An efficient and chemoselective synthesis of benzo[e][1,4]thiazepin-2(1H, 3H,5H)-ones via a microwave-assisted multi-component reaction in water

Article abstract of DOI:10.1039/b815879g

A new and efficient strategy for the synthesis of benzo[e][1,4]thiazepin- 2(1H,3H,5H)-ones via a microwave-assisted multi-component reaction in aqueous media is described. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b815879g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An efficient and chemoselective synthesis of benzo[e][1,4]thiazepin-2-
(1H,3H,5H)-ones via a microwave-assisted multi-component
reaction in water†
Shu-Jiang Tu,* Xu-Dong Cao, Wen-Juan Hao, Xiao-Hong Zhang, Shu Yan, Shan-Shan Wu,
Zheng-Guo Han and Feng Shi
Received 10th September 2008, Accepted 29th October 2008
First published as an Advance Article on the web 5th January 2009
DOI: 10.1039/b815879g
A new and efficient strategy for the synthesis of benzo[e][1,4]thiazepin-2(1H,3H,5H)-ones via a
microwave-assisted multi-component reaction in aqueous media is described.
successfully employed as a solvent for various MW promoted
organic syntheses.8c–h
Introduction
As part of our ongoing research program9 on “Heterocyclic
Privileged Medicinal Scaffolds”10 based on MCRs, we explored the
use of water as a reaction medium in conjunction with microwave
irradiation as a useful, environmentally benign treatment for the
synthesis of benzothiazepinones. Here we report a highly efficient
and chemoselective synthetic route to the benzothiazepinones 4
and thiazolidinones 5 via a microwave-assisted, three-component
reaction between an aromatic aldehyde, aniline and mercap-
toacetic acid (Scheme 1).
Because of their interesting biological properties, functional-
ized benzothiazepinones and their fused analogues represent
an important class of heterocycles that have been tested and
applied as potential drugs.1 Especially, benzo[e][1,4]thiazepin-2-
ones were used as a potential therapeutic medicine for type
II diabetes.2 Therefore, these molecules have attracted consid-
erable synthetic effort. Presently, benzo[e][1,4]thiazepin-2-ones
are generally synthesized by S-alkylation of 2-aminobenzhydrols
with methyl thioglycolate followed by cyclization. This can be
achieved (1) through a laborious multistep procedure;3(2) through
a two-step procedure with a long reaction time to complete the
S-alkylation;4 (3) through an efficient S-alkylation procedure
by using corrosive strong organic acid such as CF3COOH.2
However, the key starting material 2-aminobenzhydrol is not a
commercially available reagent and needs to be prepared itself
via complicated procedures by (1) reduction of the corresponding
3
2-aminobenzophenones using NaBH4 or LiAlH4;2 (2) selective
Scheme 1
ortho-lithiation of pivaloylanilide by n-butyllithium followed by
condensation with aromatic aldehydes.5 Furthermore, all the
above mentioned reactions suffer from time-consuming and costly
procedures, including the purification of intermediates and the
protection and deprotection of functional groups, and the use
of low temperature. Therefore, the design of new, concise, and
efficient synthetic routes for this important class of compounds
using easily accessible raw materials is highly desired.6
At the same time, because of growing environmental concerns,
organic chemists are required to develop environmentally benign
synthetic methodologies.7 Naturally abundant water appears to
be a better option as a reaction medium because of its non-
toxic, non-corrosive and nonflammable nature.8a In this respect,
one of the most promising approaches is to perform organic
reactions in aqueous media using microwave (MW) irradiation.8b
Water is a good absorber for microwave energy and has been
Result and discussion
In order to find suitable conditions for efficient microwave-
assisted formation of the benzothiazepinones, the influences of
different solvents were investigated using the reaction of p-
methylbenzaldehyde 1a with p-toluidine 2a and mercaptoacetic
acid 3 as a model reaction at 90 ◦C (Scheme 2). When the
reaction was carried out in aprotic solvents such as benzene,
dichloromethane, DMF and THF it afforded the thiazolidinones
5 with excellent yields. Interestingly, the use of protic solvents
School of Chemistry and Chemical Engineering, Xuzhou Normal University,
Key Laboratory of Biotechnology for medicinal Plant, Xuzhou, Jiangsu,
211116, P.R. China. E-mail: laotu@xznu.edu.cn; Fax: +86(516) 83403165;
Tel: +86(516) 83500365
† Electronic supplementary information (ESI) available: All NMR spectra
for the new compounds. CCDC reference number 706679. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b815879g
Scheme 2
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Table 1 Solvent effect on the synthesis of compounds 4a at 90 ◦
C
Table 2 Temperature optimization of the synthesis of compounds 4a in
water
Entry
Solvent
Time (min)
Yield (%)
Entry
Temp. (◦C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
benzene
dichloromethane
DMF
THF
glycol
ethanol
HOAc
H2O
13
13
13
13
13
13
13
13
trace
trace
trace
trace
10
17
55
1
2
3
4
5
6
7
90
95
100
105
110
115
120
13
13
10
9
9
9
65
68
70
80
94
93
92
65
9
such as glycol, ethanol, glacial acetic acid (HOAc) and wa-
ter gave low to moderate yields of the product 4a. The best
protic solvent found was water. In this solvent, 7-methyl-5-p-
tolylbenzo[e][1,4]thiazepin-2(1H,3H,5H)-one was obtained in a
better yield than with other protic solvents (Table 1, entry 8).
Furthermore, the above-mentioned reaction was performed at
temperatures ranging from 90 ◦C to 120 ◦C in water. As seen from
Table 2, when the temperature was increased from 90 ◦C to 110 ◦C,
the yield of 4a improved from 65% to 94%. However, no significant
increase in the yield was observed as the reaction temperature
was raised further from 110 ◦C to 120 ◦C. Therefore, the tem-
perature of 110 ◦C was chosen for all further microwave-assisted
reactions.
amines under the optimum reaction conditions. The results are
summarized in Table 3.
It is worthy of note that there is a delicate electronic effect on the
chemoselectivity in these reactions. In search of the reaction scope
in regard to the aldehydes, various aromatic amines with different
substituents, ranging from electron-donating groups such as
p-methoxy to electron-withdrawing groups such as p-chloro, were
allowed to react with different aromatic aldehydes (Table 3, entries
1–14), and the results indicate that aromatic aldehydes bearing
electron-donating functional groups such as methyl or methoxy
as well as heteroaromatic aldehydes are suitable for the formation
of 4. Surprisingly, the aldehydes with electron-withdrawing sub-
stituents generated no product 4. Instead, thiazolidinones 5 were
afforded with excellent yields. (Table 3, entries 26–30). It should be
pointed out that although there are many reports on the synthesis
of the thiazolidinones,11 to the best of our knowledge, the synthesis
of the biologically active derivatives 5 in aqueous media has seldom
In further investigation, the scope of the methodology was
studied; a wide range of substituted aromatic aldehydes as well
as heteroaromatic aldehydes were found to take part in reactions
with mercaptoacetic acid and different substituted aromatic
Table 3 Synthesis of benzothiazepinone derivatives 4 or thiazolidinones 5 under microwave irradiation in water at 110 ◦C
Entry
Product
Aldehydes
Amines
Time (min)
Yield (%)a
Mp (◦C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-Methylbenzaldehyde
p-Toluidine
9
8
8
9
10
9
8
8
10
9
9
11
9
9
9
9
8
9
8
9
8
9
10
9
9
8
7
9
10
10
94
92
90
90
91
92
90
94
90
91
93
92
90
95
93
93
96
96
93
93
90
91
92
92
94
92
89
90
91
92
>300
269–270
>300
249–251
206–207
214–216
268–269
>300
281–283
257
171–172
256–258
222
>300
260–263
>300
254–258
247–248
261–263
217–218
238–240
245–246
238
245–249
235–236
159–162
171–174
180
4-Methoxybenzaldehyde
4-(Dimethylamino)benzaldehyde
3,4-Methylenedioxybenzaldehyde
3,4-Dimethoxybenzaldehyde
2-Thiophenecarboxaldehyde
4-Methoxybenzaldehyde
4-(Dimethylamino)benzaldehyde
Benzaldehyde
p-Toluidine
p-Toluidine
p-Toluidine
p-Toluidine
p-Toluidine
4-Methoxybenzenamine
4-Methoxybenzenamine
Aniline
4j
4k
4l
4-Methylbenzaldehyde
Aniline
Aniline
m-Toluidine
m-Toluidine
2-Thiophenecarboxaldehyde
3,4-Methylenedioxybenzaldehyde
2-Thiophenecarboxaldehyde
4-Methylbenzaldehyde
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
5a
5b
5c
5d
5e
4-Chlorobenzenamine
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
3,4-(Methylenedioxy)aniline
p-Toluidine
4-Methylbenzaldehyde
4-Methoxybenzaldehyde
4-(Dimethylamino)benzaldehyde
3,4-Methylenedioxybenzaldehyde
3,4,5-Trimethoxybenzaldehyde
2-Thiophenecarboxaldehyde
2-Methoxybenzaldehyde
4-Bromobenzaldehyde
4-Chlorobenzaldehyde
2-Chlorobenzaldehyde
2,4-Dichlorobenzaldehyde
4-Bromobenzaldehyde
4-Fluorobenzaldehyde
p-Toluidine
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
p-Toluidine
Aniline
170–171
169–170
4-Methoxybenzenamine
a Isolated yields.
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been studied. To further explore the scope of the reactions leading
to 4, we chose 3,4-(methylenedioxy)aniline as the amine to react
with aromatic aldehydes and mercaptoacetic acid (Scheme 3). The
results indicate that in this case, aromatic aldehydes bearing either
electron-withdrawing or electron-donating functional groups such
as chloro, fluoro, bromo, methyl or methoxy uniformly give the
target products 4 (Table 3, entries 15–25) without the formation
of 5. It seems that the electronic effect on the chemoselectivity is
quite sophisticated and more comprehensive and in-depth study is
required to achieve a complete knowledge of the electronic effect.
Scheme 3
All the products were characterized by IR, 1H NMR, 13C NMR
spectra and HRMS data. The structure of 4a was also established
by X-ray crystallographic analysis (Fig. 1).12† The compounds 4i,
4n, 5a, 5b, 5c, 5d were reported in the literature.2,4,11
Fig. 1 ORTEP diagram of 4a.
Conclusion
To explain the mechanism of this one-pot multi-component
tandem reaction, we propose a plausible reaction mechanism
illustrated in Scheme 4. The nature of the groups in the aromatic
aldehydes is important in deciding the reaction path. The aromatic
aldehydes with electron-donating groups (p-OMe, sp = -0.27
or p-Me, sp = -0.17) take part in the reaction by pathway A
via initial condensation with the aromatic amine 2 to afford
the intermediates 8, which then undergo a [4 + 3] annulation
with mercaptoacetic acid to give the seven-member ring lactams
4 good yield. The aldehydes with electron-withdrawing groups
(EWG) such as p-chloro (sp = +0.23) are prone to afford
the thiazolidinones through pathway B, where the five-member
ring lactams 5 are produced by the [3 + 2] cycloaddition of
the Schiff’s base 9 with mercaptoacetic acid. In extreme cases,
when the electron-donating substituent on the aromatic amine is
sufficiently strong (as in the case of 3,4-(methylenedioxy)aniline),
the deactivating effect of the EWG on aromatic aldehydes can be
overcome, and all the aldehydes with either electron-withdrawing
or electron-donating groups are found to be compatible with
the corresponding [4 + 3] annulation pathway to give the target
compounds 4.
In conclusion, an efficient MW-assisted multi-component tandem
reaction to give benzothiazepinones has been developed. The
reaction is easy to perform using inexpensive starting materials
and generates products in high yields with a chemoselectivity
depending on the electronic effect of the substituents on the
aromatic aldehyde and the amine. The one pot operational
simplicity and the environmentally friendly nature make this new
heterocycle synthetic strategy highly attractive and promising for
the access of compounds of potential biological interest.
Experimental
General
Microwave irradiation was carried out with a microwave oven
(EmrysTM Creator from Personal Chemistry, Uppsala, Sweden).
Melting points were determined in open capillaries and were
uncorrected. IR spectra were taken on a FT-IR-Tensor 27
spectrometer in KBr pellets and reported in cm-1. 1H NMR
spectra were measured on a Bruker DPX 400 MHz spectrometer
in DMSO-d6 with chemical shifts (d) given in ppm relative to
Scheme 4
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TMS as internal standard. High-resolution mass spectra (HRMS)
were obtained on a Varian IonSpec QFT-MS spectrometer with
the technique of electrospray ionization. X-Ray crystallographic
analysis was performed with a Siemens SMART CCD and a
Semens P4 diffractometer.
130.0, 128.0, 123.8, 112.7, 112.3, 46.2, 31.4, 20.8; HRMS (ESI)
m/z: calc. for [M + Na]+ C18H20N2OS: 335.1189; found: 335.1185.
5-(Benzo[d][1,3]dioxol-6-yl)-7-methylbenzo[e][1,4]thiazepin-2-
(1H,3H,5H)-one (4d). IR (KBr, n, cm-1): 3181, 3051, 2952, 2891,
1
680, 1619, 1503, 1414, 935, 812, 752 cm-1; H NMR (400 MHz,
General procedure for the synthesis of compounds 4 with
microwave irradiation. All the reactions were performed in a
monomodal Emrys TM Creator from Personal Chemistry, Uppsala,
Sweden. In a 10 mL EmrysTM reaction vial, aldehyde 1 (1 mmol),
aromatic amine 2 (1 mmol), mercaptoacetic acid 3 (1 mmol) and
water (1.0 mL) were mixed and then capped. The mixture was
irradiated at 110 ◦C (initial power 100 W and maximum power
200 W). Upon completion of the reaction as monitored by TLC,
the reaction mixture was cooled to room temperature. The solid
product was filtered, washed with EtOH (95%). The solid was
purified by recrystallization from EtOH/acetone (V/V = 1:1).
General procedure for the synthesis of 5. In a 10 mL EmrysTM
reaction vial, aldehyde 1 (1 mmol), aromatic amine 2 (1 mmol),
mercaptoacetic acid 3 (1 mmol) and water (1.0 mL) were mixed and
then capped. The mixture was irradiated at 110 ◦C (initial power
100 W and maximum power 200 W). Upon completion of the
reaction as monitored by TLC, the reaction mixture was cooled to
room temperature. The solid product was filtered, washed with
EtOH (95%). The solid was purified by recrystallization from
EtOH.
MSO-d6) (d, ppm): 9.51 (s, 1H, NH), 7.10 (dd, J1 = 7.9 Hz, J2 =
1.60 Hz, 1H, ArH), 7.04 (d, J = 1.2 Hz, 1H, ArH), 7.03-6.98(m,
1H, ArH), 6.94 (d, J = 8.0 Hz, 2H, ArH), 6.79 (s, 1H, ArH), 6.05
(dd, J = 6.4 Hz, 2H, ArH), 5.52 (s, 1H, CH), 3.09 (d, J = 8.4 Hz,
1H, CH2); 2.86 (dd, J1 = 12.0 Hz, J2 = 1.20 Hz, 1H, CH2); 2.21
(s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, 25 oC): d = 168.7,
146.7, 145.5, 137.3, 134.6, 131.2, 129.2, 129.1, 128.9, 127.3, 127.2,
107.8, 107.4, 107.1, 105.1, 101.7, 101.4, 63.7, 46.5, 32.6, 31.0, 20.7;
HRMS (ESI) m/z: calc. for [M + Na]+ C17H15NO3S: 336.0665;
found: 336.0672.
5-(3,4-Dimethoxyphenyl)-7-methylbenzo[e][1,4]thiazepin-2(1H,
3H,5H)-one (4e). IR (KBr, n, cm-1): 3170, 3094, 2954, 2876,
1682, 1479, 1374, 1036, 932, 829, 771 cm-1; 1H NMR (400 MHz,
DMSO-d6) (d, ppm): 9.53 (s, 1H, NH), 7.12-6.99 (m, 4H, ArH),
6.93 (d, J = 8.0 Hz, 1H, ArH), 6.78 (s, 1H, ArH), 5.55 (s, 1H, CH),
3.78 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.12 (d, J = 12.0 Hz, 1H,
CH2); 2.86 (dd, J1 = 12.0 Hz, J2 = 0.8 Hz, 1H, CH2); 2.19 (s, 3H,
CH3);13C NMR (100 MHz, DMSO-d6): 168.6, 148.5, 148.3, 135.6,
134.8, 133.8, 128.7, 128.1, 123.9, 121.4, 112.9, 111.6, 55.5, 46.4,
30.7, 20.8; HRMS (ESI) m/z: calc. for [M + Na]+ C18H19NO3S:
352.0978; found: 352.0974.
7-Methyl-5-p-tolylbenzo[e][1,4]thiazepin-2(1H,3H,5H)-one
(4a). IR (KBr, n, cm-1): 3213, 3181, 3109, 2981, 2926, 1682, 1366,
818, 755, 762 cm-1; 1H NMR (400 MHz, DMSO-d6) (d, ppm): 9.51
(s, 1H, NH), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.22 (d, J = 8.0 Hz,
2H, ArH), 7.10 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 1H, ArH), 6.93
(d, J = 8.0 Hz, 1H, ArH), 6.74 (s, 1H, ArH), 5.55 (s, 1H, CH),
3.10 (d, J1 = 12.0 Hz, 1H,CH2); 2.87 (d J = 13.2 Hz, 1H, CH2);
2.18 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6): 168.6, 137.2,
135.6, 134.8, 134.5, 133.7, 129.2, 139.1, 128.7, 128.2, 124.0, 46.5,
31.1, 20.7; HRMS (ESI) m/z: calc. for [M + Na]+ C17H17NOS:
306.0923; found: 306.0926.
7-Methyl-5-(thiophen-2-yl)benzo[e][1,4]thiazepin-2(1H,3H,5H)-
one (4f). IR (KBr, n, cm-1): 3189, 3067, 2974, 2872, 1682,
1
1586, 1295, 1150, 909, 740, 695, 650 cm-1; H NMR (400 MHz,
DMSO-d6) (d, ppm): 9.53 (s, 1H, NH), 7.55-7.54 (m, 1H, ArH),
7.16-7.13 (m, 2H, ArH), 7.07-7.06 (m, 1H, ArH), 6.95-6.92 (m,
2H, ArH), 5.82 (s, 1H, CH), 3.08 (d, J1 = 12.4 Hz, J2 = 1.20 Hz,
1H, CH2); 2.94 (d, J = 12.0 Hz, 1H, CH2); 2.23 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6): 168.4, 142.0, 135.7, 134.7, 133.7,
129.2, 128.1, 127.3, 127.1, 126.2, 124.1, 42.1, 31.3, 20.7; HRMS
(ESI) m/z: calc. for [M + Na]+ C14H13NOS2: 298.0331; found:
298.0331.
5-(4-Methoxyphenyl)-7-methylbenzo[e][1,4]thiazepin-2(1H,3H,
5H)-one (4b). IR (KBr, n, cm-1): 3178, 3076, 3033, 2957, 2884,
1680, 1482, 1250, 1301, 790, 668 cm-1; 1H NMR (400 MHz,
DMSO-d6) (d, ppm): 9.51 (s, 1H, NH), 7.42 (d, J = 8.4 Hz, 2H,
ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 6.98 (d, J = 8.8 Hz, 2H,
ArH), 6.94 (d, J = 8.0 Hz, 2H, ArH), 5.56 (s, 1H, CH), 3.79(s, 3H,
OCH3), 3.12 (d, J = 12.4 Hz, 1H, CH2); 2.86 (dd, J1 = 12.0 Hz,
J2 = 1.20 Hz, 1H, CH2); 2.19 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6): 168.6, 135.6, 134.8, 133.9, 130.4, 129.2, 128.7, 138.1,
123.9, 114.0, 55.1, 46.1, 31.2, 20.7; HRMS (ESI) m/z: calc. for [M
+ Na]+ C17H17NO2S: 322.0872; found: 322.0875.
7-Methoxy-5-(4-methoxyphenyl)benzo[e][1,4]thiazepin-2(1H,
3H,5H)-one (4g). IR (KBr, n, cm-1): 3257, 3199, 3085, 1681,
1
1600, 1332, 1079, 901, 835, 755, 691 cm-1; H NMR (400 MHz,
DMSO) (d, ppm): 9.43 (s, 1H, NH), 7.42 (d, J = 8.8 Hz, 2H,
ArH), 7.01-6.97 (m, 3H, ArH), 6.88 (dd, J1 = 8.8 Hz, J2 = 3.2
Hz, 1H, ArH), 6.42 (s, 1H, ArH), 5.54 (s, 1H, CH), 3.78 (s, 3H,
OCH3), 3.64 (s, 3H, OCH3), 3.13 (d, J = 12.4 Hz, 1H, CH2), 2.86
(d, J = 12.4 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6):
168.6, 158.9, 157.4, 135.6, 130.3, 130.1, 129.1, 125.4, 114.0, 113.9,
112.5, 55.2, 55.1, 46.1, 31.2; HRMS (ESI) m/z: calc. for [M + Na]+
C17H17NO3S: 338.0821; found: 338.0829.
5-(4-(Dimethylamino)phenyl)-7-methylbenzo[e][1,4]thiazepin-2-
(1H,3H,5H)-one (4c). IR (KBr, n, cm-1): 3176, 3066, 2952, 2875,
1681, 1575, 1365, 827, 785, 705 cm-1; 1H NMR (400 MHz, DMSO-
d6) (d, ppm): 9.53 (s, 1H, NH), 7.30 (d, J = 8.0 Hz, 2H, ArH),
7.10-7.08 (m, 1H, ArH), 7.10-7.08 (m, 1H, ArH), 6.96-6.92 (m,
1H, ArH), 6.76-6.74 (m, 3H, ArH), 5.48 (s, 1H, CH), 3.12 (dd,
J1 = 12.0 Hz, J2 = 1.20 Hz, 1H, CH2); 2.92 (s, 6H, N(CH3)2), 2.81
5-(4-(Dimethylamino)phenyl)-7-methoxybenzo[e][1,4]thiazepin-
2(1H,3H,5H)-one (4h). IR (KBr, n, cm-1): 3199, 3065, 1683,
1582, 1482, 1145, 759, 701, 650 cm-1; 1H NMR (400 MHz, DMSO-
d6,) (d, ppm): 9.42 (s, 1H, NH), 7.30 (d, J = 8.8 Hz, 2H, ArH),
6.99 (d, J = 7.6 Hz, 1H, ArH), 6.87 (d, J = 8.8 Hz, 1H, ArH), 6.75
(d, J = 8.8 Hz, 1H, ArH), 6.43 (s, 1H, ArH), 5.47 (s, 1H, CH),
3.64 (s, 3H, OCH3), 3.14 (d, J = 12.0 Hz, 1H, CH2); 2.92 (s, 6H,
N(CH3)2), 2.80 (d, J = 12.0 Hz, 1H, CH2);13C NMR (100 MHz,
(dd, J1 = 12.8 Hz, J2 = 0.8 Hz, 1H, CH2); 2.18 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6): 168.6, 150.0, 135.5, 134.7, 134.2,
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DMSO-d6): 168.8, 157.4, 150.1, 136.0, 130.0, 129.9, 125.2, 124.0,
114.0, 112.2, 122.2, 55.2, 46.2, 31.3; HRMS (ESI) m/z: calc. for
[M + Na]+ C18H20N2O2S: 329. 1318; found: 329.1324.
31.0, 20.7; HRMS (ESI) m/z: calc. for [M + Na]+ C17H15NO3S:
336.0665; found: 336.0672.
10-(4-Methoxy-phenyl)-9-methyl-5,9-dihydro-1,3-dioxa-8-thia-
5-p-Tolylbenzo[e][1,4]thiazepin-2(1H,3H,5H)-one
(4j). IR
5-aza-cyclohepta[f ]inden-6-one (4p). IR (KBr, n, cm-1): 3189,
(KBr, n, cm-1): 3190, 3067, 3029, 1682, 1589, 1513, 1383, 1276,
3066, 1686, 1599, 1369, 1141, 908, 791, 757, 707, 651 cm-1; H
1
1
904, 864, 825, 730 cm-1; H NMR (400 MHz, DMSO- d6) (d,
NMR (400 MHz, DMSO-d6) (d, ppm): 9.41 (s, 1H, NH), 7.40 (d,
J = 8.4 Hz, 2H, ArH), 6.97 (d, J = 8.4 Hz, 2H, ArH), 6.64 (s, 1H,
ArH), 6.33 (s, 1H, ArH), 6.01-5.99 (m, 2H, OCH2O), 5.53 (s, 1H,
CH), 3.78 (s, 3H, OCH3), 3.16 (d, J = 12.4 Hz, 1H, CH2), 2.85
(dd, J1 = 12.0 Hz, J2 = 1.20 Hz, 1H, CH2); 13C NMR (100 MHz,
DMSO-d6): 168.8, 158.9, 146.6, 145.5, 131.1, 130.3, 129.2, 127.4,
114.0, 107.0, 105.0, 101.7, 55.1, 46.1, 31.1; HRMS (ESI) m/z: calc.
for [M + Na]+ C17H15NO4S: 352.0614; found: 352.0618.
ppm): 9.63 (s, 1H, NH), 7.38 (d, J = 8.0 Hz, 2H, ArH), 7.32-7.29
(m, 1H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 7.16 (t, J = 7.6 Hz,
1H, ArH), 7.04 (d, J = 8.0 Hz, 1H, ArH), 6.91 (dd, J1 = 8.0 Hz,
J2 = 1.20 Hz, 1H, ArH), 5.60 (s, 1H, CH), 3.13 (d, J = 12.0 Hz,
1H, CH2); 2.90 (dd, J1 = 11.6 Hz, J2 = 1.20 Hz, 1H, CH2), 2.32 (s,
3H, CH3); 13C NMR (100 MHz, DMSO-d6): 168.5, 137.4, 137.3,
134.5, 133.9, 129.2, 129.1, 128.2, 128.0, 126.4, 125.5, 124.0, 46.4,
31.1, 20.7; HRMS (ESI) m/z: calc. for [M + Na]+ C16H15NOS:
292.0767; found: 292.0772.
9-(4-Dimethylamino-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-
aza-cyclohepta[f ]inden-6-one (4q). IR (KBr, n, cm-1): 3188, 3050,
2973, 2929, 1686, 1470, 1345, 805, 747, 711 cm-1; 1H NMR
(400 MHz, DMSO-d6) (d, ppm): 9.42 (s, 1H, NH), 7.28 (d, J = 8.4
Hz, 2H, ArH), 6.75 (d, J = 8.8 Hz, 2H, ArH), 6.63 (s, 1H, ArH),
6.33 (s, 1H, ArH), 5.98 (d, J = 8.4 2H, OCH2O), 5.46 (s, 1H,
CH), 3.16 (d, J = 12.0 Hz, 1H, CH2); 2.92 (s, 6H, N(CH3)2), 2.79
(dd, J1 = 12.0 Hz, J2 = 1.20 Hz, 1H, CH2); 13C NMR (100 MHz,
DMSO-d6): 168.7, 147.5, 146.9, 146.7, 145.5, 131.3, 131.1, 127.2,
122.4, 109.4, 108.2, 107.1, 105.0, 101.7, 101.3, 46.5, 31.1; HRMS
(ESI) m/z: calc. for [M + Na]+ C18H18N2O3S: 343.1111; found:
343.1108.
5-(Thiophen-2-yl)benzo[e][1,4]thiazepin-2(1H,3H,5H)-one (4k).
IR (KBr, n, cm-1): 3191, 3068, 1683, 1591, 1194, 852, 810, 746 cm-1;
1H NMR (400 MHz, DMSO-d6) (d, ppm): 9.65 (s, 1H, NH), 7.55
(dd, J = 5.2 Hz, 1H, ArH), 7.34 (t, J = 7.6 Hz, 1H, ArH), 7.22 (t,
J = 7.6 Hz, 1H, ArH), 7.14-7.04 (m, 4H, ArH), 5.88 (s, 1H, CH),
3.10 (d, J = 12.0 Hz, 1H, CH2); 2.90 (d, J = 12.0 Hz, 1H, CH2);
13C NMR (100 MHz, DMSO-d6): 168.4, 141.8, 137.3, 133.9, 128.7,
127.8, 127.3, 127.2, 126.5, 126.3, 124.1, 42.1, 31.3; HRMS (ESI)
m/z: calc. for [M + Na]+ C13H11NOS2: 284.0174; found: 284.0179.
5-(Benzo[d][1,3]dioxol-6-yl)-8-methylbenzo[e][1,4]thiazepin-2-
(1H,3H,5H)-one (4l). IR (KBr, n, cm-1): 3188, 3066, 1682, 1491,
10-Benzo[1,3]dioxol-5-yl-9-methyl-5,9-dihydro-1,3-dioxa-8-thia-
5-aza-cyclohepta[f ]inden-6-one (4r). IR (KBr, n, cm-1): 3188,
3050, 2973, 2929, 1686, 1470, 1345, 805, 747, 711 cm-1; 1H NMR
(400 MHz, DMSO-d6) (d, ppm): 9.40 (s, 1H, NH), 7.02-6.93 (m,
3H, ArH), 6.63 (s, 1H, ArH), 6.41 (s, 1H, ArH), 6.05 (d, J = 4.4
Hz, 2H, ArH), 6.01 (d, J = 8.4 Hz, 2H, OCH2O), 5.50 (s, 1H, CH),
3.79 (s, 3H, OCH3), 3.13 (d, J = 12.0 Hz, 1H, CH2); 2.87 (dd, J1 =
12.0 Hz, J2 = 1.20 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-
d6): 168.7, 147.5, 146.9, 146.7, 145.5, 131.3, 131.1, 127.2, 122.4,
109.4, 108.2, 107.1, 105.0, 101.7, 101.3, 46.5, 31.1; HRMS (ESI)
m/z: calc. for [M + Na]+ C17H13NO5S: 366.0407; found: 366.0408.
1
1096, 970, 824, 759 cm-1; H NMR (400 MHz, DMSO-d6) (d,
ppm): 9.59 (s, 1H, NH), 7.07-6.97 (m, 3H, ArH), 6.93 (d, J = 8.0
Hz, 1H, ArH), 6.85 (d, J = 8.0 Hz, 1H, ArH), 6.05-6.04 (m, 2H,
ArH), 5.52 (s, 1H, CH), 3.11 (d, J = 12.0 Hz, 1H, CH2), 2.87 (d,
J = 12.4 Hz, 1H, CH2), 2.26 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6): 168.7, 147.4, 146.8, 137.8, 137.2, 131.4, 131.0, 127.9,
127.0, 124.3, 122.5, 109.4, 108.1, 101.2, 46.3, 31.1, 20.4; HRMS
(ESI) m/z: calc. for [M + Na]+ C17H15NO3S: 336.0665; found:
336.0669.
8-Methyl-5-(thiophen-2-yl)benzo[e][1,4]thiazepin-2(1H,3H,
5H)-one (4m). IR (KBr, n, cm-1): 3189, 3079, 1681, 1589, 1267,
9-(3,4,5-Trimethoxy-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-
aza-cyclohepta[f ]inden-6-one (4s). IR (KBr, n, cm-1): 3182, 3073,
2979, 2921, 1683, 1495, 1422, 1368, 1139, 825, 752, 621 cm-1; 1H
NMR (400 MHz, DMSO-d6) (d, ppm): 9.43 (s, 1H, NH), 6.80 (s,
1H, ArH), 6.64 (s, 1H), 6.48 (s, 1H, ArH), 6.01 (d, J = 7.6 Hz,
2H, OCH2O), 5.52 (s, 1H, CH), 3.77(s, 6H, N(CH3)2), 3.68 (s, 3H,
OCH3), 3.16 (d, J = 12.0 Hz, 1H, CH2); 2.87 (dd, J1 = 12.4 Hz,
J2 = 1.20 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6): 168.8,
152.8, 146.7, 145.5, 136.9, 133.1, 131.1, 127.0, 11.27, 107.2, 106.4,
105.0, 101.7, 60.0, 55.9, 47.1, 31.0; HRMS (ESI) m/z: calc. for [M
+ Na]+ C19H19NO6S: 412.0825; found: 412.0819.
1
1141, 817, 784 cm-1; H NMR (400 MHz, DMSO-d6) (d, ppm):
9.60 (s, 1H, NH), 7.53 (dd, J1 = 5.2 Hz, J2 = 0.80 Hz, 1H, ArH),
7.11 (s 1H, ArH), 7.07-7.03 (m, 2H, ArH), 6.98 (d, J = 8.0 Hz, 1H,
ArH), 6.85 (s, 1H, ArH), 5.82 (s, 1H, CH), 3.09 (d, J = 12.4 Hz,
1H, CH2), 2.95 (d, J = 12.4 Hz, 1H, CH2), 2.28 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6): 168.3, 142.0, 135.7, 134.7, 133.7,
129.2, 138.1, 127.2, 127.1, 126.3, 124.1, 42.1, 31.3, 20.7; HRMS
(ESI) m/z: calc. for [M + Na]+ C14H13NOS2: 298.0331; found:
298.0337.
9-Methyl-10-p-tolyl-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cyclo-
hepta[f ]inden-6-one (4o). IR (KBr, n, cm-1): 3180, 3035, 2935,
1683, 1487, 1217, 1009, 896, 823, 762, 616 cm-1; 1H NMR
(400 MHz, DMSO-d6) (d, ppm): 9.42 (s, 1H, NH), 7.36 (d, J =
7.6 Hz, 2H, ArH), 7.22 (d, J = 8.0 Hz, 2H, ArH), 6.63 (s, 1H,
ArH), 6.34 (s, 1H, ArH), 6.01-5.97 (m, 2H, OCH2O), 5.53 (s, 1H,
CH), 3.15 (s, 3H, OCH3), 3.15 (d, J = 12.0 Hz, 1H, CH2); 2.88
9-Thiophen-2-yl-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cyclohepta-
[f ]inden-6-one (4t). IR (KBr, n, cm-1): 3189, 3075, 2980, 2926,
2832, 1683, 1609, 1496, 1423, 1255, 1177, 1039, 832, 769, cm-1; 1H
NMR (400 MHz, DMSO-d6) (d, ppm): 9.41 (s, 1H, NH), 7.55 (d,
J = 5.2 Hz, 1H, ArH), 7.15 (m, 1H, ArH), 7.07(d, J = 5.2 Hz,
1H, ArH), 6.63 (s, 1H, ArH), 6.55(s, 1H, ArH), 6.02 (d, J = 8.4
Hz,2H, OCH2O), 5.79 (s, 1H, CH), 3.12 (d, J = 12.4 Hz, 1H, CH2);
2.94 (d, J = 12.4 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6):
168.5, 147.0, 145.6, 141.9, 131.2, 127.3, 127.2, 127.1, 126.2, 107.0,
(dd, J1 = 11.6 Hz, J2 = 1.20 Hz, 1H, CH2), 2.32 (s, 3H, CH3); 13
C
NMR (100 MHz, DMSO-d6): 168.7, 146.7, 145.5, 137.3, 134.6,
131.2, 129.2, 129.1, 128.9, 127.3, 127.2, 107.1, 105.1, 101.7, 46.6,
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105.2, 101.8, 42.1, 31.2; HRMS (ESI) m/z: calc. for [M + Na]+
C14H11NO3S2: 328.0073; found: 328.0068.
106.4, 105.1, 101.8, 43.2, 30.9; HRMS (ESI) m/z: calc. for [M +
Na]+ C16H11Cl2NO3S: 389.9729; found: 389.9736.
2-(4-Chlorophenyl)-3-(4-methoxyphenyl)thiazolidin-4-one (5e).
9-(2-Methoxy-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cy-
clohepta[f ]inden-6-one (4u). IR (KBr, n, cm-1): 3167, 3029, 1682,
1589, 1513, 1383, 1276, 904, 864, 825, 730 cm-1; 1H NMR
(400 MHz, DMSO-d6) (d, ppm): 9.52 (s, 1H, NH), 7.62 (dd, J1 =
7.6 Hz, J2 = 0.8 Hz, 1H, ArH), 7.39 (t, J = 8.4 Hz, 1H, ArH),
7.11-7.06 (m, 2H, ArH), 6.65 (s, 1H, ArH), 6.19 (s, 1H, ArH),
5.98 (d, J = 8.0 Hz, 2H, OCH2O), 5.94 (s, 1H, CH), 3.71 (s, 3H,
OCH3), 3.19 (d, J = 12.4 Hz, 1H, CH2); 2.84 (dd, J1 = 12.0 Hz,
J2 = 1.20 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6): 168.8,
156.2, 146.7, 145.5, 131.3, 130.0, 129.5, 126.6, 124.8, 120.4, 111.5,
106.2, 105.0, 101.7, 55.7, 31.1; HRMS (ESI) m/z: calc. for [M +
Na]+ C17H15NO4S: 352.0614; found: 352.0608.
IR (KBr, n, cm-1): 3078, 1689, 1586, 1292, 1151, 1038, 905, 809,
1
739, 695, 650 cm-1; H NMR (400 MHz, DMSO-d6) (d, ppm):
7.41 (d, J = 8.4 Hz, 2H, ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.17
(d, J = 8.8 Hz, 2H, ArH), 6.84 (d, J = 8.4 Hz, 2H, ArH), 6.41 (s,
1H, CH), 4.03 (dd, J1 = 14.6 Hz, J2 = 2.4 Hz, 1H, CH2), 3.86 (d,
J = 14.6 Hz, 1H, CH2), 3.68 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6):170.2, 157.5, 139.3, 132.9, 130.1, 129.1, 128.6, 127.2,
1134.0, 62.9, 55.1, 32.5; HRMS (ESI) m/z: calc. for [M + Na]+
C16H14ClNO2S: 342.0326; found: 342.0333.
Acknowledgements
9-(4-Bromo-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cyclo-
We are grateful to financial support from the National Science
Foundation of China (No. 20672090), Natural Science Foundation
of the Jiangsu Province (No. BK2006033), and Six Kinds of
Professional Elite Foundation of the Jiangsu Province (No. 06-
A-039).
hepta[f ]inden-6-one (4v). IR (KBr, n, cm-1): 3184, 3086, 1684,
1
1608, 1482, 1329, 1093, 1007, 837, 819, 769, 717 cm-1; H NMR
(400 MHz, DMSO-d6) (d, ppm): 9.32 (s, 1H, NH), 7.59 (d, J =
7.6 Hz, 2H, ArH), 7.41 (d, J = 8.4 Hz, 2H, ArH), 6.62 (s, 1H,
ArH), 6.50 (s, 1H, ArH), 6.02 (d, J = 7.6 Hz, 2H, ArH), 5.53 (s,
1H, CH), 3.08 (d, J = 12.0 Hz, 1H, CH2), 2.96 (d, J = 12.4 Hz,
1H, CH2); 13C NMR (100 MHz, DMSO-d6): 168.7, 146.9, 145.5,
137.9, 131.4, 131.3, 130.9, 126.9, 120.8, 107.6, 105.3, 101.8, 46.4,
30.7; HRMS (ESI) m/z: calc. for [M + Na]+ C16H12BrNO3S: 399.
9613; found: 399.9621.
References
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9-(4-Chloro-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cyclo-
hepta[f ]inden-6-one (4w). IR (KBr, n, cm-1): 3189, 3006, 1683,
1586, 1127, 817 cm-1; 1H NMR (400 MHz, DMSO-d6) (d, ppm):
9.33 (s, 1H, NH), 7.48 (q, J = 12.0 Hz, 4H, ArH), 6.62 (s, 1H,
ArH), 6.49 (s, 1H, ArH), 6.02 (d, J = 5.8 Hz, 2H, OCH2O), 5.55
(s, 1H, CH), 3.08 (d, J = 12.4 Hz, 1H, CH2), 2.96 (d, J = 12.4
Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6): 168.7, 146.9,
145.5, 137.4, 132.2, 131.3, 130.6, 128.5, 127.0, 107.6, 105.3, 101.8,
46.3, 30.7; HRMS (ESI) m/z: calc. for [M + Na]+ C16H12ClNO3S:
356.0119; found: 356.0125.
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9-(2-Chloro-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cyclo-
hepta[f ]inden-6-one (4x). IR (KBr, n, cm-1): 3167, 3008, 1683,
1
1480, 1255, 828, 784 cm-1; H NMR (400 MHz, DMSO-d6) (d,
ppm): 9.63 (s, 1H, NH), 7.79 (d, J = 7.6 Hz, 1H, ArH), 7.53 (q,
J = 13.6 Hz, 2H, ArH), 7.47-7.43 (m, 1H, ArH), 6.69 (s, 1H, ArH),
6.07 (s, 1H, ArH), 6.01 (d, J = 5.6 Hz, 2H, OCH2O), 5.91 (s, 1H,
CH), 3.20 (d, J = 12.0 Hz, 1H, CH2), 2.94 (d, J = 12.0 Hz, 1H,
CH2); 13C NMR (100 MHz, DMSO-d6): 168.6, 147.0, 145.7, 134.7,
132.9, 131.5, 130.8, 130.1, 130.0, 127.6, 125.5, 106.1, 105.1, 101.8,
43.4, 31.0; HRMS (ESI) m/z: calc. for [M + Na]+ C16H12ClNO3S:
334.0299; found: 334.0294.
10 B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger,
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9-(2,4-Dichloro-phenyl)-5,9-dihydro-1,3-dioxa-8-thia-5-aza-cy-
clohepta[f ]inden-6-one (4y). IR (KBr, n, cm-1): 3178, 3078, 1682,
1
1586, 1292, 1151, 1038, 905, 809, 739, 695, 650 cm-1; H NMR
(400 MHz, DMSO-d6) (d, ppm): 9.60 (s, 1H, NH), 7.78 (d, J =
8.4 Hz, 1H, ArH), 7.71 (s, 1H, ArH), 7.59 (dd, J1 = 8.4 Hz, J2 =
2.4 Hz, 1H, ArH), 6.68 (s, 1H, ArH), 6.16 (s, 1H, ArH), 6.03 (m,
2H, OCH2O), 5.84 (s, 1H, CH), 3.18 (d, J = 12.0 Hz, 1H, CH2),
2.96 (d, J = 12.0 Hz, 1H, CH2); 13C NMR (100 MHz, DMSO-d6):
168.6, 147.1, 145.8, 134.0, 133.8, 133.5, 132.1, 129.5, 127.8, 125.0,
562 | Org. Biomol. Chem., 2009, 7, 557–563
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Russian Journal of General Chemistry, 1997, 67, 1544; (g) K. Sugawara
and L. S. Rangappa, Basappa, Jpn. Kokai Tokkyo Koho, 2007, 76pp;
(h) S. P. Lawande and B. R. Arbad, Journal of the Indian Chemical
Society, 2000, 77, 352.
P4 diffractometer (graphite monochromator, MoKa radiation k =
˚
0.71073 A). Crystal data for 4a: Empirical formula C17 H17 N O
S colorless, crystal dimensions 0.35 ¥ 0.12 ¥ 0.10 mm, orthorhombic
pccn, space group Pccn, a = 14.4220(12), b = 25.714(3) (12), c = 7.9543
◦
Ÿ
˚
12 tThe single-crystal growth was carried out in a mixed solvent of
acetone and ethanol at room temperature. X-Ray crystallographic
analysis was performed with a Siemens SMART CCD and a Semens
(10)A, a = 90, b = 90, c = 90 ,V = 2949.8(5) A 3, Mr = 283.38, Z =
˚
8, Dc = 1.267 Mg m - 3, k = 0.71073 A, l (Mo-Ka) = 0.214 mm-1,
F(000)= 1200, S = 1.012, R1 = 0.0578, wR2 = 0.1029.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 557–563 | 563
©