One-pot multi-component approach to the synthesis of 1,4-benzothiazines in aqueous media

Article abstract of DOI:10.1080/10426500701544599

A new and rapid synthetic strategy for the oxidative cyclocondensation of 2-aminobenzenethiol and 1,3-dicarbonyls has been developed in order to obtain 2,3-disubstituted 1,4-benzothiazines at ambient temperature and in aqueous media. A mechanism is presen

Full text of DOI:10.1080/10426500701544599

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Phosphorus, Sulfur, and Silicon
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One-Pot Multi-Component
Approach to the Synthesis of
1,4-Benzothiazines in Aqueous
Media
Hassan Sheibani a , Mohammad Reza Islami a , Avid
Hassanpour a & Kazem Saidi a
a Department of Chemistry, Shahid Bahonar
University of Kerman, Kerman, Iran
Published online: 20 Feb 2008.
To cite this article: Hassan Sheibani , Mohammad Reza Islami , Avid Hassanpour &
Kazem Saidi (2007): One-Pot Multi-Component Approach to the Synthesis of 1,4-
Benzothiazines in Aqueous Media, Phosphorus, Sulfur, and Silicon and the Related
Elements, 183:1, 13-20
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Phosphorus, Sulfur, and Silicon, 183:13–20, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701544599
One-Pot Multi-Component Approach to the Synthesis
of 1,4-Benzothiazines in Aqueous Media
Hassan Sheibani, Mohammad Reza Islami,
Avid Hassanpour, and Kazem Saidi
Department of Chemistry, Shahid Bahonar University of Kerman,
Kerman, Iran
A new and rapid synthetic strategy for the oxidative cyclocondensation of 2-
aminobenzenethiol and 1,3-dicarbonyls has been developed in order to obtain 2,3-
disubstituted 1,4-benzothiazines at ambient temperature and in aqueous media. A
mechanism is presented to account for the formation of the products.
Keywords 2-Aminobenzenethiol; 1,3-dicarbonyl; 1,4-benzothiazines; cyclocondensation
INTRODUCTION
Increasing attention for environmental protection during the last
decades has led both modern academic and industrial groups to develop
chemical processes with maximum yield and minimum cost while us-
ing non-toxic reagents, solvents and catalysts. One of the tools used
to combine economic aspects with the environmental ones is the multi-
component reaction (MCR) strategy; this process consists of two or more
synthetic steps, which are carried out without isolation of any interme-
diate thus reducing time, saving money, energy and raw materials.1–3
The synthesis of heterocyclic systems is of continuing interest, at least
in part as a result on the large number of biologically active molecules
that contain heterocyclic rings.4,5 A relatively unexplored heterocyclic
ring system, with respect to both its synthesis and its biological activ-
ity, is 1,4-benzothiazines. These compounds possess a wide spectrum
of biological and pharmacological activities due to the presence ni-
trogen and sulfur groups, which are considered to be responsible as
Received 5 May 2007; accepted 18 June 2007.
The authors express appreciation to the Shahid Bahonar University of Kerman Fac-
ulty Research Committee for its support of this investigation.
Address correspondence to Hassan Sheibani, Department of Chemistry, Shahid Ba-
honar, University of Kerman, P.O. Box 76169-133, Kerman, Iran. E-mail: hassan-
sheibani@yahoo.com
13

14
H. Sheibani et al.
one of the structural features to impart their activities.6 They are
used as antihistaminics,antipsychotics,7 antiemetics,8 neuroleptics,9
tranquilizers, 10 sedatives,11and so on.
The importance and utility of benzothiazine derivatives have led
to the development of numerous synthetic routes. One of the most
widely methods employed for the preparation of 1,4-benzothiazines
involves the reaction of 2-aminobenzenethiols with alkynes,12α-
haloketones or α-haloesters13 and oxidative cyclocondensation of
2-aminobenzenethiols with 1,3-dicarbonyl compounds using dimethyl-
sulfoxide (DMSO).14,15 The former method requires the use of lachry-
matory α-haloketones or α-haloesters as one of the reactants and the
products isolated are in low yields (50–65%) and as isomeric mixtures.
In the latter method, the yields are higher, and the amount of impuri-
ties of the products are much less. A dipolar aprotic solvent with several
unfavorable properties such as dimethylsulfoxide, is necessary to act as
both solvent and oxidant.
RESULTS AND DISCUSSION
Recently Munde et al.,16 have reported an in-situ synthesis
of 1,4-benzothiazines under solvent free conditions from 2-
aminobenzenethiols and 1,3-dicarbonyls under oxidative conditions
involving the formation of dimer of 2-aminobenzenethiols.16
In this method, 2-aminobenzethiols are oxidized to the corresponding
disulfides in the presence of hydrazine hydrate and air, followed by
condensation with the 1,3-dicarbonyls to yield 1,4-benzothiazines. The
hydrazine hydrate catalyst acts as a base. Hydrazine—especially in
anhydrous form—is highly toxic and dangerously unstable.
We have recently reported the synthesis of 1,4-benzothazines by us-
ing of 1,3-bielectrophiles and binucleoplies such as 1,3- dicarbonyl,
enaminones and 2,2ꢀ-disulfanediyldianiline.17,18 The chemical and
pharmaceutical industries are under an accelerating pressure to find
eco-friendly synthetic methodologies. With the aim of developing an
efficient, economic, and clean procedure green chemistry) for prepara-
tion of 1,4-benzothiazines, we proceeded to condense equimolar quan-
tities of 2-aminobenzenethiol 2 with 1,3-dicarbonyls 1a–g in the pres-
ence of hydrogen peroxide in alkaline solution at ambient temperature
(Scheme 1).
The complete process represents an example of a one-pot and sequen-
tial steps reaction (often referred to as tandem or cascade reaction),
where reagents and catalysts are mixed together and experimental
conditions are set up in such a way to promote the reaction cascade.19,20

Bensothiazines in Aqueous Media
15
SCHEME 1
Thus, the disulfide is quantitatively produced by fast oxidation of 2-
aminobenzenethionl with hydrogen peroxide in the alkaline solution
(Scheme 2)12 proceeds through nucleophilic substitution at the S S-
bond of 2,2ꢀ-disulfanediyldianiline acting as an electrophile by β-keto
esters, dimethyl malonate, and 1,3-diketones, followed by cyclization
provides compounds 3a–f, 4, and 5 (Table I).
In fact, as clearly stated by R. A. Sheldon, it is generally recognized
that “the best solvent is no solvent and if a solvent (diluent) is needed it
SCHEME 2

16
H. Sheibani et al.
TABLE I Reaction Time, Melting Points (◦C) and Yields of Products
No.
R
Rꢀ
Time (min)
Yield (%)
M.P. (◦C)
3a
3b
3c
3d
3e
CH3
CH3
CH2CH2CH2
C6H5
CH3
15
10
25
20
20
92
96
90
95
90
183–184
174–176
161(dec)
212(dec)
188–190
CH2C(CH3)2CH2
3f
3g
4
CH3
CH3
C6H5
CH3O
CH3CH2O
PhCH2O
C6H5
10
15
30
30
92
88
95
95
141–143
155–157
132–133
169–170
5
CH3O
should preferably be water.”22 The use of water as the reaction medium
represents a remarkable benefit since this green solvent is highly polar,
and therefore, immiscible with most organic compounds thus separa-
tion of the organic materials is easy. A further advantage is that many
organic reactions like the aldol condensation, the benzoin condensation,
the Diels-Alder cycloaddition, and cyclocondensation reactions exhibit
rate enhancement in water.23 In the present protocol as exhibited in
(Scheme 1) the conversion of 1,3-diketones and 2-aminobenzenethionl
in the presence of hydrogen peroxide to 1,4-benzothiazines has been
efficiently performed in water as a “green” solvent. The easy purifi-
cation of the products simply by crystallization, the use of water as
solvent combined with the exploitation of the multicomponent strat-
egy open to this process suggest good prospects for its industrial
applicability.
The structure of compounds 3a–g and 4, 5 were determined on the
basis of their elemental analyses, mass spectrum, 1H and 13C NMR, and
IR spectroscopic data. The infrared spectrum of compound 3a revealed
a band in the carbonyl region at 1640 cm−1 and a strong band at 3255
1
cm−1 which is due to the enaminone proton. The H NMR spectrum
of 3a indicated three at different kinds of proton signals with a sig-
nal downfield (δ 9.09 ppm) which were identified as enaminone proton
along with a multiplet (δ = 7.50–6.68) for the aromatic protons (9H),
1
and a signal at δ 1.73 ppm were identified as methyl protons. The H
decoupled 13C NMR spectrum of 3a was measured in DMSO and it is
in accord with the proposed structure.
β-Diketones and β-ketoesters exhibit keto-enol tautomerism. It can
exist in two enolic forms. Hence, there is a possibility for the formation
of two isomers, but 3a is only obtained as revealed by mass spectrum
which contain PhCO+ ion at 105 as a base peak, and this is enough

Bensothiazines in Aqueous Media
17
evidence that the propose structure is 3a. In addition, this compound
did not give a positive iodoform test (Scheme 3).
SCHEME 3
EXPERIMENTAL
General Procedures
2-Aminobenzenethiol, 1,3-dicarbonyls, and hydrogen peroxide were ob-
tained from Merck Chemical Company and were used without further
purification. Melting points were measured on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were measured on a
1
Mattson 1000 FT-IR spectrometer. The H and 13C NMR spectra were
recorded with a BRUKER DRX-500 AVANCE spectrometer at 500.1 and
125.7 MHz, respectively. Mass spectra were recorded on a MS-QP2000A
Shimadzu mass spectrometer operating at an ionization potential of 70
eV. Elemental analyses were performed by using a Heracus CHN-O-
Rapid analyzer.
(3-Methyl-4H-1,4-benzothiazin-2-yl)(phenyl)methanone (3a)
The procedure for the preparation of 1-(3-methyl-4H-
benzo[b][1,4]thiazine-2-yl)ethanone 3a is described as an example. To
a magnetically stirred solution of 1.00 g acetylacetone (2 mmol), 0.25 g
2-aminobenzenethiol (2 mmol) and 0.12 g NaOH in 10 mL water were
mixed; then 5 mL hydrogen peroxide (30%) at 0◦C was added to the
reaction mixture for a period of 2 min. The reaction mixture was then
allowed to warm up to room temperature and stirred for 10 min. The
solid product was collected and recrystallized from ethanol.
1
Red crystals, m.p. 182–184◦C. IR (KBr): 3255, 1640,1590 cm−1. H
NMR (DMSO-d6): δ 9.09 (1H, s, NH), 7.50–6.68 (9H, m, arm), 1.73 (3H, s,
CH3). 13C NMR (DMSO-d6): 188.97 (C O), 154.13 (C3), 140.86, 138.69,
131.02, 128.41, 127.86, 127.06, 126.07, 124.73, 120.31, 115.07, 97.33
(C2), 21.03 (CH3). MS m/z (relative intensity) 267 (M+, 25), 162 (18),

18
H. Sheibani et al.
105 (100), 77 (60), 51 (15). Anal. Calcd. For C16H113NOS: C, 71.88; H,
4.90; N, 5.24%. Found: C, 71.70; H. 4.92; N; 4.96%.
1-(3-Methel-4H-1,4-benzothiazin-2-yl)-1-ethenone (3b)
Red crystal, m.p. 173–176◦C. IR (KBr) (νmax/cm−1): 3280, 1617,
1592.1H NMR (500 MHz, DMSO-d6): 8.85 (1H, s, NH), 6.91–6.63 (4H,
m, arm), 2.22 (3H, s, CH3), 2.18 (3H, s, CH3).13C NMR (DMSO −d6):
190.68 (C O), 153.41 (C3), 139.36 (C), 127.44, 126.36, 124.99 (3CH),
120.49 (C), 115.43 (CH), 98.15(C2), 30.24, 21.41 (2CH3). MS m/z (rel-
ative intensity) 205 (M+, 90), 162 (100), 130 (55), 118 (40), 109 (35),
77(18), 65 (20), 43 (32). Anal. Calcd. for C11H11NOS: C, 64.36; H, 5.40;
N, 6.82%. Found: C, 64..39; H. 5.33; N; 6.81%.
2,3-Dihydro-1H-phenothiazin-4(10H)-one (3c)
Dark yellow crystals. IR (KBr): 3280, 1592, 1567 cm−1 1H NMR
.
(DMSO-d6): δ 8.89 (1H, s, NH), 7.08–6.40 (4H, m, arm), 2.31 (2H, t,3JHH
= 5.93 Hz, CH2), 2.3 (2H, t, 3JHH = 6.34 Hz, CH2), 1.80 (2H, m, CH2).13C
NMR (DMSO-d6): 188.91 (C O), 155.90 (C3), 136.59, 126.75, 126.32,
124.39, 119.87, 115.56 (arm), 97.83 (C2), 36.08, 27.92, 20.06 (3CH2).
MS, m/z (%): 217 (100 parent and base peak), 162 (82), 118 (11), 94 (15),
80 (10), 69 (10), 45 (9).
2,2-Dimethyl-2,3,10,10a-tetrahydro-1H-phenothiazin-4(4aH)-
one (3d)
Orange crystals. IR (KBr): 3255, 1617, 1592 cm−1.1H NMR (DMSO-
d6): δ 8.83 (1H, s, NH), 6.84–6.51 (4H, m, arm), 2.18 (2H, s, CH2), 2.13
(2H, s, CH2), 0.97 (6H, s, 2CH3). 13C NMR (DMSO-d6): δ 188.64 (C 0),
153.98 (C3), 136.61, 126.90, 126.47, 124.60, 119.84, 115.67 (arm), 96.59
(C2), 49.75 (CH2), 41.21 (C), 31.51(CH2), 27.61 (2CH3). MS, m/z (%):245
(86, M+),186 (95), 160 (100), 118 (27), 83 (71), 39 (68) . Anal. Calcd. for
C14H15NOS: C, 68.54; H, 6.16; N, 5.71%. Found: C, 68.20; H, 6.06; N,
5.61%.
Indeno[2,1-b][1,4]benzothiazin-11(5H)-one (3e)
Black crystals. IR (KBr): 3230, 3056, 1666, 1617, 1592 cm−1.1H NMR
(DMSO-d6): 10.8 (1H, s, NH), 7.5–6.86 (8H, m, arm).13C NMR (DMSO-
d6): 184.83 (C O), 156.06 (C3), 135.70, 135.51, 133.75, 130.58, 130.08,
127.61, 125.73, 119.14, 118.16, 118.11, 117.88 (arm), 92.29 (C2). MS, m/z
(%):251 (81, M+), 219 (89), 146 (40), 121 (100), 69 (28), 45 (47). Anal.
Calcd. for C15H9NOS: C, 71.69; H, 3.61; N, 5.57%. Found: C, 71.40; H,
3.50; N, 5.34%.

Bensothiazines in Aqueous Media
19
Ethyl 3-Methyl-4H-1,4-benzothiazine-2-carboxylate (3g)
Yellow crystals. IR(KBr): 3329, 1641, 1592 cm−1.1HNMR (DMSO-d6):
3
δ 8.63 (1H, s, NH), 6.90–6.57 (4H, m, arm), 4.03 (2H, q, JHH 6.75 HZ,
3
CH2), 2.18 (3H, s, CH3), 1.17 (3H, t, JHH 6.78 HZ, CH3). 13C NMR
(DMSO-d6): 163.04(C O), 152.9 (C3), 139.20 (C), 127.01, 125.71, 124.15
(3CH), 119.58 (C), 114.72 (CH), 86.00 (C2), 59.61 (CH2), 19.73 (CH3),
14.21 (CH3). MS m/z (relative intensity) 235 (M+, 100), 207 (20), 162
(98), 130 (25), 118 (24), 109 (23), 77 (14), 65 (15), 45 (15). Anal. Calcd.
for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95%. Found: C, 60.95; H. 5.46;
N; 5.92%.
Benzyl 3-Methyl-4H-1,4-benzothiazine-2-carboxylate (3h)
Yellow crystals. IR (KBr): 3255, 1691, 1617 cm−1. 1H NMR (DMSO-
d6): δ 8.74 (1H, s, NH), 7.37–6.61 (9H, m, arm), 5.10 (2H, s, CH2), 2.21
(3H, s, CH3). 13C NMR (DMSO-d6): 163.73 (C O), 154.58 (C3), 139.93,
137.50, 129.30, 128.70, 128.54, 128.02, 126.71, 125.25, 120.46, 115.79
(arm), 86.33 (C2), 66.06 (CH2), 20.81 (CH3). MS m/z (relative intensity)
297 (M+, 83), 188 (40), 171 (75), 162 (100), 136 (55), 109 (95), 91(93), 65
(82), 39 (78). Anal. Calcd. for C17H15NO2S: C, 68.66; H, 5.08; N, 4.71%.
Found: C, 68.39; H, 5.06; N, 4.69%.
2-[(2-Aminophenyl)sulfanyl]-1,3-diphenyl-1,3-propanedione
(4)
White crystals. IR (KBr): 3329, 3056, 1691, 1666, cm−1.1H NMR
(DMSO-d6): δ 9.98 ( 1H, s, OH, enol form, major tautomer), 7.96–
7.21 (14H, m, arm), 4.55 (1H, s, CH, keto form, minor tautomer),
3.41(2H, s, NH2, minor tautomer) 3.38 (2H, s, NH2, major tautomer).
13C NMR (DMSO-d6): 194.77 (C O), 165.14, 165.05, 137.66, 135.17,
134.19, 133.65, 131.96, 131.83, 128.75, 128.60, 128.55, 127.76, 127.41,
126.12, 125.21,125.06 (arm). MS, m/z(%): 347 (8), 225 (13), 196 (11), 105
(100, base peak), 91 (10),77 (62), 69 (17), 43 (32), 41 (13). Anal. Calcd.
for C21H17NO2S: C, 72.60; H, 4.93; N, 4.03%. Found: C, 72..39; H. 4.72;
N; 3.96%.
Methyl 3-Oxo-3,4-dihydro-2H-1,4-benzothiazin-2-carboxylate
(5)
1
White crystals. IR (KBr): 3205, 1741, 1691 cm−1. H NMR (DMSO-
d6): δ 10.95(1H, s, NH), 7.37–6.98 (4H, m, arm), 4.74 (1H, s, CH), 3.62
(3H, s, OCH3). 13C NMR (DMSO-d6): 168.38, 162.78 (2C O), 137.54,
128.34, 128.32, 124.15, 117.98, 117.17 (arm), 53.92 (OCH3), 44.77(C2).
MS m/z (relative intensity) 223 (M+, 51), 164 (85), 136 (100), 109 (38),

20
H. Sheibani et al.
69 (30). Anal. Calcd. for C10H9NO3S: C, 53.80; H, 4.06; N, 6.27%. Found:
C, 53.91; H, 3.90 ; N, 6.26%.
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