Syntheses of potentially bioactive [1,2,4]oxadiazolo[5,4-d]benzothiazepines by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/jhet.479

The chalcones, 2a-2l reacted with o-aminobenzenthiol to give a series of 1,5-benzothiazepines, 3a-3l. The [3+2] 1, 3-dipolar cycloaddition reactions of 3a-3l with ethyl chlorooximidoacetate in the presence of Et₃N afforded the target compounds, 4a-4l possessing an additional 1,2,4-oxadiazole ring fused to the heptaatomic nucleus. The structures have been elucidated by spectral methods and X-ray crystallographic analysis.

Full text of DOI:10.1002/jhet.479

1350
Syntheses of Potentially Bioactive [1,2,4]Oxadiazolo
[5,4-d]benzothiazepines by 1,3-Dipolar Cycloaddition
Vol 47
Xiao-Long Wu,a Fang-Ming Liu,a,b* and Song-Wei Shenb
aCollege of Materials and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036,
Zhejiang, People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Xinjiang University,Urumqi 830046, Xinjiang,
People’s Republic of China
*E-mail: fmliu859@sohu.com
Received December 17, 2009
DOI 10.1002/jhet.479
Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
The chalcones, 2a-2l reacted with o-aminobenzenthiol to give a series of 1,5-benzothiazepines, 3a-3l.
The [3þ2] 1, 3-dipolar cycloaddition reactions of 3a-3l with ethyl chlorooximidoacetate in the presence
of Et3N afforded the target compounds, 4a-4l possessing an additional 1,2,4-oxadiazole ring fused to
the heptaatomic nucleus. The structures have been elucidated by spectral methods and X-ray crystallo-
graphic analysis.
J. Heterocyclic Chem., 47, 1350 (2010).
INTRODUCTION
chemistry. They serve as the core components of a large
number of substances that possess a wide range of inter-
esting biological activities. The 1,2,4-oxadiazole scaf-
folds are associated with significant biological activities,
such as anti-hypertensive [22], antikinetoplastid [23],
antimicrobial and anti-inflammatory [24].
The Synthesis of benzothiazepine derivatives has
attracted considerable attention of organic and medicinal
chemists due to their broad spectrum of biological activ-
ity. The 1,5-benzothiazepine derivatives have been used
as cardiovascular modulators [1], coronary vasodilators
[2], elastase [3]/ACE inhibitors [4], anti-HIV [5], anti-
hypertensives [6], anti-depressants [7], and anti-bacterial
activity [8]. In recent years, a large number of 1,5-ben-
zothiazepine derivatives containing anticancer activity
[9,10], hemodynamic effects [11], antiulcer activity
[12,13], and spasmolytic activities [14–18] have also
been reported. Some of the 1,5-benzothiazepine deriva-
tives were also used clinically for CNS disorders which
include quetiapine fumarate and thiazesim [19–21].
Oxadiazoles are naturally occurring five-membered
heterocycles with utility in synthetic and medicinal
Recent work has demonstrated the interest to fix an
additional heterocycle on 1,5-benzothiazepines. Pharma-
ceutical properties of such compounds are magnified
when the heterocycle is bound to the heptatomic nucleus
[25,26]. Keeping these observations in mind and in con-
tinuation of our interest to prepare a seven-membered
ring [27,28], we report herein the reaction of 1,5-benzo-
thiazepines 3a-3l with ethyl chlorooximidoacetate
through 1,3-dipolar cycloaddition to afford a new series
of tricyclic system, [1,2,4]oxadiazolo[5,4-d][1,5]benzo-
thiazepine derivatives, which might have useful biologi-
cal and therapeutic activities (Table 1).
C
V
2010 HeteroCorporation

November 2010 Syntheses of Potentially Bioactive [1,2,4]Oxadiazolo[5,4-d]Benzothiazepines by
1,3-Dipolar Cycloaddition
1351
Table 1
Physical and analytical data of compounds 4.
Analysis %(Calcd./found)
Comp.
Ar1
Ph
Ar2
Ph
mp(ꢁC)
Yield %
34
Molecular formula
C25H22N2O3S
C
H
N
4a
177–178
69.75
69.73
64.58
64.57
67.81
67.83
63.15
63.12
64.58
64.59
60.12
60.14
63.09
63.12
58.88
58.85
67.81
67.80
63.09
63.13
66.10
66.08
61.77
61.74
5.15
5.12
4.55
4.58
5.25
5.24
4.45
4.46
4.55
4.53
4.04
4.02
4.68
4.67
3.95
3.96
5.25
5.28
4.68
4.66
5.34
5.35
4.59
4.60
6.51
6.54
6.02
5.99
6.08
6.07
8.84
8.83
6.02
6.01
5.61
5.63
5.66
4.63
8.24
8.25
6.08
6.04
5.66
5.65
5.71
5.74
8.31
8.34
4b
4c
4d
4e
4f
Ph
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
Ph
174–175
132–133
195–196
193–194
165–166
143–144
232–233
130–131
213–214
173–174
213–214
35
35
33
31
30
23
25
26
32
36
20
C25H21ClN2O3S
C26H24N2O4S
C25H21N3O5S
C25H21ClN2O3S
C25H20Cl2N2O3S
C26H23ClN2O4S
C25H20ClN3O5S
C26H24N2O4S
C26H23ClN2O4S
C27H26N2O5S
C26H23N3O6S
Ph
Ph
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
Ph
4g
4h
4i
4j
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
4k
4l
RESULTS AND DISCUSSION
which simultaneously undergo dehydrative cyclization
to give final products in the second step. Finally, the 1,
3-dipolar cycloaddition reaction between 1,5-benzothia-
zepine derivatives, 3a-3l and nitrile oxide, generated in
situ from ethyl chlorooximidoacetate and triethylamine,
leads to the target compounds; 1,2,4-oxadiazolo[5,4-d]-
1,5-benzothiazepine derivatives, 4a-4l (Scheme 1) in
which an oxadiazole ring is fused at the ‘‘d’’ edge of
the heptatomic nucleus.
The title compounds were prepared according to the
Scheme 1. The chalcones, 2a-2l were readily prepared
by condensation of aryl aldehydes with substituted ace-
tophenones [29]. 2a-2l were subsequently reacted with
o-aminobenzenthiol in MeOH/AcOH to give the desired
2,4-diaryl-2,3-dihydro-1,5-benzothiazepines, 3a-3l. The
formation of 3 may proceeded via two steps [30,31]. In
the first step, nucleophilic attack by the sulfhydryl elec-
trons of 2-aminobenzenethiol takes place on the acti-
vated b-carbon atom of the a, b-unsaturated carbonyl
compounds to give Michael-adduct type intermediates,
The structures of title compounds have been charac-
1
terized by IR, H-NMR, mass, and elemental analysis.
The infrared spectra of these compounds show C¼¼O
absorption bands around 1740 cmꢀ1. In the nuclear
magnetic resonance spectra, title compounds exhibited
multiplet between d 8.15–6.55ppm due to the aromatic
protons, the signal for ethoxycarbonyl CH2 and CH3
appeared at d 4.30–4.38 ppm and d 1.29–1.31 ppm
respectively, 3 distinct double doublets in the ABX pat-
tern (a CH proton and 2 anisochronous protons of a
CH2) appeared at d 3.60–2.50 ppm, as has been
Scheme 1
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1352
X.-L. Wu, F.-M. Liu, and S.-W. Shen
Vol 47
Figure 1. Molecular structure of 4e.
Figure 2. Packing of molecules in a unit cell of 4e.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010 Syntheses of Potentially Bioactive [1,2,4]Oxadiazolo[5,4-d]Benzothiazepines by
1,3-Dipolar Cycloaddition
1353
Table 2
Crystal data and structure refinement for compound 4e.
3
˚
V, A
Empirical formula
C25H21ClN2O3S
1092.7(3)
Formula weight
Temperature
Wavelength
Crystal system
Space group
464.95
293(2) K
0.71073 A
Triclinic
Z
2
1.413
Dc, mg/m3
Crystal size, mm
y range, deg
0.55 ꢂ 0.45 ꢂ 0.35
3.10–27.48
0.302
P-1
l, mmꢀ1
˚
a, A
10.4744(13)
10.9320(16)
10.971(2)
61.811(3)
88.031(5)
81.064(3)
Reflections collected
Independent reflection
Data/restraints/parameters
Final R indices [I > 2r(I)]
R indices (all data)
10,141
4792 [R(int) ¼ 0.0258]
˚
b, A
˚
c, A
4792 / 0 / 290
R1 ¼ 0.0469, wR2 ¼ 0.1397
R1 ¼ 0.0568, wR2 ¼ 0.1585
a, deg
b, deg
c, deg
observed in 2,3-dihydro-1,5-benzothiazepines. In MS
spectra, molecular ion peaks of all title compounds were
obtained from EI-MS, but the intensities of molecular
ion peaks were very weak.
clic torsion angles (enumerated clockwise and starting
with S(1)AC(1)AC(6)AN(2)): 0.7(3)ꢁ, ꢀ53.6(3)ꢁ,
ꢀ1.8(3)ꢁ,
82.5(2)ꢁ,
ꢀ48.60(19)ꢁ,
ꢀ35.20(15)ꢁ,
64.81(17)ꢁ. N(2), S(1), C(12) and C(20) are coplanar,
while C(1), C(6) and C(19) are all above the plane.
Therefore, the seven-membered ring adopts a boat-like
conformation.
A plausible intramolecular 1,3-diploar cycloaddition
mechanism is proposed as shown in Scheme 2. According
to the literatures [32], the conformations of the central
heteroazepine ring in 2,4-disubstituted 2,3-dihydro-1,5-
benzothiazepines adopt boat-like conformations and the
1,3-diploar cycloaddition reactions occurred in a con-
certed mechanism. In the presence of Et3N, the nitrile ox-
ide generated in situ and C¼¼N double bond in benzothia-
zepine formed a cyclic transition state, then the r-bonds
of CAN and CAO were formed simultaneously to afford
the 1,2,4-oxadiazole ring, the central thiazepine ring of
the cycloadduct also adopts a boat-like conformation.
The X-ray crystallography of 4e identified the struc-
ture of the desired products (Fig. 1). The higher occu-
pancy in the 3-dimensional packing arrangement is
shown in Figure 2. The crystal data and structure refine-
ment of 4e are listed in Table 2. Selected bond distances
and angles of 4e are tabulated in Table 3.
Figure 1 is the stereo structure of compound 4e.
There is a five-membered ring in the molecule, resulting
from the cycloaddition reaction. All atoms [N(1), C(7),
N(2), C(12), O(3)] in the ring are nearly coplanar with
similar bond angles (N(1)AO(3) AC(12) 106.32(14)ꢁ,
O(3) AC(12) AN(2) 101.36(14)ꢁ, C(12) AN(2) AC(7)
102.60(14)ꢁ, N(2) AC(7) AN(1) 115.39(18)ꢁ, C(7)
AN(1) AO(3) 105.94(16)ꢁ), indicating the ring is stable.
The five-membered ring is characterized by the endocy-
clic torsion angles (enumerated clockwise and starting
with O(3)AN(1)AC(7)AN(2)): ꢀ2.1(2)ꢁ, 19.7(2)ꢁ,
ꢀ28.29(17)ꢁ, 25.87(17)ꢁ, ꢀ16.1(2)ꢁ. The five-membered
ring plane adopts an envelope conformation with atom
C(12) deviating from the plane defined by N(2), O(3),
CCDC-768069 (for 4e) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/const/
retrieving.html.
In conclusion, we have achieved an efficient one step
synthesis of new [1,2,4]oxadiazolo[5,4-d][1,5]benzodia-
zepinones, 4a-4l by way of highly regioselective 1,3-
dipolar cycloaddition of ethyl chlorooximidoacetate to
2,4-diaryl-2,3-dihydro-1,5-benzothiazepines, 3a-3l.
EXPERIMENTAL
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
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
Table 3
ꢁ
˚
Selected bond lengths (A) and angles ( ) of compounds 4e.
S(1)AC(20)
1.843(2) N(1)AO(3)AC(12)
106.32(14)
124.19(15)
115.39(18)
121.43(17)
126.2(2)
C(19)AC(20) 1.522(3) C(6)AN(2)AC(12)
O(3)AN(1)
O(3)AC(12)
N(2)AC(7)
N(2)AC(6)
N(2)AC(12)
O(1)AC(10)
O(1)AC(9)
1.417(2) N(1)AC(7)AN(2)
1.469(2) N(1)AC(7)AC(9)
1.393(2) O(2)AC(9)AO(1)
1.428(2) O(1)AC(9)AC(7)
1.472(2) O(3)AC(12)AC(13)
1.448(3) C(12)AC(19)AC(20) 115.18(15)
1.322(3) N(2)AC(12)AC(19) 114.91(15)
˚
N(1), C(7) of 0.1684A. The bond length of N(1)AC(7),
110.78(18)
106.65(14)
˚
1.286(3)A, indicates it is a double bond.
There is also a seven-membered ring in the molecule.
1,5-Benzothiazepine ring is characterized by the endocy-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1354
X.-L. Wu, F.-M. Liu, and S.-W. Shen
Vol 47
Table 4
Yield (%) and mp (ꢁC) of Compounds 3.
1H-NMR (CDCl3, 400 MHz) d: 8.18–6.65 (m, 13H, ArAH),
4.35 (q, 2H, CH2), 3.46 (dd, 1H, H-5x, Jbx ¼ 6.53 Hz, Jax
¼
11.62 Hz), 3.02 (dd, 1H, H-4b, Jbx ¼ 6.53 Hz, Jab ¼ 15.88
Hz), 2.60 (dd, 1H, H-4a, Jax ¼ 11.62 Hz, Jab ¼ 15.88 Hz),
1.31 (t, 3H, CH3). MS (70 eV) m/z (%): 464 (Mþ). Anal.
Calcd. for C25H21ClN2O3S: C, 64.58; H, 4.55; N, 6.02; Found:
C, 64.57; H, 4.58; N, 5.99.
Comp
Ar1
Ar2
Yield
mp
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
86
72
113–115
137–139
128–130
201–202
134–136
138–140
130–133
195–196
124–125
128–130
130–132
185–187
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
Ph
Ph
Ph
81
Ethyl 3a,4-dihydro-3a-phenyl-5-(4-methoxyphenyl)-5H-[1,2,4]
oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (4c). This
compound was obtained as colorless crystals in 35% yield, mp
43.2
65.7
70.5
75.2
47.3
44.6
65.3
43.1
41.7
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
Ph
132–133ꢁC. IR(KBr): 3032 (ArAH), 1740 (C¼¼O), 764 cmꢀ1
.
1H-NMR (CDCl3, 400 MHz) d: 7.58–6.61 (m, 13H, ArAH),
4.33 (q, 2H, CH2), 3.80 (s, 3H, OCH3), 3.45 (dd, 1H, H-5x,
Jbx ¼ 6.72 Hz, Jax ¼ 11.56 Hz), 3.01 (dd, 1H, H-4b, Jbx
¼
3j
3k
3l
p-ClC6H4
p-CH3OC6H4
p-NO2C6H4
6.72 Hz, Jab ¼ 15.70 Hz), 2.60 (dd, 1H, H-4a, Jax ¼ 11.56
Hz, Jab ¼ 15.70 Hz), 1.29 (t, 3H, CH3). MS (70 eV) m/z (%):
460 (Mþ). Anal. Calcd. for C26H24N2O4S: C, 67.81; H, 5.25;
N, 6.08; Found: C, 67.83; H, 5.24; N, 6.07.
structure was obtained using R-AXIS SPIDER X-ray diffrac-
tion. The ethyl chlorooximidoacetate was obtained according
to the known procedure [33–34].
Ethyl
3a,4-dihydro-3a-phenyl-5-(4-nitrophenyl)-5H-[1,2,4]
oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (4d). This
compound was obtained as yellow crystals in 33% yield, mp
195–196ꢁC. IR(KBr): 3041 (ArAH), 1744 (C¼¼O) 760 cmꢀ1
General procedure for the preparation of the 2,4-diaryl-
2,3-dihydro-1,5-benzothiazepines (3a-3l). Chalcone
.
1H-NMR (CDCl3, 400 MHz) d: 8.11–6.56 (m, 13H, ArAH),
2
(6
mmol) and o-aminobenzenthiol (6 mmol) were dissolved in
25 ml containing glacial acetic acid methanol. After the
mixture had cooled to room temperature, piperidine (5 drops)
was added. Yellow floccule appeared in 0.5h, then a little
methanol was added and the slurry was heated until all mate-
rial dissolved. Glacial acetic acid (2 ml) was added and the
mixture was allowed to stand overnight at a room temperature.
The solid product was collected and recrystallized from anhy-
drous ethanol and benzene to give 3a-3l as yellow crystals
(Table 4).
General procedure for the preparation of the 2,4-diaryl-
2,3-dihydro-1,5-benzothiazepine derivatives containing 1,2,
4-oxadiazole (4a-4l). To a stirred solution of 1,5-benzothiaze-
pine derivatives 3a-3l (1 mmol) and ethyl chlorooximidoace-
tate (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 temperature for 2 days. After the removal of the solvent
at reduced pressure, ethyl acetate was added to the residue and
the triethylamine hydrochloride was filtered. The solvent was
then evaporated off and the residue subjected to silica gel col-
umn chromatography with ethyl acetate/light petroleum (V:V
¼ 1:8). A series of compounds 4a-4l were crystallized from
ethyl acetate and light petroleum.
4.36 (q, 2H, CH2), 3.40 (dd, 1H, H-5x, Jbx ¼ 5.76 Hz, Jax
¼
11.33 Hz), 3.02 (dd, 1H, H-4b, Jbx ¼ 5.76 Hz, Jab ¼ 15.76
Hz), 2.58 (dd, 1H, H-4a, Jax ¼ 11.33 Hz, Jab ¼ 15.76 Hz),
1.30 (t, 3H, CH3). MS (70 eV) m/z (%): 475 (Mþ). Anal.
Calcd. for C25H21N3O5S: C, 63.15; H, 4.45; N, 8.84; Found:
C, 63.12; H, 4.46; N, 8.83.
Ethyl 3a,4-dihydro-3a-(4-chlorophenyl)-5-phenyl-5H-[1,2,4]
oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (4e). This
compound was obtained as colorless crystals in 31% yield, mp
193–194ꢁC. IR(KBr): 3063 (ArAH), 1744 (C¼¼O), 760 cmꢀ1
.
1H-NMR (CDCl3, 400 MHz) d: 8.10–6.68 (m, 13H, ArAH),
4.35 (q, 2H, CH2), 3.50 (dd, 1H, H-5x, Jbx ¼ 5.69 Hz, Jax
¼
10.11 Hz), 2.96 (dd, 1H, H-4b, Jbx ¼ 5.69 Hz, Jab ¼ 13.01
Hz), 2.64 (dd, 1H, H-4a, Jax ¼ 10.11 Hz, Jab ¼ 13.01 Hz),
1.30 (t, 3H, CH3). MS (70 eV) m/z (%): 464 (Mþ). Anal.
Calcd. for C25H21ClN2O3S: C, 64.58; H, 4.55; N, 6.02; Found:
C, 64.59; H, 4.53; N, 6.01.
Ethyl 3a,4-dihydro-3a-(4-chlorophenyl)-5-(4-chlorophenyl)-
5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate
(4f). This compound was obtained as colorless crystals in 30%
yield, mp 165–166ꢁC. IR(KBr): 3057 (ArAH), 1733 (C¼¼O),
1
765 cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 8.05–6.70 (m, 12H,
ArAH), 4.37 (q, 2H, CH2), 3.48 (dd, 1H, H-5x, Jbx ¼ 5.19 Hz,
Jax ¼ 10.56 Hz), 2.92 (dd, 1H, H-4b, Jbx ¼ 5.19 Hz, Jab
¼
13.21 Hz), 2.55 (dd, 1H, H-4a, Jax ¼ 10.56 Hz, Jab ¼ 13.21
Hz), 1.31 (t, 3H, CH3). MS (70 eV) m/z (%): 498 (Mþ). Anal.
Calcd. for C25H20Cl2N2O3S: C, 60.12; H, 4.04; N, 5.61;
Found: C, 60.14; H, 4.02; N, 5.63.
Ethyl 3a,4-dihydro-3a,5-diphenyl-5H-[1,2,4]oxadiazolo[5,4-
d][1,5]benzothiazepine-1-carboxylate (4a). This compound
was obtained as colorless crystals in 34% yield, mp 177–
178ꢁC. IR(KBr): 3072 (ArAH), 1736 (C¼¼O), 761 cmꢀ1
.
1H-
Ethyl 3a,4-dihydro-3a-(4-chlorophenyl)-5-(4-methoxyphenyl)-
5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate
(4g). This compound was obtained as colorless crystals in
23% yield, mp 143–144ꢁC. IR(KBr): 3102 (ArAH), 1736
NMR (CDCl3, 400 MHz) d: 8.21–6.78 (m, 14H, ArAH), 4.34
(q, 2H, CH2), 3.49 (dd, 1H, H-5x, Jbx ¼ 5.53 Hz, Jax ¼ 10.01
Hz), 3.06 (dd, 1H, H-4b, Jbx ¼ 5.53 Hz, Jab ¼ 14.90 Hz), 2.66
(dd, 1H, H-4a, Jax ¼ 10.01 Hz, Jab ¼ 14.90 Hz), 1.30 (t, 3H,
CH3). MS (70 eV) m/z (%): 430 (Mþ). Anal. Calcd. for
C25H22N2O3S: C, 69.75; H, 5.15; N, 6.51; Found: C, 69.73; H,
5.12; N, 6.54.
1
(C¼¼O), 763 cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 8.09–6.68
(m, 12H, ArAH), 4.34 (q, 2H, CH2), 3.82 (s, 3H, OCH3), 3.46
(dd, 1H, H-5x, Jbx ¼ 5.30 Hz, Jax ¼ 10.77 Hz), 2.91 (dd, 1H,
H-4b, Jbx ¼ 5.30 Hz, Jab ¼ 13.72 Hz), 2.56 (dd, 1H, H-4a, Jax
¼ 10.77 Hz, Jab ¼ 13.72 Hz), 1.30 (t, 3H, CH3). MS (70 eV)
m/z (%): 494 (Mþ). Anal. Calcd. for C26H23ClN2O4S: C,
63.09; H, 4.68; N, 5.66; Found: C, 63.12; H, 4.67; N, 4.63.
Ethyl 3a,4-dihydro-3a-phenyl-5-(4-chlorophenyl)-5H-[1,2,4]
oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (4b). This
compound was obtained as colorless crystals in 35% yield, mp
174–175ꢁC. IR(KBr): 3046 (ArAH), 1735 (CAO), 763 cmꢀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010 Syntheses of Potentially Bioactive [1,2,4]Oxadiazolo[5,4-d]Benzothiazepines by
1,3-Dipolar Cycloaddition
1355
[2] Jiang, L.; Wan, X.-J.; Xu, H.; Bian, J.-J.; Han, W.-J.; Zhu,
K.-M.; Deng, X.-M. J Med Coll PLA 2007, 22, 230.
[3] Skiles, J. W.; Sorcek, R.; Jacober, S.; Miao, C.; Mui, P. W.;
McNeil, D.; Rosenthal, A. S. Bioorg Med Chem Lett 1993, 3, 773.
[4] Slade, J.; Stanton, J. J.; Ben-David, D.; Mazzenga, G. C.; J
Med Chem 1985, 28, 1517.
Ethyl 3a,4-dihydro-3a-(4-chlorophenyl)-5-(4-nitrophenyl)-
5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate
(4h). This compound was obtained as colorless crystals in
25% yield, mp 232–233ꢁC. IR(KBr): 3116 (ArAH), 1744
1
(C¼¼O), 765 cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 8.10–6.62
(m, 12H, ArAH), 4.38 (q, 2H, CH2), 3.50 (dd, 1H, H-5x, Jbx
¼ 5.32 Hz, Jax ¼ 11.01 Hz), 2.92 (dd, 1H, H-4b, Jbx ¼ 5.32
Hz, Jab ¼ 13.82 Hz), 2.58 (dd, 1H, H-4a, Jax ¼ 11.01 Hz, Jab
¼ 13.82 Hz), 1.31 (t, 3H, CH3). MS (70 eV) m/z (%): 509
(Mþ). Anal. Calcd. for C25H20ClN3O5S: C, 58.88; H, 3.95;
N, 8.24; Found: C, 58.85; H, 3.96; N, 8.25.
[5] Grandolini, G.; Perioli, L.; Ambrogi, V. Eur J Med Chem
1999, 34, 701.
´
[6] Levai, A. Pharmazie 1999, 54, 719.
´ ´
[7] Darias, V.; Sanchez-Mateo, C. C.; Exposito-Orta, M. A.;
´
Albertos, L. M.; Dıaz, J. A.; Vega, S. Pharmazie 1999, 54, 783.
[8] Naik, V. R.; Naik, H. B. Asian J Chem 1999, 11, 661.
[9] Ahmed, N. K. Can. Pat. Appl CA 2,030,159 (1991); Chem
Abstr 1991, 115, 198515f.
Ethyl 3a,4-dihydro-3a-(4-methoxyphenyl)-5-phenyl-5H-[1,2,4]
oxadiazolo[5,4-d][1,5]benzothiazepine-1-carboxylate (4i). This
compound was obtained as colorless crystals in 26% yield, mp
[10] Ahmed, N. K. Eur. Pat. Appl. EP 430,036 (1991); Chem
Abstr 1992, 116, 717c.
130–131ꢁC. IR(KBr): 3107 (ArAH), 1734 (C¼¼O), 762 cmꢀ1
.
1H-NMR (CDCl3, 400 MHz) d: 8.12–6.66 (m, 13H, ArAH),
4.34 (q, 2H, CH2), 3.81 (s, 3H, OCH3), 3.42 (dd, 1H, H-5x,
[11] Kusukawa, R.; Kinoshita, M.; Shimono, Y.; Tomozana, G.;
Hoshino, T. Arzneim–Forsch 1977, 27, 878.
Jbx ¼ 6.38 Hz, Jax ¼ 11.43 Hz), 2.99 (dd, 1H, H-4b, Jbx
¼
[12] Yamamoto, H.; Asai, H. Chem Pharm Bull 1986, 34, 3844.
[13] Asano, T.; Okumura, T.; Hirano, K.; Adachi, T.; Sugiura,
M. Chem Pharm Bull 1986, 34, 4238.
6.38 Hz, Jab ¼ 15.56 Hz), 2.58 (dd, 1H, H-4a, Jax ¼ 11.42
Hz, Jab ¼ 15.56 Hz), 1.29 (t, 3H, CH3). MS (70 eV) m/z (%):
460 (Mþ). Anal. Calcd. for C26H24N2O4S: C, 67.81; H, 5.25;
N, 6.08; Found: C, 67.80; H, 5.28; N, 6.04.
[14] Kendall, M. J.; Okopski, J. V. J Clin Hosp Pharm 1986, 11,
159.
Ethyl
3a,4-dihydro-3a-(4-methoxyphenyl)-5-(4-chloro-
[15] Narita, H.; Murata, S.; Yabana, H.; Kikkawa, K.; Sugawara,
Y.; Akimoto, Y.; Nagao, T. Arzneim–Forsch 1988, 38, 515.
[16] Murata, S.; Yabana, H.; Kikkawa, K.; Sugawara, Y.; Aki-
moto, Y.; Nagao, T. Arzneim–Forsch 1988, 38, 521.
[17] Murata, S.; Kikkawa, K.; Nagao, T. Arzneim–Forsch 1988,
38, 526.
phenyl)-5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine-1-
carboxylate (4j). This compound was obtained as colorless
crystals in 32% yield, mp 213–214ꢁC. IR(KBr): 3075 (ArAH),
1
1736 (C¼¼O), 762 cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 8.02–
6.65 (m, 12H, ArAH), 4.35 (q, 2H, CH2), 3.83 (s, 3H, OCH3),
3.49 (dd, 1H, H-5x, Jbx ¼ 5.21 Hz, Jax ¼ 10.32 Hz), 2.95 (dd,
1H, H-4b, Jbx ¼ 5.21 Hz, Jab ¼ 13.44 Hz), 2.58 (dd, 1H, H-
4a, Jax ¼ 10.32 Hz, Jab ¼ 13.44 Hz), 1.30 (t, 3H, CH3). MS
(70 eV) m/z (%): 494 (Mþ). Anal. Calcd. for C26H23ClN2O4S:
C, 63.09; H, 4.68; N, 5.66; Found: C, 63.13; H, 4.66; N, 5.65.
Ethyl 3a,4-dihydro-3a-(4-methoxyphenyl)-5-(4-methoxy-
phenyl)-5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine-1-
carboxylate (4k). This compound was obtained as colorless
crystals in 36% yield, mp 173–174ꢁC. IR(KBr): 3121 (ArAH),
[18] Narita, H.; Gaino, M.; Suzuki, T.; Kurosawa, H.; Inoue, H.;
Nagao, T. Chem Pharm Bull 1990, 38, 407.
[19] Geyer, H. M.; Watzman, N.; Buckley, J. P. J Pharm Sci
1970, 59, 964.
[20] Hopenwasser, J.; Mozayani, A.; Danielson, T. J.; Harbin, J.;
Narula, H. S.; Posey, D. H.; Shrode, P. W.; Wilson, S. K.; Li, R.; San-
chez, L. A. J Anal Toxicol 2004, 28, 264.
[21] 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.
1
1739 (C¼¼O), 762 cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 8.11–
[22] Sakai, K.; Mizusawa, H.; Araki, H. Oyo Yakuri 1979, 18,
667.
6.60 (m, 12H, ArAH), 4.30 (q, 2H, CH2), 3.80 (s, 6H, OCH3),
3.38 (dd, 1H, H-5x, Jbx ¼ 6.52 Hz, Jax ¼ 11.89 Hz), 2.95 (dd,
1H, H-4b, Jbx ¼ 2.95 Hz, Jab ¼ 15.62 Hz), 2.60 (dd, 1H, H-
4a, Jax ¼ 11.89 Hz, Jab ¼ 15.62 Hz), 1.29 (t, 3H, CH3). MS
(70 eV) m/z (%): 490 (Mþ). Anal. Calcd. for C27H26N2O5S: C,
66.10; H, 5.34; N, 5.71; Found: C, 66.08; H, 5.35; N, 5.74.
[23] Cottrell, D. M.; Capers, J.; Salem, M. M.; DeLuca-Fradley,
K.; Croft, S. L.; Werbovetz, K. L. Bioorg Med Chem 2004, 12, 2815.
[24] Srivastava, R. M.; de Almeida Lima, A.; Viana, O. S.; da
Costa Silva, M. J.; Catanho, M. T. J. A.; de Morais, J. O. F. Bioorg
Med Chem 2003, 11, 1821.
Ethyl
3a,4-dihydro-3a-(4-methoxyphenyl)-5-(4-nitro-
[25] 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.
phenyl)-5H-[1,2,4]oxadiazolo[5,4-d][1,5]benzothiazepine-1-
carboxylate (4l). This compound was obtained as yellow
crystals in 20% yield, mp 213–214ꢁC. IR(KBr): 3118 (ArAH),
[26] Sarro, G. D.; Chimirri, A.; Sarro, A. D.; Gitto, R.; Grasso,
S.; Zappala, M. Eur J Med Chem 1995, 30, 925.
[27] Liu, F.-M.; Wang, B.-L.; Li, Y.-P. Chem J Chin Univ 2002,
23, 2097.
1
1738 (C¼¼O), 761 cmꢀ1. H-NMR (CDCl3, 400 MHz) d: 8.04–
6.69 (m, 12H, ArAH), 4.37 (q, 2H, CH2), 3.84 (s, 3H, OCH3),
3.45 (dd, 1H, H-5x, Jbx ¼ 5.97 Hz, Jax ¼ 11.65 Hz), 2.90 (dd,
1H, H-4b, Jbx ¼ 5.97 Hz, Jab ¼ 15.71 Hz), 2.58 (dd, 1H, H-
4a, Jax ¼ 11.65 Hz, Jab ¼ 15.71 Hz), 1.30 (t, 3H, CH3). MS
(70 eV) m/z (%): 505 (Mþ). Anal. Calcd. for C26H23N3O6S: C,
61.77; H, 4.59; N, 8.31; Found: C, 61.74; H, 4.60; N, 8.34.
[28] 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.
[29] Kohler, E. P.; Chadwell, H. M. Org Synth 1922, 2, 1.
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[31] Pant, S.; Sharma, P.; Pant, U. C. Phosphorus Sulfur Silicon
Relat Elem 2008, 183, 2974.
Acknowledgment. The authors thank the financial support of
National Natural Science Foundation of China (No:20562011,
20662009).
[32] Lu, Y. C.; Jin, S.; Xing, Q. Y. J Mol Struct (Theochem)
1988, 167, 253.
REFERENCES AND NOTES
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moto, A. Arzneim–Forsch 1971, 21, 1338.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet