd, J¼4.7, 1.4 Hz,
1H), 8.26 (dd, J¼8.2, 1.5 Hz, 1H), 8.22 (dd, J¼8.2, 1.4 Hz,1H), 7.22 (dd,
J¼8.2, 4.7 Hz, 1H), 7.15 (dd, J¼8.1, 4.7 Hz, 2H), 6.73 (dd, J¼7.7, 6.6 Hz,
1H), 4.18 (q, J¼7.1 Hz, 2H), 4.14 (q, J¼7.1 Hz, 2H), 3.97 (s, 2H), 3.94 (s,
13 was insoluble. Filtrate was concentrated under vacuum to give
the pure compound 12 (1.28 g, 76%). The insoluble part 13 was
washed with chloroform to give pure sample (0.22 g, 13%).
13
2H), 1.20 (t, J¼7.1 Hz, 3H), 1.16 (t, J¼7.1 Hz, 3H). C NMR (100 MHz,
CDCl
143.3,138.9,133.1,132.7,131.5,130.8,128.6,122.8,122.7,122.7,113.4,
85.3, 61.3 (2C), 40.7, 40.6, 14.1. max (ATR): 3284, 2983, 1721, 1634,
3
) d 170.0 (2C), 166.2, 163.9, 150.6, 147.3, 146.0, 145.5, 145.4,
4
.3.1. Ethyl 2-hydroxy-1H-pyrrolo[3,2-b]pyridine-3-carboxylate
(
2
13). White solid from chloroform, mp (decomposition)
n
ꢀ
1
72e274 C. H NMR (400 MHz, DMSO)
d
12.56 (s, 1H), 10.31 (s, 1H),
1594, 1544, 1429, 1397, 1329, 1283, 1216, 1140, 1024. HRMS: m/z
7
.51 (t, J¼6.2 Hz, 1H), 7.05 (dd, J¼7.4, 0.8 Hz, 1H), 6.78 (t, J¼6.9 Hz,
[MþNa]þ calcd for C27
26 6 7
H N O : 545.17847; found: 545.17686.
13
1
H), 4.22 (q, J¼7.1 Hz, 2H), 1.26 (t, J¼7.1 Hz, 3H). C NMR (100 MHz,
165.3, 164.1, 143.2, 131.1, 125.6, 111.6, 111.4, 82.7, 58.0, 14.7.
max (ATR): 3087, 2984, 1698, 1592, 1513, 1456, 1444, 1327, 1238,
DMSO)
n
d
4.6. Ethyl 2-(3-(3-phenylureido)pyridin-2-yl)acetate (24)
þ
1
075, 1038. HRMS: m/z [MþNa] calcd for C10
H
10
N
2
O
3
: 205.06134;
Acyl azide (14a) (1.62 g, 6.5 mmol) and aniline (0.78 g, 8.4 mmol)
ꢀ
ꢀ
found: 205.06187.
in benzene (20 mL) were stirred at 50 C for 1 h and then at 80 C
for 3 h. The solvent was evaporated and the crude product was
purified by crystallization from chloroform/hexane to give urea 24
4
.3.2. Ethyl 1-((2-(2-ethoxy-2-oxoethyl)pyridin-3-yl)carbamoyl)-2-
ꢀ
1
hydroxy-1H-pyrrolo-[3,2-b]pyridine-3-carboxylate
(12). White
as white crystals (1.3 g, 43%), mp 143e144 C. H NMR (400 MHz,
CDCl
ꢀ
1
solid from chloroform, mp (decomposition) 264e265 C. H NMR
400 MHz, CDCl
11.83 (s, 1H), 11.48 (s,1H), 8.42 (dd, J¼7.7, 0.7 Hz,
H), 8.29 (dd, J¼4.7, 1.5 Hz, 1H), 8.26 (dd, J¼8.2, 1.4 Hz, 1H), 7.55 (t,
J¼5.8 Hz, 1H), 7.20 (dd, J¼8.0, 5.0 Hz, 1H), 6.86 (dt, J¼7.1, 1.6 Hz, 1H),
.32 (q, J¼7.1 Hz, 2H), 4.16 (q, J¼7.1 Hz, 2H), 3.97 (s, 2H), 1.33 (t,
3
)
d
8.22 (dd, J¼4.7, 1.4 Hz, 1H), 8.08 (dd, J¼8.2, 1.4 Hz, 1H), 7.96
(
3
)
d
(s, 1H), 7.33e7.21 (m, 4H), 7.17 (dd, J¼8.2, 4.7 Hz, 1H), 7.07e7.01 (m,
1
1H), 6.98 (s, 1H), 4.05 (q, J¼7.1 Hz, 2H), 3.84 (s, 2H), 1.16 (t, J¼7.1 Hz,
13
3
3H). C NMR (100 MHz, CDCl ) d 172.1, 153.4, 146.2, 144.8, 138.3,
4
138.0, 134.2, 132.3, 129.2, 124.2, 123.2, 120.9, 120.8, 61.9, 41.5, 14.0.
13
J¼7.1 Hz, 3H), 1.21 (t, J¼7.1 Hz, 3H). C NMR (100 MHz, CDCl
170.1, 165.9, 164.8, 151.1, 147.0, 145.4, 145.3, 132.8, 130.7, 129.5,
27.3, 122.7, 121.8, 113.5, 83.4, 61.2, 60.4, 40.7, 14.6, 14.1. max (ATR):
3
)
n
max (ATR): 3289, 2981, 1722, 1660, 1602, 1541, 1435, 1318, 1239,
þ
d
1191, 1026. HRMS: m/z [MþNa] calcd for C16
17 3 3
H N O : 298.11971;
1
n
found: 298.11666.