Synthesis of 4H-1,4-benzothiazine-1,1-dioxides (sulfones) and phenothiazine-5,5-dioxides (sulfones)

Article abstract of DOI:10.1080/104265090917790

The study of the oxidation behavior of 4H-1,4-benzothiazines and phenothiazines by 30% hydrogen peroxide in acetic acid results in the formation of 4H-1,4-benzothiazine-1,1-dioxides (sulfones) and 10H-phenothiazine-5,5- dioxides (sulfones) respectively. T

Full text of DOI:10.1080/104265090917790

This article was downloaded by: [University of California, San Diego]
On: 03 June 2015, At: 06:49
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis of 4H-1,4-
Benzothiazine-1,1-
dioxides (Sulfones) and
Phenothiazine-5,5-dioxides
(Sulfones)
Thandi Lal Kachhee a , Vandana Gupta a , D. C.
Gautam a & R. R. Gupta a
a Department of Chemistry , University of
Rajasthan , Jaipur, India
Published online: 22 Aug 2006.
To cite this article: Thandi Lal Kachhee , Vandana Gupta , D. C. Gautam & R.
R. Gupta (2005) Synthesis of 4H-1,4-Benzothiazine-1,1-dioxides (Sulfones) and
Phenothiazine-5,5-dioxides (Sulfones), Phosphorus, Sulfur, and Silicon and the Related
Elements, 180:10, 2225-2234, DOI: 10.1080/104265090917790
To link to this article: http://dx.doi.org/10.1080/104265090917790
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any

losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 180:2225–2234, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090917790
Synthesis of 4H-1,4-Benzothiazine-1,1-dioxides
(Sulfones) and Phenothiazine-5,5-dioxides (Sulfones)
Thandi Lal Kachhee
Vandana Gupta
D. C. Gautam
R. R. Gupta
Department of Chemistry, University of Rajasthan, Jaipur, India
The study of the oxidation behavior of 4H-1,4-benzothiazines and phenoth-
iazines by 30% hydrogen peroxide in acetic acid results in the formation of 4H-
1,4-benzothiazine-1,1-dioxides (sulfones) and 10H-phenothiazine-5,5-dioxides (sul-
fones) respectively. The purity of all the synthesized compounds has been checked by
thin layer chromatography using silica “G” as an adsorbent in various nonaqueous
solvent systems. Infra-red and proton-magnetic resonance spectral studies are also
included.
INTRODUCTION
The oxidation of sulfide linkage in 4H-1,4-benzothiazines and 1-/9-
nitro-10H-phenothiazines leads to formation of their sulfones. Sul-
fones contitute an important class of heterocyclic compounds which
have been reported to find a number of applications in medicine1−13
and industry.14,15 4H-1,4-Benzothiazine-1,1-dioxides (sulfones) and
phenothiazine-5,5-dioxides (sulfones) were obtained in quantitative
yield by the oxidation of 4H,1,4-benzothiazines and phenothiazines, re-
spectively, with hydrogen peroxide.16
RESULTS AND DISCUSSION
The sulfones have been synthesized by the oxidation of 4H-1,4-
benzothiazines and phenothiazines. 4H-1,4-benzothiazines were pre-
pared by the condensation and oxidative cyclization of 2-amino-5-fluoro-
3-methyl/5-ethoxy benzenethiols with β-diketones in dimethylsulfoxide
Received October 7, 2004; accepted November 15, 2004.
RSIC and Lucknow are thanked for providing proton magnetic resonance spectra.
Address correspondence to Thandi Lal Kachhee, University of Rajasthan, Department
of Chemistry, Jaipur 302004, India. E-mail: rrg vg@yahoo.co.in
2225

2226
T. L. Kachhee et al.
reported elsewhere.17−19 Phenothiazines were prepared by the Smiles
rearrangement of 2-amino-5-fluoro-3-methyl/5-ethoxybenzenethiols
with o-halonitrobenzenes containing nitro groups at both ortho posi-
tions to the halogeno atom.
4H-1,4-Benzothiazine-1,1-dioxides (Scheme-1, IIa–h) and 1-/9-nitro-
10H-phenothiazine-5,5-dioxides (Scheme 2, IVa–d have been prepared
by treating 4H-1,4-benzothiazines and 1-/9-nitro-10H-phenothiazines,
respectively, with 30% hydrogen peroxide in glacial acetic acid.
SCHEME 1 Synthesis of 4H-1,4-benzothiazine-1,1-dioxides (sulfones).
SCHEME 2 Synthesis of 1-/9-nitro-10H-phenothiazine-5,5-dioxides (sul-
fones).
INFRARED SPECTRA
Infrared spectra have been recorded both in potassium bromide pellets
and in chloroform solution. In the solid state as well as in chloroform,

Synthesis of 4H-1,4-Benzothiazine- and Phenothiazine-Sulfones
2227
FIGURE 1
all 4H-1,4-benzothiazine sulfones and 10H-phenothiazine sulfones ex-
hibit three characteristic absorption bands viz. 1151 cm−1, 519 m−1
,
and 1361 cm−1, which can be attributed to the three strong funda-
mental absorption bands in the molecule of sulfur dioxide and can
be assigned to the three normal modes of vibrations20,21 shown in
(Figure 1).
All synthesized 4H-1,4-benzothiazine-1,1-dioxides (sulfones) and
phenothiazine-5,5-dioxides (sulfones) exhibit a sharp intense peak in
the region 1390–1310 cm−1 and 1375–1348 cm−1 in chloroform solution,
respectively, which can be assigned to the asymmetric stretching mode
ν3 of the sulfonyl group. While in a solid state, this absorption band
ν3 split into three bands and appears in the region 1410–1325 cm−1
,
1320–1285 cm−1, and 1290–1240 cm−1 for the 4H-1,4-benzothiazine-
1,1-dioxides (sulfones) and in the 1-/9-nitro-10H-phenothiazine-5,5-
dioxides (sulfones) its appears in the region 1380–1345 cm−1, 1330–
1280 cm−1, and 1285–1260 cm−1. The asymmetric stretching vibra-
tions in the sulfones are strongly affected on passing from the solu-
tion to the crystalline state. The symmetrical stretching vibrations
ν1 of 4H-1,4-benzothiazine-1,1-dioxides (sulfones) and 1-/9-nitro-10H-
phenothiazine-5,5-dioxides (sulfones) give rise to high intensity doublet
and in some cases a broad signal obtained in the KBr disc in the region
1190–1100 cm−1 and 1185–1110 cm−1, whereas in solution it appears
at 1205–1105 cm−1 and 1180–1110 cm−1, respectively. Hence, these
frequencies are slightly affected by the state of aggregation. The bend-
ing vibration ν2 in sulfur dioxide exhibits medium absorption bands in
low frequency region, 590–510 cm−1 and 585–522 cm−1. These absorp-
tion bands appear either as a doublet or singlet band with an inflection,
which have been compared with fundamental vibrations22,23 in sulfuryl
chloride appearing below 600 cm−1. Analogously, the band in the region
590–510 cm−1 and 585–522 cm−1 in 4H-1,4-benzothiazine-1,1-dioxides
(sulfones) and 1-/9-nitro-10H-phenothiazine-5,5-dioxides (sulfones) can
be ascribed to sulfur-dioxide scissoring (D) and rocking (E) vibrations
(Figure 2).

2228
T. L. Kachhee et al.
FIGURE 2
The substituent vibrations can provide information about the elec-
tron donor and electron acceptor abilities of heteroaromatic rings.24 The
present work deals with the vibrational frequencies of substituents
in IR spectra, both in dioxides (sulfones) and in their present 4H-
1,4-benzothiazines and 1-/9-nitro-10H-phenothiazines. The vibrational
frequency corresponding to each substituents is shifted to higher fre-
quency in both types of dioxides (sulfones).
In the spectra of 1-/9-nitro-10H-phenothiazine-5,5-dioxides (sul-
fones), the absorption band due to >N H stretching vibrations (fre-
quency) appears at nearly the same frequency region. In 1-/9-nitro-
10H-phenothiazines >N H stretching vibrations (frequency) appears
in the region 3400–3360 cm−1 and in 1-/9-nitro-10H-phenothiazine-
5,5-dioxides (sulfones) it appears in the region 3410–3360 cm−1. A
sharp intense peak observed in the region 3380–3260 cm−1 in 4H-1,4-
benzothiazines that was assigned to free >N H stretching vibrations
shifted to higher frequency region 3430–3380 cm−1 in the corresponding
dioxides (sulfones).
A sharp band observed in the region 1710–1590 cm−1 due to >C O
stretching vibrations in 4H-1,4-benzothiazine shifts to higher frequen-
cies 1730–1630 cm−1 in the corresponding dioxides (sulfones). This
shifting to higher frequency is assigned to the increased electron ac-
ceptor ability of heteroaromatic nucleus in the sulfones as compared to
the parent nucleus. The lone pair of electrons at nitrogen is withdrawn
more effectively towards the ring; it conjugates less effectively with the
carbonyl group and results in higher carbonyl group frequencies. The
–I effect of the SO2 group combines with the mesomeric effect operating
in the same direction and also hinders the conjugation of the lone pair
of electrons at nitrogen with the carbonyl group.
The asymmetric and symmetric stretching vibrations of methyl,
which occur in the region 2950–2890 cm−1 (asymm.) and 2925–
2840 cm−1 (symm.) in 4H-1,4-benzothiazines, is shifted to the higher
frequency region 2980–2900 cm−1 (asymm.) and 2950–2850 cm−1

Synthesis of 4H-1,4-Benzothiazine- and Phenothiazine-Sulfones
2229
(symm.) in the corresponding sulfones. Similarly, the same vibra-
tions which occur in the region 2930–2910 cm−1 (asymm.) and 2860–
2830 cm−1 (symm.) in 1-/9-nitro-10H-phenothiazines is shifted to a
higher frequency region 2960–2930 cm−1 (asymm.) and 2870–2860
cm−1 (symm.) in the corresponding sulfones.
A medium intensity band appearing in the region 1060–1010 cm−1
in 4H-1,4-benzothiazines and exhibits in the region 1045–1020 in
1-/9-nitro-10H-phenothiazine due to >C S C< stretching vibrations
is shifted to a higher frequency region 1070–1040 cm−1 and 1070–
1045 cm−1 in the corresponding sulfones.
It can be concluded that the oxidation of 4H-1,4-benzothiazines and
1-/9-nitro-10H-phenothiazines to their corresponding sulfones causes
the appearance of specific absorption peaks with the change in the
vibrational modes. These changes in the vibrational modes could be
elaborated by the strong electron-withdrawing oxygen atoms at the ox-
idized sulfide linkage. The oxidation behavior of 4H-1,4-benzothiazines
and 1-/9-nitro-10H-phenothiazines explain the similarities in their core
nuclear structure and conformations, which are responsible for phar-
maceutical activities.
NUCLEAR MAGNETIC RESONANCE SPECTRA
NMR spectral data of synthesized 4H-1,4-benzothiazine-1,1-dioxides
(sulfones) and 1-/9-nitro-10H-phenothiazine-5,5-dioxides (sulfones) are
discussed in detail below.
Each 1-/9-nitro-10H-phenothiazine-5,5-dioxide (sulfone) exhibits a
sharp peak in the region δ 9.686–9.38 ppm due to >N H proton. Com-
pounds 4c and 4d exhibit a singlet in the region δ 2.72 and δ 2.64 ppm
due to three protons of CH3 group at C1, respectively. The multiplet
in the region δ 8.38–6.72 ppm is observed due to the aromatic ring pro-
tons. Compounds 4a and 4b exhibit a quartet and triplet in the region
δ 2.61–2.26 ppm and δ 1.68–1.08 ppm due to >CH2 and CH3 protons
of OC2H5 group at C7.
All synthesized 4H-1,4-benzothiazine sulfones 2a–h exhibit a single
sharp peak in the region δ 9.984–8.88 ppm due to >N H-proton. The
multiplet observed in the region δ 8.51–5.96 ppm is attributed to the
aromatic protons. Compounds 2a–h show resonance signal in the region
δ 2.54–2.28 ppm due to allylic protons (>C C CH3) at C3. Compounds
2g and 2h exhibit a singlet at δ 2.09 ppm and 2.16 ppm due to CH3
protons at C5. Compounds 2a and 2g exhibit a singlet at 2.22 ppm and
1.96 ppm due to CH3 protons at the 3-position of the benzoyl side
chain at C2 respectively. Compounds 2a–f exhibit quartet and triplet
in region δ 4.56–3.16 ppm and 2.08–1.28 ppm due to >CH2 and CH3

2230
T. L. Kachhee et al.
protons of OC2H5 group at C7. Compound 2c exhibits quartet and
triplet in region 4.22–3.99 ppm and 1.75–1.42 ppm due to >CH2 and
CH3 protons of OC2H5 group at 4-position of benzoyl side chain at
C2. The quartet and triplet observed in the region δ 3.32–3.12 ppm and
1.36–1.24 ppm in the compound 2b can be assigned to C2H5 group at
para-position of benzoyl side chain at C2.
EXPERIMENTAL
The melting points of all synthesized compounds are uncorrected. The
purity of all synthesized compounds has been checked by thin layer
chromatography using silica “G” as an adsorbent in various nonaque-
ous solvent systems. The infrared spectra have been recorded on a
NICOLET-MAGNA FTIR spectrophotometer model 550 in potassium
bromide discs and in chloroform solution. Proton magnetic resonance
(1H NMR) spectra were recorded at 90 MHz on Jeol Fx 90Q FT NMR
spectrometer in DMSO-d6 containing TMS as an internal standard.
SYNTHESIS OF 4H-1,4-BENZOTHIAZINES 1a–h
To a stirred suspension of 0.01 mole of β-diketone 2 in 5 mL of dimethyl-
sulfoxide was added 0.01 mL of 2-aminobenzenethiols 1 and the re-
sulting mixture was refluxed for 40–60 min and cooled down to room
temperature. The solid that was separated out was filtered and washed
with petroleum ether and crystallized from methanol/solvent ether.
SYNTHESIS OF 1-/9-NITRO-10H-PHENOTHIAZINES 3a–h
To a stirred suspension of 0.01 mole of 2-amino-5-fluoro-3-methyl- and
5-ethoxybenzenethiols 1, 0.01 mole of sodium hydroxide and 20 mL of
absolute ethanol were taken in a 50 mL R.B. flask fitted with a reflux
condensor and heated for 5 min. To this solution, 0.01 mole of substi-
tuted reactive halonitrobenzene 2 in 10 mL of ethanol was added with
stirring. The color of the reaction mixture immediately darkened to
brown. The contents were refluxed for 4 h, concentrated, cooled, and
filtered. The solid separated out was washed with hot water followed
by 30 % ethanol. The crystallization from methanol/acetone afforded a
pure compound.
SYNTHESIS OF 4H-1,4-BENZOTHIAZINE-1,1-DIOXIDES
(SULFONES) 2a-h AND 1-/9-NITRO-10H-PHENOTHIAZINE-5,5-
DIOXIDES (SULFONES) 4a–d
30% Hydrogen peroxide (5 mL) was added to a solution of 0.01 mole of
4H-1,4-benzothiazine or 0.01 mole of 1-/9-nitro-10H-phenothiazine in

2231

2232

Synthesis of 4H-1,4-Benzothiazine- and Phenothiazine-Sulfones
2233
20 mL of glacial acetic acid and refluxed for 15 min at 50–60◦C. Heating
was stopped and another lot of 5 mL of 30% hydrogen peroxide was
added. The reaction mixture was again refluxed for 3–4 h. The excess
of solvent was removed by distillation under reduced pressure and the
solution was poured into a beaker containing crushed ice. The yellow
residue that separated out was collected, filtered, and crystallized from
ethanol. Physical data of 4H-1,4-benzothiazine-1,1-dioxides (sulfones)
and 1-/9-nitro-10H-phenothiazine-5,5-dioxides (sulfones) are tabulated
in Tables I and II respectively.
REFERENCES
[1] R. R. Gupta (Ed.) Phenothiazines and 1,4-benzothiazines-chemical and biomedical
aspects, Amsterdam: Elsevier (1988).
[2] S. Shinji and A. Koshiro, Biol. Pharm. Bull., 18, 586 (1995).
[3] Z. Szule, J. Mlochow, and J. Palus, J. Prakt. Chem., 330, 1023 (1988).
[4] T. P. Culbertson, J. Heterocycl. Chem., 28, 1701 (1991).
[5] S. R. El-Ezbawy and M. A. Alshaikh, J. Chem. Technol. Biotechnol., 47, 209 (1990);
Chem. Abstr., 113, 59071 (1990).
[6] M. Bogusz and Moutran Wu, J. Anal. Toxicol., 15, 188 (1991); Chem. Abstr., 115,
107963 (1991).
[7] A. Tureant, A. P. Cabie, A. Cailleux, and P. Allain, Clin. Chem., 37, 1210 (1991);
Chem. Abstr., 115, 149643 (1991).
[8] J. M. Varga, G. Kalchschmid, G. F. Klein, and P. Fritseh, Mol. Immunol., 28, 641
(1991); Chem. Abstr., 117, 277 (1992).
[9] S. Sato and A. Koshiro, Biol. Pharm. Bull., 18, 586 (1995); Chem. Abstr., 123, 131970
(1995).
[10] K. H. Mayer and A. Haberkorn, German Offen. 2, 020, 298 (1971); Chem. Abstr., 76,
72533 (1972).
[11] G. Filacchioni, V. Nacci, and G. Stfanrich, Farmaco. Ed. Sci., 31, 478 (1996); Chem.
Abstr., 85, 143048 (1976).
[12] G. Fengler, D. Arlt, K. Groche, H. J. Zeiler, and K. Metzger, German Offen. 3, 229,
125 (1984); Chem. Abstr., 101, 7176 (1984).
[13] G. Fengler, D. Arlt, and K. Groche, German Offen, 3, 329, 124 (1984); Chem. Abstr.,
101, 90953 (1984).
[14] R. Aki and S. Kito, Japan Kokai, 78, 32, 742 (Cl. CO3 C5/O6) (1978); Chem. Abstr.,
89, 207269 (1979).
[15] C. R. Rasmussen, U. S. 3, 476, 749 (1969); Chem. Abstr., 72, 21727 (1970).
[16] R. R. Gupta, R. Kumar, G. S. Kalwania, and R. K. Gautam, Ann. Soc. Sci. Bruxelles,
98, 195 (1984); Chem. Abstr., 106, 196375 (1987).
[17] R. R. Gupta, S. K. Jain, N. K. Goswami, and G. S. Kalwania, Heterocycles, 14, 831
(1980).
[18] M. Y. Hamadi, R. Gupta, and R. R. Gupta, Heterocycl. Commun., 4, 277 (1998).
[19] M. Kumar, N. Sharma, R. Gupta, and R. R. Gupta, Heterocycl. Commun., 4, 187
(1998).
[20] G. Herzberg, Infrared and Raman spectra of polyatomic molecules, D. Van Nostrand,
(ed.). New York, pp. 171 (1945).

2234
T. L. Kachhee et al.
[21] L. J. Bellamy, Infrared spectra of complex molecules, New York: John Wiley and
Sons. Inc., pp. 360 (1964).
[22] G. Malewski and H. J. Weigmann, Spectrochim. Acta 18, 725 (1962).
[23] R. J. Gillespie and E. A. Robinson, Spectrochim. Acta, 18, 1473 (1962).
[24] A. R. Katritzky and A. P. Ambler, Infrared spectra in A. R. Katritzky (Ed.), Physical
methods in heterocyclic chemistry, New York; Academic Press, vol. 2, pp. 161 (1963).