Simple and new protocol for the synthesis of novel (z)-3- arylidenebenzothiazepin-4-ones using Baylis-Hillman derivatives

Article abstract of DOI:10.1080/00397910802138249

A simple synthesis of novel (Z)-3-arylidene-2,3-dihydrobenzo[b][1,4] thiazepin-4(5H)-ones from bromo compounds derived from Baylis-Hillman adducts involving selective S-alkylation followed by a lactum formation has been described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802138249

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Simple and New Protocol for
the Synthesis of Novel (z)-3-
Arylidenebenzothiazepin-4-
ones Using Baylis–Hillman
Derivatives
Manickam Bakthadoss a & Gandhi Murugan a
a Department of Organic Chemistry , University of
Madras , Chennai, Tamil Nadu, India
Published online: 29 Sep 2008.
To cite this article: Manickam Bakthadoss & Gandhi Murugan (2008) Simple and
New Protocol for the Synthesis of Novel (z)-3-Arylidenebenzothiazepin-4-ones Using
Baylis–Hillman Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:20, 3406-3413, DOI:
10.1080/00397910802138249
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Synthetic Communications1, 38: 3406–3413, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802138249
Simple and New Protocol for the Synthesis of
Novel (z)-3-Arylidenebenzothiazepin-4-ones
Using Baylis–Hillman Derivatives
Manickam Bakthadoss and Gandhi Murugan
Department of Organic Chemistry, University of Madras, Chennai,
Tamil Nadu, India
Abstract: A simple synthesis of novel (Z)-3-arylidene-2,3-dihydrobenzo[b][1,4]
thiazepin-4(5H)-ones from bromo compounds derived from Baylis–Hillman
adducts involving selective S-alkylation followed by a lactum formation has been
described.
Keywords: 2-Amino thiophenol, Baylis–Hillman reaction, benzothiazepinones,
diltiazem, thiazesim, p-toluenesulfonic acid
INTRODUCTION
During the past few years, the Baylis–Hillman reaction has become
increasingly important because it provides multifunctionalized molecules
whose applications in synthetic organic chemistry have been well docu-
mented in the literature.[1–3] The Baylis–Hillman adducts are also utilized
very well as building blocks for many natural products and biologically
active molecules.[1–9] Because of multifunctionality present in the suitable
positions, the Baylis–Hillman adducts and bromo derivatives were fre-
quently utilized for the synthesis of various types of heterocyclic com-
pounds. Using these compounds, syntheses of a variety of five-, six-,
and seven- membered heterocyclic compounds have been reported in
the literature, which clearly proves that these Baylis–Hillman adducts
Received February 22, 2008.
Address correspondence to Manickam Bakthadoss, Department of Organic
Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamilnadu,
India. E-mail: bhakthadoss@yahoo.com
3406

Novel (Z)-3-Arylidenebenzothiazepin-4-ones
3407
and derivatives are novel sources for the synthesis of a wide range of
heterocyclic compounds.[1–3]
Thiazepinones are pharmalogically important compounds for the
treatment of cancer and heart and inflammatory diseases. These hetero-
cycles help treat disease by acting as inhibitors to angitensin converting
enzyme (ACE), neutral endopeptidase (NEP),[10] and leukocyte adher-
ence.[11] Benzothiazepinone moiety is an integral part of diltiazem (1), a
representative calcium antagonist used throughout the world as a remedy
for angina and hypertension.[12–15] Thiazesim (2) is another important
benzothiazepinone skeleton containing a molecule possessing antiplatelet
activity.[16] Benzothiazepinone derivatives are also known to possess anti-
depressant activity.[17]
Because the variety of benzothiazepinone derivatives possess various
biological activities, we planned to develop a new synthetic methodology
for benzothiazepinone derivatives containing the core unit of diltiazem
(1) and thiazesim (2) using Baylis–Hillman chemistry.
In continuation of our interest in the field of Baylis–Hillman chem-
istry,[18–20] we herein report the first synthetic route for seven-membered
(Z)-3-arylidene-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-ones from methyl
(2Z)-2-(bromomethyl)-3-arylprop-2-enoates derived from corresponding
Baylis–Hillman adducts.[18]
RESULTS AND DISCUSSION
To the best of our knowledge, there is no report available in the literature
for the synthesis of seven-membered (Z)-3-arylidene-2,3-dihydrobenzo-
[b][1,4]thiazepin 4(5H)-ones until now. We envisaged that the important
core benzothiazepin-4-one moiety could be constructed using the (Z)-
methyl-2-(bromomethyl)arylacrylates (3) derived from Baylis–Hillman
adducts. The formation of seven-membered benzothiazepinone can be
achieved by selectively tethering the sulfur atom of the ortho amino thio-
phenol with allylic carbon, which is attached to bromine atom of
compound (3), at one end and at other end by tethering the nitrogen

3408
M. Bakthadoss and G. Murugan
Figure 1. Retro synthetic strategy for the synthesis of benzothiazepinone
derivatives.
atom of the ortho amino thiophenol with the carbonyl carbon present
in the bromo derivative of the Baylis–Hillman adducts (3), shown in
Figure 1.
To execute our idea, we first selected the methyl (2Z)-2-(bromo-
methyl)-3-phenylprop-2-enoate (3a) prepared from the corresponding
Baylis–Hillman adduct and treated with 2-aminothiophenol (4) in the
presence of potassium-t-butoxide in tetrahydrofuran (THF) at room
temperature, which successfully led to a selective S-alkylated product,
(Z)-methyl2-((2-aminophe-nylthio)methyl)-3-phenylacrylate (5a), a pre-
cursor for the synthesis of (Z)-3-benzylidene-2,3-dihydrobenzo[b][1,4]
thiazepin-4(5H)-one (6a). The crude compound (5a) was treated with
p-toluenesulfonic acid using p-xylene as a solvent under reflux condition
for 12 h and successfully provided the desired (Z)-3-benzylidene-2,3-
dihydrobenzo[b][1,4]thiazepin-4(5H)-one (6a) in 71% yield, according to
Scheme 1. The structure of the compound (6a) was confirmed by IR,
1H and 13C NMR, mass spectral data, and elemental analysis.
1
The H NMR spectrum of the compound (6a) showed a doublet for
S-attached CH2 protons at d 4.00, and NH proton appeared as broad
singlet at d 7.91. The benzylic olefinic proton appeared as a doublet of
doublet (due to allylic coupling) at d 7.49 and the aromatic protons
appeared as multiplets in the region of d 7.04–7.40.
Encouraged by this result, we prepared a variety of (2Z)-2-(bromome
thyl)-3-arylprop-2-enoates (3b–k) from the corresponding Baylis–Hillman
Scheme 1. R¼H. 2-Me, 4-Me, 4-Et, 4-Pr, 2-Cl, 3-Cl, 4-Cl, 2,4-dichioro, 4-F,
4-NO2.

Novel (Z)-3-Arylidenebenzothiazepin-4-ones
3409
Table 1. Synthesis of (Z)-3-arylidene-2,3-dihydrobenzo[b][1,4]thiazepin-4-
(5H)-ones (6a–k)
Allybromide
R
Producta
Yieldb
Mp (ꢀC)
3a
3b
3c
3d
3e
3f
H
6a
6b
6c
6d
6e
6f
71
67
70
68
66
67
65
71
67
65
67
168–170
136–138
160–162
118–120
122–124
165–167
108–110
112–114
194–196
185–187
166–165
2-Me
4-Me
4-Et
4-iPr
2-Cl
3-Cl
4-Cl
2,4-Dichloro
4-F
4-No2
3g
3h
3i
6g
6h
6i
3j
3k
6j
6k
aAll the products gave satisfactory IR, 1H NMR (300 MHz), 13C NMR
(75 MHz), and mass spectral data and elemental analyses.
bYields of the pure product (6a–k) obtained after column chromatography.
adducts and treated them with 2-aminothiophenol, which led to the precur-
sors 5b–k. The crude intermediate products (5b–k) were treated with
p-toluenesulfonic acid under reflux condition for 12 h, which successfully
provided the desired (Z)-3-arylidene-2,3-dihydrobenzo[b][1,4]thiazepin-4
(5H)-ones (6b–k) in 65–71% yield according to Scheme 1. The results are
summarized in Table 1.
CONCLUSION
In conclusion, we have successfully developed for the first time a short
and simple protocol for facile transformation of Baylis–Hillman
bromides into an interesting novel class of seven-membered heterocyclic
frameworks containing an important benzothiazepinone moiety, a core
unit of diltiazem and thiazesim, thus demonstrating the synthetic poten-
tial of the Baylis–Hillman adducts in organic chemistry.

3410
M. Bakthadoss and G. Murugan
EXPERIMENTAL
General Methods
All melting points are uncorrected. IR spectra were recorded on a
Shimadzu FT-IR 8000 instrument. NMR spectra were recorded in CDCl3
by using TMS as an internal standard on a Bruker 300 instrument. Mass
spectra were recorded on a Jeol DX-303 instrument. Column chromato-
graphy was performed on silica gel (100–200 mesh). All reactions were
monitored by thin-layer chromatography (TLC) using glass plates coated
with Acme silica gel (GF-254).
Typical Experimental Procedure for the Synthesis of Compounds 6a–k
A
mixture of trisubstituted allyl bromide (3a–k) (2 mmol) and
o-aminothiophenol (2 mmol) in the presence of potassium tert-butoxide
(2.4 mmol) in dry THF (10 mL) was stirred at room temperature for 1 h.
After the completion of the reaction as indicated by TLC, the reaction
mixture was concentrated, and the resulting crude mass was diluted with
water (20 mL) and extracted with ethyl acetate (3 ꢁ 20 mL). The organic
layer was washed with brine (2 ꢁ 20 mL) and dried over anhydrous
sodium sulphate. The organic layer was concentrated, which provided a
1
crude mass (5a–k). [The H NMR of crude mass (5a–k) showed the pre-
sence of the NH2 proton.] The crude product (5a–k) was treated with a
catalytic amount of p-toluene sulphonic acid (0.4 mmol), in p-xylene
(10 mL), under reflux conditions for 12 h. After the completion of the
reaction as indicated by TLC, the reaction mixture was concentrated
under reduced pressure and worked up as mentioned previously, which
successfully provided the crude final product (6a-k). The crude final pro-
duct was purified by column chromatography on silica gel to afford the
pure desired product (6a-k) in good yield as mentioned in Table 1.
Spectral Data for Selected Compounds
(Z)-3-Benzylidene-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)one (6a)
Yield: 71%; mp 168–170ꢀC (white solid). IR (KBr, cmꢂ1); 3171, 1653, 1610.
1H NMR (CDCl3): d ¼ 4.00 (d, J¼ 1.2 Hz, 2H); 7.04–7.40 (m, 9H); 7.49 (dd,
1H, J¼ 1.2, 7.9 Hz); 7.91 (br s, 1H). 13C NMR (CDCl3): d ¼ 35.03; 122.34;
124.81; 127.73; 128.36; 128.50; 129.11; 129.30; 132.90; 133.29; 134.90;
136.04; 140.27; 170.69. MS (m=z) 268 (Mþþ 1). Anal. calcd. for C16H13NOS:
C, 71.88; H, 4.90; N, 5.24. Found: C, 71.12; H, 4.68; N, 5.79.

Novel (Z)-3-Arylidenebenzothiazepin-4-ones
3411
(Z)-3-(2-Methylbenzylidene)-2,3-dihydrobenzo[b][1,4]thiazepin-
4(5H)-one (6b)
Yield: 67%; mp 136–138 ꢀC (white solid). IR (KBr, cmꢂ1); 3126, 1653,
1610. 1H NMR (CDCl3): d ¼ 2.06 (s, 3H); 3.85 (d, J ¼ 1.2 Hz, 2H);
6.98–7.35 (m, 8H); 7.46–7.49 (dd, J ¼ 1.2, 7.8 Hz, 1H); 7.79 (br s, 1H).
13C NMR (CDCl3): d ¼ 19.55; 35.56; 122.56; 124.93; 125.65; 127.62;
128.33; 128.79; 129.25; 130.12; 133.32; 133.72; 134.02; 134.74; 137.00;
140.89; 171.30. MS m=z 282 (Mþ þ 1). Anal. calcd. for C17H15NOS: C,
72.57; H, 5.37; N, 4.98. Found: C, 72.40, H, 5.23, N, 5.02.
(Z)-3-(4-Methylbenzylidene)-2,3-dihydrobenzo[b][1,4]thiazepin-
4(5H)-one (6c)
Yield: 70%; mp 160–162 ꢀC (white solid). IR (KBr, cmꢂ1); 3151, 1658,
1615. 1H NMR (CDCl3): d ¼ 2.35 (s, 3H); 4.01 (d, J ¼ 1.2 Hz, 2H);
7.01–7.39 (m. 8H); 7.45–7.49 (dd, J ¼ 1.2, 7.8 Hz, 1H); 8.91 (br s, 1H).
13C NMR (CDCl3): d ¼ 21.29; 35.00; 122.32; 124.67; 127.78; 129.04;
129.22; 129.40; 132.03; 132.17; 133.17; 136.29; 138.52; 140.29; 170.80.
MS m=z 282 (Mþ þ 1). Anal. calcd. for C17H15NOS: C, 72.57; H, 5.37;
N, 4.98. Found: C, 72.51, H, 5.30, N, 5.11.
(Z)-3-(4-Ethylbenzylidene)-2,3-dihydrobenzo[b][1,4]thiazepin-
4(5H)-one (6d)
Yield: 68%; mp 118–120 ꢀC (white solid). IR (KBr, cmꢂ1); 3205, 1660,
1
1620. H NMR (CDCl3): d ¼ 1.24 (t, J ¼ 7.5 Hz, 3H); 2.65 (q, J ¼ 7.5 Hz,
2H); 4.00 (d, J ¼ 1.2 Hz, 2H), 7.03–7.41 (m, 8H); 7.48 (d, J ¼ 7.5 Hz,
1H), 7.79 (br s, 1H). 13 C NMR (CDCl3): d ¼ 15.34; 28.65; 34.90;
122.18; 124.71; 127.84; 128.03; 129.00; 129.49; 132.01; 132.24;
133.21; 136.44; 140.14; 144.85; 170.50. MS m=z 296 (Mþ þ 1). Anal. calcd.
for C18H17NOS: C, 73.19; H, 5.80; N, 4.74. Found: C, 73.05; H, 5.45;
N, 4.81.
ACKNOWLEDGMENTS
We thank Department of Science & Technology (New Delhi) for the
financial support under the fast track scheme. We thank Department of
Science & Technology-Fund for Improvement of Science & Technology
Infrastructure in Higher Educational Institutions for the funding program
at the Department of Organic Chemistry, University of Madras, Chennai.

3412
M. Bakthadoss and G. Murugan
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