Identification of novel chromenone derivatives as interleukin-5 inhibitors

Article abstract of DOI:10.1016/j.ejmech.2012.11.007

A series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones (4) and (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated for their IL-5 inhibitory activity. Propenone analogs 4 possess some of the structurally important characteristics of isoflavone 2 and chalcone 3 previously known as potent IL-5 inhibitor. However, the inhibitory activity of 4 was weak and therefore this structural hybridization appears to be ineffective for the design of IL-5 inhibitor. Meanwhile the potent activity profile of compounds 5 was discovered. This enhanced activity of 5 compared to 4 could be due to the effective location of hydroxyl group of allylic alcohol moiety of 5 in the 3D structure. The electron withdrawing substituents at position 4 of phenyl ring of 5 enhances the activity possibly due to an increase in the strength of hydrogen bonding property of hydroxyl group of allylic alcohol moiety.

Full text of DOI:10.1016/j.ejmech.2012.11.007

European Journal of Medicinal Chemistry 59 (2013) 31e38
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Identification of novel chromenone derivatives as interleukin-5 inhibitors
Eeda Venkateswararao a, Min-Seok Kim a, Vinay K. Sharma a, Ki-Cheul Lee a, Santhosh Subramanian a,
,
Eunmiri Roh b, Youngsoo Kim b, Sang-Hun Jung a
*
a College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764, Republic of Korea
b College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones (4) and (E)-5-alkoxy-3-(3-
hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated for their IL-5
inhibitory activity. Propenone analogs 4 possess some of the structurally important characteristics of
isoflavone 2 and chalcone 3 previously known as potent IL-5 inhibitor. However, the inhibitory activity of
4 was weak and therefore this structural hybridization appears to be ineffective for the design of IL-5
inhibitor. Meanwhile the potent activity profile of compounds 5 was discovered. This enhanced
activity of 5 compared to 4 could be due to the effective location of hydroxyl group of allylic alcohol
moiety of 5 in the 3D structure. The electron withdrawing substituents at position 4 of phenyl ring of 5
enhances the activity possibly due to an increase in the strength of hydrogen bonding property of
hydroxyl group of allylic alcohol moiety.
Received 10 August 2012
Received in revised form
1 November 2012
Accepted 7 November 2012
Available online 15 November 2012
Keywords:
Chromenone analogs
Inhibitor
Interleukin-5
Eosinophils
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
accumulate rapidly in the tissue and synthesize various proteins
and lipid mediators that cause edema, bronchoconstriction and
Millions of people around the world suffer from different types
of allergies including hay fever, rhinitis, asthma, eczema, idiopathic
eosinophilic syndromes, atopic dermatitis, pet and food allergies.
Interestingly, all of them have distinct inflammatory constituents
and described by diverse eosinophilic intrusion [1]. Minor allergies
can often be treated easily by antihistamines, but makes condition
miserable if ignored. One of the serious allergies is asthma, recog-
nized as a chronic inflammatory disease of the airways character-
ized by edema, decreased mucociliary clearance, epithelial damage,
increased neuronal responsiveness, and bronchoalveolar eosino-
philia [1].
The precise cause of asthma is still not known but it is believed
that both genetic and environmental factors play an important role
in the development of the disease. Therefore, it is necessary to
study the role of chronic pulmonary inflammation in the patho-
physiology of asthma, which involves T cells and eosinophils
invasion, increased levels of pro-inflammatory cytokines such as
interleukin-4 (IL-4), IL-5 and IL-13, and shedding of bronchial
epithelial cells (ECs) [2]. The eosinophils are formed in the bone
marrow in response to cytokine activation, and are released into
the circulation after proper stimulus. Once in the circulation they
chemotaxis [3].
The eosinophil is therefore, a perfect target for selectively
inhibiting the tissue damage that accompanies allergic diseases,
without inducing the immunosuppressive consequences that can
arise from systemic use of pleiotropic drugs such as steroids. The
development of eosinophils in bone marrow and its release in the
circulation requires interleukin-5 [4e7]. Both in humans and
animals, inhibiting interleukin-5 with monoclonal antibodies can
reduce blood and bronchoalveolar eosinophilia caused by allergic
challenges or chronic diseases [8e11]. Therefore, exclusively
inhibiting the actions of interleukin-5 can suppress at least one of
the alleged causes of asthma, namely tissue damage due to eosin-
ophil accumulation during pulmonary inflammation. In addition,
various clinical investigations indicate that the IL-5-regulated
eosinophilia plays a vital role in the pathogenesis of asthma [12e15].
The above reports confirm that IL-5 clearly emerges as an
important target for the treatment of the asthma. Consequently,
a number of IL-5 inhibitors are reported in the literature. Among
them, isothiazolones have been synthesized by the modification of
Cys 66 residue in IL-5 and reported as its antagonists [16]. However,
the most significant discovery is the natural product sophoricoside
(1, 92.1% inhibition at 50
m
M, IC50 ¼ 1.4
mM) and its analogs (2)
which showed potent IL-5 inhibitory activity [17] (Fig. 1). Inter-
estingly, it was also reported as weak IL-3 and GM-CSF inhibitor
[18]. While sophoricoside showed promising IL-5 inhibitory activity
* Corresponding author. Tel.: þ82 42 821 5939; fax: þ82 42 823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.11.007

32
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
Fig. 1. Structure modifications of chromenones.
still more diverse and concise structure activity relationship (SAR)
studies are needed. Therefore, a number of isoflavonoid analogs (1
and 2, Fig. 1) of sophoricoside [19,20] as well as chalcone deriva-
tives (3, Fig. 1) [21,22] were investigated as potent IL-5 inhibitors by
our group. The SAR studies of isoflavonoid analogs [19] revealed
that planar chromen-4-one ring and phenolic hydroxyl group at
position 4 of ring B indeed plays an important role in activity.
Similarly in chalcone analogs the hydrophobic group such as ben-
zyloxy or cyclohexylmethoxy at position 2 of ring A is necessary
[21,22]. In addition, the existence of phenolic hydroxyl at position 6
of ring A is critical. Interestingly, both the isoflavonoid analogs and
chalcone derivatives have common structural features such as
bulky hydrophobic group at position 5 and 6 of ring A respectively,
enhancing their inhibitory activity as compared to the sophorico-
side [19,20]. The most important structural features of chalcones
are the propenone motif as well as the presence of electron with-
drawing groups with hydrogen acceptor property at position 4 of
phenyl ring B which subsequently improves their activity. But in
case of isoflavone analogs, phenolic hydroxyl group at position 4 of
ring B plays an important role for the same. In addition, the
possibility of replacement of ring B in isoflavonoid analogs with
aliphatic motif was also observed in one of our previous studies
[16,23]. Thus after studying all these structural characteristics of
isoflavones and chalcones, we hypothesized that combination of
their structural characteristics may lead to more active compounds.
In this regard, hybrid type target compounds such as chromenone
derivatives 4 and 5 were designed, synthesized (Fig. 1) and evalu-
ated for their IL-5 inhibitory activity.
temperature [23]. The Wittig reagents (9aec, 9del) were obtained by
the reaction of commercially available substituted bromoacetophe-
nones and triphenylphosphine in methylene chloride at ambient
temperature [24,25]. The reaction of 5-alkoxy-4-oxo-4H-chromene-3-
carbaldehydes (8) [23] with Wittig reagents 9aec in methylene
chloride at ambient temperature for overnight produced the chro-
menone 10aec and the following deprotection of 10aec with tri-
fluoroacetic acid at ambient temperature for 3 h gave compounds 4ae
c. The reaction of 8 with Wittig reagents 9del in methylene chloride at
ambient temperature for overnight produced the desired chromenone
4del [24]. These analogs could be prepared by simple aldol conden-
sation with aldehyde 8 and substituted acetophenones in the pres-
ence of base. However, these attempts gave the multiple products. The
reasons were inferred due to the instability of aldehyde 8 under basic
condition. Finally, the racemic allylic alcohols 5ael were obtained by
the reduction of ketone function of 4ael using sodium borohydride in
presence of cerium chloride at 0e5 ꢀC. The synthesized chromenones
4 and 5 may exist as either the Z or E isomer. The coupling constants of
protons on a,b-unsaturated ketone unit appears as 12e16 Hz. Thus the
compounds 4 and 5 have E stereochemistry around double bond. All
these synthesized compounds were listed in Table 1 and characterized
by physical and spectral analysis data that confirmed their assigned
structures.
3. Pharmacology
Inhibitory activity of the chromenone analogs 4 and 5 against IL-5
was evaluated using the IL-5-dependent pro-B Y16 cell line accord-
ing to the known procedure [17]. The cells were incubated with 3
units/mL mIL-5 for 48 h, in the presence or absence of sample, and
then cell metabolism was measured as an index of proliferation,
using 2-(4-iodophenyl)-3-(nitrophenyl)-5-(2,4-disulphophenyl)-2H
tetrazolium sodium salt (WST-1). The effect of test compounds on
the IL-5 bioassay is represented as inhibition % at 30 mM samples and
also IC50 values (Table 2). Data were collected from three indepen-
dent experiments.
2. Chemistry
The synthesis of the desired compounds 4ael and 5ael was
accomplished as outlined in Scheme 1. In brief, the acetophenone 7
was prepared by the partial alkylation of 2, 6-dihydroxyacetophenone
(6) [19]. Preparation of 8 was accomplished by the cyclization of 7
using N, N-dimethylformamide and phosphoryl chloride at ambient

E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
33
9a-c
Scheme 1. Synthesis of choromone analogs. (a) ReBr, CH3CN, aqueous 95% K2CO3, NaI (cat), reflux, overnight, (b) POCl3, DMF, overnight, rt. (c) dichloromethane, overnight (d) TFA,
dichloromethane, 3 h, rt. (e) NaBH4, CeCl3, Dichloromethane/methanol. Note* ¼ substitution are located in Table 1.
4. Conformational analysis and alignment
As shown in Table 1, the size of alkoxy substituents of hybrid
analogs 4 and 5 at position 5 of chromenone ring was varied with
methoxy, isobutoxy, or cyclohexylmethoxy to investigate the effect
of size or lipophilicity of hybrid chromenones 4 and 5. For finding
the effective substitution at position 4 of phenyl ring of 4 and 5
various substituents such as hydrogen bonding group (OH),
hydrophobic electron donating groups (CH3, t-butyl), electron
donating group (OCH3) and electron withdrawing group (F, Cl, CF3,
NO2, CN) were studied for the inhibitory activity.
Molecular models of compounds 4c and 5c were constructed
using SYBYLÒ-X1.3 program package (Tripos Associates Inc.) [26]
and their geometry were optimized (Powell conjugate gradient
minimization, termination at a gradient of 0.0005 kcal/mol.) using
the Tripos standard force field [27] and Gasteiger-Hückel atomic
partial charges [28]. The 3D structures of the analyzed compounds
were assumed to be a bioactive conformation and were aligned
according to a chromenone template as shown in Fig. 2. The selected
dihedral angles and atomic distances are listed in Tables 3 and 4.
Comparison of the activity of hybrid analog 4c (IC50 ¼ 16.2
with those of corresponding isoflavone 2 (IC50 ¼ 5.8 M) and
chalcone 3 (IC50 ¼ 12.6 M) revealed decrement in the activity
mM)
m
m
(Table 2). The activity of all other analogs of 4 did not exceed the
activity of compared compounds. Thus hybridization with charac-
teristics of both isoflavone and chalcone did not give any advantage.
However, some of structure activity relationship could be
extracted from the results. Considering the activity of 4aec,
increasing the bulkiness on position 5 of ring A increases the
activity, thus making 4c the most active one. Regarding the effect of
substituents on position 4 of phenyl ring of compounds 4, the
hydroxyl group (as shown in compounds 4b and 4c) plays an
essential role for the activity. These findings are consistent with our
previous studies where the bulky hydrophobic groups at positions
5 and 6 of ring A in isoflavone and chalcones, respectively and
hydroxyl group on ring B had positive effect on the activity [21,22].
5. Results and discussion
Designed (E)-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-
ones
4 possess chromenone and phenylpropenone moieties
(Fig. 1), which have been recognized as the effective structural
motifs of isoflavone 2 and chalcone 3 for the inhibition of IL-5. Thus
the chromenones 4 could be considered as the hybrid structure.
Table 1
Chromenone analogs 4ael and 5ael with their physicochemical properties.
Compd.
R
R1
Appearance
m.p (ꢀC)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
Methyl
Isobutyl
OH
OH
OH
H
OCH3
CH3
t-butyl
Cl
White solid
Brown Solid
Yellow solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
Yellow solid
Yellow solid
White solid
Brown solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
Yellow solid
220e222 52.2
141e143 44.0
288e290 55.7
176e178 66.2
185e187 48.8
200e202 45.3
236e238 49.2
219e221 58.4
190e192 72.3
204e206 52.6
280e282 64.3
265e267 55.9
174e176 44.8
139e141 65.0
284e286 90.2
170e172 85.4
175e177 80.7
190e192 79.3
230e232 83.5
210e212 80.2
182e184 79.7
190e192 79.3
275e277 83.5
259e261 79.0
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Methyl
Table 2
Inhibitory activity of chromone analogs 4ael and 5ael against Interleukin-5.
Compd.
% Inhibition
IC50
M)a
Compd.
% Inhibition
IC50
(m
M)a
at 30
m
Ma
(
m
at 30
m
Ma
F
4a
4b
4c
4d
4e
4f
4g
4h
32.3
87.5
99.0
17.2
9.3
>30
19.1
16.2
>30
>30
25.1
18.1
>30
>30
>30
>30
>30
5.8
5a
5b
5c
5d
5e
5f
5g
5h
21.3
20.6
92.7
93.9
93.6
93.2
15.7
94.5
93.2
92.7
93.8
94.4
99.0b
79.1
>30
>30
12.5
15.0
16.0
15.0
>30
7.0
6.4
13.2
7.0
6.7
12.6
10.6
4j
4k
4l
CF3
NO2
CN
OH
OH
OH
H
OCH3
CH3
t-butyl
Cl
5a
5b
5c
5d
5e
5f
5g
5h
5i
Isobutyl
57.5
99.2
46.3
15.4
42.7
11.8
9.2
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
Cyclohexylmethyl
4i
4j
4k
5i
5j
5k
4l
5l
F
220
91.7b
55.3
322
5j
5k
5l
CF3
NO2
CN
Budesonide
27.1
Sophoricoside
a
% Inhibitions and IC50 values are taken as mean from 3 experiments.
Inhibition at 50 mM.
b

34
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
Table 4
ꢀ
Bond distances (A) in compounds 4c and 5c.
Compound 4ca
Compound 5ca
O2eO12
O2eO11
13.245
7.544
10.669
4.856
6.389
13.245
O2eO13
O2eO12
10.523
8.863
8.451
6.327
6.413
10.523
O
O
O
10eO12
10eO11
11eO12
O11eO13
O11eO12
O12eO13
O2eO12
O2eO13
a
Numbers on the atoms of 4c and 5c are presented in Fig. 2.
region of side chain of hybrid chromenone scaffolds 4c and 5c
(Fig. 2). The dihedral angle (:C6eC7eC8eC9) of compound 4c is
192.3ꢀ (Table 3). This indicates that the carbonyl function of
a,b-
unsaturated ketones moiety of 4c is stretched away from the chro-
ꢀ
menone ring. In addition, the distance (13.245 A, Table 4, Fig. 2) from
oxygen of methoxy group to oxygen at position 4 of phenyl ring of 4c
also confirms this stretch conformation. Meanwhile the corre-
sponding angles (:C6eC7eC8eC9 ¼ 108.3ꢀ, Table 3) of 5c depict that
hydroxyl group of racemic allylic alcohol moiety of 5c is located
nearly at right angle position in chromenone ring plane. The much
Fig. 2. Alignment of compound 4c (11.471 kcals/mol) and 5c (10.849 kcals/mol). Yellow
color (4c), Pink color (5c). (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)
Analogs substituted on position 4 of phenyl ring of compounds 4
with methoxy (4e), chloro (4h), fluoro (4i), trifluoromethyl (4j),
nitro (4k), or cyano (4l) did not show any activity. However,
hydrophobic substitution such as methyl or tert-butyl group as
ꢀ
shorter distance (10.523 A, Fig. 2) of methoxy group to oxygen at
position 4 of phenyl ring in 5c than in 4c also implies the folded
conformation of racemic allylic alcohol moiety. Such conformational
change might cause the enhancement of the activity in analogs 5
compared to those of the corresponding compounds 4. Therefore,
the folded conformation as shown in 5c could be much closer to the
effective conformation for binding to the putative receptor.
shown in 4f (57.5% inhibition at 30
(99.2% inhibition at 30
moderate level of activity, presumably due to their bulkiness and
electron donating properties.
m
M, IC50 ¼ 25.1
mM) and 4g
M) still possessed the
m
M, IC50 ¼ 18.1
m
As a,b-unsaturated ketone of (E)-3-(3-phenyl-3-oxoprop-1-enyl)-
4H-chromen-4-ones 4 seemed to be the reason for the loss of activity
6. Conclusion
of these chromenones, in another set of experiment the carbonyl
function of
a,b-unsaturated ketones was reduced to the racemic
A
series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-
allylic alcohols. Accordingly, compounds 5ael were prepared and
tested for their IL-5 inhibitory activity as shown in Table 2. Although
the activity was lost in the compounds with less bulky groups such as
methoxy and isobutoxy at position 5 of ring A (compounds 5a and
5b), other cyclohexylmethoxy compounds (5cef and 5hel) were
chromen-4-ones (4) and (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-
1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated
for their IL-5 inhibitory activity. Propenone analogs 4 possess some
of the structurally important characteristics of isoflavone 2 and
chalcone 3, known potent IL-5 inhibitors. However, the inhibitory
activity of 4 was weak and therefore this structural hybridization
appears to be ineffective for the design of IL-5 inhibitor. Hydrogen
bonding acceptor property of carbonyl oxygen of propenone scaf-
fold of (E)-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones 4
did not contribute for the inhibition of IL-5. However hydroxyl
function on ring B of 4 still acts as an important functional group.
better inhibitors than the corresponding
(4cef and 4hel). Exceptionally, the bulky tert-butyl 5g (15% inhibi-
tion at 30 M, IC50 > 30 M) did not turn up with any inhibitory
a,b-unsaturated ketones
m
m
activity. The above results indicate the importance of hydrogen bond
characteristic of allylic hydroxyl group for the activity.
Interestingly, the activity of 3-(3-hydroxy-3-phenylprop-1-
enyl)-4H-chromen-4-ones 5 was further improved by introducing
the electron withdrawing group at p-position of ring B such as
Meanwhile the potent activity profile of compounds
5 was
discovered. This enhanced activity of 5 compared to 4 could be due
to the effective location of hydroxyl group of allylic alcohol moiety
of 5 in the 3D structure. The electron withdrawing substituents at
position 4 of phenyl ring of 5 enhances the activity possibly due to
an increase in the strength of hydrogen bonding property of
hydroxyl group in allylic alcohol moiety of 3-(3-hydroxy-3-
phenylprop-1-enyl)-4H-chromen-4-ones (5ael).
chloro (5h, 93.5% inhibition at 30
93.2% inhibition at 30
M, IC50 ¼ 6.4
inhibition at 30 M), nitro (5k, 93.8% inhibition at
M, IC50 ¼ 13.2
M) and cyano analogs (5l, 94.4% inhibition at
M). These electron withdrawing groups on
m
M, IC50 ¼ 7.0
mM), fluoro (5i,
M), trifluoro (5j, 92.7%
m
m
m
m
30
30
m
m
M, IC50 ¼ 7.0
m
M, IC50 ¼ 6.7
m
position 4 of phenyl ring in 5 obviously increases hydrogen bonding
power of hydroxyl group of allylic alcohol moiety of 5 and therefore
the activity of these analogs should be increased.
7. Materials and methods
To further investigate the detailed structural requirements for the
potent IL-5 inhibitor we compared the structural sketches of the
compound 4c and 5c and observed a dramatic difference in the
7.1. Chemistry
Melting points (m.p.) were determined on Electrothermal 1A
9100 MK2 apparatus and are uncorrected. All commercial chemicals
were used as obtained and all solvents were purified by the standard
procedures prior to use [29]. Thin layer chromatography was per-
formed on E Merck silica gel GF-254 precoated plates and the iden-
tification was done with UV light and colorization with spray 10%
phosphomolybdic acid followed by heating. Flash column chroma-
tography was performed with E Merck silica gel (230e400 mesh).
Infrared spectrum was recorded by using sample as such on FT-IR
Table 3
Torsion angle (ꢀ) and total energy of compound 4c and 5c.
Compound 4ca (11.471 kcals/mol)b
Compound 5ca (10.849 kcals/mol)b
:C1eO2eC3eC4
:C5eC6eC7eC8
:C6eC7eC8eC9
182.4ꢀ
179.5ꢀ
192.3ꢀ
:C1eO2eC3eC4
:C5eC6eC7eC8
:C6eC7eC8eC9
182.5ꢀ
188.3ꢀ
108.3ꢀ
a
Numbers on the atoms of 4c and 5c are presented in Fig. 2.
Total energy.
b

E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
35
spectrum with Nicolet e 380 models. NMR spectra were measured
against the peak of tetramethylsilane by Varain Unity Inova 400 NMR
(400 MHz) spectrometer. High resolution mass spectra (HRMS) were
measured by using Shimadzu LCMS-IT-TOF spectrometer.
7.1.2.9. 1-(4-Nitro-phenyl)-2-(triphenylphosphosphanylidene)-etha-
none (9k). Yield 94.3%; White color solid; 1H NMR (CDCl3)
8.43
d
(d, J ¼ 8.0 Hz, 2H), 7.96e7.91 (m, 6H), 7.77e7.65 (m, 5H), 7.67e7.62
(m, 6H), 4.46 (d, J ¼ 24.0 Hz, 1H).
7.1.1. Procedure for the preparation of compounds 6, 7 and 8
The synthetic procedures for all compounds 6, 7 and 8 are fol-
lowed as described previously [19e22].
7.1.2.10. 4-[2-(Triphenylphosphosphanylidene)-acetyl]-benzonitrile
(9l). Yield 89.8%; White color solid; 1H NMR (CDCl3)
d 8.52
(d, J ¼ 16.0 Hz, 2H), 7.58e7.45 (m, 15H), 7.02 (d, J ¼ 8.0 Hz, 2H), 3.95
(d, J ¼ 24.0 Hz, 1H).
7.1.2. Procedure for the preparation of compounds 9a, 9del [24,25]
Solution of substituted bromoacetophenone (1.0 equivalent) in
methylene chloride (10 mL) was added to a solution of triphenyl-
phosphine (1.2 equivalent) in methylene chloride (10 mL) under
nitrogen. The mixture was stirred overnight and then added 100 mL
ether. After stirred for 1 h, the resulting phosphonium salt was
filtered and the precipitate was washed with ether and dried under
vacuum. The dried phosphonium salt was suspended in a mixture
of water (50 mL) and methanol (50 mL), and the mixture was
stirred for 1 h. Aqueous sodium hydroxide (2 M) was added to the
mixture until pH reached between 7 and 8. The mixture was then
stirred vigorously for 5 h. After evaporated methanol, the aqueous
layer was extracted with methylene chloride. Organic layer was
dried over Na2SO4 and evaporated to obtain the compounds 9a,
9del.
7.1.3. General procedure for the preparation for compound 4aec
Compound 8a, b or c (1.0 equivalent) was added slowly to
a mixture of 1-(4-methoxybenzyloxy-phenyl)-2-(triphenylphos-
phosphanylidene) ethanone (9a, 1.25 equivalent) in methylene
chloride (25 mL) and then the reaction mixture was stirred over-
night at ambient temperature. After evaporating the solvent under
reduced pressure, ether (100 mL) was added to the residue and the
resulted crystals were filtered and washed with ether. The above
crystals were recrystallized from methanol and dried under
vacuum to obtain the compound 10aec. Compounds 10a, b or c
were dissolved in dry methylene chloride and TFA (2 equivalent)
was added at ambient temperature. The reaction mixture was
stirred for 3 h, then washed with water and evaporated the solvent
under reduced pressure. The crude residue was further purified by
column chromatography to obtain 4aec.
7.1.2.1. 1-(4-Methoxybenzyloxy-phenyl)-2-(triphenylphosphospha-
nylidene)-ethanone (9a). Yield 90.2%; White color solid; 1H NMR
7.1.3.1. (E)-5-Methoxy-3-(3-(4-(4-methoxybenzyloxy)phenyl)-3-
(CDCl3)
d
8.43 (d, J ¼ 8.0 Hz, 2H), 7.96e7.91 (m, 6H), 7.77e7.65
oxoprop-1-enyl)-4H-chromen-4-one(10a). Yield 73.2%; Off-White
(m, 4H), 7.67e7.62 (m, 6H), 7.48e7.42 (m, 5H), 5.21 (s, 2H), 4.46
(d, J ¼ 24.0 Hz, 1H), 3.82 (s, 3H).
solid; m.p. 212e216 ꢀC; 1H NMR (CDCl3)
d
8.28 (d, J ¼ 15.4 Hz,
1H), 8.20 (d, J ¼ 8.8 Hz, 2H), 8.33 (s, 1H), 7.54 (t, J ¼ 8.4 Hz, 1H),
7.35e7.48 (m, 5H), 7.06 (d, J ¼ 8.8 Hz, 2H), 7.01 (d, J ¼ 8.3 Hz, 1H),
6.85 (d, J ¼ 8.3 Hz, 1H), 5.16 (s, 2H), 4.02 (s, 3H), 3.82 (s, 3H).
7.1.2.2. 1-Phenyl-2-(triphenylphosphanylidene)-ethanone
(9d).
Yield 71.3%; White color solid; 1H NMR (CDCl3)
d
8.00e7.97 (m, 2H),
7.75e7.69 (m, 6H), 7.56e7.45 (m, 9H), 7.36e7.34 (m, 3H), 4.44
(d, J ¼ 24.0 Hz, 1H).
7.1.3.2. (E)-5-Isobutoxy-3-(3-(4-(4-methoxybenzyloxy)phenyl)-3-
oxoprop-1-enyl)-4H-chromen-4-one (10b). Yield 71.2%; Off-White
solid; m.p. 128e130 ꢀC; 1H NMR (CDCl3)
d
8.56 (d, J ¼ 15.4 Hz,
7.1.2.3. 1-(4-Methoxy-phenyl)-2-(triphenylphosphosphanylidene)-
1H), 8.12 (d, J ¼ 8.8 Hz, 2H), 8.03 (s,1H), 7.54 (t, J ¼ 8.4 Hz,1H), 7.35e
7.48 (m, 5H), 7.06 (d, J ¼ 8.8 Hz, 2H), 7.01 (d, J ¼ 8.3 Hz, 1H), 6.85
(d, J ¼ 8.3 Hz, 1H), 5.16 (s, 2H), 3.90 (d, J ¼ 6.8 Hz, 2H), 3.84 (s, 3H),
2.32 (m, 1H), 1.15 (d, J ¼ 6.8 Hz, 6H).
ethanone (9e). Yield 82.3%; White color solid; 1H NMR (CDCl3)
d
8.42 (d, J ¼ 8.0 Hz, 2H), 7.96e7.91 (m, 6H), 7.73e7.63 (m, 9H),
6.99e6.97 (d, J ¼ 8.0 Hz, 2H), 4.45 (d, J ¼ 24.0 Hz, 1H), 3.86 (s, 3H).
7.1.2.4. 1-p-Tolyl-2-(triphenylphosphosphanylidene)-ethanone (9f).
7.1.3.3. (E)-5-(Cyclohexylmethoxy)-3-(3-(4-(4-methoxybenzyloxy)
Yield 91.5%; White color solid; 1H NMR (CDCl3)
d
8.00e7.97 (m, 2H),
phenyl)-3-oxoprop-1-enyl)-4H-chromen-4-one(10c). Yield
41.4%;
d 8.55
7.75e7.69 (m, 6H), 7.56e7.45 (m, 9H), 7.36e7.34 (m, 2H), 4.46 (d,
J ¼ 24.0 Hz, 1H), 2.35(s 3H).
Off-white solid; m.p. 170e174 ꢀC; 1H NMR (CDCl3)
(d, J ¼ 16.0 Hz, 1H), 8.12 (d, J ¼ 8.0 Hz, 2H), 8.04 (s, 1H), 7.55
(t, J ¼ 8.0 Hz, 1H), 7.43 (d, J ¼ 12.0 Hz, 1H), 7.38 (d, J ¼ 8.0, Hz, 2H),
7.06e6.99 (m, 3H), 6.96e6.91 (m, 2H), 6.85 (d, J ¼ 8.0 Hz,1H), 5.08 (s,
2H), 3.94 (d, J ¼ 4.0 Hz, 2H), 3.83 (s, 3H), 2.05e2.02 (m, 3H), 1.80e
1.71 (m, 2H), 1.40e1.21 (m, 3H), 1.27e1.21 (m, 1H), 1.14e1.05 (m, 2H).
7.1.2.5. 1-(4-tert-Butyl-phenyl)-2-(triphenylphosphosphanylidene)-
ethanone (9g). Yield 89.3%; White color solid; 1H NMR (CDCl3)
d
8.32 (d, J ¼ 8.0 Hz, 2H), 7.96e7.91 (m, 6H), 7.74e7.63 (m, 9H), 7.52
(d, J ¼ 8.0 Hz, 2H), 4.46 (d, J ¼ 24.0 Hz, 1H), 1.29 (s, 9H).
7.1.3.4. (E)-3-(3-(4-Hydroxyphenyl)-3-oxoprop-1-enyl)-5-methoxy-
4H-chromen-4-one (4a). Yield 52.2.%; off white solid; m.p. 220e
222 ꢀC; Rf 0.28 (1:1 Ethyl acetate:Hexane); IR 3429, 3160, 1666,
7.1.2.6. 1-(4-Chloro-phenyl)-2-( triphenylphosphosphanylidene)-
ethanone (9h). Yield 87.7%; White color solid; 1H NMR (CDCl3)
d
8.32 (d, J ¼ 8.0 Hz, 2H), 7.96e7.91 (m, 6H), 7.67e7.63 (m, 9H), 7.49
1640, 1470, 1268, 775 cmꢁ1; 1H NMR (DMSO-d6)
d 10.44 (s, 1H), 8.84
(d, J ¼ 8.0 Hz, 2H), 4.46 (d, J ¼ 24.0 Hz, 1H).
(s, 1H), 8.32 (d, J ¼ 16.0 Hz, 1H), 7.97 (d, J ¼ 8.0 Hz, 2H), 7.72
(t, J ¼ 8.0 Hz, 1H), 7.50 (d, J ¼ 16.0 Hz, 1H), 7.19 (dd, J ¼ 4.0, 8.0 Hz, 1H),
7.06 (d, J ¼ 8.0 Hz, 1H), 6.92 (d, J ¼ 8.0 Hz, 2H), 3.91 (s, 3H); 13C NMR
7.1.2.7. 1-(4-Fluoro-phenyl)-2-(triphenylphosphosphanylidene)-
ethanone (9i). Yield 85.6%; White color solid; 1H NMR (CDCl3)
(DMSO-d6) d 187.56, 174.76, 162.34, 159.82, 158.00, 157.15, 134.80,
d
8.46 (d, J ¼ 8.0 Hz, 2H), 7.96e7.91 (m, 6H), 7.76e7.65 (m, 9H),
134.78, 131.03, 129.20, 123.10, 119.82, 115.60, 113.94, 110.00, 107.95,
56.26; HRMS: calculated for C19H14O5 m/z 322.0841, Found: 322.0836.
7.14(t, J ¼ 8.0 Hz, 2H), 4.46 (d, J ¼ 24.0 Hz, 1H).
7.1.2.8. 1-(4-Trifluoromethyl-phenyl)-2-(triphenylphosphosphanyli-
dene)-ethanone (9j). Yield 86.8%; White color solid; 1H NMR
7.1.3.5. (E)-3-(3-(4-Hydroxyphenyl)-3-oxoprop-1-enyl)-5-isobutoxy-
4H-chromen-4-one (4b). Yield 44.0%; Brown solid; m.p. 141e143 ꢀC;
Rf 0.36 (4:6 Ethyl acetate:Hexane); IR 3212, 2923, 1697, 1676, 1244,
(CDCl3)
d
8.05 (d, J ¼ 8.0 Hz, 2H), 7.74e7.69 (m, 6H), 7.61e7.56
(m, 5H), 7.51e7.47 (m, 6H), 4.45 (d, J ¼ 24.0 Hz, 1H).
811 cmꢁ11; H NMR (DMSO-d6)
d
8.62 (d, J ¼ 16.0 Hz, 1H), 8.21 (s, 1H),

36
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
8.10 (s, 1H), 8.07 (d, J ¼ 8.0 Hz, 2H), 7.59 (t, J ¼ 8.0 Hz, 1H), 7.44 (d,
J ¼ 16.0 Hz, 1H), 7.13 (d, J ¼ 8.0 Hz, 2H), 7.05 (dd, J ¼ 4.0, 8.0 Hz, 1H),
6.89 (d, J ¼ 8.0 Hz, 1H), 3.93 (d, J ¼ 8.0 Hz, 2H), 2.34e2.38 (m, 1H),
7.1.4.4. (E)-3-(3-(4-tert-Butylphenyl)-3-oxoprop-1-enyl)-5-(cyclo-
hexylmethoxy)-4H-chromen-4-one (4g). Yield 49.2%; White color
solid; m.p. 236e238 ꢀC; Rf ¼ 0.5 (2:8 Ethyl acetate:Hexane); IR
1.07 (d, J ¼ 4.0 Hz, 6H); 13C NMR (DMSO-d6)
d
187.20, 174.20, 161.90,
(cmꢁ1): 2918, 2853, 1665, 1653, 1220, 794; 1H NMR (CDCl3)
d 8.50
158.92, 156.91, 156.85, 134.34, 134.30, 130.61, 128.77, 122.47, 119.54,
115.17,113.60,109.31,108.18, 74.56, 27.33,18.64; HRMS: calculated for
(d, J ¼ 12.0 Hz, 1H), 8.06e8.03 (m, 3H), 7.55e7.50 (m, 4H), 7.00 (d,
J ¼ 8.0 Hz, 1H), 6.85 (d, J ¼ 8.0 Hz, 1H) 3.93 (d, J ¼ 8.0 Hz, 2H), 2.06e
2.03 (m, 3H), 1.82e1.79(m, 3H), 1.39e1.13 (m, 16H); 13C NMR
C22H20O5 m/z 364.1311, Found: 364.1304.
(CDCl3)
d 190.95, 175.93, 160.31, 157.71, 156.77, 156.71, 135.55,
7.1.3.6. (E)-5-(Cyclohexylmethoxy)-3-(3-(4-hydroxyphenyl)-3-
oxoprop-1-enyl)-4H-chromen-4-one (4c). Yield 55.7%; Yellow color
solid; m.p. 288e290 ꢀC; Rf ¼ 0.38 (2:8 Ethyl acetate:Hexane); IR
134.08, 128.95, 125.65, 120.88, 115.13, 109.75, 108.25, 75.10, 37.30,
35.17, 31.18, 29.90, 26.58, 25.81; HRMS calculated for C29H32O4: m/z
444.2301, Found: 444.2294.
(cmꢁ1): 3233, 2918, 2853, 1665, 1248, 788; 1H NMR (CDCl3)
d 8.54
(d, J ¼ 15.4 Hz, 1H), 8.05e8.03 (m, 3H), 7.57e7.43 (m, 4H), 7.01 (d,
J ¼ 8.3 Hz, 1H), 6.85 (d, J ¼ 8.3 Hz, 1H) 3.93 (d, J ¼ 6.4 Hz, 2H), 2.05e
2.02 (m, 3H), 1.82e1.72(m, 3H), 1.41e1.10 (m, 5H); 13C NMR (CDCl3)
7.1.4.5. (E)-3-(3-(4-Chlorophenyl)-3-oxoprop-1-enyl)-5-(cyclo-
hexylmethoxy)-4H-chromen-4-one (4h). Yield 58.4%; White color
solid; m.p. 219e221 ꢀC; Rf ¼ 0.4 (2:8 Ethyl acetate:Hexane); IR
d
189.74,175.90,160.36,157.64,150.30,143.01,137.87,134.41,129.87,
(cmꢁ1): 2920, 2853, 1653, 1265, 734; 1H NMR (CDCl3)
d 8.54 (d,
124.55, 123.95, 120.37, 115.02, 109.79, 108.52, 75.15, 37.29, 29.90,
26.55, 25.79; HRMS: calculated for C25H24O5: m/z 404.1624, Found:
404.1618.
J ¼ 15.4 Hz, 1H), 8.05e8.03 (m, 3H), 7.57e7.43 (m, 4H), 7.01 (d,
J ¼ 8.3 Hz, 1H), 6.85 (d, J ¼ 8.3 Hz, 1H) 3.93 (d, J ¼ 6.4 Hz, 2H), 2.05e
2.02 (m, 3H), 1.82e1.72(m, 3H), 1.41e1.10 (m, 5H); 13C NMR (CDCl3)
d
189381, 175.73, 160.12, 157.47, 157.14, 139.21, 136.35, 136.29,
7.1.4. General procedure for the preparation for compounds 4bej [17]
Compound 8c (1.0 equivalent) were added slowly to a mixture of
substituted triphenylphosphorane (9del) (1.2 equivalent) in
dichloromethane (25 mL) and then the reaction mixture was stirred
overnight at room temperature. After the reaction mixture was
evaporated, ether (100 mL) was added to the crude residue. The
resulted crystals were filtered and washed with ether again. The
above crystals were recrystallized from methanol and dried under
vacuum to obtain the compound 4del.
134.05, 130.23, 128.85, 124.78, 120.46, 114.93, 109.61, 108.23, 75.03,
7.23, 29.86, 26.53, 25.76; HRMS calculated for C25H23ClO4: m/z
422.1285, Found: 422.1280.
7.1.4.6. (E)-5-(Cyclohexylmethoxy)-3-(3-(4-fluorophenyl)-3-
oxoprop-1-enyl)-4H-chromen-4-one (4i). Yield 72.3%; White color
solid; m.p. 190e192 ꢀC; Rf ¼ 0.4 (2:8 Ethyl acetate:Hexane); IR (cmꢁ1):
2900, 2853, 1665, 1653, 1201, 810; 1H NMR (CDCl3)
d 8.55(d,
J ¼ 15.4 Hz, 1H), 8.15e8.11 (m, 2H), 8.04 (s, 1H), 7.54 (t, J ¼ 8.3 Hz, 1H),
7.45 (d, J ¼ 15.4 Hz, 1H), 7.19e7.14 (m, 2H), 7.01 (d, J ¼ 8.3 Hz, 1H), 6.86
(d, J ¼ 8.3 Hz, 1H) 3.93 (d, J ¼ 6.4 Hz, 2H), 2.05e2.01 (m, 3H), 1.82e
1.70(m, 3H), 1.41e1.07 (m, 5H); 13C NMR (CDCl3) 190.15, 175.68,
160.12, 157.44, 157.37, 140.81, 136.99, 134.11, 129.04, 125.58, 125.54,
124.68, 120.34, 114.88, 109.60, 108.27, 75.02, 37.23, 29.84, 26.50, 25.74;
HRMS calculated for C25H23FO4: m/z 406.1580, Found: 406.1574.
7.1.4.1. (E)-5-(Cyclohexylmethoxy)-3-(3-oxo-3-phenylprop-1-enyl)-
4H-chromen-4-one (4d). Yield 66.2%; White color solid; m.p. 176e
178 ꢀC; Rf ¼ 0.4 (2:8 Ethyl acetate:Hexane); IR (cmꢁ1): 2918, 2853,
1653,1234, 709; 1H NMR (CDCl3)
d
8.52 (d, J ¼ 15.4 Hz, 1H), 8.10e8.08
(m, 2H), 8.04 (s, 1H), 7.59e7.44 (m, 4H), 7.01 (d, J ¼ 8.3 Hz, 1H), 6.85
(d, J ¼ 7.8 Hz, 1H), 3.93 (d, J ¼ 6.4 Hz, 2H), 2.05e2.02 (m, 3H), 1.82e
1.79 (m, 3H), 1.41e1.07 (m, 5H); 13C NMR (CDCl3)
d
191.16, 160.15,
7.1.4.7. (E)-5-(Cyclohexylmethoxy)-3-(3-oxo-3-(4-(trifluoromethyl)
phenyl)prop-1-enyl)-4H-chromen-4-one (4j). Yield 52.6%; White
color solid; m.p. 204e206 ꢀC; Rf ¼ 0.4 (2:8 Ethyl acetate:Hexane);
157.53, 156.7, 138.06, 135.77, 133.96, 132.79, 128.81, 128.53, 125.35,
120.68, 109.61, 108.19, 75.04, 37.26, 29.87, 26.55, 25.77; HRMS:
calculated for C25H24O4: m/z 388.1675, Found: 388.1670.
IR (cmꢁ1): 2934, 2840, 1665, 1653, 1198. 703; 1H NMR (CDCl3)
d 8.52
(d, J ¼ 15.4 Hz, 1H), 8.19 (d, J ¼ 8.0 Hz, 2H), 8.06 (s, 1H) 7.77 (d,
J ¼ 8.3 Hz, 2H), 7.54 (t, J ¼ 8.3 Hz, 1H), 7.48 (d, J ¼ 15.4 Hz, 1H), 7.02
(dd, J ¼ 1.0, 8.0 Hz,1H) 6.87 (d, J ¼ 7.8 Hz,1H) 3.93 (d, J ¼ 6.4 Hz, 2H),
2.05e2.02 (m, 3H), 1.82e1.72(m, 3H), 1.38e1.10 (m, 5H); 13C NMR
7.1.4.2. (E)-5-(Cyclohexylmethoxy)-3-(3-(4-methoxyphenyl)-3-
oxoprop-1-enyl)-4H-chromen-4-one (4e). Yield 48.8%; White color
solid; m.p. 185e187 ꢀC; Rf ¼ 0.38 (2:8 Ethyl acetate:Hexane); IR
(cmꢁ1): 2920, 1655, 1212, 1140, 722; 1H NMR (CDCl3)
d
8.55(d,
(CDCl3) d 190.15,175.68,160.12,157.44,157.37,140.81,136.99,134.11,
J ¼ 15.4 Hz, 1H), 8.12 (d, J ¼ 8.8 Hz, 2H), 8.03 (s, 1H), 7.54 (t,
J ¼ 8.3 Hz, 1H), 7.44 (d, J ¼ 15.4 Hz, 1H), 7.01e6.96 (m, 1H), 6.85 (d,
J ¼ 8.3 Hz, 1H), 3.93 (d, J ¼ 6.4 Hz, 2H), 3.89 (s, 3H), 2.06e2.01 (m,
129.58, 125.54, 124.68, 120.34, 114.88, 109.60, 108.27, 75.02, 37.23,
29.84, 26.50, 25.74; HRMS calculated for C26H23F3O4: m/z 456.1548,
Found: 456.1544.
3H),1.82e1.70(m, 3H),1.39e1.09 (m, 5H); 13C NMR (CDCl3)
d 189.43,
175.80, 163.42, 160.42, 157.51, 156.63, 134.96, 133.90, 131.15, 131.00,
125.30, 120.73, 115.01, 113.73, 109.62, 108.12, 75.02, 55.48, 37.23,
29.86, 26.55, 25.77; HRMS calculated for C26H26O5: m/z 418.1780,
Found: 418.1775.
7.1.4.8. (E)-5-(Cyclohexylmethoxy)-3-(3-(4-nitrophenyl)-3-oxoprop-
1-enyl)-4H-chromen-4-one (4k). Yield 64.3%; Yellow color solid;
mp. : 280e282 ꢀC; Rf ¼ 0.37 (2:8 Ethyl acetate:Hexane); IR (cmꢁ1):
2918, 1665, 1510, 1201, 751; 1H NMR (CDCl3)
d
8.60 (d, J ¼ 15.4 Hz,
1H), 8.35 (d, J ¼ 8.8 Hz, 2H), 8.23 (d, J ¼ 8.8 Hz, 2H), 7.54 (t,
J ¼ 8.3 Hz, 1H), 7.49 (d, J ¼ 15.4 Hz, 1H), 7.03 (d, J ¼ 8.3 Hz, 1H), 6.88
(d, J ¼ 8.3 Hz, 1H), 3.94 (d, J ¼ 6.3 Hz, 2H), 2.05e2.02 (m, 3H), 1.82e
7.1.4.3. (E)-5-(Cyclohexylmethoxy)-3-(3-oxo-3-p-tolylprop-1-enyl)-
4H-chromen-4-one (4f). Yield 45.3%; White color solid; m.p. 200e
202 ꢀC; Rf ¼ 0.4 (2:8 Ethyl acetate:Hexane); IR (cmꢁ1): 2928,
1.72 (m, 3H), 1.42e1.07 (m, 5H); 13C NMR (CDCl3)
d 189.50, 175.68,
1665, 1210, 801; 1H NMR (CDCl3)
J ¼ 16.0 Hz,1H), 8.7 (s,1H), 7.86 (d, J ¼ 8.0 Hz, 2H) 7.59e7.51 (m,1H),
7.02 (d, J ¼ 8.0 Hz, 1H), 6.87 (d, J ¼ 8.0 Hz, 1H) 3.94 (d, J ¼ 8.0 Hz,
2H), 2.05e2.02 (m, 3H), 1.82e1.72(m, 3H), 1.39e1.11 (m, 5H); 13C
d
8.84 (d, J ¼ 8.0 Hz, 2H), 8.5 (d,
160.16,157.78, 157.44, 150.11, 142.83,137.70, 134.24, 129.71, 124.39,
123.79, 120.22, 114.87, 109.63, 108.39, 37.25, 29.86, 26.52, 25.76;
HRMS calculated for C25H23NO6: m/z 433.1525, Found: 433.1520.
NMR (CDCl3)
d
190.90, 175.97, 160.31, 157.72, 156.84, 143.79, 135.64,
7.1.4.9. (E)-4-(3-(5-(Cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)
acryloyl)benzonitrile (4l). Yield 55.9%; Yellow color solid; m.p. 265e
267 ꢀC; Rf ¼ 0.4 (2:8 Ethyl acetate:Hexane); IR (cmꢁ1): 2956, 2248,
135.51, 134.09, 125.58, 120.86, 115.13, 109.75, 108.27, 75.10, 37.28,
29.90, 26.58, 25.80, 21.73; HRMS calculated for C26H26O4: m/z
404.1831, Found: 404.1825.
1665, 1245, 706; 1H NMR (CDCl3)
d
8.56(d, J ¼ 16.0 Hz, 1H), 8.17(d,

E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
37
J ¼ 8.0 Hz, 2H), 8.07 (s, 1H), 7.81 (d, J ¼ 8.0 Hz, 2H), 7.59e7.46 (m,
2H), 7.03 (d, J ¼ 8.0 Hz, 1H), 6.87 (d, J ¼ 8.0 Hz, 1H) 3.94 (d,
J ¼ 8.0 Hz, 2H), 2.05e2.02 (m, 3H), 1.82e1.73 (m, 3H), 1.42e1.07 (m,
(m, 3H), 1.39e1.07 (m, 5H); 13C NMR (CDCl3)
150.30, 143.01, 137.87, 134.41, 129.87, 124.55, 123.95, 120.37, 115.02,
109.79, 108.52, 75.63, 75.15, 37.29, 29.90, 26.55, 25.79; HRMS calcu-
lated for C25H26O5: m/z 406.1780, Found: 406.1776.
d
175.90, 160.36, 157.64,
5H); 13C NMR (CDCl3)
d 189.95, 175.91, 160.34, 157.88, 141.45, 137.66,
134.37, 132.60, 129.30, 124.47, 120.39, 118.33, 116.06, 115.02, 109.76,
108.48, 75.14, 37.27, 29.89, 26.54, 25.78; HRMS calculated for
7.1.5.5. (E)-5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-(4-methoxyphe-
nyl)prop-1-enyl)-4H-chromen-4-one (5e). Yield 80.7%; Yellow color
solid; m.p. 175e177 ꢀC; Rf : 0.4 (3:7 Ethyl acetate:Hexane);
IR(cmꢁ1): 3298, 3070, 2920, 2860, 2358, 1077; 1H NMR (CDCl3)
C
26H23NO4: m/z 413.1627, Found: 413.1623.
7.1.5. General procedure for preparation of compounds (5ael)
Compound (4) (1.0 equivalent) was added to a mixture of
methanol/THF (1:1) and then added CeCl3.7H20 (1.1 equivalent)
and stirred the reaction mixture for 10 min at ambient temperature.
Now cooled the reaction mixture to 0e5 ꢀC and added NaBH4
(1.0 equivalent) and further stirred the reaction mixture for 1 h at
room temperature. The reaction solvent was evaporated under
reduced pressure and the obtained crude residue was dissolved in
methylene chloride and washed with water followed by brine
solution. The organic layer was dried with anhydrous sodium
sulfate and evaporated under reduced pressure. The residue was
purified by column chromatography to afford the compounds 5.
d
7.83 (s, 1H), 7.51e7.49 (m, 1H), 7.41e7.39 (m, 2H), 7.04 (t,
J ¼ 8.0 Hz, 2H), 6.95 (d, J ¼ 15.4 Hz, 1H), 6.78 (dd, J ¼ 6.9, 15.0 Hz,
1H), 6.62 (t, J ¼ 8.0 Hz, 2H), 5.35 (d, J ¼ 4.0 Hz, 1H), 3.87 (d,
J ¼ 4.0 Hz, 2H), 2.03e1.98 (m, 3H), 1.79e1.70 (m, 3H), 1.36e1.08 (m,
5H); 13C NMR (CDCl3)
d 176.03, 163.63, 160.31, 157.71, 157.71, 156.83,
135.13, 134.07, 131.32, 131.17, 125.46, 120.46, 120.88, 115.15, 113.87,
109.76.108.76.108.26. 76.03. 75.11. 55.55. 37.28. 29.90. 26.58. 25.80;
HRMS calculated for C26H28O5: m/z 420.1937, Found: 420.1932.
7.1.5.6. (E)-5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-p-tolylprop-1-
enyl)-4H-chromen-4-one (5f). Yield 79.3%; Yellow color solid; m.p.
190e192 ꢀC; Rf ¼ 0.4 (3:7 Ethyl acetate:Hexane); IR(cmꢁ1): 3390,
7.1.5.1. (E)-3-(3-Hydroxy-3-(4-hydroxyphenyl)prop-1-enyl)-5-
methoxy-4H-chromen-4-one(5a). Yield 44.8.%; off white solid;
m.p. ¼ 174e176 ꢀC; Rf 0.25 (4:6 Ethyl acetate:Hexane); IR 3215,
3070, 2920, 2854, 2358, 1049; 1H NMR (CDCl3)
d 7.85 (s, 1H), 7.51 (t,
J ¼ 8.4 Hz, 1H), 7.18e7.25 (m, 2H), 6.96 (dd, J ¼ 0.7, 8.5 Hz, 1H),
6.82e6.86 (m, 2H), 6.80 (d, J ¼ 7.8 Hz, 1H), 6.72 (dd, J ¼ 6.1, 15.8 Hz,
1H), 6.56 (d, J ¼ 15.8 Hz, 1H), 5.41 (d, J ¼ 4.0 Hz, 1H), 3.87 (d,
J ¼ 4.0 Hz, 2H), 2.03e1.96 (m, 3H), 1.80e1.73 (m, 3H), 1.36e1.09 (m,
2978, 1655, 1471, 1236, 1090, 701 cmꢁ1; H NMR (DMSO-d6)
d 7.85 (s,
1H), 7.51 (t, J ¼ 8.0 Hz, 1H), 7.21 (d, J ¼ 16.0 Hz, 1H), 7.97 (d,
J ¼ 8.0 Hz, 2H), 7.50 (m, 1H), 7.19 (dd, J ¼ 6.5, 15.8 Hz 1H), 7.06 (d,
J ¼ 8.0 Hz, 1H), 6.92 (d, J ¼ 8.0 Hz, 2H), 4.63e4.67 (m, 1H), 3.91 (s,
5H); 13C NMR (CDCl3)
d 175.97,160.31,157.72,156.84,143.79,135.64,
135.51, 134.09, 125.58, 120.86, 115.13, 109.75, 108.27, 76.02, 75.10,
37.28, 29.90, 26.58, 25.80, 21.73; HRMS calculated for C26H28O4: m/z
404.1988, Found: 404.1981.
3H); 13C NMR (DMSO-d6)
d 187.56, 174.76, 162.34, 159.82, 158.00,
157.15, 134.80, 134.78, 131.03, 129.20, 123.10, 119.82, 115.60, 113.94,
110.00, 73.09, 56.26; HRMS: calculated for C19H16O5 m/z 324.0998,
Found: 324.0992.
7.1.5.7. (E)-3-(3-(4-tert-Butylphenyl)-3-hydroxyprop-1-enyl)-5-
(cyclohexylmethoxy)-4H-chromen-4-one (5g). Yield 83.5%; Yellow
color solid; m.p. 230e232 ꢀC; Rf ¼ 0.5 (3:7 Ethyl acetate:Hexane);
IR (cmꢁ1): 3390, 3077, 2920, 2854, 2358, 1109; 1H NMR (CDCl3)
7.1.5.2. (E)-3-(3-Hydroxy-3-(4-hydroxyphenyl)prop-1-enyl)-5-
isobutoxy-4H-chromen-4-one (5b). Yield 65.0.%; Brown solid;
m.p. ¼139e141 ꢀC; Rf 0.30 (4:6 Ethyl acetate:Hexane); IR 3212, 2961,
d
7.83 (s, 1H), 7.47 (t, J ¼ 8.0 Hz, 1H), 7.40e7.34 (m, 4H), 6.93 (d,
1655, 1478, 1236, 1098, 715 cmꢁ1; H NMR (CDCl3)
d
1H NMR (CDCl3)
J ¼ 8.0 Hz, 1H), 6.76 (d, J ¼ 15.4 Hz, 1H), 6.71e6.56 (m, 2H), 5.34 (d,
J ¼ 8.0 Hz, 1H), 3.86 (d, J ¼ 8.0 Hz, 2H), 2.04e1.98 (m, 3H), 1.80e1.66
d
7.85 (s, 1H), 7.51 (t, J ¼ 8.4 Hz, 1H), 7.18e7.25 (m, 2H), 6.96 (d,
J ¼ 8.5 Hz, 1H), 6.82e6.86 (m, 2H), 6.80 (d, J ¼ 7.8 Hz, 1H), 6.72 (dd,
J ¼ 6.1, 15.8 Hz, 1H), 6.58 (d, J ¼ 15.8 Hz, 1H), 5.26 (d, J ¼ 3.6 Hz, 1H),
(m, 3H),1.36e1.06 (m, 5H); 13C NMR (CDCl3)
d 175.93,160.31,157.71,
156.77, 156.71, 135.55, 134.08, 128.95, 125.65, 120.88, 115.13, 109.75,
108.25, 76.11 75.10, 37.30, 35.17, 31.18, 29.90, 26.58, 25.81; HRMS
calculated for C29H34O4: m/z 446.2457, Found: 446.2451.
3.93 (d, J ¼ 6.8 Hz, 2H), 2.24e2.38 (m,1H),1.06 (d, J ¼ 6.5 Hz, 6H); 13
C
NMR (CDCl3)
d 177.19, 161.89, 160.40, 157.94, 135.12, 134.72, 131.75,
130.50, 125.78, 120.95, 116.40, 115.98, 110.01, 108.51, 76.32, 75.71,
27.99, 19.54; HRMS: calculated for C22H22O5 m/z 366.1467, Found:
366.1462.
7.1.5.8. (E)-3-(3-(4-Chlorophenyl)-3-hydroxyprop-1-enyl)-5-(cyclo-
hexylmethoxy)-4H-chromen-4-one (5h). Yield 80.2%; Yellow color
solid; m.p. 210e212 ꢀC; Rf ¼ 0.4 (3:7 Ethyl acetate:Hexane);
7.1.5.3. (E)-5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-phenylprop-1-
enyl)-4H-chromen-4-one (5c). Yield 90.2%; Yellow color solid; m.p.
170e172 ꢀC; Rf ¼ 0.5 (3:7 Ethyl acetate:Hexane); IR (cmꢁ1): 3290,
IR(cmꢁ1): 3398, 3070, 2920, 2854, 2358, 2343; 1H NMR (CDCl3)
d 7.82
(s, 1H), 7.49 (t, J ¼ 8.0 Hz, 1H), 7.37e7.31 (m, 5H), 6.95 (d, J ¼ 8.0 Hz,
1H), 6.78 (d, J ¼ 15.0 Hz, 1H), 6.61 (dd, J ¼ 6.1, 15.0 Hz, 1H), 5.34 (d,
J ¼ 8.0 Hz, 1H), 3.87 (d, J ¼ 4.0 Hz, 2H), 2.03e1.97 (m, 3H), 1.80e1.70
2920, 2854, 2343, 1065, 705; 1H NMR (CDCl3)
d 7.82 (s, 1H), 7.50e
7.41 (m, 3H), 7.37e7.34 (m, 2H), 7.29 (d, J ¼ 4 Hz, 1H), 6.93 (dd,
J ¼ 6.1, 15.8 Hz, 1H), 6.76 (d, J ¼ 15.8 Hz, 1H), 6.61 (d, J ¼ 8.0 Hz, 1H),
5.36 (d, J ¼ 8.0 Hz, 1H), 3.86 (d, J ¼ 6.9 Hz, 2H), 2.03e1.95 (m, 3H),
(m, 3H), 1.36e1.08 (m, 5H); 13C NMR (CDCl3)
d 176.95, 160.32, 157.67,
157.34, 139.39, 136.46, 134.22, 130.39, 129.01, 124.94, 120.62, 115.08,
109.75, 108.37, 76.08, 75.12, 37.28, 29.89, 26.56, 25.79; HRMS calcu-
lated for C25H25ClO4: m/z 424.1441, Found: 424.1436.
1.79e1.69 (m, 3H), 1.39e1.06 (m, 5H); 13C NMR (CDCl3)
d 176.28,
160.12, 158.25, 142.79, 133.94, 133.67, 128.72, 127.84, 126.52, 122.56,
121.23, 114.91, 109.67, 107.38, 75.43, 74.91, 37.41, 29.88, 26.57, 25.83;
HRMS calculated for C25H26O4: m/z 390.1831, Found: 390.1824.
7.1.5.9. (E)-5-(Cyclohexylmethoxy)-3-(3-(4-fluorophenyl)-3-
hydroxyprop-1-enyl)-4H-chromen-4-one (5i). Yield 79.7%; Yellow
color solid; m.p. 182e184 ꢀC; Rf ¼ 0.4 (3:7 Ethyl acetate:Hexane);
IR(cmꢁ1): 3398, 3070, 2920, 2854, 2358, 2343; 1H NMR (CDCl3)
7.1.5.4. (E)-5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-(4-hydroxyphenyl)
prop-1-enyl)-4H-chromen-4-one (5d). Yield 85.4%; Yellow color solid;
m.p. 284e286 ꢀC; Rf ¼ 0.38 (3:7 Ethyl acetate:Hexane); IR(cmꢁ1):
d
7.83 (s, 1H), 7.51e7.49 (m, 1H), 7.41e7.39 (m, 2H), 7.04 (t,
J ¼ 8.0 Hz, 2H), 6.95 (d, J ¼ 15.0 Hz,1H), 6.78 (d, J ¼ 15.0 Hz,1H), 6.62
(t, J ¼ 8.0 Hz, 2H), 5.35 (d, J ¼ 4.0 Hz, 1H), 3.87 (d, J ¼ 4.0 Hz, 2H),
2.03e1.98 (m, 3H), 1.79e1.70 (m, 3H), 1.36e1.08 (m, 5H); 13C NMR
3398, 3070, 2854, 2358, 1070; 1H NMR (CDCl3)
d
8.22 (d, J ¼ 8.0 Hz,
2H), 7.83 (s, 1H), 7.62 (d, J ¼ 15.0 Hz, 2H), 7.51 (t, J ¼ 8.0 Hz, 1H), 6.96
(d, J ¼ 8.0 Hz, 1H), 6.80 (d, J ¼ 8.0 Hz, 1H), 6.67e6.60 (m, 2H), 5.47 (d,
J ¼ 4.0 Hz, 1H), 3.88 (d, J ¼ 8.0 Hz, 2H), 2.03e1.96 (m, 3H), 1.80e1.65
(CDCl3)
d 175.93, 160.35, 157.67, 157.59, 141.01, 137.18, 134.31, 129.23,
125.77, 124.86, 120.52, 109.76, 108.43, 76.06, 75.14, 37.30, 29.90,

38
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 59 (2013) 31e38
26.56, 25.79; HRMS calculated for C25H25FO4: m/z 408.1737, Found:
References
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7.1.5.10. (E)-5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-(4-(trifluorome-
thyl)phenyl)prop-1-enyl)-4H-chromen-4-one (5j). Yield 79.3%;
Yellow color solid; m.p. 190e192 ꢀC; Rf ¼ 0.4 (3:7 Ethyl acetate:-
Hexane); IR(cmꢁ1): 3398, 3070, 2920, 2854, 2358, 2343; 1H NMR
(CDCl3) d 7.83 (s, 1H), 7.52e7.47 (m, 2H), 7.42e7.39 (m, 1H), 7.24 (d,
J ¼ 15.2 Hz, 1H), 6.96 (d, J ¼ 15.0 Hz, 1H), 6.78 (d, J ¼ 8.0 Hz, 2H),
6.62e6.58 (m, 2H), 5.31 (d, J ¼ 8.0 Hz, 1H), 3.87 (d, J ¼ 8.0 Hz, 2H)
2.03e1.99 (m, 3H), 1.79e1.70 (m, 3H), 1.39e1.06 (m, 5H); 13C NMR
(CDCl3)
d 175.95, 167.12, 164.59, 160.32, 157.67, 157.22, 136.18,
134.18, 131.62, 131.53, 125.03, 120.65, 115.87, 120.65, 115.87, 115.65,
115.08, 109.75, 108.34, 75.19, 75.11, 37.28, 29.89, 26.56, 25.79;
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solid; m.p. 275e277 ꢀC; Rf : 0.37 (3:7 Ethyl acetate:Hexane);
IR(cmꢁ1): 3398, 3070, 2920, 2854, 2358, 2343; 1H NMR (CDCl3)
d
8.21 (d, J ¼ 8.0 Hz, 2H), 7.82 (s, 1H), 7.61 (d, J ¼ 15.2 Hz, 2H), 7.50 (t,
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J ¼ 8.0 Hz, 1H), 6.95 (d, J ¼ 8.0 Hz, 1H), 6.79 (d, J ¼ 8.0 Hz, 1H), 6.66e
6.59 (m, 2H), 5.46 (d, J ¼ 4 Hz,1H), 3.87 (d, J ¼ 8.0 Hz, 2H), 2.02e1.95
(m, 3H), 1.79e1.64 (m, 3H), 1.38e1.06 (m, 5H); 13C NMR (CDCl3)
d
175.90, 160.36, 157.98, 157.64, 150.30, 143.01, 137.87, 134.41, 137.87,
134.41, 129.87, 124.55, 123.95, 120.37, 115.02, 109.77, 108.52, 76.65,
75.15, 37.29, 29.90, 26.55, 25.79; HRMS calculated for C25H25NO6:
m/z 435.1682, Found: 435.1678.
7.1.5.12. (E)-4-(3-(5-(Cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)-
1-hydroxyallyl)benzonitrile (5l). Yield 79.0%; Yellow color solid;
m.p. 259e261 ꢀC; Rf ¼ 0.4 (3:7 Ethyl acetate:Hexane); IR (cmꢁ1):
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1913e1920.
3398, 3070, 2920, 2854, 2358, 2343; 1H NMR (CDCl3)
d 7.83 (s, 1H),
7.66e7.64 (m, 2H), 7.56e7.48 (m, 3H), 6.95 (d, J ¼ 15.0 Hz, 1H), 6.79
(d, J ¼ 15.0 Hz, 1H), 6.63 (t, J ¼ 8.0 Hz, 2H), 5.41 (d, J ¼ 4.0 Hz, 1H),
3.87 (d, J ¼ 8.0 Hz, 2H) 2.03e1.96 (m, 3H), 1.80e1.70 (m, 3H), 1.36e
1.09 (m, 5H); 13C NMR (CDCl3)
d 189.95, 175.91, 160.34, 157.88,
141.45, 137.66, 134.37, 132.60, 129.30, 124.47, 120.39, 118.33, 116.06,
115.02, 109.76, 108.48, 75.14, 37.27, 29.89, 26.54, 25.78; HRMS
calculated for C26H25NO4: m/z 415.1784, Found: 415.1780.
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This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (grant
number 2011-0014889).