Methyl 4-(2-chloro-5-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8- hexahydroquinoline-3-carboxylate

Article abstract of DOI:10.1107/S0108270104019468

The crystal structure and synthesis of C₂₀H₂₁ClN ₂O₅ were investigated. The structure of the sample was analyzed using IR, ¹H NMR and ¹³C NMR analyses. The 2-chloro-5-nitrophenyl ring in the sample was oriented such that the chloro substituent was in a synperiplanar orientaion with respect to the 1,4-dihydropyridine ring plane, while nitro substituent was present over the 1,4-dihydropyridine ring. The molecules in the sample were linked into chains by intermolelecular N-H···O hydrogen bonds.

Full text of DOI:10.1107/S0108270104019468

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
published elsewhere. The determination of its three-dimen-
sional conformation, presented here, is important in order to
obtain further insight into the structure±activity relationships
of these compounds.
ISSN 0108-2701
Methyl 4-(2-chloro-5-nitrophenyl)-
2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylate
Anthony Linden,a* Cihat SËafakb and Fõrat Aydõnb
aInstitute of Organic Chemistry, University of Zurich, Winterthurerstrasse 190,
È
The 1,4-DHP ring in the structure of (I) (see Fig. 1) has a
shallow boat conformation, with atoms N1 and C4 lying
Ê
0.115 (2) and 0.283 (2) A, respectively, from the plane de®ned
CH-8057 Zurich, Switzerland, and bDepartment of Pharmaceutical Chemistry,
È
Faculty of Pharmacy, Hacettepe University, 06100 Ankara, Turkey
Correspondence e-mail: alinden@oci.unizh.ch
by atoms C2, C3, C4A and C8A. The shallowness of the boat is
indicated by the puckering parameters (Cremer & Pople,
Received 4 August 2004
Accepted 6 August 2004
Online 4 September 2004
ꢀ
ꢀ
Ê
1975) Q = 0.2356 (15) A, ꢀ = 73.6 (4) and '2 = 180.2 (4) for
the atom sequence N1ÐC2ÐC3ÐC4ÐC4AÐC8A. For an
ideal boat, ꢀ and '2 are 90ꢀ and n  60ꢀ, respectively. The
conformations of 4-aryl-1,4-DHP rings have been discussed
previously (Goldmann & Stoltefuss, 1991; Linden et al., 1998,
2002; SËimsËek et al., 2000); it is usual for the ring to have a
shallow boat conformation, although considerable variation in
the shallowness of the boat is evident. The deviation of atom
The title compound, C20H21ClN2O5, has potential calcium
modulatory properties. The 1,4-dihydropyridine ring has the
usual shallow boat conformation. The 2-chloro-5-nitrophenyl
ring is oriented such that the chloro substituent is in a
synperiplanar orientation with respect to the 1,4-dihydro-
pyridine ring plane, while the nitro substituent sits over the
1,4-dihydropyridine ring. The cyclohexenone ring has a
conformation that is approximately half-way between that of
an envelope and that of a half-chair. The molecules are linked
into chains by intermolecular NÐHÁ Á ÁO hydrogen bonds.
Ê
C4 in (I) corresponds to the values of ꢁ0.30 A found most
frequently for this atom in 1,4-DHP rings (SËimsËek et al., 2000).
The deviations shown by atom N1 are generally smaller and
Ê
spread fairly evenly over the range 0.00±0.19 A (Linden et al.,
2000, 2002). The deviation shown by atom N1 in (I) falls right
in the middle of this range. In contrast, the 1,4-DHP ring in
N,N-diethyl-2,6,6-trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carboxamide was found to be com-
pletely planar (Linden et al., 2002).
Comment
Awide range of chemical substances in¯uence the ¯ow of Ca2+
ions through the channels found in cell membranes. While
some compounds, the calcium agonists, activate this ¯ow, other
compounds, the calcium antagonists, selectively inhibit the
¯ow of Ca2+ ions through the Ca2+-conducting channels
(Nayler, 1988). 1,4-Dihydropyridine (1,4-DHP) derivatives
have yielded many drugs that act as calcium-channel agonists.
Nifedipine is the prototype of this group, and both nifedipine
and its structural analogues are used as antianginal and anti-
hypertensive drugs (Janis & Triggle, 1984). Many active deri-
vatives have been synthesized by making various
modi®cations to the nifedipine structure, yielding compounds
with calcium agonist or antagonist properties (Rose, 1989,
1990). The activity displayed by these compounds may be
in¯uenced by their stereochemistry (Langs & Triggle, 1985).
Our interest is in the structure and calcium antagonistic
behaviour of condensed derivatives of 1,4-DHP. The crystal
structures of some of these derivatives have already been
reported (Linden et al., 1998, 2002; SËimsËek et al., 2000), and the
title compound, (I), has been prepared as a further potentially
active 1,4-DHP derivative. The structure of (I) was con®rmed
by IR, 1H NMR and 13C NMR analyses. Details of the
synthesis of this compound and its antagonistic activity will be
Figure 1
A view of the molecule of (I), showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level and H
atoms are represented by circles of arbitrary size.
Acta Cryst. (2004). C60, o711±o713
DOI: 10.1107/S0108270104019468
# 2004 International Union of Crystallography o711

organic compounds
Another measure of the planarity of 1,4-DHP rings is the
sum of the magnitudes of the six intra-ring torsion angles, P,
around the ring (Fossheim et al., 1988). For (I), P is 82 (1)ꢀ,
which is close to the mean value of 77 (2)ꢀ found previously
for reported 1,4-DHP rings (Linden et al., 2002), although the
P values generally vary over a wide range from 4 to 130ꢀ. For
nifedipine itself, P is 72ꢀ (Miyamae et al., 1986).
atom C7 deviates is, in the majority but not all of these
structures, the same as that in (I) (Linden et al., 2002).
An intermolecular hydrogen bond between the amine
group and the carbonyl O atom of the cyclohexenone ring of a
neighbouring molecule (Table 2) links the molecules into
extended chains that run parallel to the [010] direction and
have a graph-set motif of C(6) (Bernstein et al., 1995). The
same C(6) motif has been observed in the crystal structures of
several other 1,4-DHP compounds (Linden et al., 1998, 2002;
SËimsËek et al., 2000).
The plane of the 2-chloro-5-nitrophenyl ring of (I) is almost
parallel to the N1Á Á ÁC4 axis, with an N1Á Á ÁC4ÐC13ÐC18
torsion angle of 2.53 (15)ꢀ. This value is normal; the corre-
sponding torsion angle in related structures is clustered
around 0ꢀ and rarely exceeds Æ30ꢀ (Linden et al., 2002). The
chloro substituent lies above the C4ÐH bond in a synperi-
planar orientation, while the nitro substituent sits over the
1,4-DHP ring. Examples of 2,5-disubstitution in the phenyl
ring of 4-aryl-1,4-DHP compounds are rare, but the same
2-chloro-5-nitrophenyl ring appears in the analogous
compound dimethyl 4-(2-chloro-5-nitrophenyl)-1,4-dihydro-
2,6-dimethylpyridine-3,5-dicarboxylate (Rovnyak et al., 1988).
The orientation of the phenyl ring in this latter compound is
the same as that in (I). Such an orientation is preferred on
steric grounds, since most substituents in the 2-position of the
phenyl ring would not be allowed to sit directly over the 1,4-
DHP ring. Thus, it is not surprising that no crystal structures of
2,6-disubstituted phenyl rings in 4-aryl-1,4-DHP compounds
have been reported.
Experimental
For the synthesis of the title compound, (I), equimolar amounts
of 2-chloro-5-nitrobenzaldehyde, 5,5-dimethylcyclohexane-1,3-dione
and methyl acetoacetate plus ammonia (1 ml) were re¯uxed in
methanol for 4 h. The solution was then poured into water, and the
precipitate that formed was ®ltered off, dried and recrystallized from
ethanol (m.p. 513 K).
Crystal data
C20H21ClN2O5
Mr = 404.85
Orthorhombic, Pbca
Mo Kꢂ radiation
Cell parameters from 33 903
re¯ections
Ê
a = 14.8737 (2) A
ꢀ = 2.0±30.0ꢀ
1
Ê
b = 14.3865 (2) A
ꢃ = 0.24 mm
T = 160 (1) K
Ê
c = 17.6287 (3) A
Ê
V = 3772.20 (10) A
3
Prism, yellow
0.27 Â 0.22 Â 0.10 mm
Most of the bond lengths and angles in (I) have normal
values. There are small angular distortions about atoms C2
and C10 (Table 1), which result from steric interactions
between the methyl substituent at atom C2 and atom O10 of
Z = 8
Dx = 1.426 Mg m
3
Data collection
Nonius KappaCCD area-detector
diffractometer
' and ! scans with ꢄ offsets
Absorption correction: multi-scan
(Blessing, 1995)
Tmin = 0.845, Tmax = 0.981
68 164 measured re¯ections
5520 independent re¯ections
4106 re¯ections with I > 2ꢅ(I)
Rint = 0.069
Ê
the ester substituent at atom C3 [O10Á Á ÁC9 = 2.829 (2) A].
ꢀmax = 30.0ꢀ
The presence of ꢁ-electron conjugation keeps the ester
group at atom C3 almost coplanar [C2 C3ÐC10 O10 =
9.0 (3)ꢀ] with the endocyclic double bond and prevents the
ester group from rotating into a sterically more amenable
orientation. These properties are consistent with those of
the many other 2-methyl-3-carboxy-4-aryl-1,4-DHP com-
pounds archived in the Cambridge Structural Database
(Allen, 2002).
h = 20 ! 20
k = 20 ! 20
l = 24 ! 24
Re®nement
Re®nement on F2
R[F2 > 2ꢅ(F2)] = 0.047
wR(F2) = 0.129
S = 1.03
5517 re¯ections
261 parameters
w = 1/[ꢅ2(F2o) + (0.0606P)2
+ 1.849P]
where P = (F2o + 2Fc2)/3
(Á/ꢅ)max = 0.001
The cyclohexenone ring in (I) has a conformation that is
approximately half-way between that of a C7-envelope and
that of a half-chair twisted around the C6ÐC7 bond. This
conformation is demonstrated by the puckering paꢀrameters
3
Ê
Áꢆmax = 0.47 e A
3
Ê
0.44 e A
Áꢆmin
=
H atoms treated by a mixture of
independent and constrained
re®nement
ꢀ
Ê
Q = 0.4641 (16) A, ꢀ = 53.8 (2) and '2 = 165.5 (2) for the
atom sequence C4AÐC5ÐC6ÐC7ÐC8ÐC8A. The '2 value,
in particular, lies almost exactly half-way between the nearest
ideal values that would correspond to an envelope and to a
half-chair conformation. Atoms C6 and C7 lie 0.176 (3) and
Table 1
Selected geometric parameters (A, ).
ꢀ
Ê
O10ÐC10
O11ÐC10
N1ÐC8A
N1ÐC2
1.211 (2)
1.349 (2)
1.372 (2)
1.387 (2)
1.355 (2)
C3ÐC10
C3ÐC4
C4ÐC4A
C4AÐC8A
1.473 (2)
1.524 (2)
1.516 (2)
1.356 (2)
Ê
0.520 (3) A, respectively, from the plane de®ned by atoms
C4A, C5, C8 and C8A. The maximum deviation of these latter
Ê
four atoms from their mean plane is 0.0134 (9) A for both C4A
C2ÐC3
and C8A. Atom C7 of the ring lies on the same side of the
cyclohexenone ring plane as the 2-chloro-5-nitrophenyl
substituent of the adjacent 1,4-DHP ring. It has been found
that atom C7 is always the out-of-plane atom in structures
involving the quinolin-5-one or dioxoacridine-1,8-dione
moiety, and that the side of the cyclohexenone ring to which
C2ÐN1ÐC8A
N1ÐC2ÐC3
C3ÐC2ÐC9
N1ÐC2ÐC9
C2ÐC3ÐC4
C4AÐC4ÐC3
122.15 (14)
119.94 (14)
126.05 (15)
114.01 (14)
121.28 (13)
109.77 (12)
C4ÐC4AÐC8A
N1ÐC8AÐC4A
O10ÐC10ÐO11
O10ÐC10ÐC3
O11ÐC10ÐC3
121.71 (13)
119.97 (14)
122.40 (15)
127.60 (16)
110.00 (13)
ꢂ
o712 Anthony Linden et al.
C20H21ClN2O5
Acta Cryst. (2004). C60, o711±o713

organic compounds
Table 2
Hydrogen-bonding geometry (A, ).
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ꢀ
Ê
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The position of the amine H atom was determined from a differ-
ence Fourier map and re®ned freely along with its isotropic dis-
placement parameter. The methyl H atoms were constrained to an
Ê
ideal geometry [CÐH = 0.98 A and Uiso(H) = 1.5Ueq(C)], but were
allowed to rotate freely about the CÐC bonds. All remaining H
Ê
atoms were placed in idealized positions (CÐH = 0.95±1.00 A) and
constrained to ride on their parent atoms [Uiso(H) = 1.2Ueq(C)].
Three low-angle re¯ections were omitted from the re®nement
because their observed intensities were much lower than the calcu-
lated values as a result of being partially obscured by the beam stop.
Data collection: COLLECT (Nonius, 2000); cell re®nement:
DENZO±SMN (Otwinowski & Minor, 1997); data reduction:
DENZO±SMN and SCALEPACK (Otwinowski & Minor, 1997);
structure solution: SIR92 (Altomare et al., 1994); structure re®ne-
ment: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII
(Johnson, 1976); software used to prepare material for publication:
SHELXL97 and PLATON (Spek, 2004).
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Acta Cryst. (2004). C60, o711±o713
Anthony Linden et al. C20H21ClN2O5 o713