Derivatives of 4-(2-hydroxylphenyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepine

Article abstract of DOI:10.1107/S0108270103008345

Derivatives of 4-(2-hydroxylphenyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepine was analyzed. The atom N7 is involved in intramolecular hydrogen bonds with the hydroxy H atom, resulting in six membered ring. The crystal packing forces and the orientation of

Full text of DOI:10.1107/S0108270103008345

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
Figs. 1±3 show the structures of (IVa)±(IVc), respectively,
and selected geometric parameters are given in Tables 1, 3 and
5. In all three structures, the central seven-membered
heterocyclic rings adopt twist-boat conformations, such that
atoms C1, C5, C6 and N7 are essentially planar and the
remaining atoms lie above this plane. The distances of the
remaining atoms of the heterocyclic ring from the planes in
(IVa)±(IVc) are, respectively, 0.997 (4), 0.983 (3) and
ISSN 0108-2701
Derivatives of 4-(2-hydroxylphenyl)-
2-phenyl-2,3-dihydro-1,5-benzo-
thiazepine
Ê
Ê
0.983 (3) A for atom C2, 2.287 (3), 2.283 (2) and 2.268 (4) A
Ê
for atom S3, and 1.393 (4), 1.388 (3) and 1.375 (2) A for atom
C4. In each structure, the C1/C5/C6/N7 plane (plane 1) is
coplanar with the hydroxyphenyl ring. Atoms C1 and O24 lie
on opposite sides of plane 1, their maximum deviations from
Masood Parvez,a* Sumaira Umbreenb and Farzana Latif
Ansarib
Ê
the plane being 0.181 (2), 0.1307 (12) and 0.1531 (11) A for
aDepartment of Chemistry, The University of Calgary, 2500 University Drive NW,
Calgary, Alberta, Canada T2N 1N4, and bDepartment of Chemistry, Quaid-i-Azam
University, Islamabad 45320, Pakistan
Ê
C1, and 0.095 (2), 0.0591 (11) and 0.0590 (10) A for O24, for
compounds (IVa)±(IVc), respectively. Moreover, the C12±C17
phenyl ring (plane 2) is almost coplanar with plane 1 in (IVa)
[the angle between the mean planes is 3.48 (12)ꢀ] and is
inclined at 18.39 (7) and 65.88 (5)ꢀ in (IVb) and (IVc),
respectively. The angles between the mean planes formed by
the C1/C2/C8±C11 (plane 3) and C12±C17 (plane 4) phenyl
rings are 51.3 (9), 63.68 (5) and 64.05 (6)ꢀ, respectively, while
the C18±C23 phenyl ring (plane 5) is oriented with respect to
plane 3 at angles of 52.94 (9), 48.71 (6) and 52.49 (5)ꢀ in
compounds (IVa)±(IVc), respectively.).
Correspondence e-mail: parvez@ucalgary.ca
Received 12 March 2003
Accepted 14 April 2003
Online 10 May 2003
In the structures of 2-(4-chlorophenyl)-4-(2-hydroxyphenyl)-
2,3-dihydro-1,5-benzothiazepine, C21H16ClNOS, 4-(2-hydroxy-
phenyl)-2-(4-tolyl)-2,3-dihydro-1,5-benzothiazepine, C22H19NOS,
and 4-(2-hydroxyphenyl)-2-(3-methoxyphenyl)-2,3-dihydro-
1,5-benzothiazepine, C22H19NO2S, the central seven-mem-
bered heterocyclic rings adopt twist-boat conformations in
which the N atoms are involved in strong intramolecular
hydrogen bonds with the hydroxyl H atoms, resulting in six-
membered rings.
Comment
Many chemotherapeutic applications have been associated
with benzothiazepine derivatives such as diltiazem, which is
used as a calcium channel blocker (Chaffman & Brogden,
1985), an angiotensin-converting enzyme inhibitor (Itoh et al.,
1986), and an anticonvulsant and tranquilizing agent (Bock et
al., 1989). Calcium channel blockers are important cardio-
vascular drugs for the management of angina pectoris and
hypertension and may have applications in additional thera-
peutic areas (Godfraind et al., 1986). The importance of the
methoxyphenyl moiety in biologically active compounds
belonging to the benzothiazepine series of drugs has also been
reported (Pant et al., 1994). Following these studies and
continuing our investigations in this area (Ansari et al., 2002),
we have reacted 2-hydroxyacetophenone, (I), with substituted
benzaldehydes, (II) (see Scheme; R = Cl, CH3 or H, and
R0 = H, H or OCH3, respectively). The reaction yielded chal-
cones, (III), which on treatment with o-aminothiophenol in
equimolar quantities in acidi®ed methanol led to the forma-
tion of the 2-(4-chlorophenyl)-, 2-(4-tolyl)- and 2-(3-
methoxyphenyl)- derivatives, (IVa)±(IVc), respectively, of 4-
(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepine.
In this paper, we report the crystal structures of (IVa)±(IVc).
In all three structures, atom N7 is involved in intramolecular
hydrogen bonds with the hydroxy H atom, resulting in a six-
membered ring; details of the hydrogen-bonding geometry are
provided in Tables 2, 4 and 6 for (IVa)±(IVc), respectively.
Note that in (IVb), atom S3 is involved in a short intramol-
o298 # 2003 International Union of Crystallography
DOI: 10.1107/S0108270103008345
Acta Cryst. (2003). C59, o298±o301

organic compounds
Ê
ecular contact with a phenyl H atom (S3Á Á ÁH17 = 2.78 A). The
Ê
corresponding contact in (IVa) is 2.91 A, while (IVc) displays
no such contact. Crystal-packing forces and the orientation of
the phenyl rings are probably responsible for these differ-
ences.
The molecular dimensions in the three structures are
unexceptional. A search of the November 2002 release of the
Cambridge Structural Database (Allen, 2002) showed only
®ve structures containing a heterocyclic seven-membered ring
analogous to that in (IVa)±(IVc).
Experimental
The syntheses of compounds (III) (see Scheme) were carried out
according to the procedures described by Furniss et al. (1989).
Aqueous solutions of NaOH (60.0 ml, 4.0 M) were added to recti®ed
spirit (35.0 ml) in conical ¯asks ®tted with mechanical stirrers. The
¯asks were cooled in an ice bath and freshly distilled (I) (0.01 mol)
was added to each. To these solutions were added, with stirring,
substituted benzaldehydes, (II) (0.01 mol). The temperature was
maintained at ꢁ298 K and the reaction mixtures were stirred vigor-
ously for 2±3 h until the mixtures became thick. The reaction
mixtures were maintained at 273±277 K overnight. The solid masses
thus obtained were neutralized with HCl and the precipitates were
crystallized from aqueous ethanol. The benzothiazepine derivatives,
(IVa)±(IVc), were synthesized according to the procedure reported
by Svetlik et al. (1989). To the corresponding solutions of (III)
(0.02 mol) in dry methanol (100±150 ml), which were acidi®ed with
concentrated HCl (®ve drops), was added o-aminothiophenol
(0.02 mol). The mixtures were re¯uxed until crystalline solids sepa-
rated out. After cooling, solid benzothiazepine derivatives were
collected, washed with ether and cold methanol, and recrystallized
from aqueous ethanol.
Figure 1
ORTEPII (Johnson, 1976) drawing of (IVa), with displacement ellipsoids
plotted at the 50% probability level.
Compound (IVa)
Crystal data
Figure 2
3
C21H16ClNOS
Mr = 365.86
Dx = 1.419 Mg m
Mo Kꢁ radiation
Cell parameters from 9054
re¯ections
ORTEPII (Johnson, 1976) drawing of (IVb), with displacement ellipsoids
plotted at the 50% probability level. Only three of the disordered methyl
H atoms are shown.
Monoclinic, P21=c
Ê
a = 18.036 (9) A
ꢂ = 4.1±25.0ꢀ
ꢃ = 0.35 mm
T = 173 (2) K
Ê
b = 4.836 (2) A
1
Ê
c = 19.790 (11) A
ꢀ = 97.02 (2)ꢀ
V = 1713.2 (15) A
Z = 4
3
Ê
Needle, yellow
0.15 Â 0.08 Â 0.06 mm
Data collection
Nonius KappaCCD area-detector
diffractometer
! and ' scans
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.901, Tmax = 0.982
9054 measured re¯ections
2987 independent re¯ections
2093 re¯ections with I > 2ꢄ(I)
Rint = 0.064
ꢂmax = 25.0ꢀ
h = 21 ! 20
k = 5 ! 5
l = 23 ! 23
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.044
wR(F2) = 0.113
S = 1.02
2987 re¯ections
w = 1/[ꢄ2(F2o) + (0.058P)2]
where P = (F2o + 2Fc2)/3
(Á/ꢄ)max = 0.001
3
Ê
Áꢅmax = 0.21 e A
3
Ê
0.32 e A
Figure 3
ORTEPII (Johnson, 1976) drawing of (IVc), with displacement ellipsoids
plotted at the 50% probability level.
Áꢅmin
=
227 parameters
H-atom parameters constrained
ꢂ
Acta Cryst. (2003). C59, o298±o301
Masood Parvez et al.
C21H16ClNOS, C22H19NOS and C22H19NO2S o299

organic compounds
Table 1
Selected geometric parameters (A, ) for (IVa).
Compound (IVc)
ꢀ
Ê
Crystal data
C1ÐN7
C2ÐS3
S3ÐC4
1.418 (3)
1.776 (3)
1.836 (2)
C6ÐN7
C15ÐCl25
C23ÐO24
1.295 (3)
1.743 (3)
1.349 (3)
3
C22H19NO2S
Mr = 361.44
Monoclinic, P21=c
a = 11.973 (2) A
Ê
b = 16.224 (4) A
Dx = 1.340 Mg m
Mo Kꢁ radiation
Cell parameters from 7583
re¯ections
Ê
ꢂ = 3.7±27.5ꢀ
ꢃ = 0.20 mm
T = 173 (2) K
C2ÐS3ÐC4
103.99 (12)
C6ÐN7ÐC1
121.0 (2)
1
Ê
c = 9.250 (3) A
ꢀ = 94.437 (9)ꢀ
V = 1791.4 (8) A
Z = 4
3
Ê
Needle, yellow
0.35 Â 0.08 Â 0.07 mm
Table 2
Hydrogen-bonding geometry (A, ) for (IVa).
ꢀ
Ê
Data collection
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
Nonius KappaCCD area-detector
diffractometer
! and ' scans
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.908, Tmax = 0.990
7583 measured re¯ections
4081 independent re¯ections
3007 re¯ections with I > 2ꢄ(I)
Rint = 0.031
O24ÐH24Á Á ÁN7
0.84
1.80
2.543 (3)
146
ꢂmax = 27.5ꢀ
h = 15 ! 15
k = 21 ! 21
l = 11 ! 12
Compound (IVb)
Re®nement
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.040
wR(F2) = 0.107
S = 1.02
4081 re¯ections
w = 1/[ꢄ2(F2o) + (0.050P)2
+ 0.404P]
Crystal data
3
C22H19NOS
Mr = 345.44
Monoclinic, P21=c
Ê
a = 4.8678 (11) A
Dx = 1.335 Mg m
Mo Kꢁ radiation
where P = (F2o + 2Fc2)/3
(Á/ꢄ)max < 0.001
Cell parameters from 8207
re¯ections
3
Ê
Áꢅmax = 0.23 e A
3
Ê
0.36 e A
237 parameters
H-atom parameters constrained
Áꢅmin
=
ꢂ = 3.6±30.0ꢀ
Ê
b = 17.563 (3) A
1
Ê
c = 20.129 (5) A
ꢃ = 0.20 mm
T = 173 (2) K
ꢀ = 93.078 (8)ꢀ
V = 1718.4 (6) A
Z = 4
3
Ê
Needle, yellow
0.22 Â 0.12 Â 0.08 mm
Table 5
Selected geometric parameters (A, ) for (IVc).
ꢀ
Ê
Data collection
C1ÐN7
C2ÐS3
S3ÐC4
1.414 (2)
1.775 (2)
1.848 (2)
C6ÐN7
C23ÐO24
1.297 (2)
1.351 (2)
Nonius KappaCCD area-detector
diffractometer
! and ' scans
Absorption correction: multi-scan
(SORTAV; Blessing, 1997)
Tmin = 0.906, Tmax = 0.988
8207 measured re¯ections
4972 independent re¯ections
3195 re¯ections with I > 2ꢄ(I)
Rint = 0.037
ꢂ
max = 30.0ꢀ
C2ÐS3ÐC4
104.57 (7)
C6ÐN7ÐC1
121.32 (13)
h = 6 ! 6
k = 21 ! 24
l = 28 ! 28
Re®nement
Table 6
Hydrogen-bonding geometry (A, ) for (IVc).
ꢀ
Ê
Re®nement on F2
R[F2 > 2ꢄ(F2)] = 0.046
wR(F2) = 0.121
S = 0.99
4972 re¯ections
w = 1/[ꢄ2(F2o) + (0.0547P)2
+ 0.2349P]
where P = (F2o + 2Fc2)/3
(Á/ꢄ)max = 0.001
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
3
O24ÐH24Á Á ÁN7
0.84
1.81
2.5489 (18)
147
Ê
Áꢅmax = 0.23 e A
3
Ê
0.32 e A
228 parameters
H-atom parameters constrained
Áꢅmin
=
For the three structures, the H atoms were located from difference
Fourier syntheses and were included in the re®nements at idealized
Ê
positions, with CÐH distances of 0.95±1.00 A and an OÐH distance
Table 3
Selected geometric parameters (A, ) for (IVb).
ꢀ
Ê
Ê
of 0.84 A, and with Uiso values of 1.5 (hydroxyl H atoms) or 1.2 (the
S3ÐC2
S3ÐC4
O24ÐC23
1.7696 (17)
1.8368 (15)
1.3427 (19)
N7ÐC6
N7ÐC1
1.2952 (19)
1.4128 (19)
remaining H atoms) times the Ueq values of the parent atoms. The
methyl H atoms in (IVb) were disordered over six sites and were
included in the re®nement using the DFIX 123 command in
SHELXL97 (Sheldrick, 1997). The ®nal difference maps were free of
any chemically signi®cant features.
C2ÐS3ÐC4
103.23 (7)
C6ÐN7ÐC1
120.37 (13)
For all three compounds, data collection: COLLECT (Hooft,
1998); cell re®nement: HKL DENZO (Otwinowski & Minor, 1997);
data reduction: HKL 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.
Table 4
Hydrogen-bonding geometry (A, ) for (IVb).
ꢀ
Ê
DÐHÁ Á ÁA
DÐH
HÁ Á ÁA
DÁ Á ÁA
DÐHÁ Á ÁA
O24ÐH24Á Á ÁN7
0.84
1.80
2.5489 (17)
147
ꢂ
o300 Masood Parvez et al.
C21H16ClNOS, C22H19NOS and C22H19NO2S
Acta Cryst. (2003). C59, o298±o301

organic compounds
Furniss, B. S., Hannaford, A. J., Smith, P. W. G. & Tachell, A. R. (1989). Vogel's
Textbook of Practical Organic Chemistry, 5th ed., pp. 1034±1035. Essex,
England: Longmann Scienti®c and Technical.
Godfraind, T., Miller, R. & Wibo, M. (1986). Pharmacol. Rev. 38, 321±416.
Hooft, R. (1998). COLLECT. Nonius BV, Delft, The Netherlands.
Itoh, K., Kori, M., Indada, Y., Nishikawa, K., Kawamasu, Y. & Sugihara, H.
(1986). Chem. Pharm. Bull. 34, 2078±2089.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: FR1416). Services for accessing these data are
described at the back of the journal.
References
Johnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National
Laboratory, Tennessee, USA.
Allen, F. H. (2002). Acta Cryst. B58, 380±388.
Ansari, F., Fedorchuk, C., Parvez, M., Umbreen, S. & Saghir, S. (2002). Acta
Cryst. E58, o422±o425.
Blessing, R. H. (1997). J. Appl. Cryst. 30, 421±426.
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.
Bock, M. G., Dipardo, R. M., Evans, B. E., Rittle, K. E., Whittner, W. L., Veber,
D. F., Anderson, P. S. & Freidinger, R. M. (1989). J. Med. Chem. 32, 13±16.
Chaffman, M. & Brogden, R. N. (1985). Drugs, 29, 387±454.
Fan, H.-F. (1991). SAPI91. Rigaku Corporation, Tokyo, Japan.
Pant, U. C., Chugh, M., Sharma, C. K. & Pant, S. (1994). J. Indian Chem. Soc.
71, 637±639.
È
Sheldrick, G. M. (1997). SHELXL97. University of Gottingen, Germany.
Svetlik, J., Hanus, V. & Bella, J. (1989). Liebigs Ann. Chem. pp. 91±93.
ꢂ
Acta Cryst. (2003). C59, o298±o301
Masood Parvez et al.
C21H16ClNOS, C22H19NOS and C22H19NO2S o301