Synthesis of novel benzotriazoloazepine derivatives

Article abstract of DOI:10.1002/jhet.961

Eight new benzotriazoloazepine derivatives have been synthesized starting from 7-methoxy-2,3,4,5-tetrahydro-1H-2-benzo[c]azepin-1-one. The compounds 2a-c have been synthesized by the reaction of 7-methoxy-2,3,4,5-tetrahydro-1H-2- benzo[c]azepin-1-thione w

Full text of DOI:10.1002/jhet.961

January 2013
Synthesis of Novel Benzotriazoloazepine Derivatives
29
a
a
a
Wei Zhang,a Rong‐Bi Han,a,b Wen‐Bin Zhang, Ri‐Shan Jiang, and Feng‐Yu Piao
*
aDepartment of Chemistry, College of Science, Yanbian University, Yanji, Jilin 133002, People’s
Republic of China
bKey Laboratory of Natural Resources of Changbai Mountain & Functional Molecules (Yanbian University),
Ministry of Education, Yanji 133002, Jilin
Province, People’s Republic of China
*
E-mail: fypiao4989@yahoo.com.cn
Received August 10, 2010
DOI 10.1002/jhet.961
View this article online at wileyonlinelibrary.com.
Eight new benzotriazoloazepine derivatives have been synthesized starting from 7‐methoxy‐2,3,4,5‐tetrahydro‐
1H‐2‐benzo[c]azepin‐1‐one. The compounds 2a–c have been synthesized by the reaction of 7‐methoxy‐2,3,4,5‐tet-
rahydro‐1H‐2‐benzo[c]azepin‐1‐thione with various hydrazides. Reaction of 5 with hydrazine hydrate, followed by
treatment of the resultant hydrazone with formic acid, gave corresponding 9‐alkoxy‐6,7‐dihydro‐5H‐benzo[c]
[1,2,4]triazolo[4,3‐a]azepine(6a,b). Cyclization of 5 with methyl carbazate gave 9‐alkoxy‐6,7‐dihydro‐2H‐benzo
[c][1,2,4]triazolo[4,3‐a]azepin‐3(5H)‐one (7a–c). The structures of the compounds were confirmed by their ele-
mental analysis and spectral data. Their anticonvulsant activities have been initially screened.
J. Heterocyclic Chem., 50, 29 (2013).
INTRODUCTION
through a convenient synthetic sequence. Finding a correlation
between a compound structure and its biological activity is very
difficult, because of complexity of biological systems.
Therefore, some novel benzotriazoloazepine derivatives have
been synthesized, and their anticonvulsant activities have been
initially screened. Each compound was administered at the
dose levels of 100 mg/kg and 30 mg/kg for evaluating the
anticonvulsant activity.
Benzazepine derivatives have exhibit broad pharmacologi-
cal activity [1–4]. Synthesis and modification of their structure
is one of the research focuses in organic chemistry nowadays
[5, 6]. According to the literature reports, triazole compounds
have wide variety of biological activities, the introduction of
triazole ring to some active molecules may significantly
improve the biological activity of the parent molecule due to
the superposition of biological activity [7–10]. In the course
of work on new pharmacologically active of benzazepine
derivatives, extensive efforts have been made to find more
compounds with potential biological activity. Despite wide
applications, it has been observed that there is scant infor-
mation on the synthesis and anticonvulsant activities of
benzo[c][1,2,4]triazolo[4,3‐a]azepine derivatives in the
literature. As part of our ongoing research work on benza-
zepine derivatives, we became interested in the design and
synthesis of new fused tricyclic heterocyclic compounds
2a–c, 6a,b, and 7a–c.
RESULTS AND DISCUSSION
The compound 1 was synthesized using the method de-
scribed in a former paper of our group [1]. 7‐Methoxy‐
2,3,4,5‐tetrahydro‐1H‐benzo[c]azepin‐1‐one 1 was reacted
with phosphorus pentasulfide in the presence of triethylamine
in refluxing acetonitrile to give the thioxo derivatives, which
reacted with acetohydrazide and 2‐chlorobenzohydrazide in
n‐butanol under nitrogen atmosphere, respectively, gave the
corresponding compounds 2a–c. The compound 5 was reacted
with hydrazine hydrate in refluxing ethanol to yield monosub-
stituted hydrazine, which reacted with formic acid to provide
corresponding the compounds 6a,b. Cyclization of 5 with
Upon continuation of our studies on the synthesis of
benzazepine derivatives with potential anticonvulsant
activity, new tricyclic heterocyclic framework is designed
© 2013 HeteroCorporation

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W. Zhang, R.-B. Han, W.-B. Zhang, R.-S. Jiang, and F.-Y. Piao
Vol 50
Scheme 1. The synthesis route of compounds 2a–c, 6a,b, and 7a–c. Reagents: (a) BBr3/CH2Cl2, 16–17 h (b) RX/C2H5OH, 80–92°C; (c and e) P2S5,
(C2H5)3N /CH3CN, 86–92°C, 5–7 h; (d) H2NNHCOOCH3/ (CH3)(CH2)3OH, 140–150°C, 5–8 d; (f) H2NNHCOR/ (CH3)(CH2)3OH, 110–115°C,
28–48 h; (g) N2H4/ C2H5OH, 90–95°C, 36 h; (h) HCOOH, 90–95°C, 30–36 h.
methyl carbazate gave 9‐alkoxy‐6,7‐dihydro‐2H‐benzo[c]
[1,2,4] triazolo[4,3‐a]azepin‐3(5H)‐one 7a–c (Scheme 1). The
structures of all the new compounds were confirmed by H
NMR, MS, and elemental analyses, and their anticonvulsant
activities have been initially screened.
Compounds 1 and 4 were prepared according to a former
paper of our group [1].
After cooling, the solvent was removed under reduced
pressure, the residue was dissolved in 60 mL of ethyl acetate
or dichloromethane, washed with water (60 × 3), and dried
over anhydrous MgSO4. Drying and evaporation of the solvent
gave a crude product, which was dissolved in formic acid
(10 mL); the mixture was refluxed for 30–36 h, then the excess
acid was evaporated under reduced pressure, and the residue
was dissolved in 60 mL of ethyl acetate or dichloromethane,
washed with water (60 × 3), and dried over anhydrous MgSO4,
filtered, and evaporated. The residue was purified by silica gel
column chromatography (dichloromethane:methanol = 20:1) to
afford target compounds 6a,b.
1
General procedure for the preparation of compounds 2a–c.
Acetonitrile (1.0 mL) and triethylamine (0.6 mL) were placed
in a three‐necked round‐bottomed flask, to which P2S5
(1.9 mmol) was added slowly in an ice bath and was stirred
until dissolved [9]. Then, compound 1 (1.7 mmol) was
added while stirring. The mixture was refluxed for 5–7 h in
a nitrogen atmosphere. After removing the solvent under
reduced pressure, the residue was dissolved in 60 mL of
dichloromethane, washed with water (60 × 3), and dried
over anhydrous MgSO4. Evaporation of the solvent gave a
crude product, which reacted with various hydrazides
(2 mmol) in n‐butanol (15 mL) for 28–48 h at 110–115°C
under nitrogen atmosphere. The solvent was removed under
reduced pressure, and the residue dissolved with ethyl
acetate and washed with water three times. The ethyl acetate
layer was dried with anhydrous MgSO4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (dichloromethane:methanol = 20:1) to
afford target compounds 2a–c.
General procedure for the preparation of compounds 7a–c.
Crude product
5 (2 mmol) reacted with methyl
hydrazinocarboxylate (4 mmol) in n‐butanol 10 mL under
nitrogen atmosphere for 4–8 d, the solvent was removed
under reduced pressure, and the residue dissolved with ethyl
acetate and washed with water three times [9]. The ethyl
acetate layer was dried with anhydrous MgSO4, filtered and
evaporated. The residue was purified by silica gel column
chromatography (dichloromethane:methanol = 35:1) to
afford target compounds 7a–c.
Anticonvulsant activity. The anticonvulsant activities of
the compounds synthesized have been initially screened
(Table 1). The maximum electroshock (MES) test carried
out according to the standard described in the
Antiepileptic Drug Development Program of the National
Institutes of Health [14, 15]. All compounds were tested
for anticonvulsant activities with KunMing mice in the
18–22 g weight range purchased from the Laboratory of
Animal Research, College of Pharmacy, Yanbian
The preparation of compound 5 was done under the
same condition as mentioned earlier [9].
General procedure for the preparation of compounds 6a,b.
A stirred suspension of 5 (3 mmol) in ethanol (20 mL) and
hydrazine monohydrate (3 mL) was refluxed for 36 h [11–13].
Journal of Heterocyclic Chemistry
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January 2013
Synthesis of Novel Benzotriazoloazepine Derivatives
31
Table 1
shifts were given in parts per million relative to tetramethylsilane.
Mass spectra were measured on a HP1100LC (Agilent Technolo-
gies). Combustion analyses (C, H and N) were performed on a
PE‐2400 (SHIMADZU). Microanalyses of C, N, and H were per-
formed using a Heraeus CHN Rapid Analyzer. The major chemi-
cals were purchased from Aldrich Chemical. All other chemicals
were of analytical grade.
9‐Methoxy‐6,7‐dihydro‐5H‐benzo[c][1,2,4]triazolo[4,3‐a]
azepine (2a). Yield: 80.8%, mp. 83.5–84.6°C. 1H NMR (DMSO,
300 MHz) δ: 2.15–2.24 (m, 2H, CH2), 2.69 (t, J = 6.8 Hz, 2H, CH2),
3.82 (s, 3H, CH3), 4.01 (t, J = 6.6 Hz, 2H, CH2), 6.94–6.97 (m, 2H, Ar‐
H), 7.74 (d, 1H, J = 8.1 Hz, Ar‐H), 8.57(s, 1H, CH═N). MS (APCI,
positive mode) m/z: 216.1 [M+H]+. Anal. Calcd. for C12H13N3O: C,
66.96; H, 6.09; N, 19.52. Found: C, 66.86; H, 6.01; N, 19.38.
9‐Methoxy‐3‐methyl‐6,7‐dihydro‐5H‐benzo[c][1,2,4]triazolo
[4,3‐a]azepine (2b). Yield: 47.4 %, mp. 138.5–140.1°C. 1H NMR
(DMSO, 300 MHz) δ: 2.24–2.28 (m, 2H, CH2), 2. 45 (s, 3H,
CH3), 2.71 (t, J = 6.8 Hz, 2H, CH2), 3.82–3.90 (m, 5H, OCH3,
CH2), 6.90–6.92 (m, 2H, Ar‐H), 7.72 (d, 1H, J = 9.2 Hz, Ar‐H).
MS (APCI, positive mode) m/z: 230.1 [M+H]+. Anal. Calcd. for
C13H15N3O: C, 68.10; H, 6.59; N, 18.33. Found: C, 68.01; H,
6.51; N, 18.43.
Primary evaluation of compounds 2a–c, 6a,b, and 7a–c in anticonvulsant
activity.a
MESb,c
Comp.
100d
0/3
30d
e
2a
—
e
2b
2c
0/3
3/3
—
3/5
5/5
4/5
6a
6b
3/3
3/3
3‐(2‐Chlorophenyl)‐9‐methoxy‐6,7‐dihydro‐5H‐benzo[c]
[1,2,4]triazolo[4,3‐a]azepine (2c). Yield: 50.0 %, mp. 112.3–113.5°
C. 1H NMR (DMSO, 300 MHz) δ: 2.20–2.27 (m, 2H, CH2), 2.77 (t,
J = 6.8 Hz, 2H, CH2), 3.64 (t, J = 6.8 Hz, 2H, CH2), 3.84 (s, 3H,
CH3), 7.00–7.03 (m, 2H, Ar‐H), 7.38–7.80 (m, 5H, Ar‐H). MS
(APCI, positive mode) m/z: 326.0 [M+H]+. Anal. Calcd. for
C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90. Found: C, 66.30; H,
4.88; N, 12.65.
9‐Heptyloxy‐6,7‐dihydro‐5H‐benzo[c][1,2,4]triazolo[4,3‐a]
azepine (6a). Yield: 42.8 %, mp. 101.1–101.6°C. 1H NMR
(DMSO, 300 MHz) δ: 0.86–0.89 (m, 3H, CH3), 1.25–1.35 (m, 8H,
(CH2)4), 1.71–1.75 (m, 2H, CH2), 2.21 (t, J = 6.3 Hz, 2H, CH2),
2.70 (t, J = 6.8 Hz, 2H, CH2), 4.00–4.04 (m, 4H, (CH2)2), 6.92–6.95
(m, 2H, Ar‐H), 7.73 (d, 1H, J = 8.0 Hz, Ar‐H), 8.53 (s, 1H,
CH═N). MS (APCI, positive mode) m/z: 300.2 [M+H]+. Anal.
Calcd. for C18H25N3O: C, 72.21; H, 8.42; N, 14.03. Found: C,
72.18; H, 8.39; N, 13.98.
9‐Benzyloxy‐6,7‐dihydro‐5H‐benzo[c][1,2,4]triazolo[4,3‐a]
azepine (6b). Yield: 48.0 %, mp. 125.6–127.2°C. 1H NMR
(DMSO, 300 MHz) δ: 2.14–2.26 (m, 2H, CH2), 2.70 (t, J = 6.7
Hz, 2H, CH2), 4.02 (t, 2H, J = 6.6 Hz, CH2), 5.17 (s, 2H, CH2),
7.02–7.10 (m, 2H, Ar‐H), 7.31–7.51 (m, 5H, Ar‐H), 7.76 (d, J
= 8.4 Hz, 2H, Ar‐H), 8.56 (s, 1H, CH═N). MS (APCI, positive
mode) m/z: 292.0 [M+H]+. Anal. Calcd. for C18H17N3O: C,
74.20; H, 5.88; N, 14.42. Found: C, 72.18; H, 5.73; N, 13.98.
9‐ Methoxy ‐6,7‐dihydro‐2H‐benzo[c][1,2,4]triazolo[4,3‐a]
[2] azepin‐3(5H)‐one (7a). Yield: 45.0 %, mp. 213.1–214.5°C.
1H NMR (DMSO, 300 MHz) δ: 2.08–2.10 (m, 2H, CH2), 2.70–2.80
(m, 2H, CH2), 3.54 (t, J = 6.3 Hz, 2H, CH2), 3.81 (s, 3H, CH3),
6.92–6.96 (m, 2H, Ar‐H), 7.59 (d, 1H, J = 8.1 Hz, Ar‐H), 11.79 (s,
1H, N‐H). MS (APCI, positive mode) m/z: 232.1 [M+H]+. Anal.
Calcd. for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C,
62.41; H, 5.77; N, 18.01.
9‐Heptyloxy‐6,7‐dihydro‐2H‐benzo[c][1,2,4]triazolo[4,3‐a][2]
azepin‐3(5H)‐one (7b). Yield: 48.8 %, mp. 193.4–195.5°C. 1H
NMR (DMSO, 300 MHz) δ: 0.80–0.88 (m, CH3), 1.22–1.45 (m,
8H, (CH2)4), 1.68–1.80 (m, 2H, CH2), 2.04–2.09 (m, 2H, CH2),
2.74 (t, J = 6.3 Hz, 2H, CH2), 353 (t, J = 6.4 Hz, 2H, CH2), 4.01
(d, 2H, J = 6.1 Hz, CH2), 6.90–6.95 (m, 2H, Ar‐H), 7.57 (d, 1H,
J = 8.3 Hz, Ar‐H), 11.77 (s, 1H, N‐H). MS (APCI, positive mode)
e
7a
7b
7c
1/3
3/3
3/3
—
1/5
1/5
Carbam.f
3/3
5/5
aAll of tested compounds were dissolved in DMSO; Test Drug Adminis-
tered i.p.
bThe maximal electroshock test was carried out 30 min after administra-
tion of the test compounds.
cDoses are denoted in mg/kg.
dThe effective number in three or five tested mice is given.
eNot tested.
fThe reference drug.
University. The tested compounds were dissolved in
DMSO. Each compound was administered at the dose
levels of 100 mg/kg and 30 mg/kg for evaluating the
anticonvulsant activity. Anticonvulsant efficacy was
measured in the MES test. In the MES test, seizures were
elicited with a 60 Hz alternating current of 50 mA
intensity in mice. The current was applied via corneal
electrodes for 0.2 s. The test compounds were
administered i.p.
EXPERIMENTAL
Melting points were determined on X‐5 microscope melting
point apparatus, which were uncorrected. H‐NMR spectra were
measured on an AV‐300 (Bruker, Switzerland), and all chemical
1
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DOI 10.1002/jhet

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W. Zhang, R.-B. Han, W.-B. Zhang, R.-S. Jiang, and F.-Y. Piao
Vol 50
m/z: 316.1 [M+H]+. Anal. Calcd. for C18H25N3O2: C, 68.54; H, 7.99;
N, 13.32. Found: C, 68.47; H, 8.00; N, 13.23.
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9‐Benzyloxy‐6,7‐dihydro‐2H‐benzo[c][1,2,4]triazolo[4,3‐a]
[2] azepin‐3(5H)‐one (7c). Yield: 50.2 %, mp. 246.4–246.8°C.
1H NMR (DMSO, 300MHz) δ: 2.05–2.10 (m, 2H, CH2), 2.75
(t, J = 5.9 Hz, 2H, CH2), 3.54 (t, 2H, J = 6.4 Hz, CH2), 5.15 (s,
2H, CH2), 6.95–7.10 (m, 2H, Ar‐H), 7.30–7.50 (m, 5H, Ar‐H),
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CONCLUSIONS
During this work, we succeeded in synthesizing eight
new benzotriazoloazepine derivatives from 7‐methoxy‐
2,3,4,5‐tetrahydro‐1H‐benzo[c]azepin‐1‐one. Anticonvulsant
activities of these new compounds have been initially
screened. Further investigations are under progress to
enlarge the scope of these heterocycles and evaluate their
anticonvulsant activities.
Acknowledgments. This work was supported by the National
Natural Science Foundation of China (Nos. 30760290 and
30860340) and Important Item Foundation of Ministry of
Education P.R. China (No. 20070422029).
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet