Synthesis of 1,5-benzodiazepine derivatives containing 1,2,3-triazole moiety via 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1002/jhet.1733

A series of 1,5-benzodiazepine derivatives were synthesized by the reaction of 1,5-benzodiazepine containing 1,2,3-triazole moiety with benzohydroximinoyl chlorides at room temperature. The structural identities of these novel compounds were confirmed on

Full text of DOI:10.1002/jhet.1733

Month 2014
Synthesis of 1,5-Benzodiazepine Derivatives Containing
1,2,3-Triazole Moiety via 1,3-Dipolar Cycloaddition Reaction
Zhi-Qiang Dong,a Hai Shi,a Sen-Lin Chen,a Hong-Xiang Chen,b Wei-Bin Jiang,b
a
b
*
Fang-Ming Liu, and Mei-Lin Hong
aCollege of Material and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, Zhejiang,
People’s Republic of China
bHangzhou Heze Pharmaceutical Technology Co., Ltd, Hangzhou 310018, Zhejiang, People’s Republic of China
*
E-mail: fmliu859@sohu.com
Received February 10, 2012
DOI 10.1002/jhet.1733
Published online in Wiley Online Library (wileyonlinelibrary.com).
O
NH2
NH2
R1
O
N
N
N
N
N
CHO
R1
N
N
N
N
N
N
N
H
N
H
N
R2
C
N OH
Cl
N
N
O
R1
N
R1
R2
A series of 1,5-benzodiazepine derivatives were synthesized by the reaction of 1,5-benzodiazepine containing
1,2,3-triazole moiety with benzohydroximinoyl chlorides at room temperature. The structural identities of these
novel compounds were confirmed on the basis of IR, 1H NMR, mass spectral and elemental analysis data, and
by X-ray crystallographic analysis of a typical example of the new class of 1,5-benzodiazepine analogs.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
activities including apoptosis inducers and potential
anticancer [15], anti-HIV [16], and selective cathepsin
inhibitors [17] activities. Taking into consideration the
important biological activity of azole derivatives as well
as the combination principles for drug design, we herein
report the synthesis of new 1,5-benzodiazepine derivatives
containing 1,2,3-triazole and 1,2,4-oxadiazole moieties
via 1,3-dipolar cycloaddition reaction. The synthetic route
is shown in Scheme 1.
Design and construction of privileged structures are impor-
tant strategy in medicinal chemistry. The 1,5-benzodiazepine
is commonly used as anxiolytic and anticonvulsive drugs,
and its derivatives have attracted considerable attention to
synthetic and medicinal chemists because of their broad
spectrum of biological activities such as allosteric inhibitor
[1], antioxidants [2], anti-inflammatory [3], and native
gamma-aminobutyric acid (GABAA) receptor [4] activities.
In recent years, 1,5-benzodiazepines also serve as key inter-
mediates for the synthesis of fused ring compounds such as
triazolo-, oxadiazolo-, oxazino- or furano-benzodiazepines
[5–7], and the resulting tricyclic 1,5-benzodiazepine deri-
vatives have shown clinical interest as drugs [8–10]. For
example, clozapine, olanzapine, and quetiapine are used
to treat schizophrenia, and clonazepam, diazepam, loraze-
pam, nitrazepam, and oxazepam are used as antianxiety
drugs. In addition, the 1,2,3-triazole constitute an important
class of biologically active compounds showing remarkable
therapeutic and pharmacological properties such as anti-
bacterial [11], anti-HIV [12], antimicrobial [13] agents,
and b3-adrenergic receptor agonist [14] activities. Mean-
while, 1,2,4-oxadiazole is also a major five-membered
heterocyclic ring, which serves as the core component of
many substances that display a wide range of biological
RESULT AND DISCUSSION
A series of novel benzodiazepine derivatives containing
a 1,2,3-triazole moiety was synthesized using 2-phenyl-4-
formyl-2H-1,2,3-triazole 1 as a starting material. Then,
intermediate compounds a,b-unsaturated ketone 2a–c via
the Claisen–Schmidt condensation reaction between 2-
phenyl-4-formyl-2H-1,2,3-triazole 1 and 1-arylethanones.
After that, the benzodiazepine derivatives 3a–c were synthe-
sized by reacting equimolar quantities of a,b-unsaturated
ketone 2a–c with benzene-1,2-diamine in ethanol using
acetic acid as catalyst. Finally, the compounds 3a–c under-
went 1,3-dipolar cycloadditions with various benzohydroxi-
minoyl chlorides in the presence of Et3N leading to the
formation of cycloadducts 4a–l. Various techniques, includ-
1
ing IR, H NMR, mass spectral and elemental analysis,
© 2014 HeteroCorporation

Z.-Q. Dong, H. Shi, S.-L. Chen, H.-X. Chen, W.-B. Jiang, F.-M. Liu and M.-L. Hong
Vol 000
Scheme 1. Synthesis route for titled compounds.
O
NH2
R1
O
N
N
N
NH2
N
N
CHO
R1
N
NaOH
Acetic acid
1
2a-c
N
N
N
N
N
N
H
N
H
N
R2
C N OH
Cl
N
R1
N
O
Et3N
N
R1
R2
3a-c
4a-l
3: a
b
c
R1= H
Cl
OCH3
4: a
b
c
d
e
f
g
h
i
j
k
l
R1= H
R2= H
H
Cl
H
H
Cl
H
Cl
Cl
Cl
Cl
OCH3 OCH3 OCH3 OCH3
Cl CH3 NO2
CH3 NO2
CH3 NO2
H
Table 1
Crystal data and structure refinement for compound 4b.
and X-ray crystallographic, were utilized to confirm the
structural identities of the final products.
In IR spectra, the synthesized final compounds show a
strong stretching vibration at 1607–1581 cmÀ1 because of
the presence of C═N. For the titled compounds, the presence
of the multiplet at d 8.18–6.55 ppm is attributed to the
Empirical
formula
C
30H23ClN6O
g (ꢀ)
90
Formula weight
Temperature
Wavelength
Crystal system
Space group
a, Å
518.99
296 K
0.71073 A
V (Å3)
Z
2662.4(8)
4
1.295
1080
2.2–27.6
0.178
23,934
Dc (mg/m3)
F(000)
1
Ar―H, N―H, and triazol-H. Also, the H NMR spectrum
Monoclinic
P21/n
10.1738(18)
18.785(3)
revealed a distinct doubled doublet at d 4.41–4.30 ppm and
multiplet at d 3.02–2.83 ppm for 4a–l, which could be attrib-
uted to the characteristic peak of dihydrobenzodiazepine
moiety as ABX pattern. In MS spectra, molecular ions peaks
of all target compounds were attained from EI to MS.
We propose a conceivable intramolecular 1,3-diploar
cycloaddition mechanism. In the presence of Et3N, the
nitrile oxide generated in situ and C═N double bond in
the benzodiazepine ring forms a cyclic transition state,
and the s-bonds of C―N and C―O were formed simulta-
neously to obtain the 1,2,4-oxadiazole ring, the central
diazepine ring of the cycloadduct adopts a boat-like
conformation.
θ range (ꢀ)
m(mmÀ1
)
b, Å
Reflections
collected
c, Å
a (ꢀ)
b (ꢀ)
14.190(3)
90
Data/restraints/ 6166/0/347
parameters
Final R indices
[I > 2s(I)]
R indices
R1 = 0.0498,
wR2 = 0.1582
R1 = 0.0857,
wR2 = 0.1364
100.969(4)
(all data)
Table 2
Selected bond lengths (Å) and angles (ꢀ) of compound 4b.
To establish the exact structure of the cycloadducts,
compounds 4b was crystallized, and their atomic coordi-
nates was obtained by X-ray analysis. The crystal data
and structure refinement are shown in Table 1. Selected
bond lengths and angles are listed in Table 2. CCDC–
814232 for 4b contains the supplementary crystallographic
data for this article. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre
(CCDC) via e-mail: deposit@ccdc.cam.ac.uk.
N(2)―C(18)
1.286(3)
C(18)―N(2)―O(1)
106.51(14)
N(2)―O(1)
N(1)―C(11)
O(1)―C(11)
N(4)―C(7)
N(6)―C(8)
N(3)―C(9)
C(9)―C(10)
1.431(2)
1.467(2)
1.456(2)
1.330(3)
1.324(2)
1.471(3)
1.529(3)
N(2)―O(1)―C(11)
O(1)―C(11)―N(1)
C(18)―N(1)―C(11)
C(12)―N(3)―C(9)
C(13)―N(1)―C(11)
N(4)―N(5)―N(6)
C(9)―C(10)―C(11)
105.48(12)
101.64(13)
103.31(13)
115.97(16)
121.57(13)
115.20(15)
112.03(16)
The crystal structure of the compound 4b is shown in
Fig. 1, and a perspective view of the crystal packing in
the unit cell is tabulated in Fig. 2. The oxadiazoline ring,
resulting from the 1,3-cycloaddition reaction, adopts an
envelope conformation, only with maximum deviation
of À0.1752 Å for atom C(11) for the plane defined by
N(1)―C(11)―O(1)―N(2)―C(18), which is nearly coplanar
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of 1,5-Benzodiazepine Derivatives Containing 1,2,3-Triazole
Moiety via 1,3-Dipolar Cycloaddition Reaction
Figure 1. Molecular structure of 4b.
Figure 2. Packing of molecules in a unit cell of 4b.
due to existing a mean deviation of 0.1160 Å. The seven-
membered diazepine ring as the center is characterized by
the endocyclic torsion angles (enumerated clockwise and
starting with N(3)―C(9)―C(10)―C(11)): 46.6(2)ꢀ,
À72.5(2)ꢀ, À2.8(2)ꢀ, 55.9(2)ꢀ, À3.9(3)ꢀ, À74.3(2)ꢀ, 45.3(2)ꢀ.
N(1), C(11), C(9), and N(3) are almost coplanar, whereas
C(10), C(12), and C(13) are below the plane. So, the
seven-membered ring adopts a boat-like conformation. In
addition, the phenyl ring (C(19)―C(24)) forms dihedral
angles of 75.8ꢀ and 81.5ꢀ with the oxadiazoline ring and the
1,2,3-triazole ring. In crystal structure, there is no classic hy-
drogen bonds; thus, the structure is supported by weak
intermolecular hydrogen bond of N―H. . .N as N(3)―H
(13). . .N(2) (Fig. 2) with symmetry code 1/2 + x, 3/2 À y,
1/2 + z.
CONCLUSION
In summary, we have synthesized a series of 1,5-
benzodiazepine derivatives 4a–l bearing 1,2,3-triazole
moiety via 1,3-dipolar cycloaddition reaction. The structural
identities of these compounds were confirmed by X-ray
analysis of compound 4b as typical examples of the new
1,5-benzodiazepine analog class.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Z.-Q. Dong, H. Shi, S.-L. Chen, H.-X. Chen, W.-B. Jiang, F.-M. Liu and M.-L. Hong
Vol 000
yield 35%; mp 184–186ꢀC; 1H NMR: d 8.03–6.63 (m, 21H, Ar―H,
N―H, and N═C―H), 4.35–4.31 (dd, 1H, H5x, Jax = 12.1 Hz,
Jbx = 3.9 Hz), 2.99–2.86 (m, 2H, H4a, H4b, Jax = 12.1 Hz,
Jbx =3.9Hz, Jab = 14.0 Hz) ppm; IR (KBr): n 3298, 2983, 2890,
1594 cmÀ1; MS: m/z 484 (M+, 4); Anal. Calcd for C30H24N6O: C,
74.36; H, 4.99; N, 17.34; Found: C, 74.33; H, 5.01; N, 17.36.
1-(4-Chlorophenyl)-3a-phenyl-5-(2-phenyl-1,2,3-triazol-4-yl)-
3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]benzodiazepine
(4b). Yellow solid, yield 31%; mp 219–220ꢀC; 1H NMR: d
8.02–6.60 (m, 20H, Ar―H, N―H, and N═C―H), 4.35–4.31
(dd, 1H, H5x, Jax = 12.0 Hz, Jbx = 3.9 Hz), 2.98–2.85 (m, 2H,
H4a, H4b, Jax = 12.0 Hz, Jbx = 3.9 Hz, Jab = 14.0 Hz) ppm; IR
(KBr): n 3250, 2936, 2867, 1584 cmÀ1; MS: m/z 521 [(M++2),
2], 519 (M+, 6); Anal. Calcd for C30H23ClN6O: C, 69.43; H,
4.47; N, 16.19; Found: C, 69.41; H, 4.48; N, 16.20.
EXPERIMENTAL
Reactions were monitored by TLC. Melting points were
determined by a Mettler FP-5 melting point apparatus and were
uncorrected. Elemental analyses were conducted on a Perkin-
Elmer 2400 elemental analyzer. The IR data was recorded on
potassium bromide pellets by a Bruker Equinox 55 FTIR spectro-
1
photometer. The H NMR data was recorded on a Bruker NMR
spectrophotometer (400 MHz) using TMS as an internal reference
and CDCl3 as solvent. Multiplicities are indicated as the follow-
ing: s, singlet; m, multiplet; dd, doubled doublet. Coupling con-
stants (J values) where noted are quoted in Hertz. Mass spectra
were preformed on an Agilent 5975 apparatus (EI, 70 eV). X-ray
diffraction data were collected on a Bruker Smart Apex Duo diffrac-
tometer. Compounds 1 [18] and 2 [19] were synthesized according
to the reported literature.
General procedure for the synthesis of 3a–c. The chalcone 2
(10 mmol) and benzene-1,2-diamine (12.5 mmol) were dissolved
in anhydrous ethanol (30 mL) and dry benzene (10 mL). The
reaction mixture was heated under reflux for 5 h in the presence
of acetic acid (1.0 mL) under stirring. After reaction, the
mixture was evaporated off, and the residue was purified by
silica gel column chromatography with ethylacetate: petroleum
ether (V:V = 1:8) as eluent.
1-(4-Methylphenyl)-3a-phenyl-5-(2-phenyl-1,2,3-triazol-4-yl)-
3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]benzodiazepine
(4c). Yellow solid, yield 37%; mp 179–180ꢀC; 1H NMR: d
8.02–6.64 (m, 20H, Ar―H, N―H, and N═C―H), 4.34–4.30
(dd, 1H, H5x, Jax = 12.1 Hz, Jbx = 3.9 Hz), 2.98–2.84 (m, 2H,
H4a, H4b, Jax = 12.1 Hz, Jbx = 3.9 Hz, Jab = 14.0 Hz), 2.34
(s, 3H, ―CH3) ppm; IR (KBr):
n 3290, 2985, 2880,
1602 cmÀ1; MS: m/z 498 (M+, 4); Anal. Calcd for C31H26N6O:
C, 74.68; H, 5.26; N, 16.86; Found: C, 74.66; H, 5.27; N, 16.87.
1-(4-Nitrophenyl)-3a-phenyl-5-(2-phenyl-1,2,3-triazol-4-yl)-
3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]benzodiazepine
(4d). Yellow solid, yield 32%; mp 216–217ꢀC; 1H NMR: d
8.18–6.55 (m, 20H, Ar―H, N―H, and N═C―H), 4.40–4.36
(dd, 1H, H5x, Jax = 12.0 Hz, Jbx = 3.9 Hz), 3.01–2.87 (m, 2H,
H4a, H4b, Jax = 12.0 Hz, Jbx = 3.9 Hz, Jab = 14.0 Hz) ppm; IR
(KBr): n 3298, 2983, 2890, 1594 cmÀ1; MS: m/z 529 (M+, 4);
Anal. Calcd for C30H23N7O3: C, 68.04; H, 4.38; N, 18.52;
Found: C, 68.03; H, 4.40; N, 18.50.
2-(2-Phenyl-1,2,3-triazol-4-yl)-4-phenyl-1,5-benzodiazepine
(3a). Yellow solid, yield 67%; mp 178–179ꢀC; 1H NMR: d
8.03–6.84 (m, 16H, Ar―H, N═C―H, and N―H), 5.52–5.49
(dd, 1H, H2x, Jax = 4.3 Hz, Jbx = 8.4 Hz ), 3.35–3.30 (dd, 1H, H3a,
Jax = 4.3 Hz, Jab = 13.2 Hz), 3.18–3.13 (dd, 1H, H3b, Jbx = 8.4 Hz,
Jab = 13.2Hz) ppm; IR (KBr): n 3389, 2993, 2785, 1644cmÀ1
;
MS: m/z 365 (M+, 17); Anal. Calcd for C23H19N5: C, 75.59; H,
5.24; N, 19.16; Found: C, 75.55; H, 5.28; N, 19.18.
4-(4-Chlorophenyl)-2-(2-phenyl-1,2,3-triazol-4-yl)-1,5-
benzodiazepine (3b). Yellow solid, yield 65%; mp 192–193ꢀC; 1H
NMR: d 8.00–6.86 (m,15H, Ar―H, N═C―H, and N―H), 5.55–
5.52 (dd, 1H, H2x, Jax = 4.6Hz, Jbx = 8.6 Hz), 3.37–3.32 (dd, 1H,
H3a, Jax = 4.6 Hz, Jab = 13.2 Hz), 3.20–3.14 (dd, 1H, H3b,
Jbx = 8.6 Hz, Jab = 13.2Hz) ppm; IR (KBr): n 3418, 3052, 2893,
1612cmÀ1; MS: m/z 402 [(M++2), 7], 400 (M+, 21); Anal. Calcd
for C23H18ClN5: C, 69.08; H, 4.54; N, 17.51; Found: C, 69.02;
H, 4.56; N, 17.52.
4-(4-Methoxyphenyl)-2-(2-phenyl-1,2,3-triazol-4-yl)-1,5-
benzodiazepine (3c). Yellow solid, yield 58%; mp 200–201ꢀC;
1H NMR: d 8.04–6.93 (m, 15H, Ar―H, N═C―H, and N―H),
5.61–5.58 (dd, 1H, H2x, Jax = 4.8 Hz, Jbx = 8.9 Hz ), 3.43–3.37
(dd, 1H, H3a, Jax = 4.8 Hz, Jab = 13.2 Hz), 3.23–3.16 (dd, 1H, H3b,
Jbx = 8.9 Hz, Jab = 13.2 Hz), 3.85 (s, 3H, ―OCH3) ppm; IR (KBr):
n 3432, 3002, 2884, 1627 cmÀ1; MS: m/z 395 (M+, 41); Anal.
Calcd for C24H21N5O: C, 72.89; H, 5.35; N, 17.71; Found: C,
72.84; H, 5.37; N, 17.67.
General procedure for the synthesis of 4a–l. The reaction
mixture of compounds 3 (1.0 mmol) and benzohydroximinoyl
chlorides (1.5 mmol) were stirred in CH2Cl2 (20 mL), and the
solution of Et3N (0.5 mL) in CH2Cl2 (8 mL) was added
dropwise under stirring. The mixture was kept under stirring for
2 days at room temperature. The triethylamine hydrochloride
was filtered after the completion of the reaction. The solution
was evaporated off, and the residue was purified by silica gel
column chromatography with ethylacetate: petroleum ether (V:
V = 1:8 to 1:10) as eluent.
3a-(4-Chlorophenyl)-1-phenyl-5-(2-phenyl-1,2,3-triazol-4-yl)-
3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]benzodiazepine
(4e). Yellow solid, yield 34%; mp 186–187ꢀC; 1H NMR: d
8.06–6.68 (m, 20H, Ar―H, N―H, and N═C―H), 4.34–4.30
(dd, 1H, H5x, Jax = 12.0 Hz, Jbx = 3.9 Hz), 2.98–2.84 (m, 2H,
H4a, H4b, Jax = 12.0 Hz, Jbx = 3.9 Hz, Jab = 14.0 Hz) ppm; IR
(KBr): n 3247, 2980, 2884, 1583 cmÀ1; MS: m/z 521 [(M++2),
1], 519 (M+, 3); Anal. Calcd for C30H23ClN6O: C, 69.43; H,
4.47; N, 16.19; Found: C, 69.42; H, 4.49; N, 16.22.
1,3a-Bis-(4-chlorophenyl)-5-(2-phenyl-1,2,3-triazol-4-yl)-
3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]benzodiazepine
(4f). Yellow solid, yield 30%; mp 208–210ꢀC; 1H NMR: d
8.06–6.65 (m, 19H, Ar―H, N―H, and N═C―H), 4.35–4.31
(dd, 1H, H5x, Jax = 12.0 Hz, Jbx = 3.9 Hz), 2.97–2.83 (m, 2H,
H4a, H4b, Jax = 12.0 Hz, Jbx = 3.9 Hz, Jab = 14.0 Hz) ppm; IR
(KBr): n 3256, 2924, 2855, 1598 cmÀ1; MS: m/z 557 [(M++4),
1], 555 [(M++2), 6], 553 (M+, 9); Anal. Calcd for
C30H22Cl2N6O: C, 65.11; H, 4.01; N, 15.19; Found: C, 65.09;
H, 4.02; N, 15.21.
3a-(4-Chlorophenyl)-1-(4-methylphenyl)-5-(2-phenyl-1,2,3-
triazol-4-yl)-3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]
benzodiazepine (4g). Yellow solid, yield 32%; mp 194–195ꢀC;
1H NMR: d 8.03–6.65 (m, 19H, Ar―H, N―H, and N═C―H),
4.34–4.30 (dd, 1H, H5x, Jax = 12.0 Hz, Jbx = 4.0 Hz), 2.96–2.82
(m, 2H, H4a, H4b, Jax = 12.0 Hz, Jbx = 4.0 Hz, Jab = 14.0Hz), 2.34
(s, 3H, ―CH3) ppm; IR (KBr): n 3268, 2979, 2894, 1585 cmÀ1
;
MS: m/z 535 [(M++2), 2], 533 (M+, 6); Anal. Calcd for
C31H25ClN6O: C, 69.85; H, 4.73; N, 15.77; Found: C, 69.84; H,
4.75; N, 15,74.
1,3a-Diphenyl-5-(2-phenyl-1,2,3-triazol-4-yl)-3a,4,5,6-tetrahydro-
[1,2,4]oxadiazolo [5,4-d][1,5]benzodiazepine (4a). Yellow solid,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of 1,5-Benzodiazepine Derivatives Containing 1,2,3-Triazole
Moiety via 1,3-Dipolar Cycloaddition Reaction
3a-(4-Chlorophenyl)-1-(4-nitrophenyl)-5-(2-phenyl-1,2,3-
triazol-4-yl)-3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]
benzodiazepine (4h). Yellow solid, yield 30%; mp 195–197ꢀC;
1H NMR: d 8.17–6.56 (m, 19H, Ar―H, N―H, and N═C―H),
4.39–4.35 (dd, 1H, H5x, Jax = 12.1 Hz, Jbx = 3.9 Hz), 3.02–2.88
(m, 2H, H4a, H4b, Jax = 12.1 Hz, Jbx = 3.9 Hz, Jab = 14.0 Hz) ppm;
IR (KBr): n 3231, 2934, 2859, 1591 cmÀ1; MS: m/z 566
[(M++2), 1], 564 (M+, 3); Anal. Calcd for C30H22ClN7O3: C,
63.89; H, 3.93; N, 17.38; Found: C, 63.87; H, 3.94; N, 17.36.
3a-(4-Methoxyphenyl)-1-phenyl-5-(2-phenyl-1,2,3-triazol-4-yl)-
3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]benzodiazepine
(4i). Yellow solid, yield 38%; mp 89–91ꢀC; 1H NMR: d 8.05–6.63
(m, 20H, Ar―H, N―H, and N═C―H), 4.38–4.34 (dd, 1H, H5x,
Jax =12.1Hz, Jbx = 3.9 Hz), 3.80 (s, 3H, ―OCH3), 2.99–2.86
(m, 2H, H4a, H4b, Jax = 12.1 Hz, Jbx =3.9 Hz, Jab = 14.0 Hz) ppm;
IR (KBr): n 3301,2993, 2895, 1588 cmÀ1; MS: m/z 514 (M+, 4);
Anal. Calcd for C31H26N6O2: C, 72.36; H, 5.09; N, 16.33; Found:
C, 72.34; H, 5.11; N, 16.29.
Acknowledgments. We are grateful to the Key SCI-Tech Innovation
Team of Zhejiang Province (2010R50017) for financial help.
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R.; Emmert, D. E.; Garmon, S. A.; Graber, D. A.; Grega, K. C.; Hester, J.
B.; Hutchinson, D. K.; Morris, J.; Reischer, R. J.; Ford, C. W.; Zurenko,
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1-(4-Chlorophenyl)-3a-(4-methoxyphenyl)-5-(2-phenyl-1,2,3-
triazol-4-yl)-3a,4,5,6-tetrohydro-[1,2,4]oxadiazolo[5,4-d][1,5]
1
benzodiazepine (4j). Yellow solid, yield 33%; mp 97–98ꢀC; H
NMR: d 8.04–6.61 (m, 19H, Ar―H, N―H, and N═C―H),
4.37–4.33 (dd, 1H, H5x, Jax =12.0 Hz, Jbx = 3.9 Hz), 3.80 (s, 3H,
―OCH3), 2.97–2.83 (m, 2H, H4a, H4b, Jax =12.0Hz, Jbx =3.9Hz,
J
ab = 14.0 Hz) ppm; IR (KBr): n 3303, 2977, 2854, 1581 cmÀ1
;
MS: m/z 551 [(M++2), 3], 549 (M+, 9); Anal. Calcd for
C31H25ClN6O2: C, 67.82; H, 4.59; N, 15.31; Found: C, 67.80; H,
4.60; N, 15.33.
3a-(4-Methoxyphenyl)-1-(4-methylphenyl)-5-(2-phenyl-1,2,3-
triazol-4-yl)-3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]
benzodiazepine (4k). Yellow solid; yield 42%; mp 97–99ꢀC; 1H
NMR: d 8.05–6.60 (m, 19H, Ar―H, N―H, and N═C―H),
4.38–4.34 (dd, 1H, H5x, Jax =12.0 Hz, Jbx = 3.9 Hz), 3.80 (s, 3H,
―OCH3), 2.98–2.84 (m, 2H, H4a, H4b, Jax =12.0Hz, Jbx =3.9Hz,
Jab = 14.0 Hz), 2.33 (s, 3H, ―CH3) ppm; IR (KBr): n 3310, 2976,
2898, 1589 cmÀ1; MS: m/z 528 (M+, 4); Anal. Calcd for
C32H28N6O2: C, 72.71; H, 5.34; N, 15.90; Found: C, 72.69; H,
5.35; N, 15.88.
3a-(4-Methoxyphenyl)-1-(4-nitrophenyl)-5-(2-phenyl-1,2,3-
triazol-4-yl)-3a,4,5,6-tetrahydro-[1,2,4]oxadiazolo[5,4-d][1,5]
benzodiazepine (4l). Yellow solid, yield 35%; mp 181–183ꢀC;
1H NMR: d 8.17–6.55 (m, 19H, Ar―H, N―H, and N═C―H),
4.41–4.37 (dd, 1H, H5x, Jax = 12.0 Hz, Jbx = 3.9 Hz), 3.81 (s,
3H, ―OCH3), 3.02–2.88 (m, 2H, H4a, H4b, Jax = 12.0 Hz,
Jbx = 3.9 Hz, Jab = 14.0 Hz) ppm; IR (KBr): n 3223, 2996,
2902, 1607 cmÀ1; MS: m/z 559 (M+, 6); Anal. Calcd for
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ꢀ
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Heterocycl Chem 2005, 42, 1167.
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Cascieri, M. A.; Colwell, L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.;
Hom, G. J.; MacIntyre, D. E.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.;
Weber, A. E. Bioorg Med Chem Lett 2000, 10, 2111.
[15] Zhang, H. Z.; Kasibhatla, S.; Kuemmerle, J.; Kemnitzer, W.;
Ollis-Mason, K.; Qiu, L.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai,
S. X. J Med Chem 2005, 48, 5215.
[16] Sakamoto, T.; Cullen, M. D.; Hartman, T. L.; Watson, K. M.;
Buckheit, R. W.; Pannecouque, C.; Clercq, E. D.; Cushman, M. J Med
Chem 2007, 50, 3314.
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Med Chem 2011, 54, 396.
[18] Liu, F. M.; Cao, L. H. J Xinjianguniv 1993, 10, 70.
[19] Liu, F. M.; Wang, B. L.; Zhang, Z. F.; Sun, W. B. Acta
Chimica Sinica 2002, 60, 1095.
C
31H25N7O4: C, 66.54; H, 4.50; N, 17.52; Found: C, 66.52;
H, 4.51; N, 17.53.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet