Synthesis of 1,3,3a,5-Tetraaryl-3a,4,5,6-tetrahydro-3H-1,2,4-triazolo[4,3-a][1,5]benzodiazepines

Article abstract of DOI:10.1002/hc.1085

A series of 3a,5-diaryl-1,3-diphenyl-3a,4,5,6-tetrahydro-3H-1,2,4-triazolo[4,3a][1,5]benzodiazepines was synthesized by the cycloaddition reactions of 2,4-diaryl-2,3-dihydro-1H-1,5-benzodiazepines and N-phenylbenzonitrileimine generated from N-phenylbenzenecarbohydrazonic chloride in the presence of triethylamine in anhydrous tetrahydrofuran.

Full text of DOI:10.1002/hc.1085

Heteroatom Chemistry
Volume 12, Number 6, 2001
Synthesis of 1,3,3a,5-Tetraaryl-3a,4,5,
6-tetrahydro-3H-1,2,4-triazolo[4,3-a]
[1,5]benzodiazepines
Jiaxi Xu, Chenbo Wang, and Qihan Zhang
College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
Received 13 September 2000; revised 3 May 2001
fused 1,5-benzodiazepine derivatives have been re-
ABSTRACT: A series of 3a,5-diaryl-1,3-diphenyl-3a,
ported [13–16]. In recent years, our working group
4,5,6-tetrahydro-3H-1, 2,4-triazolo[4,3-a][1,5]benzo-
has synthesized numerous 1,5-benzothiazepine and
diazepines was synthesized by the cycloaddition
1,5-benzodiazepine tricyclic derivatives and studied
reactions of 2,4-diaryl-2,3-dihydro-1H-1,5-benzo-
their stereostructures and spectral properties due to
diazepines and N-phenylbenzonitrileimine generated
their biological and pharmaceutical importance [17–
from N-phenylbenzenecarbohydrazonic chloride in
20]. As a continuation of our work on the cycload-
the presence of triethylamine in anhydrous tetrahy-
ditions of 1,5-benzoheteroazepines, herein we report
the cycloadditions of 2,4-diaryl-2,3-dihydro-1H-1,5-
benzodiazepines with N-phenylbenzonitrileimine.
C
drofuran.
2001 John Wiley & Sons, Inc. Heteroatom
Chem 12:557–559, 2001
RESULTS AND DISCUSSION
INTRODUCTION
Although several synthetic methods have been de-
veloped for 1,2,4-triazole-fused 1,5-benzodiazepine
derivatives [13–16], in connection with our investi-
gation of the cycloaddition reactions of 1,5-benzo-
diazepines and 1,5-benzothiazepines, we have tested
the 1,3-dipolar cycloaddition of 1,5-benzodiazepines
with a nitrileimine for synthesis of 1,2,4-triazolo
[4,3-a][1,5]benzodiazepines (Scheme 1).
2,4-Diaryl-2,3-dihydro-1H-1,5-benzodiazepines
(1a–f) were synthesized from o-phenylenediamine
and ␣,␤-unsaturated ketones in good yields [17,20].
N-Phenylbenzenecarbohydrazonic chloride was pre-
pared from N0-benzoylphenylhydrazine and phos-
phorus pentachloride. 1,5-Benzodiazepines (1a–f)
reacted with N-phenylbenzonitrileimine, generated
from N-phenylbenzenecarbohydrazonic chloride in
the presence of triethylamine in anhydrous tetra-
hydrofuran, to give the new 3a,5-diaryl-1,3-diphenyl-
3a,4,5,6-tetrahydro-3H-1,2,4-triazolo[4,3-a][1,5] be-
nzodiazepines (2a–f) in low to moderate yields.
Among tricyclic benzodiazepine derivatives, tria-
zolobenzodiazepines are one of the most important
families due to their pharmaceutical interest [1–5].
Several triazolobenzodiazepines, e.g. triazolam, es-
tazolam, and flumazenil were found to be effective in
the treatment of some CNS disturbances [1]. Alpra-
zolam and triazolam were shown to have clinically
useful anxiolytic and hypnotic activity [2–4]. Several
triazolobenzodiazepines have been evaluated as an-
tagonists of platelet activating factor [5]. Hence, a
number of synthetic methods have been developed
in recent years [6,7], providing interesting and useful
routes to annulated 1,4-benzodiazepines [8]. Up to
now, much attention has been paid to the synthesis of
1,2,4- triazolo[1,4]benzodiazepines by various meth-
ods [9–12]. However, only a few of the 1,2,4-triazole-
Correspondence to: Jiaxi Xu; e-mail: jxxu@chem.pku.edu.cn.
c
2001 John Wiley & Sons, Inc.
557

558 Xu, Wang, and Zhang
SCHEME 1 Synthesis of 3a,5-diaryl-1,3-diphenyl-3a,4,5,6-tetrahydro-3H-1,2,4-triazolo[4,3-a][1,5]benzodiazepines.
1
spectra, they must be dissolved in CDCl3 prior to the
spectral determination. If not, no satisfactory spec-
trum was obtained due to their instability. They even
decompose partly in solution at room temperature.
This rationalizes the reason why the yields are so low
in this cycloaddition.
Their structures were confirmed by H NMR, MS,
IR, and elemental analyses. In their IR spectra, the
1
absorption of C N (about 1610 cm ) in the ben-
zodiazepine ring had disappeared (Tables 1 and 2).
In order to improve the yield, we have carried
out the reaction in different solvents (THF, Et2O, and
benzene) at various temperatures (RT and with re-
fluxing). Unfortunately, all attempts were unsuccess-
ful. After studying the obtained adducts, we found
that the adducts are unstable in solution, for in-
stance, in chloroform, tetrahydrofuran, diethyl ether,
benzene, etc. Even when determining their 1H NMR
EXPERIMENTAL
Melting points were obtained on a Yanaco melt-
ing point apparatus and are uncorrected. Elemen-
tal analyses were carried out on an Elementar
TABLE 1 Physical and Spectral Data
Compd.
R1
R2
Yield (%) m.p.( C)
1H NMR (CDCl3/TMS) (ppm), J (Hz)
MS m/z (m+)
2a
2-BrPh
Ph
18
26
17
34
26
18
137–139 2.79 (1H, dd, J = 11.1, 13.8),
570
3.07 (1H, d, J = 13.8), 3.70 (1H, s, br, NH), 4.84
(1H, d, J = 11.1), 6.68–7.89 (23H, m, aromatic)
258–260 2.89 (1H, dd, J = 10.5, 14.4), 2.91 (1H, d, J = 14.4),
3.86 (1H, s, br, NH), 4.25 (1H, d, J = 10.5),
2b
2c
2d
2e
2f
Ph
2-MeOPh
Ph
4-ClPh
Ph
526
522
522
526
526
6.60–7.73 (23H, m, aromatic)
259–261 2.69(1H, dd, J = 10.3, 11.7), 3.02 (1H, d, J = 10.3),
3.79 (3H, s, MeO), 3.80 (1H, s, br, NH), 4.84
(1H, d, J = 11.7), 6.60–7.96 (23H, m, aromatic)
225–228 2.83 (1H, dd, J = 9.3, 13.2), 2.93 (1H, d, J = 13.2),
3.79 (3H, s, MeO), 3.85 (1H, s, br, NH) 4.31
4-MeOPh
Ph
(1H, d, J = 9.3), 6.60–7.70 (23H, m, aromatic)
155–158 2.82 (1H, dd, J = 10.8, 14.1), 3.00 (1 H, d, J = 14.1),
3.82 (1H, s, br, NH), 4.32 (1H, d, J = 10.8),
3-ClPh
2-ClPh
6.60–8.00 (23H, m, aromatic)
Ph
135–138 2.77 (1H, dd, J = 11.1, 13.5), 3.07 (1H, d, J = 13.5),
3.71 (1H, s, br, NH), 4.88 (1H, d, J = 11.1),
6.60–7.90 (23H, m, aromatic)
TABLE 2 Elemental Analysis Data
Cald.
H
Found
Compd.
Molecular Formula
Molecular Weight
C
N
C
H
N
2a
2b
2c
2d
2e
2f
C34H27N4Br
571.51
527.06
522.64
522.64
527.06
527.06
71.45
77.48
80.43
80.43
77.48
77.48
4.76
5.16
5.79
5.79
5.16
5.16
9.80
10.63
10.72
10.72
10.63
10.63
71.09
77.57
80.77
80.31
77.13
77.22
4.49
5.37
5.39
5.41
5.05
5.47
9.57
10.44
10.70
10.67
10.30
10.29
C
C
C
34H27N4Cl
35H30N4O
35H30N4O
C
C
34H27N4Cl
34H27N4Cl

Synthesis of 1,3,3a,5-Tetraaryl-3a,4,5,6-tetrahydro-3H-1,2,4-triazolo[4,3-a][1,5]benzodiazepines 559
Vario EL elemental analyzer. The 1H NMR spec-
tra were recorded on a Varian Inova 300 spectrom-
eter with TMS as an internal standard in CDCl3.
Samples must be dissolved in CDCl3 prior to their
spectral determination. The IR spectra were taken
on a Brucker Vector 22 FT-IR spectrophotome-
ter in KBr. Mass spectra were obtained on a VG
ZAB-HS mass spectrometer. TLC separations were
performed on silica gel G plates with petroleum
ether (60–90 C)/acetone (8:1) as the eluent, and the
plates were visualized with UV light and/or iodine
vapor.
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tetrahydro-3H-1,2,4-triazolo[4,3-a]
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General Procedure. To a stirred solution of the
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N-phenylbenzenecarbohydrazonic chloride (0.69 g,
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