Synthesis of novel tricyclic 1,5-benzothiazepine derivatives bearing quinoline moiety via [2 + 2] cycloaddition reaction

Article abstract of DOI:10.1002/jhet.1808

A series of new tricyclic 1,5-benzothiazepine derivatives were synthesized by the reaction of 1,5-benzothiazepine containing 2-phenoxy-quinoline with chloracetyl chloride and phenoxyacetyl chloride. The structures of the target compounds were confirmed by IR, ¹H NMR MS, and elemental analysis.

Full text of DOI:10.1002/jhet.1808

1516
Synthesis of Novel Tricyclic 1,5-Benzothiazepine Derivatives Bearing
Quinoline Moiety via [2 + 2] Cycloaddition Reaction
Vol 51
*
Le Huang, Fang-Ming Liu, and Zhi-Qiang Dong
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, Zhejiang,
People’s Republic of China
*
E-mail: fmliu859@sohu.com
Received March 30, 2012
DOI 10.1002/jhet.1808
Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
R1
CHO
O
O
R1
CHO
Cl
OH
R2
N
N
KOH
NaOH
R2=H, Cl, OCH3
2a-c
1a-c
R1=H, CH3, OCH3
O
O
N
SH
R1
R2
NH2
S
R1
N
O
Acetic acid
3a-h
N
4a-h
O
7
Cl
hOC
2
H C
R2
P
O
N
Et3N
S
R1
O
R2
ClCH2CCl
N
O
Et3N
5
OPh
8a-h
R1
R2
O
N
a
H
H
H
Cl
R1
S
b
c
d
e
f
H
OCH3
H
R2
N
O
CH3
CH3
CH3
Cl
Cl
OCH3
H
6a-h
g
h
OCH3
OCH3
OCH3
A series of new tricyclic 1,5-benzothiazepine derivatives were synthesized by the reaction of 1,5-
benzothiazepine containing 2-phenoxy-quinoline with chloracetyl chloride and phenoxyacetyl chloride.
1
The structures of the target compounds were confirmed by IR, H NMR MS, and elemental analysis.
J. Heterocyclic Chem., 51, 1516 (2014).
© 2014 HeteroCorporation

September 2014
Synthesis of Novel Tricyclic 1,5-Benzothiazepine Derivatives Bearing
Quinoline Moiety via [2 + 2] Cycloaddition Reaction
1517
INTRODUCTION
chlorides or phenoxyacetyl chlorides in the presence of
Et3N that lead to the formation of cycloadducts 6a–h and
8a–h, respectively. Various analytical techniques, such as
IR, 1H-NMR, mass spectrum, and elemental analysis, were
utilized to confirm the structural identities of the final
products.
1,5-Benzothiazepine is an important seven-membered
heterocyclic ring system. It has attracted considerable atten-
tion to synthetic and medicinal chemists because of their
broad spectrum of biological activities. It has been used as
a calcium antagonist [1], antibacterial [2], anticancer drug
[3,4], anticonvulsant, tranquilizer [5], and antidepressant
[6]. For example, the drug diltiazem, intensively used in
clinical practice, contains this system. It is well documented
that pharmaceutical properties of such compounds are
magnified when an additional heterocyclic is bound to the
heptatomic nucleus [7–9]. To search for new potential useful
1,5-benzothiazepine derivatives, a great deal of work has
been carried out on the synthesis of tricyclic 1,5-benzothia-
zepine derivatives in recent years [10].
Quinoline ring systems represent a major class of hetero-
cycles as they occur in various natural products especially
in alkaloids [11]; it possesses diverse biological and physio-
logical activities such as antimalarial [12], anti-inflammatory
[13], antitumor [14], and antibacterial properties [15]. By all
means, quinoline acts as “privileged substructure” for drug
design.
The role of b-lactams, which are endowed with unique
structure, showed biological activities that include inhibition
of prostate-specific antigen [16], thrombin [17], human cyto-
megalovirus protein [18], human leukocyte elastase [19],
and cholesterol absorption [20]. Most importantly, antibio-
tics possess a representative structure of a b-lactam-fused
five- or six-membered heterocyclic ring containing nitrogen
and sulfur atoms [21–24], for example, tazobactams, which
have been widely used as chemotherapeutic agents to treat
bacterial infections and microbial diseases.
Considering the important biological activities of these
heterocyclic ring system as well as the combination princi-
ples for drug design, we herein report the synthesis of new
b-lactam-fused 1,5-benzothiazepine derivatives containing
quinoline moiety via [2 + 2] cycloadditions reaction. The
synthetic route is shown in Scheme 1.
In IR spectra of the final compounds, there is a strong
absorption at 1609–1588 cmÀ1 due to the presence of
C═N and a weak absorption at 1251–1234 cmÀ1 for
C–O–C single bond of the 2-phenoxy-quinoline moiety.
Meanwhile, the absorption recorded at 1787–1767 cmÀ1
1
is attributed to the C═O group. In the H-NMR spectra
of compounds 2a–h, the presence of a singlet at
d 8.66 ppm is ascribed to the quinoline-H4 and a singlet
at d 10.64 ppm is ascribed to the formyl group. For
compounds 3a–h, the protons of a,b-unsaturated carbonyl
compounds have shown two doublets at d 8.17 ppm for Hb
and 7.94 ppm for Ha with 15.6 Hz as coupling constant. So,
it was inferred that they are in a trans conformation.
For compounds 4a–h, the presence of a singlet at
d 8.35–8.30 ppm is ascribed to the quinoline-H4, and the
1H-NMR spectrum revealed three distinct doubled
doublets at d 5.67–5.60, 3.67–3.60, and 3.02–2.96 ppm,
which could be attributed to the characteristic signal of
the dihydrobenzothiazepine moiety as ABX pattern. For
the titled compounds 6a–h and 8a–h, the presence of a
singlet at d 5.09–5.06 ppm and 5.42–5.36 ppm is ascribed
to the b-lactam, respectively. Also, the 1H-NMR spectrum
revealed three distinct doubled doublets, which could be
attributed to the characteristic signal of the dihydroben-
zothiazepine moiety as ABX pattern. In the MS spectra,
molecular ion signals of all target compounds were
attained from EIMS, but the abundance of molecular ion
signals was very low.
The formation of 4 may proceed via a two-step mecha-
nism [25–27]. Nucleophilic attack by the sulfohydryl
electrons of o-aminothiophenol takes place on the activated
b-carbon atom of the a,b-unsaturated ketone to obtain
Michael-adduct type intermediates, which simultaneously
undergo dehydrative cyclization to give desired products.
RESULTS AND DISCUSSION
CONCLUSION
A series of novel benzothiazepine derivatives bearing a
2-phenoxy-quinoline moiety were synthesized by using
2-chloro-3-quinolinecarbaldehyde (1) as starting material.
The synthesis of intermediate 2-phenoxy-3-quinolinecar-
baldehyde (2a–c) was used by compound 1 with phenol
at 85–90ꢀC for 6 h. Via the Claisen–Schmidt condensation,
we can synthesize compounds a,b-unsaturated ketones
(3a–h) between 2a–c and 1-arylethanones. Using acetic
acid as catalyst, we synthesized benzothiazepine deriva-
tives (4a–h) by a,b-unsaturated ketones 3a–h with
o-aminothiophenol in ethanol. Compounds 4a–h under-
went the reaction of [2 + 2] cycloadditions with chloracetyl
In summary, we have synthesized a series of new tricyclic
1,5-benzothiazepine derivatives 6a–h and 8a–h containing
2-phenoxy-quinoline moiety by [2+ 2] cycloaddition
reaction. These compounds might have useful biological
and therapeutic activities. The structures of the target com-
pounds were confirmed by IR, 1H-NMR, MS, and elemental
analysis.
EXPERIMENTAL
General procedures. Reactions were monitored by TLC.
Melting points were determined by a mettler FP-5 melting point
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Huang, F.-M. Liu, and Z.-Q. Dong
Vol 51
1518
Scheme 1. Synthesis route for titled compounds.
1
R
CHO
1
O
R
CHO
Cl
2
OH
R
N
O
N
KOH
NaOH
2a-c
1a-c
O
SH
O
N
1
R
2
R
NH
2
1
S
N
R
N
O
Acetic acid
3a-h
4a-h
2
R
O
l
P
C
h
C
O
2
C
H
H
2
O
C
l
C
C
E
N
C
t
t 3
5
3
N
l
E
7
O
N
O
N
1
S
R
1
S
R
2
R
2
N
O
R
N
O
Cl
OPh
6a-h
8a-h
1
a
2
b
c
R1 = H CH3 CH3O
3
a
4
5
b
6
c
d
e
f
g
h
R1 = H
R2 = H
H
Cl
H
CH3 CH3 CH3
Cl CH3O
CH3O CH3O
CH3O
CH3O
H
H
apparatus and were uncorrected. Elemental analyses were
conducted on a Perkin-Elmer 2400 elemental analyzer. The IR
spectra were recorded on potassium bromide pellets using a
Bruker Equinox 55 FTIR spectrophotometer. The 1H-NMR
spectra were recorded on a Bruker NMR spectrophotometer
(400 MHz) using TMS as an internal reference and CDCl3 as
solvent. Multiplicities are indicated as the following: s, singlet;
d, doublet; t, triplet; q, quartet; m, multiplet; dd, doubled
doublet. Coupling constants (J values) were noted and are
quoted in Hertz. Mass spectra were recorded on an Agilent
5975 apparatus (EI, 70 eV). Compounds 1 [28], 2 [29], and 7
[30] were synthesized according to the reported literature.
(M+); Anal. Calcd for C24H17NO2: C, 82.30; H, 4.88; N, 3.99;
Found: C, 82.24; H, 4.85; N, 4.03.
3-(2-Phenoxy-quinolin-3-yl)-1-(4-chlorophenyl)-2-propen-1-
one (3b). Yellow solid (81%); mp 124–125ꢀC; FTIR n 1663
(C═O), 1612 (C═N), 1247 (C–O–C) cmÀ1 1H-NMR d 8.43
;
(s, 1H, quinolin-H4), 8.19 (d, 1H, J = 15.6 Hz, Hb), 7.99 (d, 1H,
J = 15.6 Hz, Ha), 8.13–6.72 (m, 13H, ArH); MS (EI): m/z 385
(M+); Anal. Calcd for C24H16ClNO2: C, 74.71; H, 4.18; N,
3.63; Found: C, 74.68; H, 4.16; N, 3.67.
3-(2-Phenoxy-quinolin-3-yl)-1-(4-methoxyphenyl)-2-propen-
1-one (3c). Yellow solid (84%); mp 187–188ꢀC; FTIR n 1660
(C═O), 1605 (C═N), 1241 (C–O–C) cmÀ1 1H-NMR d 8.42
;
(s, 1H, quinolin-H4), 8.16 (d, 1H, J = 15.6 Hz, Hb), 7.96 (d, 1H,
J = 15.6 Hz, Ha), 8.09–6.98 (m, 13H, ArH), 3.89 (s, 3H, –
OCH3); MS (EI): m/z 381 (M+); Anal. Calcd for C25H19NO3: C,
78.72; H, 5.02; N, 3.67; Found: C, 78.67; H, 4.98; N, 3.71.
3-(2-Phenoxy-7-methyl-quinolin-3-yl)-1-phenyl-2-propen-1-
Compounds 3 were prepared according to the literature [31].
3-(2-Phenoxy-quinolin-3-yl)-1-phenyl-2-propen-1-one (3a).
Pale yellow solid (86%); mp 133–134ꢀC; FTIR n 1661 (C═O),
1603 (C═N), 1242 (C–O–C) cmÀ1 1H-NMR d 8.43 (s, 1H,
;
quinolin-H4), 8.17 (d, 1H, J = 15.6 Hz, Hb), 7.98 (d, 1H,
J = 15.6 Hz, Ha), 8.11–6.71 (m, 14 H, ArH); MS (EI): m/z 351
one (3d).
Pale yellow solid (78%); mp 187–188ꢀC; FTIR n
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014
Synthesis of Novel Tricyclic 1,5-Benzothiazepine Derivatives Bearing
Quinoline Moiety via [2 + 2] Cycloaddition Reaction
1519
1659 (C═O), 1604 (C═N), 1252 (C–O–C) cmÀ1
;
1H-NMR
2,3-Dihydro-2-(2-phenoxy-quinolin-3-yl)-4-(4-methoxyphenyl)-
1,5-benzothiazepine (4c). Pale yellow solid (76%); mp
d 8.34 (s, 1H, quinolin-H4), 8.17 (d, 1H, J = 15.6 Hz, Hb),
7.94 (d, 1H, J = 15.6 Hz, Ha), 8.07–7.26 (m, 13H, ArH), 2.50
(s, 3H, –CH3); MS (EI): m/z 365 (M+); Anal. Calcd for
C25H19NO2: C, 82.17; H, 5.24; N, 3.83; Found: C, 82.09; H,
5.18; N, 3.91.
217–218ꢀC; FTIR n 1587 (C═N), 1242 (C–O–C)cmÀ1; 1H-NMR
d 8.35 (s, 1H, quinolin-H4), 8.24–7.13 (m, 17H, ArH), 5.67
(dd, 1H, H2x, Jax = 12.8 Hz, Jbx = 4.0 Hz), 3.83 (s, 3H, –OCH3),
3.66 (dd, 1H, H3b, Jbx = 4.0 Hz, Jab = 12.4 Hz), 3.02 (dd, 1H, H3a,
Jax = 12.8Hz, Jab = 12.4 Hz); MS (EI): m/z 488 (M+); Anal. Calcd
for C31H24N2O2S: C, 76.20; H, 4.95; N, 5.73; Found: C, 76.16;
H, 4.92; N, 5.78.
3-(2-Phenoxy-7-methyl-quinolin-3-yl)-1-(4-chlorophenyl)-2-
propen-1-one (3e). Pale yellow solid (80%); mp 161–162ꢀC;
FTIR n 1662 (C═O), 1611 (C═N), 1249 (C–O–C) cmÀ1 1H-
;
NMR d 8.34 (s, 1H, quinolin-H4), 8.18 (d, 1H, J = 15.6 Hz, Hb),
7.94 (d, 1H, J = 15.6 Hz, Ha), 8.09–7.18 (m, 12H, ArH), 2.51
(s, 3H, –CH3); MS (EI): m/z 399 (M+); Anal. Calcd for
C25H18ClNO2: C, 75.09; H, 4.54; N, 3.50; Found: C, 74.98; H,
4.59; N, 3.43.
2,3-Dihydro-2-(2-phenoxy-7-methyl-quinolin-3-yl)-4-phenyl-
1,5-benzothiazepine (4d). Yellow solid (67%); mp 214–215ꢀC;
FTIR n 1593 (C═N), 1251 (C–O–C)cmÀ1 1H-NMR d 8.32
;
(s, 1H, quinolin-H4), 8.20–7.16 (m, 17H, ArH), 5.62 (dd, 1H,
H2x, Jax = 12.8Hz, Jbx = 4.0 Hz), 3.60 (dd, 1H, H3b, Jbx = 4.0 Hz,
Jab = 12.4Hz), 2.96 (dd, 1H, H3a, Jax = 12.8Hz, Jab = 12.4 Hz);
MS (EI): m/z 472 (M+); Anal. Calcd for C31H24N2OS: C, 78.78;
H, 5.12; N, 5.93; Found: C, 78.71; H, 5.06; N, 5.97.
3-(2-Phenoxy-7-methyl-quinolin-3-yl)-1-(4-methoxyphenyl)-2-
propen-1-one (3f).
FTIR n 1661 (C═O), 1608 (C═N), 1253 (C–O–C)cmÀ1
Pale yellow solid (75%); mp 172–173ꢀC;
;
1H-
NMR d 8.33 (s, 1H, quinolin-H4), 8.17 (d, 1H, J = 15.6 Hz, Hb),
7.94 (d, 1H, J = 15.6 Hz, Ha), 8.06–7.25 (m, 12H, ArH), 3.89
(s, 3H, –OCH3), 2.51 (s, 3H, –CH3); MS (EI): m/z 395 (M+);
Anal. Calcd for C26H21NO3: C, 78.97; H, 5.35; N, 3.54; Found:
C, 78.88; H, 5.27; N, 3.61.
2,3-Dihydro-2-(2-phenoxy-7-methyl-quinolin-3-yl)-4-
(4-chlorophenyl)-1,5-benzothiazepine (4e). Yellow solid (65%);
1
mp 261–262ꢀC; FTIR n 1594 (C═N), 1246 (C–O–C) cmÀ1; H-
NMR d 8.30 (s, 1H, quinolin-H4), 8.18–7.18 (m, 17H, ArH), 5.60
(dd, 1H, H2x, Jax = 12.8 Hz, Jbx = 4.0 Hz), 3.61 (dd, 1H, H3b,
Jbx =4.0Hz, Jab = 12.4 Hz), 2.97 (dd, 1H, H3a, Jax = 12.8 Hz,
Jab = 12.4 Hz), 2.49 (s, 3H, -CH3); MS (EI): m/z 506 (M+); Anal.
Calcd for C31H23ClN2OS: C, 73.43; H, 4.57; N, 5.52; Found: C,
73.36; H, 4.48; N, 5.58.
3-(2-Phenoxy-7-methoxy-quinolin-3-yl)-1-phenyl-2-propen-1-
one (3g). Pale yellow solid (79%); mp 163–164ꢀC; FTIR n 1660
1
(C═O), 1607 (C═N), 1254 (C–O–C) cmÀ1; H-NMR d 8.33 (s,
1H, quinolin-H4), 8.18 (d, 1H, J = 15.6 Hz, Hb), 7.96 (d, 1H,
J = 15.6 Hz, Ha), 8.09–7.29 (m, 13H, ArH), 3.91 (s, 3H, –OCH3);
MS (EI): m/z 381 (M+); Anal. Calcd for C25H19NO3: C, 78.72;
H, 5.02; N, 3.67; Found: C, 78.64; H, 4.93; N, 3.74.
2,3-Dihydro-2-(2-phenoxy-7-methyl-quinolin-3-yl)-4-
(4-methoxyphenyl)-1,5-benzothiazepine (4f). Yellow solid (73%);
1
mp 255–256ꢀC; FTIR n 1595 (C═N), 1243 (C–O–C) cmÀ1; H-
3-(2-Phenoxy-7-methoxy-quinolin-3-yl)-1-(4-methoxyphenyl)-
2-propen-1-one (3h). Pale yellow solid (77%); mp 162–163ꢀC;
FTIR n 1661 (C═O), 1604 (C═N), 1251 (C–O–C) cmÀ1; 1H-NMR
d 8.33 (s, 1H, quinolin-H4), 8.14 (d, 1H, J = 15.6 Hz, Hb), 7.95
(d, 1H, J = 15.6 Hz, Ha), 8.08–6.97 (m, 12H, ArH), 3.92 (s, 3H, –
OCH3), 3.89 (s, 3H, –OCH3); MS (EI): m/z 411 (M+); Anal.
Calcd for C26H21NO4: C, 75.90; H, 5.14; N, 3.40; Found: C,
75.81; H, 5.06; N, 3.49.
NMR d 8.35 (s, 1H, quinolin-H4), 8.24–7.12 (m, 16H, ArH), 5.66
(dd, 1H, H2x, Jax =12.8Hz, Jbx = 4.0 Hz), 3.87 (s, 3H, –OCH3),
3.65 (dd, 1H, H3b, Jbx =4.0Hz, Jab = 12.4 Hz), 3.01 (dd, 1H, H3a,
Jax =12.8Hz, Jab = 12.4 Hz), 2.51 (s, 3H, –CH3); MS (EI): m/z 458
(M+); Anal. Calcd for C32H26N2O2S: C, 76.47; H, 5.21; N, 5.57;
Found: C, 76.38; H, 5.16; N, 5.61.
2,3-Dihydro-2-(2-phenoxy-7-methoxy-quinolin-3-yl)-4-phenyl-
1,5-benzothiazepine (4g). Yellow solid (67%); mp 218–219ꢀC;
FTIR n 1592 (C═N), 1259 (C–O–C)cmÀ1 1H-NMR d 8.33
;
General procedure for the synthesis of compounds 4.
Chalcone 3 (10 mmol) and o-aminothiophenol (1.25 g, 10 mmol)
were dissolved in anhydrous ethanol (60 mL). The reaction
mixture was heated to reflux for 2 h in the presence of acetic
acid (1.0 mL) under stirring. The solid product was separated by
filtration and recrystallized from anhydrous ethanol and benzene
to give compounds 4a–h after allowing the reaction mixture to
cool down to room temperature.
(s, 1H, quinolin-H4), 8.23–7.08 (m, 17H, ArH), 5.65 (dd, 1H, H2x,
Jax = 12.8Hz, Jbx = 4.0Hz), 3.91 (s, 3H, –OCH3), 3.67 (dd, 1H,
H3b, Jbx = 4.0Hz, Jab = 12.4 Hz), 3.01 (dd, 1H, H3a, Jax =12.8 Hz,
Jab = 12.4Hz); MS (EI): m/z 488 (M+); Anal. Calcd for
C31H24N2O2S: C, 76.20; H, 4.95; N, 5.73; Found: C, 76.11; H,
4.86; N, 5.79.
2,3-Dihydro-2-(2-phenoxy-7-methoxy-quinolin-3-yl)-4-(4-
methoxyphenyl)-1,5-benzothiazepine (4h). Yellow solid (70%);
2,3-Dihydro-2-(2-phenoxy-quinolin-3-yl)-4-phenyl-1,5-
1
mp 247–248ꢀC; FTIR n 1596 (C═N), 1248 (C–O–C)cmÀ1; H-
benzothiazepine (4a).
FTIR n 1592 (C═N), 1244 (C–O–C)cmÀ1
Yellow solid (71%); mp 223–224ꢀC;
NMR d 8.34 (s, 1H, quinolin-H4), 8.19–7.01 (m, 16H, ArH), 5.66
(dd, 1H, H2x, Jax = 12.8 Hz, Jbx = 3.9 Hz), 3.90 (s, 3H, –OCH3),
3.86 (s, 3H, –OCH3), 3.66 (dd, 1H, H3b, Jbx = 3.9 Hz,
Jab = 12.4Hz), 3.02 (dd, 1H, H3a, Jax = 12.8Hz, Jab = 12.4 Hz);
MS (EI): m/z 518 (M+); Anal. Calcd for C32H26N2O3S:
C, 74.11; H, 5.05; N, 5.40; Found: C, 74.02; H, 4.96;
N, 5.47.
;
1H-NMR d 8.35
(s, 1H, quinolin-H4), 8.23–7.15 (m, 18H, ArH), 5.65 (dd, 1H,
H2x, Jax = 12.8 Hz, Jbx = 4.0 Hz), 3.66 (dd, 1H, H3b, Jbx = 4.0 Hz,
Jab = 12.4Hz), 3.02 (dd, 1H, H3a, Jax = 12.8 Hz, Jab = 12.4 Hz);
MS (EI): m/z 458 (M+); Anal. Calcd for C30H22N2OS: C, 78.57;
H, 4.84; N, 6.11; Found: C, 78.53; H, 4.81; N, 6.16.
2,3-Dihydro-2-(2-phenoxy-quinolin-3-yl)-4-(4-chlorophenyl)-
1,5-benzothiazepine (4b).
Pale yellow solid (69%); mp
General procedure for the synthesis of compounds 6 and 8.
The reaction mixture of compounds 4 (1.0 mmol) was dissolved in
toluol (20 mL) in the presence of Et3N. The reaction mixture was
heated in an oil bath to reflux. Then, chloracetyl chlorides 5
(2.0 mmol) or phenoxyacetyl chlorides 7 (2.0mmol) dissolved in
the same solvent (10 mL) were added dropwise into the reaction
mixture, and the reaction mixture was heated to reflux for 5 h.
After allowing the reaction mixture to cool down to room
240–241ꢀC; FTIR n 1596 (C═N), 1249 (C–O–C) cmÀ1
;
1H-
NMR d 8.34 (s, 1H, quinolin-H4), 8.26–7.17 (m, 17H, ArH), 5.64
(dd, 1H, H2x, Jax = 12.8Hz, Jbx = 4.0 Hz), 3.65 (dd, 1H, H3b,
Jbx = 4.0 Hz, Jab = 12.4 Hz), 3.02 (dd, 1H, H3a, Jax = 12.8Hz,
Jab = 12.4Hz); MS (EI): m/z 492 (M+); Anal. Calcd for
C30H21ClN2OS: C, 73.08; H, 4.29; N, 5.68; Found: C, 73.04; H,
4.26; N, 5.71.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Huang, F.-M. Liu, and Z.-Q. Dong
Vol 51
1520
temperature, the by-product of triethylamine hydrochloride
was removed by filtration, and we removed the solution in vacuo.
Finally, the residue was purified by silica gel column
chromatography (ethylacetate/petroleum ether = 1:8, v/v) to afford
the desired products 6a–h and 8a–h, respectively.
2-Chloro-2a-phenyl-4-(2-phenoxy-quinolin-3-yl)-2,2a,3,4-
Calcd for C34H27ClN2O3S: C, 70.52; H, 4.70; N, 4.84; Found: C,
70.43; H, 4.62; N, 4.92.
2-Chloro-2a-phenyl-4-(2-phenoxy-7-methoxy-quinolin-3-yl)-
2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
(6g).
(C═O), 1588 (C═N), 1234 (C–O–C) cmÀ1
Yellow solid (30%); mp 195–196ꢀC; FTIR n 1787
;
1H-NMR d 8.12
(s, 1H, quinolin-H4), 7.98–7.09 (m, 17H, ArH), 5.09 (s, 1H,
ClCH), 4.55 (dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.92
(s, 1H, –OCH3), 3.72 (dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4 Hz),
3.23 (dd, 1H, H3a, Jax = 10.9 Hz, Jab = 14.4 Hz); MS (EI):
m/z 564 (M+); Anal. Calcd for C33H25ClN2O3S: C, 70.14; H,
tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-one (6a).
Yellow solid (36%); mp 181–182ꢀC; FTIR n 1785 (C═O), 1607
1
(C═N), 1251 (C–O–C)cmÀ1; H-NMR d 8.19 (s, 1H, quinolin-
H4), 7.94–6.73 (m, 18H, ArH), 5.08 (s, 1H, ClCH), 4.58 (dd, 1H,
H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.72 (dd, 1H, H3b, Jbx = 4.7 Hz,
Jab = 14.4Hz), 3.24 (dd, 1H, H3a, Jax = 10.9 Hz, Jab = 14.4Hz);
MS (EI): m/z 535 (M+); Anal. Calcd for C32H23ClN2O2S: C,
71.83; H, 4.33; N, 5.24; Found: C, 71.74; H, 4.26; N, 5.29.
2-Chloro-2a-(4-chlorophenyl)-4-(2-phenoxy-quinolin-3-yl)-2,
4.46; N, 4.96; Found: C, 70.06; H, 4.39; N, 5.05.
2-Chloro-2a-(4-methoxyphenyl)-4-(2-phenoxy-7-methoxy-quinolin-
3-yl)-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-
one (6h). Yellow solid (38%); mp 276–277ꢀC; FTIR n 1783
(C═O), 1589 (C═N), 1244 (C–O–C) cmÀ1 1H-NMR d 8.12
;
2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
(6b).
(C═O), 1597 (C═N), 1247 (C–O–C) cmÀ1
Yellow solid (32%); mp 187–188ꢀC; FTIR n 1783
(s, 1H, quinolin-H4), 7.95–6.76 (m, 16H, ArH), 5.06 (s, 1H,
ClCH), 4.57 (dd, 1H, H4x, Jax = 11.0Hz, Jbx = 4.7 Hz), 3.92
(s, 1H, –OCH3), 3.71 (s, 1H, –OCH3), 3.72 (dd, 1H, H3b,
Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.20 (dd, 1H, H3a, Jax = 11.0Hz,
Jab = 14.4Hz); MS (EI): m/z 594 (M+); Anal. Calcd for
C34H27ClN2O4S: C, 68.62; H, 4.57; N, 4.71; Found: C, 68.54; H,
;
1H-NMR d 8.16
(s, 1H, quinolin-H4), 7.95–6.74 (m, 17H, ArH), 5.06 (s, 1H,
ClCH), 4.56 (dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.72
(dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.22 (dd, 1H, H3a,
Jax = 10.9 Hz, Jab = 14.4Hz); MS (EI): m/z 568 (M+); Anal. Calcd
for C32H22Cl2N2O2S: C, 67.49; H, 3.89; N, 4.92; Found: C,
4.49; N, 4.81.
2-Phenoxy-2a-phenyl-4-(2-phenoxy-quinolin-3-yl)-2,2a,3,4-
67.41; H, 3.79; N, 5.07.
2-Chloro-2a-(4-methoxyphenyl)-4-(2-phenoxy-quinolin-3-yl)-
tetrahydro-1-1H-azeto[2,1-d][1,5]benzothiazepine-1-one (8a).
Yellow solid (32%); mp 247–248ꢀC; FTIR n 1772 (C═O), 1588
2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
1
(C═N), 1241 (C–O–C)cmÀ1; H-NMR d 8.14 (s, 1H, quinolin-
(6c). Yellow solid (37%); mp 212–213ꢀC; FTIR n 1784 (C═O),
1609 (C═N), 1252 (C–O–C) cmÀ1 1H-NMR d 8.20 (s, 1H,
;
H4), 7.95–6.71 (m, 23H, ArH), 5.41 (s, 1H, PhOCH), 4.63
(dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.70 (dd, 1H, H3b,
Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.30 (dd, 1H, H3a, Jax = 10.9Hz,
Jab = 14.4Hz); MS (EI): m/z 592 (M+); Anal. Calcd for
C38H28N2O3S: C, 77.00; H, 4.76; N, 4.73; Found: C, 76.92; H,
quinolin-H4), 7.96–6.77 (m, 17H, ArH), 5.08 (s, 1H, ClCH), 4.59
(dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.72 (s, 3H, –OCH3),
3.71 (dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.23 (dd, 1H, H3a,
Jax = 10.9 Hz, Jab = 14.4 Hz); MS (EI): m/z 564 (M+); Anal. Calcd
for C33H25ClN2O3S: C, 70.14; H, 4.46; N, 4.96; Found: C,
4.87; N, 4.81.
2-Phenoxy-2a-(4-chlorophenyl)-4-(2-phenoxy-quinolin-3-yl)-
70.02; H, 4.37; N, 4.91.
2-Chloro-2a-phenyl-4-(2-phenoxy-7-methyl-quinolin-3-yl)-2,
2,2a,3,4-tetrahydro-1-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
(8b). Yellow solid (36%); mp 202–203ꢀC; FTIR n 1771 (C═O),
(6d).
(C═O), 1589 (C═N), 1241 (C–O–C) cmÀ1
Yellow solid (39%); mp 203–204ꢀC; FTIR n 1786
1597 (C═N), 1247 (C–O–C) cmÀ1 1H-NMR d 8.16 (s, 1H,
;
;
1H-NMR d 8.14
quinolin-H4), 8.03–6.62 (m, 22H, ArH), 5.39 (s, 1H, PhOCH),
4.61 (dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.8 Hz), 3.70 (dd, 1H, H3b,
Jbx = 4.8 Hz, Jab = 14.4 Hz), 3.30 (dd, 1H, H3a, Jax = 10.9 Hz,
Jab = 14.4 Hz); MS (EI): m/z 626 (M+); Anal. Calcd for
C38H27ClN2O3S: C, 72.77; H, 4.34; N, 4.47; Found: C, 72.69; H,
(s, 1H, quinolin-H4), 8.01–7.17 (m, 17H, ArH), 5.09 (s, 1H,
ClCH), 4.58 (dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.72
(dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.24 (dd, 1H, H3a,
Jax = 10.9 Hz, Jab = 14.4 Hz), 2.52 (s, 1H, –CH3); MS (EI):
m/z 548 (M+); Anal. Calcd for C33H25ClN2O2S: C, 72.18; H,
4.26; N, 4.56.
2-Phenoxy-2a-(4-methoxyphenyl)-4-(2-phenoxy-quinolin-3-yl)-
4.59; N, 5.10; Found: C, 72.09; H, 4.67; N, 5.14.
2-Chloro-2a-(4-chlorophenyl)-4-(2-phenoxy-7-methyl-quinolin-
2,2a,3,4-tetrahydro-1-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
3-yl)-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]benzothiazepine-1-
(8c). Yellow solid (30%); mp 217–218ꢀC; FTIR n 1767 (C═O),
one (6e). Yellow solid (31%); mp 219–220ꢀC; FTIR n 1786
1590 (C═N), 1239 (C–O–C) cmÀ1 1H-NMR d 8.15 (s, 1H,
;
(C═O), 1601 (C═N), 1239 (C–O–C) cmÀ1
;
1H-NMR d 8.13
quinolin-H4), 7.97–6.71 (m, 22H, ArH), 5.41 (s, 1H, PhOCH),
4.58 (dd, 1H, H4x, Jax = 11.0 Hz, Jbx = 4.7 Hz), 3.71 (dd, 1H, H3b,
Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.67 (s, 1H, –OCH3), 3.31 (dd, 1H,
H3a, Jax = 11.0 Hz, Jab = 14.4 Hz); MS (EI): m/z 622 (M+); Anal.
Calcd for C39H30N2O4S: C, 75.22; H, 4.86; N, 4.50; Found: C,
(s, 1H, quinolin-H4), 8.02–7.19 (m, 16H, ArH), 5.07 (s, 1H,
ClCH), 4.57 (dd, 1H, H4x, Jax = 10.9 Hz, Jbx = 4.7 Hz), 3.72
(dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.23 (dd, 1H, H3a,
Jax = 10.9 Hz, Jab = 14.4 Hz), 2.52 (s, 1H, –CH3); MS (EI):
m/z 582 (M+); Anal. Calcd for C33H24Cl2N2O2S: C, 67.92; H,
4.15; N, 4.80; Found: C, 67.86; H, 4.07; N, 4.85.
2-Chloro-2a-(4-methoxyphenyl)-4-(2-phenoxy-7-methyl-
quinolin-3-yl)-2,2a,3,4-tetrahydro-1H-azeto[2,1-d][1,5]
75.13; H, 4.79; N, 4.56.
2-Phenoxy-2a-phenyl-4-(2-phenoxy-7-methyl-quinolin-3-yl)-
2,2a,3,4-tetrahydro-1-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
(8d). Yellow solid (36%); mp 251–252ꢀC; FTIR n 1751 (C═O),
benzothiazepine-1-one (6f).
Yellow solid (35%); mp 235–
1596 (C═N), 1241 (C–O–C) cmÀ1 1H-NMR d 8.01 (s, 1H,
;
236ꢀC; FTIR n 1785 (C═O), 1592 (C═N), 1241 (C–O–C)cmÀ1
;
quinolin-H4), 7.71–6.65 (m, 22H, ArH), 5.36 (s, 1H, PhOCH),
5.26 (dd, 1H, H4x, Jax = 11.0 Hz, Jbx = 4.7 Hz), 3.94 (dd, 1H, H3b,
Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.30 (dd, 1H, H3a, Jax = 11.0 Hz,
Jab = 14.4 Hz), 2.49 (s, 3H, –CH3); MS (EI): m/z 606 (M+); Anal.
Calcd for C39H30N2O3S: C, 77.20; H, 4.98; N, 4.62; Found: C,
77.11; H, 4.89; N, 4.71.
1H-NMR d 8.14 (s, 1H, quinolin-H4), 7.96–7.03 (m, 16H, ArH),
5.06 (s, 1H, ClCH), 4.59 (dd, 1H, H4x, Jax = 10.9Hz,
Jbx = 4.8 Hz), 3.72 (s, 3H, –OCH3), 3.71 (dd, 1H, H3b,
Jbx = 4.8 Hz, Jab = 14.4 Hz), 3.22 (dd, 1H, H3a, Jax = 10.9Hz,
Jab = 14.4Hz), 2.51 (s, 1H, –CH3); MS (EI): m/z 578 (M+); Anal.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014
Synthesis of Novel Tricyclic 1,5-Benzothiazepine Derivatives Bearing
Quinoline Moiety via [2 + 2] Cycloaddition Reaction
1521
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Voronia, S. S. Khim Farm Zh 1989, 23, 1226.
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[18] Borthwick, A. D.; Weingarten, G.; Haley, T. M.; Tomaszewski,
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2-Phenoxy-2a-(4-chlorophenyl)-4-(2-phenoxy-7-methyl-quinolin-
3-yl)-2,2a,3,4-te-trahydro-1-1H-azeto[2,1-d][1,5]benzothiazepine-
1-one (8e). Yellow solid (39%); mp 242–243ꢀC; FTIR n 1772
(C═O), 1594 (C═N), 1232 (C–O–C) cmÀ1 1H-NMR d 8.15
;
(s, 1H, quinolin-H4), 7.99–6.74 (m, 21H, ArH), 5.42 (s, 1H,
PhOCH), 4.56 (dd, 1H, H4x, Jax = 11.2Hz, Jbx = 4.8 Hz), 3.70
(dd, 1H, H3b, Jbx = 4.8 Hz, Jab = 14.4 Hz), 3.31 (dd, 1H, H3a,
Jax = 11.2 Hz, Jab = 14.4 Hz), 2.51 (s, 3H, –CH3); MS (EI):
m/z 640 (M+); Anal. Calcd for C39H29ClN2O3S: C, 73.06; H,
4.56; N, 4.37; Found: C, 72.95; H, 4.47; N, 4.48.
2-Phenoxy-2a-(4-methoxyphenyl)-4-(2-phenoxy-7-methyl-
quinolin-3-yl)-2,2a,3,4-tetrahydro-1-1H-azeto[2,1-d][1,5]
benzothiazepine-1-one (8f).
Yellow solid (32%); mp 233–
234ꢀC; FTIR n 1772 (C═O), 1589 (C═N), 1246 (C–O–C)cmÀ1
;
1H-NMR d 8.17 (s, 1H, quinolin-H4), 8.01–6.67 (m, 21H, ArH),
5.39 (s, 1H, PhOCH), 4.65 (dd, 1H, H4x, Jax = 10.9 Hz,
Jbx = 4.7 Hz), 3.71 (dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.67
(s, 3H, –OCH3), 3.30 (dd, 1H, H3a, Jax = 10.9Hz, Jab = 14.4 Hz),
2.52 (s, 3H, –CH3); MS (EI): m/z 636 (M+); Anal. Calcd for
C40H32N2O4S: C, 75.45; H, 5.07; N, 4.40; Found: C, 75.36; H,
4.99; N, 4.48.
2-Phenoxy-2a-phenyl-4-(2-phenoxy-7-methoxy-quinolin-3-yl)-
2,2a,3,4-tetrahydro-1-1H-azeto[2,1-d][1,5]benzothiazepine-1-one
(8g). Yellow solid (30%); mp 257–258ꢀC; FTIR n 1768 (C═O),
1592 (C═N), 1236 (C–O–C) cmÀ1 1H-NMR d 8.16 (s, 1H,
;
quinolin-H4), 8.03–6.65 (m, 22H, ArH), 5.41 (s, 1H, PhOCH),
4.62 (dd, 1H, H4x, Jax = 11.1 Hz, Jbx = 4.7 Hz), 3.92 (s, 3H, –
OCH3), 3.69 (dd, 1H, H3b, Jbx = 4.7 Hz, Jab = 14.4Hz), 3.31
(dd, 1H, H3a, Jax = 11.1Hz, Jab = 14.4Hz); MS (EI): m/z 622
(M+); Anal. Calcd for C39H30N2O4S: C, 75.22; H, 4.86; N, 4.50;
Found: C, 75.14; H, 4.77; N, 4.59.
2-Phenoxy-2a-(4-methoxyphenyl)-4-(2-phenoxy-7-methoxy-
quinolin-3-yl)-2,2a,3,4-tetrahydro-1-1H-azeto[2,1-d][1,5]
[19] Cvetovich, R. J.; Chartran, M.; Hartner, W. F.; Roberge, C.;
Amato, J. S.; Grabowski, E. J. J Org Chem 1996, 61, 6575.
[20] Wang, Y. B.; Zhang, H. B.; Huang, W. L.; Kong, J.; Zhou,
J. P.; Zhang, B. B. Euro J Med Chem 2009, 44, 1638.
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1988, 66, 279.
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Dayal, B. J Org Chem 1974, 39, 2877.
[23] Firestone, R. A.; MacieJewicz, N. S.; Christensen, B. G. J Org
Chem 1974, 39, 3384.
benzothiazepine-1-one (8h).
Yellow solid (37%); mp 211–
222ꢀC; FTIR n 1773 (C═O), 1589 (C═N), 1235 (C–O–C)cmÀ1
;
1H-NMR d 8.17 (s, 1H, quinolin-H4), 7.99–6.66 (m, 21H, ArH),
5.38 (s, 1H, PhOCH), 4.64 (dd, 1H, H4x, Jax = 10.9 Hz,
Jbx = 4.7 Hz), 3.92 (s, 3H, –OCH3), 3.71 (dd, 1H, H3b,
Jbx = 4.7 Hz, Jab = 14.4 Hz), 3.66 (s, 3H, –OCH3) 3.28 (dd, 1H,
H3a, Jax = 10.9 Hz, Jab = 14.4 Hz); MS (EI): m/z 652 (M+); Anal.
Calcd for C40H32N2O5S: C, 73.60; H, 4.94; N, 4.29; Found: C,
73.51; H, 4.87; N, 4.18.
[24] Hegedus, L. S.; Imwinkelried, R.; Sargent, A. M.; Dvorak, D.;
Satoh, Y. J. Am Chem Soc 1990, 112, 1109.
[25] Xing, Q. Y.; Wang, H. Z.; Zhou, X.; Jin, S.; Li, Y. M.; Chan,
A. S.C. J Heterocyclic Chem 2001, 38, 561.
Acknowledgment. We are grateful to the Key SCI-Tech Innovation
Team of Zhejiang Province (2010R50017) for financial help.
[26] Huang, X.; Xu, J. X. Heteroatom Chemistry 2003, 14, 564.
[27] Qi, H. Z.; Yang, Z. H.; Xu, J. X. Synthesis 2011, 5, 723.
[28] Devi, I.; Baruah, B.; Bhuyan, P. J. Synlett 2006, 16, 2593.
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2011, 15, 963.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet