Carboxylated, heteroaryl-substituted chalcones as inhibitors of vascular cell adhesion molecule-1 expression for use in chronic inflammatory diseases

Article abstract of DOI:10.1021/jm0614230

Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion molecule-1 (VCAM-1) expression. Corr

Full text of DOI:10.1021/jm0614230

1304
J. Med. Chem. 2007, 50, 1304-1315
Carboxylated, Heteroaryl-Substituted Chalcones as Inhibitors of Vascular Cell Adhesion
Molecule-1 Expression for Use in Chronic Inflammatory Diseases
Charles Q. Meng,* Liming Ni, Kimberly J. Worsencroft, Zhihong Ye, M. David Weingarten, Jacob E. Simpson,
Jason W. Skudlarek, Elaine M. Marino, Ki-Ling Suen, Charles Kunsch, Amy Souder, Randy B. Howard, Cynthia L. Sundell,
Martin A. Wasserman, and James A. Sikorski
AtheroGenics, Inc., 8995 Westside Parkway, Alpharetta, Georgia 30004
ReceiVed December 11, 2006
Starting from a simple chalcone template, structure-activity relationship (SAR) studies led to a series of
carboxylated, heteroaryl-substituted chalcone derivatives as novel, potent inhibitors of vascular cell adhesion
molecule-1 (VCAM-1) expression. Correlations between lipophilicity determined by calculated logP values
and inhibitory efficacy were observed among structurally similar compounds of the series. Various substituents
were found to be tolerated at several positions of the chalcone backbone as long as the compounds fell into
the right range of lipophilicity. The chalcone R,â-unsaturated ketone moiety seemed to be the pharmacophore
required for inhibition of VCAM-1 expression. Compound 19 showed significant antiinflammatory effects
in a mouse model of allergic inflammation, indicating that this series of compounds might have therapeutic
value for human asthma and other inflammatory disorders.
Introduction
Results and Discussion
The chalcone compounds reported herein were synthesized
through aldol condensation between properly substituted ac-
etophenones and benzaldehydes. Bromobenzaldehyde 2 was
converted to benzothienylbenzaldehyde 3 using a modified
Suzuki coupling condition. Compound 3 was then condensed
with commercially available 4-acetylbenzoic acid (4), affording
chalcone 5 after acidification.13 Derivatization could also be
carried out after the aldol condensation step. For example,
compound 5 was converted to amide 6 using 1-(3-dimethy-
laminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (Scheme
1).
In addition to the heteroaryl moiety at the 5-position, various
substituents were also introduced to the 2- and/or 4-positions
of ring B before the aldol condensation step. Benzaldehyde 7,
which was obtained from 5-bromo-2-hydroxy-4-methoxyben-
zaldehyde and thiophene-2-boronic acid using a Suzuki coupling
reaction in the same fashion as in Scheme 1, was treated with
mesylate 814 to give aldehyde 9 (Scheme 2). The silyl protecting
groups in 9 were removed after the aldol condensation step.
VCAM-1 is a key regulator of leukocyte trafficking to sites
of inflammation and has been implicated in numerous inflam-
matory diseases such as asthma, rheumatoid arthritis (RA), and
atherosclerosis. While it is endogenously expressed at very low
levels in healthy tissues, increased expression of VCAM-1 has
been observed in inflammatory disease states in humans and in
animal models. Increased plasma levels of soluble VCAM-1
have also been observed in some patient populations. Antibodies
directed against VCAM-1 and inhibitors of VCAM-1 expression
have shown antiinflammatory effects in animal models.1-6
Natalizumab, a specific humanized monoclonal antibody to very
late antigen-4 (VLA-4, the counter receptor of VCAM-1),
showed efficacy in treating patients with multiple sclerosis7,8
and might also be promising for patients with Crohn’s di-
sease.9,10
The chalcone class of compounds, with a common 1,3-
diphenyl-2-propen-1-one framework (1), has been known for
over a century. Natural chalcones occur mainly as petal pigments
and have also been found in the heartwood, bark, leaf, fruit,
and root of a variety of trees and plants. Chalcone-containing
plants such as Glycyrrhiza species have long been used as folk
remedies. Naturally occurring and synthetic chalcone compounds
have shown interesting biological activity as antioxidant,
antiinflammatory, anticancer, or antiinfective agents.11 Recently
we disclosed the discovery of some chalcone derivatives as
inhibitors of VCAM-1 expression.12 Herein we report on the
lead evolution from our initial discovery, subsequent SAR
studies, and biological activities of a novel series of carboxy-
lated, heteroaryl-substituted chalcones.
Alternatively, protected benzaldehyde 10 was converted to
boronic ester 11 which then underwent a Suzuki coupling to
give protected thiazolylbenzaldehyde 12. Hydrolysis of the ketal
of 12 gave benzaldehyde 13 (Scheme 3).
For the introduction of an indolyl group to ring B, an indole
synthesis route was developed due to the limited availability of
indole-boronic acids or esters for Suzuki coupling. Iodide 1415
was coupled using a modified Castro-Stephens reaction with
2-ethynylaniline generated in situ from 2-[(trimethylsilyl)-
ethynyl]aniline to give alkyne 15. A pivaloyl group was
introduced to 15 to afford compound 16. Treatment of com-
pound 15 or 16 with PdCl2 caused indole formation to give
compound 17 or 18, respectively. Aldol condensation of 17 or
18 with 4-acetylbenzoic acid (4) gave chalcone 19. The pivaloyl
group in 18 was cleaved during this aldol condensation (Scheme
4). By having the pivaloyl group, compound 16 was less prone
to form side products than 15 during the indole formation step.
Compound 2012 (Figure 1) exhibits weak inhibitory potency
on VCAM-1 expression (IC50 ) 29 µM). When the methoxy
* Corresponding author. 678-336-2540 (Tel.); 678-336-2501 (Fax);
cmeng@atherogenics.com.
10.1021/jm0614230 CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/27/2007

Chalcones as Inhibitors of VCAM-1 Expression
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1305
Scheme 1a
a Reagents and conditions: (a) benzo[b]thiophene-2-boronic acid, KF, Pd(t-Bu3P)2, THF, reflux, 97%; (b) 1. LiOMe, MeOH, DMF, rt; 2. H2SO4, 54%;
(c) 2-(morpholin-4-yl)ethylamine, EDCI, CH2Cl2, rt, 77%.
Scheme 2
Scheme 3a
a Reagents and conditions: (a) 4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
2-(dicyclohexylphosphino)biphenyl, Pd(OAc)2, Et3N, dioxane, reflux, 59%;
(b) 2-bromothiazole, aqueous Na2CO3, Pd(PPh3)4, DME, reflux, 19% from
10 (one pot); (c) p-toluenesulfonic acid, acetone, water, rt, 83%.
Figure 1. Evolution of carboxylated, heteroaryl-substituted chalcones.
led us to explore chalcone derivatives containing a para-
carboxylated ring A and a meta-heteroaryl-substituted ring B
for potent inhibitors of VCAM-1 expression.
Scheme 4a
Using 23 as a template, compounds with various substituents
at the 2-position of ring B were prepared to study the SAR of
that position (Table 1). When two units of ethylene glycol ether
are inserted between the methoxy group and the phenyl ring of
23 at this position, the potency improves by threefold (24).
However, when a third unit of ethylene glycol ether is added
and the lipophilicity further decreased, the potency drops to IC50
of 4.0 µM (25). When the methoxy group at the 2-position of
23 is replaced with a morpholinoethoxy group the potency
increases to IC50 of 0.8 µM (26), further showing that this
position can tolerate bulky groups. When the morpholinoethoxy
group is extended by one methylene unit to morpholinopropoxy
group (27), the potency remains likely because the lipophilicity
does not change by much although the spatial requirement is
different. However, when a methylene unit of the morpholinoe-
thoxy group of 26 is converted to a carbonyl and hence the
lipophilicity is decreased significantly, the potency drops to an
IC50 of 6.0 µM (28). To take advantage of the fact that the
2-position of ring B tolerates a variety of substitution, at least
in the context of 23, a diol was introduced to this position to
a Reagents and conditions: (a) 2-[(trimethylsilyl)ethynyl]aniline, PdCl2-
(PPh3)2, CuI, Et3N, TBAF, THF, reflux, 92%; (b) pivaloyl chloride, CH2Cl2,
rt, 79%; (c) PdCl2, acetonitrile or DMF, reflux, 60-72%; (d) 1. 4, LiOMe,
MeOH, DMF, rt; 2. H+, 66%.
group on ring A is replaced with a carboxy group for potential
enhancement of solubility, the potency improves about 2-fold
(compound 21, IC50 ) 15 µM). When an alkyl group isintro-
duced to the 5-position of ring B of 21, the potency drops from
IC50 of 15 µM to 22 µM (22). However, when a heteroaryl group
is introduced to the 5-position, the potency is dramatically
increased (compound 23, IC50 ) 3.8 µM). Thus, the combination
of a carboxylic group on ring A and a heteroaryl group on ring
B contributes to the observed in vitro efficacy. These findings

1306 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Meng et al.
Table 1. Inhibiting Profile of
Table 3. Inhibiting Profile of
4-[3E-(2-Substituted-4-methoxy-5-thien-2-yl)acryloyl]benzoic Acids on
TNF-R-Induced VCAM-1 Expression
4-[3E-(2,4-Dimethoxy-5-heteroarylphenyl)acryloyl]benzoic Acids on
TNF-R-Induced VCAM-1 Expression
Table 2. Inhibiting Profile of
4-[3E-(2-Methoxy-4-substituted-5-thien-2-yl)acryloyl]benzoic Acids on
TNF-R-Induced VCAM-1 Expression
IC50 ) 6.5 µM). Compound 24 (Table 1) is more potent than
its regioisomer 32. Compounds 33 (Table 2) and 29 (Table 1)
are another pair of regioisomers with the same lipophilicity but
different potencies (IC50 ) 41 and 21 µM, respectively),
indicating that the 2-position of ring B tolerates substitution to
a greater degree than the 4-position.
Compounds with various heteroaryl groups at the 5-position
of ring B were prepared to study the SAR of that position (Table
3). When the thien-2-yl on ring B of 23 is replaced with thien-
3-yl, the ClogP value does not change and the potency improves
slightly (34, IC50 ) 2.1 µM), indicating that substitution pattern
of a thienyl heterocycle on ring B does not affect the efficacy.
The introduction of a methyl to the thienyl ring of 23 brings
the IC50 value from 3.8 µM to 1 µM, presumably due to an
increase in lipophilicity (35). When a carbon atom of the
potentially increase solubility of the compound (29). However,
29 turned out to be 10-fold less potent, likely due to lowered
lipophilicity.
Compounds with various substituents at the 4-position of ring
B were also prepared using 23 as a template to probe the SAR
of that position (Table 2). Removal of the methoxy group leads
to a compound (30, IC50 ) 3.1 µM) with comparable efficacy
on VCAM-1 expression. When the methoxy group is replaced
with an ethoxy group, the potency drops slightly (31, IC50
)
4.9 µM). When the length of the 4-substituent is extended to
methoxyethoxyethoxy group, the potency further decreases (32,

Chalcones as Inhibitors of VCAM-1 Expression
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1307
Table 4. Inhibiting Profile of
Table 5. Effects of Carboxylic Substitution Positions on
3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-1-(4-substituted-
phenyl)propenones on TNF-R-Induced VCAM-1 Expression
TNF-R-Induced VCAM-1 Expression of Chalcone Compounds
compd. no.
R
VCAM-1 IC50 (µM)
ClogP
23
45
46
4-COOH
3-COOH
2-COOH
3.8 ( 2.0
4.2 ( 1.5
8.6 ( 1.5
4.55
4.55
4.55
45 although the three compounds have the same ClogP value.
This shows again that spatial configuration prevails over
lipophilicity in determining efficacy of compounds and the
lipophilicity-potency trends are only true within certain closely
related structures.
The R,â-unsaturated ketone portion of the chalcone structure
is most likely the pharmacophore of this class of compounds
as inhibitors of VCAM-1 expression since its reduction to the
corresponding saturated ketone leads to complete loss of
activity.12 When the olefinic double bond of the R,â-unsaturated
ketone in 23 is converted to a cyclopropane (47), the effect on
VCAM-1 expression is eliminated, further confirming that the
R,â-unsaturated ketone portion is essential for efficacy.
thienyl ring of 35 is replaced with a nitrogen atom (thiazole),
the compound is still potent (36, IC50 ) 2.5 µM).
When the thienyl group of 23 is fused to a benzene ring, the
potency is dramatically enhanced (5, IC50 ) 0.6 µM). From 23
to 35 and 5, the ClogP value increases from 4.55 to 4.88 and
5.60, respectively, indicating a correlation between lipophilicity
and potency among these compounds. The potency is retained
when the benzothienyl group of 5 is replaced with a benzo-
Since VCAM-1 is implicated in numerous inflammatory
diseases, the chalcone compounds that potently inhibit the
expression of VCAM-1 reported herein could work in disease
models and potentially benefit patients with disorders such as
asthma. A chronic inflammatory disease of the airways, asthma
entails a complex interaction involving resident, recruited, and
structural cells. These cells synthesize an array of cytokines and
cell mediators that ultimately contribute to, or result in,
bronchoconstriction, airway edema, mucus plug formation, and
airway wall remodeling. Despite being a minority constituent
of circulating leucocytes, eosinophils are a prominent cell type
in, and their products make a major contribution to, allergic
and asthmatic diseases. There is as much as a 100-fold increase
in the accumulation of eosinophils versus neutrophils in the
airways of patients with asthma.
Compound 19 was evaluated for its effects on eosinophil
levels in bronchoalveolar lavage fluid (BALF) in a 14-day
mouse model of allergic airway inflammation.16 Dosed subcu-
taneously at 50, 100, and 150 mg/kg twice a day on days 11
through 13, compound 19 significantly and dose-dependently
reduced eosinophil levels in BALF (Figure 2). Plasma drug
levels taken roughly 3-4 h after the last dose were also dose-
related and were 10, 14, and 19 µM, respectively. Compound
19 also exhibited activity when dosed at 100 mg/kg twice a
day orally, reducing eosinophil levels in BALF by 43%.
Compound 19 was well tolerated by the animals at all dose
levels and in both subcutaneous and oral routes of dosing.
Compound 5 inhibited E-selectin and MCP-1 expression in
cultured, TNF-R-induced human pulmonary arterial endothelial
cells (HPAECs) besides inhibiting VCAM-1 expression. In
furanyl (37, IC50 ) 0.3 µM) or an indolyl group (19, IC50
)
0.9 µM). When a Boc group is introduced to the indole nitrogen
of 19, the potency is retained (38, IC50 ) 1.2 µM), further
indicating that the 5-position of ring B can tolerate a bulky
group. The dependence of potency on lipophilicity becomes
more obvious when a nitrogen atom is incorporated into the
indole ring of 19, which lowers the ClogP from 4.16 to 3.72
and the potency from IC50 ) 0.9 µM to 4.4 µM (39).
To investigate the SAR of the 4-carboxylic group on ring A,
compounds with various substituents on the group were prepared
using 5 as a template (Table 4). Esterification of 5 increases
the lipophilicity and decreases the potency (40, IC50 ) 3.1 µM).
When 5 is converted to amide 41, the potency increases (IC50
) 0.2 µM) presumably due to slight lowering of lipophilicity.
N-Substituted amides are also potent as long as they are in the
right lipophilicity range, such as 6, 42, and 43. When two
additional methyl groups are introduced to the acetyl group of
43 and the lipophilicity increases, the potency decreases
(compound 44, IC50 ) 1.7 µM).
Compounds 23, 45, and 46 are regioisomers with a carboxy
group at different positions of ring A (Table 5). The potency
remains more or less the same when the carboxy group is moved
between the 3- and 4-positions (23, IC50 ) 3.6 µM; 45, IC50
)
4.2 µM). However, with the carboxy group moved to the
2-positon, compound 46 is about 2-fold less potent than 23 or

1308 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Meng et al.
Figure 2. Inhibitory effects of compound 19 on airway eosinophilia in a mouse model. Animals were sensitized intraperitoneally (i.p.) with
ovalbumin on days 0 and 5 and then challenged with aerosolized ovalbumin twice on day 12. Compound 19 was dosed on days 11 through 13
subcutaneously at 150, 100, and 50 mg/kg, twice a day. The animals were sacrificed on day 14, and BALF was collected. Cell differentials were
conducted and data reported as percentage of eosinophilia in the BALF. Dexamethasone (3 mg/kg, given i.p. at the time of challenge) was used as
positive control. Numbers of animals in each group are given in a square on or above each bar. Inhibition of eosinophilia in percentage is given
above each bar and * indicates p < 0.05 as determined by ANOVA, followed by Fisher’s PLSD post hoc test.
as internal standard. Mass spectra were obtained on a VG 70S (for
EI) or Micromass Q-TOF (for ES) instrument. Elemental analyses
were performed by Atlantic Microlabs, Norcross, GA. Silica gel
60 (E. Merck, 230-400 mesh) was used for preparative column
chromatography. Calculated logP was obtained by using ChemDraw
Ultra 7.0. All compounds reported herein had 95% or higher purity
cultured, LPS-induced human peripheral blood mononuclear
cells (HPBMCs), 5 completely inhibited IL-1â secretion at 5
µM. After prophylactic, subcutaneous dosing at 25 and 75 mg/
kg, 5 dose-dependently inhibited both paw swelling and
splenomegaly in a rat adjuvant arthritis model. It also improved
histological bone resorption and inflammation scores. These data
indicate that 5 has the potential to be a disease-modifying
antirheumatic drug (DMARD). Compound 5 also inhibited paw
swelling in a dose-dependent manner when dosed therapeutically
and showed oral efficacy when dosed prophylactically in this
model.17
In an ovalbumin-sensitized/challenged mouse model of al-
lergic asthma, compound 5 dose-dependently inhibited airway
and tissue eosinophilia, reduced serum IgE levels, and reduced
elevated lung mRNA levels of T helper 2 (Th2) cytokines such
as IL-4, IL-13, and IL-5 without affecting mRNA levels of Th1
cytokines such as IFN-γ and IL-2. Compound 5 also reduced
airway hyperresposiveness in this model.18
In summary, a series of novel carboxylated, heteroaryl-
substituted chalcone derivatives has been discovered as potent
inhibitors of VCAM-1 expression. SAR studies have shown that
a variety of substituents can be tolerated at several positions of
the chalcone backbone. The R,â-unsaturated ketone moiety of
the chalcone seems to be the pharmacophore of this series of
compounds for inhibition of VCAM-1 expression. No other
structural features are essential for potency though a correlation
between lipophilicity and inhibitory efficacy has been observed
among structurally similar compounds within the series. A
representative compound (19) of the series showed significant
antiinflammatory effects in a mouse model of allergic inflam-
mation, indicating that this series of compounds might have
therapeutic value for human asthma and other inflammatory
disorders.
1
according to H NMR spectra and analytical HPLC.
5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (3). 5-Bromo-
2,4-dimethoxybenzaldehyde (20 g), benzo[b]thiophene-2-boronic
acid (16 g), and THF (200 mL) were sequentially charged into a
clean reaction vessel fitted with a reflux condenser, mechanical
stirrer, and nitrogen inlet adapter. Nitrogen was bubbled into the
resulting solution for 20 min followed by the sequential addition
of KF (10 g) and Pd(t-Bu3P)2 (0.417 g). The solution was
immediately heated to 60 °C and aged for 1.5 h. Upon completion,
as determined by HPLC, the reaction was diluted with H2O (200
mL) and transferred to a separatory funnel containing EtOAc (200
mL) and H2O (200 mL). The layers were cut, and the aqueous layer
was extracted with EtOAc (100 mL). The combined organic cuts
were filtered through a prewashed pad of Solka-Floc (5 g). The
pad of Solka-Floc and spent catalyst were washed with fresh EtOAc
(200 mL), and this wash was combined with the batch. The resultant
filtrate was batch concentrated and solvent switched to 33 wt %
5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde in THF in prepa-
ration for crystallization. (Note: The internal temperature during
batch concentration should be kept above 45 °C to prevent
premature crystallization.) The resulting THF solution of 5-(benzo-
[b]thien-2-yl)-2,4-dimethoxybenzaldehyde was then charged with
heptane (20 mL) and slowly cooled to rt. Crystallization was then
completed with the slow addition of heptane (175 mL) and cooling
to 4 °C. After being aged for 1 h, the batch was filtered and then
dried on a filter funnel under a stream of N2. The semiwet cake
was then transferred to clean trays and dried to a constant weight
in a vacuum oven (40 °C, 20 in Hg), affording 23.74 g (97% yield)
of the title compound as a light orange crystalline solid, mp 134-
1
136 °C. H NMR (CDCl3): δ 10.36 (s, 1H), 8.20 (s, 1H), 7.83-
7.78 (m, 2H), 7.68 (s, 1H), 7.36-7.27 (m, 2H), 6.54 (s, 1H), 4.06
Experimental Section
(s, 3H), 4.00 (s, 3H).
1
Chemistry. Melting points are uncorrected. H NMR spectra
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-
benzoic Acid (5). To a solution of 4-acetylbenzoic acid (1.50 g,
9.1 mmol) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde
were recorded on a QE300 spectrometer and chemical shifts are
reported in parts per million (ppm, δ) relative to tetramethylsilane

Chalcones as Inhibitors of VCAM-1 Expression
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1309
(3.27 g, 11.0 mmol) in DMF (76 mL) was added a solution of
sodium hydroxide (5 M, 7.3 mL, 36.5 mmol). The reaction mixture
was allowed to stir at rt for 2 h and was then diluted with water to
a volume of 150 mL. The solution was washed with dichlo-
romethane and acidified with concentrated sulfuric acid to pH )
3. The resulting solution was then extracted with dichloromethane.
The dichloromethane extract was washed with brine, dried over
sodium sulfate, and concentrated. The resulting oily product
solidified in ethanol. The solid was further stirred in ethanol for 1
day and collected by filtration. The solid was washed with ethanol,
then dried in vacuo to afford the title compound as a yellow solid
(2.2 g, 54%), mp 223-224 °C (dec). 1H NMR (DMSO-d6): δ 8.36
(s, 1H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H), 7.82 (d, 1H),
7.32 (m, 2H), 6.86 (s, 1H), 4.08 (s, 3H), 4.00 (s, 3H). Anal.
(C26H20O5S·1/6H2O): C, H, S.
to afford 29.5 g (97%) of the title compound as a yellow oil (97%
yield). 1H NMR (CDCl3): δ 4.29 (d, 2H, J ) 5.7 Hz), 3.61-3.68
(m, 4H), 2.99 (s, 3H), 2.04-2.11 (m, 1H), 0.88 (s, 18H), 0.049 (s,
12H). HRMS (ESI) calcd for C17H40O5SSi2: 413.2213; found:
413.2226.
2-[3-(tert-Butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-
silanyloxymethyl)-propoxy]-4-methoxy-5-thien-2-yl-benzalde-
hyde (9). To a solution of 2-hydroxy-4-methoxy-5-thien-2-yl-
benzaldehyde (10.0 g, 42.7 mmol) in DMF (100 mL) was added
potassium carbonate (11.8 g, 85.4 mmol), and the resulting yellow
slurry was heated to 80 °C. Once at 80 °C, 8 (19.5 g, 46.9 mmol)
was added dropwise and the reaction was stirred for an additional
24 h at 80 °C and cooled to rt. The mixture was diluted with water
(500 mL) and extracted with ethyl acetate (3 × 150 mL). The
combined organic layers were sequentially washed with saturated
sodium bicarbonate (1 × 150 mL), water (1 × 150 mL), and brine
(1 × 150 mL), dried over sodium sulfate, and concentrated to a
brown oil. Silica gel chromatography (0-10% ethyl acetate in
hexanes) gave 19.0 g (81%) of the title compound as an off-white
solid, mp 91-92 °C. 1H NMR (CDCl3): δ 10.37 (s, 1H), 8.12 (s,
1H), 7.44 (dd, J ) 3.6, 1.2 Hz, 1H), 7.29 (d, J ) 5.1 Hz, 1H), 7.07
(dd, J ) 5.1, 3.6 Hz, 1H), 6.54 (s, 1H), 4.19 (d, J ) 6.0 Hz, 2H),
3.99 (s, 3H), 3.72-3.82 (m, 4H), 2.28 (pentet, J ) 6.0 Hz, 1H),
0.88 (s, 18H), 0.048 (s, 12H). MS (EI) m/z ) 550 ([M]+, 100%).
Anal. (C28H46O5SSi2): C, H, S.
2-(5-Bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane (10). 5-Bro-
mo-2,4-dimethoxybenzaldehyde (4.92 g, 20.1 mmol) was dissolved
in benzene (41 mL). Ethylene glycol (3 mL, 54 mmol) and
p-toluenesulfonic acid (25 mg, 0.13 mmol) were added, and the
solution was refluxed with a Dean-Stark trap attached. After 6 h,
the reaction was cooled and washed with water (1 × 20 mL),
saturated NaHCO3 (1 × 20 mL), and water (1 × 20 mL). The
organic phase was dried over sodium sulfate, filtered, concentrated,
and dried to provide 5.32 g of the title compound as a faint yellow
oil which solidified upon standing (92% yield). 1H NMR (CDCl3):
δ 7.67 (s, 1H), 6.47 (s, 1H), 6.06 (s, 1H), 4.11-4.13 (m, 2H), 3.98-
4.03 (m, 2H), 3.91 (s, 3H), 3.87 (s, 3H).
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-
N-(2-morpholin-4-yl-ethyl)-benzamide (6). To a solution of 4-[3E-
(5-benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid
(0.44 g, 1 mmol) and 2-morpholin-4-yl-ethylamine (0.18 mL) in
dichloromethane (20 mL) was added EDCI (0.38 g, 2 mmol), and
the mixture was stirred at rt for four h. It was poured into brine
(100 mL) and extracted with dichloromethane (2 × 50 mL). The
organic phase was dried and evaporated. Chromatography (dichlo-
romethane/methanol 50:1) gave the title compound as a yellow solid
(0.43 g, 77%). 1H NMR (CDCl3): δ 8.12 (d, J ) 16 Hz, 1H), 8.09
(d, J ) 8 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J ) 8 Hz, 2H), 7.77-7.85
(m, 2H), 7.68 (s, 1H), 7.56 (d, J ) 16 Hz, 1H), 7.29-7.40 (m,
2H), 6.80-6.85 (br s, 1H), 6.58 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H),
3.75 (t, J ) 5 Hz, 4H), 3.59 (q, J ) 5 Hz, 2H), 2.64 (t, J ) 5 Hz,
2H), 2.53 (t, J ) 5 Hz, 4H). Anal. (C32H32N2O5S·H2O): C, H, N.
2-Hydroxy-4-methoxy-5-thien-2-yl-benzaldehyde (7). 2-Hy-
droxy-4-methoxybenzaldehyde (6.0 g, 39 mmol) was dissolved in
dichloromethane (50 mL) and cooled with an ice/water bath.
Bromine (6.8 g, 43 mmol) in dichloromethane (2 mL) was added
dropwise to the cooled solution and stirred for 2 h at 0 °C. The
mixture was warmed to rt and stirred for an additional 1 h, and the
resulting yellow precipitate was collected. Recrystallization (ethyl
acetate/hexanes) yielded 7.1 g (80%) of 5-bromo-2-hydroxy-4-
2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-4,4,5,5-tetra-
methyl-[1,3,2]dioxaborolane (11). 2-(5-Bromo-2,4-dimethoxy-
phenyl)-[1,3]dioxolane (4.78 g, 10.5 mmol) was dissolved in
dioxane (75 mL), and the solution was purged with nitrogen for
15 min. Pd(OAc)2 (188 mg, 0.84 mmol), Et3N (6.91 mL, 49.6
mmol), and 2-(dicyclohexylphosphino)biphenyl (1.16 g, 3.31 mmol)
were added. 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (3.6 mL, 24.8
mmol) was then added slowly, accompanied by gas evolution and
the darkening of the reaction solution. The solution was heated at
reflux for 2.5 h and then cooled. Saturated NH4Cl (60 mL) and
water (20 mL) were added, and the solution was extracted with
EtOAc (1 × 100 mL). The organic phase was dried over sodium
sulfate, filtered, and concentrated to a dark oil. The oil was purified
by silica gel chromatography (1:1 EtOAc/hexanes in a column
prewashed with 5% Et3N in 1:1 EtOAc/hexanes) to provide 3.27 g
of the title compound as a yellow solid (with some starting borolane
1
methoxybenzaldehyde as white needles, mp 63-64 °C. H NMR
(CDCl3): δ 11.43 (s, 1H), 9.69 (s, 1H), 7.68 (s, 1H), 6.48 (s, 1H),
3.95 (s, 3H). Anal. (C8H7BrO3): calcd C 41.59, H 3.05; found C
41.86, H 3.05.
5-Bromo-2-hydroxy-4-methoxybenzaldehyde (1.5 g, 6.5 mmol)
and thiophene-2-boronic acid (0.91 g, 7.1 mmol) were dissolved
in tetrahydrofuran (15 mL). Nitrogen was bubbled into the solution
for 10 min followed by the sequential addition of potassium fluoride
(0.80 g, 14 mmol, spray-dried) and bis(tri-t-butylphosphine)-
palladium (0) (0.033 g, 0.065 mmol). The solution was immediately
heated to 60 °C and aged for 1.5 h. Upon completion, as determined
by HPLC, the reaction was diluted with water (25 mL) and extracted
with ethyl acetate (3 × 30 mL). The combined organic extracts
were dried over sodium sulfate and concentrated to a brown solid.
Silica gel chromatography (ethyl acetate/hexanes, 1:3) gave 1.46 g
(97%) of the title compound as a yellow solid, mp 118-119 °C.
1H NMR (CDCl3): δ 11.48 (s, 1H), 9.79 (s, 1H), 7.72 (s, 1H),
7.37 (dd, J ) 3.6 Hz, 1H), 7.31 (dd, J ) 5.1, 1.5 Hz, 1H), 7.08
(dd, J ) 5.1, 3.6 Hz, 1H), 6.54 (s, 1H), 3.98 (s, 3 H). Anal.
(C12H10O3S): C, H, S.
1
present), 59% yield. H NMR (CDCl3): δ 7.85 (s, 1H), 6.39 (s,
1H), 6.07 (s, 1H), 4.13-4.18 (m, 2H), 3.98-4.02 (m, 2H), 3.89
(s, 3H), 3.84 (s, 3H), 1.33 (s, 9H).
2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-thiazole (12).
2-(5-Bromo-2,4-dimethoxy-phenyl)-[1,3]dioxolane (1.50 g, 5.19
mmol) was dissolved in dioxane (10 mL). Pd(OAc)2 (59 mg, 0.26
mmol), Et3N (2.9 mL, 21 mmol), and 2-(dicyclohexylphosphino)-
biphenyl (363 mg, 1.04 mmol) were added, and the solution was
purged with nitrogen for 15 min. 4,4,5,5-Tetramethyl-[1,3,2]-
dioxaborolane (1.1 mL, 16.2 mmol) was then added slowly,
accompanied by gas evolution and the darkening of the reaction
solution. The solution was heated at reflux for 1.5 h and then cooled.
Na2CO3 (2 M, 7.8 mL, 15.6 mmol) and then 2-bromothiazole (0.48
mL, 5.3 mmol) were added, and the solution was heated to 100 °C
for 6 h. Water (30 mL) was added and the solution extracted with
CH2Cl2 (3 × 30 mL). The organic phase was washed with water
(1 × 10 mL), then dried over sodium sulfate, filtered, and
concentrated to a dark oil. The oil was purified Via silica gel
Methanesulfonic Acid 3-(tert-Butyl-dimethyl-silanyloxy)-2-
(tert-butyl-dimethyl-silanyloxymethyl)-propyl Ester (8). To a
solution of 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-
14
silanyloxymethyl)-propan-1-ol
(25.0 g, 74.3 mmol) and tri-
ethylamine (22.6 g, 223 mmol) in dichloromethane (150 mL) at 0
°C was added mesyl chloride (12.8 g, 111 mmol), and the resulting
slurry was stirred at 0 °C for 15 min and allowed to warm to rt.
The solution was stirred for an additional 3 h at rt and diluted with
water (130 mL) and ethyl acetate (350 mL). The layers were
separated and the aqueous layer was extracted with ethyl acetate
(1 × 150 mL). The combined organic extracts were washed with
saturated sodium bicarbonate (1 × 200 mL) and 50% sodium
chloride (2 × 200 mL), dried over sodium sulfate, and concentrated

1310 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Meng et al.
chromatography (30-50% EtOAc/hexanes) to provide 286 mg of
the title compound as a semi-pure yellow oil (19% yield). 1H NMR
(CDCl3): δ 8.54 (s, 1H), 7.85 (d, J ) 3 Hz, 1H), 7.29 (d, J ) 4
Hz, 1H), 6.50 (s, 1H), 6.13 (s, 1H), 4.09-4.16 (m, 2H), 4.00 (s,
3H), 3.89 (s, 3H), 3.78-3.87 (m, 2H).
the mixture was cooled to rt and filtered. The filtrate was treated
with 5 g of 3-mercaptopropyl functionalized silica gel with stirring
for 30 min and filtered. The filtrate was concentrated, and the
residue was recrystallized from EtOAc/hexane to give 0.84 g (60%)
1
of the title compound. H NMR (DMSO-d6): δ 11.29 (br s, 1H),
10 24 (s, 1H), 8.10 (s, 1H), 7.47 (d, J ) 8 Hz, 1H), 7.37 (d, J )
7 Hz, 1H), 7.01-7.05 (m, 1H), 6.91-6.95 (m, 1H), 6.85-6.86 (m,
2H), 4.06 (s, 3H), 3.99 (s, 3H).
2,4-Dimethoxy-5-thiazol-2-yl-benzaldehyde (13). 2-(5-[1,3]-
Dioxolan-2-yl-2,4-dimethoxy-phenyl)-thiazole (286 mg, 0.97 mmol)
was dissolved in acetone (20 mL), and p-toluenesulfonic acid (13
mg, 0.068 mmol) and water (0.5 mL) were added. The solution
was stirred overnight at rt, then diluted with water (25 mL) and
extracted with EtOAc (3 × 25 mL). The organic phase was washed
with saturated NaHCO3 (1 × 30 mL), dried over sodium sulfate,
filtered, and concentrated. Silica gel chromatography (2.5% MeOH/
CH2Cl2) provided 202 mg of the title compound as an off-white
5-[1-(2,2-Dimethylpropionyl)-1H-indol-2-yl]-2,4-dimethoxy-
benzaldehyde (18). N-[2-(5-Formyl-2,4-dimethoxy-phenylethynyl)-
phenyl]-2,2-dimethylpropionamide (19.86 g, 54.4 mmol) was
dissolved in nitrogen-purged DMF (189 mL) and heated to 80 °C,
followed by the addition of palladium(II) chloride (754 mg). After
1 h, the reaction mixture was diluted with water (300 mL) and
extracted with EtOAc (2 × 200 mL). The combined organic phase
was washed with brine, dried over sodium sulfate, and concentrated
to a brown oil. The oil was purified by silica gel chromatography
(30-50% ethyl acetate/hexanes) to yield 14.31 g (72%) of the title
1
solid (83% yield). H NMR (CDCl3): δ 10.34 (s, 1H), 8.86 (s,
1H), 7.89 (d, J ) 3 Hz, 1H), 7.36 (d, J ) 4 Hz, 1H), 6.56 (s, 1H),
4.12 (s, 3H), 4.02 (s, 3H).
5-Iodo-2,4-dimethoxybenzaldehyde (14). To a solution of 2.4-
dimethoxybenzaldehye (20.0 g, 120.4 mmol) in methanol (550 mL)
was added iodine monochloride (23.5 g in 60 mL methanol)
dropwise over 20 min at ambient temperature. The solution was
allowed to stir at this temperature. HPLC showed about 94%
conversion after 3 h. The reaction mixture was then poured into a
solution of HCl (0.5 M, 600 mL). The precipitate was collected by
filtration, washed with water, and dried in vacuo (40 °C) to give a
crude product. The crude product was further purified by recrys-
tallization from THF/heptane (1:1) to give the title compound as
an off-white solid (27.5 g, mp 170-172 °C). The mother liquid
was concentrated to dryness. The residual material was dissolved
in EtOH (100 mL) and acetone (20 mL) followed by addition of
water (20 mL) to give additional product (3.12 g, mp 169-171
1
compound as a light yellow solid. H NMR (CDCl3): δ 10.21 (s,
1H), 7.69 (s, 1H), 7.57 (d, J ) 37.8 Hz, 1H), 7.30 (d, J ) 8.10 Hz,
1H), 7.20 (t, J ) 6.9 Hz, 1H), 7.12 (t, J ) 6.9 Hz, 2H), 6.85 (s,
1H), 6.70 (s, 1H), 4.00 (s, 3H), 3.87 (s, 3H), 0.95 (s, 9H).
4-{3E-[5-(1H-Indol-2-yl)-2,4-dimethoxy-phenyl]-acryloyl}-
benzoic Acid (19). The title compound was prepared by condensing
5-(1H-indol-2-yl)-2,4-dimethoxy-benzaldehyde and 4-acetylbenzoic
acid in a similar manner as described for compound 5. Red solid,
mp 210-212 °C, 66% yield. 1H NMR (Acetone-d6): δ 10.53 (br,
s, 1H), 8.32 (s, 1H), 8.14-8.21 (m, 5H), 7.89 (d, J ) 15 Hz, 1H),
7.52 (d, J ) 8 Hz, 1H), 7.38 (d, J ) 7 Hz, 1H), 6.97-7.07(m,
3H), 6.87(s, 1H), 4.07 (s, 3H), 4.02(s, 3H). MS m/z ) 427 ([M]+).
HMRS (EI) calcd for C26H21NO5: 427.1420, found: 427.1435.
Anal. (C26H21NO5‚1/4H2O): C, H, N.
1
°C). Overall isolated yield of this reaction was 87.5%. H NMR
(CDCl3): δ 10.20 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H),
3.95 (s, 3H). HRMS calcd for C9H9IO3: 291.9596 (M+), found:
291.9602. Anal. (C9H9IO3): C, H; I: calcd 43.3, found 43.3.
5-(2-Aminophenylethynyl)-2,4-dimethoxybenzaldehyde (15).
To a solution of 5-iodo-2,4-dimethoxybenzaldehyde (11.7 g, 40
mmol) in 250 mL of THF were added PdCl2(PPh3)2 (0.56 g, 0.8
mmol), CuI (0.3 g, 1.6 mmol), Et3N (6.06 g, 60 mmol), and
2-[(trimethylsilyl)ethynyl]aniline (7.92 g, 42 mmol). The mixture
was stirred to a homogeneous solution, and then TBAF (10.4 g, 40
mmol) was added. The reaction mixture was aged at rt for 4 h and
then filtered. The filtrate was concentrated to about 50 mL, and
the precipitate was filtered to give a first portion of the title compound
(8.5 g) as light yellow crystals. The filtrate was concentrated, and
the residue was recrystallized from EtOAc/hexanes to give 1.85 g
4-[3E-(2,4-Dimethoxy-phenyl)-acryloyl]-benzoic Acid (21).
4-[3E-(5-Bromo-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid was
prepared in a similar manner as described for compound 5. 1H NMR
(DMSO-d6): δ 8.28 (s, 1H), 8.21 (d, J ) 8 Hz, 2H), 8.04 (d, J )
8 Hz, 2H), 7.95 (d, J ) 16 Hz, 1H), 7.84 (d, J ) 16 Hz, 1H),
6.78(s, 1H), 3.93 (s, 6H).
4-[3E-(5-Bromo-2,4-dimethoxy-phenyl)-acryloyl]-benzoic acid
(0.83 g, 2.0 mmol) was suspended in 20 mL of acetonitrile, and
the mixture was bubbled with N2 for 15 min. Pyrimidine-5-boronic
acid (0.25 g, 2.0 mmol) and Pd(PPh3)4 (0.23 g, 0.2 mmol) were
added, and the mixture was bubbled with N2 for 10 min. Then, 5
mL of NaCO3 (2M) was added. The mixture was stirred at reflux
overnight under N2. Upon cooling, the mixture was filtered and
the filtrate was acidified to pH 1 with 3 N HCl. The yellow
precipitate was filtered and purified by column chromatography
(10% MeOH in dichloromethane) to give 100 mg of the title
compound (instead of the expected Suzuki coupling product) as a
yellow solid, mp 189-191 °C. 1H NMR (DMSO-d6): δ 8.13 (d, J
) 8 Hz, 2H), 8.04 (d, J ) 8 Hz, 2H), 7.98 (d, J ) 15 Hz, 1H),
7.90 (d, J ) 9 Hz, 1H), 7.73 (d, J ) 15 Hz, 1H), 6.58-6.62(m,
2H), 3.87 (s, 3H), 3.81 (s, 3H). MS m/z: 312([M]+, 45%), 281
(100%). HMRS calcd for C18H16O5: 313.1076 (M + H), found:
313.1067. Anal. (C18H16O5·1/5H2O): C, H.
4-[3E-(5-Ethyl-2,4-dimethoxy-phenyl)-acryloyl]-benzoic Acid
(22). To a solution of N-methylpyrrole (0.81 g, 10 mmol) in 50
mL of THF was added t-BuLi (1.7 M in pentane, 7.1 mL, 12 mmol)
at 0 °C and the mixture stirred at rt for 1 h. BEt3 (1.0 M in THF,
12 mL, 12 mmol) was added, and the mixture was stirred for another
1 h. 5-Bromo-2,4-dimethoxybenzaldehyde (3.7 g, 15 mmol) and
PdCl2(PPh3)2 (0.35 g, 0.5 mmol) were added to the mixture, and
the mixture was stirred at 60 °C for 30 min. Upon cooling, 50 mL
of NaOH (10%) and 5 mL of H2O2 (30%) were added at 0 °C and
the mixture was stirred for 10 min. The mixture was extracted with
EtOAc, and the combined organic phase was washed with brine,
dried over MgSO4, and concentrated. The residue was purified by
column chromatography (hexane/EtOAc, 2:1) to give 5-ethyl-2,4-
dimethoxy-benzaldehyde (instead of the expected Suzuki coupling
product). 1H NMR (CDCl3): δ 10.30 (s, 1H), 7.64 (s, 1H), 6.40 (s,
1
of additional product (total 10.35 g, 92%), mp 180-181 °C. H
NMR (CDCl3): δ 10.30 (s, 1H), 7.99 (s, 1H), 7.36 (d, J ) 8 Hz,
1H), 7.11-7.17 (m, 1H), 6.69-6.75 (m, 2H), 6.46 (s, 1H), 4.41
(brs, 2H), 4.02 (s, 3H), 4.00 (s, 3H). HRMS calcd for C17H15NO3:
281.1052 (M+), found: 281.1056. Anal. (C17H15NO3): C, H, N.
N-[2-(5-Formyl-2,4-dimethoxyphenylethynyl)phenyl]-2,2-dim-
ethylpropionamide (16). Pyridine (12.6 mL, 156.24 mmol) was
added to a suspension of 5-(2-aminophenylethynyl)-2,4-dimethoxy-
benzaldehyde (20.90 g, 74.4 mmol) in anhydrous methylene
chloride (572 mL) and chilled to 0 °C. The reaction mixture was
treated dropwise with pivaloyl chloride (9.25 mL, 75.1 mmol) and
then aged at rt for 2 h. The reaction was quenched with 1 N HCl
(200 mL), and the layers were cut. The organic layer was washed
with brine, dried over sodium sulfate, and concentrated to dryness
to afford 21.47 g (79%) of the title compound as a light brown
solid. 1H NMR (DMSO-d6): δ 10.14 (s, 1H), 8.74 (br s, 1H), 7.89
(d, J ) 8.1 Hz, 1H), 7.80 (s, 1H), 7.50 (dd, J ) 1.2, 7.8 Hz, 1H),
7.35 (dt, 1.8, 9.3 Hz, 1H), 7.12 (t, J ) 9.0 Hz, 1H), 6.82 (s, 1H),
3.99 (s, 3H), 3.98 (s, 3H), 1.23 (s, 9H).
5-(1H-Indol-2-yl)-2,4-dimethoxybenzaldehyde (17). A solution
of PdCl2 (0.066 g, 0.373 mmol) in 200 mL of acetonitrile was heated
to reflux. To this solution was added 5-(2-amino-phenylethynyl)-
2,4-dimethoxybenzaldehyde (1.4 g, 5 mmol) portion by portion
slowly so that no cloudiness of the solution occurred. After the
addition, the reaction was kept at reflux for another 10 min. Then

Chalcones as Inhibitors of VCAM-1 Expression
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1311
1H), 3.92 (s, 3H), 3.93 (s, 3H), 2.56 (q, J ) 7 Hz, 2H), 1.16 (t, J
) 7 Hz, 3H).
3.94 (t, J ) 4.2 Hz, 2H), 3.74 (m, 2H), 3.59 (m, 2H), 3.40 (s, 3H).
HRMS (EI) calcd for C17H20O5S: 336.1031, found: 336.1027.
4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thien-2-yl-benzal-
dehyde (0.13 g, 0.37 mmol) and 4-acetylbenzoic acid (0.061 g, 0.37
mmol) were dissolved in a tetrahydrofuran-methanol solution (2
mL, 7:3). After complete dissolution, lithium methoxide (0.057 g,
1.5 mmol) was added, and the resulting bright orange slurry was
stirred in the dark at rt for 4 h. Upon completion, as determined by
HPLC, the mixture was diluted with water (10 mL), acidified with
a 1 N hydrochloric acid, and extracted with ethyl acetate (3 × 15
mL). The combined organic extracts were dried over sodium sulfate
and evaporated to dryness. The crude oil was taken up in ethyl
alcohol (3 mL) and warmed to 60 °C to obtain complete dissolution
and allowed to cool to rt. The resulting precipitate was collected
and dried in Vacuo to yield 0.14 g (85%) of the title compound as
The title compound was prepared in a similar manner as
described for compound 5 from 5-ethyl-2,4-dimethoxy-benzalde-
1
hyde. Yellow solid, mp 192-194 °C. H NMR (acetone-d6): δ
8.11-8.15 (m, 5H), 7.73 (d, J ) 16 Hz, 1H), 7.67 (s, 1H), 6.71 (s,
1H), 3.92 (s, 3H), 3.96 (s, 3H), 2.56 (q, J ) 7 Hz, 2H), 1.14 (t, J
) 7 Hz, 3H). HMRS (EI) calcd for C20H20O5: 340.1311, found:
340.1305. Anal. (C20H20O5‚1/3H2O): C, H.
4-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)-acryloyl]-benzo-
ic Acid (23). 5-Bromo-2,4-dimethoxybenzaldehyde (20.3 g),
thiophene-2-boronic acid (11.6 g) and THF (200 mL) were
sequentially charged into a clean reaction vessel fitted with a reflux
condenser, mechanical stirrer, and nitrogen inlet adapter. Nitrogen
was bubbled into the resulting solution for 20 min followed by the
sequential addition of KF (10.1 g), and Pd(t-Bu3P)2 (0.424 g). The
solution was immediately heated to 60 °C and aged for 1.5 h. The
reaction was diluted with H2O (200 mL) and transferred to a
separatory funnel containing EtOAc (200 mL) and H2O (200 mL).
The layers were cut, and the aqueous layer was extracted with
EtOAc (100 mL). The combined organic cuts were filtered through
a prewashed pad of Solka-Floc (5 g). The pad of Solka-Floc and
spent catalyst were washed with fresh EtOAc (200 mL), and this
wash was combined with the batch. The resultant filtrate was
concentrated to dryness. The crude product was dissolved in THF
(38 mL) and crystallized upon heptane (152 mL) addition. The
product was filtered and then dried to a constant weight in the
vacuum oven (38 °C, 20 in Hg), affording 19.32 g (94% yield) of
the desired 2,4-dimethoxy-5-thien-2-yl-benzaldehyde as a light off-
white solid, mp 125-126 °C. 1H NMR (CDCl3): δ 10.34 (s, 1H),
8.12 (s, 1H), 7.44 (dd, J ) 3.5 and 1.5 Hz, 1H), 7.31 (dd, J ) 5.2
and 1.5 Hz, 1H), 7.07 (dd, J ) 5.2 and 3.5 Hz, 1H), 6.51 (s, 1H),
4.02 (s, 3H), 3.99 (s, 3H).
2,4-Dimethoxy-5-thien-2-yl-benzaldehyde (7.81 g), 4-acetylben-
zoic acid (4.9 g), MeOH (60 mL), and DMF (150 mL) were
sequentially charged into a clean reaction vessel fitted with a stir
bar and nitrogen inlet adapter. After complete dissolution, LiOMe
(4.60 g) was added and the resulting solution was aged for 5 h.
The reaction was diluted with H2O (200 mL) and transferred to a
separatory funnel containing i-PrOAc (100 mL). The layers were
cut, and the aqueous layer was acidified to pH 1 with 3 N HCl.
The resulting precipitate was filtered and then dried on the filter
funnel under a stream of N2. The crude product was then dissolved
in THF (60 mL) and crystallized with the addition of heptane (60
mL). The product was filtered and then dried to a constant weight
in the vacuum oven affording 8.9 g (75%) of the title compound
as a yellow solid, mp 213-216 °C. 1H NMR (CDCl3): δ 8.20 (d,
J ) 8.5 Hz, 2H), 8.09 (d, J ) 16.1 Hz, 1H), 8.06 (d, J ) 8.5 Hz,
2H), 7.85 (s, 1H), 7.52 (d, J ) 16.1 Hz, 1H), 7.40 (m, 1H), 7.30
(dd, J ) 5.2 and 1.7 Hz, 1H), 7.08 (dd, J ) 5.2 and 3.6 Hz, 1H),
6.53 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H). EIMS m/z ) 394 (M+).
Anal. (C22H18O5S): C, H, S.
4-(3E-{4-Methoxy-2-[2-(2-methoxyethoxy)ethoxy]-5-thien-2-
yl-phenyl}-acryloyl)-benzoic Acid (24). To a solution of 2-hy-
droxy-4-methoxy-5-thien-2-yl-benzaldehyde (7, 0.10 g, 0.43 mmol)
in N,N-dimethylformamide (3 mL) was added potassium carbonate
(0.18 g, 1.3 mmol), and the resulting yellow slurry was heated to
80 °C. Once at 80 °C, 1-bromo-2-(2-methoxyethoxy)ethane (0.24
g, 1.3 mmol) was added dropwise in three equal portions with
stirring at 1 h intervals. After the last addition, the reaction was
stirred for an additional 1 h at 80 °C and cooled to rt. The mixture
was diluted with water (15 mL) and extracted with ethyl acetate (3
× 15 mL). The combined organic layers were sequentially washed
with a saturated ammonium chloride solution (1 × 15 mL), water
(1 × 15 mL), and brine (1 × 15 mL), dried over sodium sulfate,
and concentrated to a brown oil. Silica gel chromatography (ethyl
acetate/hexanes, 4:1) afforded 0.13 g (87%) of 4-methoxy-2-[2-
(2-methoxyethoxy)ethoxy]-5-thien-2-yl-benzaldehyde as a pale yel-
low oil. 1H NMR (CDCl3) δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (dd,
J ) 3.6, 1.5 Hz, 1H), 7.30 (d, J ) 1.5 Hz, 1H), 7.07 (dd, J ) 5.1,
3.6 Hz, 1H), 6.57 (s, 1H), 4.33 (t, J ) 4.2 Hz, 2H), 4.00 (s, 3H),
1
a yellow solid, mp 145-146 °C. H NMR (DMSO-d6) δ 8.19-
8.22 (m, 3H), 8.09 (d, J ) 8.4 Hz, 2H), 7.91-8.03 (m, 3H), 7.66
(dd, J ) 3.6, 1.5 Hz, 1H), 7.52 (d, J ) 5.1 Hz, 1H), 7.13 (dd, J )
5.1, 3.9 Hz, 1H), 6.88 (s, 1H), 4.36 (t, J ) 4.2 Hz, 2H), 4.00 (s,
3H), 3.88 (t, J ) 4.2 Hz, 2H), 3.63-3.67 (m, 2H), 3.45-3.48 (m,
2H), 3.22 (s, 3H). Anal. calcd for C26H26O7S: C, H, S.
4-[3E-(4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-
5-thien-2-yl-phenyl)-acryloyl]-benzoic Acid (25). Methane-
sulfonic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester was
prepared in an analogous fashion as described for compound 8 using
2-[2-(2-methoxy-ethoxy)-ethoxy]-ethanol. The crude orange oil was
dried in vacuo to give the expected product (oil) and was used
without any further purification (99%). 1H NMR (CDCl3): δ 4.37-
4.40 (m, 2H), 3.76-3.78 (m, 2H), 3.61-3.70 (m, 6H), 3.53-3.57
(m, 2H), 3.38 (s, 3H), 3.08 (s, 3H). MS (ESI) m/z ) 243 ([M +
H]+, 100%). HRMS (ESI) calcd for C8H18O6S: 243.0902, found:
243.0914.
4-Methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thien-
2-yl-benzaldehyde was prepared in an analogous fashion as
described for compound 9 using methanesulfonic acid 2-[2-(2-
methoxy-ethoxy)-ethoxy]-ethyl ester and 2-hydroxy-4-methoxy-5-
thien-2-yl-benzaldehyde. Silica gel chromatography (ethyl acetate/
hexanes, 8:1) gave the expected product as a pale yellow oil (70%).
1H NMR (CDCl3): δ 10.38 (s, 1H), 8.12 (s, 1H), 7.44 (d, J ) 3.6
Hz, 1H), 7.30 (d, J ) 5.4 Hz, 1H), 7.07 (dd, J ) 5.4, 3.6 Hz, 1H),
6.57 (s, 1H), 4.31 (t, J ) 4.8 Hz, 2H), 3.99 (s, 3H), 3.94 (t, J )
4.8 Hz, 2H), 3.74-3.78 (m, 2H), 3.62-3.69 (m, 4H), 3.53-3.56
(m, 2H), 3.37 (s, 3H). MS (EI) m/z ) 380 ([M]+, 100%).
The title compound was prepared by condensing 4-methoxy-2-
{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thien-2-yl-benzalde-
hyde and 4-acetylbenzoic acid in a similar manner as described
1
for compound 5. Yellow solid, mp 137-138 °C, 82% yield. H
NMR (DMSO-d6): δ 8.20-8.23 (m, 3H), 8.09 (d, J ) 8.3 Hz,
2H), 8.01 (m, 2H), 7.66 (d, J ) 3.6 Hz, 1H), 7.52 (d, J ) 5.1 Hz,
1H), 7.13 (dd, J ) 5.1, 3.6 Hz, 1H), 6.88 (s, 1H), 4.37 (t, J ) 3.6
Hz, 2H), 4.01 (s, 3H), 3.89 (t, J ) 3.6 Hz, 2H), 3.64-3.67 (m,
2H), 3.53-3.56 (m, 2H), 3.47-3.50 (m, 2H), 3.36-3.95 (m, 2H),
3.19 (s, 3H). MS (ESI) m/z ) 527 ([M + H]+, 100%). Anal.
(C28H30O8S): C, H, S.
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-yl-
phenyl]-acryloyl}-benzoic Acid Hydrochloride (26). 4-Methoxy-
2-(2-morpholin-4-yl-ethoxy)-5-thien-2-yl-benzaldehyde was pre-
pared in an analogous fashion as described for compound 24 using
4-(2-chloroethyl)morpholine and 2-hydroxy-4-methoxy-5-thien-2-
yl-benzaldehyde. Silica gel chromatography (80-100% ethyl acetate
in hexanes and then 5% methanol in methylene chloride) gave the
1
expected product as an off-white solid (81%). H NMR (CDCl3):
δ 10.36 (s, 1H), 8.12 (s, 1H), 7.44 (dd, J ) 3.6, 1.5 Hz, 1H), 7.30
(dd, J ) 5.1, 1.5 Hz, 1H), 7.07 (dd, J ) 5.1, 3.6 Hz, 1H), 6.53 (s,
1H), 4.27 (t, J ) 6.3 Hz, 2H), 4.00 (s, 3H), 3.72-3.76 (m, 4H),
2.89 (t, J ) 6.3 Hz, 2H), 2.60-2.63 (m, 4H). MS (ESI) m/z ) 348
([M + H]+, 100%). HRMS (EI) calcd for C18H21NO4S: 347.1191,
found: 347.1188.
4-Methoxy-2-(2-morpholin-4-yl-ethoxy)-5-thien-2-yl-benzalde-
hyde (0.15 g, 0.43 mmol) and 4-acetylbenzoic acid (0.071 g, 0.43
mmol) were dissolved in a DMF/methanol solution (3.0 mL, 7:3).

1312 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Meng et al.
After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol)
was added and the resulting bright orange slurry was stirred in the
dark at rt for 2 h. Upon completion, as determined by HPLC, the
mixture was diluted with water (10 mL), acidified with a 1 N
hydrochloric acid solution, and extracted with an ethyl acetate/
tetrahydrofuran mixture (1:1, 6 × 20 mL). The combined organic
extracts were dried over sodium sulfate and evaporated to dryness.
The crude solid was slurried in ethyl alcohol (5 mL) to remove
residual impurities, and the resulting solid was collected on filter
paper and dried in vacuo to yield 0.21 g (98%) of the title compound
The title compound was prepared by condensing 2-(3-hydroxy-
2-hydroxymethyl-propoxy)-4-methoxy-5-thien-2-yl-benzaldehyde
and 4-acetylbenzoic acid in a similar manner as described for
1
compound 5; light orange solid, mp 219-220 °C, 61% yield. H
NMR (DMSO-d6): δ 8.36 (s, 1H), 8.20 (d, J ) 7.5 Hz, 2H), 8.05-
8.11 (m, 3H), 7.93 (d, J ) 16.2 Hz, 1H), 7.67 (d, J ) 3.0 Hz, 1H),
7.52 (d, J ) 5.1 Hz, 1H), 7.13 (dd, J ) 5.1, 3.0 Hz, 1H), 6.88 (s,
1H), 4.66 (brs, 2H), 4.23 (d, J ) 6.3 Hz, 2H), 4.01 (s, 3H), 3.55-
3.66 (m, 4H), 2.09-2.14 (m, 1H). MS (ESI) m/z ) 469 ([M +
H]+, 100%). Anal. (C25H24O7S‚H2O): C, H, S.
1
4-[3E-(2-Methoxy-5-thien-2-yl-phenyl)-acryloyl]-benzoic Acid
(30). 2-Methoxy-5-(thien-2-yl)-benzaldehyde was prepared from
5-bromo-2-methoxybenzaldehyde and thiophene-2-boronic acid in
a similar manner as described for compound 3. 1H NMR (CDCl3):
δ 10.49 (s, 1H), 8.07 (d, J ) 3 Hz, 1H), 7.79 (dd, J ) 3, 9.0 Hz,
1H), 7.28-7.26 (m, 2H), 7.09-7.06 (m, 1H), 7.02 (d, J ) 9 Hz,
1H), 3.97 (s, 3H).
as a dark yellow solid, mp: 255 °C (dec). H NMR (DMSO-d6):
δ 8.34 (s, 1H), 8.26 (d, J ) 8.7 Hz, 2H), 8.11 (d, J ) 8.7 Hz, 2H),
8.08 (s, 1H), 7.95 (d, J ) 15.9 Hz, 1H), 7.71 (d, J ) 3.3 Hz, 1H),
7.55 (d, J ) 4.5 Hz, 1H), 7.15 (dd, J ) 4.5, 3.3 Hz, 1H), 6.94 (s,
1H), 4.68 (br s, 2H), 4.04 (s, 3H), 3.98 (br s, 2H), 3.81-3.88 (br
m, 2H), 3.70 (brs, 2H), 3.54-3.58 (br m, 2H), 3.29 (br s, 2H). MS
(ESI) m/z ) 494 ([M + H]+, 100%). Anal. (C27H27NO6S‚HCl):
C, H, N, S; Cl: calcd 6.69, found 6.16.
4-{3E-[4-Methoxy-2-(3-morpholin-4-yl-propoxy)-5-thien-2-yl-
phenyl]-acryloyl}-benzoic Acid Hydrochloride (27). 4-Methoxy-
2-(3-morpholin-4-yl-propoxy)-5-thien-2-yl-benzaldehyde was pre-
pared in a similar manner as described for 24, 78% yield. 1H NMR
(DMSO-d6): δ 10.21 (s, 1 H), 7.88 (s, 1H), 7.48 (d, J ) 5.4 Hz,
1H), 7.45 (d, J ) 3.9 Hz, 1H), 7.06 (dd, J ) 5.1, 3.9 Hz, 1H), 6.82
(s, 1H), 4.24 (t, J ) 6.3 Hz, 2H), 4.00 (s, 3H), 3.53 (t, J ) 5.1 Hz,
4H), 2.34 (t, J ) 4.5 Hz, 4H), 1.93 (pentet, J ) 6.6 Hz, 2H).
The title compound was prepared by condensing 4-methoxy-2-
(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde and
4-acetylbenzoic acid in a similar manner as described for compound
5; yellow solid, 72% yield, mp 188-191 °C (dec). 1H NMR
(DMSO-d6): δ 12.72 (br s, 1 H), 11.08 (br s, 1H), 8.33 (s, 1H),
8.19 (d, J ) 8.1 Hz, 2H), 8.02-8.08 (m, 3H), 7.89 (d, J ) 15.6
Hz. 1H), 7.65 (d, J ) 3.3 Hz, 1H), 7.49 (d, J ) 4.5 Hz, 1H), 7.10
(t, J ) 5.1 Hz, 1H), 6.84 (s, 1H), 4.30 (t, J ) 6.0 Hz, 2H), 3.98 (s,
3H), 3.84 (br s, 4H), 3.21-3.51 (m, 6H), 2.08-2.16 (m, 2H). MS
m/z ) 508 ([M + H]+, 100%). Anal. (C28H29NO6S‚HCl‚H2O): C,
H, S.
The title compound was prepared by condensing 2-methoxy-5-
(thien-2-yl)-benzaldehyde and 4-acetylbenzoic acid in a similar
manner as described for compound 5; yellow solid, mp 195-196
1
°C. H NMR (DMSO-d6): δ 8.23-8.20 (m, 3H), 8.08-7.96 (m,
4H), 7.67 (dd, J ) 2.1, 6.8 Hz, 1H), 7.55 (d, J ) 3.8 Hz, 1H), 7.49
(d, J ) 5.1 Hz, 1H), 7.16-7.11 (m, 2H), 3.90 (s, 3H). MS m/z )
364 (M+, 100%). Anal. (C21H16O4S): C, H, S.
4-[3E-(4-Ethoxy-2-methoxy-5-thien-2-yl-phenyl)-acryloyl]-
benzoic Acid (31). 5-Bromo-4-hydroxy-2-methoxy-benzaldehyde
was prepared in an analogous fashion as described in section for
compound 7 using 4-hydroxy-2-methoxybenzaldehyde. The crude
solid was slurried in water to remove residual HBr and dried in
vacuo to give the bromide as an off-white solid (98%), mp 199-
201 °C. 1H NMR (DMSO-d6): δ 11.58 (s, 1H), 10.07 (s, 1H), 7.75
(s, 1H), 6.69 (s, 1H), 3.87 (s, 3H). MS (EI) m/z ) 230 ([M]+,
100%). Anal. (C8H7BrO3‚1/4H2O): calcd C 40.79, H 3.21, found
C 40.66, H 3.01.
4-Hydroxy-2-methoxy-5-thien-2-yl-benzaldehyde was prepared
in an analogous fashion as described for compound 7. Silica gel
chromatography (ethyl acetate/hexanes, 2:1) gave the expected
1
product as a solid (85%), mp 200 °C (dec). H NMR (CDCl3): δ
10.31 (s, 1H), 7.89 (s, 1H), 7.42 (dd, J ) 4.8, 1.2 Hz, 1H), 7.14-
7.19 (m, 2H), 6.59 (s, 1H), 6.14 (brs, 1H), 3.94 (s, 3H). MS (EI)
m/z: 234 ([M]+, 100%). Anal. (C12H10O3S‚H2O): calcd C 57.13,
H 4.79, S 12.71, found C 57.16, H 4.47, S 12.48.
4-{3E-[4-Methoxy-2-(2-morpholin-4-yl-2-oxo-ethoxy)-5-thien-
2-yl-phenyl]-acryloyl}-benzoic Acid (28). 4-Methoxy-2-(2-mor-
pholin-4-yl-2-oxo-ethoxy)-5-thien-2-yl-benzaldehyde was prepared
in an analogous fashion as described for 24 using 4-(2-chloroacetyl)-
morpholine. Silica gel chromatography (80% ethyl acetate/hexanes
to 100% ethyl acetate) gave the expected product as a pale yellow
Reaction of 4-hydroxy-2-methoxy-5-thien-2-yl-benzaldehyde and
(2-ethoxy-5-hydroxymethyl-[1,3]dioxolan-4-yl)methanol was pre-
formed under Mitsunobu conditions using triphenylphosphine and
diethyl azodicarboxylate in THF. However, the expected product,
4-(2-ethoxy-5-hydroxymethyl-[1,3]dioxolan-4-ylmethoxy)-2-meth-
oxy-5-thien-2-yl-benzaldehyde, was not obtained. Instead, 4-ethoxy-
2-methoxy-5-thien-2-yl-benzaldehyde was formed Via cleavage of
the cyclic ethyl orthoformate group under the reaction conditions.
Silica gel chromatography (ethyl acetate/hexanes, 1:2) gave 0.16 g
(90%) of 4-ethoxy-2-methoxy-5-thien-2-yl-benzaldehyde, mp 101-
103 °C. 1H NMR (CDCl3): δ 10.33 (s, 1H), 8.15 (s, 1H), 7.48 (d,
J ) 3.6 Hz, 1H), 7.29 (d, J ) 5.2 Hz, 1H), 7.07 (dd, J ) 5.2, 3.6
Hz, 1H), 6.50 (s, 1H), 4.25 (q, J ) 7.2 Hz, 2H), 3.97 (s, 3H), 1.59
(t, J ) 7.2 Hz, 3H). MS (EI) m/z ) 262 ([M]+, 100%). HMRS
(EI) calcd for C14H14O3S: 262.0664, found: 262.0667.
1
solid, mp 200-201 °C. H NMR (CDCl3): δ 10.33 (s, 1H), 8.12
(s, 1H), 7.44 (d, J ) 3.6 Hz, 1H), 7.31 (d, J ) 5.1 Hz, 1H), 7.08
(dd, J ) 5.1, 3.6 Hz, 1H), 6.74 (s, 1H), 4.89 (s, 2H), 4.00 (s, 3H),
3.67 (brs, 8H). MS (ESI) m/z ) 362 ([M + H]+, 100%). Anal.
(C18H19NO5S): C, H, N, S.
The title compound was prepared by condensing 4-methoxy-2-
(2-morpholin-4-yl-2-oxo-ethoxy)-5-thien-2-yl-benzaldehyde and
4-acetylbenzoic acid in a similar manner as described for compound
1
5; orange solid, mp 231-233 °C, 70% yield. H NMR (DMSO-
d6): δ 8.28-8.35 (m, 3H), 8.21 (s, 1H), 8.07-8.11 (m, 3H), 7.66
(d, J ) 3.3 Hz, 1H), 7.52 (d, J ) 5.1 Hz, 1H), 7.13 (dd, J ) 5.1,
3.3 Hz, 1H), 6.87 (s, 1H), 5.13 (s, 2H), 4.00 (s, 3H), 3.65 (brm,
4H), 3.54-3.55 (m, 4H). MS (EI) m/z ) 507 ([M]+, 100%). Anal.
(C27H25NO7S‚1/2EtOH): C, H, N, S.
The title compound was prepared by condensing 4-ethoxy-2-
methoxy-5-thien-2-yl-benzaldehyde and 4-acetylbenzoic acid in a
similar manner as described for compound 5; yellow solid, mp
4-{3E-[2-(3-Hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-
5-thien-2-yl-phenyl]-acryloyl}-benzoic Acid (29). 2-(3-Hydroxy-
2-hydroxymethyl-propoxy)-4-methoxy-5-thien-2-yl-benzaldehyde
was prepared by treating compound 9 with tetrabutylammonium
fluoride in THF. Silica gel chromatography (ethyl acetate/hexanes,
1
210-212 °C, 76% yield. H NMR (DMSO-d6): δ 8.31 (s, 1H),
8.23 (d, J ) 9.0 Hz, 2H), 8.06-8.11 (m, 3H), 7.92 (d, J ) 16.2
Hz, 1H), 7.71 (d, J ) 3.9 Hz, 1H), 7.52 (d, J ) 5.1 Hz, 1H), 7.13
(dd, J ) 5.1, 3.9 Hz, 1H), 6.82 (s, 1H), 4.33 (q, J ) 6.1 Hz, 2H),
3.99 (s, 3H), 1.48 (t, J ) 6.1 Hz, 3H). MS (ESI) m/z ) 409 ([M +
H]+, 100%). Anal. (C23H20O5S‚1/6H2O): C, H, S.
1
1:9) gave the expected product as an off-white solid. H NMR
(CDCl3): δ 10.17 (s, 1H), 8.03 (s, 1H), 7.43 (dd, J ) 3.6, 1.2 Hz,
1H), 7.31 (d, J ) 5.1 Hz, 1H), 7.08 (dd, J ) 5.1, 3.6 Hz, 1H), 6.58
(s, 1H), 4.32 (d, J ) 6.0 Hz, 2H), 4.01 (s, 3H), 3.95-3.99 (m,
4H), 2.51 (t, J ) 5.1 Hz, 2H), 2.33 (pentet, J ) 5.4 Hz, 1H). MS
(EI) m/z ) 322 ([M]+, 100%). HRMS (EI) calcd for C16H18O5S:
322.0875, found: 322.0873.
4-(3E-{2-Methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thien-
2-yl-phenyl}-acryloyl)-benzoic Acid (32). To a solution of 4-hy-
droxy-2-methoxy-5-thien-2-yl-benzaldehyde and tri(ethylene glycol)
monomethyl ether (0.38 g, 3.2 mmol) in tetrahydrofuran (20 mL)
was added triphenylphosphine (0.84 g, 3.2 mmol), and the resulting

Chalcones as Inhibitors of VCAM-1 Expression
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1313
mixture was cooled to 0 °C. Diethyl azodicarboxylate (0.55 g, 3.2
mmol) was then added dropwise, stirred at 0 °C for 30 min, and
allowed to warm to rt. The solution was stirred for an additional
24 h and concentrated under reduced pressure to a brown oil. Silica
gel chromatography (ethyl acetate/hexanes, 8:1) afforded 0.31 g
(45%) of the expected 2-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-
5-thien-2-yl-benzaldehyde as a viscous clear oil. 1H NMR
(CDCl3): δ 10.34 (s, 1H), 8.13 (s, 1H), 7.48 (d, J ) 3.6 Hz, 1H),
7.30 (t, J ) 5.1 Hz, 1H), 7.06 (dd, J ) 5.1, 3.6 Hz, 1H), 6.56 (s,
1H), 4.34 (t, J ) 5.1 Hz, 2H), 3.94 (t, J ) 5.1 Hz, 2H), 3.96 (s,
3H), 3.72-3.75 (m, 2H), 3.56-3.59 (m, 2H), 3.39 (s, 3H). MS
(ESI) m/z ) 337 ([M + H]+, 100%). HRMS (EI) calcd for
C17H20O5S: 336.1031, found: 336.1028.
The title compound was prepared in a similar manner as
described for compound 23; yellow solid, mp 217-219 °C. H
NMR (CDCl3): δ 8.19 (d, J ) 9 Hz, 2H), 8.10 (s, 1H), 8.06 (d, J
) 17 Hz, 1H), 8.05 (d, J ) 9 Hz, 2H), 7.85 (d, J ) 17 Hz, 1H),
7.76 (m, 1H), 7.545 (s, 1H), 7.541 (s, 1H), 6.77 (s, 1H), 3.96 (s,
3H), 3.93 (s, 3H). Anal. (C22H18O5S‚1/4H2O): C, H, S.
1
4-{3E-[2,4-Dimethoxy-5-(5-methyl-thien-2-yl)-phenyl]-acry-
loyl}-benzoic Acid (35). 2,4-Dimethoxy-5-(5-methyl-thien-2-yl)-
benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzal-
dehyde and 5-methyl-thiophene-2-boronic acid in a similar manner
1
as described for compound 3; 100% yield. H NMR (CDCl3): δ
10.33 (s, 1H), 8.05 (s, 1H), 7.22 (d, J ) 4 Hz, 1H), 6.72 (d, J )
4 Hz, 1H), 6.49 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.50 (s, 3H).
HMRS (EI) calcd for C14H14O3S: 262.0664, found: 262.0665.
The title compound was prepared by condensing 2-methoxy-4-
[2-(2-methoxy-ethoxy)-ethoxy]-5-thien-2-yl-benzaldehyde and 4-ace-
tylbenzoic acid in a similar manner as described for compound 5;
The title compound was prepared by condensing 2,4-dimethoxy-
5-(5-methyl-thien-2-yl)-benzaldehyde and 4-acetylbenzoic acid in
a similar manner as described for compound 5; yellow solid, mp
1
yellow solid, mp 174-175 °C, 61% yield. H NMR (DMSO-d6):
δ 8.28 (s, 1H), 8.23 (d, J ) 8.1 Hz, 2H), 8.05-8.11 (m, 3H), 7.91
(d, J ) 15.3 Hz, 1H), 7.72 (d, J ) 2.7 Hz, 1H), 7.52 (d, J ) 4.2
Hz, 1H), 7.11-7.15 (m, 1H), 6.86 (s, 1H), 4.39 (t, J ) 3.9 Hz,
2H), 3.99 (s, 3H), 3.89 (t, J ) 3.9 Hz, 2H), 3.64 (t, J ) 3.9 Hz,
2H), 3.48 (t, J ) 3.9 Hz, 2H), 3.25 (s, 3H). MS (ESI) m/z ) 483
([M + H]+, 100%). Anal. (C26H26O7S): C, H, S.
1
213-215 °C, 27% yield. H NMR (DMSO-d6): δ 8.18 (d, J ) 7
Hz, 2H), 8.17 (s, 1H), 8.00-8.06 (m, 3H), 7.85 (d, J ) 15 Hz,
1H), 7.42(d, J ) 4 Hz, 1H), 6.78(m, 2H), 3.96 (s, 3H), 3.95(s,
3H), 2.42 (s, 3H). MS m/z ) 408 ([M]+, 100%). HMRS (EI) calcd
for C23H20O5S: 408.1031, found: 408.1023. Anal. (C23H20O5S):
C, H, S.
4-{3E-[4-(3-Hydroxy-2-hydroxymethyl-propoxy)-2-methoxy-
5-thien-2-yl-phenyl]-acryloyl}-benzoic Acid (33). 4-[3-(tert-Butyl-
dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pro-
poxy ]-2-methoxy-5-thien-2-yl-benzaldehyde was prepared in an
analogous fashion as described for compound 9 using methane-
sulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dim-
ethyl-silanyloxymethyl)-propyl ester. Silica gel chromatography
(ethyl acetate/hexanes, 1:6) gave the expected product as a pale
4-{3E-[2,4-Dimethoxy-5-(2-methyl-thiazol-4-yl)-phenyl]-acry-
loyl}-benzoic Acid (36). A solution of 2-bromo-1-(3,4-dimethoxy-
phenyl)-ethanone (0.62 g, 2.39 mmol) and thioacetamide (0.18 g,
2.39 mmol) in ethanol (30 mL) was refluxed for 2 h, and the solvent
was removed under reduced pressure. The product, 4-(3,4-dimethoxy-
phenyl)-2-methyl-thiazole (0.56 g, 100%) was obtained as a white
solid and used without further purification. To a suspension of
4-(3,4-dimethoxy-phenyl)-2-methyl-thiazole obtained above (0.70
g, 2.97 mmol) in dichloromethane (60 mL) at 0 °C was added
dichloromethyl methyl ether (0.40 mL, 4.46 mmol) followed by
addition of titanium tetrachloride (1.0 M solution in dichlo-
romethane, 8.9 mL, 8.9 mmol) dropwise. The reaction mixture was
allowed to stir overnight at ambient temperature and then poured
into ice. The aqueous solution was extracted with dichloromethane.
The solution of dichloromethane was washed with hydrochloric
acid (0.5 M), saturated solution of sodium bicarbonate and brine,
dried over sodium sulfate, and concentrated. The product, 2,4-
dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde, was obtained as
1
green solid, 90% yield. H NMR (CDCl3): δ 10.34 (s, 1H), 8.13
(s, 1H), 7.41 (dd, J ) 3.6, 1.2 Hz, 1H), 7.28 (dd, J ) 5.1, 1.2 Hz,
1H), 7.05 (dd, J ) 5.1, 3.6 Hz, 1H), 6.54 (s, 1H), 4.22 (d, J ) 5.7
Hz, 2H), 3.96 (s, 3H), 3.80 (d, J ) 5.7 Hz, 4H), 2.33 (pentet, J )
5.7 Hz, 1H), 0.88 (s, 18H), 0.012 (s, 12H). MS (ESI) m/z ) 551
([M + H]+, 100%). HRMS (EI) calcd for C28H46O5SSi2: 550.2604,
found: 550.2593.
To a solution of 4-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-
butyl-dimethyl-silanyloxymethyl)-propoxy]-2-methoxy-5-thien-2-
yl-benzaldehyde (0.78 g, 1.41 mmol) in tetrahydrofuran (5 mL)
was added tetrabutylammonium fluoride (1 M in tetrahydrofuran,
3.0 mL, 2.9 mmol), and the mixture was stirred at rt for 30 min.
The reaction was diluted with ethyl acetate (50 mL) and washed
with a 50% ammonium chloride solution (1 × 30 mL), water (2 ×
30 mL), and brine (1 × 30 mL), dried over sodium sulfate, and
concentrated to a crude yellow solid. Silica gel chromatography
afforded 0.37 g (99%) of the expected 4-(3-hydroxy-2-hydroxym-
ethyl-propoxy)-2-methoxy-5-thiophen-2-yl-benzaldehyde as a pale
1
a white solid. H NMR (CDCl3): δ 10.33 (s, 1H), 8.67 (s, 1H),
7.56 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 3.99 (s, 3H), 2.75 (s, 3H).
The title compound was prepared by condensing 2,4-dimethoxy-
5-(2-methyl-thiazol-4-yl)-benzaldehyde and 4-acetylbenzoic acid in
a similar manner as described for compound 5; yellow solid, mp
1
201-202 °C (dec). H NMR (DMSO-d6): δ 8.47 (s, 1H), 8.14-
7.97 (m, 5H), 7.76 (s, 1H), 7.65 (d, J ) 15.8 Hz, 1H), 6.81 (s,
1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.69 (s, 3H). MS m/z ) 409 (M+,
70%), 378 ([M - OCH3]+, 100%). Anal. (C22H19NO5S‚5/4H2O):
C, H, N, S.
1
yellow solid, 90% yield, mp 144-145 °C. H NMR (CDCl3): δ
10.33 (s, 1H), 8.10 (s, 1H), 7.38 (dd, J ) 3.6, 1.5 Hz, 1H), 7.30
(dd, J ) 5.1, 1.5 Hz, 1H), 7.07 (dd, J ) 5.1, 3.6 Hz, 1H), 6.59 (s,
1H), 4.35 (d, J ) 6.0 Hz, 2H), 4.02 (t, J ) 4.8 Hz, 4H), 3.96 (s,
3H), 2.33 (pentet, J ) 6.0 Hz, 1H), 1.89 (t, J ) 4.8 Hz, 2H). MS
(ESI) m/z ) 323 ([M + H]+, 100%).
4-[3E-(5-Benzofuran-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-
benzoic Acid (37). 5-Benzofuran-2-yl-2,4-dimethoxy-benzaldehyde
was prepared in a similar manner as described for compound 3. 1H
NMR (CDCl3): δ 10.36(s, 1H), 8.55(s, 1H), 7.50-7.58 (m, 2H),
7.19-7.28 (m, 3H), 6.52 (s, 1H), 4.08 (s, 3H), 3.99 (s, 3H).
The title compound was prepared in a similar manner as
described for compound 5; yellow solid, mp 227-229 °C. 1H NMR
(DMSO-d6): δ 8.42 (s, 1H), 8.13-8.22 (m, 5H), 7.85 (d, J ) 15
Hz, 1H), 7.51-7.61 (m, 2H), 7.18-7.30 (m, 3H), 6.93 (s, 1H), 4.14
(s, 3H), 4.06 (s, 3H). MS m/z: 428 ([M]+, 100%). HMRS calcd
for C26H20O6: 429.1338 (M + H); found: 429.1331. Anal.
(C26H20O6): C, H.
The title compound was prepared by condensing 4-(3-hydroxy-
2-hydroxymethyl-propoxy)-2-methoxy-5-thien-2-yl-benzaldehyde
and 4-acetylbenzoic acid in a similar manner as described for
compound 5; yellow solid, mp 199-201 °C, 60% yield. 1H NMR
(DMSO-d6): δ 8.31 (s, 1H), 8.23 (d, J ) 8.7 Hz, 2H), 8.06-8.11
(m, 3H), 7.93 (d, J ) 15.0 Hz, 1H), 7.71 (d, J ) 3.3 Hz, 1H), 7.54
(d, J ) 5.1 Hz, 1H), 7.13-7.16 (m, 1H), 6.87 (s, 1H), 4.62 (brs,
2H), 4.27 (d, J ) 5.1 Hz, 2H), 4.00 (s, 3H), 3.62 (brs, 4H), 2.11-
2.15 (m, 1H). MS (ESI) m/z ) 469 ([M + H]+, 100%). Anal.
(C25H24O7S‚1/4H2O): C, H, S.
4-[3E-(2,4-Dimethoxy-5-thien-3-yl-phenyl)-acryloyl]-benzo-
ic Acid (34). 2,4-Dimethoxy-5-thien-3-yl-benzaldehyde was pre-
pared in a similar manner as described for compound 23. 1H NMR
(CDCl3): δ 10.35 (s, 1 H), 7.99 (s, 1 H), 7.55 (dd, 1 H, J ) 3 and
1 Hz), 7.40 (dd, 1 H, J ) 6 and 1 Hz), 7.33 (dd, 1 H, J ) 3 and
6 Hz), 6.52 (s, 1 H), 3.99 (s, 3 H), 3.98 (s, 3 H).
2-{5-[3-(4-Carboxy-phenyl)-3-oxo-E-propenyl]-2,4-dimethoxy-
phenyl}-indole-1-carboxylic Acid tert-Butyl Ester (38). 2-(5-
Formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl
ester was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and
N-Boc-indole-2-boronic acid in a similar manner as described for
1
compound 3; yellow oil, 79% yield. H NMR (CDCl3): δ 10.36
(s, 1H), 8.15 (d, J ) 8 Hz, 1H), 7.88 (s, 1H), 7.45 (d, J ) 8 Hz,

1314 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6
Meng et al.
3H), 7.27-7.35 (m, 1H), 7.19-7.27 (m, 1H), 6.52 (s, 1H), 6.47
(s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 1.42 (s, 9H).
a similar manner as described for compound 6; yellow solid, mp
174-176 °C, 66% yield. H NMR (DMSO-d6): δ 8.36 (s, 1H),
1
8.20 (d, J ) 8.8 Hz, 2H), 8.06 (d, J ) 15.0 Hz, 1H), 7.94-7.87
(m, 5H), 7.82 (d, J ) 7.5 Hz, 1H), 7.37-7.27 (m, 2H), 6.85 (s,
1H), 4.28 (s, 3H), 3.99 (s, 4H), 3.71 (s, 3H). MS (EI): 474 (M +
H). Anal. (C27H23NO5S): C, H, N, S.
The title compound was prepared by condensing 2-(5-formyl-
2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester and
4-acetylbenzoic acid in a similar manner as described for compound
5; yellow solid, 8% yield, mp 182-183 °C. 1H NMR (CDCl3): δ
8.21 (d, J ) 8 Hz, 2H), 8.19 (d, J ) 13 Hz, 1H), 8.16 (d, J ) 7
Hz, 1H), 8.07 (d, J ) 8 Hz, 2H), 7.69 (s, 1H), 7.54 (d, J ) 7 Hz,
1H), 7.52 (d, J ) 13 Hz, 1H), 7.29-7.35 (m, 1H), 7.23 (d, J ) 7
Hz, 1H), 6.55 (s, 1H), 6.50 (s, 1H), 4.00 (s, 3H), 3.85 (s, 3H), 1.42
(s, 9H). MS m/z ) 528 ([M + H]+, 100%). Anal. (C31H29NO7‚
H2O): C, H, N.
N-Acetyl-4-[3E-(5-benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-
acryloyl]-benzamide (43). A suspension of 4-[3E-(5-benzo[b]-
thiophen-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide (0.5 g,
1.13 mmol) in THF (15 mL) was cooled to -78 °C followed by
the addition of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.3
mL, 2.3 mmol). The mixture was stirred at this temperature for 1
h and warmed up to 0 °C. Acetic anhydride (0.48 mL, 6.8 mmol)
was then added dropwise. After the addition was complete the
reaction mixture was warmed up to ambient temperature and stirred
for 2 h. The reaction was quenched with water. The aqueous
solution was extracted with ethyl acetate. The combined extract
was washed with NH4Cl solution, brine, dried, and concentrated.
Flash chromatography (50% EtOAc/hexanes) gave the title com-
4-{3E-[5-(1H-Benzimidazol-2-yl)-2,4-dimethoxy-phenyl]-acry-
loyl}-benzoic Acid (39). A solution of benzene-1,2-diamine (2.60
g, 24.1 mmol) and 2,4-dimethoxy-benzaldehyde (4.0 g, 24.1 mmol)
in ethanol (60 mL) containing a catalytic amount of acetic acid
was refluxed overnight. The solvent was then evaporated under
reduced pressure, and the residual oil was triturated in ethyl acetate
to give 2-(2,4-dimethoxy-phenyl)-1H-benzimidazole (0.76 g, 12%).
The crude product was used without further purification. To a
solution of 2-(2,4-dimethoxy-phenyl)-1H-benzimidazole obtained
above (0.76 g, 2.99 mmol) in dichloromethane (20 mL) was added
dichloromethyl methyl ether (0.41 mL, 4.48 mmol) followed by
the addition of titanium tetrachloride (1.0 M in dichloromethane,
9.0 mL, 9.0 mmol) at 0 °C. The reaction mixture was allowed to
stir overnight at ambient temperature and then poured into ice. A
solution of sodium hydroxide (5 M) was added dropwise until the
pH of the solution was about 12. The basic solution was extracted
with dichloromethane. The combined solution of dichloromethane
was subsequently washed with brine, dried over sodium carbonate,
and concentrated. The product, 5-(1H-benzimidazol-2-yl)-2,4-
dimethoxy-benzaldehyde (0.40 g, 47%), was obtained and used
1
pound as yellow solid (0.16 g, 29%), mp 228-229 °C. H NMR
(CCDl3): δ 8.52 (s, 1H), 8.15-8.10 (m, 3H), 7.96 (d, J ) 7.6 Hz,
2H), 7.85-7.77 (m, 2H), 7.67 (s, 1H), 7.55 (d, J ) 16.7 Hz, 1H),
7.34-7.29 (m, 3H), 6.58 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 2.65
(s, 3H). MS m/z ) 485 (M+, 100%). Anal. (C28H23NO5S): C, H,
N, S.
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-
N-isobutyryl-benzamide (44). The title compound was prepared
in a similar manner as described for compound 43 from 4-[3E-(5-
benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-benzamide and
isobutyric anhydride; yellow solid, mp 208-209 °C. 1H NMR
(CCDl3): δ 8.14 (s, 1H), 8.15-8.10 (m, 3H), 7.96 (d, J ) 7.2 Hz,
2H), 7.85-7.77 (m, 2H), 7.67 (s, 1H), 7.56 (d, J ) 16.2 Hz, 1H),
7.38-7.29 (m, 3H), 6.59 (s, 1H), 4.05 (s, 3H), 4.01 (s, 3H), 3.68-
3.59 (m, 1H), 1.28 (d, J ) 6.2 Hz, 6H). MS m/z ) 513 (M+, 93%),
425 (100%). Anal. (C30H27NO5S‚1/2H2O): C, H, N, S.
1
without further purification. H NMR (CDCl3): δ 10.32 (s, 1H),
10.27 (bs, 1H), 9.03 (s, 1H), 7.83 (d, J ) 9 Hz, 1H), 7.48-7.45
(m, 1H), 7.31-7.22 (m, 1H), 6.58 (s, 1H), 4.18 (s, 3H), 4.01 (s,
3H). MS m/z ) 282 (M+, 100%).
3-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)-acryloyl]-benzo-
ic Acid (45). The title compound was prepared by condensing 2,4-
dimethoxy-5-(thien-2-yl)-benzaldehyde and 3-acetylbenzoic acid in
a similar manner as described for compound 5; yellow solid, 65%
The title compound was prepared by condensing 5-(1H-benz-
imidazol-2-yl)-2,4-dimethoxy-benzaldehyde and 4-acetylbenzoic
acid in a similar manner as described for compound 5; yellow solid,
1
1
mp >240 °C (dec); H NMR (DMSO-d6): δ 8.72 (s, 1H), 12.10
yield, mp 179-182 °C. H NMR (DMSO-d6): δ 13.24 (s, 1H),
(s, 1H), 8.18 (d, J ) 8.4 Hz, 2H), 8.08-8.02 (m, 3H), 7.80 (d, J
) 15.4 Hz, 1H), 7.59 (s, 2H), 7.17-7.13 (m, 2H), 6.89 (s, 1H),
4.10 (s, 3H), 4.03 (s, 3H). MS m/z ) 429 ([M + H]+, 100%). Anal.
(C25H20N2O5‚H2O): C, H, N.
8.54 (s, 1 H), 8.39 (d, J ) 7.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J )
8.4 Hz, 1H), 8.05 (d, J ) 15.9 Hz, 1H), 7.89 (d, J ) 15.0 Hz, 1H),
7.63-7.70 (m, 2H), 7.48 (d, J ) 5.1 Hz, 1H), 7.09(dd, J ) 3.9,
5.4 Hz, 1H), 6.81 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H). MS m/z )
394 ([M]+, 72%), 363 (100%). Anal. (C22H18O5S): C, H, S.
2-[3E-(2,4-Dimethoxy-5-thien-2-yl-phenyl)-acryloyl]-benzo-
ic Acid (46). The title compound was prepared by condensing 2,4-
dimethoxy-5-(thien-2-yl)-benzaldehyde and 2-acetylbenzoic acid in
a similar manner as described for compound 5; yellow solid, 47%
yield, mp 196-198 °C. 1H NMR (DMSO-d6): δ 8.00 (s, 1H), 7.91
(s, 1H), 7.85 (dd, J ) 7.5, 1.5 Hz, 1H), 7.67-7.55 (m, 3H), 7.48-
7.43 (m, 3H), 7.20 (d, J ) 15.9 Hz, 1H), 7.05 (dd, J ) 3.9, 5.1 Hz,
1H), 6.76 (s, 1H), 3.95 (s, 3H), 3.86 (s, 3H). MS m/z ) 394 ([M]+,
100%). Anal. (C22H18O5S): C, H, S.
4-[2-(2,4-Dimethoxy-5-thiophen-2-yl-phenyl)-cyclopropane-
carbonyl]-benzoic Acid (47). To a clean reaction vessel fitted with
a stir bar and nitrogen inlet adapter was sequentially charged 60
wt % NaH (42 mg, 1.05 mmol), trimethylsulfoxonium iodide (231
mg, 1.05 mmol), and DMSO (3 mL). After aging for 1 h at rt,
4-[3E-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-benzoic acid
(100 mg, 0.25 mmol) was added dropwise over 5 min as a DMSO
(2 mL) solution. The reaction was aged overnight at rt, diluted with
1 N HCl (11 mL), and transferred to a separatory funnel containing
EtOAc (11 mL). The layers were cut, and the aqueous layer was
extracted with additional EtOAc (15 mL). The organic cuts were
combined and washed with brine (30 mL). The resulting organic
phase was concentrated to a crude solid and purified by silica gel
chromatography (MeOH/CH2Cl2/AcOH, 49:49:2) to afford 54 mg
(52% yield) of the title compound, mp 92-96 °C. 1H NMR (CDCl3)
δ 8.20 (d, J ) 8.3 Hz, 2H), 8.09 (d, J ) 8.3 Hz, 2H), 7.44 (m,
1H), 7.37 (dd, J ) 3.6 and 1.4 Hz, 1H), 7.28 (s, 1H), 7.07 (dd, J
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-
benzoic Acid Ethyl Ester (40). The title compound was prepared
starting from compound 5 and ethanol in an ester formation reaction
using EDCI in a similar manner as described for compound 6;
1
orange solid, mp 167-169 °C, 44% yield. H NMR (CDCl3): δ
8.17 (d, J ) 8.1 Hz, 2H), 8.11 (d, J ) 15.9 Hz, 1H), 8.06 (d, J )
7.8 Hz, 2H), 7.95 (s, 1H), 7.83 (d, J ) 7.5 Hz, 1H), 7.78 (d, J )
7.5 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J ) 16.5 Hz, 1H), 7.28-7.37
(m, 2H), 6.57 (s, 1H), 4.42 (q, J ) 7.5 Hz, 2H), 4.03 (s, 3H), 4.00
(s, 3H), 1.43 (t, J ) 6.6 Hz, 3H). HRMS (EI) calcd for C28H25O5S:
473.1422, found: 473.1429. Anal. (C28H24O5S): C, H, S.
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-
benzamide (41). To a solution of 4-acetyl-benzamide (0.3 g, 1.84
mmol) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (0.55
g, 1.84 mmol) in a mixture of DMF (7 mL) and methanol (3 mL)
was added lithium methoxide (0.14 g, 3.68 mmol). The reaction
mixture was allowed to stir at ambient temperature for 9 h. The
resulting precipitate was collected by filtration, washed with
methanol, and dried in vacuo to give the title compound as a yellow
1
solid (5.56 g, 68%), mp 240-241 °C. H NMR (DMSO-d6): δ
8.37 (s, 1H), 8.19 (d, J ) 7.8 Hz, 2H), 8.12 (d, J ) 15.3 Hz, 1H),
8.04-7.91 (m, 6H), 7.83 (d, J ) 7.5 Hz, 1H), 7.55 (s, 1H), 7.36-
7.30 (m, 2H), 6.87 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H). MS m/z )
444 ([M + H]+, 100%). Anal. (C26H21NO4S‚1/6H2O): C, H, N, S.
4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxy-phenyl)-acryloyl]-
N-methoxy-benzamide (42). This compound was synthesized by
treating compound 5 with O-methyl-hydroxylamine and EDCI in

Chalcones as Inhibitors of VCAM-1 Expression
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 6 1315
References
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2.77 (m, 2H), 1.95 (m, 1H), 1.65 (m, 1H). Anal. (C23H20O5S‚1/
3H2O): C, H, S.
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Supporting Information Available: Elemental analysis data.
This material is available via the Internet at http://pubs.acs.org.
JM0614230