Synthesis and crystal structure of (2S,6R) Ethyl 1,2,6-triphenyl-4- (phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate

Article abstract of DOI:10.1007/s10870-011-0015-9

The title compound, (2S,6R), Ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6- tetrahydropyridine-3-carboxylate (C₃₂H₃₀N ₂O₂), was synthesised by the reaction of benzaldehyde, aniline and ethylacetoacetate, in the

Full text of DOI:10.1007/s10870-011-0015-9

J Chem Crystallogr (2011) 41:868–873
DOI 10.1007/s10870-011-0015-9
ORIGINAL PAPER
Synthesis and Crystal Structure of (2S,6R) Ethyl 1,2,6-triphenyl-4-
(phenylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
•
•
•
Ambika Sambyal R. K. Bamezai T. K. Razdan
Vivek K. Gupta
Received: 30 November 2010 / Accepted: 31 January 2011 / Published online: 13 February 2011
ꢀ Springer Science+Business Media, LLC 2011
Abstract The title compound, (2S,6R), Ethyl 1,2,6-tri-
phenyl-4-(phenylamino)-1,2,5,6-tetrahydropyridine-3-car-
boxylate (C32H30N2O2), was synthesised by the reaction of
benzaldehyde, aniline and ethylacetoacetate, in the pres-
ence of L (-) proline–Fe(III) complex, formed in situ, at
room temperature. The compound was characterized by
spectral methods and X-ray diffraction studies. The com-
pound crystallizes in the triclinic space group P - 1 with
the following unit-cell parameters: a = 9.651(4), b = 10.909(5),
[1–4]. The products derived from 1,2,5,6-tetrahydro-pyri-
dine have been reported as potential 5HT1A receptors and
are useful in the management of neurodisorders [5],
including Alzheimer’s disease [6] and symptoms of senile
cognitive decline [7, 8]. Some compounds derived from
this nucleus have also been found to exhibit insecticidal,
acaricidal [9], muscarinic [6, 10–12] and antiaschemic
properties [13–16]. Moreover, 2,6-disubstituted tetrahy-
dropyridine derivatives serve as valuable substrates for the
construction of polysubstituted piperidines.
˚
c = 13.737(7) A, a = 106.597(7), b = 108.664(8), c =
99.779(6)ꢁ, Z = 2. The crystal structure was solved by
direct methods using single-crystal X-ray diffraction data
collected at 100 K and refined by full-matrix least-squares
procedures to a final R-value of 0.0633 for 3415 observed
reflections. The 1,2,5,6-tetrahydropyridine ring exhibits a
flat boat conformation. The structure has intra- and inter-
molecular hydrogen bonds of the type N–HÁÁÁO, C–HÁÁÁO
and C–HÁÁÁp, which help to stabilize the crystal structure.
Several methodologies for the preparation of 1,2,5,6-tet-
rahydropyridines are known. They have been synthesized by
partial reduction of corresponding pyridinium salts or
4-piperidone derivatives [17, 18]. Normally, substituted tet-
rahydropyridines, especially the products possessing 1-aryl
function, are difficult to prepare [19]. However, some
exciting strategies for their synthesis have been developed.
These include the synthesis via iminium ion intermediate
[20–25], phosphine catalyzed (4 ? 2) p-electron electrocy-
clic annulations [26], acid catalyzed cyclisation of ene
derivatives [27], base catalyzed aza [2, 3]—Wittig rear-
rangement [28–32], aza-Diels–Alder reaction [33–36], enyne
cross metathesis and intramolecular allyl silane–nitrone
cycloaddition [37] reaction. Herein, we describe a new
asymmetrical synthesis of the title compound and its struc-
tural elucidation by spectral methods and XRD analysis.
Keywords Asymmetric synthesis Á Crystal structure Á
Direct methods Á Hydrogen bonding Á C–HÁÁÁp stacking
interactions Á Chiral tetrahydropyridine
Introduction
1,2,5,6-Tetrahydropyridine constitutes the core nucleus of
a small group of naturally occurring bioactive alkaloids
Experimental
A. Sambyal Á R. K. Bamezai Á T. K. Razdan
Department of Chemistry, University of Jammu,
Jammu Tawi 180006, India
Synthesis
V. K. Gupta (&)
Department of Physics, University of Jammu,
Jammu Tawi 180006, India
e-mail: vivek_gupta2k2@hotmail.com
A mixture of benzaldehyde 1 (2 9 10-3 mol), aniline 2
(2 9 10-3 mol), ethylacetoacetate (1 9 10-3 mol) and the
catalyst L (-) proline (15 mol %) and anhydrous FeCl3
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869
J = 12.8, 5.6 Hz), 2.82 (1H, dd, J = 12.8, 3.7 Hz), 4.22
(2H, q, J = 7.2 Hz), 4.45 (1H, dd, J = 5.6, 3.7 Hz), 5.04
(1H, s), 6.59 (4H, m), 7.01–7.36 (16H, m), 10.30 (1H, s br,
NH). 13C NMR (CDCl3; 75 MHz): dc 13.86, 32.6, 55.5,
57.2, 60.1, 97.6, 111.9, 115.1, 115.3, 124.8, 125.12, 125.2,
125.3, 125.4, 126.6, 127.6, 127.7, 127.8, 127.9, 136.9,
137.0, 143.06, 146.0, 155.1, 167.8. MS: m/z (rel. int.)
474.6141 (M?) (calcd. for C32H30N2O2 474.6059) (100),
467(72), 446(32), 402(53), 293(33), 221(51), 201(43),
181(69), 160(76) 129(67), 107(77), 92(59). Anal. calcd. for
C32H30N2O2: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.89;
H, 6.45; N, 5.91.HPLC : retention time: tr (minor),
6.58 min; tr (major) 8.75 min.
H
N
N
O
H
O
NH2
O
O
+
L (-) proline - FeCl
THF, r.t. 20-36 hrs
3
+
H
O
OEt
1
2
3
Scheme 1 Preparation of ethyl 1,2,6-triphenyl-4-(phenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate
(5 mol%) (Scheme 1), in dry tetrahydrofuran (THF), were
stirred at room-temperature. The reaction was monitored
by thin layer chromatography (TLC). After the completion
of the reaction (24–36 h.), THF was evaporated under
pressure. The residue was triturated with water and
extracted twice with ethylacetate. The combined ethyl-
acetate extract was washed with water, dried over anhy-
drous sodium sulphate and filtered. The filtrate was
concentrated at low pressure and allowed to stand at room
temperature, for 24 h., when a solid separated out. The
products 3 was re-crystallized from ethyl acetate (yield
89%) (Scheme 1). For XRD studies, compound 3 (500 mg)
was further purified by column chromatography, on silica
gel, using chloroform–ethylacetate (9:1 v/v). The product 3
(487 mg) thus obtained was crystallized from chloroform–
methanol to give colorless crystals, m.p. 175.1 ꢁC. Single
crystals were obtained by slow evaporation of the ethyl-
acetate solution.
Crystal Structure Determination and Refinement
X-ray intensity data of 8025 reflections (of which 5774
unique) were collected at 100 K on Bruker CCD area-
detector diffractometer equipped with graphite monochro-
˚
mated MoK a radiation (k = 0.71073 A). The crystal used
for data collection was of dimensions 0.30 9 0.20 9
0.1 mm. The cell dimensions were determined by least-
square fit of angular settings of 1144 reflections in the h
range 2.61–24.30ꢁ. The intensities were measured by U and
x scan mode for h ranges 2.28–28.34ꢁ. 3415 reflections
were treated as observed (I [ 2r(I)). Data were corrected
for Lorentz and polarisation factors. The structure was
solved by direct methods using SHELXS97 [38]. All non-
hydrogen atoms of the molecule were located in the best
E-map. Full-matrix least-squares refinement was carried
out using SHELXL97 [38]. All the hydrogen atoms were
located on a difference electron density map and their
positional and isotropic thermal parameters were included
in the refinement. The final refinement cycles converged to
an R = 0.0633 and wR (F2) = 0.1501 for the observed
data. Residual electron densities ranged from -0.256 to
Spectral Analysis
TLC was performed on 0.5 mm thick plates using silica gel
G adsorbent. Column chromatography was performed on
silica gel (mesh size 60–120) using graded solvent systems
of petroleum (40–60 ꢁC) benzene, pet ether–chloroform and
chloroform–methanol. The calculated mass values are based
on the values obtained by Chem.4D Draw (Chem innova-
tions) software. IR, on KBr discs, was taken on Perkin-
0.239 eA-3. Atomic scattering factors were taken from
˚
International Tables for X-ray Crystallography (1992, Vol.
C, Tables 4.2.6.8 and 6.1.1.4). The crystallographic data
are summarized in Table 1. CCDC—780253 contains the
supplementary crystallographic data for this paper.
1
Elmer FTIR spectrophotometer. H-NMR (200 MHz) and
13C-NMR (50.3 MHz) were recorded in CDCl3 using Bru-
ker Ac DPX-200 spectrometer. HRMS were recorded on
JEOL D-300 mass spectrometer at 70 eV. [a]D (conc.
0.1 M) was measured on Perkin-Elmer 241 polarimeter,
using acetonitrile as solvent. The distereomeric excess (de)
of the products was determined by HPLC, using Diacel OD-
H column and solvent system n-hexane–isoPrOH (7:3 v/v).
Results and Discussion
The reaction of benzaldehyde (2 mmol), aniline (2 mmol)
and ethylacetoacetate (1 mmol) in THF was stirred vigor-
ously in the presence of L (-) proline and anhydrous ferric
chloride, at room temperature. The reaction was monitored
by thin layer chromatography. On completion of the
reaction (24 h) and work up, the product (3) was isolated
with ethylacetate. After concentrating the ethylacetate
solution, the contents of the flask were left as such (2 days)
Spectral Data of Compound 3
IR (KBr) : tmax 3047, 2973, 1653, 1589, 1500, 1449, 1373,
1328, 1256, 1171, 1071, 944, 750 cm-1. 1H-NMR (CDCl3,
300 MHz): d 1.45 (3H, t, J = 7.0 Hz), 2.76 (1H, dd,
123

870
J Chem Crystallogr (2011) 41:868–873
Table 1 Crystal data and other
experimental details
CCDC Number
780253
Crystal description
Crystal size
White transparent plate
0.3 9 0.2 9 0.1 mm
Empirical formula
Formula weight
C
32H30N2O2
474.58
Mo Ka, 0.71073 A
˚
Radiation, Wavelength
Unit cell dimensions
˚
a = 9.651(4), b = 10.909(5), c = 13.737(7) A
a = 106.597(7), b = 108.664(8), c = 99.779(6)
Triclinic, P - 1
Crystal system, space group
Unit cell volume
3
˚
1257.6(10) A
No. of molecules per unit cell, Z
Absorption coefficient
F(000)
2
0.078 mm-1
504
h range for entire data collection
Reflections collected/unique
Reflections observed (I [ 2r(I))
No. of parameters refined
Final R-factor
2.28 \ h \ 28.34o
8025/5774
3415
245
0.0633
wR(F2)
0.1501
Goodness-of-fit
1.000
(D/r)max
0.000 for U33 O7’
-3
˚
Final residual electron density
Data collection
-0.256 \ Dq \ 0.239 eA
Bruker SMART [40]
Bruker SMART [40]
Bruker SAINT [40]
Cell refinement
Data reduction
when colorless crystals of (3) separated out as a single
compound (TLC). The compound was recrystallized from
chloroform–methanol (19:1 v/v) and was characterized as
ethyl 1,2,6-triphenyl-4-(phenylamino)-1,2,5,6-tetra-hydro-
pyridine-3-carboxylate, by spectral methods. Optimization
of the reaction conditions showed that for obtaining the
maximum yield of the product, the requisite concentration
of L (-) proline and ferric chloride was 30 mol% and
10 mol%, respectively.
The structure of the products 3 was elucidated by
spectral methods (HRMS, IR, 1H-NMR, 13C-NMR and
DEPT 1350) and elemental analysis. The IR spectra of 3
exhibited characteristic absorption bands at tmax 1653
(conjugated C=O), 2973 (C–N), 1589, 1449 (C=C) cm-1
,
in addition to the other expected aromatic absorption
1
bands. The H-NMR spectrum of the compound, besides
displaying the expected aromatic proton resonance signals,
exhibited the characteristic resonance signals at d 1.45 (3H,
t, J = 7.2 Hz), 4.22 (2H, q, J = 7.2 Hz), for ester ethoxy
group, and a broad resonance signal near d 10.30, attrib-
utable to the hydrogen bonded proton of secondary amino
group at C-4. The diastereotopic methylene protons at C-5
Fig. 1 ORTEP view of the molecule with displacement ellipsoids
drawn at 40%. H atoms are shown as small spheres of arbitrary radii
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J Chem Crystallogr (2011) 41:868–873
871
displayed two double doublets at d 2.76 (J = 12.8, 5.6 Hz)
and 2.82 (J = 12.8, 3.7 Hz). The double doublet at d 4.45
(J = 3.7, 5.6 Hz) was attributable to the equatorial proton
at C-6. This placed the phenyl group at C-6 in axial posi-
tion. The single proton singlet at d 5.04 was assigned to the
proton geminal to the phenyl group at C-2. 13C-NMR and
DEPT 135ꢁ spectra displayed the ethoxy and ring methy-
lene resonance signals near dc 59.9 and 32.8, respectively.
The resonance signals due to the double bond carbons of
the tetrahydropyridine ring were observed at dc 97.6 (C-3)
and 155.10 (C-4), while as the signals due to C-2 and C-6
were displayed at dc 55.6 and 57.2, respectively.
compound with atomic labeling is shown in Fig. 1 [39].
The 1,2,5,6-tetrahydro-pyridine ring (THP) exhibits a boat
conformation. The C2 and C5 atoms lie 0.440(2) and
˚
0.699(2) A, respectively, from the least-squares plane
defined by the remaining four atoms of the THP ring.
The absolute stereochemistry (2R,6S) at C-2 and C-6 was
assigned from XRD studies and by the comparison with
the stereochemistry of 2a-phenyl-2,3-dihydrobenzopyran-
4-one [25], Although, the compounds 3, [a]D ? 250 (conc.
0.1 M), possesses two chiral centers HPLC showed the
presence of only two distereoisomers of which one was
present in excess. The enentiomeric excess was not deter-
mined. The mechanism of the reaction may be rationalized
as involving the condensation of arylaldehyde and arylamine
to form Schiffs’ base which may undergo stereospecific
The structure of 3 and stereochemistry of the substitu-
ents on tetrahydropyridine ring was confirmed by X-ray
studies (CCDC No. 780253). An ORTEP view of the title
Scheme 2 Probable
mechanism for the formation
of 1,2,6-triaryl-1,2,5,
6-tetrahydropyridines
H2N
N
+
cat. L(-) proline- Fe( III)
THF, r.t.
O
EtO
O
O
Fe
Pr
N
CH
H
N
Fe
Pr
.
H
.
N
N
H
CH2
-H+
O
H
O
H
H
O
Fe
Pr
H
EtO
O
OEt
H
N
-
Fe
Pr
H
H
N
N
H
N
N
Fe
Pr
- H2O
H
:
O
EtO
H
O
EtO
O
H
N
N
H
H
O
EtO
123

872
J Chem Crystallogr (2011) 41:868–873
Fig. 2 The packing arrangement of molecules viewed down the a-axis. H atoms are shown as small spheres of arbitrary radii
Table 2 Hydrogen-bonding geometry (e.s.d.’s in parentheses)
˚
D–H (A)
˚
˚
D–HÁÁÁA
DÁÁÁA (A)
HÁÁÁA (A)
D–HÁÁÁA (ꢁ)
N2–H2NÁÁÁO7
0.84(2)
0.97(2)
0.99(3)
1.01(3)
1.02(2)
0.96(3)
2.696(2)
3.467(3)
3.375(4)
3.381(3)
3.630(3)
3.630(4)
2.03(2)
2.54(2)
2.50(3)
2.75(3)
2.73(3)
2.93(3)
136(2)
160(2)
147(2)
121(2)
147(2)
131(2)
C23–H23…O7i
C14–H14…O7ii
C32–H32…Cg2ii
C9–H92…Cg3iii
C12–H12…Cg5iv
Cg2, Cg3 and Cg5 represent the centre of gravity of the phenyl rings (C10–C15), (C16–C21) and (C28–C33), respectively
Symmetry code: (i) -x, -y ? 1, -z ? 1; (ii) -x, -y, -z ? 1; (iii) 1 - x, 1 - y, 1 - z; (iv) -1 ? x, y, z
double Mannich-type addition by enolised six membered
ethylacetoacetate (Scheme 2) to form an intermediate car-
rying one tertiary and one secondary amino group. The
intramolecular rearrangement and subsequent annulation
followed by dehydration with released arylamine may lead
to the formation of the compound 3.
link the molecules within layers. Details of N–HÁÁÁO,
C–HÁÁÁO and C–HÁÁÁp hydrogen bonds are given in Table 2.
Supplementary Material
The original compound and spectra are available with the
authors and can be provided free of cost for reference pur-
poses. CCDC-780253 contains the supplementary crystal-
lographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Crystal Packing
Hydrogens H23 and H14 on atoms C123 and C14,
respectively form two intermolecular hydrogen bonds with
the carbonyl oxygen O7 of neighbouring centrosymmetri-
cally related molecules. These interactions link the mole-
cules into C–HÁÁÁO hydrogen bonded dimers. The dimers
are packed in layers (Fig. 2). Three C–HÁÁÁp hydrogen
bonds are also present. These intermolecular interactions
Acknowledgments The authors are thankful to Prof. P. K. Bhar-
adwaj, Department of Chemistry, IIT, Kanpur, India, for the use of the
data collection facility and to Dr. R.G.Bhat (IISER, Pune) for spectral
analysis and HPLC.
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