An efficient ligand-free ferric chloride catalyzed synthesis of annulated 1,4-thiazine-3-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.04.005

A straight forward route for the synthesis of coumarin-, quinolone-annulated 1,4-thiazine-3-one derivatives has been achieved by using sodium sulfide as the sulfur source and ferric chloride as catalyst in a ligand-free condition. The synthetic procedure is simple, inexpensive, and affords the products in good yields. This methodology is also applicable to naphthalene and benzene systems.

Full text of DOI:10.1016/j.tetlet.2014.04.005

Tetrahedron Letters 55 (2014) 3108–3110
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient ligand-free ferric chloride catalyzed synthesis
of annulated 1,4-thiazine-3-one derivatives
⇑
K. C. Majumdar , Debankan Ghosh
Department of Chemistry, University of Kalyani, Kalyani 741235, W.B., India
a r t i c l e i n f o
a b s t r a c t
Article history:
A
straight forward route for the synthesis of coumarin-, quinolone-annulated 1,4-thiazine-3-one
Received 14 February 2014
Revised 31 March 2014
Accepted 1 April 2014
Available online 12 April 2014
derivatives has been achieved by using sodium sulfide as the sulfur source and ferric chloride as catalyst
in a ligand-free condition. The synthetic procedure is simple, inexpensive, and affords the products in
good yields. This methodology is also applicable to naphthalene and benzene systems.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C–S coupling
Ferric chloride
Sodium sulfide
1,4-Thiazine-3-one
Among the sulfur containing heterocyclic compounds 1,4-ben-
zothiazine-3-one derivatives have gained much importance due
to their occurrence in a large number of biologically active com-
pounds and natural products.1 The compounds containing 1,4-ben-
zothiazine-3-one derivatives act as potent SGLT2 inhibitors,2 Ca2+
activated potassium channel openers,3 and show anticonvulsant,4
antidiabetic,5 and antiarrhythmic activities.6
There are a few reports in the literature regarding the synthesis
of benzo[1,4]thiazine-3-one.7 But unavailability/toxicity of the
starting materials/reagents, harsh reaction conditions, or use of
large amount of catalysts/bases and costly ligands are some flaws
found in the available reaction conditions. Also most of the
available methodologies suffer from low yields of the products.
Furthermore, there is no report of construction of diversely annu-
lated 1,4-thiazine-3-one frameworks, that is, coumarin, quinolone,
and naphthalene-annulated 1,4-thiazine-3-one derivatives are yet
to be synthesized. So, construction of annulated 1,4-thiazine-3-one
derivatives by a simple, easy, and economical method is still
demanding. Coumarin- and quinolone are very much interesting
molecules as they exist in a large number of natural products
and agrochemicals.8 Moreover, a large number of compounds
derived from coumarin and quinolone are also well-known for
their profound bioactivity.9
by the results and in our quest for the synthesis of various bioac-
tive heterocycles,11 we have decided to test the efficiency of this
methodology that is, iron catalyzed C–S coupling using sodium sul-
fide as the sulfur source, for the synthesis of various annulated 1,4-
thiazine-3-one derivatives. Herein we report the results of our
observations.
We have initially chosen 5-bromo-1-ethyl-6-(methylamino)-
quinolin-2(1H)-one12 1a as a starting material. The compound 1a
was treated with chloroacetyl chloride (2 equiv), potassium car-
bonate (1.5 equiv), and TBAHS (0.1 equiv) in 2:1 (v/v) DCM: H2O
at room temperature for 5 h to access the required precursor
N-(5-bromo-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-chloro-N-
methylacetamide 2a. The other precursors (2b–l) were also
prepared by the aforesaid method from the respective starting
materials (Scheme 1).
When the precursor 2a was treated with 3 equiv of sodium sul-
fide and 10 mol % ferric chloride as catalyst in DMF at 120 °C for
8 h10 full consumption of 2a was observed with the formation of
a new product (Scheme 2).
The product was isolated in 70% yield and was characterized as
7-ethyl-4-methyl-2H-[1,4]thiazino[2,3-f]quinoline-3,8(4H,7H)-
dione 3a from its elemental and spectral data. The reaction
condition was then optimized to obtain better yield of the desired
product (Table 1).
Recently, our group reported an effective route for the forma-
tion of annulated-thiazole derivatives via iron-mediated C–S cross
coupling followed by acid-promoted condensation.10 Encouraged
From the optimization of the reaction condition it was evident
that the decrease in the concentration of Na2S in the reaction from
3 equiv to 2 equiv increases the yield of 3a (entry 2), but further
reduction of Na2S to 1 equiv lowers the yield (entry 5).
Furthermore, when the reaction time is reduced to 6 h, the yield
⇑
Corresponding author. Tel.: +91 33 25828750; fax: +91 33 25828282.
E-mail address: kcmklyuniv@gmail.com (K.C. Majumdar).
http://dx.doi.org/10.1016/j.tetlet.2014.04.005
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

K. C. Majumdar, D. Ghosh / Tetrahedron Letters 55 (2014) 3108–3110
3109
in DMF at 120 °C for 6 h afforded the optimum yield of 3a (87%).
Encouraged by the result, the other precursors 2b–l were also
treated similarly to give the desired annulated 1,4-thiazine-3-one
derivatives 3b–l in good to excellent yields (75–90%). The synthe-
sized substrates 2a–l and the products 3a–l are listed in Table 2.
The formation of the products 3 can be explained as shown in
Scheme 3. The precursors 2 may participate in the reaction in
two possible ways. In path-A, precursor 2 in the presence of
Cl
Br
H
N
Br
O
O
R
(i)
X
N
O
X
R
2a: X = NEt; R = Me
2b: X = NEt; R = Et
1a: X = NEt; R = Me
1b: X = NEt; R = Et
2c:
1c:
X = NEt; R = Bn
X = NEt; R = Bn
2d: X = NMe; R = Et
1d: X = NMe; R = Et
2e:
1e:
X = O; R = Me
X = O; R = Me
2f: X = O; R = Et
2g: X = O; R = Pr
1f: X = O; R = Et
1g: X = O; R = Pr
2h:
1h:
X = O; R = Bn
X = O; R = Bn
Cl
I
I
H
N
O
Me
(i)
(i)
Table 2
Synthesized products
N
Me
1i
2i
Entry
Precursors
Products
Yield
87
R1
I
R1
I
Cl
Cl
S
S
R2
N
H
Br
Br
O
N
Et
O
N
O
O
N
Et
O
O
N
R2
2j-l
1j-l
1
N
Me
1
1j:
1k:
R
= H; R2 = Me
2j: R1 = H; R2 = Me
2k: R1 = Cl; R2 = Me
2l: R1 = Cl; R2 = Bn
3a
Me
R
1 = Cl; R2 = Me
1l: R1 = Cl; R2 = Bn
2a
Cl
O
N
Et
O
O
O
O
O
O
N
Et
Scheme 1. Synthesis of the precursors. Reaction condition: (i) chloroacetyl chloride
(2 equiv), TBAHS (0.1 equiv), K2CO3 (1.5 equiv) in DCM/H2O (2:1); room temper-
ature, 4–6 h.
N
N
2
3
88
80
82
77
89
80
85
75
82
86
90
N
Et
3b
3c
3d
3e
Et
Cl
2b
2c
S
S
S
S
Br
Br
Br
Br
Br
Br
O
N
Et
O
N
Et
O
O
O
O
Cl
Bn
Et
N
Br
S
Bn
O
O
O
O
Na2S.xH2O (3 eqiv),
FeCl3 (10 mol%)
DMF, 120 oC, 8h
Cl
N
N
N
N
Me
O
Et
Me
Et
3a
2a
O
N
N
4
N
N
Me
Me
Et
Cl
Scheme 2. Synthetic route for the formation of product 3a from precursor 2a.
2d
2e
O
O
N
Me
O
O
5
Table 1
O
O
N
Me
Optimization of the reaction condition
Cl
Br
Cl
S
O
O
O
O
O
O
N
Na2S.xH2O , FeCl3 (10 mol%)
DMF, 120 o
6
N
N
N
N
Me
Et
Pr
N
C
3f
3g
3h
Et
Me
Et
Et
Cl
3a
2a
2f
2g
2h
S
S
Entry
Catalyst (mol %)
Equiv of Na2S
Time (in hour)
Yielda
O
O
O
O
O
O
O
O
N
7
1
2
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (05)
FeCl3 (20)
FeCl3 (10)
FeCl3 (10)
3
2
2
2
1
2
2
2
2
8
8
6
4
6
6
6
6
6
70
78
87
52
47
64
86
30
72
O
O
N
Pr
Cl
3b
4
O
O
5
6
7
N
8
N
Bn
Bn
8c
9d
Cl
S
I
O
a
b
c
Isolated yield.
O
N
Me
9
Optimized reaction condition.
Reaction was carried out at 100 °C.
Reaction was carried out at 140 °C.
N
Me
3i
2i
d
Cl
S
I
O
O
N
10
11
12
N
Me
3j
Me
2j
of 3a increases to 87% (entry 3). However further decrease in the
reaction time lowers the yield of 3a, probably due to the incom-
plete conversion of 2a to 3a (entry 4). Decrease in the amount of
catalyst decreases the yield whereas increasing the amount of cat-
alyst does not show any change in the yield of 3a (entry 6, 7,
respectively). Decrease of reaction temperature (100 °C) dramati-
cally reduces the yield to 30% whereas increase in reaction temper-
ature (140 °C) leads to the reduced yield (72%) perhaps due to
decomposition of the product. So from the above table we observe
that 2 equiv of sodium sulfide, 10 mol % ferric chloride as catalyst
Cl
S
I
O
O
O
O
Cl
N
Me
Cl
Cl
N
N
3k
Me
Cl
2k
S
I
Cl
N
Bn
3l
Bn
2l

3110
K. C. Majumdar, D. Ghosh / Tetrahedron Letters 55 (2014) 3108–3110
)
I
I
I
(
Cl
Cl
SNa
e
F
O
R
FeCl3
O
R
SNa
X
X
Cl
N
N
R
N
Na2S.xH2O
+
O
Path A
Iron-catalyzed
intermolecular
C-S coupling
2
A
B
Intermolecular
substitution
reaction
Intramolecular
substitution
reaction
Path B
)
I
I
I
(
e
F
SNa
FeCl3
O
SNa
S
X
O
O
R
X
N
R
N
N
R
Iron-catalyzed
intramolecular
C-S coupling
C
D
3
Scheme 3. Plausible mechanistic route.
sodium sulfide as the sulfur source and iron(III) chloride as the cat-
alyst, may undergo iron-mediated intermolecular C–S coupling
similar to Cu-catalyzed
Supplementary data
r
-bond metathesis13 reaction to form the
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.
005.
intermediate B via transition state A, which in turn may undergo
intramolecular cyclization to produce the cyclized product 3. We
have earlier demonstrated the possibility of formation of B type
intermediate in the iron-catalyzed C–S coupling step by the inter-
mediate trapping method.10 However, the occurrence of other
pathway (path-B) cannot be ruled out. In path-B intermolecular
substitution reaction may take place in between sodium sulfide
and the terminal chlorine atom present in the precursors 2 to give
intermediate C, which may undergo iron-mediated intramolecular
C–S coupling14,15 to give the cyclized products 3 via transition state
D. Here both the pathways can afford the same products 3. How-
ever, further work is necessary to establish the mechanism of the
reaction.
References and notes
1. (a) Zhang, L. L.; Yan, Y.; Liu, Z.; Abliz, Z.; Liu, Z. J. Med. Chem. 2009, 52, 4419; (b)
Borate, H. B.; Maujan, S. R.; Sawargave, S. P.; Chandavarkar, M. A.; Vaiude, S. R.;
Kelkar, R. G.; Chavan, S. P.; Kunte, S. S. Bioorg. Med. Chem. Lett. 2010, 20, 722; (c)
Gowda, J.; Khader, A.; Shree, P.; Shabaraya, A. B.; Kalluraya, B. Eur. J. Med. Chem.
2011, 46, 4100.
2. Li, A.-R.; Zhang, J.; Greenberg, J.; Lee, T.; Liu, J. Bioorg. Med. Chem. Lett. 2011, 21,
2472.
3. Calderone, V.; Spogli, R.; Martelli, A.; Manfroni, G.; Testai, L.; Sabatini, S.;
Tabarrini, O.; Cecchetti, V. J. Med. Chem. 2008, 51, 5085.
4. Zhang, L.-Q.; Guan, L.-P.; Wei, C.-X.; Deng, X.-Q.; Quan, Z.-S. Chem. Pharm. Bull.
2010, 58, 326.
In summary, we have developed a versatile, easy, clean, and
economical route for the formation of diversely annulated 1,4-thi-
azine-3-one derivatives. A number of substituted 2-chloro-N-
methylacetamide derivatives 2a–h were successfully reacted to
generate quinolone and coumarin-annulated 1,4-thiazine-3-one
derivatives 3a–h in 75–90% yields. Moreover, this methodology is
also applicable to naphthalene and benzene systems. The precursor
2i under the same reaction condition leads to the formation of the
corresponding naphthalene-annulated 1,4-thiazine-3-one deriva-
tive 3i and the precursors 2j–l afford 1,4-benzothiazine-3-one
derivatives 3j–l in good yields. This demonstrates the versatility
of the methodology. This method utilizes inexpensive and easy to
handle sodium sulfide as the sulfur source instead of the use of
expensive and toxic organo-sulfur reagents. Furthermore, no
ligands are required in this method which makes this method more
attractive to the synthetic organic chemists.
5. Kawashima, Y.; Ota, A.; Mibu, H. WO Patent 9405647, 1993.
6. Fujita, M.; Ito, S.; Ota, A.; Kato, N.; Yamamoto, K.; Kawashima, Y.; Yamauchi, H.;
Iwao, J. Eur. J. Med. Chem. 1990, 33, 1898.
7. (a) Huang, W.-S.; Xu, R.; Dodd, R.; Shakespeare, W. C. Tetrahedron Lett. 2013, 54,
5214; (b) Krapcho, J.; Szabo, A.; Williams, J. J. Med. Chem. 1963, 6, 214; (c) Chen,
D.; Wang, Z.-J.; Bao, W. J. Org. Chem. 2010, 75, 5768; (d) Cecchetti, V.; Fravolini,
A.; Fringuelli, R.; Mascellani, G.; Pagella, P.; Palmioli, M.; Segre, G.; Terni, P. J.
Med. Chem. 1987, 30, 465; (e) Zuo, H.; Li, Z.-B.; Ren, F.-K.; Falck, J. R.; Meng, L.;
Ahn, C.; Shin, D.-S. Tetrahedron 2008, 64, 9669; (f) Zhao, Y.; Wu, Y.; Jia, J.; Zhang,
D.; Ma, C. J. Org. Chem. 2012, 77, 8501; (g) Xu, X.-B.; Liu, J.; Zhang, J.-J.; Wang,
Y.-W.; Peng, Y. Org. Lett. 2013, 15, 550.
8. Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642.
9. (a) Boyd, D. R.; Sharma, N. D.; Barr, S. A.; Carroll, J. G.; Mackerracher, D.;
Malone, J. F. J. Chem. Soc., Perkin Trans. 1 2000, 3397; (b) Lee, Y. R.; Kim, B. S.;
Kweon, H. I. Tetrahedron 2000, 56, 3867; (c) Dickinson, J. M. Nat. Prod. Rep.
1993, 10, 71; (d) Pirrung, M. C.; Blume, F. J. Org. Chem. 1999, 64, 3642; (e) Bar,
G.; Parsons, A. F.; Thomas, C. B. Tetrahedron 2001, 57, 4719.
10. Majumdar, K. C.; Ghosh, D. Tetrahedron Lett. 2013, 54, 4422.
11. For some of our recent synthesis of heterocycles, see: (a) Majumdar, K. C.;
Mondal, S.; Ghosh, D. Synthesis 2010, 7, 1176; (b) Majumdar, K. C.; Mondal, S.;
Ghosh, D.; Chattopadhyay, B. Synthesis 2010, 8, 1315; (c) Majumdar, K. C.;
Ponra, S.; Ghosh, D.; Taher, A. Synlett 2011, 104; (d) Majumdar, K. C.; Mondal,
S.; Ghosh, D. Tetrahedron Lett. 2009, 50, 4781; (e) Majumdar, K. C.; Ghosh, D.;
Mondal, S. Synthesis 2011, 4, 599; (f) Majumdar, K. C.; Ghosh, D.; Ponra, S.
Synthesis 2013, 45, 2983; (g) Majumdar, K. C.; Nandi, R. K.; Ponra, S. Synlett
2012, 113; (h) Majumdar, K. C.; Ganai, S.; Nandi, R. K.; Ray, K. Tetrahedron Lett.
2012, 53, 1553.
Acknowledgements
K.C.M. is thankful to UGC (New Delhi) for UGC Emeritus
Fellowship and D.G. is grateful to CSIR (New Delhi) for a senior
research fellowship. We also thank DST (New Delhi) for providing
Bruker NMR spectrometer (400 MHz) and Perkin–Elmer CHN
analyzer, UV–VIS spectrometer, and Perkin–Elmer FT-IR under
FIST program.
12. Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2008, 49, 2418.
13. Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries, J. G. Dalton Trans. 2010,
39, 10338.
14. Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880.
15. Wu, J.-R.; Lin, C.-H.; Lee, C.-F. Chem. Commun. 2009, 4450.