Novel synthesis of 1,4-benzothiazines in water accelerated by β-cyclodextrin

Article abstract of DOI:10.1007/s13738-015-0752-3

Novel one-pot synthetic protocol has been developed for obtaining 2, 3-disubstituted 1,4-benzothiazines with excellent yields, carrying cyclocondensation of 1,3-dicarbonyl compounds with substituted 2-(2-(2-aminophenyl)disulfanyl)benzenamines, under supra

Full text of DOI:10.1007/s13738-015-0752-3

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0752-3
ORIGINAL PAPER
Novel synthesis of 1,4‑benzothiazines in water accelerated
by β‑cyclodextrin
Balaji S. Londhe1,2 · Sudhakar L. Padwal2 · Manisha R. Bhosale1 ·
Ramrao A. Mane1
Received: 24 June 2015 / Accepted: 24 September 2015
© Iranian Chemical Society 2015
Abstract Novel one-pot synthetic protocol has been
developed for obtaining 2, 3-disubstituted 1,4-benzothia-
zines with excellent yields, carrying cyclocondensation of
1,3-dicarbonyl compounds with substituted 2-(2-(2-ami-
nophenyl)disulfanyl)benzenamines, under supramolecular
catalysis of β-Cyclodextrin (β-CD) in water at neutral pH.
The role of β-CD in accelerating the cyclocondensation has
been demonstrated. This biomimic catalyzed route is sim-
ple, economic, relatively rapid and environmentally benign.
Because of their diverse biological significance, syn-
thetic chemists have developed number of routes for the
syntheses of 1,4-benzothiazine derivatives. The most
popularly employed route for the preparation of 1,4-ben-
zothiazines is the oxidative cyclocondensation of 2-ami-
nothiophenols with 1,3-dicarbonyl compounds, using
DMSO/MW/basic alumina/hydrazine hydrate/H2O2–NaOH
[15–18]. Recently we reported the Baker’s yeast catalyzed
synthesis of 1,4-benzothiazines, from 2-aminobenzenethi-
ols and 1,3-dicarbonyls performed under ultrasonication
[19]. Another route consists of the condensation of 2-ami-
nothiophenols with alkynes [20, 21] and α-haloketones or
α-haloesters [22].
Keywords 1,4-Benzothiazines · Supramolecular
catalyst · β-Cyclodextrin · Biomimetic catalysis
These reported methods suffer from one or more of the
drawbacks such as the use of volatile organic solvents,
organic/inorganic bases and explosive/corrosive oxidants.
In case of biocatalytic route, there is a problem of solid
waste management [19]. Therefore, we thought about
replacing the biocatalyst with biomimetic catalyst, in order
to accelerate the reaction rate and minimize the problem of
solid waste. Further, it has been also kept in mind to replace
the organic solvent by water.
While revealing the literature it was observed that
β-cyclodextrin, a biomimetic catalyst [23] has been
recently employed for carrying variety of organic transfor-
mations [24–30]. It was also revealed that, β-cyclodextrin
does not find use in the cyclocondensation of substi-
tuted 2-(2-(2-aminophenyl)disulfanyl)benzenamines with
1,3-dicarbonyl compounds leading to 1,4-benzothiazines.
β-Cyclodextrin (β-CD) is cyclic oligosaccharide con-
taining inner hydrophobic cavity. It exerts micro-envi-
ronmental effects on the reactant molecules which lead
to selective reactions under mild reaction conditions [24–
30]. Reactions catalyzed by them involve supramolecular
catalysis due to non-covalent bonding, forming reversible
Introduction
1,4-Benzothiazines are molecules of great interest and con-
sidered as important targets because of their broad spec-
trum of biological activities [1]. Literature survey reveals
that 1,4-benzothiazines exhibit wide pharmacological activ-
ities such as antagonists [2, 3], anticancer [4], vasorelaxant
[5], antidiabetic [6], antihypertensive [7], antimicrobial [8],
analgesic [9], anti-HCV [10], antimalarial [11], antithyroid
[12] and antitubercular [13]. 1,4-Benzothiazines have also
been used as dyestuff in industry [14].
* Balaji S. Londhe
bslondhe@gmail.com
* Ramrao A. Mane
manera2011@gmail.com
1
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad, M.S. 431004, India
2
Department of Chemistry, Karmaveer Bhaurao Patil
Mahavidyalaya, Pandharpur, M.S. 413304, India
1 3

J IRAN CHEM SOC
complexes between substrates and β-cyclodextrin as seen
in the enzymes [31, 32]. These biomimetic reactions can be
effectively carried out in water at neutral pH without gen-
erating any toxic waste products; thus, exactly mimicking
biocatalytic conditions. Owing to these facts cyclodextrins
are perfectly considered as enzyme models/biomimics [33–
38] and reactions under supramolecular catalysis will be
superior to chemical catalysis.
cooled to 0 °C; in which β-cyclodextrin reappeared as
white solid. Thus, obtained white solid mass then filtered
and washed with cold water to recover β-cyclodextrin. It
was noticed that, the cyclocondensation has been found to
be completed within 50 min, resulting in better to excellent
yields of the 1,4-benzothiazines.
Spectral data of selected compounds
Inspired by these attractive features of cyclodextrin as
a biomimic, i.e., biomimetic catalyst and as a part of our
drive towards the syntheses of bioactive molecules [39],
accelerated by biocatalysts [19]/biomimics [40], here for
the first time we report the biomimetic route for the synthe-
sis of 1,4-benzothiazines by carrying the cyclocondensation
of various 2-(2-(2-aminophenyl)disulfanyl)benzenamines
and 1,3-dicarbonyls in aqueous β-cyclodextrin.
1‑(3‑Methyl‑4H‑benzo[b][1, 4]thiazine‑2‑yl) ethanone (3a)
1H NMR (400 MHz, DMSOd6): δ = 2.16 (s, 3H), 2.22 (s,
3H, CH3), 6.61–6.86 (m, 4H), and 8.74 (s, 1H, NH).
13C NMR (100 MHz, DMSOd6): δ = 21.40, 29.89,
97.59, 115.31, 120.36, 124.71, 126.14, 127.05, 139.51,
153.81 and 191.23.
HRMS (ESI+ mode) (m/z): Calculated for C11H11NOS
[M + Na]+: 228.0456; found: 228.0461.
Experimental
General
1‑(3,7‑Dimethyl‑4H‑benzo[b][1,4]thiazin‑2‑yl) ethanone
(3b)
Melting points were determined by open capillary method
and are uncorrected. Progress of the reaction was moni-
tored by thin layer chromatography on MERK’s silica
1H NMR (300 MHz, CDCl3): δ = 1.96 (s, 3H), 2.20 (s,
3H), 2.45 (s, 3H), 5.91 (s, 1H, NH), 7.01 (t, 1H, J = 4.0 and
8.0 Hz), 6.37 (d, 1H, J = 8.0 Hz), 6.75 (d, 1H, J = 4.0 Hz).
13C NMR (75 MHz, CDCl3): δ = 22.49, 28.96, 29.92,
110.12, 114.61, 127.33, 129.37, 133.49, 135.13, 136.17,
153.54 and 194.13.
1
plates. H NMR and 13C NMR spectra were recorded on
Bruker DRX-300 (300 MHz FTNMR) and Bruker DRX-
400 (400 MHz FTNMR) using TMS as an internal stand-
ard. Mass spectral data were determined by ESI-TOF (time
of flight) mode on JEOL AccuTOF DART mass spectrom-
eter and on maXis impact 282001.00081 mass spectrom-
eter. β-Cyclodextrin used was of HiMedia Laboratories. All
chemicals used were reagent grade and used without fur-
ther purification.
ESI DARTMS: Calculated for C12H13NOS [M + 1]:
220.0717; found: 220.1154.
Ethyl 3,7‑dimethyl‑4H‑benzo[b][1,4]
thiazine‑2‑carboxylate (3c)
1H NMR (300 MHz, CDCl3): δ = 1.19 (t, 3H), 2.08 (s,
3H), 2.38 (s, 3H), 4.13 (q, 3H), 6.15 (s, 1H, NH), 7.15 (d,
1H, J = 8.0 Hz), 7.24 (t, 1H, J = 4.0 and 8.0 Hz), 7.63 (d,
1H, J = 4.0 Hz).
General experimental procedure
β-Cyclodextrin (1 mmol) was dissolved in water (20 ml)
with stirring at 60 °C until a clear solution was formed
and then 1,3-dicarbonyl compound (2 mmol) dissolved in
ethanol (2 ml) was added slowly with stirring. To this then
2-(2-(2-aminophenyl)disulfanyl)benzenamine (1 mmol dis-
solved in 2 ml ethanol) was added and the reaction mass
was further stirred at 60 °C. The progress of the reaction
was monitored by thin layer chromatography using ethyl
acetate: n-Hexane (2:8) as a solvent system. After 50 min,
the reaction mixture was extracted with ethyl acetate
(2 × 10 ml). The organic layer was washed with water,
saturated brine solution and dried over anhydrous sodium
sulfate. The combined organic layer was evaporated under
reduced pressure and thus obtained crude product was fur-
ther purified by column chromatography with ethyl acetate:
n-hexane (2:8) as an eluent. The aqueous layer was then
ESI DARTMS: Calculated for C13H15NO2S [M + 1]:
250.0823; found: 250.0796.
Results and discussion
Keeping in mind the need of safer medium like water and
the importance of biomimetic catalysts, we attempted the
cyclocondensations of 2-(2-(2-aminophenyl)disulfanyl)
benzenamine (1a) and acetyl acetone (2a) in aqueous
solution of β-cyclodextrin (Scheme 1). It was observed
that the condensation successfully led to 1,4-benzothia-
zines, when reactants are stirred in hot aqueous solution
of β-cyclodextrin. Encouraged by these observations we
tried to optimize the appropriate reaction conditions for
1 3

J IRAN CHEM SOC
Scheme 1 Synthesis of
1,4-benzothiazine
H2N
O
S
O
O
S
S
CH3
CH3
CD
H3C
CH3
H2O
N
H
NH2
1a
2a
3a
Table 1 Optimization for appropriate reaction temperaturea
Table 2 Optimization for optimum reaction timea (Scheme 1)
(Scheme 1)
Entry
Stirring temperature (°C)
Time
Yieldsb (%)
Entry
Stirring temperature (°C)
Time (h)
Yieldsb (%)
1
2
3
4
5
60
60
60
60
60
30 min
40 min
45 min
50 min
1 h
75
82
88
90
90
1
2
3
4
30
50
60
70
2
2
2
2
Trace
62
91
87
a
Reaction conditions: 2-(2-(2-aminophenyl)disulfanyl)benzenamine
(5 mmol), acetylacetone (10 mmol), β-CD (5 mmol) in water
(100 ml)
the reaction. The condensation has been carried at various
reaction temperatures for fixed reaction time (Table 1). It
was noticed that stirring at 60 °C is the appropriate reaction
condition for obtaining excellent yield (91 %) of 1,4-ben-
zothiazine (Table 1, entry 4). Further attempts were made
to find the appropriate reaction time for this cycloconden-
sation at fixed temperature 60 °C (optimized). It was found
that 50 min is the sufficient reaction time (Table 2, entry 4)
and there was no significant increase in the yield of desired
product when reaction time increased further (Table 2,
entry 5). It was further noticed that excellent yield of the
4H-1,4-benzothiazine (3a) was obtained when 2-(2-(2-ami-
nophenyl)disulfanyl)benzenamines and acetyl acetone (in
1:2 molar proportion) were stirred in aqueous solution of
β-cyclodextrin at 60 °C, for 50 min.
Subsequently the other substituted 2-(2-(2-aminophenyl)
disulfanyl)benzenamines and 1,3-dicarbonyl compounds
were allowed to react under the optimized reaction condi-
tions to obtain the respective 1,4-benzothiazines (3a–i).
The results are recorded in Table 4 (Scheme 2). Here, rate
enhancement of the cyclocondensations has been observed.
It was noticed that the time required for the completion of
the reaction as compared to the time required for the cyclo-
condensation carried by baker’s yeast [19] has been found
to be distinctly reduced from 3 h to 50 min which makes
the route rapid and use of water as reaction medium makes
it environmentally benign as compared with the previously
reported methods (Table 3) for these target molecules.
The rate acceleration of this condensation can be attrib-
uted to (1) aqueous β-cyclodextrin provides a unique
hydrophobic truncated cone shaped cavity and hydro-
philic outwardly hydroxyl groups. The dicarbonyl com-
pound might be forming non covalent reversible supra-
molecular complexes with β-cyclodextrin, enhancing the
localized concentration of the dicarbonyl, resulting in the
b
Yield refers to isolated product
dissolution of reactant in aqueous medium. Because of
this, 1,3-dicarbonyl compound become readily available to
interact with 2-(2-(2-aminophenyl)disulfanyl)benzenamine
which might have encapsulated in the hydrophobic cavity
of β-cyclodextrin and (2) the electrophilic behavior of car-
bonyl carbon of the dicarbonyl would have been enhanced
because of intermolecular hydrogen bonding between out-
wardly hydroxyl groups of β-cyclodextrin and carbonyl
oxygen of the dicarbonyl compounds (Fig. 1). Increase in
the localized concentration of reactants and enhanced elec-
trophilic behavior of carbonyl carbon would be responsible
to accelerate the condensation rate compared to the con-
densation carried by biocatalyst [19].
To generalize this biomimetic synthetic route (Scheme 1)
for the synthesis of substituted 4H-1,4-benzothiazines, we
have tried the reactions for various substituted 1,3-dicar-
bonyl compounds and substituted 2-(2-(2-aminophenyl)
disulfanyl)benzenamine for getting corresponding targets
1,4-benzothiazines. As expected all the reactions proceeded
smoothly to afford the desired products with good to excel-
lent yields (Scheme 2; Table 4).
Conclusions
For the first time, we report use of β-cyclodextrin as a bio-
mimetic catalyst to accelerate the cyclocondensation of
substituted 2-(2-(2-aminophenyl)disulfanyl)benzenamines
and 1,3-dicarbonyl compounds in water and obtained
1,4-benzothiazines. The role of β-cyclodextrin as supramo-
lecular catalyst in accelerating the cyclocondensation has
1 3

J IRAN CHEM SOC
Scheme 2 Synthesis of
1,4-benzothiazine derivatives
H2N
O
R
S
CD, Water
O
O
R
S
S
R1
R
60 C, 50 Min.
H3C
R1
N
H
CH3
NH2
Table 3 Comparative study of
aq. β-CD and other catalysts
reported for synthesis of
1,4-benzothiazines
Entry
Catalyst/Solvent
Reaction conditions
Reaction time
Yield (%)
References
1
2
3
4
5
6
7
NaOH/H2O2
DMSO
0 °C—RT
Reflux
10–25 min
20 min
12–13 min
1 h
90–96
46–84
83–96
45–72
73–84
51–82
70–91
[17]
[18]
[39]
[41]
[42]
[19]
–
NH2NH2H2O
DMSO
100 °C
Reflux
Basic alumina/chloroform
Baker’s yeast/MeOH
β-CD/Water
MW
6–11 min
3 h
US, 25–30 °C
60 °C
50 min
R2
O
R1
H2N
O
O
O
R1
S
H
O
S
R1
S
R2
NH2
NH2
NH2
S
R1
O
R1
S
R2
-H2O
H
N
R1
R2
R2
O
O
O
R2
H
O
H
O
H
O
H
O
S
H
O
H
NH2
S
S
N
HN
HN
S
R1
R1
R1
Fig. 1 Plausible mechanism for the cyclocondensation in β-CD cavity
also been mentioned and possible mechanism has also been
demonstrated. This protocol is superior as compared to
previously reported routes, as it is not accompanying with
solid waste, relatively rapid and environmentally benign.
This biomimetic strategy could be useful for other similar
cyclocondensations leading to value-added products.
1 3

J IRAN CHEM SOC
Table 4 Synthesis
β-cyclodextrina
of
1,4-benzothiazines,
catalyzed
by
13. S.A. Coughlin, D.W. Danz, R.G. Robinson, K.M. Klingbeil,
M.P. Wentland, T.H. Corbett, W.R. Waud, L.A. Zwelling, E.
Altschuler, E. Bales, J.B. Rake, Biochem. Pharmacol. 50, 111
(1995)
(Scheme 2)
Entry
R
R1
Productc
Yieldb (%)
M. P. (°C)
14. R. Tanaka, K. Teramura, S. Yokoyama, Chem. Abstr. 65, 9062
(1966)
15. P.R. Sharma, V. Gupta, D.C. Gautam, R.R. Gupta, Phosphorus,
1
2
3
4
5
6
7
8
9
H
CH3
CH3
OEt
OEt
Ph
3a
3b
3c
3d
3e
3f
91
78
75
90
86
71
85
80
70
189–190
187–188
177–178
141–142
188–189
141–142
192–193
148–150
124–125
CH3
CH3
H
Sulfur Silicon Relat. Elem. 178, 1483 (2003)
16. A. Dandia, P. Sarawgi, M.B. Hursthouse, A.L. Bingham, M.E.
Light, J.E. Drake, R. Ratnani, J. Chem. Res. 7, 445 (2006)
17. H. Sheibani, M.R. Islami, A. Hassanpour, K. Saidi, Phosphorus,
Sulfur Silicon Relat. Elem. 183, 13 (2008)
H
CH3
Cl
Ph
18. N. Gautam, N. Ajmera, S. Gupta, D.C. Gautam, Eur. J. Chem.
CH3
OEt
Ph
3g
3h
3i
106, 3 (2012)
Cl
19. U.R. Pratap, D.V. Jawale, B.S. Londhe, R.A. Mane, J. Mol.
Catal. B: Enz. 68, 94 (2011)
Cl
20. G. Liso, G. Trapani, V. Berardi, A. Latrofa, P. Marchini, J. Het-
a
Reaction conditions:2-(2-(2-aminophenyl)disulfanyl)benzenamine
(1 mmol), 1,3-dicarbonyl (2 mmol), β-cyclodextrin (1 mmol) in water
(20 ml) at 60 °C for 50 min
erocycl. Chem. 793 (1980)
21. S. Mitra, A. Chakraborty, S. Mishra, A. Majee, A. Hajra, Org.
Lett. 16, 5652 (2014)
b
Yield refers to isolated products
22. A. R. Katritzky, C. W. Rees, E. F. V. Scrivener, Comprehensive
c
Heterocyclic Chemistry II (Elsevier) (1996)
Physical constants and spectral data of the known compounds are in
23. R. Breslow, D.D. Steven, Chem. Rev. 98, 1997 (1998)
24. K. Gong, H. Wang, X. Ren, Y. Wang, J. Chen, Green Chem. 17,
3141 (2015)
a good agreement with the earlier reports [41–43]
Acknowledgments Authors are thankful to Professor D. B. Ingle
for his valuable discussions.
25. S. Chaudhuri, T. Phelan, M. Levine, Tetrahedron Lett. 56, 1619
(2015)
26. Q. Zhang, Y.Z. Huang, J.H. Yang, B.W. Ma, G.R. Qu, H.M. Guo,
Tetrahedron Lett. 55, 1203 (2014)
27. D.R. Patil, Y.B. Wagh, P.G. Ingole, K. Singh, D.S. Dalal, New J.
Chem. 37, 3261 (2013)
References
28. S.N. Murthy, B. Madhav, V.P. Reddy, Y.V.D. Nageswar, Tetrahe-
1. R.R. Gupta, In Phenothiazines and 1,4‑Benzothiazines (Chemi-
cal and Biomedical Aspects, Elsevier, 1988)
2. Y. Watanabe, K. Osanai, T. Nishi, N. Miyawaki, D. Shii, T.
Honda, T. Shibano, Bioorg. Med. Chem. Lett. 6, 1923 (1996)
3. I. Schwarzl, U. Stark, M. Brodmann, U. Haiden, H.A. Tritthart,
G. Stark, J. Cardiovasc. Pharmacol. 35, 309 (2000)
dron Lett. 51, 3649 (2010)
29. V.P. Kumar, V.P. Reddy, R. Sridhar, B. Srinivas, M. Narender,
K.R. Rao, J. Org. Chem. 73, 1646 (2008)
30. S.V. Bhosale, Mini. Rev. Org. Chem. 4, 143 (2007)
31. Y.A. Tayade, D.R. Patil, Y.B. Wagh, A.D. Jangle, D.S. Dalal, Tet-
rahedron Lett. 56, 666 (2015)
4. A. Niewiadomy, J. Matysiak, M. Karpinska, Arch. Pharm. Chem.
32. J. Szejtli, Comprehensive Supramolecular Chemistry, vol. 3
Life Sci. 11, 224 (2011)
(Pergamon, New York, 1996)
5. A. Martelli, G. Manfroni, P. Sabbatini, M.L. Barreca, L. Testai,
M. Novelli, S. Sabatini, S. Massari, O. Tabarrini, P. Masiello, V.
Calderone, V. Cecchetti, J. Med. Chem. 56, 4718 (2013)
6. E. Meltzer-Mats, G. Babai-Shani, L. Pasternak, N. Uritsky, T.
Getter, O. Viskind, J. Eckel, E. Cerasi, H. Senderowitz, S. Sas-
son, A. Gruzman, J. Med. Chem. 56, 5335 (2013)
33. R. Breslow, Artificial Enzymes (Wiley-VCH, Weinheim, 2005)
34. M.A. Mateos-Timoneda, M. Crego-Calama, D.N. Reinhoudt,
Chem. Soc. Rev. 33, 363 (2004)
35. S. Leininger, B.B. Olenyuk, P.J. Stang, Chem. Rev. 100, 853
(2000)
36. E. Rizzarelli, G. Vecchio, Coord. Chem. Rev. 188, 343 (1999)
37. J.L. Atwood, J.E.D. Davies, D.D. MacNicol, F. Vogtle, J. Szejtli,
T. Osa, Comprehensive Supramolecular Chemistry, vol. 3 (Per-
gamon, Oxford, 1996)
7. V. Cecchetti, F. Schiaffella, O. Tabarrini, A. Fravolini, Bioorg.
Med. Chem. Lett. 10(5), 465 (2000)
8. J.P. Brincat, E. Caroti, S. Sabatini, G. Manfroni, A. Fravolini,
J.L. Raygada, D. Patel, G.W. Kaatz, G. Cruciani, J. Med. Chem.
54, 354 (2011)
38. E. Lindbäck, Y. Zhou, C.M. Pedersen, M. Bols, Tetrahedron Lett.
53, 5023 (2012)
9. B.K. Warren, E.E. Knaus, Eur. J. Med. Chem. 22, 411 (1987)
10. R.T. Hendricks, J.B. Fell, J.F. Blake, J.P. Fischer, J.E. Robinson,
S.R. Spencer, P.J. Stengel, A.L. Bernacki, V.J.P. Leveque, S.L.
Pogam, S. Rajyaguru, I. Najera, J.A. Josey, J.R. Harris, S. Swal-
low, Bioorg. Med. Chem. Lett. 19, 3637 (2009)
11. A. Barazarte, G. Lobo, N. Gamboa, J.R. Rodrigues, M.V. Cap-
parelli, A. Alvarez-Larena, S.E. Lopez, J.E. Charris, Eur. J. Med.
Chem. 44, 1303 (2009)
39. S.B. Munde, S.P. Bondge, V.E. Bhingolikar, R.A. Mane, Green
Chem. 5, 278 (2003)
40. B.S. Londhe, U.R. Pratap, J.R. Mali, R.A. Mane, Bull. Korean
Chem. Soc. 31, 2329 (2010)
41. R.R. Gupta, G.S. Kalwania, R. Kumar, Bull. Chem. Soc. Jpn 57,
2343 (1984)
42. S. Paul, R. Gupta, A. Loupy, B. Rani, A. Dandia, Synth. Com-
mun. 31, 711 (2001)
12. K. Hasegawa, S. Ito, S. Inoue, K. Wakamatsu, H. Ozeki, I. Ishig-
43. S. Miyano, N. Abe, K. Sumoto, K. Teramoto, J. Chem. Soc. Per-
kin Trans. 1, 1146 (1976)
uro, Biochem. Pharmacol. 53, 1435 (1997)
1 3