cis-6-phenyl-4bH,6H,11H,13H-isoindolo[1,2-c]benz[2,4]oxazepin-13-one

Article abstract of DOI:10.1107/S0108270101003870

The title compound, C₂₂H₁₇NO₂, contains an isoindolinone moiety joined to a phenyl-substituted benzoxazepine ring. The isoindolinone moiety is essentially planar and the oxazepine ring adopts a distorted chair conformation, with the phenyl substituent equatorial. Owing to the severe puckering of the central oxazepine ring, the molecule as a whole is non-planar; the benzene ring of the benzoxazepine fragment makes an angle of 67.7 (1)° with respect to the isoindoline ring.

Full text of DOI:10.1107/S0108270101003870

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organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
in good agreement with the comparable bond lengths found in
cyclic amino acids (Benedetti et al., 1983). A similar pattern of
bond distances and angles within the isoindolinone moiety has
ISSN 0108-2701
cis-6-Phenyl-4bH,6H,11H,13H-isoin-
dolo[1,2-c]benz[2,4]oxazepin-13-one
Jan Lokaj,a Viktor Kettmann,b* Stefan Marchalina and Jana
Sikoraiovaa
aFaculty of Chemical Technology, Slovak Technical University, Radlinskeho 9,
Bratislava 81237, Slovak Republic, and bFaculty of Pharmacy, Comenius University,
Odbojarov 10, Bratislava 83232, Slovak Republic
Correspondence e-mail: kettmann@fpharm.uniba.sk
Received 2 February 2001
Accepted 1 March 2001
The title compound, C22H17NO2, contains an isoindolinone
moiety joined to a phenyl-substituted benzoxazepine ring. The
isoindolinone moiety is essentially planar and the oxazepine
ring adopts a distorted chair conformation, with the phenyl
substituent equatorial. Owing to the severe puckering of the
central oxazepine ring, the molecule as a whole is non-planar;
the benzene ring of the benzoxazepine fragment makes an
angle of 67.7 (1)ꢀ with respect to the isoindoline ring.
been found in other compounds incorporating this molecular
fragment (Barrett et al., 1995; McNab et al., 1997; Khan et al.,
1998), as revealed by a search of the Cambridge Structural
Database (Allen & Kennard, 1993).
As mentioned above, the main purpose of the present
structure determination was to establish the relative three-
dimensional disposition of the phenyl rings and the two O
atoms (and the orientation of the lone pairs on them), which
are assumed to constitute the interaction pharmacophore
responsible for the binding of the compound to the CNS-
subtype of the BDZ receptor. Obviously, the disposition of
these structural elements depends primarily on the confor-
mation of the seven-membered oxazepine ring, which is the
most ¯exible part of the molecule. A comparison of the
endocyclic torsion angles for the oxazepine ring (Table 1)
reveals that it adopts a distorted chair conformation, with an
Comment
The work presented here is part of a continuing study aimed at
designing modulators of hormonal/neurotransmitter systems
as potential drugs to treat neuronal and cardiovascular
disorders. Based on the recent pharmacophore/receptor
model of the benzodiazepine (BDZ) receptor subtype located
in the central nervous system (CNS; Huang et al., 2000), we
designed the title compound, (IV), as a potential anxiolytic
agent. Synthesis of (IV) was achieved by a sequential reaction
(see Scheme below) and led to a 5:1 diastereomeric (racemic)
mixture of cis and trans isomers, (IVa) and (IVb), respectively.
In order to establish the detailed stereochemistry of the two
diastereomers, viz. the spatial relationship between the puta-
tive pharmacophoric elements (the phenyl rings and the two O
atoms), which is indispensable for future molecular-modelling
studies, the crystal structure determination of (IVa) and (IVb)
has been undertaken. In this communication, we report on the
structure of the cis isomer, (IVa).
The molecular structure of (IVa) is shown in Fig. 1. As
expected, the isoindolinone ring is nearly planar, with an
average deviation of the ring atoms from the least-squares
Ê
plane of 0.016 (3) A. As shown in Table 1, the N1ÐC2 bond is
much shorter than the N1ÐC9 and N1ÐC18 bonds. More-
over, the N1 atom is sp2 hybridized, as evidenced by the sum of
the valence angles at this atom [360.0 (2)ꢀ]. These data are
consistent with conjugation of the lone-pair electrons on N1
with the adjacent carbonyl function, similar to what is
observed for amides. Indeed, the NÐC bond lengths at N1 are
Figure 1
The molecular structure of (IVa), showing the atom-labelling scheme.
Displacement ellipsoids are shown at the 30% probability level and H
atoms are drawn as small circles of arbitrary radii.
ꢁ
Acta Cryst. (2001). C57, 735±736
# 2001 International Union of Crystallography
Printed in Great Britain ± all rights reserved 735

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organic compounds
Data collection
approximate mirror plane passing through C9 and the
midpoint of the C12ÐC17 bond; N1, C18, O10 and C11 lie in
the plane and C9, C12 and C17 are, respectively, 0.640 (2),
Syntex P21 diffractometer
ꢃ/2ꢃ scans
3271 measured re¯ections
3271 independent re¯ections
2513 re¯ections with I > 2ꢅ(I)
ꢃmax = 26.6ꢀ
h = 0 ! 8
k = 11 ! 11
l = 15 ! 15
Ê
1.115 (2) and 1.146 (2) A out of it. The puckering para-
=
2 standard re¯ections
every 98 re¯ections
intensity decay: 2%
meters according to Cremer & Pople (1975) are q2
Ê
Ê
0.465 (2) A, '2
=
111.5 (3)ꢀ, q3 = 0.624 (3) A and '3
=
29.6 (2)ꢀ for the sequence N1/C9/O10/C11/C12/C17/C18. The
deviation from ideal Cs symmetry described by the asymmetry
parameter ÁCs(C9) is 0.046 (1) (Nardelli, 1983).
Re®nement
Re®nement on F2
R(F) = 0.047
w = 1/[ꢅ2(Fo2) + (0.0478P)2
+ 0.3839P]
wR(F2) = 0.133
S = 1.10
where P = (Fo2 + 2Fc2)/3
(Á/ꢅ)max = 0.001
As a result of the relatively severe puckering of the central
oxazepine ring, the molecule as a whole is non-planar; the two
(planar) terminal segments of the molecule (the isoindoline
ring and the benzene ring fused to the oxazepine moiety) are
inclined at an angle of 67.7 (1)ꢀ to each other. The phenyl
group at C11 is in a pseudo-equatorial orientation and is
rotated around the C11ÐC19 bond in such a manner that the
O10ÐC11ÐC19ÐC20 torsion angle is 10.5 (2)ꢀ.
3
Ê
3271 re¯ections
226 parameters
H-atom parameters constrained
Áꢆmax = 0.17 e A
3
Ê
0.23 e A
Áꢆmin
=
Table 1
Selected geometric parameters (A, ).
ꢀ
Ê
N1ÐC2
N1ÐC9
N1ÐC18
1.350 (3)
1.439 (3)
1.443 (3)
C2ÐO2
C9ÐO10
O10ÐC11
1.217 (2)
1.399 (2)
1.439 (2)
C2ÐN1ÐC9
C2ÐN1ÐC18
C9ÐN1ÐC18
O2ÐC2ÐN1
O2ÐC2ÐC3
113.90 (16)
124.57 (17)
121.53 (16)
126.21 (19)
127.74 (19)
N1ÐC2ÐC3
O10ÐC9ÐN1
O10ÐC9ÐC8
N1ÐC9ÐC8
C9ÐO10ÐC11
106.04 (17)
113.94 (16)
109.38 (16)
102.13 (16)
114.19 (14)
Experimental
As noted above, the diastereomers (IVa) and (IVb) were synthesized
by a three-step reaction (see Scheme). In the ®rst step, to bromo-
methylbenzophenone, (I), freshly prepared from 2-methylbenzo-
phenone (1.96 g, 0.01 mol) and N-bromosuccinimide (1.76 g,
0.01 mol), were added phthalimide (1.5 g, 0.01 mol), potassium
carbonate (1.1. g, 8 mmol) and N,N-dimethylformamide (25 ml). The
mixture was stirred overnight, diluted with water, extracted with
diethyl ether (3 Â 20 ml) and dried (magnesium sulfate). The solvent
was evaporated under reduced pressure and the solid recrystallized
from ethanol to give 2-(N-phthalimidomethyl)benzophenone, (II)
(77% yield, m.p. 388 K). In the second step, to a mixture of (II) (0.5 g,
15 mmol) in dry methanol (20 ml) at 273±283 K was added sodium
borohydride (0.69 g, 30 mmol) in portions. The mixture was stirred
for 2 h and monitored by thin-layer chromatography (dichloro-
methane/acetone 5:1). After 2 h, the starting material disappeared
and the excess of sodium borohydride was decomposed by addition
of cold water (10 ml) and 10% hydrochloric acid to neutral pH. The
precipitate was separated by ®ltration, washed with water, dried,
concentrated under reduced pressure and recrystallized from ethanol
to afford a 5:1 ratio of the diastereomers of (III) (79% yield). Finally,
compound (IV) was prepared when the diols (III) (0.5 g, 1.5 mmol)
were stirred in dry dichloromethane (20 ml) with a catalytic amount
of p-toluenesulfonic acid for 30 min at room temperature. The solu-
tion was washed with saturated sodium hydrogen carbonate and then
with water, then dried and concentrated under reduced pressure.
Separation by ¯ash chromatography, followed by recrystallization
from ethanol, gave a 5:1 ratio of the oxazepines (IVa) and (IVb)
[70% yield; m.p. 496 K for (IVa) and 482 K for (IVb)].
C18ÐN1ÐC9ÐO10
N1ÐC9ÐO10ÐC11
C9ÐO10ÐC11ÐC12
O10ÐC11ÐC12ÐC17
60.7 (2)
66.4 (2)
88.91 (18)
68.1 (2)
C11ÐC12ÐC17ÐC18
C9ÐN1ÐC18ÐC17
C12ÐC17ÐC18ÐN1
O10ÐC11ÐC19ÐC20
1.1 (3)
74.4 (2)
59.1 (2)
10.5 (2)
Ê
All H atoms were treated as riding, with CÐH = 0.93 A (aromatic)
Ê
or 0.97 A, and with Uiso set to 1.2 (1.5 for the methyl-H atoms) times
Ueq of the parent atom.
Data collection and cell re®nement: P21 Software (Syntex, 1973);
ÏÂ
data reduction: XP21 (Pavelcõk, 1987); program(s) used to solve
structure: SHELXS97 (Sheldrick, 1997); program(s) used to re®ne
structure: SHELXL97 (Sheldrick, 1997); molecular graphics:
ORTEPII (Johnson, 1976).
This work was supported by the Grant Agency of the
Slovak Republic (Project Nos. 1/8216/01 and 1/6095/99).
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: GD1142). Services for accessing these data are
described at the back of the journal.
References
Allen, F. H. & Kennard, O. (1993). Chem. Des. Autom. News, 8, 1, 31±37.
Barrett, D. M. Y., Kahwu, I. A., Mague, J. T. & McPherson, G. L. (1995). J. Org.
Chem. 60, 4946±4953.
Benedetti, E., Bavoso, A., DeBlasio, B., Pavone, V. & Pedone, C. (1983).
Biopolymers, 22, 305±317.
Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354±1359.
Huang, Q., He, X., Ma, C., Liu, R., Yu, S., Dayer, C. A., Wenger, G. R.,
McKernan, R. & Cook, J. M. (2000). J. Med. Chem. 43, 71±95.
Johnson, C. K. (1976). ORTEPII. Report ORNL-5138. Oak Ridge National
Laboratory, Tennessee, USA.
Khan, M. W., Guha, S., Mukherjee, A. K. & Kundu, N. G. (1998). Acta Cryst.
C54, 119±121.
McNab, H., Parsons, S. & Shannon, D. A. (1997). Acta Cryst. C53, 1098±1099.
Nardelli, M. (1983). Acta Cryst. C39, 1141±1142.
ÏÂ
Pavelcõk, F. (1987). XP21. Comenius University, Bratislava, Slovakia.
Crystal data
3
C22H17NO2
Mr = 327.37
Triclinic, P1
a = 7.153 (3) A
Ê
b = 8.961 (4) A
c = 13.156 (7) A
ꢀ = 92.69 (5)ꢀ
ꢁ = 106.83 (5)ꢀ
ꢂ = 96.79 (4)ꢀ
V = 798.6 (6) A
Z = 2
Dx = 1.361 Mg m
Dm = 1.36 (1) Mg m
Dm measured by ¯otation in
bromoform/c-hexane
Mo Kꢀ radiation
Ê
Cell parameters from 15
re¯ections
Ê
ꢃ = 10±26ꢀ
ꢄ = 0.09 mm
T = 293 (2) K
1
È
Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of Gott-
ingen, Germany.
3
Ê
Prism, colourless
0.50 Â 0.35 Â 0.30 mm
Syntex (1973). P21 Software. Syntex Analytical Instruments, Cupertino,
California, USA.
3
ꢁ
736 Jan Lokaj et al.
C22H17NO2
Acta Cryst. (2001). C57, 735±736