Thermolysis of 3-azido-N-phenylthieno-[2,3-b]pyridine-2-carboxamides

Full text of DOI:10.1007/s10593-013-1390-2

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
THERMOLYSIS OF 3-AZIDO-N-PHENYLTHIENO-
[2,3-b]PYRIDINE-2-CARBOXAMIDES
E. A. Kanishcheva1, V. K. Vasilin1*, T. A. Stroganova1, and G. D. Krapivin1
Keywords: condensed pyridothienodiazepines, thieno[2,3-b]pyridine-2-carboxamides, azido group,
thermolysis.
Annelated 1,4-diazepines are of interest as they are often compounds possessing different forms of
biological and pharmacological activity [1]. Many methods for the synthesis of diazepines have been reported
up until now, but the search for novel methods still of interest for scientific community. One of the known
methods for closing a diazepine ring is the intramolecular transformation of aromatic azides. The formation of
the diazepine ring occurs via photolysis of azides [2] or by an intramolecular cycloaddition of the azide group at
a carbon–carbon multiple bond [3-6].
Continuing our study on the synthesis of 1,4-diazepines condensed with a thienopyridine fragment [7]
we have developed a method for the preparation of polycyclic 1,4-diazepine derivatives based on the thermal
decomposition of thieno[2,3-b]pyridine azides 2a-c.
We have selected the N-phenyl-substituted tertiary 3-aminothieno[2,3-b]pyridine-2-carboxamides 1a-c
as starting materials and carried out successive diazotization and azide formation reactions to give the
corresponding azides 2a-c.
10
11
9
8
1) NaNO2, H2SO4
AcOH, H2O
7–10°C, 15 min
12
HN
R
N
R
1
R
N
11a
N3
NH2
7a
Xylene, 
15–30 min
X
X
12b
4a
12a
X
7 N
R1
N
R1
N
R1
2
6
2) NaN3, H2O
30 min
5a
S
S
S
3
O
O
Me
O
Me
N
Me
5
4
1a–c
3a–c
2a–c
a R = R1 = Me, X = H; b R = R1 = Me, X = Br; c R = CH2OMe, R1 = Ph, X = H
The IR spectra of compounds 2a-c show the presence of characteristic azide group absorption bands at
2111-2123 cm-1. Azides 2a-c are quite unstable compounds and are used for the subsequent stage without
additional purification.
_______
*To whom correspondence should be addressed, e-mail: vasvk@mail.ru.
1Kuban State Technological University, 2 Moskovskaya St., Krasnodar 350072, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1488-1491, September, 2013.
Original article submitted July 29, 2013.
0009-3122/13/4909-1387©2013 Springer Science+Business Media New York
1387

The thermal decomposition of azides 2a-c was carried out by refluxing in xylene for 15-30 min and
gave the pyridothienobenzodiazepines 3a-c as the thermolysis products in 59-68% yields. The IR spectra of
compounds 3a-c contained secondary amino group absorption bands at 3418-3484 and 3319-3351 cm-1 and
1
amide carbonyl absorption bands at 1631-1668 cm-1. The H NMR spectra showed signals for the secondary
amino group hydrogen atom at 7.62-8.79 ppm. The structure of compounds 3a-c was unambiguously elucidated
1
from H and 13C NMR spectroscopy employing the COSY, HSQC, and HMBC homo- and heteronuclear
correlation methods.
Hence, the thermal decomposition of 3-azido-N-phenylthieno[2,3-b]pyridine-2-carboxamides is accom-
panied by an intramolecular cyclization to give the novel 7,12-dihydro-6H-pyrido[3',2':4,5]thieno[3,2-b][1,5]-
benzodiazepin-6-one condensed heterocyclic system.
IR spectra were recorded on a Perkin-Elmer Spectrum Two instrument using an ATR accessory. 1H and
13C NMR spectra were recorded on an Agilent 400/MR instrument (400 and 100 MHz, respectively) using
DMSO-d6 with TMS as internal standard. Mass spectra were recorded on a Kratos MS-30 instrument with
70 eV ionization. Elemental analysis was performed on a Flash EA 1112 CHN analyzer. Melting points were
determined on a Stuart SMP 30 apparatus and are not corrected. TLC was performed on Silufol UV-254 and
Sorbfil (JSC "Sorbpolymer") plates with PhMe–EtOH (20:3) as eluent and visualized using iodine and bromine
vapors.
Compounds 1a-c were prepared by the reported method [7] via alkylation of the corresponding
pyridinethiones by N-phenyl-substituted chloroacetamides in the presence of aqueous KOH solution.
3-Amino-N,4,6-trimethyl-N-phenylthieno[2,3-b]pyridine-2-carboxamide (1a). Yield 65%. Pale-
yellow crystals. Mp 169-170°C. IR spectrum, ν, cm-1: 3484, 3319, 1584, 1549, 1455, 1416, 1359, 1301, 1288,
1106, 860, 745, 695. 1Н NMR spectrum, δ, ppm: 2.37 (3Н, s, 6-СН3); 2.68 (3Н, s, 4-СН3); 3.29 (3Н, s, NСН3);
6.87 (1Н, s, Н-5); 6.96 (2Н, s, NН2); 7.27-7.46 (5Н, m, Н Ph). Mass spectrum, m/z (Irel, %): 311 [M]+ (74), 206
(25), 205 (64), 177 (35), 133 (14), 107 (100), 106 (16), 79 (12), 77 (20), 46 (11), 43 (22). Found, %: С 65.29;
Н 5.55; N 13.38. C17H17N3OS. Calculated, %: С 65.57; Н 5.50; N 13.49.
3-Amino-5-bromo-N,4,6-trimethyl-N-phenylthieno[2,3-b]pyridine-2-carboxamide (1b). Yield 86%.
Pale yellow powder. Mp 223-224°C. IR spectrum, ν, cm-1: 3467, 3279, 1573, 1534, 1493, 1464, 1411, 1365,
1
1343, 1296, 1269, 1110, 1007, 762, 748, 698. Н NMR spectrum, δ, ppm: 2.54 (3Н, s, 6-СН3); 2.82 (3Н, s, 4-
СН3); 3.31 (3Н, s, NСН3); 6.91 (2Н, s, NН2); 7.26-7.47 (5Н, m, Н Ph). Mass spectrum, m/z (Irel, %): 391
[M (81Br)]+ (40), 390 (5), 389 [M (79Br)]+ (40), 284 (36), 283 (10), 282 (36), 257 (17), 255 (16), 108 (18), 107
(100), 106 (20), 77 (27), 43 (36). Found, %: С 52.27; Н 4.21; N 10.69. C17H16BrN3OS. Calculated, %: С 52.32;
Н 4.13; N 10.77.
3-Amino-4-methoxymethyl-6-methyl-N,N-diphenylthieno[2,3-b]pyridine-2-carboxamide
(1c).
Yield 83%. Yellow crystals. Mp 185-186°C (mp 187-188°C [8]).
Synthesis of Compounds 2a-c (General Method). H2SO4 (0.52 ml, 10 mmol) was added with stirring
to a solution of compound 1a-c (10 mmol) in acetic acid (75 ml). The mixture obtained was cooled to 7-10ºC
and NaNO2 (1.02 g, 15 mmol) in water (2 ml) was added. Stirring was continued for 15 min, excess HNO2
neutralized using crystalline urea (monitored using starch iodine paper), and a solution of NaN3 (0.96 g,
15 mmol) in water (2 ml) was added. After 30 min, the reaction mixture was poured into water (200 ml), and the
precipitate formed was filtered off, thoroughly washed with water, and dried in a vacuum desiccator. Since the
azides 2a-c are unstable compounds they were used in the next stage without additional purification.
3-Azido-N,4,6-trimethyl-N-phenylthieno[2,3-b]pyridine-2-carboxamide (2a). Yield 90%. Yellow
crystals. Mp 151-152°C. IR spectrum, ν, cm-1: 2111, 1630, 1594, 1494, 1412, 1383, 1341, 1277, 1146, 1094,
1031, 977, 801, 767, 734, 697. 1Н NMR spectrum, δ, ppm: 2.42 (3Н, s, 6-СН3); 2.59 (3Н, s, 4-СН3); 3.40 (3Н,
s, NСН3); 7.06 (1Н, s, Н-5); 7.20-7.40 (5Н, m, Н Ph). Found, %: С 60.57; Н 4.45; N 20.75. C17H15N5OS.
Calculated, %: С 60.52; Н 4.48; N 20.76.
3-Azido-5-bromo-N,4,6-trimethyl-N-phenylthieno[2,3-b]pyridine-2-carboxamide (2b). Yield 92%.
Light-yellow powder. Mp 148-149°C. IR spectrum, ν, cm-1: 2123, 1638, 1592, 1545, 1493, 1409, 1315, 1269,
1388

1
1212, 1145, 1006, 812, 736, 695. Н NMR spectrum , δ, ppm: 2.60 (3Н, s, 6-СН3); 2.76 (3Н, s, 4-СН3); 3.43
(3Н, s, NСН3); 7.00-7.40 (5Н, m, Н Ph). Found, %: С 48.98; Н 3.41; N 16.77. C17H14BrN5OS. Calculated, %:
С 49.05; Н 3.39; N 16.82.
3-Azido-4-methoxymethyl-6-methyl-N,N-diphenylthieno[2,3-b]pyridine-2-carboxamide (2c). Yield
93%. Light-yellow powder. Mp 174-175°C (mp 177-178°C [8]).
Thermolysis of the Azides 2a-c (General Method). A solution of azide 2a-c (3 mmol) in anhydrous
xylene (15 ml) was refluxed to full conversion of the azide (15-30 min, TLC monitoring). After cooling, the
precipitated crystals were filtered off, dried, and recrystallized from DMF to give the diazepines 3a-c as light-
yellow crystals.
1,3,7-Trimethyl-7,12-dihydro-6H-pyrido[3',2':4,5]thieno[3,2-b][1,5]benzodiazepin-6-one
(3a).
Yield 68%. Light-yellow crystals. Mp 122-123°C. IR spectrum, ν, cm-1: 3484, 3319, 1648, 1584, 1549, 1455,
1
1416, 1359, 1301, 1105, 863, 745, 695. Н NMR spectrum, δ, ppm (J, Hz): 2.48 (3Н, s, 3-СН3); 2.86 (3Н, s,
1-СН3); 3.30 (3Н, s, NСН3); 7.06 (1Н, s, Н-2); 7.10 (1H, d, J = 7.6, H-11); 7.13 (1H, t, J = 7.6, H-10); 7.16
(1H, t, J = 7.6, H-9); 7.25 (1H, d, J = 7.6, Н-8); 7.62 (1Н, s, NH). 13С NMR spectrum, δ, ppm: 20.6 (1-CH3);
24.2 (3-CH3); 37.3 (NCH3); 113.5 (C-5); 122.8 (C-10); 122.9 (C-11); 123.0 (C-12b); 123.4 (C-8); 125.4 (C-9);
125.9 (C-2); 136.7 (C-7a); 142.6 (C-11a); 144.6 (C-1); 146.4 (C-12a); 159.1 (C-3); 160.5 (C-4a); 165.9 (C-6).
Mass spectrum, m/z (Irel, %): 309 [M]+ (100), 307 (29), 292 (44), 281 (92), 280 (12), 266 (54), 264 (13), 140
(22), 77 (14), 44 (10), 43 (34), 42 (15). Found, %: С 66.06; Н 4.81; N 13.59. C17H15N3OS. Calculated, %:
С 66.00; Н 4.89; N 13.58.
2-Bromo-1,3,7-trimethyl-7,12-dihydro-6H-pyrido[3',2':4,5]thieno[3,2-b][1,5]benzodiazepin-6-one
(3b). Yield 63%. Yellow crystals. Mp 209-210°C. IR spectrum, ν, cm-1: 3481, 3351, 1668, 1595, 1533, 1492,
1
1397, 1364, 1292, 1246, 1130, 1025, 823, 762, 707. Н NMR spectrum, δ, ppm (J, Hz): 2.65 (3Н, s, 3-СН3);
3.00 (3Н, s, 1-СН3); 3.31 (3Н, s, NСН3); 7.15 (1H, d, J = 7.8, H-11); 7.16 (1H, dd, J = 7.8, J = 7.6, H-10); 7.17
(1H, dd, J = 7.6, J = 7.8, H-9); 7.26 (1H, d, J = 7.8, H-8); 7.79 (1H, s, NH). 13С NMR spectrum , δ, ppm: 20.8
(1-CH3); 27.0 (3-CH3); 37.3 (NCH3); 115.9 (C-5a); 121.7 (C-2); 123.3 (C-11); 123.5 (C-8); 124.5 (C-12b);
125.6 (C-9); 126.0 (C-10); 137.0 (C-7a); 142.4 (C-11a); 144.0 (C-1); 145.6 (C-12a); 157.5 (C-3); 158.3 (C-4a);
165.6 (C-6). Mass spectrum, m/z (Irel, %): 389 [M (81Br)]+ (100), 388 (21), 387 [M (79Br)]+ (96), 385 (26), 373
(11), 372 (62), 371 (13), 370 (63), 362 (13), 361 (18), 360 (24), 359 (26), 358 (21), 346 (53), 344 (53), 342
(10), 326 (13), 308 (17), 291 (10), 280 (11), 279 (10), 278 (12), 265 (16), 263 (18), 249 (13), 237 (11), 220
(12), 219 (12), 180 (13), 179 (11), 146 (10), 119 (14), 118 (12), 104 (11), 79 (10), 78 (12), 77 (27), 51 (15), 43
(36). Found, %: С 52.54; Н 3.54; N 10.88. C17H14BrN3OS. Calculated, %: С 52.59; Н 3.63; N 10.82.
1-Methoxymethyl-3-methyl-7-phenyl-7,12-dihydro-6H-pyrido[3',2':4,5]thieno[3,2-b][1,5]benzodiazepin-
6-one (3c). Yield 59%. Light-yellow crystals. Mp 195-196°C. IR spectrum, ν, cm-1: 3418, 3322, 1631, 1586,
1563, 1489, 1383, 1332, 1117, 1083, 1021, 902, 855, 751, 696. 1Н NMR spectrum, δ, ppm (J, Hz): 2.56 (3H, s,
3-CH3); 3.51 (3H, s, CH2OCH3); 4.98 (2H, s, CH2OCH3); 6.68 (1H, d, J = 8.5, H-11); 6.95 (1H, dd, J = 8.5,
J = 8.4, H-10); 7.00 (1Н, d, J = 8.5, H-8); 7.09 (1H, dd, J = 8.5, J = 8.4, H-9); 7.13 (1H, s, Н-2); 7.32 (1H, t,
J = 7.8, H-4 Ph); 7.38 (2H, d, J = 7.9, H-2,6 Ph); 7.48 (2H, dd, J = 7.9, J = 7.8, H-3,5 Ph); 8.79 (1H, s, NH). 13С
NMR spectrum, δ, ppm: 24.4 (3-CH3); 58.2 (CH2OCH3); 72.6 (CH2OCH3); 112.8 (C-5a); 121.8 (C-2); 121.9
(C-8); 122.6 (C-12b); 125.0 (C-10); 126.6 (C-9); 127.3 (C-11); 127.6 (C-4 Ph); 129.4 (C-2,6 Ph); 129.5 (C-3,5
Ph); 135.2 (C-7a); 142.8 (C-i Ph); 143.0 (C-1); 143.4 (C-11a); 146.4 (C-12a); 159.9 (C-3); 161.1 (C-4a); 164.6
(C-6). Mass spectrum, m/z (Irel, %): 401 [M]+ (65), 387 (38), 386 (100), 374 (15), 373 (14), 370 (15), 358 (14),
344 (17), 343 (15), 341 (29), 299 (12), 284 (12), 267 (10), 265 (28), 237 (11), 180 (10), 76 (11). Found, %:
С 68.86; Н 4.69; N 10.53. C23H19N3O2S. Calculated, %: С 68.81; Н 4.77; N 10.47.
This study was carried out within the State Program of the Russian Federation Ministry of Education
and Science (contract 3.1578.2011) and with the support of the Russian Federation Ministry of Education and
Science (contract 14.B37.21.0829).
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