N-(X-chlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1 -dioxide (with X = 2 and 4)

Article abstract of DOI:10.1107/S0108270107059173

The structures of N-(2-chlorophenyl)-4-hydroxy-2-methyl-2H-1,2- benzothiazine-3-carboxamide 1,1-dioxide and N-(4-chlorophenyl)-4-hydroxy-2- methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, both C₁₆H ₁₃ClN₂O₄

Full text of DOI:10.1107/S0108270107059173

organic compounds
Acta Crystallographica Section C
Crystal Structure
piroxicam [an oxicam, 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-
,2-benzothiazine-3-carboxamide 1,1-dioxide] and a wide
1
Communications
variety of its derivatives have been reported (Koji c -Prodi c &
Ru zÇ i c -Toro sÏ , 1982; Reck et al., 1988; Drebushchak et al., 2006;
Bordner et al., 1984; Bhatt et al., 2005; Hammen et al., 1989;
Bordner et al., 1989; Chiesi-Villa et al., 1998). The structures of
a few derivatives of meloxicam (a 5-methyl-2-thiazolyl
analogue of piroxicam) have also been reported (Fabiola et al.,
ISSN 0108-2701
N-(X-Chlorophenyl)-4-hydroxy-
2
3
-methyl-2H-1,2-benzothiazine-
-carboxamide 1,1-dioxide (with
1
998; Luger et al., 1996). In continuation of our research in this
important area (Siddiqui et al., 2006a,b, 2007), we have
synthesized analogues of piroxicam and meloxicam wherein
the pyridyl ring of the former and 5-methoxy-2-thiazolyl group
of the latter have been replaced by a chlorophenyl ring. A new
facile procedure has been adopted that leads to an excellent
yield and product purity. In this paper, we report the struc-
tures of the 2-chloro- and 4-chlorophenyl derivatives of the
title compound, viz. (I) and (II), respectively.
X = 2 and 4)
a
b
Waseeq Ahmad Siddiqui, Saeed Ahmad,
a
c
Muhammad Ilyas Tariq, Hamid Latif Siddiqui and
d
Masood Parvez *
a
b
Department of Chemistry, University of Sargodha, Sargodha, Pakistan, Department
c
of Chemistry, University of Science and Technology, Bannu, Pakistan, Institute of
d
Chemistry, University of the Punjab, Lahore, Pakistan, and Department of
Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta,
Canada T2N 1N4
Correspondence e-mail: parvez@ucalgary.ca
Received 1 September 2007
Accepted 14 November 2007
Online 14 December 2007
The structure of (I) contains independent molecules sepa-
rated by normal van der Waals distances (Fig. 1). The
heterocyclic thiazine ring in (I) adopts a half-chair confor-
The structures of N-(2-chlorophenyl)-4-hydroxy-2-methyl-2H-
1,2-benzothiazine-3-carboxamide 1,1-dioxide and N-(4-
chlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
mation, with atoms S1 and N1 displaced by � 0.468 (3) and
Ê
.328 (3) A, respectively, from the plane de®ned by atoms C1/
0
C6/C7/C8; the puckering parameters (Cremer & Pople, 1975)
carboxamide 1,1-dioxide, both C H ClN O S, are stabilized
4
1
6
13
2
by extensive intramolecular hydrogen bonds. The 4-chloro
derivative forms dimeric pairs of molecules lying about
inversion centres as a result of intermolecular NÐHÁ Á ÁO
ꢀ
ꢀ
Ê
are Q = 0.522 (1) A, ꢀ = 117.8 (2) and ' = 204.3 (2) . Similar
conformations of the thiazine ring have been reported in the
above-mentioned structures of piroxicams and meloxicams.
The conformations about the bonds C8ÐC9 and C9ÐN2 in
hydrogen bonds, forming 14-membered rings representing an
2
R (14) motif; the 2-chloro derivative is devoid of any such
intermolecular hydrogen bonds. The heterocyclic thiazine
rings in both structures adopt half-chair conformations.
2
(I) are both EZ, as determined by the intramolecular
hydrogen bonds O1ÐH1OÁ Á ÁO4 and N2ÐH2NÁ Á ÁN1,
resulting in graph-set patterns S(6) and S(5), respectively
(Bernstein et al., 1994). The intramolecular hydrogen bonds
Comment
In recent years, there has been a rapid growth in the literature
dealing with 1,2-benzothiazine-3-carboxamide 1,1-dioxide
derivatives, due to their importance as analgesic and anti-
in¯ammatory agents belonging to the oxicams, a new class of
nonsteroidal anti-in¯ammatory drugs (NSAIDs) (Lombar-
dino & Wiseman, 1972; Hirai et al., 1997; Khalil et al., 2000;
Yaltirik et al., 2001; Myung et al., 2002). These drugs are free
from steroidal side effects, although they have little effect on
the progression of bone and cartilage destruction (Katzung,
1
994). The search for more effective anti-in¯ammatory agents
has led to the exploration of a wide variety of compounds that
may inhibit cartilage destruction associated with NSAIDs, or
at least reduce their severity. Besides great therapeutic
potential, these are very motivating polyfunctional hetero-
cyclic molecules by virtue of their dynamic structural features,
including different tautomeric forms and their possible poly-
morphism (Banerjee & Sarkar, 2002). The crystal structures of
Figure 1
A drawing of the molecule of (I), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii.
o4 # 2008 International Union of Crystallography
DOI: 10.1107/S0108270107059173
Acta Cryst. (2008). C64, o4±o6

organic compounds
Ê
maximum deviation from the plane being 0.053 (2) A for atom
N2ÐH2NÁ Á ÁCl1 and C16ÐH16Á Á ÁO4 also represent S(5) and
S(6) motifs, respectively; details of the hydrogen-bonding
geometry are given in Table 1. In the structures of oxicams, EZ
and ZZ conformations about the corresponding bonds have
been reported previously, depending on the environment of
the drug molecules. In (I), the C10 and O3 methyl groups are
axial, while atoms O1 and O2 are equatorial to the thiazine
ring. Atoms N2/O4/C8/C9/C11 in (I) are essentially planar,
with the maximum deviation from the plane being
N2. However, the chlorophenyl ring in (II) is inclined at
ꢀ
33.0 (2) to the plane formed by atoms N2/O4/C8/C9/C11.
The molecular dimensions in the two structures are unex-
ceptional and agree with the reported values for the corre-
sponding dimensions for oxicams.
Ê
ꢀ
0
to the plane of the 2-chlorophenyl ring.
.0077 (11) A for atom N2; the plane is inclined at 27.18 (6)
The structure of (II) (Fig. 2) contains dimeric pairs of
molecules lying about inversion centres resulting from N2Ð
H2NÁ Á ÁO2 hydrogen bonds, thus forming 14-membered rings
2
2
that can be best described in the graph-set notation as R (14)
(
Bernstein et al., 1994) (Fig. 3); the structure of (I) is devoid of
any such intermolecular interactions. However, similar
hydrogen-bonded dimers have been reported in piroxicams
(
Koji c -Prodi c & Ru zÇ i c -Toro sÏ , 1982; Drebushchak et al., 2006).
The structure of (II) is also stabilized by extensive intra-
molecular interactions involving hydrogen bonds: N2Ð
H2NÁ Á ÁN1, O1ÐH1OÁ Á ÁO4 and C12ÐH12Á Á ÁO4, repre-
senting S(5), S(6) and S(6) motifs, respectively; details of the
hydrogen-bonding geometry are given in Table 2. The thiazine
ring in (II) also adopts a half-chair conformation, with atoms
Ê
S1 and N1 displaced by � 0.485 (5) and 0.358 (5) A, respec-
tively, from the plane formed by atoms C1/C6/C7/C8. The
Ê
values of the puckering parameters in (II) are Q = 0.556 (2) A,
ꢀ
ꢀ
ꢀ
= 117.0 (3) and ' = 205.1 (4) , and these are close to the
Figure 3
The unit-cell packing of (II), showing the inter- and intramolecular
interactions as dashed lines. Only H atoms involved in the hydrogen
bonds are shown.
corresponding values observed in (I) and other related
compounds. The conformations about the bonds C8ÐC9 and
C9ÐN2 in (II) are also both EZ, due to the strong intra-
molecular hydrogen bonds O1ÐH1OÁ Á ÁO4 and N2Ð
H2NÁ Á ÁN1. Intramolecular hydrogen bonds N2ÐH2NÁ Á ÁCl1
and C16ÐH16Á Á ÁO4 also represent S(5) and S(6) motifs,
respectively (Table 2). The C10 and O3 methyl groups in (II)
are axial, while atoms O1 and O2 are equatorial to the thiazine
ring. Atoms N2/O4/C8/C9/C11 are essentially planar, with the
Experimental
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
carboxylate 1,1-dioxide (67.3 g, 250 mmol) and o- or p-chloroaniline
(35.7 g, 280 mmol) in xylene (250 ml) was re¯uxed for 4±12 h in a
Soxhlet apparatus having Linde type A molecular sieves. Half of the
4
xylene was then distilled off and the remaining contents were allowed
to stand overnight at room temperature. The precipitates obtained
were ®ltered off, washed with hexane and dried at room temperature
to obtain the crystalline products (I) and (II), respectively. The
products were crystallized from CHCl
at 313 K.
3
solutions by slow evaporation
�
1
Analysis for (I): IR (neat, ꢁmax, cm ): NH 3325 (s), CO 1742 (m),
1
SO
.26±7.30 (d, J = 6.8 Hz, 2H), 7.31±7.45 (d, J = 7.5 Hz, 2H), 7.69±7.73
m, 2H), 7.76±7.88 (d, J = 6.8 Hz, 1H), 7.90±8.06 (d, J = 7.5 Hz, 1H),
2 3 3
1380 and 1155; H NMR (300 MHz, CDCl ): ꢂ 2.75 (s, 3H, CH ),
7
(
1
3
8
1
8
.21 (s, 1H, NH); C NMR: ꢂ 167.5, 157.3, 136.1, 134.7, 133.4, 132.6,
30.2, 129.1, 128.7, 126.2, 124.3, 121.7, 120.5, 118.3, 111.5, 42.3. Yield:
4.9 g (233 mmol, 93%); m.p. 457±459 K.
�
1
Analysis for (II): IR (neat, ꢁmax, cm ): NH 3337 (s), CO 1744 (m),
1
SO
.30±7.31 (d, J = 6.7 Hz, 2H), 7.34±7.58 (d, J = 7.6 Hz, 2H), 7.70±7.75
m, 2H), 7.76±7.90 (d, J = 6.9 Hz, 1H), 7.91±8.07 (d, J = 7.6 Hz, 1H),
2 3 3
1341 and 1156; H NMR (300 MHz, CDCl ): ꢂ 2.94 (s, 3H, CH ),
7
(
Figure 2
1
3
8
1
.38 (s, 1H, NH); C NMR: ꢂ 166.6, 158.2, 135.0, 134.3, 133.2, 132.5,
30.5, 129.2, 128.5, 126.8, 124.8, 121.8, 120.6, 118.0, 111.6, 40.1. Yield:
A drawing of the molecule of (II), showing the atom-numbering scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are shown as small spheres of arbitrary radii.
87.5 g (240 mmol, 96%); m.p. 496±498 K.
ꢁ
Acta Cryst. (2008). C64, o4±o6
Siddiqui et al.
Two isomers of C16
2 4
H13ClN O S
o5

organic compounds
Compound (I)
For both structures, H atoms bonded to C atoms were included in
the re®nements in geometrically idealized positions, with CÐH = 0.98
Ê
and 0.95 A for methyl and benzene H atoms, respectively, and with
Crystal data
Ê
3
C
16
H13ClN
2 4
O S
V = 1596.2 (6) A
Z = 4
U
iso(H) = 1.2Ueq(C). H atoms bonded to N and O atoms were allowed
M
r
= 364.79
to re®ne, with Uiso(H) = 1.2Ueq(parent). The ®nal difference maps
were free of chemically signi®cant features.
Monoclinic, P2 =c
Mo Kꢄ radiation
1
Ê
a = 7.750 (2) A
� 1
ꢅ = 0.39 mm
T = 173 (2) K
Ê
b = 28.588 (7) A
For both compounds, data collection: COLLECT (Nonius, 1998);
cell re®nement: DENZO (Otwinowski & Minor, 1997); data reduc-
tion: SCALEPACK (Otwinowski & Minor, 1997); program(s) used to
solve structure: SAPI91 (Fan, 1991); program(s) used to re®ne
structure: SHELXL97 (Sheldrick, 1997); molecular graphics:
ORTEPII (Johnson, 1976); software used to prepare material for
publication: SHELXL97.
Ê
ꢀ
c = 7.5190 (10) A
ꢃ = 106.630 (12)
0.22 Â 0.20 Â 0.11 mm
Data collection
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
6588 measured re¯ections
3610 independent re¯ections
3003 re¯ections with I > 2ꢆ(I)
(
T
SORTAV; Blessing, 1997)
min = 0.918, Tmax = 0.958
Rint = 0.027
Re®nement
2
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: GZ3109). Services for accessing these data are
described at the back of the journal.
2
R[F > 2ꢆ(F )] = 0.034
wR(F ) = 0.090
S = 1.02
H atoms treated by a mixture of
independent and constrained
re®nement
2
Ê
� 3
Áꢇmax = 0.30 e A
3
2
610 re¯ections
26 parameters
Áꢇmin = � 0.37 e AÊ
� 3
References
Table 1
Hydrogen-bond geometry (A, ) for (I).
Banerjee, R. & Sarkar, M. (2002). J. Lumin. 99, 255±263.
Bernstein, J., Etter, M. C. & Leiserowitz, L. (1994). Structure Correlation,
Vol. 2, edited by H.-B. B uÈ rgi & J. D. Dunitz, pp. 431±507. New York:
VCH.
Bhatt, P. M., Ravindra, N. V., Banerjee, P. & Desiraju, G. R. (2005). Chem.
Commun. pp. 1073±1075.
Ê
ꢀ
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
O1ÐH1OÁ Á ÁO4
N2ÐH2NÁ Á ÁN1
N2ÐH2NÁ Á ÁCl1
C16ÐH16Á Á ÁO4
0.87 (2)
0.85 (2)
0.85 (2)
0.95
1.75 (2)
2.29 (2)
2.58 (2)
2.38
2.563 (2)
2.733 (2)
2.953 (2)
2.908 (2)
153 (2)
113 (2)
108 (2)
115
Blessing, R. H. (1997). J. Appl. Cryst. 30, 421±426.
Bordner, J., Hammen, P. D. & Whipple, E. B. (1989). J. Am. Chem. Soc. 111,
6
572±6578.
Bordner, J., Richards, J. A., Weeks, P. & Whipple, E. B. (1984). Acta Cryst. C40,
89±990.
9
Chiesi-Villa, A., Rizzoli, C., Amari, G., Delcanale, M., Redenti, E. & Ventura,
P. (1998). Supramol. Chem. 10, 111±119.
Compound (II)
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354±1358.
Drebushchak, T. N., Pankrushina, N. N., Shakhtshneider, T. P. & Apenina, S. A.
(2006). Acta Cryst. C62, o429±o431.
Fabiola, G. F., Pattabhi, V., Manjunatha, S. G., Rao, G. V. & Nagarajan, K.
(1998). Acta Cryst. C54, 2001±2003.
Fan, H.-F. (1991). SAPI91. Rigaku Corporation, Tokyo, Japan.
Hammen, P. D., Berke, H., Bordner, J., Braisted, A. C., Lombardino, J. G. &
Whipple, E. B. (1989). J. Heterocycl. Chem. 26, 11±16.
Hirai, T., Matsumoto, S. & Kishi, I. (1997). J. Chromatogr. B, 692, 375±388.
Johnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National
Laboratory, Tennessee, USA.
Crystal data
ꢀ
C
M
16
H
13ClN
= 364.79
Triclinic, P1
2
O
4
S
ꢈ = 86.32 (2)
Ê
3
r
V = 787.6 (8) A
Z = 2
Ê
a = 7.970 (5) A
Mo Kꢄ radiation
Ê
� 1
b = 10.945 (6) A
ꢅ = 0.40 mm
T = 173 (2) K
Ê
c = 11.133 (7) A
ꢀ
ꢄ = 60.61 (3)
0.14 Â 0.10 Â 0.04 mm
ꢀ
ꢃ = 69.81 (3)
Data collection
Katzung, B. G. (1994). Editor. Basic and Clinical Pharmacology, 7th ed., pp.
5
89±590. Stampford, CT, USA: Appleton & Lange.
Nonius KappaCCD diffractometer
Absorption correction: multi-scan
6690 measured re¯ections
3595 independent re¯ections
2197 re¯ections with I > 2ꢆ(I)
Khalil, S., Borham, N. & El-Ries, M. A. (2000). Anal. Chim. Acta, 441, 215±219.
Ï
Koji c -Prodi c , B. & Ru zÇ i c -Toro sÏ , Z. (1982). Acta Cryst. B38, 2948±2951.
Lombardino, J. G. & Wiseman, E. H. (1972). J. Med. Chem. 15, 848±849.
Luger, P., Daneck, K., Engel, W., Trummlitz, G. & Wagner, C. (1996). Eur. J.
Pharm. Sci. 4, 175±187.
Myung, S. P., Eun, S. C., Myung, S. L. & Soon-kyoung, K. (2002). Bull. Korean
Chem. Soc. 23, 1836±1838.
Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276,
Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M.
Sweet, pp. 307±326. New York: Academic Press.
(
T
SORTAV; Blessing, 1997)
min = 0.946, Tmax = 0.984
Rint = 0.057
Re®nement
2
2
R[F > 2ꢆ(F )] = 0.050
wR(F ) = 0.127
S = 1.02
H atoms treated by a mixture of
independent and constrained
re®nement
2
Ê
� 3
Áꢇmax = 0.34 e A
3
2
595 re¯ections
24 parameters
Áꢇmin = � 0.37 e AÊ
� 3
Reck, G., Dietz, G., Laban, G., Gunter, W., Bannier, G. & Hohne, E. (1988).
Pharmazie, 43, 477±481.
Sheldrick, G. M. (1997). SHELXL97. University of G oÈ ttingen, Germany.
Siddiqui, W. A., Ahmad, S., Khan, I. U., Siddiqui, H. L. & Weaver, G. W.
Table 2
Hydrogen-bond geometry (A, ) for (II).
Ê
ꢀ
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
(
2007). Synth. Commun. 37, 767±773.
Siddiqui, W. A., Ahmad, S., Ullah, I. & Malik, A. (2006a). J. Chem. Soc. Pak.
8, 583±589.
Siddiqui, W. A., Ahmad, S., Ullah, I. & Malik, A. (2006b). Synth. Commun. 37,
67±773.
O1ÐH1OÁ Á ÁO4
N2ÐH2NÁ Á ÁN1
0.88 (3)
0.80 (3)
0.80 (3)
0.95
1.74 (3)
2.27 (3)
2.30 (3)
2.51
2.560 (3)
2.734 (4)
3.006 (3)
2.966 (4)
153 (3)
118 (3)
148 (3)
110
2
i
N2ÐH2NÁ Á ÁO2
7
C12ÐH12Á Á ÁO4
Yaltirik, M., Oral, C. K., Oral, I., Kasaboglu, G. & Cebi, V. (2001). Turk. J.
Med. Sci. 31, 151±154.
Symmetry code: (i) � x; � y ‡ 1; � z ‡ 1.
ꢁ
o6 Siddiqui et al.
Two isomers of C16
H
13ClN
2
4
O S
Acta Cryst. (2008). C64, o4±o6