Solvent-free synthesis of 1,5-benzothiazepines and benzodiazepines on inorganic supports

Article abstract of DOI:10.1081/SCC-120034159

1,5-Benzothiazepines and 1,5-benzodiazepines have been synthesized in solvent-free conditions from chalcones and o-aminothiophenol or o-phenylenediamine in the presence of inorganic support. Silica gel was found to be an effective support for the synthesi

Full text of DOI:10.1081/SCC-120034159

This article was downloaded by: [McGill University Library]
On: 13 October 2012, At: 01:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Solvent‐Free Synthesis of 1,5‐Benzothiazepines and
Benzodiazepines on Inorganic Supports
a
a
b
Mitsuo Kodomari , Tomohiro Noguchi & Tadashi Aoyama
a
Department of Applied Chemistry, Shibaura Institute of Technology, Shibaura,
Minato‐ku, Tokyo, 108‐8548, Japan
b
Department of Materials and Applied Chemistry, Faculty of Science and Engineering,
Nihon University, Chiyoda‐ku, Tokyo, Japan
Version of record first published: 20 Aug 2006.
To cite this article: Mitsuo Kodomari, Tomohiro Noguchi & Tadashi Aoyama (2004): Solvent‐Free Synthesis of
1,5‐Benzothiazepines and Benzodiazepines on Inorganic Supports, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:10, 1783-1790
To link to this article: http://dx.doi.org/10.1081/SCC-120034159
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 10, pp. 1783–1790, 2004
Solvent-Free Synthesis of 1,5-
Benzothiazepines and Benzodiazepines
on Inorganic Supports
1
,
1
*
Mitsuo Kodomari, Tomohiro Noguchi,
and Tadashi Aoyama
2
1
Department of Applied Chemistry, Shibaura Institute of Technology,
Shibaura, Minato-ku, Tokyo, Japan
2
Department of Materials and Applied Chemistry, Faculty of Science and
Engineering, Nihon University, Chiyoda-ku, Tokyo, Japan
ABSTRACT
1
,5-Benzothiazepines and 1,5-benzodiazepines have been synthesized
in solvent-free conditions from chalcones and o-aminothiophenol or
o-phenylenediamine in the presence of inorganic support. Silica gel was
found to be an effective support for the synthesis of 1,5-benzothiazepines,
whereas alumina was effective for the synthesis of 1,5-benzodiazepines.
Key Words: Benzothiazepine; Benzodiazepine; Silica gel; Alumina;
Solvent-free synthesis.
*
Correspondence: Mitsuo Kodomari, Department of Applied Chemistry, Shibaura Insti-
tute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan; E-mail: kodomari@
sic.shibaura-it.ac.jp.
1
783
DOI: 10.1081/SCC-120034159
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
1
784
Kodomari, Noguchi, and Aoyama
Benzothiazepines and benzodiazepines are very important compounds
because of their pharmacological properties, and have become increasingly
[1]
interesting since 1,5-benzothiazepines show antifungal, antibacterial, anti-
[
2]
[3]
[4]
feedant, analgesic, and anticonvulsant activity. Benzodiazepines are
used as tranquilizing, anti-inflammatory and anticonvulsant agents. In
addition, 1,5-benzothiazepines and benzodiazepines are used as starting
[
5]
materials for the preparation of fused ring compounds such as triazolo-
[6]
and oxadiazolo-benzodiazepines. Despite their importance from a pharma-
cological and synthetic point of view, few methods for the preparation of
1,5-benzodiazepines are reported in the literature. These include condensa-
tion reactions of o-phenylenediamine with a,b-unsaturated carbonyl com-
[
7]
pounds, b-haloketones, or ketones in the presence of polyphosphoric
[8]
[
acid, silica gel, Yb(Otf) ,
9]
[9]
[10]
[11]
[12]
MgO and POCl3,
Amberlyst-15,
and
1,5-Benzodiazepines are also prepared by reaction
3
[
13]
acetic acid under MW.
of a,b-unsaturated ketones with o-nitroanilines induced by TiCl -Sm
[14]
and
1,5-Benzothiazepines have generally
been synthesized by the reaction of o-aminothiophenol with a,b-unsaturated
4
[15]
o-nitrophenylazide induced by SmI2.
[
16]
ketones.
aminothiophenol, v-bromoacetophenones and aromatic aldehydes,
the reaction of a,b-unsaturated ketones with bis(2-nitrophenyl)disulfide by
1,5-benzothiazepines have also been synthesized from o-
[17]
and by
[
18]
use of TiCl /Sm
4
has been reported. There are few reports on the use of
inorganic solid supports such as alumina, silica gel and clay for the synthesis
of 1,5-benzodiazepines and benzothiazepines under solvent-free condition.
Recently, Danidia reported a solvent-free synthesis of 1,5-benzothiazepines
[19]
in the presence of a solid support under microwave irradiation.
We report herein the solvent-free synthesis of 1,5-benzodiazepines and
benzothiazepines by the reaction of chalcones with o-phenylenediamine or
o-aminothiophenol in the presence of an inorganic solid support. Chalcone
reacts with o-aminothiophenol in refluxing toluene to afford the adduct,
b-phenyl-b-(2-aminophenylmercapto)propiophenone, which could be con-
verted to 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine by cyclization in
[
16]
the presence of an acid catalyst.
with o-aminothiophenol in the presence of silica gel was carried out at
08C under solvent-free conditions to obtain 2,3-dihydro-2,4-diphenyl-1,5-
benzothiazepine in one-step.
In contrast, the reaction of chalcone
8

ORDER
REPRINTS
1
,5-Benzothiazepines and Benzodiazepines
1785
The results of the reaction of o-aminothiophenol with chalcone in the presence
of various solid supports were shown in Table 1. From these results it is
obvious that silica gel is the most adaptable solid support for the synthesis
of 1,5-benzothiazepines since comparatively higher yield is achieved under
same conditions. Acidic alumina was ineffective in spite of being an acidic
solid like silica gel.
The reaction of o-aminothiophenol with chalcones was carried out with-
out solvent in the presence of silica gel at 808C for 3 hr to afford the corre-
sponding 1,5-benzothiazepines in good yields (Table 2). In the reaction of
o-aminothiophenol with chalcones in refluxing toluene, from chalcones
with electron-donating substituents such as methyl and methoxy group, only
b-phenyl-b-(2-aminophenylmercapto)-propiophenones were formed, whereas
from chalcones with electron-withdrawing substituents such as nitro group,
[16]
only 1,5-benzothiazepines were formed.
In contrast, the reaction using
silica gel under solvent-free conditions gave only 1,5-benzothiazepines in
good yield independent of the chalcone substituents, with the exception of
nitro and hydroxy groups. In the case of chalcones having nitro and hydroxy
groups, the yields were lower than that of chalcones with the other substitu-
ents. It seems that low reactivity of chalcones having nitro and hydroxy groups
is due to these groups being absorbed more strongly on the surface of silica gel
than that of a carbonyl group in the same molecule. Therefore the carbonyl
group in chalcones having nitro or hydroxy groups is less activated than
that in chalcones with the other substituents.
It has been reported previously that the reaction of 2-aminoethanethiol
with chalcone in benzene gives a mixture of mono-adducts 4 and 5 or a bis-
[20]
adduct, depending on the molar ratios used.
When the reaction was
Table 1. Reaction of o-aminothiophenol 1 with
a
chalcone 2 in the presence of various supports.
Yield of
benzothiazepine (%)
Support
Silica gel
87
28
2
Acidic alumina
Basic alumina
Neutral alumina
21
30
5
˚
Molecular sieves (5 A)
Kieselguhr
None
22
a
Mole ratio of 1/2 ¼ 1.5, support: 2 g, 808C, 3 hr.

ORDER
REPRINTS
1
786
Kodomari, Noguchi, and Aoyama
a
Table 2. Synthesis of 1,5-benzothiazepines.
1
Ar
2
Ar
b
Yield (%)
Compound
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
C H
6
C H
6 5
87
75
73
61
44
78
83
74
44
68
5
4-ClC
3 6 4
4-CH C H
6
H
4
C
C
6
H
H
5
5
5
5
6
4-CH OC H
6
C H
6
3
4
4
4-CH
3
OC
6
H
6
C H
C
C H
6
H
5
5
5
5
5
4-ClC
6
H
4
g
h
i
4-CH OC H
3 6
6
4
4
C H
6
4-CH OC H
3
6
C
C
6
H
H
4-HOC
4-NO
6
H
4
j
6
2
C
6
H
4
a
Mole ratio 1/2 ¼ 1.5, 808C, 3 hr, SiO (2 g).
2
b
Isolated yield.
carried out in the presence of silica-gel under solvent-free condition, the
tetrahydrothiazepine 6 was obtained and no other adducts were formed.
The reaction of chalcones with o-phenylenediamine was performed in the
presence of alumina (neutral) under solvent-free conditions at 808C for 3 hr to
afford the corresponding 2,4-dihydro-1H-1,5-benzodiazepines in good yield.
The results are summarized in Table 3.
Alumina was most effective among the solid supports tested. Silica
gel was ineffective at promoting the reaction with o-phenylenediamine.
As shown in Table 3, both chalcones with electron-donating groups and
with electron-withdrawing groups except for nitro and hydroxy groups reacted
with o-phenylenediamine without any significant difference to give the corre-
sponding 1,5-benzodiazepines in good yields.

ORDER
REPRINTS
1
,5-Benzothiazepines and Benzodiazepines
Table 3. Synthesis of 1,5-benzodiazepines.
1787
a
1
Ar
2
Ar
b
Yield (%)
Compound
8
8
8
8
8
8
8
8
8
a
b
c
d
e
f
C H
6
C H
6 5
81
84
77
70
12
89
73
69
43
5
4-ClC
3 6 4
4-CH C H
6
H
4
C
C
6
H
H
5
5
5
5
6
4-CH OC H
3
C H
6
6
4
4
4-CH
3
OC
6
H
6
C H
C
C H
6
H
5
5
5
5
4-ClC
6
H
4
g
h
i
4-CH OC H
3 6
6
4
4
C H
6
4-CH OC H
3
6
C
6
H
4-NO
2
C
6
H
4
a
Mole ratio 1/2 ¼ 1.5, 808C, 3 hr, Al
2 3
O
(2 g).
b
Isolated yield.
EXPERIMENTAL
Silica gel and alumina for column chromatography were used as a solid
support without any treatment. All reactions were conducted under nitrogen
atmosphere. Melting points were uncorrected. IR spectra were recorded on
2
1 1
a Horiba FT-710 spectrometer in KBr with absorptions in cm . H-NMR
spectra were recorded on JEOL JNM-LA300 and TMS was used as internal
standard. Mass spectra were recorded on JEOL JMS-600H at 70 eV. Products
1
were characterized by comparison of their spectroscopic data ( H-NMR, IR,
and Mass) and mps with those reported in the literature.
General Procedure for the Synthesis of 1,5-Benzothiazepines
2
,3-Dihydro-2,4-diphenyl-1,5-benzothiazepine (3a). A solution of chal-
cone (2mmol) in diethyl ether (30 mL) was mixed with silica gel (4g) in a
0mL flask. The solvent was removed by evaporation under reduced pressure.
o-Aminothiophenol (3mmol) was added to the mixture, and stirred at 808C for
hr under nitrogen atmosphere. Silica gel was separated by filtration after stir-
5
3
ring with ethyl acetate (40 mL) for 15min at room temperature. After evaporat-
ing the solvent under reduced pressure, the crude product was crystallized from
[
21]
methanol to give 3a (87%) as yellow crystals, m.p. 113–1158C (lit.
1
1
14–1158C). H-NMR (CDCl , 300 MHz) d 3.06 (t, 1H, J ¼ 12.7Hz), 3.30
3
(
dd, 1H, J ¼ 13.0Hz, J ¼ 4.8 Hz), 4.98 (dd, 1H, J ¼ 12.6Hz, J ¼ 4.8 Hz),
7
.14 (td, 1H, J ¼ 7.4 Hz, J ¼ 1.5 Hz), 7.23–7.32 (m, 6H), 7.44–7.52 (m, 4H),
.62 (dd, 1H, J ¼ 7.7 Hz, J ¼ 1.3 Hz), 8.06 (dd, 2H, J ¼ 7.7 Hz, J ¼ 2.0 Hz).
7

ORDER
REPRINTS
1
788
Kodomari, Noguchi, and Aoyama
,3,6,7-Tetrahydro-5,7-diphenyl-1,4-thiazepine (6). Chalcone (1 mmol)
2
and 2-aminoethanthiol (2 mmol) were dissolved in diethyl ether (20 mL). Silica
gel (2 g) was then added to the mixture and stirred for a while followed by
removal of the solvent under reduced pressure. The mixture was stirred at
808C for 3 hr under nitrogen atmosphere. Silica-gel was separated by filtration
after eluting the product with ethyl acetate (20 mL). After evaporating the solvent
under reduced pressure, the residue was purified by recrystallization from
hexane–diethyl ether (1 : 1) to give 6 (55%) as white crystals, m.p. 88–908C.
1
H-NMR (CDCl , 300 MHz), d 2.72 (dd, 1H J ¼ 14.7 Hz, J ¼ 6.7 Hz), 3.02
3
(
dd, 1H, J ¼ 14.7 Hz, J ¼ 9.9 Hz), 3.59 (d, 1H, J ¼ 14.1 Hz), 3.82 (dd, 1H,
J ¼ 14.1 Hz, J ¼ 10.2 Hz), 4.00 (d, 1H, J ¼ 10.3 Hz), 4.19 (dd, 1H, J ¼ 12.5
Hz, J ¼ 10.0 Hz), 4.55 (dd, 1H, J ¼ 12.6 Hz, J ¼ 6.8 Hz), 7.25–7.70 (m, 10H).
General Procedure for the Synthesis of 1,5-Benzodiazepines
2,3-Dihydro-2,4-diphenyl-1H-1,5-benzodiazpine (8a). Chalcone (1 mmol)
and o-phenylenediamine (1.5 mmol) were dissolved in diethyl ether (20 mL).
Alumina (neutral, 2 g) was then added to the mixture and stirred for a while
followed by removal of the solvent under reduced pressure. The mixture
was stirred at 808C for 3 hr under nitrogen atmosphere. Alumina was
separated by filtration after eluting the product with ethyl acetate (20 mL).
After evaporating the solvent under reduced pressure, the residue was purified
by column chromatography on silica-gel (hexane–ethyl acetate ¼ 10 : 1) to
[
22]
yield 8a (81%) as a yellow solid, m.p. 129–1308C (lit.
129–129.58C).
1
H-NMR (CDCl , 300 MHz), d 3.04 (dd, 1H, J ¼ 13.5 Hz, J ¼ 9.2 Hz), 3.24
3
(
dd, 1H, J ¼ 13.5 Hz, J ¼ 3.8 Hz), 3.77 (br s, 1H), 5.19 (dd, 1H, J ¼ 9.1 Hz,
J ¼ 3.8 Hz), 6.82 (dd, 1H, J ¼ 7.2 Hz, J ¼ 1.7 Hz), 7.00–7.43 (m, 11H), 7.84
(
dd, 2H, J ¼ 7.9 Hz, J ¼ 1.7 Hz).
REFERENCES
1
. (a) Mane, R.A.; Ingle, D.B. Synthesis and biological activity of some new
,5-benzothiazepines containing thiazol moiety: 2-aryl-4-(4-methyl-2-
1
substituted-aminothiazol-5-yl)-2,3-dihydro-1,5-benzothiazepines. Indian
J. Chem. Sect. B 1982, 21B, 973; (b) Jadhav, K.P.; Ingle, D.B. Synthesis
of 2,4-diaryl-2,3-1,5-benzothiazepines and their 1,1-dioxides as anti-
bacterial agents. Indian J. Chem. Sect. B 1983, 22B, 180.
0
0
2
. Reddy, R.J.; Ashok, D.; Sarma, P.N. Synthesis of 4,6-bis(2 -substituted-2 ,
0
0
3
-dihydro-1,5-benzothiazepine-4 -yl)resorcinols as potential antifeedants.
Indian J. Chem. Sect. B 1993, 32B, 404.

ORDER
REPRINTS
1
,5-Benzothiazepines and Benzodiazepines
1789
3
4
5
6
7
8
9
. Satyanarayana, K.; Rao, M.N.A. Synthesis of 3-[4-[2,3-dihydro-2-
(substituted aryl)-1,5-benzothiazepin-4-yl]penyl]sydnones as potential
anti-inflammatory agents. Indian J. Pharm. Sci. 1993, 55, 230.
. DeSarro, G.; Chimirri, A.; DeSarro, A.; Gitto, R.; Zappala, M.
5H-[1,2,4]Oxadiazolo[5,4-d][1,5]benzothiazepines as anticonvulsant
agents in DBA/2 mice. Eur. J. Med. Chem. 1995, 30, 925.
. Aversa, M.C.; Ferlazzo, A.; Giannetto, P.; Kohnke, F.H. A convenient
synthesis of novel [1,2,4]triazolo[4,3-a][1,5]benzodiazepine derivatives.
Synthesis 1986, 230.
. Chimirri, A.; Grasso, S.; Ottana, R.; Romeo; Zappala, G.M. Synthesis and
stereochemistry of novel [1,2,4]oxadiazolo[4,5-a][1,5]benzodiazepine
derivatives. J. Heterocycl. Chem. 1990, 27, 371.
. Stahlhofen, P.; Ried, W. Heterocyclic seven-membered ring systems.
V: Reaction of o-phenylenediamine with a,b-unsaturated carbonyl
compounds. Chem. Ber. 1957, 90, 815.
. Ried, W.; Torinus, E. Heterocyclic seven-ring systems. X: Syntheses of
condensed 5,7-, and 8-membered heterocycles with 2 nitrogen atoms.
Chem. Ber. 1959, 92, 2902.
. Jung, D.I.; Choi, T.W.; Kim, Y.Y.; Kim, I.S.; Park, Y.M.; Lee, Y.G.;
Jung, D.H. Synthesis of 1,5-benzodiazepine derivatives. Synth. Commun.
1999, 29, 1941.
1
1
1
1
0. Curini, M.; Epifano, F.; Marcotullio, M.C.; Rosati, O. Ytterbium triflate
promoted synthesis of 1,5-benzodiazepine derivatives. Tetrahedron Lett.
2001, 42, 3193.
1. Balakrishna, M.S.; Kaboundin, B. A simple and new method for the syn-
thesis of 1,5-benzodiazepine derivatives on a solid surface. Tetrahedron
Lett. 2001, 42, 1127.
2. Yadav, J.S.; Reddy, B.V.S.; Eshwaraian, B.; Anuradha, K. Amberlyst-15:
a novel and recyclable reagent for the synthesis of 1,5-benzodiazepines in
ionic liquids. Green Chem. 2000, 4, 592.
3. Pozarentzi, M.; Stephanidou-Stephanatou, J.; Tsoleridis, C.A. An effi-
cient method for the synthesis of 1,5-benzodiazepine derivatives
under microwave irradiation without solvent. Tetrahedron Lett. 2002,
43, 1755.
1
4. Ma, Y.; Zhang, Y. Derivatives of 2,3-dihydro-1H-1,5-benzodiazepine
from o-nitroanilines and chalcones induced by low-valent titanium.
Synth. Commun. 2002, 32, 165.
1
5. Zhong, W.; Zhang, Y.; Chen, X.J. Samarium diiodide mediated simulta-
neous reduction of nitro group and the azide group in o-nitrophenylazide:
a new access to 2,3-dihydro-1H-1,5-benzodiazepines. J. Chem. Res.
(
Synop.) 2000, 532.

ORDER
REPRINTS
1
790
Kodomari, Noguchi, and Aoyama
16. Levai, A.; Bognar, R. Oxazepines and thiazepines. II: Synthesis of
2
2
,3-dihydro-2,4-diphenyl-1,5-benzothiazepines by the reaction of
-aminotiophenol with chalcones substituted in ring B. Acta Chim.
Acad. Sci. Hung. 1976, 88, 293.
1
7. Rao, D.M.; Giridhar, T.; Reddy, R.B.; Mouli, G.V.P.C. A novel synthesis
of benzothiazepines. Indian J. Heterocycl. Chem. 1995, 5, 145.
8. Zhong, W.; Chen, X.; Zhang, Y. Low-valent titanium induced simul-
taneous reduction of nitro group and S–S bond in nitrodisulfides:
a novel method for the synthesis of benzothiazoline, benzothiazoles and
1
2,3-dihydro-1,5-benzothiazepines. Synth. Commun. 2000, 30, 4451.
1
9. Dandia, A.; Sati, M.; Loupy, A. Dry-media one-pot synthesis of fluori-
nated-2,3-dihydro-1,5-benzothiazepines under microwave activation.
Green Chem. 2002, 4, 599.
20. Hankovszky, O.H.; Hideg, K.; Lloyd, D. Reaction products from
4-phenylbut-3-yn-2-ome and aliphatic diamines or 2-aminoethanethiol,
and from 2-aminoethane-thiol and some a,b-enones. J. Chem. Soc.
Perkin Trans. 1 1974, 1619.
2
1. Katrizky, A.R.; Rogovoy, B.V.; Chassaing, C.; Vvedensky, V.;
Forood, B.; Flatt, B.; Nakai, H. Synthesis of 2,4-diaryl-2,3-dihydro-1,5-
benzothiazepines. J. Heterocycl. Chem. 2000, 37, 1655.
2. Orlov, V.D.; Kolos, N.N.; Abramov, A.F. Conformational analysis of
aromatic derivatives of 2,3-dihydro-1H-1,5-benzodiazepine. Khim.
Geterotskl. Soedin. 1984, 12, 1662.
2
Received in Japan December 11, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(
AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120034159