Synthesis, crystal structure, and molecular modeling (AM1) of methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-2-methyl-1, 4-dihydropyridine-3-carboxylate

Article abstract of DOI:10.1023/a:1009539005669

The synthesis and structural characterization of Methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate is described. The structure was refined to R₁ = 0.0470 for 2665 reflections (with I > 2σ(I)). Crystal data:

Full text of DOI:10.1023/a:1009539005669

Journal of Chemical Crystallography, Vol. 30, No. 4, 2000
Synthesis, crystal structure, and molecular modeling (AM1)
of Methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-2-methyl-1,
4-dihydropyridine-3-carboxylate
(
1)
�
(1)
(1)
H e´ ctor Novoa de Armas,
Norbert M. Blaton, Oswald M. Peeters,
(2) (2)
(
1)
(2)
Camiel J. De Ranter, Margarita Su a´ rez, Estael Ochoa, Yamila Verdecia,
(
2)
and Esperanza Salfr a´ n
Received May 5, 2000
The synthesis and structural characterization of Methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-
2
0
-methyl-1,4-dihydropyridine-3-carboxylate is described. The structure was refined to R
1
=
.0470 for 2665 reflections (with I > 2�(I)). Crystal data: C15
H C12NO , monoclinic, space
13 3
3
˚
˚
group P2
1
/c, a = 11.163(9), b = 14.484(8), c = 9.422(7) A, V = 1512.9(19) A , Z = 4. The re-
sults of crystallographic and molecular modeling (AM1) were compared. The Cl atom attached
to the phenyl group has two possible orientations, having 75% (sp) and 25% (ap) occupancy,
respectively. The molecules in the crystal are held together by means of intermolecular hydro-
gen bonds of the type N -- -- H ���O and by C -- -- H ���O interactions.
KEY WORDS: Crystal structure; AM1; x-ray diffraction; dihydropiridines.
5
Introduction
4
-dihydropyridine derivatives by X-ray analysis and
semiempirical (AM1) calculations and both methods
show a boat conformation for the 1,4-dihydropyridine
ring witha pseudoaxialorientationof the aryl groupin
position 4. The conformational features reported for
Much effort has been devoted to the study of
,4-dihydropyridines (1,4-DHPs) due to their cal-
1
cium antagonist effect useful in the treatment of car-
1
diovascular diseases. It is well established that the
1
,4-DHP calcium modulators are preserved for these
fundamental requirement for the pharmacological
activity of the members of this family is the pres-
ence in the 1,4-DHP ring of an aromatic substituent
at position 4, alkyl groups (preferably methyl) at-
tached at the 2 and 6 positions, ester groups on C3
and C5 atoms and an H atom on N1.2 Recently,
we have developed the experimental and theoretical
structural study of 2-pyridyl- and 4-hydroxyphenyl-1,
compounds.
In spite of the widely developed chemistry of
the 1,4-DHPs,6 much less is known about the
structure of 1,4-DHPs bearing substituent other
than hydrogen atoms or alkyl groups in C2 and
,7
–4
8
C6. In this paper we report the x-ray struc-
ture of methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-
2
-methyl-1,4-dihydropyridine-3-carboxylate (II). The
title compound (II) was obtained as a crystalline solid
in good yield from 4-(2-chlorophenyl)-6-methyl-3,
(
1)
9
Laboratorium voor Analytische Chemie en Medicinale Fysic-
ochemie, Faculteit Farmaceutische Wetenschappen, Katholieke
Universiteit Leuven, Van Evenstraat 4, B-3000 Leuven, Belgium.
4
-dihydropyridone-5-carboxylate (I) (see Scheme 1)
and has proved to be an excellent intermediate in
the synthesis of other heterocyclic fused 1,4-DHPs
(
2)
´
´
Laboratorio de Sintesis Org a´ nica, Facultad de Quimica. Univer-
10
like pyrazolo[3,4-b]pyridines
pyridines.
and thieno[2,3-b]
sidad de La Habana, 10400 La Habana, Cuba.
To whom correspondence should be addressed.
�
11
2
37
1
074-1542/00/0400-0237$18.00/0 �C 2000 Plenum Publishing Corporation

238
Novoa de Armas, Blaton, Peeters, De Ranter, Su a´ rez, Ochoa, Verdecia, and Salfr a´ n
Experimental
able starting materials and reagents were purchased
from commercial sources (BDH and Fluka) and were
Synthesis of methyl 6-chloro-4-(2-chlorophenyl)-5-
formyl-2-methyl-1,4-dihydropyridine-3-carboxylate
used without further purification. Aromatic aldehy-
des were distilled before used.
(
II)
Methyl 6-chloro-4-(2-chlorophenyl)-5-formyl-2-
methyl-1,4-dihydropyridine-3-carboxylate (II)
A solution of anhydrous N,N-dimethylforma-
mide (40 mmol, 3.1 mL) in dry chloroform (10 mL)
was added dropwise to a stirred solution of phos-
phorus oxychloride (40 mmol, 3.85 mL) under a
nitrogen atmosphere at room temperature. After
� 1
IR (KBr, cm ): 3250 (NH), 2850 (CO), 1712
1
(
(
CO), 1612 (C == C); H NMR (DMSO---- d6): � 10.36
s, 1H, NH, deuterium oxide exchangeable), 9.65 (s,
3
4
0 min a solution of 4-(2-chlorophenyl)-6-methyl-3,
1
H, HCO), 7.30-719 (m, 4H, aromatics), 5.27 (s, 1H,
-dihydropyridone-5-carboxylate (I) (10 mmol)11
13
CH), 3.49(s, 3H, OCH3), 2.26(s, 3H, CH3); CNMR�
in 40 mL of dry chloroform was added. After 18 h
stirring at room temperature, a solution of sodium
acetate (40 g) in water (60 mL) was slowly added.
After 0.5 h, the mixture was partitioned between
water and chloroform, and the aqueous phase was
extracted with ethyl acetate. The organic phases
were mixed and dried with anhydrous magnesium
sulphate. The organic solvent was removed in vacuum
and the solid recrystallized from ethanol (yield 80%),
1
1
87.3 (HC == O), 167.3 (C == O), 145.7 (C2), 144.2 (C5),
44.1 (C2 ), 132.7 (C1 ), 132.1, 130.1, 128.9, 128.1, (C3 ,
0
0
0
0
0
0
C4 , C5 , C6 ), 111.6 (C3), 105.3 (C6), 51.7 (OCH3),
3
4
7.6 (C4), 18.4 (CH3); Anal. Calculated C: 55.23, H:
.02, N: 4.02; Found C: 55.31, H: 4.10, N: 4.41.
Crystallography
Suitable crystals were obtained from slow evap-
�
m.p. 197–198 C.
oration in ethanol at room temperature. The struc-
tures were solved by direct methods and Fourier syn-
Characterization and spectroscopy
12
thesis using the program SHELXS97 and refined
on F2 with SHELXTL97 with scattering factors
13
Melting points were determined in a capillary
tube in an Electrothermal C14500 apparatus and are
uncorrected. The NMR spectra were recorded on
14
from International Tables. Other programs used:
DIF415 for computing data collection and cell re-
1
5
15
1
finement, REDU4 and EMPIR for data reduc-
a Bruker DPX300 spectrometer (300 MHz- H and
1
6
13
tion; DIAMOND for computing molecular graph-
ics, PLATON17 for computing publication material.
Non-H-atoms were refined anisotropically by full-
matrix least-squares techniques. H atoms were calcu-
lated geometrically and included in the refinement,
but were restrained to ride on their parent atoms.
TheisotropicdisplacementparametersoftheHatoms
were fixed to 1.3 times Ueq of their parent atoms. The
Cl atom attached to the phenyl group was located
from the 1F map and found to be in two possible posi-
tions (Cl2a and Cl2b), with 75% and 25% occupancy
respectively. Crystallographic data for compound II
is given in Table 1; final atomic coordinates are in
Table 2; and a comparison of geometrical parameters
for the observed and calculated structure of II is given
in Table 3.
7
5.47 MHz- C). Chemical shifts are given as � val-
ues against tetramethylsilane as the internal standard
and J values are given in Hz. The IR spectra were
measured with a Shimadzu FTIR 8300 instrument as
potassium bromide pellets. Microanalyses were per-
formed in a Perkin Elmer 2400 CHN by Servicio de
Microan a´ lisis, Universidad Complutense de Madrid.
The reactions were monitored by TLC and performed
on silica-gel plates (Merck 60F250) using hexane:
ethyl acetate (8:2) as the eluent. Commercially avail-
Molecular modeling
Full energy minimization in vacuo was carried
18
out using semiempirical AM1 calculations with the
aid of the MOPAC19 molecular orbitals set. The
Scheme 1

Synthesis, crystal structure and molecular modeling
239
Table 1. Crystal Data and Structure Refinement Details for (II)
Compound
CCDC no.
Color/shape
Chemical formula
Formula weight
Temperature
Crystal system
Space group
C15H13Cl2NO3
CCDC-141913-1003/5852
Colorless/prism
C15H13Cl2NO3
326.16
293(2)
Monoclinic
P21/c
Unit cell dimensions
˚
a = 11.163(9) A
b = 14.484(8) A � = 96.71(6)�
˚
˚
c = 9.422(7) A,
(
from 24 reflections, 15 < � < 25)
˚
3
3
Volume
1512.9(19) A
4
Z
�
1
Density (calculated)
Absorption coefficient
Diffractometer/scan
Radiation/wave length
F(000)
1.432 Mg m
�
0.437 mm
Stoe STADI4/ω
˚
0.71073 A
672
Crystal size
0.53 � 0.38 � 0.15 mm
�
range for data collection, deg
1.84 to 25
Index ranges
� 13 � h � 13, � 17 � k � 2, � 2 � l � 11
4185
2665 (Rint = 0.024)/1645[I > 2�(I)]
Reflections measured
Independent/observed
reflections
Absorption correction
Range of rel. transm. factors
Data/restraints/parameters
Goodness-of-fit on F2
SHELXL97 weight parameters
Final R indices [I > 2�(I)]
R indices (all data)
Semi-empirical from � -scans30
0.833/0.924
2665/48/0/203
1.020
0.0457, 0.5257
R1 = 0.0470, wR2 = 0.1021
R1 = 0.1027, wR2 = 0.1183
0.28/� 0.21
Largest diff. Peak/hole
crystallographic coordinates were used as starting
geometry for calculations. Previously, the molecular
geometry was optimized using Allinger’s Molecular
Mechanics20 with PCMODEL program. The struc-
tures with lowest energies following the AM1 opti-
mization were used for comparison with the X-ray
structures. Calculations were performed on an IBM-
RS6000 workstation.
possible conformers within the range of less than
2 Kcal (Scheme 2). The most stable by about 0.3
Kcal/mol, is presented in Fig. 1. The crystal structure
with the atomic numbering scheme and showing the
Cl atom attached to the phenyl group with the two
possible orientations (Cl2a and Cl2b, with 75% and
25% occupancy, respectively), is shown in Fig. 2.
Semiempirical AM1 method showed that the 1,4-
dihydropyridine ring adopts a flattened boat confor-
mation, in which the carbon atoms of the olefinic dou-
ble bonds are in the same boat main plane and the aryl
substituent on C4 in a pseudoaxial disposition (see
Fig. 1).
The calculated heats of formation for this com-
pound, using the AM1 semiempirical method, re-
vealed that conformer sp (synperiplanar) is slightly
more stable (0.15 kcal/mol) than conformer ap (an-
tiperiplanar). In the crystal both conformers are
present with a distribution population of 75% for sp
21
Discussion
We have previously confirmed that semiempiri-
cal calculations at the AM1 level (see experimental
section) reproduce adequately the geometry of 3,4-
dihydropyridones.1
1,22
Therefore, we have used the
AM1 method to find out the stability of the several
conformers of the title compound (II). The semiem-
pirical (AM1) calculations for (II) resulted in eight

240
Novoa de Armas, Blaton, Peeters, De Ranter, Su a´ rez, Ochoa, Verdecia, and Salfr a´ n
4
Table 2. Atomic Coordinates (� 10 ) and Equivalent Isotropic
2
˚
3
Displacement Parameters (A � 10 ) for Compound (II)
x
y
z
U(eq)a
Cl1
Cl2a
Cl2b
N1
O3
O5
O7
C2
C3
C4
C5
C6
5929(1)
2111(1)
2925(4)
4234(2)
4975(2)
1372(3)
1990(2)
4800(2)
4502(2)
3437(2)
2949(3)
3333(3)
2036(3)
1098(4)
2937(3)
5183(3)
2459(3)
1852(3)
991(3)
6054(1)
5546(1)
3012(2)
6631(2)
3423(2)
6417(2)
4988(2)
5849(2)
5000(2)
4877(2)
5806(2)
6617(2)
5794(2)
4889(3)
7566(2)
4195(2)
4276(2)
4517(2)
3948(3)
3128(3)
2871(2)
3430(2)
1349(1)
736(1)
72(1)
58(1)
75(1)
52(1)
66(1)
110(1)
67(1)
48(1)
44(1)
42(1)
43(1)
47(1)
55(1)
83(1)
69(1)
55(1)
44(1)
47(1)
62(1)
73(1)
73(1)
57(1)
5066(4)
2761(3)
3002(3)
5390(4)
5801(2)
2415(3)
2854(3)
3706(3)
4147(3)
3665(3)
5150(4)
6774(4)
4017(4)
2571(4)
2897(3)
1576(3)
850(4)
C7
C8
C9
C10
0
0
0
0
0
0
C1
C2
C3
C4
C5
C6
705(3)
1276(4)
2140(3)
1446(5)
2744(5)
3461(4)
aU(eq) is defined as one third of the trace of the orthogonalized Ui j
tensor.
˚
Table 3. More Relevant Bond Distances [A], Valence Angles
[
�
�
] and Torsion Angles [ ] for the More Stable Conformation of
Compounds (II)
AM1
X-ray
Bond distances
N1 ---- C2
C2 ---- C3
C3 ---- C4
C4 ---- C5
1.397
1.355(4)
1.352(4)
1.520(4)
1.527(4)
1.347(4)
1.392(4)
1.529(4)
1.221(4)
1.323(4)
1.727(3)
1.364
1.507
1.499
1.372
1.393
1.508
1.232
1.238
1.712
C5 ---- C6
C6 ---- N1
C4 ---- C1’
C7 ---- O5
C7 ---- O7
C2 ---- Cl1
Valence angles
C2 ---- N1 ---- C6
C3 ---- C4 ---- C5
O5 ---- C7 ---- C3
O7 ---- C7 ---- C5
119.7
121.7(3)
111.5(2)
123.8(3)
112.1(3)
Scheme 2
111.9
125.6
128.6
Dihedral angles
N1 ---- C2 ---- C3 ---- C4
C2 ---- C3 ---- C4 ---- C5
C3 ---- C4 ---- C5 ---- C6
C4 ---- C5 ---- C6 ---- N1
C5 ---- C6 ---- N1 ---- C2
C6 ---- N1 ---- C2 ---- C3
and 25% ap, respectively. The cis (sp) disposition be-
2.9
� 17.4
17.7
� 3.1
� 13.5
13.7
68.3
22.8
16.3
106.4
106.2
3.8(5)
� 8.8(4)
7.9(4)
� 1.8(4)
� 4.3(4)
3.3(5)
tween the endocyclic double bonds and the C == O at
C3 was found more stable that the trans one by AM1.
This is not the case of the crystal structure where this
carbonyl group has a trans (ap) disposition, induced
probably by packing interactions due to the fact that
it is involved in an intermolecular hydrogen bond
P
a
|
�|
29.9(5)
O5 ---- C7 ---- C3 ---- C2
O7 ---- C7 ---- C5 ---- C6
C2 ---- C3 ---- C4 ---- C1’
C3 ---- C4 ---- C1’ ---- C2’
176.7(3)
� 163.3(3)
117.4(3)
� 61.7(3)
with the N1 of the neighboring molecule [N1���O3:
˚
2
.861(4) A]. The ester group at C5 was found to be
P
a
nearly coplanar with the nearest double bond in the
DHP ring (both, in AM1 and in the crystal structure),
|
�| Sum of the modular values of internal dihedral angles of
16
the dihydropyridine ring.

Synthesis, crystal structure and molecular modeling
241
Fig. 1. Plot showing the lowest energy conformer for com-
pounds (II) obtained by semiempirical calculations (AM1), 1H =
�
71.23 kcal/mol.
and having a sp orientation, as found in the major-
ity of the more than 30 crystal structures of members
2
of the nifedipine family. It is thought that only the
sp conformation of the ester group permits hydrogen
bonding to the carbonyl O atom as acceptor atom
when the drug binds to its receptor site.4
,23
The geometrical features predicted for the mini-
mum energy conformation of (II) calculated by AM1
along with the results obtained by X-ray crystallogra-
phy analysis are listed in Table II, showing the most
relevant bond distances, valence angles and dihedral
angles. Most bond lengths and angles are in good
agreement with values retrieved from the Cambridge
Structural Database24 (Version 5.18, October 1999).
The torsion angles predicted by AM1 do not agree
wellwiththoseinthecrystalstructure(TableII)show-
ing clearly the differences in the conformations found
in the solid state and by minimization in vacuo. The
mean value of the C == C in the 1,4 DHP ring is 1.350(4)
Fig. 2. Plot showing the atomic numbering scheme. The Cl atom
attached to the phenyl group has two possible orientations (Cl2a
and Cl2b), having 75% (A) and 25% (B) occupancy, respectively.
Displacement ellipsoids are drawn at 50% probability level for non-
H-atoms.
˚
25
A, which is closer to that found by Krajewski in a
˚
related compound (1.365A).
X-ray crystallography data shows that the 1,4
DHP ring has a slight twofold axis along C4 ���N1
and can be described as being mainly in a boat-like
conformation, a common feature for cyclohexa-1,4-
chair (20% chair with N1 pointing down, 21% twist
boat with axis through C5 and C4 pointing up, 59%
boat with bowsprit at N1 pointing up).
When the plane of the aromatic ring attached
to C4 is perpendicular to the pseudoplane of the
26
27
dienes, with puckering parameters Q = 0.0873(3)
˚
�
�
A, � = 71.9(2) and � = 8(2) . This ring conforma-
tion represents 14% of puckering in ideal cyclohexane

242
Novoa de Armas, Blaton, Peeters, De Ranter, Su a´ rez, Ochoa, Verdecia, and Salfr a´ n
base of the DHP boat, activity of DHP’s increases.4,28
The torsion angle that describes this parameter is
The C
-
--- H���O intramolecular interaction [C9���
˚
˚
O5: 2.833(5) A, H9a���O5: 2.14 A, and
0
0
�
C3---- C4---- C1 ---- C2 . The bisection of the aromatic
ring with respect to the DHP ring can be expressed
as the difference between this torsion angle and the
C9
˚
-
--- H9a���O5: 128 ; and C10���Cl1: 3.081(4)
˚
----
�
A, H10���Cl1: 2.67 A, and C10 H10���Cl1: 107 ]
stabilizes the molecular conformation in the crystal.
�
ideal value of 60 . This torsion angle shows that the
plane of the phenyl ring is approximately bisecting
the pyridine ring. The dihedral angle between their re-
spective least-squares planes is 87.79(16) . This inter-
Acknowledgments
�
ring orientation is preferred because it minimizes the
This work was supported in part by the K.U.
Leuven (Belgium) through an IRO scholarship for
H. Novoa. M. Su a´ rez is indebted to Proyectos Alma
Mater (U.H.) for its financial support.
steric strain imposed by the ortho phenyl substituent.
0
The value of the dihedral angle C1 ---- C4---- C3---- C2,
�
lowerthan120 , showsthatthephenylgroupisinaxial
position.
�
This compound exhibits a deviation of 1.7(3)
References
from the ideal value. The sum, 6|�|, of the absolute
values of the internal torsion angles of the DHP ring is
a measure of its planarity (Table II). Published struc-
ture activity ratios indicate that increased planarity
of this ring (6|�| tending to zero) correlates with
higher activity of the compound. Larger 6|�| values
are observed, in general, for parent compounds with a
nitro group in the meta position. Deviations from pla-
narity in the DHP ring, defined as the sum of the nu-
meric values of the six-intraring torsion angles, range
1
2
. Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291.
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3
4
2
5. Novoa de Armas, H.; Blaton, N.; Peeters, O.M.; De Ranter,
´
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�
�
from 52.1 to 112.5 in the investigated nifedipines
29
2
derivatives. Compound (II) exhibits a 6|�| value of
�
2
9.9(5) , which is one of the lowest values ever found.
3
However, it is difficult to justify in this case the activity
comparing the degree of planarity of the ring in the
solid state. Presumably, activity should be determined
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8. Guzman, A.; Romero, M.; Maddox, A.; Muchowski, J. J. Org.
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´
9
. Verdecia, Y.; Su a´ rez M.; Morales, A.; Rodriguez, E.; Ochoa,
´
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´
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Quinteiro, M.; Seoane, C.; Soto, J.L. J. Heterocyclic. Chem.
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1
1
1. Morales, A.; Ochoa, E.; Su a´ rez, M.; Verdecia, Y.; Gonzalez, L.;
´
Martin, N.; Quinteiro, M.; Seoane, C.; Soto, J.L. J. Heterocyclic.
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2. Sheldrick, G.M. SHELXS97, Program for the Solution of Crys-
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4
and coworkers, the authors noted an apparent corre-
lation between activity (as measured by IC50 for tonic
CD response in guinea pig ileal longitudinal muscle)
andtheplanarityoftheDHPring(asindicatedby�ave,
the average of the absolute value of the torsion angles
13. Sheldrick, G.M. SHELXL97, Program for the Refinement of
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1
4. International Tables for X-Ray Crystallography, Vol. C;
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Version 1.03). Darmstadt: Germany.
(
7
(
C2---- C3---- C4---- C5 and C3---- C4---- C5---- C6). The value
�
�
ave < 15 corresponds to the most potent compounds
�
in that series. In compound (II) �ave is 8.4(4) , which
16. Bergerhoff, G. DIAMOND-Visual Crystal Structure Informa-
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5
3121 Bonn, Germany, 1996.
1
7. Spek, A.L. (1990). PLATON, An Integrated Tool for the Anal-
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The molecules in the crystal are held to-
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1
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˚
˚
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�
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