Synthesis, characterization and structural conformation studies of 2-amino-3-ethoxycarbonyl-4-(4"-methoxy phenyl)-4H-pyrano-[3,2-c]-chromene- 6-methyl-5-one

Article abstract of DOI:10.1007/s10870-007-9241-6

2-amino-3-ethoxycarbonyl-4-(4'-methoxy Phenyl)-4H-pyrano-[3,2-c]-chromene- 6-methyl-5-one was synthesized by the two-component reaction of 6-methyl-4-hydroxy coumarin with 4'-methoxy-2-cyano cinnamate, which was synthesized by Knoevenagel reaction with 88

Full text of DOI:10.1007/s10870-007-9241-6

J Chem Crystallogr (2007) 37:733–738
DOI 10.1007/s10870-007-9241-6
ORIGINAL PAPER
Synthesis, Characterization and Structural Conformation Studies
of 2-Amino-3-ethoxycarbonyl-4-(40-methoxy Phenyl)-4H-pyrano-
[3,2-c]-chromene-6-methyl-5-one
S. Naveen Æ S. Lakshmi Æ Dinesh Manvar Æ Alpesh Parecha Æ Anamik Shah Æ
M. Anandalwar Sridhar Æ J. Shashidhara Prasad
Received: 19 December 2006 / Accepted: 10 August 2007 / Published online: 14 September 2007
ꢀ Springer Science+Business Media, LLC 2007
Abstract 2-amino-3-ethoxycarbonyl-4-(40-methoxy Phe-
nyl)-4H-pyrano-[3,2-c]-chromene-6-methyl-5-one was
Hydroxycoumarins, a diverse class of natural products, pos-
sess a wide range of biological activities[1] including
anti-coagulant,[2] fungicides,[3] anti-inflammatory,[4] anti-
tumour agents[5] and HIV protease inhibition effects.[6] It
forms the key intermediate for the extensive use as oral anti-
coagulants[7] and rodenticides.[8] Chromene derivatives can
be used as immuno modulators and for the prophylaxis and
treatment of different diseases of connective tissues, diabetes,
psoriasis, anti-viral, ulcerous colitis and chronic hepatitis.
Several natural or synthetic coumarins with various hydroxyl
and other substituents were found to inhibit lipid peroxidation
and to scavenge hydroxyl radicals and superoxide anions.[9]
4H-Chromenes with amino and cyano groups are also the
synthons of some special natural products.
synthesized by the two-component reaction of 6-methyl-4-
hydroxy coumarin with 40-methoxy-2-cyano cinnamate,
which was synthesized by Knoevenagel reaction with
88% yield. The compound obtained was characterized by
spectroscopic techniques and confirmed by X-ray crystal-
lographic studies. The crystallographic data analysis reveals
that the title compound crystallizes in the triclinic space
˚
group P1 with cell parameters a = 7.7750(8) A, b =
˚
˚
9.0310(6) A, c = 15.6120(17) A, a = 77.249(7)ꢁ, b =
3
˚
115.860(3)ꢁ, c = 70.139(7)ꢁ, V = 1,003.0(16) A for Z = 4.
The structure has been solved by direct methods
and refined to R1 = 0.0552 for 3,164 observed reflections
with I [ 2 r(I). The pyran ring is in a flattened boat
conformation. The carbonyl group is oriented in a
-synperiplanar(cis) conformation.
In continuation of the search for such potent molecules
and as a part of our ongoing research, we planned to syn-
thesize the hybrid structure having the lipophilic
functionality on the pyran ring. We selected 4-OCH3 as an
electron donating group. The current work highlights the
synthesis as well as the crystallographic studies of the
important coumarin scaffold. The title compound was
synthesized by the reaction of 4-hydroxycoumarin and ethyl
40-methoxy-2-cyanocinnamate in the presence of piperidine
as a base catalyst. Ethyl-40-methoxy-2-cyanocinnamate was
prepared by performing Knoevenagel reaction of 4-meth-
oxy benzaldehyde with ethylcyanoacetate in quantitative
yield. The structure of the title compound was established
on the basis of Fourier transform infrared (FTIR) absorption
spectroscopy, NMR and elemental analysis and finally
confirmed by X-ray crystallography.
Keywords Knoevenagel reaction ꢀ Crystal structure ꢀ
Flattened boat ꢀ Hydrogen bonds
Introduction
4-Hydroxycoumarin comprises the structural nucleus of
large number of important drug entities. 4-
S. Naveen ꢀ S. Lakshmi ꢀ M. A. Sridhar (&) ꢀ
J. Shashidhara Prasad
Department of Studies in Physics, University of Mysore, Mysore
570 006, India
e-mail: mas@physics.uni-mysore.ac.in
Experimental
D. Manvar ꢀ A. Parecha ꢀ A. Shah
Department of Chemistry, Saurashtra University, Rajkot 360
005, India
The melting point was determined in an open capillary
melting point apparatus. The FTIR absorption spectrum
123

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J Chem Crystallogr (2007) 37:733–738
was recorded on Shimadzu FTIR-8400 spectrometer (KBr
Pellet sample technique, 400–4,000 cm–1 frequency range).
1H NMR spectrum was recorded on a Bruker AC 300 MHz
FT–NMR spectrometer where TMS was used as internal
reference and DMSOd6 as solvent (chemical shifts in d
values, J in Hz). Mass spectrum was obtained using a Jeol
SX 102/DA-6000 spectrometer (for FAB). Elemental
analysis was done on CHN EA 1108 Elemental Analyser.
Analytical TLC was performed on 0.25 mm silica gel
plates (Merck 60 F254) by using solvent system ethylace-
tate:Hexane (4:6).
on a steam bath for 7 h. The solution was cooled at room
temperature for overnight. The separated solid product was
collected and washed with chilled methanol and filtered.
The solid product was then crystallized from DMF. Yield
37%, m.p.200ꢁ C. (Scheme 2)
IR (KBr): Amine, [ NH str 3,417 cm–1; CH str (asym)
2,925 cm–1, C=O str. 1,739 cm–1, C=O str.(pyran ring)
cm–1; Aromatic C=C str. 1,452 cm–1; C-N str. 1,523 cm–1;
substituted phenyl ring str. 750 & 763 cm–1.
1H NMR (300 MHz): d1.31(t, 3H, CH3); d 2.356 (s, 3H,
CH3); d 3.726 (s, 3H, CH3); d 4.17(q, 2H, CH2); d 5.17 (s,
1H); d 6.52 (s, broad, 2H, NH2); d 7.23 (m, 4H, J = 9 Hz &
1.8 Hz, phenyl-H); d 7.46 (m, 4H, Phenyl-H).
Preparation of Ethyl 2-cyano-3-(4-methoxy phenyl)
acrylate:
FAB Ms m/z (%) = 400[M+1], 368(100%) (Base peak).
Anal. Calcd. for C23H21NO6 (407.4): C = 67.80%;
H = 5.20%; N = 3.44%; O = 16.50; Found: C = 67.89%;
H = 6.28%. N = 3.39%; O = 16.50%.
In a clean dry beaker, 4-methoxy benzaldehyde (2.72 g,
0.01 mol) was taken and was cooled to 5ꢁ C. Ethyl cyano
acetate (1.98 g, 0.02 mol) was added dropwise. Piperidine
(0.3 ml) was added immediately as a base catalyst. After
thorough mixing and keeping at room temperature, the
reaction mass was poured in to ice cold water, filtered and
washed with water, dried and recrystallized from methanol.
Yield: 88%. (Scheme 1)
IR (KBr): CH str. (assym.) 2,925 cm–1, C=N str.
1,737 cm–1, Aromatic C=C str. 1,451 cm–1; 1,528 cm–1;
substituted phenyl ring str. 742 and 769 cm–1.
Crystal Structure Determination and Refinements
A single crystal of the title compound with dimensions 0.25
· 0.25 · 0.2 mm was chosen for an X-ray diffraction
study. The data were collected on a DIPLabo Image Plate
system equipped with a normal focus, 3 kW sealed X-ray
source [graphite monochromated MoKa]. The crystal to
detector distance is fixed at 120 mm with a detector area of
441 · 240 mm2. A total of 36 frames of data were col-
lected at room temperature by the oscillation method. Each
exposure of the image plate was set to a period of 400 s.
Successive frames were scanned in steps of 5ꢁ per minute
with an oscillation range of 5ꢁ. Image processing and data
reduction were done using Denzo.[10] The reflections were
merged with Scalepack. All of the frames could be indexed
using a primitive triclinic lattice. The structure was solved
by direct methods using SHELXS-97.[11] All the non-
hydrogen atoms were revealed in the first Fourier map
itself. Full-matrix least squares refinement using SHELXL-
97 [11] with isotropic temperature factors for all the atoms
converged the residuals to R1 = 0.1547. Refinement of
non-hydrogen atoms with anisotropic parameters was
started at this stage. The hydrogen atoms were placed at
chemically acceptable positions and were allowed to ride
on the parent atoms. Refinement of 275 parameters with
1H NMR (300 MHz): d 1.36(t, 3H, CH3); d 3.81 (s, 3H,
CH3); d 4.19(q, 2H, CH2); d 6.71 (d, 2H, J = 9 Hz &
1.8 Hz, phenyl-H); d 7.14 (d, 2H, J = 9 Hz & 1.8 Hz,
Phenyl-H). FAB Ms m/z (%) = 232 [M+1].
Anal. Calcd. for C13H13NO3 (2312): C = 67.52%,
H = 5.67%, N = 6.06%, O = 20.76%; Found: C = 67.6%,
H = 5.68%, N = 6.01%, O = 20.03%.
Preparation of 2-amino-3-ethoxycarbonyl-4-(4-
methoxy Phenyl)-4H-pyrano-[3,2-c]-chromene-6-
methyl-5-one
A mixture of 4-hydroxy-6-methyl coumarin (1.76 g,
0.01 mol) and Ethyl 2-cyano-3-(4-methoxy phenyl) acry-
late (2.17 g, 0.01 mol) in absolute ethanol (30 ml) and
piperidine (0.5 ml) was added. The mixture was refluxed
H3C
Scheme 1 First reaction
scheme
H3C
CH 3
CH 3
O
O
O
O
Piperidine
Stirring
O
+
O
O
N
H
N
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J Chem Crystallogr (2007) 37:733–738
735
CH 3
Table 1 Crystal data and Structure refinement table
H
O
O
CCDC Deposition Number
CCDC 615274
NC
+
Empirical formula
Formula weight
Temperature
C23H21NO6
407.41
COOEt
H3C
O
295(2) K
OH
CH 3
˚
0.71073 A
Wavelength
Crystal system
Space group
Triclinic
Methanol
Piperidine
P1
˚
a = 7.7750(8)A
Cell dimensions
˚
b = 9.0310(6) A
NH2
O
˚
c = 15.6120(17) A
a = 77.249(7)ꢁ
b = 81.890(3)ꢁ
c = 70.139(7)ꢁ
O
CH 3
O
O
H
H3C
3
˚
Volume
1003.0(16) A
O
O
Z
2
1.349 Mg/m3
0.098 mm–1
428
CH 3
Density(calculated)
Absorption coefficient
F000
Scheme 2 Second reaction scheme
Crystal size
0.25 · 0.25 · 0.2mm
2.44ꢁ–25.03ꢁ
–9 £ h £ 9
–9 £ k £ 10
–17 £ l £ 18
4783
3,164 unique reflections converged the residuals to
R1 = 0.0552. The details of the crystal data and refinement
are given in Table 1.1
Theta range for data collection
Index ranges
Reflections collected
Results and Discussion
Independent reflections
Absorption correction
Refinement method
3164 [R(int) = 0.0238]
None
Full-matrix least-squares on F2
Spectroscopic Analysis
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I [ 2 r(I)]
R indices (all data)
3164 / 0 / 275
The FTIR spectrum reveals the presence of all the func-
tional groups present in the molecule. Here, the methylene
group has asymmetric and symmetric C–H stretching
vibration modes which occur near 2,926 cm–1 and
2,853 cm–1. The bands due to the aromatic system occur
near 1,600 cm–1, 1,580 cm–1, 1,530 cm–1 and 1,450 cm–1.
The out of plane wagging vibrations for the aromatic sys-
tem are observed at 815 cm–1 and 756 cm–1. The C=N
stretching band is observed at 2,235 cm–1 in the interme-
diate product. In the final product, the peak at 2,235 cm–1
disappears and formation of new broad peak at 3,417 cm–1
indicates the presence of amino group. Carbonyl of ethyl
ester and pyran ring appears at 1,739 cm–1 and 1,679 cm–1.
1.062
R1 = 0.0552, wR2 = 0.1639
R1 = 0.0657, wR2 = 0.1800
0.042(8)
Extinction coefficient
Largest diff. peak and hole
–3
˚
0.296 and –0.203 e.A
and d = 7.46 ppm. The mass spectrum shows the M+ peak
at 408 m/e and the base peak at 368 m/e. The elemental
analyses values are in good agreement with the theoretical
values.
Table 2 gives the list of bond distances and bond angles
of non-hydrogen atoms respectively. The bond lengths and
bond angles are in good agreement with the standard val-
ues. Fig. 1 represents the ORTEP [12] of the molecule with
thermal ellipsoids drawn at 50% probability. Fig. 2 depicts
the packing of the molecules when viewed down the b axis.
The X-ray crystal structure determination shows that the
1
In H NMR, due to the presence of ethyl group triplet
and quartets were observed. The methyl protons show
signals at d = 2.356 ppm and OCH3 shows singlet at
3.726 ppm. Stereogenic center shows a sharp singlet at
d = 5.17 ppm. Aromatic protons appeared at d = 7.23 ppm
1
˚
interatomic distances 1.343(3) A for C3–C8 and
‘‘CCDC 615274 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44-1223-336033. email: deposit@ccdc.cam.ac.uk’’
˚
1.356(3) A for C5–C6 are near to that of a typical C–C
˚
double bond (1.34 A). The bond angles for C3–C8–O7,
C8–C3–C4, C4–C5–C6 and C5–C6–C7 are 122.67(17)ꢁ,
123

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J Chem Crystallogr (2007) 37:733–738
˚
Table 2 Bond Lengths (A) and Bond Angles (ꢁ)
Atoms
Length
Atoms
Length
O1–C14
O1–C2
C2–O16
C2–C3
C3–C8
C3–C4
C4–C5
C4–C23
C5–C6
C5–C18
C6–N17
C6–O7
O7–C8
C8–C9
C9–C14
C9–C10
C10–C11
1.374(2)
1.377(2)
1.208(2)
1.445(3)
1.343(3)
1.508(3)
1.517(3)
1.535(3)
1.356(3)
1.444(3)
1.334(3)
1.382(2)
1.365(2)
1.440(3)
1.389(3)
1.396(3)
1.383(3)
C11–C12
C11–C15
C12–C13
C13–C14
C18–O19
C18–O20
O20–C21
C21–C22
C23–C24
C23–C28
C24–C25
C25–C26
C26–O29
C26–C27
C27–C28
O29–C30
1.397(3)
1.502(3)
1.374(3)
1.387(3)
1.224(3)
1.342(2)
1.447(3)
1.488(4)
1.378(3)
1.382(3)
1.383(3)
1.381(3)
1.376(3)
1.377(3)
1.388(3)
1.426(3)
Atoms
Angle
Atoms
Angle
C14–O1–C2
O16–C2–O1
O16–C2–C3
O1–C2–C3
C8–C3–C2
C8–C3–C4
C2–C3–C4
C3–C4–C5
C3–C4–C23
C5–C4–C23
C6–C5–C18
C6–C5–C4
C18–C5–C4
N17–C6–C5
N17–C6–O7
C5–C6–O7
C8–O7–C6
C3–C8–O7
C3–C8–C9
O7–C8–C9
C14–C9–C10
C14–C9–C8
C10–C9–C8
C11–C10–C9
121.67(15)
116.61(17)
125.16(18)
118.23(17)
118.85(17)
122.00(17)
119.14(16)
108.87(15)
111.83(15)
110.53(15)
119.06(18)
121.07(17)
119.41(17)
128.35(19)
109.36(17)
122.29(18)
118.46(15)
122.67(17)
123.17(18)
114.14(17)
119.33(18)
115.86(18)
124.76(18)
120.85(19)
C10–C11–C12
C10–C11–C15
C12–C11–C15
C13–C12–C11
C12–C13–C14
O1–C14–C13
O1–C14–C9
118.30(19)
120.9(2)
120.8(2)
121.84(19)
119.09(19)
117.50(18)
121.90(17)
120.59(19)
122.41(18)
126.1(2)
C13–C14–C9
O19–C18–O20
O19–C18–C5
O20–C18–C5
C18–O20–C21
O20–C21–C22
C24–C23–C28
C24–C23–C4
C28–C23–C4
C23–C24–C25
C26–C25–C24
O29–C26–C27
O29–C26–C25
C27–C26–C25
C26–C27–C28
C23–C28–C27
C26–O29–C30
111.46(17)
117.01(18)
107.2(2)
117.37(19)
122.18(17)
120.34(17)
121.8(2)
119.8(2)
124.8(2)
115.72(19)
119.5(2)
119.6(2)
121.81(19)
117.80(19)
122.00(17)ꢁ, 121.07(17)ꢁ and 122.29(18)ꢁ respectively,
which illustrate that C3, C5, C6 and C8 all adopt sp2 hybrid
orbit to form C=C double bonds. The bond angle C6–O7–
C8 = 118.46(15)ꢁ is nearer to 120ꢁ, which indicates that
the O7 atom adopts sp2 hybrid orbit to conjugate the in-
tercyclic C=C bonds C5–C8 and C8–C3. The bond length
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J Chem Crystallogr (2007) 37:733–738
737
˚
Table 3 Hydrogen-bonding geometry (A.ꢁ)
D–H…A
D–H
H–A
D–A
D–H…A
Symmetry Codes
N17–H17B…O16
C25–H25…O29
0.8600
0.9300
2.1400
2.5900
2.969(4)
3.518(5)
161.00
177.00
1 + x, y, z
1 – x, –y, 2 – z
*
The D–H and H–A distances are essentially standard values and are not derived from the experiment.
Fig. 1 ORTEP diagram of the
molecule with thermal
ellipsoids drawn at 50%
probability
Fig. 2 Packing diagram of the
molecules when viewed down
the b axis. The dashed lines
represent the hydrogen bonds
2
˚
of C8–O7 (1.365(2) A) is a little bit shorter than that of
˚
C6–O7 (1.382(2) A) becuase of the conjugate effect. Due
˚
length of 1.334(3) A is shorter than the typical Csp –N
bond distance [13]. The pyran ring [O1/C2/C3/C8/C9/C14]
of the coumarin core is planar. A study of the torsion
to the existence of a conjugated system, the C6–N17 bond
123

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J Chem Crystallogr (2007) 37:733–738
Acknowledgements The authors would like to express their thanks
to Department of Chemistry, Saurashtra University, Rajkot for the
laboratory facility and DST, Government of India for financial
assistance under the project SP/I2/FOO/93.
angles, asymmetric parameters and least-squares plane
calculations reveals that the pyran ring [C3/C4/C5/C6/O7/
C8] in the structure adopts a flattened boat conformation
˚
with the atoms C4 and O7 deviating by –0.150(2) A and –
˚
0.098(17) A from the Cremer and Pople plane [14] defined
by the atoms C3/C5/C6/C8. This is also confirmed by the
˚
References
puckering parameters Q = 0.2240(21) A, h = 73.60(54)ꢁ
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Ethyl
2-amino-3-ethoxycarbonyl-7,8-dimethyl-4-
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the C6 = C5 bond adopts a cis conformation as indicated
by the torsion angle value of –3.41(3)ꢁ for C6–C5–C18–
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intramolecular N–H…O hydrogen bonding involving the
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the ester substituted analogs the carbonyl oxygens gener-
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123