Studies in synthesis of furoflavones possessing anti-cancer activity

Article abstract of DOI:10.1002/jhet.5570450626

(Chemical Equation Presented) Several new furoflavanones (3a-3l) have been synthesized from the in-situ generated chalcones by the reaction of ortho-hydroxy acetyl benzofuran and aryl aldehyde in presence of piperidine. Ethanolic sodium hydroxide (1%) gav

Full text of DOI:10.1002/jhet.5570450626

Nov-Dec 2008
1729
Studies in Synthesis of Furoflavones Possessing Anti-cancer
Activity
Jagdish M. Patel and Shubhangi S. Soman*
Department of Chemistry, Faculty of Science,
The Maharaja Sayajirao University of Baroda, Vadodara 390 002, India.
E-mail: shubhangiss@rediffmail.com, jakpatel21@yahoo.com
Received May 28, 2007
R'
R'
R'
OH
O
O
Ar
O
O
Ar
O
R
O
O
ArCHO, piperidine
ethanol, reflux
DDQ
O
dry toluene, reflux
R
R
Hax
Pheq
O
C=O
Heq
Hax
quasi chair conformation
Several new furoflavanones (3a-3l) have been synthesized from the in-situ generated chalcones by the
reaction of ortho-hydroxy acetyl benzofuran and aryl aldehyde in presence of piperidine. Ethanolic sodium
hydroxide (1%) gave chalcones (2a-2l) as the exclusive product. Flavindogenides (3-arylidene flavanones)
(5a-5d) have been isolated as the co-product along with chalcones and flavanones in cases where excess of
aryl aldehyde was used. The stereochemistry of 3-arylidene flavanones has been established by the
preparation of both Z (6) and E (5a-5d) diastereomers. Single crystal X-ray diffraction data shows the
flavanone ring to exist in quasi chair conformation with phenyl ring equatorial. Furoflavanones were
finally dehydrogenated to furoflavones (4a-4l) using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone).
The compounds have been screened for in-vitro cytotoxicity against human cancer cell lines.
J. Heterocyclic Chem., 45, 1729 (2008).
INTRODUCTION
furoflavanones and furochalcones have been reported to
possess interesting pharmacological properties [12],
which prompted us to synthesize some new furoflavones
and study their cytotoxicity behaviour, which has not been
reported till date. It was also of considerable interest to
study the orientation and conformation of flavanone ring
in furoflavanones, since no such data was available in
literature.
Herein, a facile one-pot method for the synthesis of
some new furoflavanones and its crystal structure has
been reported. Two of the furoflavones have been
screened for in-vitro cytotoxicity against human cancer
cell lines. The quasi chair conformation of the flavanone
ring has been established on the basis of X-ray
crystallography. The reaction sequence for different title
compounds is outlined in Scheme 1.
2-Phenyl chromones are a group of flavonoids widely
occurring in plants where they play several biological
functions [1]. Naturally occurring flavone derivatives like
Pongachalcone I, Quercetin, Acacetin, Apigenin,
Kaempferol, Kanjone and Pongaglaborrone are known to
exhibit variety of pharmacological activities [2-4].
Alkylaminomethyl furoflavones can be used as
gastroprotective agents [5]. Quercetin and related
flavonoids are known to inhibit the growth of tumor cells.
Flavone-8-acetic
acid
inhibits
endothelial
cell
proliferation in-vitro and selectively destroys tumor
vasculature, leading to tumor cell death by ischemia.
Flavonoids have also been used as modulators of P-
glycoprotein in tumor cells [6]. Several methods have
been reported for the synthesis of flavonoids in literature
[7,8]. Most of the study done hitherto shows the formation
of chalcones and flavanones (or flavones) from ortho-
hydroxy acetophenone in acidic or alkaline conditions [9].
The disadvantage with the basic conditions is the
decomposition or retro-Aldol reaction [10], whereas acid
catalyzed condensation is known to give mixture of
chalcones, flavanones and 3-benzylidene flavanones
RESULTS AND DISCUSSION
Ortho-hydroxy acetyl benzofurans (1a-1d) [13], were
condensed with different aryl aldehydes in 1 % ethanolic
sodium hydroxide to give corresponding chalcones (2a-2l).
Though such a low concentration of alkali was used, there
was no evidence of formation of flavanones, which was
contradictory to the reports in literature which indicated
that low concentration of alkali favoured ring closure
(flavindogenides)
[11].
Several
furoflavones,

1730
J. M. Patel and S. S. Soman
Vol 45
Scheme 1
R
R'
H
Ar
R'
CH3
C6H5
2 a
OH
O
ArCHO, NaOH
ethanol, rt
p-C6H4(OCH3) 2 b
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 2 e
p-C6H4(Cl)
2 c
2 d
O
CH3
CH3
H
R
2 f
2 g
Ar
C6H5
C6H5
p-C6H4(OCH3) 2 h
p-C6H4(Cl)
C6H5
2 i
2 j
C6H5 CH3
p-C6H4(OCH3) 2 k
p-C6H4(Cl) 2 l
R'
OH
O
R
O
R
R'
CH3
H
1 a
CH3 1 b
1 c
CH3 1 d
R'
R'
C6H5
H
O
O
Ar
O
O
Ar
O
O
ArCHO, Piperidine
ethanol, reflux
DDQ
dry toluene, reflux
R
R
R
R'
H
Ar
C6H5
R
R'
H
Ar
C6H5
CH3
3 a
CH3
4 a
p-C6H4(OCH3) 3 b
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 3 e
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 3 h
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 3 k
p-C6H4(Cl) 3 l
p-C6H4(OCH3) 4 b
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 4 e
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 4 h
p-C6H4(Cl)
C6H5
p-C6H4(OCH3) 4 k
p-C6H4(Cl) 4 l
3 c
3 d
4 c
4 d
CH3
CH3
H
CH3
CH3
H
3 f
3 g
4 f
4 g
C6H5
C6H5
3 i
3 j
4 i
4 j
C6H5 CH3
C6H5 CH3
whereas high concentration of alkali favoured ring fission
presence of catalytic amount of piperidine, it gave a
mixture of chalcones and flavanones (3a-3l). Flavanone
being the major product, crystallized out from the mixture
[14]. 1H nmr of chalcone E-3-(4-chloro-phenyl)-1-(6-
hydroxy-3,7-dimethyl-benzofuran-5-yl)-propenone
2f
1
exhibited two doublets corresponding to one proton each at
ꢀ 7.70-7.74 ppm with J = 15.48 Hz and ꢀ 7.88-7.92 ppm
with J = 15.48 Hz for C(ꢁ)H and C(ꢂ)H respectively,
showing the formation of chalcone in E configuration. The
broad and shallow ir absorption at 3445 cm-1 (s) for
phenolic –OH indicates strong intramolcular hydrogen
bonding. The carbonyl absorption at 1633 cm-1 (s) along
with absorption at 1556 cm-1 indicated presence of ꢁ,ꢂ-
unsaturated carbonyl system, which further supports the E
configuration of chalcone 2f. The furan ring (-C=C-)
stretching was observed at 1609 cm-1 (s). The lcms for
chalcone 2f was obtained as m/z: 349 (M+23, 14 %), 329.2
(M+2, 37), 327.1 (M+1, 100), 301.2 (11), 300.3 (26), 295.1
(20), 293.2 (17), 279.2 (9) and 269.2 (6). The UV spectrum
in ethanol showed absorption at 323, 247 and 225 nm.
However when ortho-hydroxy acetyl benzofuran (1a-
1d) were condensed with different aryl aldehydes in
of ethanol:toluene (3:7). In the H nmr of 7-(4-chloro-
phenyl)-3,9-dimethyl-6,7-dihydrofuro[3,2-g]chromen-5-
one 3f, the flavanone ring proton C(2)H appeared as a
doublet of doublet at ꢀ 5.48-5.52 ppm. The double
doublet for one proton at ꢀ 3.02-3.10 ppm with J = 16.8
Hz (geminal coupling – diastereotopic protons) and J =
12.4 Hz (vicinal diaxial coupling) indicated C(3)H proton
to be axial, and a doublet of doublet at ꢀ 2.89-2.94 ppm
with J = 3.2 Hz (vicinal coupling) and J = 16.8 Hz
(geminal coupling – diastereotopic protons) indicated
another proton at C(3) to be equatorial; forming an ABX
system. The coupling constant of C(2)H proton, 12.4 Hz
(vicinal diaxial coupling) and 3.2 Hz (vicinal axial-
equatorial coupling) indicated it to be axial in the quasi
chair conformation of the flavanone ring, with phenyl ring
equatorial [15], as shown in Figure 1. The 13C nmr of the
same compound with signals at ꢀ 44.61 ppm (C-3

Nov-Dec 2008
Studies in Synthesis of Furoflavones Possessing Anti-cancer Activity
1731
methylene), 77.76 ppm (C-2 oxymethine) and 192.29 ppm
(C-4 >C=O) further confirmed the structure of flavanone.
The lower ir absorption at 1681 cm-1 (s) indicated
conjugation and hence coplanarity of the carbonyl group
with the phenyl ring. The band at 1629 cm-1 (s) indicated
(-C=C-) stretching vibration of the furan ring. The lcms
for flavanone 7-(4-methoxy-phenyl)-3,9-dimethyl-6,7-
dihydro-furo[3,2-g]chromen-5-one 3e was obtained as
m/z: 345.2 (M+23, 16 %), 324.3 (M+2, 26) and 323.3
(M+1, 100). The UV spectrum in ethanol showed
absorption at 340, 242 and 227 nm. The quasi chair
conformation of the flavanone ring is further confirmed
by single crystal X-ray diffraction data of 3f.
deshielded due to the diamagnetic anisotropy of the
carbonyl group [16]. The E configuration of 3-arylidene
flavanone was further confirmed by converting compound
5a into its Z isomer 6 photochemically, using mercury arc
450 W lamp and toluene as solvent (Scheme 2). Z-6-
Benzylidene-3-methyl-7-phenyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 6 was purified by column chromatography
using neutral alumina, as silica gel showed some
conversion back into the E isomer. The 1H nmr of
compound 6 showed two singlets at ꢀ 6.15 and 6.7 ppm
for one proton each indicating C(2)H flavanone proton
and vinylic proton respectively. Since the vinylic proton is
now shielded, it confirmed compound 6 to be in Z
configuration. It was further supported by the ir
absorption band of carbonyl group at 1670 cm-1 (s) for the
E isomer and at 1661 cm1(s) for the Z isomer. The
absorption bands at 1624 cm-1 (s) and 1604 cm-1 (s)
indicated furan ring (-C=C-) stretching and alkene
(-C=C-) stretching respectively in both E and Z isomers.
The UV spectrum in ethanol showed absorption at 309,
257 and 227 nm for the E isomer and 306, 248 and 227
nm for the Z isomer.
Hax
Pheq
O
C=O
Heq
Hax
Figure 1. Quasi chair conformation of the flavanone ring.
When excess of aryl aldehyde was used during the
reaction, it was observed that along with flavanones, 3-
arylidene flavanones (5a-5d) were also formed. They were
isolated by column chromatography and characterized
(whether E or Z) by carrying out reaction of some of the
ortho-hydroxy acetyl benzofuran with excess aryl
aldehyde in a specific experiment. When two moles of
aryl aldehyde were condensed with one mole of ortho-
hydroxy acetyl benzofuran in presence of piperidine, 3-
arylidene flavanone was the major product obtained.
Stereochemistry of 3-arylidene flavanones has been
determined by carrying out synthesis of both Z and E
diastereomers. In the 1H nmr of E-6-benzylidene-3-
methyl-7-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-one 5a,
two singlets at ꢀ 6.6 ppm and 8.1 ppm for one proton each
indicated C(2)H flavanone proton and vinylic proton
respectively. This shows the formation of 3-arylidene
flavanones in E configuration since the vinylic proton is
Finally, all the flavanones were dehydrogenated to
flavones (4a-4l) using DDQ (2,3-dichloro-5,6-dicyano-
1,4-benzoquinone) in dry toluene. In the H nmr of 7-(4-
1
methoxy-phenyl)-3,9-dimethyl-furo[3,2-g]chromen-5-one
4e, singlet at ꢀ 6.82 ppm for one proton corresponding to
C(3)H of the flavone ring confirms that dehydrogenation
has taken place (disappearance of all double doublets).
The 13C nmr of this compound showed values at ꢀ 104.49
ppm (C-3) and 163.32 ppm (C-2), which supports the
dehydrogenated product. In the ir spectrum, the carbonyl
absorption was further lowered and observed at 1651 cm-1
(s), while (-C=C-) stretching vibration of flavone and
furan ring was observed at 1610 cm-1 (s) and 1621 cm-1 (s)
respectively. The UV spectrum in ethanol showed
absorption at 307, 278, 245 and 227 nm. The lcms for
flavone 3,7-diphenyl-furo[3,2-g]chromen-5-one 4g was
obtained as m/z: 361.1 (M+23, 11 %), 340.1 (M+2, 22)
and 339.1 (M+1, 100).
Scheme 2. Photoisomerization of E-3 Arylidene flavanones to Z-3 Arylidene flavanones.
R'
R'
O
Ar
O
O
Ar
O
Mercury arc lamp
toluene
Ar
H
R
R
O
H
O
Ar
E-3 Arylidene flavanones
Z -3 Arylidene flavanones
R
R'
Ar
R
R'
H
Ar
CH3
CH3
CH3
H
H
CH3
C6H5
p-C6H4(Cl)
p-C6H4(OCH3) 5 c
p-C6H4(OCH3) 5 d
5 a
5 b
CH3
C6H5
6
C6H5 CH3

1732
J. M. Patel and S. S. Soman
Vol 45
The structures of all compounds have been established
proves the existence of flavanone ring in quasi chair
conformation with phenyl ring at equatorial position and H-
7 hydrogen at axial position. The values of final R indices
R1= 0.0691 and WR2= 0.1634 indicates the crystal structure
is well resolved. Selected torsion angles are shown below.
on the basis of their elemental analyses and spectral (ir,
nmr) data. The long range coupling between C3-CH3 and
C2-H of the furan ring in the compounds synthesized
from 1a and 1b has been confirmed by 1H-COSY spectra.
Crystal structure of flavanone (7-(4-chloro-phenyl)-
3,9-dimethyl-6,7-dihydro-furo[3,2-g]chromen-5-one 3f).
Crystallization of flavanones (3a-3l) was studied in ethanol:
toluene mixture (3:7). Compound 3f gave good quality
needle like crystals, which were submitted for single crystal
X-ray analysis. Compound 3f crystallizes in a centro
symmetric monoclinic space group P21/c. The asymmetric
unit consists of a single flavanone molecule at a normal
position. As can be seen from Figure 2 (ORTEP diagram)
flavanone ring exists in quasi-chair conformation, with
phenyl ring at equatorial position. The crystal structure
shows the (S)-configuration of furoflavanone. All the atoms
Selected Atoms
H7-C7-C8-H8A
H7-C7-C8-H8B
C6-C7-C8-H8A
C6-C7-C8-H8B
H7-C7-C6-C5
H7-C7-C6-C1
Torsion Angle
-54.31
-171.97
66.51
-51.16
-81.77
95.76
Crystal structure data & structure refinement for the molecule is shown below:
Empirical formula
Formula weight
Temperature
C19H15ClO3
326.76
273(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Monoclinic
P21/c
Unit cell dimensions
a = 14.401(3) Å ꢀ = 90°
b = 5.4980(11) Å ꢁ =
109.841(3)°
c = 21.006(4)Å ꢂ = 90°
1564.4(6) Å3
4
Volume
Z
Density (calculated)
Absorption coefficient
(ꢃMoKꢀ)
1.387 mg/m3
0.257 mm-1
F(000)
Crystal size
Theta range for data
collection
680
0.24 x 0.15 x 0.10 mm
1.50° to 28.26°
Index ranges
-18<=h<=19, -5<=k<=7, -
26<=l<=26
8544
3574 [R(int) = 0.0311]
Full-matrix least-squares on F2
3574 / 0 / 210
Figure 2. ORTEP diagram of 7-(4-chloro-phenyl)-3,9-dimethyl-6,7-
dihydro-furo[3,2-g]chromen-5-one 3f (50% probability factor for thermal
ellipsoid with atom numbering scheme).
Reflections collected
Independent reflections
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2ꢄ(I)]
R indices (all data)
1.085
apart from C-7 are coplanar. Atom C-7 deviates from the
plane defined by atoms C8/C9/C10/C11/O1 by 0.610 Å.
The dihedral angle between the planes formed by O1/C7/C8
and C8/C9/C10/C11/O1 is 47.20° whereas the dihedral
angle between C1/C2/C3/C4/C5/C6 and C8/C9/C10/
C11/O1 planes is 4.56°. The torsion angle –54.31 for H7-
C7-C8-H8A indicates that H-7 and H8A are not in one plane
i.e. H-7 is axial and H-8A is equatorial, while the torsion
angle –171.97 for H7-C7-C8-H8B indicates that H-7 and H-
8B are almost in one plane i.e. H-7 is axial and H-8B is also
axial. The torsion angle –51.16 for C6-C7-C8-H8B indicates
that phenyl ring and H-8B are not in one plane (i.e. phenyl
ring is equatorial and H-8B is axial). Further, the torsion
angle –81.77 for H7-C7-C6-C5 and 95.76 for H7-C7-C6-C1
clearly indicates that phenyl ring and H-7 are almost
perpendicular to each other i.e. H-7 is axial and phenyl ring
is equatorial and parallel to the plane formed be
C8/C9/C10/C11/O1. The torsion angle values for selected
atoms as observed for the molecule is shown below which
R1 = 0.0691, wR2 = 0.1634
R1 = 0.0935, wR2 = 0.1765
0.421 and -0.234 e.A-3
Largest diff. peak and hole
Crystallographic data (excluding structure factors) for the structure in
this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC 621173.
Physiological activity.
Anticancer activity. Compounds 7-(4-chlorophenyl)-3-
methyl-furo[3,2-g]chromen-5-one 4c and 3,7-diphenyl-
furo[3,2-g]chromen-5-one 4g were randomly selected
from the group of furoflavones (4a-4l) synthesized and
were evaluated for in-vitro cytotoxicity against human
cancer cell lines. The human cancer cell lines produced
from National Cancer Institute, Frederick, U.S.A. were
used in present study. Cells were grown in tissue culture
flasks in complete growth medium (RPMI-1640 medium
with 2 mM glutamine, 100 ꢃg/mL streptomycin, pH 7.4,
sterilized by filtration and supplemented with 10 % fetal

Nov-Dec 2008
Studies in Synthesis of Furoflavones Possessing Anti-cancer Activity
1733
Table 1
Cell Line Type
Cell line
Colon
Colon
HT-29
Colon
Prostate
DU-145
Liver
Breast
502713
SW-620
HEP-2
MCF-7
Compound
Conc. (M)
1 X 10-6
1 X 10-5
1 X 10-4
1 X 10-6
1 X 10-5
1 X 10-4
5 X 10-5
1 X 10-5
1 X 10-5
1 X 10-6
Growth Inhibition (%)
4c
0
0
10
12
-
0
0
3
-
0
-
6
8
11
0
-
0
3
30
-
4g
0
5
0
-
0
6
29
32
41
67
41
-
5
15
30
-
35
74
-
-
-
40
31
79
-
5FU
25
84
26
-
36
63
76
-
Mito-C
-
65
-
Paclitaxel
-
Adriamycin
67
47
78
calf serum and 100 units/mL penicillin before use) at 37
°C in an atmosphere of 5 % CO2 and 90 % relative
humidity in a carbon dioxide incubator. The cells at
subconfluent stage were harvested from the flask by
treatment with trypsin (0.05 % in PBS containing 0.02 %
EDTA) for determination of cytotoxicity. Cells with
viability of more than 98 %, as determined by trypan blue
exclusion, were used for assay. The cell suspension of 1 x
105 cells/mL was prepared in complete growth medium
for determination of cytotoxicity.
Stock solutions of 2 x 10-2 M of 4c and 4g were
prepared in DMSO. The stock solutions were serially
diluted with complete growth medium containing 50
ꢀg/mL of gentamycin to obtain working test solutions of
required concentrations.
optical density (OD) was recorded on ELISA reader at
540 nm. The cell growth was calculated by subtracting
mean OD value of respective blank from the mean OD
value of experiment set. Percent growth in presence of
test material was calculated considering the growth in
absence of any test material as 100 % and in turn percent
growth inhibition in presence of test material was
calculated.
Compound 4g showed 74 % growth inhibition against
Breast MCF-7 cell line and 40 % growth inhibition
against Prostate DU-145 cell line at
1
x
10-4
concentrations. 5FU, Mito-C, Paclitaxel and Adriamycin
are the standard drugs used. The results are shown in
Table 1.
CONCLUSIONS
In-vitro cytotoxicity against six human cancer cell lines
was determined by two different experiments, using 96-
well tissue culture plates. The 100 ꢀL of cell suspension
was added to each well of the 96-well tissue culture plate.
The cells were incubated for 24 hours. Test materials in
complete growth medium (100 ꢀL) were added after 24
hours incubation to the wells containing cell suspension.
The plates were further incubated for 48 hours (at 37 °C
in an atmosphere of 5 % CO2 and 90 % relative humidity
in a carbon dioxide incubator) after addition of test
material and then the cell growth was stopped by gently
layering trichloroacetic acid (50 % TCA, 50 ꢀL) on top of
the medium in all the wells. The plates were incubated at
4 °C for one hour to fix the cells attached to the bottom of
the wells. The liquid of all the wells was gently pipetted
out and discarded. The plates were washed five times with
distilled water to remove TCA, growth medium low
molecular weight metabolites, serum proteins etc. and air-
dried. Cell growth was measured by staining with
Sulforhodamine B dye. The adsorbed dye was dissolved
in Tris-Buffer (100 ꢀL, 0.01 M, pH 10.4) and plates were
gently shaken for 10 minutes on a mechanical shaker. The
Present investigation provides a one-pot process for the
synthesis of furoflavanones. The reaction when carried
out in ethanolic sodium hydroxide gave chalcone as the
exclusive product, while reaction in piperidine gave
flavanone as the major product. Molar excess of aryl
aldehyde in the preparation of flavanones using
piperidine, leads to the formation of 3-arylidene
flavanones as a co-product. The quasi chair conformation
of the flavanone ring has been confirmed by its X-ray
crystal structure. One of the furoflavone 4g, shows growth
inhibition up to 74 % against Breast MCF–7 cancer cell
line and 40 % against Prostate DU-145 cell line, so other
compounds can also be explored for anti-cancer activity.
EXPERIMENTAL
1H and 13C nmr spectra were recorded on Bruker NMR
spectrometer. Chemical shifts are given in ꢀ ppm downfield
from tetramethylsilane as internal standard and coupling
constants are in Hertz. Infrared spectra were recorded on
Perkin-Elmer FT-IR spectrometer (spectrum RX1) using
potassium bromide optics. UV spectra were recorded on

1734
J. M. Patel and S. S. Soman
Vol 45
Perkin Elmer Lambda 35 UV/Vis spectrophotometer.
Elemental analyses were carried out on Perkin-Elmer C, H,
N, S analyzer (Model-2400) and are given in percentage. The
mass spectrum was obtained on Perkin-Elmer Sciex Triple
Quadrupole LC/MS/MS Mass Spectrometer (Model-016932)
with Ion Spray source using mobile phase Acetonitrile:
Ammonium acetate 1mM (90:10 % v/v). X-ray diffraction
data were collected using Mo Kꢀ (ꢁ=0.71073 Å) radiation on
a SMART APEX diffractometer equipped with a CCD area
detector. Data collection, data reduction, structure
solution/refinement were carried out using the software
package of SMART APEX. Graphics were generated using
MERCURY 1.4.1 [17]. Melting points are uncorrected and
were determined using a scientific capillary melting point
apparatus. Purity of the compounds was checked by tlc on
Acme’s silica gel G plates using UV/I2 vapor as visualizing
agent. Acme’s silica gel (60-120 mesh) and neutral alumina
powder was used for column chromatographic purification.
Single crystal X-ray diffraction. X-ray quality single
crystals of 3f were grown in a slow evaporation condition at
room temperature. Crystals were obtained from a mixture of
ethanol and toluene (3:7). The structure was solved by direct
methods and refined in a routine manner. All hydrogen atoms
were geometrically fixed and refined.
7.65 (2H, d, J = 8.36, C(2')H and C(6')H), 7.68-7.72 (1H, d, J =
15.44, C(ꢁ)H), 7.88-7.91 (1H, d, J = 15.44, C(ꢂ)H), 8.00 (1H, s,
C(4)H), 12.97 (1H, s, C(6)OH). Anal. Calcd. for C18H13O3Cl
(312.75): C, 69.12; H, 4.18. Found: C, 68.78; H, 3.98.
E-1-(6-Hydroxy-3,7-dimethyl-benzofuran-5-yl)-3-phenyl-
propenone 2d. 77 %; orange crystals; mp 113-114 °C; ꢀmax
/
cm-1: 3445, 3115, 2956, 1644, 1566, 1528, 1209 and 1163; H
nmr (300 MHz; CDCl3; Me4Si): ꢂ 2.29 (3H, d, J = 1.2,
C(3)CH3), 2.48 (3H, s, C(7)CH3), 7.34 (1H, d, J = 1.2, C(2)H),
7.46-7.49 (3H, m, C(3')H, C(4')H, C(5')H), 7.70-7.75 (1H, d , J
= 15.6, C(ꢁ)H), 7.73-7.74 (2H, m, C(2')H and C(6')H), 7.94-
7.99 (1H, d, J = 15.6, C(ꢂ)H), 8.1 (1H, s, C(4)H) and 13.1 (1H,
s, C(6)OH). Anal. Calcd. for C19H16O3 (292.33): C, 78.06; H,
5.51. Found: C, 78.12; H, 5.55.
1
E-1-(6-Hydroxy-3,7-dimethyl-benzofuran-5-yl)-3-(4-methoxy-
phenyl)-propenone 2e. 51 %; orange crystals; mp 144-145 °C;
ꢀmax/cm-1: 3441, 3121, 2923, 1631, 1590, 1560, 1518, 1181,
1
1163 and 1149; H nmr (400 MHz; CDCl3; Me4Si): ꢂ 2.28 (3H,
d, J = 1.2, C(3)CH3), 2.41 (3H, s, C(7)CH3), 3.89 (3H, s,
C(4')OCH3), 6.976-6.998 (2H, d, J = 8.8, C(3')H and C(5')H),
7.38 (1H, d, J = 1.2, C(2)H), 7.63-7.67 (1H, d, J = 15.6, C(ꢁ)H),
7.673-7.695 (2H, d, J = 8.8, C(2')H and C(6')H), 7.904 (1H, s,
C(4)H), 7.921-7.960 (1H, d, J = 15.6, C(ꢂ)H) and 13.418 (1H, s,
C(6)OH). Anal. Calcd. for C20H18O4 (322.35): C, 74.51; H, 5.62.
Found: C, 74.21; H, 5.34.
General procedure for (2a-2l).
E-3-(4-Chloro-phenyl)-1-(6-hydroxy-3,7-dimethyl-benzo-
furan-5-yl)-propenone 2f. 74.5 %; orange crystals; mp 206-
207 °C; ꢀmax/cm-1: 3445, 3114, 2916, 1633, 1609, 1556, 1500,
E-1-(6-Hydroxy-3-methyl-benzofuran-5-yl)-3-phenyl-pro-
penone 2a. A mixture of 1-(6-hydroxy-3-methyl-benzofuran-5-
yl)-ethanone 1a (0.0043 moles) and benzaldehyde (0.0043
moles) in ethanolic sodium hydroxide (50 mL, 1%) was stirred
for 8 hours at room temperature. The excess of ethanol was
distilled off in vacuo and the reaction mixture was poured into
ice hydrochloric acid and the solid collected by filtration. The
product was purified by column chromatography using
petroleum ether (60-80 °C): ethyl acetate (9:1) mixture as eluent
to give E-1-(6-hydroxy-3-methyl-benzofuran-5-yl)-3-phenyl-
propenone 2a (81 %) as orange crystals, mp 127-128 °C;
ꢀmax/cm-1: 3437, 3110, 2986, 1632, 1556, 1521, 1217 and 1164;
1H nmr (300 MHz; CDCl3; Me4Si): ꢂ 2.27 (3H, d, J = 1.1,
C(3)CH3), 7.02 (1H, s, C(7)H), 7.34 (1H, d, J = 1.1, C(2)H),
7.45-7.47 (3H, m, C(3')H, C(4')H, C(5')H), 7.70-7.75 (1H, d, J =
15.5, C(ꢁ)H), 7.71-7.72 (2H, m, C(2')H and C(6')H), 7.92-7.97
(1H, d, J = 15.5, C(ꢂ)H), 8.01 (1H, s, C(4)H) and 13.05 (1H, s,
C(6)OH). Anal. Calcd. for C18H14O3 (278.30): C, 77.68; H, 5.07.
Found: C, 77.59; H, 5.01.
1
1178, 1163 and 1141; H nmr (400 MHz; CDCl3; Me4Si): ꢂ 2.3
(3H, d, J = 1.4, C(3)CH3), 2.4 (3H, s, C(7)CH3), 7.37 (1H, d, J =
1.4, C(2)H), 7.42-7.44 (2H, d, J = 8.4, C(3')H and C(5')H), 7.64-
7.66 (2H, d, J = 8.4, C(2')H and C(6')H), 7.70-7.74 (1H, d, J =
15.48, C(ꢁ)H), 7.88-7.92 (1H, d, J = 15.48, C(ꢂ)H), 8.05 (1H, s,
C(4)H), 12.99 (1H, s, C(6)OH); lcms: m/z 349 (M+23, 14 %),
329.2 (M+2, 37), 327.1 (M+1, 100), 301.2 (11), 300.3 (26),
295.1 (20), 293.2 (17), 279.2 (9), 269.2 (6). Anal. Calcd. for
C19H15O3Cl (326.77): C, 69.83; H, 4.62. Found: C, 69.57; H,
4.60.
E-1-(6-Hydroxy-3-phenyl-benzofuran-5-yl)-3-phenyl-pro-
penone 2g. 89 %; orange crystals; mp 159-160 °C; ꢀmax/cm-1:
3433, 2933, 1639, 1611, 1555, 1511, 1467, 1376, 1247 and
1135; 1H nmr (300 MHz; CDCl3; Me4Si): ꢂ 7.12 (1H, s, C(7)H),
7.43-7.69 (12H, m, C(ꢁ)H, C(2)H, C(2')H to C(6')H, C(2'')H to
C(6'')H), 7.93-7.99 (1H, d, J = 15.38, C(ꢂ)H), 8.30 (1H, s,
C(4)H), and 13.03 (1H, s, C(6)OH). Anal. Calcd. for C23H16O3
(340.37): C, 81.16; H, 4.73. Found: C, 80.52; H, 4.40.
E-1-(6-Hydroxy-3-methyl-benzofuran-5-yl)-3-(4-methoxy-
phenyl)-propenone 2b. 55 %; orange crystals; mp 127-129 °C;
ꢀmax/cm-1: 3452, 3124, 2926, 1637, 1601, 1561, 1508, 1188,
E-1-(6-Hydroxy-3-phenyl-benzofuran-5-yl)-3-(4-methoxy-
phenyl)-propenone 2h. 59.5 %; orange crystals; mp 175-177
°C; ꢀmax/cm-1: 3449, 3113, 2926, 1639, 1605, 1567, 1512, 1207
1
1167 and 1144; H nmr (400 MHz; CDCl3; Me4Si): ꢂ 2.26 (3H,
1
and 1172; H nmr (400 MHz; CDCl3; Me4Si): ꢂ 3.87 (3H, s,
d, J = 1.1, C(3)CH3), 3.89 (3H, s, C(4')OCH3), 6.95-6.97 (2H, d,
J = 8.44, C(3')H and C(5')H), 7.01 (1H, s, C(7)H), 7.33 (1H, d, J
= 1.1, C(2)H), 7.58-7.62 (1H, d, J = 15.32, C(ꢁ)H), 7.65-7.67
(2H, d, J = 8.44, C(2')H and C(6')H), 7.90-7.94 (1H, d, J =
15.32, C(ꢂ)H), 8.01 (1H, s, C(4)H) and 13.14 (1H, s, C(6)OH).
Anal. Calcd. for C19H16O4 (308.33): C, 74.01; H, 5.23. Found: C,
73.71; H, 4.93.
C(4'')OCH3), 6.94-6.96 (2H, d, J = 8.48, C(3'')H and C(5'')H),
7.12 (1H, s, C(7)H), 7.42-7.46 (1H, m, C(4')H), 7.53-7.57 (1H,
d, J = 15.28, C(ꢁ)H), 7.54-7.57 (2H, d, J = 8.48, C(2'')H and
C(6'')H), 7.61-7.63 (4H, m, C(2')H, C(3')H, C(5')H, C(6')H),
7.70 (1H, s, C(2)H), 7.92-7.96 (1H, d, J = 15.28, C(ꢂ)H), 8.31
(1H, s, C(4)H) and 13.16 (1H, s, C(6)OH). Anal. Calcd. for
C24H18O4 (370.40): C, 77.82; H, 4.89. Found: C, 77.98; H, 4.91.
E-3-(4-Chloro-phenyl)-1-(6-hydroxy-3-phenyl-benzofuran-
5-yl)-propenone 2i. 81 %; orange crystals; mp 152-153 °C;
ꢀmax/cm-1: 3439, 3122, 2928, 1633, 1611, 1566, 1528, 1222 and
1151; 1H nmr (300 MHz; CDCl3; Me4Si): ꢂ 7.14 (1H, s, C(7)H),
7.41-7.69 (10H, m, C(2')H, C(3')H, C(4')H, C(5')H, C(6')H,
E-3-(4-Chloro-phenyl)-1-(6-hydroxy-3-methyl-benzofuran-
5-yl)-propenone 2c. 68 %; orange crystals; mp 159-160 °C;
ꢀ
max/cm-1: 3444, 3122, 2916, 1629, 1611, 1569, 1511, 1178,
1
1156 and 1139; H nmr (400 MHz; CDCl3; Me4Si): ꢂ 2.27 (3H,
d, J = 1.1, C(3)CH3), 7.03 (1H, s, C(7)H), 7.35 (1H, d, J = 1.1,
C(2)H), 7.42-7.44 (2H, d, J = 8.36, C(3')H and C(5')H), 7.63-

Nov-Dec 2008
Studies in Synthesis of Furoflavones Possessing Anti-cancer Activity
1735
C(2'')H, C(3'')H, C(5'')H, C(6'')H, C(ꢀ)H), 7.71 (1H, s, C(2)H),
7.89-7.94 (1H, d, J = 15.4, C(ꢁ)H), 8.29 (1H, s, C(4)H) and
12.98 (1H, s, C(6)OH). Anal. Calcd. for C23H15O3Cl (374.82): C,
73.70; H, 4.03. Found: C, 73.34; H, 4.01.
1.1, C(2)H), 7.42-7.45 (2H, d, J = 8.63, C(2')H and C(6')H) and
8.14(1H, s, C(4)H). Anal. Calcd. for C19H16O4 (308.33): C,
74.01; H, 5.23. Found: C, 73.71; H, 4.93.
7-(4-Chloro-phenyl)-3-methyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 3c. 50.5 %; light yellow crystals; mp 136-138
°C; ꢂmax/cm-1: 3126, 2922, 1689, 1619, 1611, 1520, 1470, 1355,
1271, 1241 and 1144; 1H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.24
(3H, d, J = 1.11, C(3)CH3), 2.89-2.96 (1H, dd, Jvicinal = 3.18 and
E-1-(6-Hydroxy-7-methyl-3-phenyl-benzofuran-5-yl)-3-
phenyl-propenone 2j. 85.5 %; orange crystals; mp 188-189 °C;
ꢂmax/cm-1: 3437, 2932, 1638, 1588, 1556, 1500, 1451, 1386,
1
1255 and 1175; H nmr (400 MHz; CDCl3; Me4Si): ꢀ 2.48 (3H,
Jgeminal = 16.88, C(6)equatorial H), 3.03-3.13 (1H, dd, Jvicinal
=
s, C(7)CH3), 7.44-7.74 (12H, m, C(2)H, C(ꢀ)H, C(2')H to
C(6')H, C(2'')H to C(6'')H), 7.96-8.00 (1H, d, J = 15.6, C(ꢁ)H),
8.19 (1H, s, C(4)H) and 13.31 (1H, s, C(6)OH). Anal. Calcd. for
C24H18O3 (354.40): C, 81.33; H, 5.11. Found: C, 81.16; H, 4.81.
E-1-(6-Hydroxy-7-methyl-3-phenyl-benzofuran-5-yl)-3-(4-
methoxy-phenyl)-propenone 2k. 61 %; orange crystals; mp
210-212 °C; ꢂmax/cm-1: 3441, 3110, 2946, 1644, 1615, 1560,
1522, 1201 and 1177; 1H nmr (400 MHz; CDCl3; Me4Si): ꢀ 2.49
(3H, s, C(7)CH3), 3.89 (3H, s, C(4'')OCH3), 6.95-6.97 (2H, d, J =
8.5, C(3'')H and C(5'')H), 7.43-7.47 (1H, m, C(4')H), 7.53-7.57
(1H, d, J = 15.3, C(ꢀ)H), 7.56-7.59 (2H, d, J = 8.48, C(2'')H and
C(6'')H), 7.62-7.64 (4H, m, C(2')H, C(3')H, C(5')H, C(6')H),
7.70 (1H, s, C(2)H), 7.93-7.97 (1H, d, J = 15.3, C(ꢁ)H), 8.33
(1H, s, C(4)H) and 13.19 (1H, s, C(6)OH). Anal. Calcd. for
C25H20O4 (384.42): C, 78.10; H, 5.24. Found: C, 77.82; H, 5.03.
E-3-(4-Chloro-phenyl)-1-(6-hydroxy-7-methyl-3-phenyl-
12.58 and Jgeminal = 16.89, C(6)axial H), 5.46-5.51 (1H, dd, Jvicinal
= 3.12 and Jvicinal = 12.58, C(7)axial H), 7.07 (1H, s, C(9)H), 7.36
(1H, d, J = 1.11, C(2)H), 7.40-7.43 (2H, d, J = 8.77, C(3')H and
C(5')H), 7.44-7.47 (2H, d, J = 8.74, C(2')H and C(6')H) and 8.14
(1H, s, C(4)H). Anal. Calcd. for C18H13O3Cl (312.75): C, 69.12;
H, 4.18. Found: C, 68.78; H, 3.98.
3,9-Dimethyl-7-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-
one 3d. 54 %; light yellow crystals; mp 153-154 °C; ꢂmax/cm-1:
1
3440, 2936, 1689, 1621, 1474, 1229 and 1130; H nmr (300
MHz; CDCl3; Me4Si): ꢀ 2.26 (3H, d, J = 1.1, C(3)CH3), 2.39
(3H, s, C(9)CH3), 2.92-2.99 (1H, dd, Jvicinal = 3.1 and Jgeminal
=
16.6, C(6)equatorial H), 3.08-3.19 (1H, dd, Jvicinal = 12.83 and
Jgeminal = 16.4, C(6)axial H), 5.5-5.55 (1H, dd, Jvicinal = 2.98 and
Jvicinal = 12.8, C(7)axial H), 7.39 (1H, d, J = 1.1, C(2)H), 7.4-7.59
(5H, m, C(7)phenyl protons) and 8.19 (1H, s, C(4)H). Anal.
Calcd. for C19H16O3 (292.33): C, 78.06; H, 5.51. Found: C,
78.12; H, 5.55.
benzofuran-5-yl)-propenone 2l.
84 %; orange crystals; mp
198-199 °C; ꢂmax/cm-1: 3455, 3105, 2966, 1634, 1560, 1522,
1
1207 and 1167; H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.50 (3H,
7-(4-Methoxy-phenyl)-3,9-dimethyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 3e. 42.6 %; light yellow crystals; mp 138-139
°C; ꢂmax/cm-1: 3116, 2924, 1680, 1624, 1600, 1518, 1477, 1352,
1272, 1251 and 1142; 1H nmr (400 MHz; CDCl3; Me4Si): ꢀ 2.24
(3H, d, J = 1.2, C(3)CH3), 2.39 (3H, s, C(9)CH3), 2.92-2.97 (1H,
dd, Jvicinal = 2.8 and Jgeminal = 16.8, C(6)equatorial H), 3.08-3.15
(1H, dd, Jvicinal = 12.8 and Jgeminal = 16.8, C(6)axial H), 3.86 (3H,
s, C(4')OCH3), 5.44-5.48 (1H, dd, Jvicinal = 3.2 and Jvicinal = 12.8,
C(7)axial H), 6.97-7.00 (2H, d, J = 8.8, C(3')H and C(5')H), 7.38
(1H, d, J = 1.2, C(2)H), 7.45-7.47 (2H, d, J = 8.8, C(2')H and
C(6')H) and 8.01 (1H, s, C(4)H); lcms: m/z 345.2 (M+23, 16 %),
324.3 (M+2, 26) and 323.3 (M+1, 100). Anal. Calcd. for
C20H18O4 (322.35): C, 74.51; H, 5.62. Found: C, 74.21; H, 5.34.
7-(4-Chloro-phenyl)-3,9-dimethyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 3f. 59 %; light yellow crystals; mp 169-170 °C;
ꢂmax/cm-1: 3126, 2929, 1681, 1629, 1597, 1515, 1471, 1357,
s, C(7)CH3), 7.44-7.71 (10H, m, C(2')H, C(3')H, C(4')H, C(5')H,
C(6')H, C(2'')H, C(3'')H, C(5'')H, C(6'')H, C(ꢀ)H), 7.71 (1H, s,
C(2)H), 7.90-7.95 (1H, d, J = 15.52, C(ꢁ)H), 8.32 (1H, s, C(4)H)
and 12.99(1H, s, C(6)OH). Anal. Calcd. for C24H17O3Cl
(388.84): C, 74.13; H, 4.40. Found: C, 73.88; H, 4.43.
General procedure for (3a-3l).
3-Methyl-7-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-one
3a.
A mixture of 1-(6-hydroxy-3-methyl-benzofuran-5-yl)-
ethanone 1a (0.0043 moles) and benzaldehyde (0.0043 moles)
was refluxed in absolute ethanol (15 mL) with catalytic amount
(3-4 drops) of piperidine for 36 hours. Reaction was monitored
on tlc. The excess of ethanol was distilled off in vacuo and the
reaction mixture was then poured into ice hydrochloric acid and
solid collected by filtration. The product was crystallized from
ethanol:toluene mixture to give 3-methyl-7-phenyl-6,7-dihydro-
furo[3,2-g]chromen-5-one 3a (49.5 %) as light yellow crystals,
mp 128-129 °C; ꢂmax/cm-1: 3438, 2928, 1677, 1617, 1469, 1233
and 1129; 1H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.24 (3H, d, J =
1
1277, 1255 and 1149; H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.2
(3H, d, J = 1.12, C(3)CH3), 2.4 (3H, s, C(9)CH3), 2.93-2.98 (1H,
dd, Jvicinal = 3.2 and Jgeminal = 16.8, C(6)equatorial H), 3.02-3.10
(1H, dd, Jvicinal = 12.4 and Jgeminal = 16.8, C(6)axial H), 5.48-5.52
(1H, dd, Jvicinal = 3.2 and Jvicinal = 12.4, C(7)axial H), 7.40-7.40
(1H, d, J = 1.2, C(2)H), 7.42-7.44 (2H, d, J = 8.4, C(3')H and
C(5')H), 7.47-7.49 (2H, d, J = 8.4, C(2')H and C(6')H) and
8.02(1H, s, C(4)H); 13C nmr (100MHz; CDCl3; Me4Si): ꢀ 7.87
(C3-CH3), 8.45 (C9-CH3), 44.61 (C-6), 78.76 (C-7), 109.75 (C-
9), 115.60 (C-3), 116.58 (C-4a), 117.45 (C-4), 123.79 (C-3a),
127.33 (C-3' and C-5'), 129.00 (C-2' and C-6'), 134.33 (C-4'),
137.81 (C-1'), 142.28 (C-2), 156.92 (C-8a), 158.96 (C-9a) and
192.29 (C5->C=O). Anal. Calcd. for C19H15O3Cl (326.77): C,
69.83; H, 4.62. Found: C, 69.57; H, 4.60.
0.96, C(3)CH3), 2.91-2.98 (1H, dd, Jvicinal = 3.04 and Jgeminal
=
16.9, C(6)equatorial H), 3.09-3.19 (1H, dd, Jvicinal = 12.85 and
Jgeminal = 16.9, C(6)axial H), 5.49-5.54 (1H, dd, Jvicinal = 2.88 and
Jvicinal = 12.85, C(7)axial H), 7.08 (1H, s, C(9)H), 7.36 (1H, d, J
= 0.96, C(2)H), 7.38-7.57 (5H, m, C(7)phenyl protons) and 8.15
(1H, s, C(4)H). Anal. Calcd. for C18H14O3 (278.30): C, 77.68; H,
5.07. Found: C, 77.59; H, 5.01.
7-(4-Methoxy-phenyl)-3-methyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 3b. 38 %; light yellow crystals; mp 125-126
°C; ꢂmax/cm-1: 3440, 2931, 1688, 1621, 1467, 1230 and 1130; 1H
nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.24 (3H, d, J = 1.1,
C(3)CH3), 2.87-2.94 (1H, dd, Jvicinal = 2.86 and Jgeminal = 16.88,
3,7-Diphenyl-6,7-dihydro-furo[3,2-g]chromen-5-one 3g.
48 %; light yellow crystals; mp 230-231 °C; ꢂmax/cm-1: 3439,
1
2925, 1689, 1620, 1470, 1231 and 1139; H nmr (300 MHz;
C(6)equatorial H), 3.10-3.20 (1H, dd, Jvicinal = 12.96 and Jgeminal
=
(CD3)2SO; Me4Si): ꢀ 2.90-2.97 (1H, dd, Jvicinal = 3.15 and
16.88, C(6)equatorial H), 3.07-3.16 (1H, dd, Jvicinal = 12.56 and
Jgeminal = 16.88, C(6)axial H), 5.50-5.54 (1H, dd, Jvicinal = 3.07 and
=
16.88, C(6)axial H), 3.84 (3H, s, C(4')OCH3), 5.43-5.48 (1H, dd,
Jvicinal = 2.7 and Jvicinal = 12.9, C(7)axial H), 6.95-6.98 (2H, d, J =
8.68, C(3')H and C(5')H), 7.05 (1H, s, C(9)H), 7.36 (1H, d, J =

1736
J. M. Patel and S. S. Soman
Vol 45
Jvicinal = 12.55, C(7)axial H), 7.18 (1H, s, C(9)H), 7.38-7.82
(11H, m, C(2)H, C(3)phenyl protons, C(7)phenyl protons) and
8.43(1H, s, C4-H). Anal. Calcd. for C23H16O3 (340.37): C, 81.16;
H, 4.73. Found: C, 80.52; H, 4.40.
7-(4-Methoxy-phenyl)-3-phenyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 3h. 39.8 %; light yellow crystals; mp 162-163
°C; ꢀmax/cm-1: 3440, 2930, 1682, 1623, 1469, 1232 and 1131; 1H
nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.90-2.97 (1H, dd, Jvicinal = 2.9
(0.005 moles) and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone) (0.0055 moles) was refluxed in dry toluene (15 mL) for 12
hours. The reaction mixture was washed with water followed by
washing with 10 % potassium carbonate solution and then again
with water. The toluene layer was dried over sodium sulfate and
solvent was distilled off in vacuo. The product was purified by
column chromatography using petroleum ether (60-80 °C): ethyl
acetate (7:3) mixture as eluent to give 3-methyl-7-phenyl-furo[3,2-
g]chromen-5-one 4a (86.6 %) as light brown crystals, mp 194 °C
dec; ꢀmax/cm-1: 2918, 1648, 1636, 1619, 1525, 1479, 1358, 1260 and
1133; 1H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.30 (3H, d, J = 0.58,
C(3)CH3), 6.8 (1H, s, C(6)H), 7.44-8.00 (7H, m, C(2)H, C(9)H,
C(7)phenyl protons) and 8.43 (1H, s, C(4)H). Anal. Calcd. for
C18H12O3 (276.28): C, 78.25; H, 4.37. Found: C, 78.58; H, 4.61.
7-(4-Methoxy-phenyl)-3-methyl-furo[3,2-g]chromen-5-one
4b. 69.8 %; light brown crystals; mp 238-240 °C dec; ꢀmax/cm-1:
2935, 1647, 1636, 1612, 1518, 1477, 1361, 1259, 1127 and 831;
1H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.32 (3H, d, J = 0.58,
C(3)CH3), 3.91 (3H, s, C(4')OCH3), 6.76 (1H, s, C(6)H), 7.03-
7.06 (2H, d, J = 8.88, C(3')H and C(5')H), 7.51 (1H, d, J = 0.58,
C(2)H), 7.60 (1H, s, C(9)H), 7.90-7.93 (2H, d, J = 8.88, C(2')H
and C(6')H) and 8.41 (1H, s, C(4)H). Anal. Calcd. for C19H14O4
(306.31): C, 74.50; H, 4.60. Found: C, 74.62; H, 4.69.
7-(4-Chloro-phenyl)-3-methyl-furo[3,2-g]chromen-5-one
4c. 86 %; light brown crystals; mp 250-252 °C dec; ꢀmax/cm-1:
2920, 1661, 1623, 1601, 1519, 1478, 1359, 1262, 1133 and 838;
1H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.30 (3H, d, J = 0.58,
C(3)CH3), 6.85 (1H, s, C(6)H), 7.42-7.44 (2H, d, J = 8.8, C(3')H
and C(5')H), 7.45-7.95 (4H, m, C(2)H, C(9)H, C(2')H, C(6')H)
and 8.48 (1H, s, C(4)H). Anal. Calcd. for C18H11O3Cl (310.73):
C, 69.57; H, 3.56. Found: C, 69.33; H, 3.40.
3,9-Dimethyl-7-phenyl-furo[3,2-g]chromen-5-one 4d. 91
%; light brown crystals; mp 180 °C dec; ꢀmax/cm-1: 2933, 1655,
1622, 1617, 1519, 1479, 1361, 1263, 1128 and 821; 1H nmr (300
MHz; CDCl3; Me4Si): ꢀ 2.33 (3H, d, J = 0.6, C(3)CH3), 2.74
(3H, s, C(9)CH3), 6.83 (1H, s, C(6)H), 7.50 (1H, d, J = 0.6,
C(2)H), 7.52-8.01 (5H, m, C(7)phenyl protons) and 8.44 (1H, s,
C(4)H). Anal. Calcd. for C19H14O3 (290.31): C, 78.60; H, 4.86.
Found: C, 78.44; H, 4.69.
and Jgeminal = 16.88, C(6)equatorial H), 3.12-3.22 (1H, dd, Jvicinal
=
12.87 and Jgeminal = 16.88, C(6)axial H), 5.46-5.51 (1H, dd, Jvicinal
= 2.7 and Jvicinal = 12.83, C(7)axial H), 6.96-6.99 (2H, d, J =
8.66, C(3')H and C(5')H), 7.16 (1H, s, C(9)H), 7.37-7.75 (8H,
m, C(2)H, C(3)phenyl protons, C(2')H, C(6')H) and 8.45(1H, s,
C(4)H). Anal. Calcd. for C24H18O4 (370.40): C, 77.82; H, 4.89.
Found: C, 77.98; H, 4.91.
7-(4-Chloro-phenyl)-3-phenyl-6,7-dihydro-furo[3,2-g]-
chromen-5-one 3i.
°C; ꢀmax/cm-1: 3448, 2931, 1682, 1629, 1471, 1229 and 1130; 1H
nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.92-2.98 (1H, dd, Jvicinal
61 %; light yellow crystals; mp 186-187
=
3.15 and Jgeminal = 16.88, C(6)equatorial H), 3.06-3.16 (1H, dd,
Jvicinal = 12.56 and Jgeminal = 16.88, C(6)axial H), 5.50-5.55 (1H,
dd, Jvicinal = 3.07 and Jvicinal = 12.55, C(7)axial H), 7.18 (1H, s,
C(9)H), 7.38-7.76 (10H, m, C(2)H, C(3)phenyl protons,
C(7)phenyl protons) and 8.45(1H, s, C(4)H). Anal. Calcd. for
C23H15O3Cl (374.82): C, 73.70; H, 4.03. Found: C, 73.34; H,
4.01.
9-Methyl-3,7-diphenyl-6,7-dihydro-furo[3,2-g]chromen-5-
one 3j. 52.2 %; light yellow crystals; mp 189-190 °C; ꢀmax/cm-1:
1
3441, 2937, 1688, 1623, 1471, 1238 and 1132; H nmr (300
MHz; (CD3)2SO; Me4Si): ꢀ 2.43 (3H, s, C(9)CH3), 2.92-2.98
(1H, dd, Jvicinal = 3.1 and Jgeminal = 16.84, C(6)equatorial H), 3.09-
3.17 (1H, dd, Jvicinal = 12.6 and Jgeminal = 16.85, C(6)axial H),
5.51-5.54 (1H, dd, Jvicinal = 3.1 and Jvicinal = 12.66, C(7)axial H),
7.4-7.84 (11H, m, C(2)H, C(3)phenyl protons, C(7)phenyl
protons) and 8.44(1H, s, C(4)H). Anal. Calcd. for C24H18O3
(354.40) requires C, 81.33; H, 5.11. Found: C, 81.16; H, 4.81.
7-(4-Methoxy-phenyl)-9-methyl-3-phenyl-6,7-dihydrofuro-
[3,2-g]chromen-5-one 3k. 41 %; light yellow crystals; mp 211-
213 °C; ꢀmax/cm-1: 3439, 2928, 1679, 1617, 1465, 1233 and
1
1131; H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.92-2.99 (1H, dd,
7-(4-Methoxy-phenyl)-3,9-dimethyl-furo[3,2-g]chromen-5-
one 4e. 67.6 %; light brown crystals; mp 248 °C dec; ꢀmax/cm-1:
Jvicinal = 2.8 and Jgeminal = 16.8, C(6)equatorial H), 3.13-3.23 (1H,
dd, Jvicinal = 12.85 and Jgeminal = 16.82, C(6)axial H), 5.48-5.53
(1H, dd, Jvicinal = 2.8 and Jvicinal = 12.8, C(7)axial H), 6.96-6.99
(2H, d, J = 8.62, C(3')H and C(5')H), 7.40-7.75 (8H, m, C(2)H,
C(3)phenyl protons, C(2')H, C(6')H) and 8.49(1H, s, C(4)H).
Anal. Calcd. for C25H20O4 (384.42): C, 78.10; H, 5.24. Found: C,
77.82; H, 5.03.
7-(4-Chloro-phenyl)-9-methyl-3-phenyl-6,7-dihydrofuro-
[3,2-g]chromen-5-one 3l. 59.7 %; light yellow crystals; mp 202-
203 °C; ꢀmax/cm-1: 3441, 2930, 1688, 1622, 1471, 1233 and 1129;
1H nmr (400 MHz; CDCl3; Me4Si): ꢀ 2.46 (3H, s, C(9)CH3), 2.95-
3.00 (1H, dd, Jvicinal = 3.6 and Jgeminal =16.8, C(6)equatorial H),
3.04-3.11 (1H, dd, Jvicinal = 12.4 and Jgeminal = 16.8, C(6)axial H),
5.50-5.54 (1H, dd, Jvicinal = 3.2 and Jvicinal = 12.4, C(7)axial H),
7.39-7.52 (7H, m, C(3)phenyl protons, C(3')H, C(5')H), 7.65-7.67
(2H, d, J = 8.4, C(2')H and C(6')H), 7.79 (1H, s, C(2)H) and 8.32
(1H, s, C(4)H). Anal. Calcd. for C24H17O3Cl (388.84): C, 74.13; H,
4.40. Found: C, 73.88; H, 4.43.
1
2921, 1651, 1621, 1610, 1507, 1477, 1361, 1254 and 1133; H
nmr (400 MHz; CDCl3; Me4Si): ꢀ 2.29 (3H, d, J = 1.2, C(3)CH-
3), 2.72 (3H, s, C(9)CH3), 3.91 (3H, s, C(4')OCH3), 6.82 (1H, s,
C(6)H), 7.04-7.06 (2H, d, J = 8.8, C(3')H and C(5')H), 7.51 (1H,
d, J = 1.2, C(2)H), 7.92-7.94 (2H, d, J = 8.8, C(2')H and C(6')H)
and 8.25(1H, s, C(4)H); 13C nmr (100MHz; CDCl3; Me4Si): ꢀ
7.92 (C3-CH3), 8.75 (C9-CH3), 55.53 (C4'-OCH3), 104.49 (C-6),
109.79 (C-9), 113.32 (C-3' and C-5'), 114.52 (C-3), 116.58 (C-
4a), 119.71 (C-4), 124.35 (C-3a), 126.88 (C-2' and C-6'), 127.95
(C-1'), 143.41 (C-2), 152.10 (C-8a), 156.80 (C-4'), 162.39 (C-
9a), 163.32 (C-7) and 179.33 (C5->C=O). Anal. Calcd. for
C20H16O4 (320.34): C, 74.98; H, 5.03. Found: C, 75.24; H, 5.37.
7-(4-Chloro-phenyl)-3,9-dimethyl-furo[3,2-g]chromen-5-
one 4f. 88 %; light brown crystals; mp 210 °C dec; ꢀmax/cm-1:
2933, 1656, 1621, 1615, 1515, 1472, 1360, 1263, 1129 and 821;
1H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.30 (3H, d, J = 0.58,
C(3)CH3), 2.73 (3H, s, C(9)CH3), 6.87 (1H, s, C(6)H), 7.42-7.44
(2H, d, J = 8.8, C(3')H and C(5')H), 7.50 (1H, d, J = 0.58,
C(2)H), 7.56-7.58 (2H, d, J = 8.8, C(2')H and C(6')H) and 8.50
(1H, s, C(4)H). Anal. Calcd. for C19H13O3Cl (324.76): C, 70.26;
H, 4.03. Found: C, 70.21; H, 4.01.
General procedure for (4a-4l).
3-Methyl-7-phenyl-furo[3,2-g]chromen-5-one 4a. A mixture
of 3-methyl-7-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-one 3a

Nov-Dec 2008
Studies in Synthesis of Furoflavones Possessing Anti-cancer Activity
1737
3,7-Diphenyl-furo[3,2-g]chromen-5-one 4g. 71 %; light
brown crystals; mp 200 °C dec; ꢀmax/cm-1: 2933, 1658, 1622,
1599, 1511, 1471, 1359, 1260, 1131 and 833; 1H nmr (400 MHz;
CDCl3; Me4Si): ꢀ 6.92 (1H, s, C(6)H), 7.43-8.01 (12H, m,
C(2)H, C(9)H, C(7)phenyl protons, C(3)phenyl protons) and
8.75 (1H, s, C(4)H); lcms: m/z 361.1 (M+23, 11 %), 340.1
(M+2, 22) and 339.1 (M+1, 100). Anal. Calcd. for C23H14O3
(338.36): C, 81.64; H, 4.17. Found: C, 81.49; H, 4.05.
(1H, s, C(9)H), 7.25-7.51 (11H, m, C(2)H, C(7)phenyl protons,
C(2')H, C(3')H, C(4')H, C(5')H, C(6')H), 8.12 (1H, s, vinylic
proton) and 8.15 (1H, s, C(4)H). Anal. Calcd. for C25H18O3
(366.41): C, 81.94; H, 4.95. Found: C, 81.76; H, 4.83.
E-6-(4-Chloro-benzylidene)-7-(4-chloro-phenyl)-3-methyl-
6,7-dihydro-furo[3,2-g]chromen-5-one 5b. 76.5 %; yellow
crystals; mp 189-190 °C; ꢀmax/cm-1: 3095, 1672, 1624, 1488,
1
1471 and 1132; H nmr (300 MHz; CDCl3; Me4Si): ꢀ 2.18-2.18
(3H, d, J = 0.9, C(3)CH3), 6.53 (1H, s, C(7)H), 6.95 (1H, s,
C(9)H), 7.19-7.42 (9H, m, C(2)H, C(7)phenyl protons, C(2')H,
C(3')H, C(5')H, C(6')H), 8.09 (1H, s, vinylic proton) and 8.12
(1H, s, C(4)H). Anal. Calcd. for C25H16O3Cl2 (435.30): C, 68.98;
H, 3.70. Found: C, 69.01; H, 3.84.
7-(4-Methoxy-phenyl)-3-phenyl-furo[3,2-g]chromen-5-one
4h. 80 %; light brown crystals; mp 258 °C dec; ꢀmax/cm-1: 2919,
1642, 1616, 1612, 1525, 1477, 1361, 1262, 1133 and 836; 1H nmr
(400 MHz; (CD3)2SO; Me4Si): ꢀ 3.92 (3H, s, C(4')OCH3), 6.91
(1H, s, C(6)H), 7.04-7.06 (2H, d, J = 8.8, C(3')H and C(5')H),
7.43-8.01 (9H, m, C(2)H, C(9)H, C(2')H, C(6')H, C(3)phenyl
protons) and 8.73 (1H, s, C(4)H). Anal. Calcd. for C24H16O4
(368.38) requires C, 78.25; H, 4.37. Found: C, 78.49; H, 4.65.
7-(4-Chloro-phenyl)-3-phenyl-furo[3,2-g]chromen-5-one
4i. 89 %; light brown crystals; mp 210 °C dec; ꢀmax/cm-1: 2929,
E-6-(4-Methoxy-benzylidene)-7-(4-methoxy-phenyl)-3,9-
dimethyl-6,7-dihydro-furo[3,2-g]chromen-5-one 5c. 61.8 %;
yellow crystals; mp 150-152 °C; ꢀmax/cm-1: 3119, 2999, 1669,
1
1628, 1600, 1519, 1472, 1249, 1188 and 1120; H nmr (300
MHz; CDCl3; Me4Si): ꢀ 2.18 (3H, d, J = 0.9, C(3)CH3), 2.36
(3H, s, C(9)CH3), 3.74 (3H, s, C(4”)OCH3), 3.83 (3H, s,
C(4')OCH3), 6.69 (1H, s, C(7)H), 6.81-6.84 (2H, d, J = 8.64,
C(3”)H and C(5”)H), 6.88-6.91 (2H, d, J = 8.64, C(3')H and
C(5')H), 7.25-7.29 (3H, m, C(2)H, C(2”)H, C(6”)H), 7.41-7.44
(2H, d, J = 8.57, C(2')H and C(6')H), 8.00 (1H, s, vinylic proton)
and 8.10 (1H, s, C(4)H). Anal. Calcd. for C28H24O5 (440.49): C,
76.34; H, 5.49. Found: C, 76.21; H, 5.37.
1
1646, 1622, 1588, 1525, 1476, 1361, 1260, 1131 and 834; H
nmr (400 MHz; CDCl3; Me4Si): ꢀ 6.88 (1H, s, C(6)H), 7.4-8.00
(11H, m, C(2)H, C(9)H, C(7)phenyl protons, C(3)phenyl
protons) and 8.56 (1H, s, C(4)H). Anal. Calcd. for C23H13O3Cl
(372.80): C, 74.10; H, 3.51. Found: C, 73.87; H, 3.39.
9-Methyl-3,7-diphenyl-furo[3,2-g]chromen-5-one 4j. 76 %;
light brown crystals; mp 220-222 °C dec; ꢀmax/cm-1: 2919, 1648,
1
E-6-(4-Methoxy-benzylidene)-7-(4-methoxy-phenyl)-9-
methyl-3-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-one 5d.
59 %; yellow crystals; mp 164-166 °C; ꢀmax/cm-1: 3123, 2993,
1621, 1611, 1525, 1479, 1359, 1262 and 1133; H nmr (400
MHz; CDCl3; Me4Si): ꢀ 2.80 (3H, s, C(9)CH3), 6.94 (1H, s,
C(6)H), 7.41-8.1 (11H, m, C(2)H, C(7)phenyl protons,
C(3)phenyl protons) and 8.77 (1H, s, C(4)H). Anal. Calcd. for
C24H16O3 (352.38): C, 81.80; H, 4.57. Found: C, 81.84; H, 4.61.
7-(4-Methoxy-phenyl)-9-methyl-3-phenyl-furo[3,2-g]-
chromen-5-one 4k. 79 %; light brown crystals; mp 200 °C dec;
ꢀmax/cm-1: 2933, 1651, 1626, 1602, 1515, 1480, 1359, 1261, 1133
1
1671, 1621, 1602, 1509, 1477, 1251, 1181 and 1115; H nmr
(300 MHz; CDCl3; Me4Si): ꢀ 2.38 (3H, s, C(9)CH3), 3.75 (3H, s,
C(4”)OCH3), 3.83 (3H, s, C(4')OCH3), 6.70 (1H, s, C(7)H),
6.82-6.84 (2H, d, J = 8.6, C(3”)H and C(5”)H), 6.88-6.90 (2H, d,
J = 8.64, C(3')H and C(5')H), 7.26-7.29 (2H, d, J = 8.6Hz,
C(2”)H and C(6”)H), 7.40-7.92 (8H, m, C(2)H, C(2')H, C(6')H,
C(3)phenyl protons), 8.01 (1H, s, vinylic proton) and 8.13 (1H,
s, C(4)H). Anal. Calcd. for C33H26O5 (502.56): C, 78.86; H, 5.21.
Found: C, 78.97; H, 5.52.
1
and 819; H nmr (400 MHz; (CD3)2SO; Me4Si): ꢀ 2.70 (3H, s,
C(9)CH3), 3.93 (3H, s, C(4')OCH3), 6.90 (1H, s, C(6)H), 7.05-
7.07 (2H, d, J = 8.8, C(3')H and C(5')H), 7.40-8.05 (8H, m,
C(2)H, C(2')H, C(6')H, C(3)phenyl protons) and 8.75 (1H, s,
C(4)-H). Anal. Calcd. for C25H18O4 (382.41): C, 78.52; H, 4.74.
Found: C, 78.51; H, 4.70.
Photo chemical isomerization of E-6-Benzylidene-3-
methyl-7-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-one 5a to
Z-6-Benzylidene-3-methyl-7-phenyl-6,7-dihydro-furo[3,2-g]-
7-(4-Chloro-phenyl)-9-methyl-3-phenyl-furo[3,2-g]chromen-
chromen-5-one 6.
E-6-Benzylidene-3-methyl-7-phenyl-6,7-
5-one 4l. 83.2 %; light brown crystals; mp 230 °C dec; ꢀmax
/
cm-1: 2936, 1656, 1622, 1611, 1519, 1477, 1361, 1260, 1135 and
836; 1H nmr (400 MHz; CDCl3; Me4Si): ꢀ 2.80 (3H, s,
C(9)CH3), 6.90 (1H, s, C(6)H), 7.42-7.95 (10H, m, C(2)H,
C(7)phenyl protons, C(3)phenyl protons) and 8.59 (1H, s,
C(4)H). Anal. Calcd. for C24H15O3Cl (386.83): C, 74.51; H, 3.90.
Found: C, 74.31; H, 3.81.
dihydro-furo[3,2-g]chromen-5-one 5a (0.005 moles) was
dissolved in toluene (15 mL) and kept in a chamber containing
450 W mercury arc lamp for 12 hours. Excess of toluene was
distilled off in vacuo and the product was purified by column
chromatography on neutral alumina using petroleum ether (60-
80 °C): ethyl acetate (9:1) mixture as eluent. Use of silica gel
was showing some conversion of Z isomer back into the E
isomer. Z-6-Benzylidene-3-methyl-7-phenyl-6,7-dihydro-furo-
[3,2-g]chromen-5-one 6 (81.2 %) was obtained as yellow
crystals, mp 101-103 °C; ꢀmax/cm-1: 3069, 2942, 1661, 1624,
1583, 1468, 1453, 1224, 1182, 1128 and 737; 1H nmr (300 MHz;
CDCl3; Me4Si): ꢀ 2.25 (3H, d, J = 1.5, C(3)CH3), 6.15 (1H, s,
C(7)H), 6.77 (1H, s, vinylic proton), 7.09 (1H, s, C(9)H), 7.26-
7.70 (11H, m, C(2)H, C(7)phenyl protons, C(2')H, C(3')H,
C(4')H, C(5')H, C(6')H) and 8.12 (1H, s, C(4)H). Anal. Calcd.
for C25H18O3 (366.41): C, 81.94; H, 4.95. Found: C, 81.76; H,
4.83.
General procedure for (5a-5d).
E-6-Benzylidene-3-methyl-7-phenyl-6,7-dihydro-furo[3,2-
g]chromen-5-one 5a. A solution of 1-(6-hydroxy-3-methyl-
benzofuran-5-yl)-ethanone 1a (0.026 moles) and freshly distilled
benzaldehyde (0.065 moles) and 2-3 drops of piperidine in
ethanol (15 mL) was refluxed for 18 hours. Reaction mixture
was poured into ice hydrochloric acid mixture and the solid
collected by filtration. The crude product was purified by
column chromatography using petroleum ether (60-80 °C): ethyl
acetate (8:2) mixture as eluent to give E-6-benzylidene-3-
methyl-7-phenyl-6,7-dihydro-furo[3,2-g]chromen-5-one 5a (71
%) as yellow crystals; mp 212-214 °C; ꢀmax/cm-1: 3099, 1670,
1621, 1481, 1477 and 1129; 1H nmr (300 MHz; CDCl3; Me4Si):
ꢀ 2.17-2.17 (3H, d, J = 1.5, C(3)CH3), 6.66 (1H, s, C(7)H), 6.96
Acknowledgements. The authors are thankful to the
Department of Chemistry, The Maharaja Sayajirao University of
Baroda for providing the necessary facilities. The authors are
also thankful to BIOARC-Alembic and Sun Pharma, Baroda for

1738
J. M. Patel and S. S. Soman
Vol 45
[8] Simonis, H. Chem. Ber., 1913, 46, 2014; Simonis, H.; Alfred
Lehman, C. B. Chem. Ber., 1914, 47, 692; Simonis, H.; Remmert, P.
Chem. Ber., 1914, 47, 2229; Chakravarti J. Indian Chem. Soc., 1931, 31,
407.
nmr spectra. One of the authors (JMP) is thankful to AICTE
(National Doctoral Fellowship) and UGC, New Delhi for
providing the financial assistance. The authors are also thankful
to Regional Research Laboratory, Jammu for anti-cancer
screening.
[9] Elderfield, R. C.; Wawzonek, S. Heterocyclic compounds,
John Wiley and Sons, New York, 1950, Vol 2, Chapter 10
-
Chromanones, Flavanones, Chromanols and Flavanols: Catechin,
Brazilin and Hematoxylin, 343.
[10] Sagrera, G.; Lopez, V.; Pandol, fi E.; Seoane, G.; Eicher, T.
Informacion Tecnologica, 1998, 9, 11.
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