Regio-controlled synthesis of 1, 4-benzothiazinones

Article abstract of DOI:10.3987/COM-10-12096

Regio-controlled cyclization of gem-dicyanoepoxides with 2-aminothiophenol and its hydrochloride to form 1,4-benzothiazine-2-one or 3-one is described. The cyclization is highly regioselective and the reaction of the epoxides with 2-aminothiophenol under neutral reaction condition gave 1,4-benzothiazine-2-one as a sole cyclized product, whereas that with hydrochloride of 2-aminothiophenol afforded 1,4-benzothiazine-3-one predominantly. The regioselectivity resulted from the reaction condition is discussed. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12096

HETEROCYCLES, Vol. 83, No. 2, 2011
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HETEROCYCLES, Vol. 83, No. 2, 2011, pp. 357 - 363. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd November, 2010, Accepted, 20th December, 2010, Published online, 13th January, 2011
DOI: 10.3987/COM-10-12096
REGIO-CONTROLLED SYNTHESIS OF 1, 4-BENZOTHIAZINONES
Touria Ghailane,1 Mohammed Saadouni,1 Said Boukhris,1 Nouzha Habbadi,1
Amina Hassikou,1 Abdelali Kerbal,2 Bernard Garrigues,3 and Abdelaziz
Souizi1*
1Laboratoire de Synthèse Organique, Organométallique et Théorique, Faculté des
Sciences, Université Ibn Tofail, B.P. 133-Kénitra, Maroc
2 Laboratoire de Chimie Organique, Faculté des Sciences Dhar El Mehraz, 30000
Fès, Maroc
3 Laboratoire d’Hétérochimie Fondamentale et Appliquée, 118 route de Narbonne,
Université Paul Sabatier, Toulouse, France
* Author to whom correspondence should be addressed; E-mail:
Souizi@yahoo.com; Tel. + 00 212 6 61 18 32 60; Fax 00 212 5 37 32 94 33
Abstract – Regio-controlled cyclization of gem-dicyanoepoxides with
2-aminothiophenol and its hydrochloride to form 1,4-benzothiazine-2-one or
3-one is described. The cyclization is highly regioselective and the reaction of the
epoxides with 2-aminothiophenol under neutral reaction condition gave
1,4-benzothiazine-2-one as a sole cyclized product, whereas that with
hydrochloride of 2-aminothiophenol afforded 1,4-benzothiazine-3-one
predominantly. The regioselectivity resulted from the reaction condition is
discussed.
The biological and pharmacological properties of the 1, 4-benzothiazinones were largely studied,1
particularly, antifungal activity2-5 as well as a powerful antimicrobial activity.6,7
In addition the 1,4-benzothazinones derivatives, which are always of topicality,8-10 are known for their
potential antihypertensive activity,11 a vasorelaxant activity,12 inhibiting angiogenesis,13 anti-Candida,14
and antimycobacterial agents.15
The potential bielectrophile character of two carbons of the epoxide ring,16a-h makes it possible to
consider the study of their reactivity to reach new heterocycles on the one hand or with heterocycles

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HETEROCYCLES, Vol. 83, No. 2, 2011
already described but obtained by more complex and/or less selective ways of other part.17-25 Within this
framework there, the reaction with the 2-aminothiophénol 2 was studied, under moderated conditions to
reach 1,4-benzothiazinones.
Thus, the direct reaction of epoxides 1 with 2-aminothiophenol 2 performed at reflux in acetonitrile, led
in one step to the 2-arylbenzothiazin-3-ones 3 with good yields (Scheme 1, Table).
Ar
Ar
HO
S
H
MeCN
HS
O
+
H2N
reflux, 22 h
H2N
NC
CN
NC
CN
[A]
1
2
S
Ar
-HCN
-HCN
Ar
S
H2N
CN
N
H
O
O
3
[B]
Scheme 1. Synthesis of the 1,4-benzothiazines-3-ones 3
The reaction is regioselective and the 2-aryl-1,4-benzothiazin-3-ones were obtained with excellent yields.
We propose a mechanism (Scheme 1) with passage by a cyanhydrin aminothioether [A], resulting from
the nucleophilic attack of sulfur on the carbon related to the aryl group of epoxide. This intermediate [A]
then lead to a second cyanoformyl intermediate [B] by losing a molecule of hydrogen cyanide.
The latter can then by a second intramolecular nucleophilic attack of nitrogen of the amine function on
carbonyl lead to the cyclization and the formation of the 2-aryl-1,4-benzothiazin-3-ones 3. Furthermore
we do not observe the formation of 3-aryl-1,4-benzothiazin-2-ones which could be obtained by the
nucleophilic attack of sulfur on the other carbon of epoxide. The strong nucleophilicity of sulfur
compared with nitrogen of the amine function explains the selectivity of the nucleophilic attack on
epoxide.
In addition, one also observes selectivity on the level of the electrophilic carbons of epoxide. In effect,
carbon related to the grouping aryl is proven to be most electrophilic of the cycle. This selectivity is
remarkable because no other competing product is obtained.
All products 3a-3c were characterized by the conventional physico-chemical methods (IR, NMR and
mass spectrometry). Moreover, the compound 3a in high-resolution mass spectrometry, the MIKE (Mass
analyzed Ion Kinetic Energy) spectrum shows the presence of fragment ion of mass m/z = 136 (calcd:
136.0346; found: 136.0340) coming from the molecular ion and corresponding to: (4-MeC6H4CHS)+.

HETEROCYCLES, Vol. 83, No. 2, 2011
359
This confirms the exact position of sulfur in the ring.
The regioselectivity of the reaction can be reversed in the presence of acids HX. Indeed, the reaction of
the 2-aminothiophenol hydrochloride with epoxides 1 leads to the isomers 3-aryl-1,4-benzothiazin-2-ones
4 resulting from the opposite addition. This is due to the presence of Cl anion in the medium whose
nucleophilicity is much larger than that of sulfur.
In this context, the attack of Cl is favoured kinetically, and always takes place on the most electrophilic
site, namely the carbon related to the aryl group. This reaction therefore leads selectively to compounds 4
(Scheme 2, Table).
Ar Cl
Ar
H
HS
MeCN
H+
+
HO
NC
[C]
O
reflux, 3 h
HCl,
H2N
CN
NC
CN
2. HCl
1
Ar
O
Cl
H
N
Ar
Cl
Ar
-HCl
-HCN
+ 2
H2N
-HCN
S
4
S
O
CN
O
[D]
[E]
Scheme 2. Synthesis of the 1,4-benzothiazin-2-ones 4
Table. Synthesis of 2-aryl-1,4-benzothiazin-3-ones 3 and 3-aryl-1,4-benzothiazin-2-ones 4
Entry
Ar
Mp (°C)
Yields (%)
Compounds
1
2
3
4
5
6
4-MeC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-ClC6H4
C6H5
198-199
186-187
202-203
180-181
143-144
182-183
80
90
45
78
80
76
3a
3b
3c
4a
4b
4c
This reaction is interpreted by an electrophilic assistance of the epoxidic cycle by action of HCl, leading
to an unstable chlorocyanhydrin [C] (Scheme 2). This one easily loses a molecule of hydrogen cyanide to
give intermediate cyanoformyl [D], which reacts with the 2-aminothiophenol 2 to give α-chloroketone
aminothioether [E].

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The latter evolves through a heterocyclization reaction to give the 1,4-benzothiazin-2-ones 4 (Scheme 2).
The proximity of sulfur with the carbonyl group was confirmed by the presence of a fragment ion of mass
m/z = 136 coming from the molecular ion 4a-4c and corresponding to (C7H4OS)+.
1
13
The structures of heterocycles 4 were established and confirmed by spectroscopic data of H NMR, C
NMR and by mass spectrometry.
In conclusion, the reaction of epoxides 1 with the 2-aminothiophenol and its hydrochloride constitute a
simple, and selective method for the synthesis of a new series of 1,4-benzothiazin-2-ones and 3-ones.
These compounds are likely to present interesting biological and pharmacological properties.
EXPERIMENTAL
Melting points were taken with a KOFLER hot stage apparatus and are uncorrected. The 1H NMR spectra
were measured in DMSO-d6 or (CDCl3 + CF3CO2H) solutions on a Bruker 300 MHz spectrometer using
13
TMS as an internal reference (chemical shift in δ ppm), C NMR spectra were recorded at 75 MHz.
Infrared spectra were determined with a PERKIN ELMER 1600 Series FT-IR Spectrometer using KBr
pellets. Mass spectra were recorded on a VARIAN MAT 311 and Thermo DSQII-Focus mass
Spectrometer.
General procedure for the preparation of 1,4-benzothiazin-3-ones 3a-c
To a solution of epoxide 1 (5 mmol) in MeCN (20 mL), are added the 2-aminothiophenol 2 (5 mmol).
The mixture is refluxed for 22 h. The solvent was removed under reduced pressure and the residue
obtained is added to a mixture of Et2O/petroleum ether, the 2-arylbenzothiazin-3-ones 3a-c (Table)
precipitate slowly and are then purified by flash chromatography on alumina column eluted with acetone
to give solids which are recrystallized in EtOH.
2-(4-Methylphenyl)-1,4-benzothiazin-3-one (3a): (1.02g, 80%); mp 198-199 °C (mp 200-2002 lit.26); IR
(KBr): 3200, 1655 cm-1; 1H NMR (300 MHz, CDCl3 + CF3CO2H) δ 2.30 (s, 3H, CH3), 4.75 (s, 1H, CHS),
13
7.01-7.32 (m, 8H, Ar), 9.84 (s, 1H, NH); C NMR (75 MHz, CDCl3 + CF3CO2H) δ 21.4, 45.8, 118.3,
120.4, 125.9, 127.3, 127.7, 128.1, 130.1, 130.9, 134.7, 139.3, 170.0; HRMS calcd. for (C15H13NOS) [M+]
255.0718; found: 255.0716.
2-(4-Chlorophenyl)-1,4-benzothiazin-3-one (3b): (1.23g, 90%); mp 196-197 °C (mp 198.5-199.5 lit.26);
IR (KBr): 3220, 1660 cm-1; 1H NMR (300 MHz, CDCl3 + CF3CO2H) δ 4.71 (s, 1H, CHS), 6.93-7.34 (m,
13
8H, Ar), 10.00 (s, 1H, NH); C NMR (75 MHz, CDCl3 + CF3CO2H) δ 45.7, 118.2, 119.8, 122.4, 125.7,
126.1, 127.7, 129.2, 132.4, 133.1, 135.2, 169.8; MS m/z (%): 275 (M+, 1%), 151 (100), 96 (78), 123 (73).
2-(4-Nitrophenyl)-1,4-benzothiazin-3-one (3c): (0.64g, 45%); mp 202-203 °C; IR (KBr): 3233, 1650

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cm-1; 1H NMR (300 MHz, CDCl3 + CF3CO2H) δ 4.77 (s, 1H, CHS), 7.02-7.29 (m, 8H, Ar), 10.11 (s, 1H,
13
NH); C NMR (75 MHz, CDCl3 + CF3CO2H) δ 45.1, 118.1, 119.5, 119.9, 125.9, 127.9, 128.0, 129.09,
131.8, 133.9, 134.9, 169.6; HRMS calcd. for (C14H10N2O3S) [M+] 286.0381; found: 286.0360.
Preparative procedure for 1,4-benzothiazines-2-ones 4a-c
A suspension of 2-aminothiophenol hydrochloride 2 HCl (1.5 mmol) in MeCN (10 mL), was added
epoxide 1 (1 mmol) dissolved in MeCN (5 mL). The reaction mixture is refluxed for 3 h, after
evaporation of the solvent the crude oil is dissolved in CHCl3.
The solution is washed with the water, dried over sodium sulfate and evaporated. The residue is dissolved
in a mixture of Et2O and petroleum ether. The 3-aryl-1,4-benzothiazin-2-ones 4a-c (Table) precipitate
after one night in ice and are recrystallized in EtOH.
3-(4-Methylphenyl)-1,4-benzothiazines-2-ones (4a): (0.19g, 78%); mp 180-181 °C; IR (KBr): 3280,
1670 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.4 (s, 3H, CH3), 4.89 (s, 1H, CHN), 6.95-7.29 (m, 8H, Ar),
10.83 (s, 1H, NH); 13C NMR (75 HMz, DMSO-d6) δ 21.1, 44.8, 117.4, 118.6, 123.6, 127.6, 127.9, 128.1,
129.5, 133.6, 137.5, 137.6, 166.1; MS m/z (%): 255 (M+, 31), 105 (100), 136 (58), 226 (19).
3-(4-Chlorophenyl)-1,4-benzothiazines-2-ones (4b): (0.22g, 80%); mp 143-144 °C; IR (KBr): 3211,
1669 cm-1. 1H NMR (300 MHz, CDCl3 + CF3CO2H) δ 4.68 (s, 1H, CHN), 6.88-7.56 (m, 8H, Ar), 9.27 (s,
1H, NH); 13C NMR (75 HMz, CDCl3 + CF3CO2H) δ 45.6, 117.3, 119.9, 122.2, 125.8, 127.1, 127.8, 129.1,
131.4, 132.2, 135.7, 166.4; MS m/z (%): 275 (M+, 20), 125 (100), 136 (55), 89 (44).
3-Phenyl-1,4-benzothiazines-2-ones (4c): (0.18g, 76%); mp 182-183 °C; IR (KBr): 3122, 1674 cm-1; 1H
13
NMR (300 MHz, DMSO-d6) δ 4.95 (s, 1H, CHN), 6.94-7.31 (m, 9H, Ar), 10.86 (s, 1H, NH); C NMR
(75 MHz, DMSO-d6) δ 45.1, 117.4, 118.6, 132.6, 127.6, 127.9, 128.2, 128.3, 129.0, 136.6, 137.4, 166.0;
MS m/z (%): 242 (M+, 15), 91 (68), 136 (52), 212 (23), 241 (100).
REFERENCES (AND NOTES)
1. R. R. Gupta and K. G. Ojha, In Phenothiazines and 1,4-Benzothiazines: Chemical and Biochemical
Aspects; ed. by R. R. Gupta; Elsevier: Amsterdam, 1988, pp. 163-269.
2. R. Fringuelli, F. Schiafella, F. Bistoni, L. Pitzurra, and A. Vecchiarelli, Bioorg. Med. Chem., 1998, 6,
103.
3. R. Fringuelli, F. Schiafella, and A. Vecchiarelli, J. Chemother., 2001, 13, 9.
4. A. Macchiarulo, G. Costantino, D. Fringuelli, A.Vecchiarelli, F. Schiafella, and R. Fringuelli, Bioorg.
Med. Chem., 2002, 10, 3415.
5. G. Grandolini, V. Ambrogi, L. Baiocchi, M. Giannangeli, A. Furlani, A. Papaioannou, L. V. Perioli,
and V. Scarcia, Heterocycl. Commun., 1995, 1, 265.

362
HETEROCYCLES, Vol. 83, No. 2, 2011
6. L. Milanese, N. Giacche, F. Schiaffella, A. Vecchiarelli, A. Macchiarulo, and R. Fringuelli, Chem.
Med. Chem., 2007, 2, 1208.
7. V. Molteni, X. He, J. Nabakka, K. Yang, A. Kreusch, P. Gordon, B. Bursulaya, I. Warner, T. Shin, T.
Biorac, N. S. Ryder, R. Goldberg, J. Doughty, and Y. He, Bioorg. Med. Chem. Lett., 2004, 14, 1477.
8. L. V. Saloutina, A. Ya. Zapevalov, V. I. Saloutin, P. A. Slepukhin, M. I. Kodess, V. E. Kirichenko,
M. G. Pervova, and O. N. Chupakhin, J. Fluorine Chem., 2007, 128, 769.
9. K. G. Nazarenko, N. A. Shtil, M. O. Lozinskiia, and A. A. Tolmachev, Tetrahedron, 2007, 63, 7727.
10. K. G. Nazarenko, N. A. Shtil, S. A. Buth, A. N. Chernega, M. O. Lozinskii, and A. A. Tolmachev,
Tetrahedron, 2008, 64, 4478.
11. V. Cecchetti, F. Schiaffella, O. Tabarrini, and A. Fravolini, Bioorg. Med. Chem. Lett., 2000, 10, 465.
12. V. Calderone, R. Spogli, A. Martelli, G. Manfroni, L. Testai, S. Sabatini, O. Tabarrini, and V.
Cecchetti, J. Med. Chem., 2008, 51, 5085.
13. T. Honda, H. Tajima, K. Fujisawa, M. Murai, H. Aono, and M. Ban, PCT Int. Appl., WO
2008053863 A1 20080508, 2008.
14. H. B. Borate, S. R. Maujan, S. P. Sawargave, M. A. Chandavarkar, S. R. Vaiude, V. A. Joshi, R. D.
Wakharkar, R. Iyer, R. G. Kelkar, S. P. Chavan, and S. S. Kunte, Bioorg. Med. Chem. Lett., 2010, 20,
722.
15. V. Makarov, G. Manina, K. Mikusova, U. Möllmann, O. Ryabova, B. Saint-Joanis, N. Dhar, M. R.
Pasca, S. Buroni, A. P. Lucarelli, A. Milano, E. De Rossi, M. Belanova, A. Bobovska, P. Dianiskova,
J. Kordulakova, C. Sala, E. Fullam, P. Schneider, J. D. McKinney, P. Brodin, T. Christophe, S.
Waddell, P. Butcher, J. Albrethsen, I. Rosenkrands, R. Brosch, V. Nandi, S. Bharath, S. Gaonkar, R.
K. Shandil, V. Balasubramanian, T. Balganesh, S. Tyagi, J. Grosset, G. Riccardi, and S. T. Cole,
Science, 2009, 324, 801.
16. (a) S. Boukhris, A. Souizi, and A. Robert, Tetrahedron Lett., 1996, 37, 4693; (b) A. El Ouali Lalami,
S. Boukhris, N. Habbadi, N. Bitit, and A. Souizi, J. Marocain Chim. Hétérocycl., 2002, 1, 37; (c) F.
Ammadi, S. Boukhris, A. Souizi, and G. Coudert, Terahedron Lett., 1999, 40, 6517; (d) A. Gaz, A.
Souizi, and G. Coudert, Synth. Commun., 1999, 29, 3459; (e) A. Gaz, F. Ammadi, S. Boukhris, A.
Souizi, and G. Coudert, Heterocycl. Commun., 1999, 5, 413; (f) S. Boukhris, A. Souizi, and A.
Robert, Tetrahedron Lett., 1998, 39, 6281; (g) S. Boukhris, A. Souizi, and A. Robert, Tetrahedron
Lett., 1996, 37, 179; (h) S. Boukhris, A. Souizi, and A. Robert, Tetrahedron Lett., 1996, 37, 4693.
17. T. Giannopoulos, J. R. Ferguson, B. J. Wakefield, and G. Varvounis, Tetrahedron, 2000, 56, 447.
18. W. Zhong and Y. Zhanga, Tetrahedron Lett., 2001, 42, 3125.
19. C. L. Lee, K. P. Chan, Y. Lam, and S. Y. Lee, Tetrahedron Lett., 2001, 42, 1167.
20. V. L. M. Guarda, M. Perrissin, F. Thomasson, E. A. Ximenes, S. L. Galdino, I. R. Pitta, C. Luu-Duc,

HETEROCYCLES, Vol. 83, No. 2, 2011
363
and J. Barbe, Eur. J. Med. Chem., 2003, 38, 769.
21. A. A. Esmaili, M. Ghereghloo, M. R. Islami, and H. R. Bijanzadeh, Tetrahedron, 2003, 59, 4785.
22. A. S. Trifilenkov, A. P. Ilyin, M. V. Dorogov, and A. V. Ivachtchenko, Khimiya i Khim. Tekhnol.,
2006, 49, 111.
23. J. Ilas, P. T. Anderluh, M. S. Dolenc, and D. Kikelj, Tetrahedron, 2005, 61, 7325.
24. O. A. Attanasi, P. Filippone, S. Lillini, F. Mantellini, S. Nicolini, J. de los Santos, M. R. Ignacio, D.
Aparicio, and F. Palacios, Tetrahedron, 2008, 64, 9264.
25. A. V. Dolzhenko and W. Chui, Heterocycles, 2004, 63, 2623.
26. N. Jacobsen and H. Kolind-Andersen, Synthesis, 1990, 10, 911.