A novel photoisomerzation of 1,2-benzothiazine 1,1-dioxides to 1,3-benzothiazine 1,1-dioxides

Article abstract of DOI:10.1002/jhet.5570440416

(Chemical Equation Presented) A novel facile photoconversion of 4-hydroxy-1,2-bezothiazine 1,1-dioxides (3a-e) into 4-oxo-1,3-2H-benzothiazine 1,1-dioxides (4a-e) and 4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide (PRX) into N-methyl saccharin (2) upon 254 nm irradiation in methanol or acetonitrile is reported. The structures of the products have been elucidated by spectroscopic methods and single crystal X-ray structure determination for 4a and 4d.

Full text of DOI:10.1002/jhet.5570440416

Jul-Aug 2007
849
A Novel Photoisomerzation of 1,2-Benzothiazine 1,1-dioxides to
1,3-Benzothiazine 1,1-dioxides
Ibrahim Elghamry*‡, Dietrich Döpp and Gerald Henkel
Institute of Chemistry, University Duisburg-Essen, D-47048 Duisburg, Germany
e-mail: elghamry@hotmail.com
Received August 7, 2006
O
OH
R2
R1
R1
R2
N
hꢀ
N
254 nm
S
S
O
O
O
O
4
3
A novel facile photoconversion of 4-hydroxy-1,2-bezothiazine 1,1-dioxides (3a-e) into 4-oxo-1,3-2H-
benzothiazine 1,1-dioxides (4a-e) and 4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-1,2-benzothiazine-3-
carboxamide 1,1-dioxide (PRX) into N-methyl saccharin (2) upon 254 nm irradiation in methanol or
acetonitrile is reported. The structures of the products have been elucidated by spectroscopic methods and
single crystal X-ray structure determination for 4a and 4d.
J. Heterocyclic Chem., 44, 849 (2007).
INTRODUCTION
studies have shown that PRX has twelve possible
tautomers, which result from the unusual fast intra-
molecular proton transfer from the hydroxyl group of the
benzothiazine ring either to the ortho-carbonyl, the amide
nitrogen, the benzothiazine ring nitrogen, or the pyridine
ring nitrogen [11-14]. While a previous study has also
reported that a similar behavior was noticed for methyl
4-hydroxy-2-methyl-1,2-benzothiazine-1,1-dioxide 3-car-
boxylate (3a), which is used as one of the PRX precursors
[15,16]. Therefore, these results prompted us to study the
photoreactivity of PRX precursors and analogues.
Piroxicam (4-hydroxy-2-methyl-N-(pyridin-2-yl)-2H-
1,2-benzothiazine-3-carboxamide 1,1-dioxide) (PRX-
Scheme 1), is a non-steroidal anti-inflammatory drug
(NSAID) used for treatment of arthritis [1-3]. It belongs
to the oxicams group of chemicals, which have the 1,2-
thiazine 1,1-dioxide as a main nucleus fused with either
benzene or heterocycles ring systems. Shortly after the
PRX became widely available for the therapeutic use it
was associated with development of adverse light-induced
biological effects, which were demonstrated mainly as a
phototoxicity [4-8].
RESULTS AND DISCUSSION
The implication of the photoproducts of the drug in the
phototoxicity has been suggested in the literature [9].
Therefore, it has been reported that the phototoxicity of
PRX is a result of the preferential synthesis and
accumulation of 2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-
dioxide (1) (Scheme 1) in human skin cells. The latter
compound is a minor metabolite of PRX, and has been
reported to be phototoxic to Lymphocytes in vivo [4,5].
Herein we report a new photoisomerization of the
3-substituted 4-hydroxy-1,2-benzothiazines 3a-e into
2-substituted 4-oxo-1,3-benzothiazines 4a-e. Therefore,
the 1,2-benzothiazine 1,1-dioxides 3a-e were prepared
using literature procedures [17] and were subjected to 254
nm photolysis experiments in methanol using a low-
pressure mercury lamp (15 W input) for the period listed
in Table 1. A single photoproduct was obtained in
moderate yields varying from 50% to 75% (Scheme 2,
Table 1) which was demonstrated to be the 2-substituted
4-oxo-1,3-2H-benzothiazine 1,1-dioxide 4. Interestingly,
the author has recently reported a related ring system was
obtained via a new photochemical ring expansion of N-
alkyl 1,2-benzothiazole 1,1-dioxides [18].
O
O
OH
O
N
N
NH
N
S
R
S
N
S
O
O
O
O
O
O
2
PRX
1
a, R = H
b, R = Me
O
OH
Scheme 1
R2
R1
R1
R2
hꢀ
N
The photodegradation of PRX into N-methyl saccharin
(2) and N-(2-pyridyl) oxamic acid by direct irradiation
under aerobic conditions has been reported [10]. This
was explained in terms of a plausible mechanism via a
dioxetane intermediate [10,11]. The physicochemical
N
254 nm
S
S
O
O
O
O
3
4
Scheme 2

850
I. Elghamry, D. Döpp and G. Henkel
Vol 44
Table 1
To investigate the scope and limitation of this
photoisomerization and the role of the R1 group, the
3,4-dihydro-1,2-benzothiazine (1a) and the N-methyl
derivative (1b) were prepared [28] and subjected to
photolysis under the same conditions and the course of
the reaction was monitored by NMR. Unsurprisingly
photoisomerization was not observed and the
substrates were recovered without change after
irradiation for 24 hours. Therefore the presence of
R1 (electron-withdrawing) is proven to be essential
for the photoisomerization which enhances the
formation and stabilization of either or both of the
intermediate 6 and 8 (Scheme 3). Furthermore, it
was noticed that there was no effect on the photo-
isomerization, whether with respect to the yield or
the nature of the photoproduct when the photolysis
was carried out in aprotic (acetonitrile) or protic
(methanol) solvents.
Photoconversion of 1,2-benzothiazine 1,1-dioxide 3 to 1,3-benzothiazine
1,1-dioxide 4.
3, 4
R1
R2
Period
of irradiation (h)
Yield
of 4 (%)[a]
a
b
c
d
e
CO2Me
CN
COPh
CN
CO2Me
H
H
H
CH3
CH3
7
6
15
7
7
54
75
50
60
55
[a] Based on the consumed starting material.
The rationale explaining the possible pathways of this
photoisomerization is depicted in Scheme 3. Thus,
photoexcited 3 first undergoes S-N bond homolysis [19-23]
to give biradical 5 which can undergo cyclization to form a
more stable captodative aziridine radical [24,25] 6 (R1 =
CO2Me, CN, COPh). Then, subsequent bond formation
between S and C3 gives rise the bicyclic intermediate 7.
The latter is an analogous to intermediates suggested to
rationalize the phototranspositions of methylisothiazoles to
methylthiazoles [26] and of 2-phenylthiophene to 3-
phenylthiophene [27]. Intermediate 7 in turn undergoes
subsequent C-C bond cleavage with protonation at C-2 to
form the final isolable photoisomerization product 4.
Alternatively, 3 may first be photocyclized to give the
tricyclic zwitterionic intermediate 8 [26]. Final S-N bond
rupture results in the aforementioned bicyclic intermediate
7 which proceeds to product 4.
The structure of the photoisomerization products
4a-e was delineated primarily from the mass spectral
1
and H / 13C NMR data but was firmly supported by
a single crystal X-ray structure determination for
compounds 4a and 4d (Fig 1 and 2). The spectral
data of the photoisomerization products revealed
new signals attributed to formation of
a new
stereogenic centre at C-2. Thus, 13C-NMR and H-
NMR spectra reveal signals at ꢀ = 46.1- 75.3, 159.8-
168.5 and 5.75-7.15 ppm attributed to the new
asymmetric carbon in the 1,3-benzothiazine ring at
C-2, the new ring carbonyl at C-4 and the proton
bonded to the stereogenic carbon, respectively.
Also, a signal is observed at 1675-1699 cm-1 in the
IR spectra is assigned to the new amidic carbonyl.
1
OH
OH
R1
R2
R1
R2
:
N
N
S
S
O
O
O
O
3
hꢀ
OH
OH
OH
R1
R2
R1
R2
R1
.
N
N
.
.
.
S
N
S
S
R2
O
O
O
O
O
O
5
8
H
OH
O
R1
R2
N
R2
.
R1
.
N
S
S
O
O
O
O
7
6
4
Figure 1. ORTEP-plot of molecular structure 4a in the crystal. The
Scheme 3
crystallographic numbering does not reflect the systematic number.

Jul-Aug 2007
A Novel Photoisomerization of 1,2-Benzothiazine 1,1-dioxides
851
EXPERIMENTAL
General. All commercially available solvents and reagents
were purchased from commercial sources and used without
further purification unless otherwise noted. NMR spectra were
recorded on a Bruker WM 300 and DRX 500 spectrometers (300
MHz and 500 MHz, respectively for 1H, 75 and 125 MHz,
respectively, for 13C) using TMS as internal standard and the
deuterated solvent as lock. IR spectra were obtained by using a
Perkin-Elmer 983 spectrophotometer.
Electron impact
ionisation mass spectrometry (EIMS) was performed on a
Varian AMD 604 instrument using 70 eV ionization energy.
Melting points are uncorrected. All the chromatographic
separations were performed on 48 x 20 cm glass plates covered
with an air-dry layer (1 cm thick) of silica gel (Merck Kiesegel
PF254).
General Photolysis Procedure. Samples of 7a-e (1.0 mmol
each) in methanol (or acetonitrile) (100 ml) were irradiated for
the period listed (see Table 1) using a quartz immersion well in
connection with a Hanau TNN 15 low-pressure mercury lamp
(15 W input) with continuous argon purging. After concen-
tration the residue was subjected to chromatography on two
silica gel plates each with EtOAc-hexane (1:1). The Rf values of
the appropriate zones are given below.
Figure 2. ORTEP-plot of molecular structure 4d in the crystal. The
crystallographic numbering does not reflect the systematic number.
Table 2
Selected bond lengths and angles of compounds 4a and 4d in the crystal.
The crystallographic numbering does not reflect systematic numbering.
Cpd
Bond length [Å]
Bond angles [^ ꢁ]
Methyl 3,4-dihydro-1,1-dioxide-5-oxo-1,3-2H-benzothia-
zine 2-carboxlate (4a). Rf 0.51 Colourless crystals (from
acetone) mp 198-199 °C, ir: NH 3191, C=O 1758, C=O 1677,
4a
S-C(1)
S-C(8)
1.756 (16)
1.813 (15)
C(1)-S-C(8) 99.82 (7)
S-C(8)-N
109.47 (10)
C(8)-N 1.444 (19)
C(8)-C(9) 1.533 (2)
N-C(7) 1.354 (2)
O(5)-C(7) 1.234 (19)
O(3)-C(9) 1.199 (19)
C(7)-N-C(8) 126.53 (13)
N-C(7)-C(6) 118.83 (13)
1
SO2 1326, 1203 cm-1; H nmr: (DMSO) ꢀ: 3.75 (s, 3H, CH3),
5.75 (d, J = 6.0,1H, HC-2), 7.85 (m, 3H, Ar-H), 8.15 (m, 1H,
Ar-H), 9.21ppm (d, J = 6.0, 1H, NH); 13C nmr: (DMSO) ꢀ: 54.1
(OCH3), 72.5 (C-2), 122.9 (Ar-CH), 128.9 (Ar-Cq), 129.5,
133.5, 134.1 (Ar-CH), 136.2 (Ar-Cq), 161.1 (C=O, ring), 164.5
ppm (C=O, ester); ei ms: m/z 256 (M+ + 1). Anal. Calcd. for
C10H9NO5S: C, 47.05; H, 3.55; N, 5.49. Found: C, 46.91; H,
3.45; N, 5.29.
4d
S-C(1)
S-C(8)
1.763 (5)
1.22 (5)
C(1)-S-C(8) 98.62 (2)
S-C(8)-N(1) 109.81 (3)
C(7)-N(1)-C(8)122.83 (4)
N(1)-C(7)-C(6)121.23 (4)
C(8)-N(1) 1.448 (6)
C(8)-C(10)1.501 (7)
C(6)-C(7) 1.497 (7)
C(10)-N(2)1.122 (6)
C(9)-N(1) 1.462 (6)
O(1)-C(7) 1.228 (6)
O(3)-C(9) 1.199 (19)
2-Cyano-3,4-dihydro-1,1-dioxide-1,3-2H-benzothiazin-4-
one (4b). Rf 0.42 Colourless crystals (from ethanol) mp 175 °C,
1
ir: NH 3220, C=O 1675, SO2 1340, 1150 cm-1; H nmr (DMSO)
ꢀ: 7.15 (d, J = 6.0, 1H, HC-2), 8.13 (m, 4H, Ar-H), 10.35 ppm
(d, J = 6.0, 1H, NH); 13C nmr (DMSO) ꢀ: 60.9 (C-2), 113.1
(CN), 117.5 123.5 (Ar-CH), 126.9 (Ar-Cq), 130.5 (Ar-CH),
134.4 (Ar-Cq), 135.5 (Ar-CH), 160.5 ppm (C=O), ei ms: m/z
222 (M+). Anal. Calcd. for C9H6N2O3S: C, 48.64; H, 2.72; N,
12.61. Found: C, 48.56; H, 2.55; N, 12.54.
A preliminary result from our laboratory indicated that
one of the aerobic photodegradation products of PRX was
isolated in 40% yield and identified as N-methylsaccharin
(2) after subjecting the PRX to photolysis for seven hours
using a low-pressure mercury lamp with continuous argon
purging. However, it has been reported that PRX is
photostable under inert atmosphere where the aerobic
photodegradation was only explained in terms of singlet
oxygen involvement in the process [5, 10, 29].
Finally, a new photoisomerization of 4-hydroxy 3-
substituted 1,2 -benzothiazine 1,1-dioxides (3a-e) into 4-
oxo-2-substituted 1,3-bezothiazine 1,3-dioxides (4a-e)
was achieved in reasonable yields and a rationale for this
transformation has been proposed. Thus, based on the
above mentioned photoisomerzation and the degradation
of PRX under inert conditions it is likely that PRX
degrades into 2 via 1, 3 –benzothiazine intermediate.
Therefore, further studies in this direction are under way.
2-Benzoyl-3,4-dihydro-1,1-dioxide-1,3-2H-benzothiazin-4-
one (4c). Rf 0.51 Colourless crystals (benzene/n-hexane 3:1) mp
218-219 °C; ir: NH 3264, C=O 1734, C=O 1699, SO2 1375,
1
1179 cm-1; H nmr (CDCl3) ꢀ: 5.81 (s, 1H, HC-2), 7.52 (m,4H,
Ar-H), 8.05 (m, 4H, Ar-H), 8.38 (m, 1H, Ar-H), 9.92 ppm (s,
1H, NH); 13C nmr (CDCl3)) ꢀ: 46.1 (C-2), 127.4, 128.7, 129.8,
130.2 (Ar-CH), 131.4, 131.9(Ar-Cq), 133.9 (Ar-CH), 134.3
(Ar-Cq), 135.6, 136.6 (Ar-CH), 168.5 (C=O, ring), 191.3 ppm
(C=O, ketonic); ei ms: m/z 302 (M+ +1). Anal. Calcd. for
C15H11NO4S: C, 59.79; H, 3.68; N, 4.65. Found: C, 59.68; H,
3.67; N, 4.54.
2-Cyano-3,4-Dihydro-1,1-dioxide-N-methyl-1,3-2H-benzo-
thiazin-4-one (4d). Rf 0.48 Colourless crystals (acetone) mp
200-201 °C; ir: C=O 1675, SO2 1340, 1150 cm-1; 1H nmr
(DMSO) ꢀ: 3.10 (s, 3H, CH3), 6.54 (s, 1H, HC-2), 7.98 ppm (m,
4H, Ar-H); 13C nmr (DMSO) ꢀ: 35.8 (CH3), 66.1 (C-2), 112.4
(CN), 117.8, (Ar-Cq), 123.7, 126.7, 134.6 (Ar-CH), 135.1 (Ar-
Cq), 135.7 (Ar-CH), 159.8 ppm (C=O); ei ms m/z 336 (M+).

852
I. Elghamry, D. Döpp and G. Henkel
Vol 44
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Rheumatol. 1983, 22, 139-242.
Anal Calcd. for C10H8N2O3S: C, 50,84; H, 3.41; N, 11.86.
Found: C, 50.77; H, 3.32; N, 11.78.
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Methyl 3,4-dihydro-1,1-dioxide-N-methyl-5-oxo-1,3-2H-
benzothiazine-2-carboxlate (4e). Rf 0.50 Colourless crystals
(acetone) mp 205-206°C; ir: C=O 1760, C=O 1679, SO2 1330,
1
1210 cm-1; H nmr (DMSO) ꢀ: 2.95 (s, 3H,CH3), 3.65 (s, 3H,
CH3), 5.94 (s, 1H, HC-2), 7.85 (m, 2H, Ar-H), 8.21 ppm (m, 2H,
Ar-H); 13C nmr (DMSO) ꢀ: 29.2 (CH3), 54.3 (CH3), 75.3 (C-2),
123.5, (Ar-CH) 128.0 (Ar-Cq), 129.5, 132.9, 133.2 (Ar-CH),
136.9 (Ar-Cq), 166.2 (C=O ring), 169.1 ppm (C=O ester); ei ms:
m/z 270 (M+ + 1). Anal. Calcd for C11H11NO5S: C, 49.06; H,
4.12; N, 5.20: Found: C, 48.95; H, 4.10; N, 5.19.
Photolysis of Piroxicam. A solution of 0.14 g (0.50 mmol) of
Piroxicam in methanol (100 ml) was irradiated for 7 hours using
a quartz immersion well in connection with a Hanau TNN 15
low-pressure mercury lamp (15 W input) with continuous argon
purging. After concentration the residue was subjected to
chromatography on two silica gel plates with EtOAc- hexane
(1:1).
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N-Methylsaccharin (2). Rf 0.50, Colourless crystals (from
methanol) mp 128 °C (lit [30] 130 °C, lit [31] 131 °C); ir: C=O
1
1739, SO2 1325, 1174 cm-1; H nmr (CDCl3) ꢀ: 3.39 (s, 3H,
methyl-H), 7.95 ppm (m, 4H, aryl-H); 13C nmr (CDCl3) ꢀ: 23.2
(CH3), 121.0, 125.2 (Ar-CH) 127.6 (Ar-Cq), 134.4, 134.7 (Ar-
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Acknowledgement. I. Elghamry am deeply indebted to the
Alexander-von-Humboldt-foundation for the award of a research
fellowship at the Institute of Chemistry, University Duisburg-
Essen, Duisburg, Germany. Financial support by Fonds der
Chemischen Industrie is gratefully acknowledged.
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‡
Current address, Misr International University, faculty of
pharmacy, department of pharmaceutical organic chemistry, P.O. Box 1
Heliopolis 11341, Cairo, Egypt.
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