Design and synthesis of novel chromenone derivatives as interleukin-5 inhibitors

Article abstract of DOI:10.1016/j.bmc.2013.02.037

A novel series of chromenone analogs were synthesized and evaluated for their inhibitory activity against interleukin-5. Among them 5- (cyclohexylmethoxy)-3-[3-hydroxy-3-(4-hydroxyphenyl)propyl]-4H-chromen-4-one (9b, 94% inhibition at 30 μM, IC₅₀ = 4.0 μM) and 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4H-chromen-4-one (9c, 94% inhibition at 30 μM, IC₅₀ = 6.5 μM) showed the most potent activity. According to the SAR studies introduction of propanone unit in between chromenone and ring B as in 5-(cyclohexylmethoxy)-3-[3-(4-phenyl)-3- oxopropyl]-4H-chromen-4-ones (8) moderately increased the activity. However, the reduction of these propanones 8 to propanols 9 remarkably enhanced the activity. A small substituent at position 4 of ring B in 9, especially with hydrogen bonding capability, provides favorable contribution. Disappearance of IL-5 inhibitory activity upon saturation of chroman-4-one of 9 to chroman-4-ones 10 proves the critical importance of planar chromen-4-one unit of this scaffold in the IL-5 inhibition.

Full text of DOI:10.1016/j.bmc.2013.02.037

Bioorganic & Medicinal Chemistry 21 (2013) 2543–2550
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of novel chromenone derivatives
as interleukin-5 inhibitors
Eeda Venkateswararao a, Vinay K. Sharma a, Ki-Cheul Lee 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 novel series of chromenone analogs were synthesized and evaluated for their inhibitory activity against
Received 28 December 2012
Revised 21 February 2013
Accepted 24 February 2013
Available online 5 March 2013
interleukin-5. Among them 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-hydroxyphenyl)propyl]-4H-chro-
men-4-one (9b, 94% inhibition at 30
methoxyphenyl)propyl]-4H-chromen-4-one (9c, 94% inhibition at 30
l
M, IC50 = 4.0
l
M) and 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-
M, IC50 = 6.5 M) showed the
l
l
most potent activity. According to the SAR studies introduction of propanone unit in between chrome-
none and ring B as in 5-(cyclohexylmethoxy)-3-[3-(4-phenyl)-3-oxopropyl]-4H-chromen-4-ones (8)
moderately increased the activity. However, the reduction of these propanones 8 to propanols 9 remark-
ably enhanced the activity. A small substituent at position 4 of ring B in 9, especially with hydrogen bond-
ing capability, provides favorable contribution. Disappearance of IL-5 inhibitory activity upon saturation
of chroman-4-one of 9 to chroman-4-ones 10 proves the critical importance of planar chromen-4-one
unit of this scaffold in the IL-5 inhibition.
Keywords:
Chromenone analogs
Inhibitor
Interleukin-5
Eosinophils
Asthma
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
crucial for IL-5 inhibitory activity.11,12 Later the importance of
hydrophobic group such as cyclohexylmethoxy group at 5-position
Asthma is the common chronic inflammatory disease of the air-
ways described by variable and periodic symptoms, reversible air-
flow impediment, and bronchospasm.1 It is linked with intrusion of
T cells and eosinophils, increased levels of pro-inflammatory cyto-
kines such as interleukin-4 (IL-4), IL-5 and IL-13, and shedding of
bronchial epithelial cells (ECs).2 Eosinophils are the major effector
cells in allergic inflammation which are produced by the cytokine
IL-5. Level of both eosinophil and IL-5 is increased in the circula-
tion and sputum depending upon the severity of the disease.3–7
As IL-5 is directly involved in the eosinophil production it became
an important target in the treatment of asthma.
A numerous synthetic and natural derivatives have been studies
for their IL-5 inhibitory activity.8,9 Among them sophoricoside, a
natural product, showed the potent inhibitory activity.10 Though
sophoricoside showed good IL-5 inhibitory activity still the need
of potential IL-5 inhibitors persists to treat the disease like asthma.
Therefore, in an attempt to find better IL-5 inhibitors, we have
investigated a number of isoflavone and chalcone derivatives.11–14
The SAR studies of these derivatives revealed several important
points. We initially observed that the planar chromen-4-one ring
as well as phenolic hydroxyl group at 4-position of ring B are
of isoflavone (1b and 1d, Fig. 1) was also proven for good IL-5
inhibitory activity. In further exploration of SAR the effect of meth-
ylene unit by inserting it between phenyl and chromenone (2,
Fig. 1) was studied for proving the necessity of isoflavone scaf-
fold.15 Surprisingly, the results indicate that ring B is not essential
for the potent IL-5 activity.15 To further elaborate this point novel
5-(cyclohexylmethoxy)-3-(1-alkyl-2-hydroxyethylaminomethyl)
chromones were investigated (4, Fig. 1) and the results established
the role of ring B in isoflavone as a simple linker between chrome-
none and hydroxyl function. Recently, keeping the activity of ami-
no alcohol derivative of chromenone in mind we designed and
synthesized a number of N-substituted hydroxyethylaminometh-
ylchromenone derivatives (5) and tested them for their IL-5 inhib-
itory activity (Fig. 1).16 Interestingly, N-substituted derivatives (5)
showed far better activity than the compounds 4 substituted with
hydrophobic groups at position 1 of hydroxyethylaminomethyl-
chromenone.17 In another study we envisioned if the hybrid mole-
cule of isoflavone and chalcone can come up with some good
activity against IL-5.18 Therefore, to exploit their combined struc-
tural characteristics novel hybrid chromenone derivatives (6 and
7) were studied. These hybrid chromenones did not show good
activity but on reducing the
a,b-unsaturated ketones of hybrid
chromenone (6) to the racemic allylic alcohols (7), potent IL-5
inhibitory activity was observed. In addition, the activity of these
⇑
Corresponding author. Tel.: +82 42 821 5939; fax: +82 42 823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmc.2013.02.037

2544
E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
R3
O
O
R1
O
O
O
O
O
OH
OH
R2
OH
1
2
3
1a: Sophoricoside R1,R2 = OH, R3 = OGlu
1b: R1 = benzyloxy, R2 = H, R3 = OH
1c: R1 = H, R2 = benzyloxy, R3 = OH
1d: R1 = cyclohexylmethoxy, R2 =H, R3 = OH
O
O
R
O
O
O
OH
OH
N
N
R
H
O
4
5
Where, R = bulky hydrophobic
groups
Where, R = bulky hydrophobic
groups
O
O
O
O
O
O
O
OH
OH
OH
7
6
Figure 1. Interleukin-5 inhibitors.
allylic alcohols (7) was further increased on introduction of elec-
tron withdrawing groups at position 4 of ring B.18 We additionally
studied the conformational analysis and alignment of these deriv-
characteristics strengthen our view point that there is a need to
explore more SAR studies of these hybrid chromenones to under-
stand the correlation between their structure and activity. There-
fore, in the current article, we have further modified our previous
designs and synthesized newer analogs of chromenones 8, 9 and
10 (Fig. 2) and studied them for their IL-5 inhibitory activity.
atives and observed that the carbonyl function of a,b-unsaturated
ketones moiety is stretched away from the chromenone ring. How-
ever, the corresponding angles of derivatives depicted that hydro-
xyl group of racemic allylic alcohol moiety is located nearly at right
angle position in the chromenone ring plane.18 These structural
2. Chemistry
The synthesis of the desired compounds 8a–k and 9a–k and
10a–b were accomplished as outlined in Scheme 1 and the results
are listed in Table 1. In brief, the acetophenone 12 was prepared by
the partial alkylation of 2,6-dihydroxyacetophenone (11).11
Preparation of 13 was accomplished by the cyclization of 12 using
N,N-dimethylformamide and phosphoryl chloride at ambient tem-
perature.15 The Wittig reagent was obtained by the reaction of
commercially available substituted bromoacetophenone and tri-
phenylphosphine in methylene chloride at ambient tempera-
ture.19,20 The chromenone 14 was prepared by the reaction of
compound 3-formyl-5-(cyclohexylmethoxy)-4H-chromen-4-one
(13) with Wittig reagent in methylene chloride at ambient temper-
ature for overnight.19 To get the compounds 8a–k initial attempt
for the reduction of double bond of propenone linkage in 14 with
O
O
O
O
O
O
O
O
R
R
R
6
8
9
O
O
O
OH
O
O
O
R
O
10
Figure 2. Structural modifications for target IL-5 inhibitors 8, 9 and 10.
OH O
O
O
O
O
O
O
O
O
O
c
e
a
b
H
R
OH
11
OH
O
12
14
d
13
O
O
OH
O
O
O
R
R
O
O
8
f
9
O
O
O
O
R
10
Scheme 1. Synthesis of choromone analogs 8a–k, 9a–k and 10a–b. Reagents and conditions: (a) R-Br, CH3CN, aqueous 95% K2CO3, NaI (cat), reflux, overnight, (b) POCl3, DMF,
overnight, rt, (c) 13 and Wittig reagent, dichloromethane, overnight, rt, (d) Pd/C, cyclohexene, THF/methanol (1:1), reflux, 5 h, (e) cerium chloride, NaBH4/methanol, 0–5 °C, (f)
Pd/C, cyclohexene, THF/methanol (1:1), reflux, 18 h. Note = substituents are located in Table 1.

E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
2545
Table 1
tography. Therefore, the reaction condition was changed to Pd/c
with cyclohexene in THF/methanol (1:1) under reflux condition.
This condition converted 14–8 within 5 h however, on extending
the reaction time over 5 h resulted in the formation of mixture
therefore the reaction period was fixed up to 5 h to obtain the com-
pounds 8a–k only. The compounds 9a–k were prepared by the
reduction of 8a–k in the presence of cerium chloride and sodium
borohydride in methanol at 0–5 °C. Finally, the chromanones 10a
and 10b were obtained by reducing the double bond of chrome-
none ring of 8c and 8i, respectively, using Pd/c with cyclohexene
in THF/methanol (1:1) under reflux condition. Prolongation of the
reaction time to 18 h completely converted 8 to the chromanones
10. All these synthesized compounds were characterized by phys-
ical and spectral analysis data that confirmed their assigned
structures.
Chromenone analogs 8a–k, 9a–k and 10a–b with their physicochemical properties
Compd
Ra
Appearance
mp (°C)
Yield (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
H
OH
OCH3
CH3
t-Butyl
Cl
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
White solid
Colorless liquid
Colorless liquid
99–101
158–160
97–99
106–108
150–152
129–131
98–100
95–97
103–105
116–118
128–130
96–98
147–149
92–94
102–104
187–189
96–98
109–111
118–120
118–120
106–108
121–123
—
43.2
66.7
68.7
64.6
77.8
65.0
60.4
56.1
38.2
65.0
52.1
65.6
62.0
85.0
82.0
82.0
62.0
76.0
88.0
43.0
76.0
62.0
23.8
33.0
F
CF3
3,4-Cl
CN
8j
8k
9a
9b
9c
9d
9e
9f
9g
9h
9i
Naphthylb
H
OH
OCH3
CH3
t-Butyl
Cl
F
3. Conformational analysis and alignment
CF3
3,4-Cl
CN
Molecular model of the compounds 8b and 9b were constructed
using SYBYLÒ-X2.0 program package (Tripos Associates Inc.)21 and
their geometry were optimized (Powell conjugate gradient mini-
mization, termination at a gradient of 0.0005 kcal/mol) using the
Tripos standard force field22 and Gasteiger–Hückel atomic partial
charges.23 The 3D structures of the analyzed compounds were as-
sumed to be a bioactive conformation and were aligned according
to a chromenone template as shown in Figure 3. The selected dihe-
dral angles and atomic distances are listed in Tables 3 and 4.
9j
9k
10a
10b
Naphthylb
OCH3
3,4-Cl
—
a
Location of R is position 4 unless noted.
Naphthyl as ring B.
b
10
11
10
O
11
O
4
4
2
2
O
OH
9
3 O
3 O
1
1
4. Pharmacology
7
5
7
9
5
8
6
8
6
12
OH
12
OH
O
O
Inhibitory activity of the chromenone analogs (8a–k, 9a–k and
10a–b) against IL-5 was evaluated using the IL-5-dependent pro-B
Y16 cell line according to the previously reported procedure.24 The
cells were incubated with 3 U/mL mIL-5 for 48 h, in the presence or
absence of sample, and then measured cell metabolism as an index
of proliferation, using 2-(4-iodophenyl)-3-(nitrophenyl)-5-(2,4-
disulphophenyl)-2H tetrazolium sodium salt (WST-1). Data were
collected from three independent experiments. The effect of test
compounds on the IL-5 bioassay is represented as per cent inhibi-
9b
8b
tion at 30 lM samples and IC50 values were calculated (Table 2).
Figure 3. Alignment of compound 8b (9.651 kcal/mol) and 9b (10.058 kcal/mol).
Slat color (8b), Yellow color (9b).
5. Results and discussion
the Pd/c with H2 gas under atmospheric pressure at ambient tem-
perature resulted in a mixture of compounds 8 and 10 with closed
Rf values and we could not separate them using column chroma-
We have previously described that compound 6 possesses effec-
tive structural motifs of isoflavone 215 and chalcone 314 that is both
Table 2
Inhibitory activity of chromone analogs 8a–k, 9a–k and 10a–b against Interleukin-5
Ma
IC50
(l
M)
Compd
% Inhibition at 30
l
Ma
IC50
(l
M)
a
a
Compd
% Inhibition at 30
l
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
9a
12.3
80.0
91.0
70.0
6.7
94.0
93.0
5.3
68.0
93.0
10.0
94.0
94.0
91.7b
55.3
>30
15.0
16.0
>30
>30
14.0
20.0
>30
22.0
17.0
>30
12.0
4.0
9c
94.0
13.5
6.6
6.5
9d
9e
9f
9g
9h
9i
>30
>30
9.0
9.0
>30
7.9
15.0
17.0
>30
>30
94.0
94.0
55.0
94.0
94.0
86.0
34.0
40.0
9j
9k
10a
10b
9b
1d12
5.8
27.1
215
98.0
79.1
3.0
10.6
Budesonide
Sophoricoside
a
% Inhibitions and IC50 values are taken as mean from 3 experiments.
Inhibition at 50 lM.
b

2546
E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
Table 3
with planar naphthyl as ring B showed fairly good inhibition. How-
ever, analogs 9d–e and 9h with bulky functional groups still did
not show any activity. Therefore, the above results support the
importance of hydrogen bond characteristics of hydroxyl group
and small size of substituent at position 4 of ring B for the activity.
In another set of experiment, the effect of saturation in chrome-
none ring of 8 was investigated. Accordingly, chroman-4-ones 10a
and 10b were synthesized and tested for their IL-5 inhibitory activ-
ity but their activity was very low (Table 2). Upon saturation of
conjugate system in chromen-4-one ring, the conformational
change is obviously enormous and their conjugation of pyrenone
system is demolished. Thus the increased bulkiness of chroman-
4-one compared to chromen-4-one would block its fitting into
the binding site of the putative receptor or the loss of the reso-
nance within the pyrenone unit of chromen-4-one of 8 in chro-
man-4-ones 10 would diminish the power of binding capability
of chromen-4-one moiety remarkably. Therefore, these results
again prove the critical importance of chromen-4-one structural
unit of this scaffold in their IL-5 inhibition.
Torsion angle (°) and Total energy of compound 8b and 9b
Compound 8ba (9.651 kcal/mol)b Compound 9ba (10.058 kcal/mol)b
<C1–O2–C3–C4
<C5–C6–C7–C8
<C6–C7–C8–O11
<C6–C7–C8–C9
182.5
180.0
359.8
179.8
<C1–O2–C3–C4
<C5–C6–C7–C8
<C6–C7–C8–O11
<C6–C7–C8–C9
182.5
176.6
183.5
58.1
a
Numbers on the atoms of 8b and 9b are presented in Figure 3.
Total energy.
b
Table 4
Distance (Å) in compounds 8b and 9b
Compound 8ba
Compound 9ba
O2–O10
O2–O11
O2–O12
2.706
7.612
13.516
4.907
10.894
6.393
O2–O10
O2–O11
O2–O12
O10–O11
O10–O12
O11–O12
2.706
9.187
9.465
6.552
7.338
6.439
O
10–O11
O10–O12
11–O12
O
Since analogs 9 were more active than the corresponding 8 in
spite of their structural similarity, the detailed structural require-
ments of compounds 8b and 9b were also studied for their potent
IL-5 inhibitory activity. We compared the three dimensional struc-
tural sketches of compounds 8b and 9b and observed that there
was much difference not only in their torsional angles (Table 3)
but also in the distance (Å) from oxygen of cyclohexylmethoxy
group to oxygen at para-position of phenyl ring (Table 4). Specially,
comparison in the region of side chain at position 8 of chromenone
scaffolds of saturated ketone (8b) and alcohol (9b) is illustrated in
Figure 3. As mentioned in Table 3 the dihedral angle (<C6–C7–C8–
C9) of compound 8b is 179.8° which indicates that the propanone
side chain of 8b is stretched away from the chromenone ring. In
addition, the distance (13.516 Å, Table 4, Fig. 3) from oxygen of
cyclohexylmethoxy to oxygen at para-position of phenyl ring of
8b also confirms this stretched conformation. Meanwhile the cor-
responding angles (<C6–C7–C8–C9 = 58.1°, Table 3) of 9b depicts
that its propanol side chain is more folded and the alcoholic hydro-
xyl group is located nearly at right angle position in the chrome-
none ring plane. The much shorter distance (9.465 Å, Fig. 3) from
oxygen of cyclohexylmethoxy to oxygen at para-position of phenyl
ring in 9b compared to 8b also implies the folded conformation.
Such conformational changes might cause the enhancement of
the activity in analogs 9 compared to those of the corresponding
compounds 8. Therefore, the folded conformation as shown in 9b
could be much closer to the effective conformation for binding to
the putative receptor.
a
Numbers on the atoms of 8b and 9b are presented in Figure 3.
chromenone and phenylpropenone moieties (Fig. 1) for effective
IL-5 inhibition.18 However, chromenones 6 show weak IL-5 inhib-
itory activity. We hypothesized that it could be the planarity of ste-
rically strained trans
a,b-unsaturated ketone of chromenones 6
which restricts the conformation and thus the compound failed
to show IL-5 activity. Therefore, we further designed various ana-
logs (8–10, Fig. 2) of 6 by reducing the unsaturated ketone to sat-
urated ketone and studied the effect of various substituents such as
hydrogen bonding group, hydrophobic electron donating groups
(CH3, t-butyl), electron donating group (OCH3) and electron with-
drawing group (F, Cl, CF3, CN) at position 4 of ring B for their IL-5
inhibitory activity.
Accordingly, the compounds 8a–k were prepared and studied
for their IL-5 inhibitory activity and the compounds 8b–c, 8f–g
and 8i–j showed good IL-5 inhibitory activity while the compounds
8a, 8d–e, 8h and 8k did not turn up with any activity. These results
indicate that the compounds containing relatively small functional
groups regardless their electronic properties at position 4 of ring B
showed IL-5 inhibitory activity. However, the compounds having
bulky hydrophobic groups at the same position did not show any
activity. On comparing the activity of these saturated ketones 8
with their counterpart
a
,b-unsaturated ketone (14),18 the former
showed far better activity most probably due to their flexibility
of saturated ketone moiety of 8 to form an effective conformation
fitting to the active site of the target IL-5. However, these chrome-
nones exerted still lower activity compared to isoflavone 215
though it was better than isoflavone 1d.12
6. Conclusion
A series of 5-(cyclohexylmethoxy)-3-[3-(4-phenyl)-3-oxopro-
pyl]-4H-chromen-4-ones (8) and 5-(cyclohexylmethoxy)-3-
[3-hydroxy-3-(4-phenyl)propyl]-4H-chromen-4-ones (9) and 5-
(cyclohexylmethoxy)-3-[3-(phenyl)-3-oxopropyl]chroman-4-ones
(10) were synthesized and evaluated for their IL-5 inhibitory activ-
ity. Among the synthesized compounds, the inhibitory activity of
saturated ketones 8 was relatively weak and therefore this struc-
tural modification is not sufficient for the design of IL-5 inhibitor.
However, the alcohols 9 showed potent inhibition, especially the
compounds 9b and 9c containing hydroxyl in propyl linkage and
a small electron donating group with hydrogen bonding capability
at position 4 of ring B. In addition, the IL-5 inhibitory activity of
compounds 9f–g and 9i also prove the importance of small substit-
uents at position 4 of ring B. Disappearance of IL-5 inhibitory activ-
ity upon saturation of chroman-4-one of 9 to chroman-4-ones 10
again demonstrates the importance of planar chromen-4-one unit.
Considering the point that reduction of a,b-unsaturated ketone
of 6 to allylic alcohol of 7 dramatically increased the activity,18 in
another set of experiment the carbonyl function of ketone moiety
of 8 was reduced to the alcohol. Accordingly, compounds 9a–k
were prepared and tested for their IL-5 inhibitory activity as shown
in Table 2. Although the activity was lost in the compounds with
bulky groups such as methyl, tert-butyl and trifluoromethyl at po-
sition 4 of ring B (compounds 9d, 9e and 9h), other alcoholic com-
pounds 9a–c, 9f, 9g and 9i–k were better inhibitors than the
corresponding ketones 8. Exceptionally, 9b (94% inhibition at
30
lM, IC50 = 4.0
lM) and 9c (94% inhibition at 30 lM,
IC50 = 6.5
l
M) with hydrogen bonding capable electron donating
group at 4-position of ring B showed highly potent inhibition. In
addition the compounds containing electron withdrawing group
at position 4 of ring B such as 9f–g and 9i also showed quite good
inhibition against IL-5. Analog 9j with cyano at this position and 9k

E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
2547
7.1.1.4. 5-(Cyclohexylmethoxy)-3-(3-oxo-3-p-tolylpropyl)-4H-
chromen-4-one (8d). Yield 64.6%; white solid; mp 106.0 °C; IR
7. Materials and methods
7.1. Chemistry
2922, 1650, 1494, 1092, 815, 702 cmÀ1 1H NMR (CDCl3) d 7.86
;
(d, J = 8 Hz, 2H), 7.84 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.23 (d,
J = 8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0, 1H), 3.87 (d,
J = 4.0 Hz, 2H), 3.33 (t, J = 4.0 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H), 2.39
(s, 3H), 2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.40–1.21 (m, 3H),
1.27–1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3) d 178.5,
177.7, 159.7, 158.7, 151.5, 140.8, 133.4, 129.2, 128.2 124.3, 114.9,
109.7, 106.9, 37.2, 36.9, 29.8, 26.4, 24.8, 22.5, 21.5, 20.7; HRMS:
calcd for C26H28O4 m/z 404.1988, found: 404.1983.
Melting points were determined on Electro thermal 1A 9100
MK2 apparatus and are uncorrected. All commercial chemicals
were used as obtained and all solvents were purified by the stan-
dard procedures prior to use.25 Thin layer chromatography was
performed on E Merck silica gel GF-254 precoated plates and the
identification was done with UV light and colorization with spray
10% phosphomolybdic acid followed by heating. Flash column
chromatography was performed with E Merck silica gel (230–400
mesh). Infra-red spectrum was recorded by using sample as such
on FT-IR spectrum with Nicolet — 380 models. NMR spectra were
measured against the peak of tetramethylsilane by JEOL JNM-
EX90 NMR (89.45 MHz) and Varain Unity Inova 400 NMR
(400 MHz) spectrometers. High resolution mass spectra (HRMS)
were measured by using Shimadzu LCMS-IT-TOF spectrometer.
7.1.1.5. 3-[3-(4-tert-Butylphenyl)-3-oxopropyl]-5-(cyclohexyl-
methoxy)-4H-chromen-4-one (8e). Yield 77.8%; white solid; mp
150.0 °C; IR 2924, 1635, 1454, 1266, 1066, 833 cmÀ1 1H NMR
;
(CDCl3) d 7.65 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.74 (d,
J = 8.0, 1H), 3.93 (d, J = 4.0 Hz, 2H), 3.24 (t, J = 4.0 Hz, 2H), 2.83 (t,
J = 4.0 Hz, 2H), 2.39 (s, 3H), 2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H),
1.36 (s, 9H) 1.40–1.21 (m, 3H), 1.27–1.21 (m, 1H), 1.14–1.05 (m,
2H); 13C NMR (CDCl3) d 199.3, 160.1, 159.2, 159.0, 150.9, 137.1,
133.8, 128.6, 125.1, 109.7, 107.3, 75.2, 72.7, 55.5, 40.3, 38.8, 37.6,
31.4, 26.7, 26.0, 22.2; HRMS: calcd for C29H34O4 m/z 446.2457,
found: 446.2451.
7.1.1. General procedure for preparation of compounds (8)
The mixture of compound (14) (1 equiv) and cyclohexene
(2 equiv) was added to THF/methanol (1:1) and 20% Pd/c and the
reaction mixture was refluxed for 5 h. After the reaction mixture
was filtered using celite and the filtrate was evaporated under re-
duced pressure. The residue was purified by column chromatogra-
phy to afford the compound 8.
7.1.1.6. 3-[3-(4-Chlorophenyl)-3-oxopropyl]-5-(cyclohexylmeth-
oxy)-4H-chromen-4-one (8f). Yield 65.0%; white solid; mp
129.0 °C; IR 2933, 1632, 1266, 833, 780 cmÀ1 1H NMR (CDCl3) d
;
7.1.1.1. 5-(Cyclohexylmethoxy)-3-(3-oxo-3-phenylpropyl)-4H-
8.06 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.49 (t,
J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0, 1H), 3.87 (d,
J = 4.0 Hz, 2H), 3.38 (t, J = 4.0 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H), 2.39
(s, 3H), 2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.36 (s, 9H) 1.40–
1.21 (m, 3H), 1.27–1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3)
d 198.4, 179.1, 158.2, 159.0, 150.8, 138.1, 137.7, 134.8, 133.0, 128.6,
125.1, 118.8, 110.7, 109.3, 78.2, 38.8, 37.6, 31.4, 26.7, 26.0, 22.2;
HRMS: calcd for C26H25ClO4 m/z 424.1441, found: 424.1435.
chromen-4-one (8a).
Yield 43.2%; white solid; mp 99.0 °C;
IR 2923, 1697, 1676, 832, 811 cmÀ1
;
1H NMR (CDCl3) d 7.66 (s,
1H), 7.49 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.38–7.24 (m,
5H), 6.95 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0, 1H), 3.87 (d,
J = 8.0 Hz, 2H), 3.33 (t, J = 4.0 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H),
2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.40–1.21 (m, 3H), 1.27–
1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3) d 185.5, 177.7,
159.7, 158.7, 151.5, 143.79, 133.4, 129.2, 128.2 124.3, 114.9,
109.7, 106.9, 37.2, 36.9, 29.8, 26.4, 25.7, 21.5, 20.7; HRMS: calcd
for C25H26O4 m/z 390.1831, found: 390.1825.
7.1.1.7.5-(Cyclohexylmethoxy)-3-[3-(4-fluorophenyl)-3-oxopro-
pyl]-4H-chromen-4-one (8g). Yield 60.4%; white solid; mp
98.0 °C; IR 2923, 1697, 1676, 832, 811 cmÀ1 1H NMR (CDCl3) d
;
8.01 (t, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.10 (t,
J = 8 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0, 1H), 3.87 (d,
J = 8.0 Hz, 2H), 3.33 (t, J = 4.0 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H),
2.05-2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.40–1.21 (m, 3H), 1.27–
1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3) d 198.48,
177.7, 169.0, 159.7, 158.7, 151.5, 143.8, 133.4, 129.2, 128.2 124.3,
115.9, 109.7, 106.9, 37.2, 36.9, 29.8, 26.4, 25.7, 21.5, 20.7; HRMS:
calcd for C25H25FO4 m/z 408.1737, found: 408.1733.
7.1.1.2. 5-(Cyclohexylmethoxy)-3-[3-(4-hydroxyphenyl)-3-oxo-
propyl]-4H-chromen-4-one (8b).
Yield 66.7%; white solid;
mp 158.0 °C; IR 3428, 2923, 1659, 1453, 1243, 1066 cmÀ1
;
1H
NMR (CDCl3) d 7.93 (s, 1H), 7.72 (d, J = 4.0 Hz, 2H), 7.51 (t,
J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H),
6.78 (d, J = 8.0, 2H), 3.89 (d, J = 4.0 Hz, 2H), 3.22 (t, J = 4.0 Hz, 2H),
2.84 (t, J = 4.0 Hz, 2H), 2.39 (s, 3H), 2.05–2.02 (m, 3H), 1.80–1.71
(m, 2H), 1.36 (s, 9H) 1.40–1.21 (m, 3H), 1.27–1.21 (m, 1H), 1.14–
1.05 (m, 2H); 13C NMR (CDCl3) d 199.4, 177.7, 162.7, 158.7,
151.4, 143.7, 134.4, 133.3, 129.2, 128.2, 124.3, 114.9, 109.7,
106.9, 99.1, 91.7, 89.6, 50.1, 37.3, 29.8, 21.5, 20.7; HRMS: calcd
for C25H26O5 m/z 406.1780, found: 406.1773.
7.1.1.8.5-(Cyclohexylmethoxy)-3-{3-[4-(trifluoromethyl)phenyl]
-3-oxopropyl}-4H-chromen-4-one (8h). Yield 56.1%; white solid;
mp 95.0 °C IR 2924, 1660 1453, 1250, 1293, 833 cmÀ1 1H NMR
;
(CDCl3) d 8.07 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.51 (t, J = 8.0 Hz,
1H), 7.48 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.74 (d,
J = 8.0, 1H), 3.87 (d, J = 4.0 Hz, 2H), 3.38 (t, J = 4.0 Hz, 2H), 2.85 (t,
J = 4.0 Hz, 2H), 2.39 (s, 3H), 2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H),
1.36 (s, 9H) 1.40–1.21 (m, 3H), 1.27–1.21 (m, 1H), 1.14–1.05 (m,
2H); 13C NMR (CDCl3) d 198.5, 177.7, 169.0 159.7, 158.7, 151.5,
143.8, 133.4, 129.2, 128.2 124.3, 115.9, 109.7, 106.9, 37.2, 36.9,
29.8, 26.4, 25.7, 21.5, 20.7; HRMS: calcd for C26H25F3O4 m/z
458.1705, found: 458.1697.
7.1.1.3. 5-(Cyclohexylmethoxy)-3-[3-(4-methoxyphenyl)-3-oxo-
propyl]-4H-chromen-4-one (8c).
Yield 68.7%; white solid;
mp 97.0 °C; IR 2931, 1632, 1453, 1243, 833 cmÀ1; 1H NMR (CDCl3)
d 7.86 (d, J = 8.0 Hz), 7.84 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.23 (d,
J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0, 1H), 3.87
(d, J = 4.0 Hz, 2H), 3.24 (t, J = 4.0 Hz, 2H), 2.83 (t, J = 4.0 Hz, 2H),
2.39 (s, 3H), 2.05-2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.40–1.21 (m,
3H), 1.27–1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3) d
178.3, 160.1, 159.2, 159.0, 150.9, 137.1, 133.8, 127.5, 125.5,
115.1, 114.1, 109.7, 107.3, 75.2, 72.7, 55.5, 38.8, 37.6, 30.1, 26.7,
7.1.1.9. 3-[3-(3,4-Dichlorophenyl)-3-oxopropyl]-5-(cyclohexyl-
methoxy)-4H-chromen-4-one (8i).
mp 103.0 °C; IR 2931, 1653, 1453, 1243, 833,776 cmÀ1
(CDCl3) d 8.00 (s, 1H), 8.07 (d, J = 4.0 Hz, 2H), 7.81 (dd, J = 8.0,
Yield 38.2%; white solid;
1H NMR
26.0, 22.2; HRMS: calcd for
420.1932.
C26H28O5 m/z 420.1937, found:
;

2548
E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
4.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.52 (d,
J = 8.0 Hz, 1H), 6.49 (d, J = 8.0, 1H), 3.87 (d, J = 4.0 Hz, 2H), 3.38 (t,
J = 4.0 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H), 2.39 (s, 3H), 2.05–2.02 (m,
3H), 1.80–1.71 (m, 2H), 1.36 (s, 9H) 1.40–1.21 (m, 3H), 1.27–1.21
(m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3) d 199.4, 177.7,
159.7, 158.7, 151.4, 143.7, 134.4, 133.3, 129.2, 128.2, 124.3,
114.9, 109.7, 106.9, 99.1, 91.7, 89.6, 51.0, 37.3, 29.8, 21.5, 20.7;
HRMS: calcd for C25H24Cl2O4 m/z 458.1052, found: 458.1047.
3.07 (br s, 1H), 2.59–2.70 (m, 1H), 2.45–2.55 (m, 1H), 1.95–2.06
(m, 4H), 1.73–1.82 (m, 3H), 1.18–1.37 (m, 3H), 1.03–1.16 (m,
3H); 13C NMR (CDCl3) d 177.1, 159.5, 158.4, 150.2, 141.3, 136.6,
133.1, 128.8, 125.5, 124.9, 114.4, 109.3, 106.7, 76.9, 76.7, 76.4,
74.6, 72.3, 38.3, 37.0, 29.5, 29.5, 26.1, 25.4, 21.5, 20.7; HRMS: calcd
for C25H28O5 m/z 408.1937, found: 408.1933.
7.1.2.3.
5-(Cyclohexylmethoxy)-3-[3-hydroxy-3-(4-methoxy-
phenyl)propyl]-4H-chromen-4-one (9c). Yield 85%; white solid;
mp 92.0 °C; IR 3398, 2919, 1644, 1245, 827 cmÀ1; 1H NMR (CDCl3)
d 7.64 (s, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.94 (d,
J = 8.5 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 8.2 Hz, 1H), 4.62
(dd, J = 4.5, 8.9 Hz, 1H), 3.86 (d, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.07 (br
s, 1H), 2.59–2.70 (m, 1H), 2.45–2.55 (m, 1H), 1.95–2.06 (m, 4H),
1.73–1.82 (m, 3H), 1.18–1.37 (m, 3H), 1.03–1.16 (m, 3H); 13C
NMR (CDCl3) d 176.1, 160.1, 159.3, 159.1, 150.9, 137.1, 133.8,
127.5, 125.5, 115.1, 114.1, 109.9, 107.3, 77.6, 77.5, 77.3, 75.2,
72.7, 55.5, 38.9, 37.6, 30.1, 30.1, 26.8, 26.0, 22.2; HRMS: calcd for
7.1.1.10. 4-{3-[5-(Cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl]
propanoyl}benzonitrile (8j). Yield 65.0%; white solid; mp
116.0 °C; IR 2930, 2245, 1649, 1453, 833 cmÀ1 1H NMR (CDCl3) d
;
8.06 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.49
(t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0, 1H), 3.87
(d, J = 4.0 Hz, 2H), 3.38 (t, J = 4.0 Hz, 2H), 2.85 (t, J = 4.0 Hz, 2H),
2.39 (s, 3H), 2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.36 (s, 9H)
1.40–1.21 (m, 3H), 1.27–1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C
NMR (CDCl3) d 198.4, 179.1, 158.2, 159.0, 150.8, 139.1, 134.8,
133.0, 128.6, 125.1, 118.8, 117.6, 110.7, 109.3, 78.2, 38.8, 37.6,
31.4, 26.7, 26.0, 22.2; HRMS: calcd for C26H25NO4 m/z 415.1784,
found: 415.1778.
C29H30O5 m/z 422.2093, found: 422.2088.
7.1.2.4. 5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-p-tolylpropyl)-
4H-chromen-4-one (9d). Yield 82%; white solid; mp 102.0 °C;
7.1.1.11. 5-(Cyclohexylmethoxy)-3-[3-(naphthalen-3-yl)-3-oxo-
IR 3389, 2928, 1666, 1264, 659 cmÀ1 1H NMR (CDCl3) d 7.65 (s,
;
propyl]-4H-chromen-4-one (8k). Yield 52.1%; white solid; mp
1H), 7.49 (t, J = 8.41 Hz, 1H), 7.25 (d, J = 8.05 Hz, 2H), 7.13 (d,
J = 8.05 Hz, 2H), 6.94 (d, J = 8.54 Hz, 1H), 6.76 (d, J = 8.29 Hz, 1H),
4.63 (dd, J = 4.15, 8.78 Hz, 1H), 3.86 (d, J = 6.10 Hz, 2H), 3.16 (br
s, 1H), 2.61–2.71 (m, 1H), 2.52 (dd, J = 5.12, 8.05 Hz, 1H), 2.32 (s,
3H), 1.89–2.07 (m, 5H), 1.73–1.82 (m, 2H), 1.18–1.40 (m, 5H),
1.03–1.16 (m, 1H); 13C NMR (CDCl3) d 177.1, 159.5, 158.4, 150.2,
141.3, 136.6, 133.1, 128.8, 125.5, 124.9, 114.4, 109.3, 106.7, 76.9,
76.7, 76.4, 74.6, 72.3, 38.3, 37.0, 29.5, 29.5, 26.1, 25.4, 21.5, 20.7;
HRMS: calcd for C26H30O4 m/z 406.2144, found: 406.2139.
128.0 °C; IR 2928, 1650, 1454, 1243, 833 cmÀ1 1H NMR (CDCl3) d
;
8.56 (s, 1H), 8.04 (dd, J = 4.0, 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz,
1H),7.90–7.85 (m, 3H), 7.61–7.52 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H),
6.94 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 3.88 (d, J = 4.0 Hz,
2H), 3.52 (t, J = 4.0 Hz, 2H), 2.92 (t, J = 4.0 Hz, 2H), 2.39 (s, 3H),
2.05–2.02 (m, 3H), 1.80–1.71 (m, 2H), 1.36 (s, 9H) 1.40–1.21 (m,
3H), 1.27–1.21 (m, 1H), 1.14–1.05 (m, 2H); 13C NMR (CDCl3) d
199.4, 177.7, 162.7, 158.7, 151.4, 143.7, 135.6, 134.3, 132.5,
129.5, 128.2, 124.3, 114.9, 111.4, 109.7, 106.9, 99.1, 91.7, 89.6,
51.0, 37.3, 29.8, 21.5, 20.7; HRMS: calculated for C29H28O4 m/z
440.1988, found: 440.1981.
7.1.2.5.
hexylmethoxy)-4H-chromen-4-one (9e). Yield 82%; white solid;
mp 187.0 °C; IR 3402, 2850, 1644, 1266, 1066 cmÀ1 1H NMR
3-[3-(4-tert-Butylphenyl)-3-hydroxypropyl]-5-(cyclo-
;
7.1.2. General procedure for preparation of compounds (9)
CeCl3Á7H20 (1.1 equiv) was added to a solution of chromen-4-
one (8) (1.0 equiv) in a 1:1 mixture of methanol and THF and stir-
red for 10 min at ambient temperature then cooled to 0–5 °C and
then NaBH4 (1.0 equiv) was added at once. The reaction was con-
tinued stirred until disappearance of the starting material on TLC
analysis. After reaction mixture was evaporated, the residue was
dissolved in methylene chloride and washed with water followed
by brine solution. After dehydration with anhydrous sodium sul-
fate, the organic layer was evaporated and the residue purified
by column chromatography to afford 9.
(CDCl3) d 7.65 (s, 1H), 7.49 (t, J = 8.41 Hz, 1H), 7.33–7.37 (m, 2H),
7.27–7.32 (m, 2H), 6.94 (dd, J = 0.73, 8.54 Hz, 1H), 6.76 (d,
J = 8.29 Hz, 1H), 4.64 (dd, J = 4.39, 8.78 Hz, 1H), 3.86 (d,
J = 5.85 Hz, 2H), 3.09 (br s, 1H), 2.60–2.71 (m, 1H), 2.47–2.58 (m,
1H), 1.89–2.09 (m, 5H), 1.67–1.84 (m, 4H), 1.24–1.37 (m, 13H),
1.07–1.15 (m, 2H); 13C NMR (CDCl3) d 178.2, 160.0, 158.8, 150.6,
150.4, 141.7, 133.6, 125.8, 125.4, 125.3, 114.9, 109.7, 107.1, 77.4,
77.1, 76.8, 75.0, 72.8, 38.5, 37.4, 34.5, 31.4, 29.9, 29.9, 26.6, 25.9,
22.0; HRMS: calcd for C29H36O4 m/z 448.2614, found: 448.2610.
7.1.2.6. 3-[3-(4-Chlorophenyl)-3-hydroxypropyl]-5-(cyclohexyl-
methoxy)-4H-chromen-4-one (9f). Yield 62%; white solid; mp
7.1.2.1. 5-(Cyclohexylmethoxy)-3-(3-hydroxy-3-phenylpropyl)-
96.0 °C; IR 3402, 2928, 1652, 767, 659 cmÀ1 1H NMR (CDCl3) d
;
4H-chromen-4-one (9a). Yield 65.6%; white solid; mp 96.0 °C;
7.70 (s, 1H), 7.46–7.54 (m, 1H), 7.27–7.40 (m, 5H), 6.93–6.99 (m,
1H), 6.74–6.82 (m, 1H), 4.65 (ddd, J = 4.39, 9.45, 13.96 Hz, 1H),
3.87 (d, J = 6.34 Hz, 2H), 3.69 (br s, 1H), 2.64–2.77 (m, 1H), 2.43–
2.57 (m, 1H), 2.05–1.88 (m, 5H), 1.79–1.69 (m, 3H), 1.38–1.23
(m, 3H), 1.15–1.06 (m, 2H); 13C NMR (CDCl3) d 187.9, 177.0,
166.0, 163.5, 158.9, 157.5, 135.9, 134.4, 134.0, 131.0, 131.1,
127.1, 124.3, 115.7, 113.6, 109.3, 108.3, 74.6, 72.0, 38.5, 38.4,
29.7, 26.4, 27.3, 21.0; HRMS: calcd for C25H27ClO4 m/z 426.1598,
found: 426.1593.
IR 3388, 2923, 1650, 1264, 659 cmÀ1 1H NMR (CDCl3) d 7.66 (s,
;
1H), 7.49 (t, J = 8.0 Hz, 1H), 7.38–7.30 (m, 5H), 6.95 (d, J = 8.0 Hz,
1H), 6.77 (d, J = 8.0 Hz, 1H), 4.68–4.65 (m, 1H), 3.87 (d, J = 4.0 Hz,
2H), 3.36 (br s, 1H), 2.73–2.66 (m, 1H), 2.55–2.49 (m, 1H), 2.05–
1.88 (m, 5H), 1.79–1.69 (m, 3H), 1.38–1.23 (m, 3H), 1.15–1.06
(m, 2H); 13C NMR (CDCl3) d 178.8, 159.5, 158.4, 150.3, 144.3,
133.1, 128.0, 125.5, 124.8, 114.4, 109.2, 106.7, 74.5, 38.5, 36.9,
29.4, 25.4, 21.5; HRMS: calcd for C25H28O4 m/z 392.1988, found:
392.1982.
7.1.2.7. 5-(Cyclohexylmethoxy)-3-[3-(4-fluorophenyl)-3-hydroxy-
7.1.2.2. 3-[3-(4-Hydroxyphenyl)-3-hydroxypropyl]-5-(cyclohexyl-
propyl]-4H-chromen-4-one (9g). Yield 76%; white solid; mp
methoxy)-4H-chromen-4-one (9b). Yield 62.0%; white solid; mp
109.0 °C; IR 3402, 2848, 1635, 1460, 1064, 696 cmÀ1 1H NMR
;
147.0 °C; IR 3424, 2923, 1659, 1454, 1266, 1066 cmÀ1
;
1H NMR
(CDCl3) d 7.67 (s, 1H), 7.50 (t, J = 8.41 Hz, 1H), 7.30–7.35 (m, 2H),
7.00 (t, J = 8.78 Hz, 2H), 6.96 (dd, J = 0.73, 8.54 Hz, 1H), 6.77 (d,
J = 8.29 Hz, 1H), 4.63 (dd, J = 3.90, 9.27 Hz, 1H), 3.86 (d,
J = 4.00 Hz, 2H), 3.53 (br s, 1H), 2.66–2.76 (m, 1H), 2.44–2.53 (m,
(CDCl3) d 7.55 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.7 Hz,
2H), 6.98 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.78 (d,
J = 8.0, 2H), 4.66 (dd, J = 4.5, 8.9 Hz, 1H), 3.86 (d, J = 6.1 Hz, 2H),

E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
2549
1H), 1.89–2.03 (m, 5H), 1.67–1.82 (m, 4H), 1.22–1.37 (m, 3H),
1.03–1.16 (m, 2H); 13C NMR (CDCl3) d 187.9, 174.1, 166.0, 163.5,
158.9, 157.5, 135.9, 134.4, 134.0, 131.0, 130.9, 122.1, 119.3,
115.7, 113.6, 109.3, 108.3, 74.6, 72.0, 38.5, 38.4, 29.8, 29.7, 26.4,
27.3, 21.0, 18.6; HRMS: calcd for C25H27FO4 m/z 410.1893, found:
410.1887.
was evaporated under reduced pressure. The residue was purified
by column chromatography to afford the compound 10.
7.1.3.1. 5-(Cyclohexylmethoxy)-2,3-dihydro-3-[3-(4-methoxy-
phenyl)-3-oxopropyl]chromen-4-one (10a).
Yield 23.8%;
color less liquid; IR 2931, 1632, 1602, 1453, 1243, 833 cmÀ1
;
1H
NMR (CDCl3) 7.96 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.29 Hz, 1H),
6.90–6.96 (m, 2H), 6.45–6.54 (m, 2H), 4.53–4.49 (m, 1H), 4.29–
4.24 (m, 1H), 3.86–3.88 (m, 3H), 3.81 (d, J = 6.34 Hz, 2H), 3.14 (t,
J = 7.32 Hz, 2H), 2.67–2.78 (m, 1H), 2.23–2.28 (m, 1H), 1.99–1.90
(m, 3H), 1.77 (d, J = 12.68 Hz, 2H), 1.23–1.37 (m, 4H), 1.05–1.15
(m, 2H); 13C NMR (CDCl3) d 199.3, 197.0, 160.1, 159.2, 159.0,
150.9, 137.1, 133.8, 127.5, 125.5, 115.0, 114.1, 109.7, 107.3, 75.2,
72.7, 55.5, 38.8, 37.6, 30.1, 26.7, 26.0, 22.2; HRMS: calcd for
7.1.2.8. 5-(Cyclohexylmethoxy)-3-{3-[4-(trifluoromethyl)phenyl]-
3-hydroxypropyl}-4H-chromen-4-one (9h). Yield 88%; white
solid; mp 118.0 °C; IR 3399, 2919, 1650, 1255, 833 cmÀ1 1H
;
NMR (CDCl3) d 7.69 (s, 1H), 7.57 (d, J = 8.29 Hz, 2H), 7.52–7.46
(m, 3H), 6.99–6.94 (m, 1H), 6.78 (d, J = 8.05 Hz, 1H), 4.76–4.65
(m, 1H), 4.02 (d, J = 3.66 Hz, 1H), 3.99 (d, J = 3.6, 2H), 2.77 (d,
J = 6.10 Hz, 1H), 2.50 (s, 1H), 2.02–1.92 (m, 4H), 1.82–1.69 (m,
4H), 1.36–1.25 (m, 3H), 1.11 (br s, 3H); 13C NMR (CDCl3) d 187.9,
174.1, 166.0, 163.5, 158.9, 157.5, 135.9, 134.4, 134.0, 131.0,
130.9, 127.1, 124.3, 115.7, 113.6, 109.3, 108.3, 74.6, 72.0, 38.5,
38.4, 29.8, 29.7, 26.4, 27.3, 21.0, 19.2; HRMS: calcd for
C26H30O5 m/z 422.2093, found: 422.2089.
7.1.3.2. 3-[3-(3,4-Dichlorophenyl)-3-oxopropyl]-5-(cyclohexyl-
methoxy)-2,3-dihydrochromen-4-one (10b). Yield 33.0%;
color less liquid; IR 2921, 1666, 1645, 750, 620 cmÀ1 1H NMR
C26H27F3O4 m/z 460.1861, found: 460.1855.
;
(CDCl3) d 8.07 (d, J = 1.4 Hz, 1H), 7.81 (dd, J = 1.3, 8.41 Hz, 1H),
7.54 (d, J = 8.29 Hz, 1H), 7.33 (t, J = 8.29 Hz, 1H), 6.49 (d,
J = 8.54 Hz, 1H), 6.52 (d, J = 8.29 Hz, 1H), 4.52–4.48 (m, 1H),
4.29–4.24 (m, 1H), 3.81 (d, J = 6.34 Hz, 2H), 3.11–3.22 (m, 2H),
2.66–2.76 (m, 1H), 2.19 (d, J = 7.80 Hz, 1H), 1.86–2.01 (m, 4H),
1.77–1.69 (m, 3H), 1.17–1.39 (m, 4H), 1.04–1.14 (m, 2H); 13C
NMR (CDCl3) d 199.4, 196.7, 177.65, 159.7, 158.7, 151.4, 143.7,
134.4, 133.3, 129.2, 128.2, 124.3, 114.9, 109.7, 106.9, 99.1, 91.7,
89.6, 51.0, 37.3, 29.8, 21.5, 20.7; HRMS: calcd for C25H26Cl2O4 m/z
460.1208, found: 460.1203.
7.1.2.9. 3-[3-(3,4-Dichlorophenyl)-3-hydroxypropyl]-5-(cyclo-
hexylmethoxy)-4H-chromen-4-one (9i). Yield 43.0%; white
solid; mp 118.0 °C; IR 3387, 2921, 1643, 750, 620 cmÀ1 1H NMR
;
(CDCl3) d 7.64 (s, 1H), 7.48 (t, J = 8.41 Hz, 1H), 7.25 (d, J = 8.05 Hz,
2H), 7.13 (d, J = 7.80 Hz, 2H), 6.94 (dd, J = 0.98, 8.54 Hz, 1H), 6.76
(d, J = 8.29 Hz, 1H), 4.60–4.67 (m, 1H), 3.86 (d, J = 5.85 Hz, 2H),
3.06–3.11 (m, 1H), 2.61–2.71 (m, 1H), 2.46–2.55 (m, 1H), 1.95–
2.06 (m, 4H), 1.73–1.80 (m, 2H), 1.21–1.37 (m, 3H), 1.04–1.16
(m, 3H); 13C NMR (CDCl3) d 188.2, 179.0, 166.3, 163.5, 158.0,
158.9, 157.5, 135.9, 134.4, 134.0, 131.0, 131.1, 127.1, 124.3,
115.7, 113.6, 109.3, 108.3, 74.6, 72.0, 38.5, 38.4, 29.7, 26.4, 27.3,
21.0; HRMS: calcd for C25H26Cl2O4 m/z 460.1208, found: 460.1204.
Acknowledgment
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 num-
ber 2011-0014889).
7.1.2.10. 3-[3-(4-Cyano)-3-hydroxypropyl]-5-(cyclohexylmeth-
oxy)-4H-chromen-4-one (9j).
Yield 76%; white solid; mp
106.0 °C; IR 3394, 2923, 2245, 1650, 1260, 655 cmÀ1
;
1H NMR
(CDCl3) d 7.71 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 8.41 Hz,
1H), 7.48 (d, J = 8.29 Hz, 2H), 6.97 (dd, J = 0.73, 8.54 Hz, 1H), 6.79
(d, J = 7.81 Hz, 1H), 4.68 (m, 1H) 4.35 (d, J = 3.66 Hz, 2H), 3.91–
3.84 (m, 2H), 2.75–2.87 (m, 1H), 2.42–2.53 (m, 1H), 1.93–2.04
(m, 3H), 1.86–1.93 (m, 2H), 1.71–1.82 (m, 2H), 1.24–1.37 (m,
3H), 1.05–1.17 (m, 2H); 13C NMR (CDCl3) d 177.9, 174.1, 166.0,
163.5, 158.9, 157.5, 135.9, 134.4, 134.0, 131.0, 130.9, 122.1,
119.3, 115.7, 113.6, 109.3, 74.6, 72.0, 38.5, 38.4, 29.8, 29.7, 26.4,
27.3, 21.0, 18.6; HRMS: cald for C26H27NO4 m/z 417.1940, found:
417.1932.
References and notes
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;
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(CDCl3) d 7.77–7.85 (m, 4H), 7.66 (s, 1H), 7.41–7.48 (m, 4H), 6.94
(d, J = 8.29 Hz, 1H), 6.76 (d, J = 8.29 Hz, 1H), 4.83 (dd, J = 4.27,
8.90 Hz, 1H), 3.86 (d, J = 6.10 Hz, 2H), 3.54 (br s, 1H), 2.68–2.78
(m, 1H), 2.49–2.58 (m, 1H), 1.97–2.06 (m, 4H), 1.73–1.81 (m,
3H), 1.24–1.37 (m, 3H), 1.04–1.16 (m, 3H); 13C NMR (CDCl3) d
178.8, 159.5, 158.4, 157.3, 156.2, 154.3, 154.2, 150.3, 144.3,
133.1, 128.0, 127.8, 127.6, 127.4, 127.1, 125.5, 124.8, 114.4,
109.2, 106.7, 74.5, 38.5, 36.9, 29.44, 25.4, 21.5, 19.2; HRMS: calcd
for C29H30O4 m/z 442.2144, found: 442.2138.
7.1.3. General procedure for preparation of compounds (10)
The mixture of compound (8) (1 equiv) and cyclohexene
(2 equiv) was added to THF/methanol (1:1) and 20% Pd/c and the
resulted mixture was refluxed for 18 h. After the reaction was com-
pleted, the reaction mixture was filtered using celite and the fitrate

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E. Venkateswararao et al. / Bioorg. Med. Chem. 21 (2013) 2543–2550
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