Synthesis and structure characterization of new [1,2,4]triazolo[5,4-d][1,5] benzothiazepine derivatives through 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1002/jhet.587

Reaction of 1,5-benzothiazepines 3, obtained from chalcones 2 and o-aminobenzenthiol, with the (phenylhydrazino) chloromethylenecarboxylates 4 in the presence of Et₃N leads to a series of new [1,2,4]triazolo[5,4-d] [1,5]benzothiazepine derivatives 5. Their structures were established using spectroscopic methods and that of compound 5d was confirmed using X-ray diffraction analysis.

Full text of DOI:10.1002/jhet.587

368
Synthesis and Structure Characterization of New
[1,2,4]Triazolo[5,4-d][1,5]benzothiazepine Derivatives Through
1,3-Dipolar Cycloaddition Reaction
Vol 48
Xiao-Long Wu,a Fang-Ming Liu,a,b* and Ying-Lei Zhoua
aCollege of Materials and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036,
China
bCollege of Chemistry and Chemical Engineering, Xinjiang University, Urumqi 830046, Xinjiang,
China
*E-mail: fmliu859@sohu.com
Received March 16, 2010
DOI 10.1002/jhet.587
Published online 22 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Reaction of 1,5-benzothiazepines 3, obtained from chalcones 2 and o-aminobenzenthiol, with the
(phenylhydrazino) chloromethylenecarboxylates 4 in the presence of Et3N leads to a series of new
[1,2,4]triazolo[5,4-d][1,5]benzothiazepine derivatives 5. Their structures were established using spectro-
scopic methods and that of compound 5d was confirmed using X-ray diffraction analysis.
J. Heterocyclic Chem., 48, 368 (2011).
INTRODUCTION
Inspired by the biological profile of 1,5-benzothiaze-
pine and 1,2,4-triazole derivatives and in continuation of
our interest in the synthesis of new 1,5-benzothiazepine
derivatives [10,11], we reported herein the reaction of
1,5-benzothiazepines 3 with the nitrileimines 4 through
1,3-dipolar cycloaddition to afford a new series of
[1,2,4]triazolo[5,4-d][1,5]benzothiazepine derivatives 5.
(Table 1). It was thought worthwhile to synthesize the
title compounds with both active pharmacophores in a
single molecular framework, which may have potential
biological and medical applications.
The synthesis of benzothiazepine derivatives has
attracted considerable attention of organic and medicinal
chemists because of their broad spectrum of biological
activities, such as cardiovascular modulator, coronary
vasodilators, ACE inhibitors, anti-HIV, antihypertensive,
antidepressant, and antibacterial and anticancer activity
[1,2]. Recently, progress has been made into fix an addi-
tional heterocycle on the heptatomic nucleus of 1,5-ben-
zothiazepine for the preparation of fused ring com-
pounds. The presence of the conformational preferences
of the seven-membered ring is possibly correlated with
biological activity, and the fusion of a heterocyclic nu-
cleus to the thiazepine system could induced an increase
of the ring inversion barrier and consequently modify
the activity profile [3,4].
RESULTS AND DISCUSSION
The synthetic route used is shown in Scheme 1. The
chalcones 2 were readily prepared by condensation of
aryl aldehydes with acetophenone. The reaction of 2
with o-aminobenzenthiol, in methanol in the presence of
acetic acid at reflux temperature for 4 h, to get the
required 2,4-diaryl-2,3-dihydro-1,5-benzothiazepines 3
in good to excellent yields. 1,3-Dipolar cycloaddition
reaction of 3 with nitrileimines, generated in situ from
Furthermore, 1,2,4-triazole derivatives have been re-
ported to exhibit antifungal, anti-inflammatory, and anti-
microbial activity [5]. For example, itraconazole and flu-
conazole are clinically used as antimicrobial drugs [6,7].
In addition, a 1,2,4-triazole is a key subunit in the struc-
ture of a potential anticancer and anti-HIV agents [8,9].
C
V
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March 2011
Synthesis and Structure Characterization of New [1,2,4]Triazolo[5,4-d][1,5]
benzothiazepine Derivatives Through 1,3-Dipolar Cycloaddition Reaction
369
Table 1
Physical and analytical data of compounds 5.
Analysis % (Calcd./Found)
Entry
1
Comp.
R1
H
R2
H
mp (ꢁC)
237–238
Yield (%)
25
Molecular formula
C31H27N3O2S
C
H
N
5a
73.64
73.61
68.94
68.92
73.96
73.98
68.94
68.95
64.81
64.79
69.36
69.32
71.75
71.77
67.42
67.40
72.11
72.10
67.62
67.61
63.64
63.66
68.07
68.08
5.38
5.40
4.85
4.86
5.62
5.61
4.85
4.82
4.39
4.40
5.09
5.11
5.46
5.45
4.95
4.96
5.68
5.67
4.76
4.75
4.31
4.30
5.00
4.99
8.31
8.33
7.78
7.80
8.09
8.07
7.78
7.79
7.31
7.34
7.58
7.59
7.84
7.82
7.37
7.39
7.64
7.67
10.18
10.21
9.58
9.55
9.92
9.94
2
5b
5c
5d
5e
5f
H
H
Cl
CH3
H
199–200
189–190
217–218
254–255
215–216
178–179
244–245
221–222
179–180
230–231
170–171
31
30
26
32
29
21
27
33
22
31
28
C31H26ClN3O2S
C32H29N3O2S
3
4
Cl
C31H26ClN3O2S
C31H25Cl2N3O2S
C32H28ClN3O2S
C32H29N3O3S
5
Cl
Cl
6
Cl
CH3
H
7
5g
5h
5i
OCH3
OCH3
OCH3
NO2
NO2
NO2
8
Cl
C32H28ClN3O3S
C33H31N3O3S
9
CH3
H
10
11
12
5j
C31H26N4O4S
5k
5l
Cl
C31H25ClN4O4S
C32H28N4O4S
CH3
(phenylhydrazino) chloromethylenecarboxylates 4 in the
presence of Et3N, to yield the target compounds 5a–5l.
The structures of the title compounds have been char-
given in Figure 1. The higher occupancy in the three-
dimensional packing arrangement is shown in Figure 2.
The crystal data and structure refinement of 5d are listed
in Table 2. Selected bond distances and angles of 5d are
tabulated in Table 3.
1
acterized by IR, H-NMR, MS, and elemental analysis.
For example, the infrared spectra of these compounds
showed a characteristic absorption band at 1730 cmꢀ1
because of the presence of the ester-carbonyl group.
Figure 1 is the stereostructure of compound 5d. There
is a five-membered ring in the molecule, resulting from
the cycloaddition reaction. All atoms [N(1), C(7), N(2),
N(3), and C(17)] in the ring are nearly coplanar with
similar bond angles [N(1)AC(7)AN(2) 114.71(19)ꢁ,
1
Also, their H-NMR spectra revealed multiplet between
d 7.60 and 6.60 ppm because of the aromatic protons,
the signal for ethoxycarbonyl CH2 and CH3 appeared at
d 4.19–4.21 ppm and 1.19–1.20 ppm, respectively, and
three distinct double doublets in the ABX system (a CH
proton and tow anisochronous protons of a CH2)
appeared at d 2.65–4.56 ppm, as has been observed in
2,3-dihydro-1,5-benaothiazepine. In MS spectra, the
compounds exhibit a stable molecular ion, and the base
peak is the [M-(EtOCOþR1C6H5CH¼¼CH2)] ion in all
the compounds analyzed. The relative abundance of the
main fragmentation in the compounds has some com-
mon features. The most important ions are as follows:
Mþ, [M-77], [M-(R1C6H5CH¼¼CH2)], and [M-(EtO-
COþR1C6H5CH¼¼CH2)]. The main fragmentation was
consistent with the assigned structures.
C(7)AN(2)AN(3)
106.34(17)ꢁ,
N(2)AN(3)AC(17)
and
111.98(15)ꢁ,
N(3)AC(17)AN(1)
97.98(15)ꢁ,
Scheme 1
Subsequently, the absolute configuration of the reac-
tion products 5 has been further elucidated from X-ray
diffraction analysis of a single crystal. The general view
of the molecule 5d and its principal characteristics are
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370
X.-L. Wu, F.-M. Liu, and Y.-L. Zhou
Vol 48
Figure 2. Packing of molecules in a unit cell of 5d.
11.2(2)ꢁ, ꢀ82.5(2)ꢁ, 56.0(2)ꢁ, 43.8(2)ꢁ, and ꢀ76.0(3)ꢁ.
N(1), S(1), C(17), and C(19) are coplanar, whereas C(1),
C(6), and C(18) are all below the plane, with their devia-
˚
tions being ꢀ0.4046, ꢀ0.2090, and ꢀ0.6481 A. Therefore,
the seven-membered ring adopts a boat-like conformation.
CCDC-769643 (for 5d) contains the supplementary
crystallographic data for this article. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/const/
retrieving.html.
Figure 1. The molecular structure of the title compound 5d.
C(17)AN(1)AC(7) 107.28(16)ꢁ], indicating the ring is
stable. The five-membered ring is characterized by the
endocyclic torsion angles [enumerated clockwise and
starting with C(7)AN(2)AN(3)AC(17)]: 7.5(3)ꢁ, 1.3(3)ꢁ,
ꢀ9.4(3)ꢁ, 12.1(2)ꢁ, and ꢀ12.1(2)ꢁ. The five-membered
ring plane adopts an envelope conformation with atom
C(17) deviating from the plane defined by N(3), N(2),
In conclusion, we have achieved an efficient one-step
synthesis of new [1,2,4]triazolo[5,4-d][1,5]benzothiaze-
pines 5a–5l by way of highly regioselective 1,3-dipolar
cycloaddition of the (phenylhydrazino) chloromethylene-
carboxylates 4a–4c to 2,4-diary-2,3-dihydro-1,5-benzo-
thiazepines 3a–3d.
˚
C(7), and N(1) of 0.0737 A. The bond length of
˚
N(2)AC(7), 1.281(3) A, indicates that it is a double
bond.
EXPERIMENTAL
There is also a seven-membered ring in the molecule.
1,5-Benzothiazepine ring is characterized by the en-
docyclic torsion angles (enumerated clockwise and
starting with S(1)AC(1)AC(6)AN(1)): ꢀ1.9(3)ꢁ, 41.8(2)ꢁ,
All reagents were of commercial availability. Reactions
were monitored by thin-layer chromatography (TLC). Melting
points were measured on a mettler FP-5 capillary melting point
Table 2
Crystal data and structure refinement for compound 5d.
3
V (A )
˚
Empirical
Formula
C31H26ClN3
O2S
540.06
2643.3(3)
Formula weight
Temperature
Wavelength
Crystal system
Space group
Z
4
1.357
293(2) K
0.71073 A
Orthorhombic
P2(1)2(1)2(1)
9.7747(7)
11.0448(8)
24.4840(17)
90
Dc (mg/m3)
Crystal size (mm)
y range (ꢁ)
0.72 ꢂ 0.45 ꢂ 0.10
3.10–27.48
0.258
l (mmꢀ1
)
Reflections collected
˚
a (A)
26123
6060 [R(int) ¼ 0.0353]
˚
b (A)
Independent reflection
Data/restraints/parameters
Final R indices [I > 2r(I)]
R indices (all data)
˚
c (A)
6060/0/344
R1 ¼ 0.0445, wR2 ¼ 0.1125
R1 ¼ 0.0628, wR2 ¼ 0.1309
a (ꢁ)
b (ꢁ)
c (ꢁ)
90
90
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Synthesis and Structure Characterization of New [1,2,4]Triazolo[5,4-d][1,5]
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371
Table 3
Ethyl 3a,4-dihydro-3,3a,5-triphenyl-5H-[1,2,4]triazolo[5,4-
d][1,5]benzothiazepine-1-carboxylate (5a). This compound
was obtained as yellow crystals in 25% yield, mp 237–238ꢁC.
ꢁ
˚
Selected bond lengths (A) and angles ( ) of compounds 5d.
IR(KBr) t: 3051, 1730, 758 cmꢀ1 1H-NMR (CDCl3, 400
.
N(1)AC(7)
N(2)AC(7)
N(2)AN(3)
N(1)AC(17)
N(3)AC(17)
O(1)AC(8)
O(2)AC(8)
C(7)AC(8)
1.388(3)
1.281(3)
1.392(2)
1.495(3)
1.493(3)
1.320(3)
1.206(3)
1.485(3)
C(1)AS(1)AC(19)
C(7)AN(1)AC(6)
C(7)AN(1)AC(17)
N(2)AN(3)AC(11)
N(2)AC(7)AN(1)
O(2)AC(8)AC(7)
C(7)AN(2)AN(3)
O(2)AC(8)AO(1)
107.30(10)
124.45(18)
107.28(16)
116.82(17)
114.71(19)
123.4(2)
MHz) d: 7.60–6.60 (m, 19H, Ar-H), 4.55 (dd, 1H, H-5x, Jax
¼
1.56 Hz, Jbx ¼ 11.52 Hz), 4.20 (q, 2H, OACH2ACH3), 2.86
(dd, 1H, H-4a, Jax ¼ 1.56 Hz, Jab ¼ 16 Hz), 2.71 (dd, 1H, H-
4b, Jbx ¼ 11.52 Hz, Jab ¼ 16 Hz), 1.19 (t, 3H, OACH2ACH3).
MS: m/z 505 (Mþ). Anal. Calcd. for C31H27N3O2S: C, 73.64;
H, 5.38; N, 8.31; Found: C, 73.61; H, 5.40; N, 8.33.
106.34(17)
124.7(2)
Ethyl 3a,4-dihydro-3-(4-chlorophenyl)-3a,5-diphenyl-5H-[1,2,
4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (5b). This
compound was obtained as yellow crystals in 31% yield, mp
.
199–200ꢁC. IR(KBr) t: 3047, 1725, 763 cmꢀ1 1H-NMR
C(17)AC(26) 1.322(3) C(17)AC(18)AC(19) 112.36(18)
apparatus and were uncorrected. Elemental analyses were per-
formed on a Perkin-Elmer 2400 elemental analyzer. The IR
spectra were determined as potassium bromide pellet on a
Bruker Equinox 55 FTIR spectrophotometer. The 1H-NMR
spectra were recorded on a Varian Inova-400 spectrophotome-
ter using TMS as an internal standard. EI-MS spectra were
recorded with an Agilent 5975 apparatus. X-ray crystal struc-
ture was obtained using R-AXIS SPIDER X-ray diffraction.
Chalcones 2 were obtained according to the known procedure
[12]. The (phenylhydrazino) chloromethylenecarboxylates 4a–
4c (4a: R2 ¼ H; 4b: R2 ¼ Cl; 4c: R2 ¼ CH3) were obtained
according to the known procedure [13].
(CDCl3, 400 MHz) d: 7.60–6.60 (m, 18H, Ar-H), 4.52 (dd,
1H, H-5x, Jax ¼ 1.60 Hz, Jbx ¼ 11.60 Hz), 4.21 (q, 2H,
OACH2ACH3), 2.87 (dd, 1H, H-4a, Jax ¼ 1.60 Hz, Jab ¼ 16
Hz), 2.77 (dd, 1H, H-4b, Jbx ¼ 11.60 Hz, Jab ¼ 16 Hz), 1.20
(t, 3H, OACH2ACH3). MS: m/z 539 (Mþ). Anal. Calcd. for
C31H26ClN3O2S: C, 68.94; H, 4.85; N, 7.78; Found: C, 68.92;
H, 4.86; N, 7.80.
Ethyl 3a,4-dihydro-3-(4-methylphenyl)-3a,5-diphenyl-5H-[1,2,
4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (5c). This
compound was obtained as yellow crystals in 30% yield, mp
189–190ꢁC. IR(KBr) t: 3043, 1721, 762 cmꢀ1 1H-NMR
.
(CDCl3, 400 MHz) d: 7.60–6.60 (m, 18H, Ar-H), 4.55 (dd,
1H, H-5x, Jax ¼ 1.43 Hz, Jbx ¼ 11.77 Hz), 4.20 (q, 2H,
OACH2ACH3), 2.88 (dd, 1H, H-4a, Jax ¼ 1.43 Hz, Jab ¼ 16
Hz), 2.72 (dd, 1H, H-4b, Jbx ¼ 11.77 Hz, Jab ¼ 16 Hz), 2.22
(s, 3H, Ar-CH3), 1.20 (t, 3H, OACH2ACH3). MS: m/z 519
(Mþ). Anal. Calcd. for C32H29N3O2S: C, 73.96; H, 5.62; N,
8.09; Found: C, 73.98; H, 5.61; N, 8.07.
Ethyl 3a,4-dihydro-3,3a-diphenyl-5-(4-chlorophenyl)-5H-[1,2,
4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (5d). This
compound was obtained as yellow crystals in 26% yield, mp
.
217–218ꢁC. IR(KBr) t: 3055, 1730, 765 cmꢀ1 1H-NMR
General procedure for the preparation of the 2,4-diaryl-
2 (6
2,3-dihydro-1,5-benzothiazepines (3a–3d). Chalcones
mmol) and o-aminobenzenthiol (6 mmol) were dissolved in 25
mL hot methanol [14]. After the mixture had cooled to room
temperature and piperidine (five drops) was added, yellow
solid appeared in 0.5 h, then a little methanol was added and
the slurry heated until all material dissolved. Glacial acetic
acid (2 mL) then was added, and the mixture was stirred under
reflux for 4 h and allowed to stand overnight at a room tem-
perature. The yellow precipitate formed was filtered, dried,
and crystallized from anhydrous ethanol and benzene to give 3
as yellow crystals. Purity of the compounds was checked by
TLC.
(CDCl3, 400 MHz) d: 7.60–6.60 (m, 18H, Ar-H), 4.53 (dd,
1H, H-5x, Jax ¼ 1.45 Hz, Jbx ¼ 11.35 Hz), 4.20 (q, 2H,
OACH2ACH3), 2.86 (dd, 1H, H-4a, Jax ¼ 1.45 Hz, Jab ¼ 16
Hz), 2.70 (dd, 1H, H-4b, Jbx ¼ 11.35 Hz, Jab ¼ 16 Hz), 1.20
(t, 3H, OACH2ACH3). MS: m/z 539 (Mþ). Anal. Calcd. for
C31H26ClN3O2S: C, 68.94; H, 4.85; N, 7.78; Found: C, 68.95;
H, 4.82; N, 7.79.
3a: Yield 86%, mp 113–115ꢁC (lit. [14], 114–115ꢁC), yel-
low crystals.
3b: Yield 72%, mp 137–139ꢁC (lit. [15], 128ꢁC), yellow
crystals.
3c: Yield 81%, mp 128–130ꢁC (lit. [15], 127–128ꢁC), yel-
low crystals.
Ethyl 3a,4-dihydro-3-(4-chlorophenyl)-3a-phenyl-5-(4-chloro-
phenyl)-5H-[1,2,4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxy-
late (5e). This compound was obtained as yellow crystalsꢀi1n
3d: Yield 43.2%, mp 201–202ꢁC (lit. [16], 140ꢁC; lit. [17],
185ꢁC), yellow crystals.
32% yield, mp 254–255ꢁC. IR(KBr) t: 3062, 1733, 763 cm
.
General procedure for the preparation of the ethyl 3a,
4-dihydro-3a-phenyl-3,5-diaryl-5H-[1,2,4]triazolo[5,4-d][1,5]
benzothiazepine-1-carboxylate (5a-5l). To a stirred solution
of 1,5-benzothiazepine derivatives 3 (1 mmol) and the (phenyl-
1H-NMR (CDCl3, 400 MHz) d: 7.60–6.60 (m, 17H, Ar-H),
4.51 (dd, 1H, H-5x, Jax ¼ 1.54 Hz, Jbx ¼ 11.68 Hz), 4.19 (q,
2H, OACH2ACH3), 2.84 (dd, 1H, H-4a, Jax ¼ 1.54 Hz, Jab
¼
16 Hz), 2.69 (dd, 1H, H-4b, Jbx ¼ 11.68 Hz, Jab ¼ 16 Hz),
1.20 (t, 3H, OACH2ACH3). MS: m/z 573 (Mþ). Anal. Calcd.
for C31H25Cl2N3O2S: C, 64.81; H, 4.39; N, 7.31; Found: C,
64.79; H, 4.40; N, 7.34.
hydrazino) chloromethylenecarboxylates
4 (1.5 mmol) in
CH2Cl2 (20 mL), a solution of triethylamine (0.5 mL) in the
same solvent (5 mL) was added dropwise over a few minutes.
The reaction mixture was kept under stirring at room tempera-
ture for 3 days. After the removal of the solvent under reduced
pressure, ethyl acetate was added to the residue and the trie-
thylamine hydrochloride was filtered. The solvent was then
evaporated off and the residue subjected to silica gel column
chromatography with ethyl acetate/light petroleum (V:V ¼
1:8) as an eluent. A series of compounds 5 were cultured from
ethyl acetate and light petroleum.
Ethyl 3a,4-dihydro-3-(4-methylphenyl)-3a-phenyl-5-(4-chlor-
ophenyl)-5H-[1,2,4]triazolo[5,4-d][1,5]benzothiazepine-1-car-
boxylate (5f). This compound was obtained as yellow crystals
in 29% yield, mp 215–216ꢁC. IR(KBr) t: 3107, 1730, 762
1
cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 7.59–6.60 (m, 17H, Ar-
H), 4.54 (dd, 1H, H-5x, Jax ¼ 1.42 Hz, Jbx ¼ 11.40 Hz), 4.20
(q, 2H, OACH2ACH3), 2.85 (dd, 1H, H-4a, Jax ¼ 1.42 Hz, Jab
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X.-L. Wu, F.-M. Liu, and Y.-L. Zhou
Vol 48
¼ 16 Hz), 2.73 (dd, 1H, H-4b, Jbx ¼ 11.40 Hz, Jab ¼ 16 Hz),
2.20 (s, 3H, Ar-CH3), 1.19 (t, 3H, OACH2ACH3). MS: m/z
553 (Mþ). Anal. Calcd. for C32H28ClN3O2S: C, 69.36; H,
5.09; N, 7.58; Found: C, 69.32; H, 5.11; N, 7.59.
16 Hz), 2.70 (dd, 1H, H-4b, Jbx ¼ 11.36 Hz, Jab ¼ 16 Hz),
1.19 (t, 3H, OACH2ACH3). MS: m/z 584 (Mþ). Anal. Calcd.
for C31H25ClN4O4S: C, 63.64; H, 4.31; N, 9.58; Found: C,
63.66; H, 4.30; N, 9.55.
Ethyl 3a,4-dihydro-3,3a-diphenyl-5-(4-methoxyphenyl)-5H-[1,
2,4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (5g). This
compound was obtained as yellow crystals in 21% yield, mp
Ethyl 3a,4-dihydro-3-(4-methylphenyl)-3a-phenyl-5-(4-nitro-
phenyl)-5H-[1,2,4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxy-
late (5l). This compound was obtained as yellow crystalsꢀi1n
178–179ꢁC. IR(KBr) t: 3072, 1730, 765 cmꢀ1
.
1H-NMR
28% yield, mp 170–171ꢁC. IR(KBr) t: 3097, 1745, 764 cm
.
(CDCl3, 400 MHz) d: 7.60–6.60 (m, 18H, Ar-H), 4.56 (dd,
1H, H-5x, Jax ¼ 1.54 Hz, Jbx ¼ 11.26 Hz), 4.21 (q, 2H,
1H-NMR (CDCl3, 400 MHz) d: 7.60–6.60 (m, 17H, Ar-H),
4.54 (dd, 1H, H-5x, Jax ¼ 1.51 Hz, Jbx ¼ 11.29 Hz), 4.20 (q,
OACH2ACH3), 3.73 (s, 3H, OCH3), 2.86 (dd, 1H, H-4a, Jax
¼
2H, OACH2ACH3), 2.85 (dd, 1H, H-4a, Jax ¼ 1.51 Hz, Jab ¼
1.54 Hz, Jab ¼ 16 Hz), 2.70 (dd, 1H, H-4b, Jbx ¼ 11.26 Hz,
Jab ¼ 16 Hz), 1.20 (t, 3H, OACH2ACH3). MS: m/z 535 (Mþ).
Anal. Calcd. for C32H29N3O3S: C, 71.75; H, 5.46; N, 7.84;
Found: C, 71.77; H, 5.45; N, 7.82.
16 Hz), 2.72 (dd, 1H, H-4b, Jbx ¼ 11.29 Hz, Jab ¼ 16 Hz),
2.20 (s, 3H, Ar-CH3), 1.20 (t, 3H, OACH2ACH3). MS: m/z
564 (Mþ). Anal. Calcd. for C32H28N4O4S: C, 68.07; H, 5.00;
N, 9.92; Found: C, 68.08; H, 4.99; N, 9.94.
Ethyl
3a,4-dihydro-3-(4-chlorophenyl)-3a-phenyl-5-(4-
methoxyphenyl)-5H-[1,2,4]triazolo[5,4-d][1,5]benzothiazepine-1-
carboxylate (5h). This compound was obtained as yellow crys-
tals in 27% yield, mp 244–245ꢁC. IR(KBr) t: 3110, 1736, 763
Acknowledgment. The authors thank the financial support of
National Natural Science Foundation of China (Nos.: 20562011,
20662009).
1
cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 7.60–6.60 (m, 17H, Ar-
H), 4.55 (dd, 1H, H-5x, Jax ¼ 1.62 Hz, Jbx ¼ 11.10 Hz), 4.20
(q, 2H, OACH2ACH3), 3.72 (s, 3H, OCH3), 2.85 (dd, 1H, H-
REFERENCES AND NOTES
4a, Jax ¼ 1.62 Hz, Jab ¼ 16 Hz), 2.72 (dd, 1H, H-4b, Jbx
¼
11.10 Hz, Jab ¼ 16 Hz), 1.20 (t, 3H, OACH2ACH3). MS: m/z
569 (Mþ). Anal. Calcd. for C32H28ClN3O3S: C, 67.42; H,
4.95; N, 7.37; Found: C, 67.40; H, 4.96; N, 7.39.
[1] Bariwal, J. B.; Upadhyay, K. D.; Manvar, A. T.; Trivedi, J.
C.; Singh, J. S.; Jain, K. S.; Shah, A. K. Eur J Med Chem 2008, 43,
2279.
Ethyl
3a,4-dihydro-3-(4-methylphenyl)-3a-phenyl-5-(4-
[2] Slade, J.; Stanton, J. L.; Ben-David, D.; Mazzenga, G. C. J
Med Chem 1985, 28, 1517.
methoxyphenyl)-5H-[1,2,4]triazolo[5,4-d][1,5]benzothiazepine-1-
carboxylate (5i). This compound was obtained as yellow crys-
tals in 33% yield, mp 221–222ꢁC. IR(KBr) t: 3102, 1720, 762
[3] Greco, G.; Novellino, E.; Fiorini, I.; Nacci, V.; Campiani,
G.; Ciani, S. M.; Garofalo, A.; Bernasconi, P.; Mennini, T. A. J Med
Chem 1994, 37, 4100.
1
cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 7.53–6.60 (m, 17H, Ar-
H), 4.56 (dd, 1H, H-5x, Jax ¼ 1.52 Hz, Jbx ¼ 11.29 Hz), 4.20
[4] Sarro, G. D.; Chimirri, A.; Sarro, A. D.; Gitto, R.; Grasso,
S.; Zappala, M. Eur J Med Chem 1995, 30, 925.
[5] Havaldar, F. H.; Patil, A. R. Eur J Chem 2008, 5, 347.
[6] Sun, S.; Lou, H.; Gao, Y.; Fan, P.; Ma, B.; Ge, W.; Wang,
X. J Pharm Biomed Anal 2004, 34, 1117.
(q, 2H, OACH2ACH3), 3.74 (s, 3H, OCH3), 2.85 (dd, 1H, H-
4a, Jax ¼ 1.52 Hz, Jab ¼ 16 Hz), 2.74 (dd, 1H, H-4b, Jbx
¼
11.29 Hz, Jab ¼ 16 Hz), 2.22 (s, 3H, Ar-CH3), 1.19 (t, 3H,
OACH2ACH3). MS: m/z 549 (Mþ). Anal. Calcd. for
C33H31N3O3S: C, 72.11; H, 5.68; N, 7.64; Found: C, 72.10; H,
5.67; N, 7.67.
[7] Verreck, G.; Six, K.; Van den Mooter, G.; Baert, L.; Pee-
ters, J.; Brewster, M. E. Int J Pharm 2003, 251, 165.
[8] Holla, B. S.; Poojary, K. N.; Rao, B. S.; Shivananda, M. K.
Eur J Med Chem 2002, 37, 511.
Ethyl 3a,4-dihydro-3,3a-diphenyl-5-(4-nitrophenyl)-5H-[1,2,
4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (5j). This
compound was obtained as yellow crystals in 22% yield, mp
.
179–180ꢁC. IR(KBr) t: 3118, 1731, 764 cmꢀ1 1H-NMR
(CDCl3, 400 MHz) d: 7.60–6.60 (m, 18H, Ar-H), 4.52 (dd,
1H, H-5x, Jax ¼ 1.48 Hz, Jbx ¼ 11.42 Hz), 4.19 (q, 2H,
OACH2ACH3), 2.87 (dd, 1H, H-4a, Jax ¼ 1.48 Hz, Jab ¼ 16
Hz), 2.70 (dd, 1H, H-4b, Jbx ¼ 11.42 Hz, Jab ¼ 16 Hz), 1.20
(t, 3H, OACH2ACH3). MS: m/z 550 (Mþ). Anal. Calcd. for
C31H26N4O4S: C, 67.62; H, 4.76; N, 10.18; Found: C, 67.61;
H, 4.75; N, 10.21.
[9] Liu, F.-M.; Wang, B.-L.; Li, Y.-P. Chem J Chin Univ 2002,
23, 2097.
[10] Lagoja, I. M.; Pannecouque, C.; Musumeci, L.; Froeyen,
M.; Aerschot, A. V.; Balzarini, J.; Herdewijn, P.; Clercq, E. D. Helv
Chim Acta 2002, 85, 1883.
[11] Yang, D.-B.; Liu, F.-M.; Xu, F.; Yang, C.; Ye, J.-W.; Shen,
S.-W.; Zhou, Y.-L.; Li, W. Mol Divers 2008, 12, 103.
[12] Kohler, E. P.; Chadwell, H. M. Org Synth 1922, 2, 1.
[13] Anderson, W. K.; Jones, A. N. J Med Chem 1984, 27,
1559.
Ethyl 3a,4-dihydro-3-(4-chlorophenyl)-3a-phenyl-5-(4-nitro-
phenyl)-5H-[1,2,4]triazolo[5,4-d][1,5]benzothiazepine-1-carboxy-
late (5k). This compound was obtained as yellow crystalsꢀi1n
[14] Stephens, W. D.; Field, L. J Org Chem 1959, 24, 1576.
[15] Orlov, V. D.; Kolos, N.; Ruzhitskaya, N. N. Khim Geterot-
sikl Soedin 1983, 12, 1638.
31% yield, mp 230–231ꢁC. IR(KBr) t: 3075, 1733, 762 cm
.
[16] Ansari, F. L.; Umbreen, S.; Hussain, L.; Makhmoor, T.;
Nawaz, S. A.; Lodhi, M. A.; Khan, S. N.; Shaheen, F.; Choudhary, M.
I.; Atta-ur-Rahman. Chem Biodivers 2005, 2, 487.
[17] Braun, R. U.; Mu¨ller, T. J. J. Tetrahedron 2004, 60, 9463.
1H-NMR (CDCl3, 400 MHz) d: 7.57–6.60 (m, 17H, Ar-H),
4.50 (dd, 1H, H-5x, Jax ¼ 1.68 Hz, Jbx ¼ 11.36 Hz), 4.19 (q,
2H, OACH2ACH3), 2.86 (dd, 1H, H-4a, Jax ¼ 1.68 Hz, Jab
¼
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet