Structure of a β-amino dicarbonyl compound: 2-[(4-chloro-phenyl)- pyrrolidin-1-yl-methyl]-malonic acid diethyl ester

Article abstract of DOI:10.1007/s10870-011-0044-4

The titled new functionalized ligand 2-[(4-chloro-phenyl)-pyrrolidin-1-yl- methyl]-malonic acid diethyl ester (4) is prepared in good yield through condensation of pyrazole and 3,5-dimethyl-pyrazole, respectively, with 2-arylidene-malonic acid diethyl est

Full text of DOI:10.1007/s10870-011-0044-4

J Chem Crystallogr (2011) 41:891–894
DOI 10.1007/s10870-011-0044-4
COMMUNICATION
Structure of a b-Amino Dicarbonyl Compound: 2-[(4-Chloro-
Phenyl)-Pyrrolidin-1-yl-Methyl]-Malonic Acid Diethyl Ester
•
Ihssan Meskini Loic Toupet Maria Daoudi
•
•
•
Abdelali Kerbal Taibi Ben Hadda
Received: 21 October 2009 / Accepted: 7 March 2011 / Published online: 29 March 2011
Ó Springer Science+Business Media, LLC 2011
Abstract The titled new functionalized ligand 2-[(4-
chloro-phenyl)-pyrrolidin-1-yl-methyl]-malonic acid die-
thyl ester (4) is prepared in good yield through condensation
of pyrazole and 3,5-dimethyl-pyrazole, respectively, with
2-arylidene-malonic acid diethyl esters (3). The structures
metal complexes, in many cases exploring the known-well
polydentate ligands, appear in this scenario as the most
promising concept to employ in either enzyme/drug inter-
action or electron transfer process, in the last case
involving the biological oxygen transfer [4–6]. Another
exciting example of application for such polydentate ligand
involves the synergic water activation, that occurs via the
so-called ‘‘remote metallic atoms’’. Such organometallic
compounds are structurally deemed to promote or block the
H–I activity [7]. These explanations above detailed clearly
demonstrate that polydentate ligands are of special interest
in the bioorganometallic chemistry field [8].
1
of (4) is determined by spectral (IR, H NMR), elemental
analyses and X-ray diffraction data. The structure of (4) was
solved in triclinic, space group P-1, with a = 5.6858(2),
˚
b = 10.0716(4), c = 16.2885(7) A, a = 94.338(3, b =
3
˚
91.453(4), c = 97.750(3)°, V = 921.00(6) A , Z = 2.
Keywords b-Amino dicarbonyl derivatives ꢀ Malonate ꢀ
Michael reaction
Looking for the design of new bimetallic coordinating
ligands to further explore in the building of intermolecular
system involving H–I/inhibitor/metal complexation, we
have targeted to study the crystallographic structure of
polydendate malonates (4).
Introduction
The rational design of new HIV-1 Integrase (H–I) inhibi-
tors, one validated target for chemotherapeutic intervention
[1], is fundamentally based on intermolecular coordination
To prepare such polydentate ligands, aza-Michael reac-
tions appear to be key-step to lead the b-amino esters. In fact,
this kind of reaction has been largely employed to generate
structurally diverse b-amino dicarbonyl compounds, where
the undoubtedly importance of this aza-Michael step it is
viewed by the large number of unconventional methodolo-
gies as well as the broadened of applications [9–11].
between H–I/chemical inhibitor/metals (Mg?2 and Mn?2
,
co-factors of the enzyme), leading in the formation of
bimetallic complexes [2, 3]. Thereby, several bimetallic
I. Meskini ꢀ M. Daoudi ꢀ A. Kerbal
´
Laboratoire de Chimie Organique, Universite Sidi Mohammed
`
Ben Abdellah, Fes, Morocco
Results and Discussion
Chemistry
L. Toupet
´
Institut de Physique-IPR-UMR CNRS 6251, Universite de
Rennes 1, Rennes, France
The treatment of 2-(4-chloro-benzylidene)-malonic acid
diethyl esters (3) in the presence of pyrrol or 3,5-dimethyl-
pyrazole, in an aqueous medium at room temperature
brings about highly and efficient regioselective aza-
Michael addition to produce the corresponding b-amino
T. Ben Hadda (&)
Laboratoire Chimie des Materiaux, FSO, Universite Mohammed 1,
´
´
Oujda, Morocco
e-mail: taibi.ben.hadda@gmail.com
123

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J Chem Crystallogr (2011) 41:891–894
Table 1 Crystal data and structure refinement for (4)
X-ray data
Compound (4)
Empirical formula
Formula weight
C18H24Cl1N1O4
353.83
Temperature
50(2) K
˚
0.71073 A
Wavelength
Crystal system, space group
Unit cell dimensions
Triclinic, P-1
˚
a = 5.6858(2) A
˚
b = 10.0716(4) A
˚
c = 16.2885(7) A
a = 94.338(3)°
b = 91.453(4)°
c = 97.750(3)°
3
˚
Volume
921.00(6) A
Z
2
Calculated density
F(000)
1.276 Mg/m3
376
Absorption coefficient
Crystal size
0.228 mm-1
0.18 9 0.12 9 0.12 mm
3.11 to 26.99°
-7 B h B 7, -12 B k B 12,
-20 B l B 20
Scheme 1 (i) Piperidine, CH3CO2H, EtOH/D; (ii) Pyrrolidine [this
work] or 3,5-dimethyl-pyrazole and amines [16, 17]
Theta range for data collection
Limiting indices
dicarbonyl compounds (4) which is similar to previously
published compound (5) [16, 17] (Scheme 1).
Reflections collected/unique
Completeness to h = 26.99
Absorption correction
Refinement method
12152/3678 [R(int) = 0.0344]
91.5%
None
Full-matrix least-squares on F2
X-Ray Structure Determination of (4)
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2sigma(I)]
R indices (all data)
3678/0/217
0.897
Suitable single crystal of malonate derivatives (4) is
obtained by recrystallization from ethanol. White-trans-
parent crystals of C18H24Cl1N1O4 (4) are mounted on a
glass fibre. All measurements were made in the x-scan
technique on a CCD Saphire 3 Xcalibur diffractometer
(Oxford diffraction) with graphite monochromatized
MoKa radiation. The detials of the data collection and
refinement are given in Table 1. Intensity controls without
appreciable decay (1.2%) gives 3678 unique reflections
from which 2459 with I [ 2.0r(I). The structure was
solved by direct methods using the program SIR-97 and the
non-hydrogen atoms were refined anisotropically by the
full-matrix least-square techniques using the program
SHELXL97 [12–14]. All the hydrogen atoms bonded to C
atoms were located geometrically and treated using a riding
R1 = 0.0386, wR2 = 0.0930
R1 = 0.0620, wR2 = 0.0972
-3
˚
0.211 and -0.249 eA
Largest diff. peak and hole
CCDC number
734196
˚
Table 2 Bond lengths [A] and angles [°] for (4)
N(1)–C(15)
1.457(2)
O(3)–C(6)
1.1990(18)
1.4560(19)
1.329(2)
N(1)–C(1)
1.470(2)
O(4)–C(7)
N(1)–C(18)
1.466(2)
O(4)–C(6)
O(1)–C(3)
1.197(2)
C(1)–C(9)
1.523(2)
O(2)–C(3)
1.3375(19)
1.455(2)
C(2)–C(6)
1.523(2)
O(2)–C(4)
C(4)–C(5)
1.502(3)
O(1)–C(3)–C(2)
O(1)–C(3)–O(2)
O(2)–C(3)–C(2)
O(2)–C(4)–C(5)
O(3)–C(6)–O(4)
O(3)–C(6)–C(2)
O(4)–C(7)–C(8)
O(4)–C(6)–C(2)
125.05(15)
124.46(16)
110.47(15)
106.42(18)
125.16(15)
124.69(16)
109.46(15)
110.15(13)
N(1)–C(1)–C(2)
N(1)–C(1)–C(9)
N(1)–C(15)–C(16)
N(1)–C(18)–C(17)
C(3)–C(2)–C(1)
C(3)–C(2)–C(6)
C(3)–O(2)–C(4)
C(6)–O(4)–C(7)
107.99(12)
115.36(14)
104.14(13)
102.47(13)
108.68(13)
108.89(13)
116.05(14)
117.51(12)
˚
model, with C–H = 0.93–0.97 A and Uiso(H) = 1.2 or
1.5Ueq(C). The details of the crystal and experimental data
were listed in Table 1. Selected bond distances and bond
angles are given in Table 2. The molecular structure of the
title ligand is shown in Fig. 1. Packing and hydrogen
bonding interactions are illustrated in Fig. 2.
In the molecular structure of (4), the nitrogen and the
two carbonyl groups of two carboxylate pocess dihedral
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J Chem Crystallogr (2011) 41:891–894
893
recorded on AC 250 MHz NMR Bruker spectrometer at
ambient temperature and chemical shifts were reference to
the internal tetramethylsilane. Infrared spectra were recor-
ded in KBr pellets using a Perkin-Elmer 1310 spectropho-
tometer. Mass spectra were determined by platform II
Micromass (ESI?, CH3CN/H2O: 50/50). Elemental analy-
ses were performed by CNRST Service central d’analyse
`
CURI (Fes, Morocco) Table 4.
Synthesis of Diethyl (4-Chlorobenzyl)Propanedioate (3)
To a solution of ethyl malonate (2) (15 g, 93 mmol) in
40 mL of ethanol, were added the respective aldehyde
(4-chloro-benzaldehyde (1) (15 g, 107 mmol)] and 1.5 mL
of piperidine and 1 mL of glacial acetic acid. Then the
mixture was stirred at refluxing temperature of ethanol for
12 h, until thin-layer chromatography indicated the com-
plete consume of the starting material. After removing
solvent, the crude product was washed with a saturated
solution of sodium bisulfite (20 ml). The product was
extracted by diethyl ether (2 9 20 mL), dried with sodium
sulphate and evaporated to give the pure oil.
Fig. 1 ORTEP viewsof (4) with the atom numbering scheme.
Displacement ellipsoids for non-H atoms are drawn at the 50%
probability level. H atoms were omitted for clarity
Yellow oil. 77% yield, Rf 0.73 (ether/hexane, 1/1). IR
(KBr, m cm-1): 2906-2982 (CH), 1724 (CO) 1591/1631
1
(C=C), 1254/1308 (C–O). H-NMR (300 MHz, CDCl3) d
ppm: 7.7 (s, 1H, C=CH-ph), 7.45–7.30 (m, 4H, Ph), 4.31–4.4
3
(2 q, 4H, 2CH2–CH3, J = 7.12 Hz), 1.31–1.25 (2 t, 6H,
2H2C–CH3, 3J = 7.11 Hz). 13C-NMR (300 MHz, CDCl3) d
ppm: 166.36–163.86 (2C=O); 140.01 (ClPh–CH=), 132.90
(Cquat, C–Cl–Ph), 130.30 (2Cmeta), 130.49 (Cquat, para/Cl),
129.07 (2Cortho), 125.40 (C=C-(CO2Et)2), 61.44–61.79
(2CH2–CH3), 13.74–13.88 (2CH3–CH2). MS (IE): Calcd for
[M]?ꢀC14H15ClO4: 282.07; [M ? H]? = 283 (100%).
Fig. 2 View of the packing of the title ligand (4) in the unitcell
angles of -17.8(5), 101.1(1)° and -145.8(6)° for O1–C3–
C6–O2, O1–C3–C1–N1 and O3–C6–C1–N1, respectively.
By the same way we note a trans addition around initial
C1=C2 double band; the angles are different of 180°
[H1–C1–C2–H2 = 177.1(3)°, C3–C2–C1–C9 = 174.4(4)°
and N1–C1–C2–C6 = 176.6(4)°]. The trans chacater of
this trans addition is confirmed again by the angle of
atoms in trans positions which is always different of 180°
[N1–C1–C2–H2 = 62.5(6)°]. The crystal structure of the
title ligand is stabilized by intra-molecular C–HꢀꢀꢀO = C
type-hydrogen bonding interactions forming a 3D network
(Table 3 and Fig. 2).
Synthesis of 2-[(4-Chloro-phenyl)-Pyrrolidin-1-yl-
Methyl]-Malonic Acid Diethyl Ester (4)
To a solution of the 2-(4-chloro-benzylidene)-malonic acid
diethyl ester (3) (8.1 mmol) in water (25 mL) was added
the respective secondary amine (6 mmol) and the mixture
and the stirring was continued at room temperature until
the complete consume of the starting material. After
removing solvent, the crude products were dissolved in
diethyl ether (2 9 40 mL) and washed with water until the
pH became neutral. The organic solvent was dried with
sodium sulphate and then evaporated to give the pure
compounds (4).
Experimental Section
White powder, Mp 77–79 °C. Rf = 0.68 (ether/hexane:
1/1). IR (KBr, m cm-1): 2969 (C–H, Ph), 2674/2806 (C–H),
1747/1720 (C=O), 1592/1464 (C=C), 1329/1256 (C–O).
1H-NMR (300 MHz, CDCl3) d ppm: 7.29–7.29 (m, 2H,
aromat), 7.14–7.18 (m, 2H, Ph), 4.5 (d, 1H, PhC3H,
All materials and solvents used were of reagent grade as
received from commercial sources. The starting material
2-(4-chloro-benzylidene)-malonic acid diethyl ester (3) was
synthesized and transformed to the malonate derivative as
described in our previous work [15]. 1H NMR spectra were
123

894
J Chem Crystallogr (2011) 41:891–894
Table 3 Torsion angles [°] for (4)
N(1)–C(1)–C(2)–C(3)
N(1)–C(1)–C(9)–C(10)
N(1)–C(1)–C(9)–C(14)
N(1)–C(15)–C(16)–C(17)
N(1)–C(1)–C(2)–C(6)
C(1)–N(1)–C(15)–C(16)
C(1)–C(9)–C(10)–C(11)
C(1)–C(2)–C(3)–O(1)
C(1)–C(2)–C(3)–O(2)
C(1)–C(2)–C(6)–O(4)
-57.06(16)
-90.71(18)
88.33(18)
C(1)–C(9)–C(14)–C(13)
-178.12(15)
-172.38(14)
35.8(2)
C(1)–N(1)–C(18)–C(17)
C(1)–C(2)–C(6)–O(3)
Cl(1)–C(12)–C(13)–C(14)
C(2)–C(1)–C(9)–C(10)
C(2)–C(1)–C(9)–C(14)
C(3)–O(2)–C(4)–C(5)
C(3)–C(2)–C(6)–O(3)
C(3)–C(2)–C(6)–O(4)
C(4)–O(2)–C(3)–O(1)
-22.51(18)
-176.64(13)
171.86(14)
178.75(15)
-62.0(2)
178.64(13)
33.8(2)
-147.13(15)
176.28(18)
-83.6(2)
95.75(16)
3.2(2)
119.46(14)
-144.80(14)
˚
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Table 4 Hydrogen-bond parameters for (4) (A, °)
D–HꢀꢀꢀA
d(D–H)
0.99
d(HꢀꢀꢀA)
d(DꢀꢀꢀA)
\(D–HꢀꢀꢀA)
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18:4521–4524
C7 H7A O1
2.54(6)
3.23(2)
126.3(1)
`
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8998
3J = 11.40 Hz), 4.09 (d, 1H, C2H(CO2Et)2, 3J =
11.40 Hz), 4.25 (q, 2H, CH2OCH3, 3J = 7.1 Hz), 3.95 (m,
0
2H, CH2OCH3), 2.49 (m, 2H, N-C10 H2, pyrol), 2.35 (m,
0
0
2H, NC1 H2, pyrol), 1.59 (m, 4H, 2C1 H2C2 H2, pyrol), 1.30
3
(t, 3H, CH2OCH3, J = 7.1 Hz), 1.03 (t, 3H, CH2OCH3,
3J = 7.1 Hz). 13C-NMR (300 MHz, CDCl3) d ppm:
166.97/167.88 (2C=O), 133.35 (Cquat, CCl, Ph), 133.22
(Cquat, Ph, para/Cl), 130.35 (Ctert, 2C ortho, Ph), 128.05
(Ctert, 2Cmeta, Ph), 64.05 (Ctert, C3HPh), 61.40 (C,
7. Zeng LF, Jiang XH, Sanchez T, Zhang HS, Dayam R, Neamati N,
Long YQ (2008) Bioorg Med Chem 16:7777–7787
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OCH2CH3, ester), 61.30 (C, OCH2CH3, ester), 56.50 (Ctert
,
0
C2H(CO2Et)2),0 48.41/46.88 (2C, 2C1 H2N, pyrol), 22.84
0
(2C, 2C1 H2C2 H2), pyrol), 13.91/14.12 (2C, 2OCH2CH3).
2D-NMR confirms the observed signals. MS (IE): Calcd
for [M]? C18H24ClNO4: 353.14, [M ? H]? (m/z) = 354
(18%), [M-CH(CO2Et)2]? (m/z) = 194 (100%), [M- pyrol]?
(m/z) = 283. Elemental analysis for C18H24ClNO4 Calcd
(Found): C 62.12 (62.10), H 7.08 (7.28), N 3.18 (4.04).
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Acknowledgements This work was supported by the Centre
National de Recherche Scientifique, University of Rennes 1 (France)
and University of Mohammed 1 of Oujda (Morocco).
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