A synthesis of 4H-1,4-benzothiazines

Article abstract of DOI:10.3184/030823408X356323

A convenient synthesis of 4H-1, 4-benzothiazines is described. The key step is the coupling between 2-amino-5-chlorophenyl disulfide (3) and ethyl acetylenecarboxylate (4) in the presence of Cul as a catalyst or by microwave irradiation in moderate yield.

Full text of DOI:10.3184/030823408X356323

566 RESEARCH PAPER
OCTOBER, 566–567
JOURNAL OF CHEMICAL RESEARCH 2008
A synthesis of 4H-1, 4-benzothiazines
Lizhi Fu, Jinyi Xu*, Hequan Yao and Xiaoming Wu
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
A convenient synthesis of 4H-1, 4-benzothiazines is described. The key step is the coupling between 2-amino-5-
chlorophenyl disulfide (3) and ethyl acetylenecarboxylate (4) in the presence of CuI as a catalyst or by microwave
irradiation in moderate yield.
Keywords: 4H-1, 4-benzothiazines, synthesis, CuI catalysis
The 3-ethoxycarbonyl-4-quinolone 1 has been identified
as an interesting lead compound for ligand binding at the
benzodiazepine site of GABAA receptors.1 As a receptor
agonist, 1 exhibited sedative and anti-anxiety activities.
A number of high-affinity ligands for the benzodiazepine
site have been obtained through pharmacophore-guided
optimisation of this lead compound.2 Recently we modified
this lead compound to obtain bio-isosteric 4H-1, 4-benzo-
thiazines 2.
An alternative method for the coupling between 3 and 4
uses microwave irradiation to promote this coupling reaction
(Scheme 1). When the coupling reaction was performed
in sealed tube, irradiated by microwaves for only 25 min at
100°C, compound 5 was obtained in over 75% yield. Finally,
cyclisation of compound 5 in DMSO, followed by the oxidation
using m-CPBA afforded the 4H-1, 4-benzothiazines 2.
Similar examples were observed by treatment of 2-amino-
phenyl disulfide and 2-amino-5-bromophenyl disulfide with
ethyl acetylenecarboxylate in the presence of CuI as a catalyst
to give the corresponding products in yields 60% and 57%,
respectively. These products were also obtained by microwave
irradiation in yields 70% and 73%, respectively.
It has been reported3,4 that 4H-1, 4-benzothiazines can be
synthesised by reaction of 2, 2'-dithiodianiline with ethyl
acetylenecarboxylate in a sealed tube or autoclave. However,
both methods need a high reaction temperature, high pressure
and long reaction time, which limit the preparation of the
relatively large scale amounts for clinical tests. We now report
a convenient synthesis of 4H-1, 4-benzothiazines.
Conclusions
We describe here a convenient synthesis of 4H-1, 4-benzo-
thiazines. The key step is the efficient coupling between
2-amino-5-chlorophenyl disulfide and ethyl acetylene-
carboxylate catalysed by CuI or promoted by microwave
irradiation. Microwave irradiation can more efficiently
shorten the coupling reaction time from a few hours to half
an hour, dramatically reduce the side products and improve
the preparative efficiency. The methods reported here can be
applied for the preparation of 4H-1, 4-benzothiazines and
their derivatives. This facilitate the synthesis of a series of
derivatives of compound 2 for further biological experiments.7
O
O
NH
O
O
NH
S
O
O
CF3
Cl
2
1
Results and discussion
Recently, a large number of heterocyclic compounds have
been synthesised via cyclisation of alkene, alkyne and enyne,
catalysed by transition metal such as palladium, rhodium,
cobalt or nickel. Copper(1) iodide is the most used metal
catalyst due to its cheap and high efficiency, exemplified by
the efficient cyclisation reaction of an alkynyl and amino
group.5 Encouraged by this result, we tried CuI as a catalyst
(Scheme 1) for the coupling reaction between 2-amino-5-
chlorophenyl disulfide (3) and ethyl acetylenecarboxylate (4).
After optimisation of the reaction conditions, we found that
the coupling reaction could be catalysed by 5% of CuI in over
62% yield to give compound 5.
Experimental
All melting points were determined on a XT-4 melting point apparatus
and were uncorrected. Mass spectra were performed on a Finnigan
FTMS-2000 mass instrument. 1H NMR spectra were performed on a
AM-300 Bruker NMR spectrometer with TMS as internal standard.
IR spectra were performed on a Nicolet Impact 410 instrument and
recorded as KBr discs. TLC was carried out using silica GF254
.
Column chromatography was carried out using silica gel (100-200
mesh). Elemental analysis was performed on a Elementar Vario EL
III instrument. All reagents and solvents are commercially available.
Cl
S
COOC2H5
Cl
SH COOC2H5
+ 2
CuI
or MW, EtOH
DMSO
NH2
2
N
H
5
3
4
O
S
Cl
COOC2H5
Cl
S
COOC2H5
m-CPBA
EtOH
N
H
N
H
2
6
Scheme 1
* Correspondent. E-mail: jinyixu@china.com

JOURNAL OF CHEMICAL RESEARCH 2008 567
(E)-ethyl 3- (4-chloro-2-mercaptophenylamino) acrylate (5)
Ethyl 7-chloro-4H-1, 4-benzothiazine-2-carboxylate-1-oxide (2):4
To a solution of 6 (1.2 g, 4.7 mmol) in absolute ethanol (60 ml), a
solution of m-CPBA (1.64 g, 5.2 mmol) in absolute ethanol (15 ml)
was added dropwise at room temperature. After stirring for 1 h, the
reation mixture was diluted with H2O (80 ml), extracted with EtOAc.
The organic layer was washed with saturated NaHSO3, saturated
NaHCO3 and brine, dried over anhydrous Na2SO4. After filtration and
concentration, the result residue was crystallised in ethanol to get the
title compound 2 (0.76 g, 60%) as a yellow solid. M.p. 157–159°C;
1H NMR (500 MHz, CDCl3) δ: 11.84 (s, 1 H), 8.10 (d, J = 6.5 Hz,
1 H), 7.91(d, J = 2.3 Hz, 1 H), 7.72 (dd, J = 6.5 Hz, J = 2.3 Hz, 1 H),
7.46 (d, J = 8.9 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 1.27 (t, J = 7.1 Hz,
3 H); IR (KBr), ν/cm-1: 3453, 3264, 2990, 1678, 1619, 1529, 1478,
1248, 829; EIMS (75eV), m/z (%): 271 (M +, 100). Elemental anal.
Calcd for C11H10ClNO3S: C, 48. 62; H, 3.71; N, 5.15; found: C, 48.
85; H, 3.56; N, 4.91%.
Method 1: A solution of 2-amino-5-chlorophenyl disulfide 3 (316 mg,
1 mmol) and ethyl acetylenecarboxylate 4 (196 mg, 2 mmol) in
ethanol (10 ml) was refluxed with a catalytic amount of CuI (5%) for
8 hours. After cooling to room temperature, the reaction mixture was
filtered, concentrated and the residue was purified by chromatography
(petroleum ether: EtOAc = 15:1) on silica gel to give the title ester
5 (320 mg, 62.3%) as a yellow solid. M.p. 102–104°C; 1H NMR
(300 MHz, CDCl3) δ: 7.38 (d, J = 2.4 Hz, 1 H), 7.15 (dd, J = 8.6 Hz,
J = 2.4 Hz, 1 H), 6.92 (d, J = 10.0 Hz, 1 H), 6.71 (d, J = 8.6 Hz,
1 H), 5.95 (d, J = 10.0 Hz, 1 H), 4.30 (s, 1 H), 4.26 (q, J = 7.1 Hz,
2 H), 1.30 (t, J = 7.1 Hz, 3 H); EIMS (75eV), m/z (%): 257 (M +,
100). Elemental anal. Calcd for C11H12ClNO2S: C, 51.26; H, 4.69; N,
5.43; found: C, 51.52; H, 4.54; N, 5.62%.
Method 2: Microwave irradiation
2-Amino-5-chlorophenyl disulfide 3 (100 mg, 0.3 mmol), ethyl
acetylenecarboxylate 4 (60 mg, 0.6 mmol) was dissolved in ethanol
(2 ml) in a sealed tube (CEM designed 10-ml pressurerated reaction
vial). The reaction mixture was exposed to microwave irradiation
at 100°C for 25 min. After cooling to room temperature, the
reaction mixture was concentrated and the residue was purified by
chromatography (petroleum ether: EtOAc = 15:1) on silica gel to
yield ester 5 (120 mg, 75.5%) as a yellow solid. M.p. 102–104°C.
Ethyl7-chloro-4H-1,4-benzothiazine-2-carboxylate(6):6Asolution
of 5 (1.3 g, 5 mmol) in dimethyl sulfoxide (20 ml) was heated
to 140°C for 1.5 h. The reaction mixture was cooled to room
temperature, poured in water and extracted with chloroform. The
organic layer was washed with water, dried over anhydrous Na2SO4.
After filtration and concentration, the result residue was purified
by chromatography (petroleum ether: EtOAc = 10:1) on silica gel
to afford 6 (0.91 g, 70.6%) as a pale red solid. M.p. 180–182°C;
1H NMR (500 MHz, CDCl3) δ: 8.76 (d, J = 6.6 Hz, 1 H), 7.01(d,
J = 6.5 Hz, 1 H), 6.89 (dd, J = 6.5 Hz, J = 2.3 Hz, 1 H), 6.79 (d,
J = 2.3 Hz, 1 H), 6.43 (d, J = 8.4 Hz, 1 H), 4.07 (q, J = 7.1 Hz,
2 H), 1.18 (t, J = 7.1 Hz, 3 H); EIMS (75eV), m/z (%): 255 (M+, 100).
Elemental anal. Calcd for C11H10ClNO2S: C, 51.66; H, 3.94; N, 5.48;
found: C, 51.38; H, 4.12; N, 5.23%.
Received 8 June 2008; accepted 11 August 2008
Paper 08/5317 doi: 10.3184/030823408X356323
Published online: 8 October 2008
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