The scope of thallium nitrate oxidative cyclization of chalcones; synthesis and evaluation of isoflavone and aurone analogs for their inhibitory activity against interleukin-5

Article abstract of DOI:10.1016/j.bmc.2010.04.075

The oxidative cyclization of 2′-hydroxy-6′-cyclohexylmethoxychalcones 5 using thallium (III) nitrate (TTN) in alcoholic solvents produced isoflavones 2 and (or) aurones 3 depending on the electronic nature of p-substituents on ring B. Chalcones with stron

Full text of DOI:10.1016/j.bmc.2010.04.075

Bioorganic & Medicinal Chemistry 18 (2010) 4441–4445
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
The scope of thallium nitrate oxidative cyclization of chalcones; synthesis
and evaluation of isoflavone and aurone analogs for their inhibitory
activity against interleukin-5
P. Thanigaimalai a, Hyun-Mo Yang a, Vinay Kumar Sharma a, 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
The oxidative cyclization of 20-hydroxy-60-cyclohexylmethoxychalcones 5 using thallium (III) nitrate
(TTN) in alcoholic solvents produced isoflavones 2 and (or) aurones 3 depending on the electronic nature
of p-substituents on ring B. Chalcones with strong electron donating substituents (OH, OCH3) were exclu-
sively converted to isoflavones 2. Chalcone with weak electron donating substituents (CH2CH3) was
transformed into isoflavone 2 and the aurone 3 in approximate ratio 1:1. Chalcones with hydrogen or
electron withdrawing substituents (Cl, CHO, COOCH3, and NO2) formed aurones 3. Synthesized isoflav-
ones 2 and aurones 3 were evaluated for their inhibitory activity against interleukin-5. Among them,
Article history:
Received 4 March 2010
Revised 21 April 2010
Accepted 22 April 2010
Available online 26 April 2010
Key words:
Isoflavone
Aurone
Inhibitor
Interleukin-5
Eosinophils
5-(cyclohexylmethoxy)-3-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (2h, >100% inhibition at 50
IC50 = 6.1 M) gave most potent activity. All the aurones 3 were inactive.
lM,
l
Ó 2010 Elsevier Ltd. All rights reserved.
Thallium (III) nitrate (TTN)
1. Introduction
reaction shows a great deal of diversity to form the different prod-
ucts such as 2, 3 and 4 (Fig. 1).13,16,17 Some findings indicate that
the reaction pathway of cyclic oxidation depends on the nature
of substituents present at the starting chalcones. They observed
that 20-hydroxychalcones substituted with chloro or nitro group
at ring A on reaction with TTN gave aurone 3 through the corre-
Isoflavones are the naturally abundant compounds with
remarkably diverse biological properties. They have been reported
for antioxidant1,2 antitumor,3,4 anticataracts,5 anti-inflammatory6
and antifertility7 activity. As isoflavones show various pharmaco-
logical properties, these compounds have been important target
for the research.
sponding (
a
-methoxybenzyl) coumaranones.17,18 On contrary to
Recently, a number of isoflavones have also been reported as
inhibitors of interleukin-5 (IL-5),8,9 which is a proven target for
finding new therapeutics for eosinophilia-associated allergic
inflammation.10,11 Naturally occurring isoflavone, sophoricoside
OH
O
OH
O
O
OH
O
O
OH
R2
OH
(1, 92.1% inhibition at 50 lM, IC50 = 1.4 lM, Fig. 1), show selective
inhibitory activity against the bioactivity of IL-5.12 Thus, we stud-
ied the structure–activity relationship (SAR) of isoflavonoid ana-
logs.8,9 In order to define the more detail structure–activity
relationship of isoflavone analogs, various substitutions on ring B
of isoflavone are required. However, their preparation has been
hampered due to limitations of available synthetic methods.
The oxidative cyclization of chalcones by the treatment with the
thallium (III) nitrate (TTN) has been considered as a standard pro-
cedure for the preparation of isoflavones 2.13–15 However, this
R1
O
2
HO
R1
1
Isoflavone
Sophoricoside
O
H3CO
HO
O
R
H3CO
H3CO
R2
O
O
3
4
Quinone acetal
Aurone
* Corresponding author. Tel.: +82 42 821 5939; 10 02665 5939 (M); fax: +82 42
823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
Figure 1. Structures of sophoricoside 1, isoflavone 2, aurone 3 and quinone acetal 4.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.04.075

4442
P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4441–4445
these studies, Thakkar and co-workers19,20 claimed that the TTN
oxidation of 20-hydroxy-50-methoxychalcones gave only thermo-
dynamically stable Z-isomers of aurones 3 regardless of the
presence of electron donating or withdrawing groups attached at
p-position of ring B or substitutions on the starting chalcones.
However, some researchers observed that TTN oxidation of a 20-hy-
droxy-40,50,60-trioxygenated chalcones in methanol gave quinone
acetal 4 instead of isoflavones 2 and aurones 3 by the oxidation
of ring A (Fig. 1).16,21 In our previous work,8,9 we have observed
the formation of isoflavone analogs of 1 from chalcones with
p-methoxymethoxy substituents using TTN oxidative cyclization
for investigating their inhibitory activity against IL-5. In this
regard, we examine the scope of this reaction based on the substit-
uents of ring B of 20-hydroxy-60-cyclohexylmethoxychalcones as
starting materials and the inhibitory activity of the synthesized
compounds against IL-5.
Table 1
The results of oxidative cyclization of chalcones 5
Starting material
Yield (%)
Chalcone
5
R
Chalcone 5 %
(recovered)
Isoflavone 2 %
(compd No.)
Aurone 3 %
(compd No.)
5a
5b
5c
5d
OH
OCH2OCH3
OCH3
3,4-
(OCH3)2
2,4-
(OCH3)2
3-OCH3, 4-
OCH2Ph
3-OCH3, 4-
OH
3,4,5-
(OCH3)3
CH2CH3
H
0
—
0
61.5 (2a)9
80.5 (2b)a
48.6 (2c)
49.7 (2d)
0 (3a)
—
0 (3c)
0 (3d)
0
5e
5f
0
44.3 (2e)
53.4 (2f)
0 (3e)
0 (3f)
—
0
b
5g
5h
—
0
98.1 (2g)
48.2 (2h)
0 (3h)
5i
5j
35.7
38.2
44.0
40.1
50.1
0
24.3 (2i)
0 (2j)
0 (2k)
0 (2l)
0 (2m)
0 (2n)
0
21.7 (3i)
44.8 (3j)
38.7 (3k)
32.7 (3l)
42.7 (3m)
74.5 (3n)
0
2. Results and discussion
5k
5l
5m
5n
5o
Cl
CHO
COOCH3
NO2
COOH
2.1. Synthesis and characterization of isoflavones 2 and
aurones 3
95.4
In continuation of our previous work8,9 on the modification of
ring B of isoflavones 2, we have synthesized a series of new isoflav-
one and aurone analogs starting from chalcones 5 prepared accord-
ing to the literature.22,23 Sequential treatments of compounds 5
with thallium (III) nitrate in methanol solvent at room temperature
for 24 h and then heating at 65 °C followed by addition of hydro-
chloric acid in one pot (oxidative cyclization) afforded the corre-
sponding isoflavones 2 or (and) aurones 3 (Scheme 1). This
conversion has been known as a key step for the classical prepara-
tion of isoflavone.24,25 This oxidative cyclization with 5b provided
2a, which was treated with methoxymethyl chloride to get
5-(cyclohexylmethoxy)-3-(4-(methoxymethoxy)phenyl)-4H-chro-
men-4-one (2b) with 80.5% yield as indicated in Table 1. The reac-
tion with 20-hydroxyl-60-cyclohexylmethoxy-400-methoxychalcone
(5c) only gave the desired isoflavone 2c. Similarly, the preparation
of other isoflavone derivatives with substituents on ring B such as
3,4-(OCH3)2 (2d), 2,4-(OCH3)2 (2e), 3-OCH3, 4-CH2Ph (2f) and 3,4,5-
(OCH3)3 (2h) has been done. In these reactions, we observed only
the formation of isoflavone analogs. However, presence of ethyl
substituent at the p-position of 20-hydroxy-60-cyclohexylmethoxy-
chalcone 5 led to formation of approximately 1:1 mixture of iso-
flavone 2i and aurone 3i. This result supported a previous finding
of Cummins et al.26 in which they observed that oxidative cycliza-
tion of 20-hydroxy-60-methoxychalcone yielded 4-methoxyaurone
and 5-methoxyisoflavone (1:1). Further, on decreasing the electron
density around ring B of 20-hydroxy-60-cyclohexylmethoxychal-
cone by introduction of H, Cl, CHO, COOCH3 and NO2 group we
ended up having respective aurone derivatives 3j–n. The 1H NMR
of the aurone derivatives shows that this oxidative cyclization pro-
cedure yields only Z-geometrical isomer, as reported in litera-
tures.20,27 These results are contradictory to another study of
Thakkar and Cushman,20 which showed only aurone formation
regardless the presence of electron donating or withdrawing
a
The reaction was started with 5b to give 2a in 61.5% yield, which was then
converted to 2c by the treatment with methoxymethyl chloride in 80.5% yield.
b
A product 2g was obtained from 2f by H2/Pd-reduction.
groups attached at the p-position of ring B. Interestingly, the chal-
cone 5o substituted with carboxylic group did not undergo any
reaction in this condition.
The major products obtained from these reactions were sepa-
rated by flash column chromatography and evaluated for their
IL-5 inhibitory activity. The yield of above obtained compounds
was moderate as shown in Table 1. Thus, the electronic nature of
p-substituents on ring B of chalcone determines the product in this
oxidative cyclization of 20-hydroxy-60-cyclohexylmethoxychal-
cones 5 using thallium (III) nitrate (TTN) in alcoholic solvent. From
the above study it can be concluded that the strong electron donat-
ing substituents (OCH2OCH3, OCH3) led to exclusive formation of
isoflavones 2, while the weak electron donating substituent
(CH2CH3) proceeded to the formation of isoflavones 2 and the auro-
nes 3 in approximate ratio 1:1. Only aurones 3 are produced with
hydrogen or electron withdrawing substituents (Cl, CHO, COOCH3,
NO2) of 5.
2.2. Pharmacology
The measurement of inhibitory activity of IL-5 of these analogs
was performed with the comparison of cell proliferation of Y16 cell
with/without the samples.12 An Y16 cell line originated from mur-
ine early B cell is proliferated in the presence of IL-5, which was
used as the parameter of IL-5 bioactivity. Non-radioactive proce-
dures that measure cell metabolism as an index of proliferation
have now become popular. 2-(4-Iodophenyl)-3-(4-nitrophenyl)-
5-(2,4-disulphophenyl)-2H538 tetrazolium sodium salt (WST-1)
R
O
O
O
O
O
O
B
a
and (or)
A
C
O
A
C
A
B
O
OH
R
B
3
2
5
R
Scheme 1. Synthesis of isoflavones 2 or (and) aurones 3. Reagents and conditions: (a) TTN, methanol, overnight at room temperature; hydrochloric acid, 50 °C, 5 h.
*
Substituents R and the ratio of formation of 2 and (or) 3 are listed in Table 1.

P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4441–4445
4443
was used to form soluble formazan product on exposure to the
3k (12.2% inhibition at 50
at 50 M, IC50 P 30
30 M) and 3n (5.7% inhibition at 50
studied for their activity against IL-5. These did not show any nota-
ble inhibitory activity against IL-5. These results indicate the
importance of isoflavone ring with electron donating group.
l
M, IC50 >30
l
M), 3l (8.0% inhibition
dehydrogenase activity in metabolizing cells. Proliferation of Y16
cells in the presence of IL-5 was specifically blocked by treatment
of polyclonal antibody against IL-5 or monoclonal antibody against
IL-5Ra. Sample and IL-5 were simultaneously added to the Y16
cells, and the bioassay system can identify the IL-5 antagonist
l
l
M), 3m (3.5% inhibition at 50
lM, IC50 P
l
lM, IC50 P 30 M) were also
l
and its signal inhibitor. Data for % inhibition at 50 lM and IC50 val-
ues are mean values from three separate experiments as shown in
Table 2.
3. Conclusion
The novel isoflavone derivatives were synthesized by oxidative
cyclization of substituted 20-hydroxy-60-cyclohexylmethoxychal-
cones using thallium (III) nitrate and tested them for their IL-5
inhibitory activity. This reaction proceeded to isoflavone 2 and
(or) aurone 3 depending on the electronic nature of p-substituents
on ring B of chalcone. The strong electron donating groups at p-po-
sition of ring B gives only isoflavones 2, the weak electron donating
group leads to the mixture and the electron withdrawing groups
end with aurones 3. The isoflavones gave inhibitory activity to-
wards IL-5 while the aurones did not. The structural requirement
for the isoflavone possessing the inhibitory activity against IL-5
could be summarized as (1) importance of hydrophobic group such
as cyclohexylmethoxy at C-5 position of ring A, (2) requirement of
ring B with high electron density groups and (3) planar nature of
chromen-4-one ring.
2.3. Structure–activity relationship of 2 and 3 for the inhibition
of IL-5
Previously we have synthesized a number of isoflavones for
their IL-5 inhibitory activity (Table 2) and found that 4-hydroxyl
on the ring B and benzyloxy (or cyclohexylmethoxy) group on
the ring A play an important role in modulating inhibitory activity
of IL-5.8,9 The isoflavone 2a (91.7% inhibition at 50
lM,
IC50 = 5.8
l
M) gave best inhibitory activity against IL-5.9 This indi-
cates that ring B of isoflavone analogs needs a strong electron
donating group with hydrogen bonding acceptor property. For
the confirmation of our point here, we studied the effect of electron
donating and electron withdrawing groups on their IL-5 inhibitory
activity. For that we first introduced methoxy group at p-position
of ring B as in 2c (15.4% inhibition at 50 lM, IC50 >30 lM). Surpris-
ingly, the compound 2c was very weak as compared to 2a (Table
2). This implies that the small size of hydrogen bonding group like
hydroxyl as well as a strong electron donating group at this posi-
tion might be important factor in the activity. In continuation,
4. Materials and methods
4.1. Chemistry
the other derivatives such as 2d (30.6% inhibition at 50
>30 M), 2e (15.6% inhibition at 50 M, IC50 >30 M), 2f (99.8%
inhibition at 50 M, IC50 = 17.4 M), 2g (15.7% inhibition at
50 M, IC50 >30 M) and 2h (>100% inhibition at 50 M,
IC50 = 6.1 M) were also tested for their inhibitory activity against
IL-5. Among them compounds 2f and 2h gave good inhibition
against IL-5. Especially, the compound 2h exhibited best potency
which is almost comparable to 2a. For more insight of SAR we also
lM, IC50
Melting points (mp) were determined on Electro thermal 1A
9100 MK2 apparatus and were uncorrected. All commercial chem-
icals were used as obtained and all solvents were purified by the
standard procedures prior to use. 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). A FT-IR spectrum was recorded with Nicolet—
380 models. NMR spectra were measured against the peak of
tetramethylsilane by Varain Unity Inova 400 NMR (400 MHz)
spectrometers. High resolution mass spectrum (HRMS) was re-
corded on API2000 mass spectrometer (PE Sciex, Toronto, Canada).
l
l
l
l
l
l
l
l
l
introduced some other electron donating groups such as
–
M)
M)
OCH2OCH3 group in 2b (10.5% inhibition at 50
and –CH2CH3 group in 2i (9.7% inhibition at 50
l
l
M, IC50 >30
M, IC50 >30
l
l
at p-position of ring B. These substitutions did not turn up with
any inhibition at all as shown in Table 2. This enforces our point
again that the importance of electron density or strong electron
donating group on phenyl ring is vital for the activity.
4.1.1. General procedure24,25 for the preparation of compounds
2b–i and 3i–n
In the next set of experiment, aurones 3i (3.8% inhibition at
50
lM, IC50 >30
lM), 3j (3.1% inhibition at 50
lM, IC50 >30 lM),
To a 2% solution of chalcone 5 in methanol was added 2 equiv of
thallium nitrate trihydrate. The resulting solution was stirred at
room temperature for one day. After concentration to about its half
volume, two equivalents of hydrochloric acid (2 M) was added,
with the resulting mixture stirred at 65 °C for 5 h. After removal
of the insoluble material by filtration, the filtrate was concentrated
under vacuum at room temperature. The crude product was dis-
solved in chloroform, and then washed three times with water.
The organic layer was dried with anhydrous sodium sulfate, and
then concentrated under vacuum. The crude product was purified
by flash column chromatography to give isoflavone 2 and (or) aur-
one 3.
Table 2
Inhibitory activity against IL-5 of 2a–i and 3i–n
b
Compound No.
R
% Inhibition (at 50
lM)
IC50
(
lM)
2aa
2b
2c
2d
2e
2f
2g
2h
4-OH
4-OCH2OCH3
4-OCH3
91.7
10.5
15.4
30.6
15.6
99.8
15.7
>100
9.7
5.8
>30
>30
>30
>30
17.4
>30
6.1
>30
>30
>30
>30
>30
>30
>30
26.2
3,4-(OCH3)2
2,4-(OCH3)2
3-OCH3,4-OCH2Ph
3-OCH3, 4-OH
3,4,5-(OCH3)3
4-CH2CH3
4-CH2CH3
4-H
2i
3i
3j
3.8
3.1
4.1.1.1. 5-(Cyclohexylmethoxy)-3-[4-(methoxymethoxy)phenyl]
-4H-chromen-4-one (2b). The reaction was started with 5b to give
2a in 61.5% yield, which was then converted to 2b by the treatment
with methoxymethyl chloride8; yellow solid; yield 80.5%; mp 105–
3k
3l
4-Cl
4-CHO
12.7
8.0
3m
3n
4-COOCH3
4-NO2
3.5
5.7
106 °C; IR (neat) 2950, 1650, 1510 cmꢀ1 1H NMR (CDCl3): d 1.10–
;
Budesonide
70.3
a
1.14 (m, 2H), 1.18–1.29 (m, 3H), 1.67–1.76 (m, 3H), 1.95–2.03 (m,
3H), 3.48 (s, 3H), 3.86 (d, J = 6.4 Hz, 2H), 5.20 (s, 2H), 6.78 (d,
Analytical data of compound 2a is consistent with Ref. 9.
IC50 values are taken as a mean from three experiments.
b

4444
P. Thanigaimalai et al. / Bioorg. Med. Chem. 18 (2010) 4441–4445
J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.45
(d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H). HRMS calcd
for C24H26O5 m/z 394.1780, found 394.1774.
35.7%; mp 120–124 °C; IR (neat) 3200, 2850, 1700, 1600 cmꢀ1
;
1H NMR (CDCl3): d 1.09–1.37 (m, 8H), 1.69–1.79 (m, 3H), 1.93–
1.96 (m, 3H), 2.69 (q, J = 7.6 Hz, 2H), 3.94 (d, J = 6.0 Hz, 2H), 6.58
(d, J = 8.4 Hz, 1H), 6.78 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.27 (d,
J = 8.4 Hz, 2H), 7.51 (t, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H). HRMS
calcd for C24H26O3 m/z 362.1882, found 362.1876.
4.1.1.2. 5-(Cyclohexylmethoxy)-3-(4-methoxyphenyl)-4H-chro-
men-4-one (2c). The reaction was started with 5c; white solid;
yield 48.6%; mp 105–106 °C; IR (neat) 2950, 1650, 1510 cmꢀ1 1H
,
NMR (CDCl3): d 1.05–1.10 (m, 2H), 1.18–1.35 (m, 3H), 1.67–1.76
(m, 3H), 1.95–2.03 (m, 3H), 3.80 (s, 3H), 3.86 (d, J = 6.4 Hz, 2H),
6.78 (d, J = 8.4 Hz, 1H), 6.93–6.99 (m, 3H), 7.44–7.52 (m, 3H),
7.78 (s, 1H). HRMS calcd for C23H24O4 m/z 364.1675, found
364.1671.
4.1.1.9. (Z)-2-(Benzylidene)-4-(cyclohexylmethoxy)benzofuran-
3(2H)-one (3j). The reaction was started with 5j; yellow solid;
yield 44.8%; starting chalcone recovered 38.2%; mp 125–126 °C;
IR (neat) 3100, 2950, 1700, 1600 cmꢀ1 1H NMR (CDCl3): d 1.08–
;
1.96 (m, 11H), 3.94 (d, J = 6.0 Hz, 2H), 6.58 (d, J = 8.4 Hz, 1H),
6.78 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 7.35–7.39 (m, 1H), 7.42–7.45
(m, 2H), 7.52 (t, J = 8.4 Hz, 1H), 7.88–7.90 (m, 2H). HRMS calcd
for C22H22O3 m/z 334.1569, found 334.1562.
4.1.1.3. 5-(Cyclohexylmethoxy)-3-(3,4-dimethoxyphenyl)-4H-
chromen-4-one (2d). The reaction was started with 5d; yellow so-
lid; yield 49.7%; mp 112–114 °C; IR (neat) 2922, 2850, 1645, 1601,
1502 cmꢀ1
;
1H NMR (CDCl3): d 1.08–2.04 (m, 11H), 3.81 (d,
4.1.1.10.
(Z)-2-(4-Chlorobenzylidene)-4-(cyclohexylmethoxy)
J = 6.0 Hz, 2H), 3.87 (s, 6H), 6.68 (d, J = 8.4 Hz, 1H), 6.87 (d,
J = 8.4 Hz, 1H), 6.91–7.22 (m, 2H), 7.23 (s, 1H), 7.20–7.33 (m, 2H),
7.33 (t, J = 8.4 Hz, 1H), 7.81 (s, 1H). HRMS calcd for C24H26O5 m/z
394.1780, found 394.1773.
benzofuran-3(2H)-one (3k). The reaction was started with 5k;
white solid; yield 38.7%; starting chalcone recovered 44.0%; mp
179–180 °C; IR (neat) 3100, 2850, 1710, 1600 cmꢀ1 1H NMR
;
(CDCl3): d 1.08–1.95 (m, 11H), 3.95 (d, J = 6.0 Hz, 2H), 6.60 (d,
J = 8.4 Hz, 1H), 6.71 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 7.40 (d,
J = 8.4 Hz, 2H), 7.53 (t, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H). HRMS
calcd for C22H21ClO3 m/z 368.1179, found 368.1174.
4.1.1.4. 5-(Cyclohexylmethoxy)-3-(2,5-dimethoxyphenyl)-4H-
chromen-4-one (2e). The reaction was started with 5e; yellow so-
lid; yield 44.3%; mp 132–134 °C; IR (neat) 2927, 2851, 1642, 1593,
1507 cmꢀ1 1H NMR (CDCl3): d 1.07–2.01 (m, 11H), 3.73 (s, 3H),
;
4.1.1.11. (Z)-4-{[4-(Cyclohexylmethoxy)-3-oxobenzofuran-2(3H)-
ylidene]methyl}benzaldehyde (3l). The reaction was started with
5l; yellow solid; yield 32.7%; starting chalcone recovered 40.1%;
3.77 (s, 3H), 3.84 (d, J = 6.0 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.87–
6.92 (m, 3H), 6.97 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.51
(s, 1H). HRMS calcd for C24H26O5 m/z 394.1780, found 394.1774.
mp 163–165 °C; IR (neat) 3100, 2950, 1700, 1600 cmꢀ1 1H NMR
;
(CDCl3): d 1.08–1.96 (m, 11H), 3.96 (d, J = 6.0 Hz, 2H), 6.63 (d,
J = 8.4 Hz, 1H), 6.78 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 7.57 (t,
J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H),
10.05 (s, 1H). HRMS calcd for C23H22O4 m/z 362.1518, found
362.1515.
4.1.1.5. 3-(4-(Benzyloxy)-3-methoxyphenyl)-5-(cyclohexylmeth-
oxy)-4H-chromen-4-one (2f). The reaction was started with 5f;
yellow solid; yield 53.4%; mp 128–130 °C; IR (neat) 2922, 2854,
1647, 1596, 1497, 1459 cmꢀ1 1H NMR (CDCl3): d 1.08–1.99 (m,
;
11H), 3.82 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 5.19 (s, 2H), 6.78 (d,
J = 8.0 Hz, 1H), 6.90–6.99 (m, 2H), 7.16 (s, 1H), 7.28–7.53 (m, 8H),
7.77 (s, 1H). HRMS calcd for C30H30O5 m/z 470.2093, found
470.2088.
4.1.1.12. Methyl(Z)-4-[4-(cyclohexylmethoxy)-3-oxobenzofu-
ran-2(3H)-ylidene]methylbenzoate (3m). The reaction was
started with 5m; yellow solid; yield 42.7%; starting chalcone
recovered 50.1%; mp 152–153 °C; IR (neat) 3100, 2920, 1700,
4.1.1.6. 5-(Cyclohexylmethoxy)-3-(4-hydroxy-3-methoxyphenyl)-
4H-chromen-4-one (2g). The reaction was started with 2f by
catalytic hydrogenolysis (H2, Pd–C); yellow solid; yield 98.1%; mp
1600 cmꢀ1 1H NMR (CDCl3): d 1.09–1.12 (m, 2H), 1.25–1.34 (m,
;
3H), 1.73–1.80 (m, 3H), 1.93–1.95 (m, 3H), 3.94 (s, 3H), 3.96 (m,
2H), 6.61 (d, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H),
7.54 (t, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz,
2H). HRMS calcd for C24H24O5 m/z 392.1624, found 392.1620.
72–75 °C; IR (neat) 2957, 2850, 1700, 1619, 1527, 1437 cmꢀ1 1H
;
NMR (CDCl3): d 0.87–2.00 (m, 11H), 3.82 (d, J = 6.0 Hz, 2H), 3.92
(s, 3H), 6.48 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.86 (m,
3H), 7.49 (t, J = 8.4 Hz, 1H), 7.78 (s, 1H). HRMS calcd for C23H24O5
m/z 380.1624, found 380.1620.
4.1.1.13. (Z)-4-(Cyclohexylmethoxy)-2-(4-nitrobenzylidene)ben-
zofuran-3(2H)-one (3n). The reaction was started with 5n; yellow
solid; yield 74.5%; mp 171–173 °C; IR (neat) 3150, 2950, 1700,
4.1.1.7. 5-(Cyclohexylmethoxy)-3-(3,4,5-trimethoxyphenyl)-4H-
chromen-4-one (2h). The reaction was started with 5h; yellow so-
lid; yield 48.2%; mp 89–90 °C; IR (neat) 2926, 2857, 1642, 1594,
1650 cmꢀ1 1H NMR (CDCl3): d 1.06–1.38 (m, 5H), 1.62–1.80 (m,
;
3H), 1.92–1.95 (m, 3H), 3.95 (d, J = 6.0 Hz, 2H), 6.63 (d, J = 8.4 Hz,
1H), 6.74 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 8.4 Hz, 1H),
8.01 (d, J = 8.8 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H). HRMS calcd for
C22H21NO5 m/z 379.1420, found 379.1414.
1503, 1453 cmꢀ1 1H NMR (CDCl3): d 0.85–2.17 (m, 11H), 3.85 (d,
;
J = 4.8 Hz, 2H), 3.88 (s, 9H), 6.73 (s, 2H), 6.81 (d, J = 8.4 Hz, 1H),
7.00 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 8.4 Hz, 1H), 7.81 (s, 1H). HRMS
calcd for C25H28O6 m/z 424.1886, found 424.1881.
Acknowledgment
4.1.1.8. 5-(Cyclohexylmethoxy)-3-(4-ethylphenyl)-4H-chromen-
4-one (2i) and (Z)-4-(cyclohexylmethoxy)-2-(4-ethylbenzylid-
ene)benzofuran-3(2H)-one (3i). The reaction was started with 5i.
Compound (2i): yellow solid; yield 24.3%; mp 118–120 °C; IR
This work was supported by Priority Research Centers Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry Education, Science and Technology (2009-
0093815).
(neat) 2920, 2852, 1747, 1645 cmꢀ1 1H NMR (CDCl3): d 1.095 (t,
;
J = 3.4 Hz, 3H), 1.17–2.00 (m, 1H), 2.62 (q, J = 7.6 Hz, 2H), 3.87 (d,
J = 6.4 Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H),
7.12–1.24 (m, 4H), 7.28 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H).
HRMS calcd for C24H26O3 m/z 362.1882, found 362.1875. Com-
pound (3i): yellow solid; yield 21.7%; starting chalcone recovered
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