Synthesis and antimicrobial evaluation of 3-methanone-6-substituted- benzofuran derivatives

Article abstract of DOI:10.1016/j.ejmech.2012.05.013

Seventeen benzofuran derivatives were synthesized and screened for their antibacterial activities against Escherichia coli, Staphylococcus aureus, Methicillin-resistant S. aureus, Bacillus subtilis, and Pseudomonas aeruginosa. Seven of them have showed excellent antibacterial activities compared to the positive controls (Cefotaxime and Sodium Penicillin). The substitutions at C-6 and C-3 positions of these derivatives were found to greatly impact on the antibacterial activity and strains specificity, respectively. Specifically, compounds bearing a hydroxyl group at C-6 (5a, 5b, 5c and 12) offered excellent antibacterial activities against all five above-mentioned strains (MIC ₈₀ = 0.78-12.5 ug/mL), and those with imine (15) and (3, 4, 5-trimethoxyphenyl) methanone (7e), respectively, at C-3 position showed selective activity against S. aureus among five tested strains with great MIC₈₀ values (3.12-12.5 ug/mL).

Full text of DOI:10.1016/j.ejmech.2012.05.013

European Journal of Medicinal Chemistry 54 (2012) 879e886
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antimicrobial evaluation of 3-methanone-6-substituted-
benzofuran derivatives
1
1
*
Jingbao Liu , Faqin Jiang , Xizhen Jiang, Wei Zhang, Jingjing Liu, Wenlu Liu, Lei Fu
School of Pharmacy, Shanghai Jiao Tong University, No. 800 Dongchuan Rd., Shanghai 200240, PR China
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
< Seventeen
substituted-benzofuran derivatives
were prepared.
3-methanone-6-
O
R2
< Seven of them have showed excel-
lent
antibacterial
activities
R1
R3
compared to the positive controls.
< The SAR studies confirmed that the
hydroxyl group at C-6 position is
essential to antibacterial activities.
< The functional groups at C-3 posi-
tion plays important role in the
antibacterial selectivity of these
compounds.
O
O
a r t i c l e i n f o
a b s t r a c t
Article history:
Seventeen benzofuran derivatives were synthesized and screened for their antibacterial activities against
Escherichia coli, Staphylococcus aureus, Methicillin-resistant S. aureus, Bacillus subtilis, and Pseudomonas
aeruginosa. Seven of them have showed excellent antibacterial activities compared to the positive
controls (Cefotaxime and Sodium Penicillin). The substitutions at C-6 and C-3 positions of these deriv-
atives were found to greatly impact on the antibacterial activity and strains specificity, respectively.
Specifically, compounds bearing a hydroxyl group at C-6 (5a, 5b, 5c and 12) offered excellent antibac-
terial activities against all five above-mentioned strains (MIC80 ¼ 0.78e12.5 ug/mL), and those with
imine (15) and (3, 4, 5-trimethoxyphenyl) methanone (7e), respectively, at C-3 position showed selective
activity against S. aureus among five tested strains with great MIC80 values (3.12e12.5 ug/mL).
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 28 November 2011
Received in revised form
8 May 2012
Accepted 9 May 2012
Available online 17 May 2012
Keywords:
Benzofuran
Antimicrobial
Synthesis
1. Introduction
Natural products containing benzofurans are attractive drug
leads due to their broad spectrum of biological activities, such as
Infections caused by multi-drug resistant bacteria are major
health problem worldwide. Methicillin- and vancomycin-resistant
Staphylococcus aureus strains are responsible for most infections
of this type [1,2]. Due to serious side effects observed in recently
developed antibiotics, imminent development of structurally
diversified chemical entities is believed to be the key to the
discovery of new antibiotics [3].
antimicrobial, antitumor, and anti-inflammation [4e8]. Benzofu-
rans with substituents at C-2 and/or C-3 positions have been
extensively researched for unique biological and pharmacological
properties [4,9], notably, antimicrobial activities [10e14].
Early, our group reported the synthesis and antimicrobial eval-
uation of two families of chemicals, benzofuran and propanoic acid
derivatives [15,16]. We discovered that the benzofuran derivatives
bearing aryl substituents at the C-3 position through a methanone
linker (Fig. 1) exhibited high antibacterial activities against Gram-
negative and Gram-positive bacteria [15], and the hydroxyl groups
on the aromatic ring at C-3 position significantly enhanced such
* Corresponding author. Tel.: þ86 21 34204791; fax: þ86 21 34204787.
E-mail address: leifu@sjtu.edu.cn (L. Fu).
1
Co-first authors.
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.05.013

880
J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
3-methanone-benzofuran
Chiral 2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic
derivatives; MIC80=0.39-3.12 ug/mL acid derivatives; MIC80=1.56-6.25 ug/mL
Fig. 1. The structures of our recently published antibacterial agents.
activities. We also demonstrated that the chiral 2-(substituted-
hydroxyl)-3-(benzo[d]oxazol-5-yl) propanoic acid derivatives were
excellent antibacterial agents, and the activities could be altered by
their respective hydrophobicities (Log P value) [16].
Based on our published antimicrobial results of two families of
chemicals, benzofuran and propanoic acid derivatives with
hydrophobic groups showed excellent antibacterial activities. We
speculate hydrophobicities should be important to antimicrobial
activities of 3-methanone-benzofuran derivatives. Therefore, we
Most intermediates were obtained in accordance with commonly
used procedures [17e23]. Compound 7 was prepared according to
Scheme 1. Starting from 2, 4-dihydroxybenzaldehyde 1, 4-(benzy-
loxy)-2-hydroxybenzaldehyde 2 was prepared from coupling with
benzyl chloride, and then in the presence of ZneTiCl4eTHF under
refluxing, compound 2 was treated with aromatic aldehyde to
afford dipenylethene 3, which underwent an intra-molecular
cyclization in K2CO3 and I2 to furnish an important skeleton
benzofuran 4. The benzyl group of compound 4 was removed with
designed
a
series of 3-methanone-6-substituted-benzofuran
TiCl4 to give intermediate 5 in high yield. (5-methyl-2-
derivatives with hydroxyl or (5-methyl-2-phenyloxazol-4-yl) eth-
yloxy at C-6 position of benzofuran (Fig. 2). Herein, we report the
synthesis and antibacterial evaluation of a new series of 3-
methanone-6-substituted-benzofuran derivatives with hydroxyl
or (5-methyl-2-phenyloxazol-4-yl)ethyloxy at C-6 position of
benzofuran.
phenyloxazol-4-yl)ethyloxy was introduced to C-6 position of
compound 5 by electrophilic substitution with 2-(5-methyl-2-
phenyloxazol-4-yl) ethyl methanesulfonate 11 to afford 6-
substituted-benzofuran 6. Treatment of compound 6 with acyl
chloride and SnCl4, using the FriedeleCrafts procedure furnished
compound 7. Intermediate compound 11 was synthesized with the
known procedure shown in Scheme 2.
2. Synthetic chemistry and biological evaluation
1-(6-hydroxy-2-(5-methylfuran-2-yl)
benzofuran-3-yl)etha-
none 12 was easily obtained from a starting material 4c, which was
treated with acetyl chloride and SnCl4 as shown in Scheme 3.
Synthesis of compound 13 was followed by the procedure in
Scheme 4. Compound 7b was reacted with 3, 4, 5-
trimethoxybenzaldehyde and KOH under refluxing to produce
2.1. Synthetic chemistry
The synthetic routes for the 3-methanone-6-substituted-
benzofuran compounds are outlined in Schemes 1, 2, 3, 4 and 5.
substituted
Fig. 2. Design of novel 3-methanone-6-substituted-benzofuran derivatives antimicrobial agents. a: The contents in the rectangular figure of Ref. [15,16] represent the skeleton
nucleus of 3-methanone-benzofuran, and hydrophobic tail of benzo[d]oxazole, which showed important impact to the antibacterial activity of chiral 2-(substituted-hydroxyl)-3-
(benzo[d]oxazol-5-yl) propanoic acid derivatives; b:Based on our published results in Ref. [15,16], we designed a series of benzofuran derivatives with hydrophobic tail at C-6
position of 3-methanone-benzofuran.

J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
881
OH
OH
R1
CHO
OH
Cl
CHO
+
a
b
O
O
HO
3
2
1
O
R1
d
R1
+
c
O
O
O
HO
N
11
OMs
5
4
O
R2
R1
O
O
e
f
N
N
R1
O
O
O
O
7
6
R1
R2
7a
5-methylf uran-2-yl
4-methoxyphenyl
5-methylf uran-2-yl
5-methylfuran-2-yl
5-methylfuran-2-yl
methyl
methyl
furan-2-yl
4-trifluoromethylphenyl
3,4,5--trimethoxyphenyl
3a,4a,5a,6a phenyl
R1:
7b
7c
7d
7e
3b,4b,5b,6b 4-methoxyphenyl
3c,4c,5c, 6c 5-methylf uran-2-yl
Scheme 1. Synthesis of compounds 7a, Reagents and conditions: (a) KI, NaHCO3, CH3CN, reflux, 67%; (b) R1CHO, ZneTiCl4eTHF, 20e59.7%; (c) K2CO3, I2, THF, 14.6e54%; (d) TiCl4,
CH2Cl2, 31.8e90% (e) K2CO3, CH3CN, reflux, 48.1e66.3%; (f) R2COCl, SnCl4, CH2Cl2, 13.9e51%.
O
O
OMs
OH
O
O
c
a
b
N
N
N
O
O
O
Br
O
11
8
9
10
Scheme 2. Synthesis of compound 11a, Reagents and conditions: (a) Benzamide, toluene, reflux, 40%; (b) LiAlH4, ether, 96%; (c) CH3SO2Cl, CH2Cl2, 80.2%.
compound 13. Compound 16 was prepared according to the
procedure in Scheme 5. Reaction of compound 6a with POCl3 and
DMF gave aldehyde 14, which was condensed with 3,4,5-
trimethoxyaniline to yield imine 15, finally, reduction of
compound 15 with NaBH4 afforded compound 16.
All intermediates and final compounds were characterized by
the NMR and HRMS spectroscopies, and new compounds were
further characterized by element analyses spectroscopies.
according to the National Committee for Clinical Laboratory Stan-
dards (NCCLS) [15,16,24,25], and evaluated against the Gram-
positive bacteria Staphylococcus aureus (ATCC 29213), Bacillus sub-
tilis (ATCC 33712), and Methicillin-resistant S. aureus (ATCC
700699), the Gram-negative bacteria Escherichia coli (ATCC 11303)
and P. aeruginosa (ATCC 49189) by following the procedures
previously reported [15]. The MIC80 value is defined as the lowest
antibiotic concentration that resulted in visible growth after incu-
bation at 37 ꢀC for 24 h. Ceftazidime, Cefotaxime, Cefradine and
Sodium Penicillin were used as control drugs. The antimicrobial
activity data of the compounds and the control drugs were there-
fore determined and the MIC80 (ug/mL) values were given in
Table 1.
2.2. Biological evaluation
All synthesized benzofuran derivatives were each dissolved in
DMSO and diluted by the microtiter broth dilution method
O
a
O
O
O
O
O
HO
4c
12
Scheme 3. Synthesis of compound 12a, Reagents and conditions: (a) CH3COCl, SnCl4, CH2Cl2, 32.5%.

882
J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
O
O
O
O
O
O
O
a
N
O
N
OMe
O
O
O
O
7b
13
Scheme 4. Synthesis of compound 13a, Reagents and conditions: (a) 3, 4, 5-trimethoxybenzaldehyde, KOH, MeOH, reflux, 25%.
O
O
N
a
N
CHO
O
O
O
14
O
6a
O
O
O
O
O
N
c
O
O
N
b
N
H
O
O
N
O
O
O
16
15
Scheme 5. Synthesis of compound 15 and 16a, Reagents and conditions: (a) POCl3, DMF, (CH2Cl)2, reflux, 37%; (b) 3,4,5-trimethoxyaniline, toluene, reflux, 33%; (c) NaBH4, CH3OH,
HOAC, r.t, 100%.
3. Results and discussion
(Fig. 2) at C-2 position of benzofuran all showed good antibacterial
activity with MIC80 values between 0.78 and 6.25 ug/mL, which are
comparable to those of control drugs. In contrast, Compounds 6a
and 6b, of which hydroxyl group was blocked at the C-6 position of
benzofuran, exhibited no antibacterial activity to any of five tested
strains, indicating the hydroxyl group at C-6 position of benzofuran
is essential for the activity. This conclusion was further supported
by the observation that most of chemicals, such as 4a, 4b, 4c, 6a, 6b,
7a, 7b, 7c, 7d, 13 and 16 didn’t exhibit antibacterial activities, as all
of them were lack of the essential hydroxyl group at C-6 position,
The anti-microorganism tests with all seventeen compounds
(Table 1) have established some interesting structureeactivity
relationships. Compounds 5a, 5b and 5c with different R1 groups
Table 1
In vitro antimicrobial activity of 3-substituted-6-substituted-benzofuran
derivatives.
Compounds
MIC80 (ug/mL)a,b
S. aureus MRSA
P. aeruginosa B. subtilis E. coli
whereas the activity was restored from 7a to 12 (MIC80
6.25e12.5 ug/mL).
:
4a
4b
4c
100
>200
>200
>200
>200
12.5
1.56
0.78
3.12
>200
>200
>200
>200
>200
>200
>200
100
>200
>200
100
>200
>200
>200
>200
>200
The strain-specific was also observed in compounds 7e and 15.
While fixed the C-6 position with a 5-methyl-2-phenyloxazole-4-
ethyloxy group, the C-3 position was occupied by either a (3, 4, 5-
trimethoxyphenyl)methanone group (7e) or an imine group (15).
These two compounds displayed antibacterial activities only
against S. aureus with MIC80 values of 12.5 ug/mL and 3.12 ug/mL,
respectively, similar to those of Cefotaxime and Sodium Penicillin.
We speculated that the strain-specific may be owe to the meth-
anone group or imine group between the 3, 4, 5-trimethoxyphenyl
and benzofuran nucleus, which may play a specific role with the
biological target of S. aureus, and the strain-specific lost when the
double bond (13) was introduced between the 3, 4, 5-
trimethoxyphenyl and methanone or the imine was reduced to
amine (16).
5a
6.25
0.78
3.12
6.25
5b
5c
1.56
1.56
1.56
0.78
1.56
1.56
3.12
3.12
6a
>200
>200
>200
>200
6b
7a
7b
7c
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
50
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
7d
7e
12
13
15
12.5
6.25
>200
3.12 >200
6.25
>200
12.5
12.5
12.5
>200
>200
>200
>200
>200
>200
>200
50
>200
>200
>200
25
16
>200
>200
0.78
>200
>200
12.5
3.12
3.12
Cefradine
Ceftazidime
Cefotaxime
Sodium Penicillin
12.5
6.25
0.78
>200
>200
3.12
3.12
e
e
4. Conclusions
<0.39
0.78
a
E. coli: Escherichia coli, S. aureus: Staphylococcus aureus, MRSA: methicillin-
resistant Staphylococcus aureus, B. subtilis: Bacillus subtilis, P. aeruginosa: Pseudo-
monas aeruginosa.
In summary, we have synthesized seventeen 3-methanone-6-
substituted-benzofuran derivatives and evaluated for their
in vitro antibacterial activities. Seven compounds showed excellent
b
The sign (_) referred to compounds that didn’t be tested.

J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
883
antibacterial activities against all five tested strains with MIC80
value comparable to those of Cefotaxime and Sodium Penicillin.
Specially, compound 7e and 15 displayed the strain-specific to
S. aureus (MIC80 ¼ 3.12e12.5 ug/mL). The structureeactivity
relationship (SAR) studies showed that the hydroxyl group at
C-6 position is essential to antibacterial activities, and the func-
tional groups at C-3 position plays important role in the antibac-
terial selectivity of these compounds. Further, complete
structureeactivity relationship (SAR) and mechanistic approach
should be taken into account while considering designing and
screening of much more compounds. More research in this direc-
tion is under progress and results will be published in due course of
times.
ArH, J ¼ 3 Hz, 8.7 Hz), 6.951e6.989 (d, 1H, CH, J ¼ 11.4 Hz),
7.133e7.155 (d, 1H, ArH, J ¼ 6.6 Hz), 7.365e7.548 (m, 8H, ArH, CH);
EI-MS m/z: 333.1.
5.1.2.1. (E)-5-(benzyloxy)-2-styrylphenol (3a). Compound 3a (2.1 g,
31.8%) as a yellow solid; m.p.: 94e96 ꢀC; 1H NMR (300 MHz, CDCl3)
d
5.079 (s, 2H, CH2), 6.474e6.482 (d, 1H, ArH, J ¼ 2.4 Hz),
6.523e6.531 (d, 1H, ArH, J ¼ 2.4 Hz), 6.608e6.644 (d, 1H, CH ¼ CH,
J ¼ 10.8 Hz), 6.993e7.048 (d, 1H, CH ¼ CH, J ¼ 16.5 Hz), 7.138 (s, 1H,
ArH), 7.365e7.534 (m, 5H, ArH), 8.105e8.133 (brs, 1H, OH); EI-
MS m/z: 303.1.
5.1.2.2. (E)-5-(benzyloxy)-2-(2-(5-methylfuran-2-yl) vinyl) phenol
(3c). Compound 3c (4 g, 59.7%) as a yellow solid; m.p.: 72e74 ꢀC;
5. Materials and methods
1H NMR (300 MHz, CDCl3)
d 2.355 (s, 3H, CH3), 5.057 (s, 2H, CH2),
6.149e6.177 (d, 1H, CHCH, J ¼ 8.4 Hz), 6.189e6.200 (d, 1H, CHCH,
J ¼ 3.3 Hz), 6.472e6.480 (d, 1H, ArH, J ¼ 2.4 Hz), 6.571e6.579 (d,
1H, ArH, J ¼ 2.4 Hz), 6.688 (s, 1H, ArH), 6.765e6.819 (d, 1H,
CH ¼ CH, J ¼ 16.2 Hz), 7.073e7.128 (d, 1H, CH ¼ CH, J ¼ 16.5 Hz),
7.372e7.426 (m, 5H, ArH), 8.634e8.653 (brs, 1H, OH); EI-MS m/z:
307.1.
5.1. Chemistry
1H NMR and 13C NMR were recorded on either a Brucker
300 MHz Avance DPX or a Bruker 500 MHz Avance DRX instrument.
Splitting patterns are designated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet. Chemical shift values are given in parts per
million and coupling constants (J) in Hertz. Elemental analyses
were determined by a LECO CHNSO-932 auto elemental analysis
apparatus. Analysis indicated by the symbols of the elements of
functions was within ꢁ0.4% of the theoretical values. High resolu-
tion mass spectroscopy was conducted using Micromass LCT
system. All reactions were followed by TLC (silica gel, aluminum
sheets 60 F254).
5.1.3. General procedure for the synthesis of 6-(benzyloxy)-2-(4-
methoxyphenyl) benzofuran (4b)
To the solution of (E)-5-(benzyloxy)-2-(4-methoxystyryl)-
phenol (3b) (280 mg, 0.84 mmol) in THF (15 mL) was added
anhydrous K2CO3 (695 mg, 5.04 mmol), then I2 (1.28 g, 5.04 mmol)
was added and the mixture was stirred at ambient temperature
until the 3b was consumed. The mixture was poured into saturated
aqueous NaHCO3 (30 mL) and treated with saturated aqueous
NaHSO3 to remove the unconsumed iodine. The mixture was
extracted with ethyl acetate, and the organic layer was dried over
sodium sulphate anhydrous, concentrated, and purified by flash
chromatography (petroleum ether: ethyl acetate ¼ 5:1) to yield
a yellow solid. Yield 54%; m.p.: 108e110 ꢀC; 1H NMR (300 MHz,
5.1.1. 4-(benzyloxy)-2-hydroxybenzaldehyde (2)
2,4-dihydroxybenzaldehyde (100 mg, 0.72 mmol), potassium
iodide (179.3 mg, 1.08 mmol) and sodium bicarbonate (90.7 mg,
1.08 mmol) were dissolved in acetonitrile (15 mL), then benzyl
chloride (100 uL, 0.87 mmol) were added slowly to the resulted
solution. The mixture was stirred at refluxing overnight, and then
the reaction was quenched with water and extracted with ethyl
acetate (20 mL ꢂ 3). The combined organic layer was washed with
brine (15 mL ꢂ 3), dried with sodium sulphate anhydrous,
concentrated under vacuum, and purified by flash chromatography
with eluent (petroleum ether: ethyl acetate ¼ 10:1), to get
a colorless solid. Yield 67%; m.p. 70e72 ꢀC; 1H NMR (300 MHz,
CDCl3) d 3.87 (s, 3H, OCH3), 5.14 (s, 2H, OCH2Ph), 6.826 (s, 1H, ArH),
6.889e6.918 (d, 1H, ArH, J ¼ 8.7 Hz), 6.968e6.991 (d, 2H, ArH,
J ¼ 6.9 Hz), 7.132 (s, 1H, CH), 7.350e7.503 (m, 6H, ArH), 7.739e7.768
(d, 2H, ArH, J ¼ 8.7 Hz); 13C NMR (125 MHz, CDCl3)
d 159.6, 156.8,
155.5, 137.1, 128.6, 127.9, 125.9, 123.6, 123.1, 120.6, 114.3, 112.5, 99.5,
97.2, 70.7, 55.4; HRMS [ESI (þ)-MS]: C22H18O3 [M þ H2O]þ m/z, calc.
330.1, found 348.1; Anal. Calc. for C22H18O3 (%): C, 78.98; H, 5.49.
Found: C, 78.94; H, 5.52.
CDCl3),
d 5.12 (s, 2H, OCH2Ph), 6.40e6.64 (m, 2H, ArH), 7.41e7.43
(m, 6H, ArH), 9.73 (s, 1H, CHO), 11.44 (brs, 1H, OH); EI-MS m/z:
229.1.
5.1.3.1. 6-(benzyloxy)-2-phenylbenzofuran (4a). Compound 4a
(1.1 g, 53.8%) as a yellow solid; m.p.: 92e94 ꢀC; 1H NMR (300 MHz,
5.1.2. General procedure for the synthesis of (E)-5-(benzyloxy)-2-
(4-methoxystyryl)-phenol (3b)
CDCl3)
7.116e7.141 (m, 1H, ArH), 7.257e7.465 (m, 10H, ArH), 7.822 (s, 1H,
CH); 13C NMR (125 MHz, CDCl3)
157.1, 155.7, 136.9, 130.6, 128.7,
128.0, 127.5, 126.5, 124.5, 121.0, 112.7, 101.2, 97.2, 70.6; HRMS [ESI
(þ)-MS]: C21H16O2 [M þ H]þ m/z, calc. 300.1, found 301.1; Anal.
Calc. for C21H16O2 (%): C, 83.98; H, 5.37. Found: C, 83.95; H,
5.41.
d 5.134 (s, 2H, CH2), 6.937e6.972 (m, 2H, ArH),
Zinc powder (1.4 g, 22 mmol) was added to THF (20 mL) under
nitrogen atmosphere and the resulted mixture was cooled to ꢃ5 to
d
0
ꢀC. Then TiCl4 (1.2 mL, 11 mmol) was added slowly with the
temperature under 0 ꢀC. The mixture was warmed to room
temperature and stirred for 0.5 h, then refluxed for 2.5 h. The
mixture was cooled to ꢃ5 to 0 ꢀC, and the solution of 4-(benzy-
loxy)-2-hydroxybenzaldehyde (2) (1 g, 4.4 mmol) and 4-
methoxybenzaldehyde (721 mg, 5.3 mmol) in THF (15 mL) was
added slowly. After addition, the reaction mixture was refluxed
until the carbonyl compounds were consumed (monitored by TLC).
The reaction was cooled, quenched with 10% aqueous NaHCO3
solution and extracted with CH2Cl2 (20 mL ꢂ 3). The combined
organic layer was concentrated and purified by flash chromatog-
raphy (petroleum ether: ethyl acetate ¼ 5:1) to obtain a colorless
5.1.3.2. 6-(benzyloxy)-2-(5-methylfuran-2-yl) benzofuran (4c).
Compound 4c (581 mg, 14.6%) as a brown solid; m.p.: 72e74 ꢀC;
1H NMR (300 MHz, CDCl3)
d 2.385 (s, 3H, CH3), 5.112 (s, 2H, CH2),
6.085e6.093 (d, 1H, CHCH, J ¼ 2.4 Hz), 6.611e6.600 (d, 1H, CHCH,
J ¼ 3.3 Hz), 6.754 (s, 1H, ArH), 6.923e6.931 (d, 1H, ArH,
J ¼ 2.4 Hz), 6.952e6.959 (d, 1H, ArH, J ¼ 2.1 Hz), 7.256 (s, 1H, CH),
7.375e7.452 (m, 5H, ArH); 13C NMR (125 MHz, CDCl3)
d 157.0,
155.3, 152.8, 144.6, 136.9, 128.6, 127.5, 120.8, 112.6, 107.8, 99.9,
97.2, 70.6, 13.7; HRMS [ESI (þ)-MS]: C20H16O3 [M þ H]þ m/z, calc.
304.1, found 305.1; Anal. Calc. for C20H16O3 (%): C, 78.93; H, 5.30.
Found: C, 78.94; H, 5.27.
solid. Yield 20%; m.p.: 96e98 ꢀC; 1H NMR (300 MHz, CDCl3)
d 3.84
(s, 3H, OCH3), 5.05 (s, 2H, OCH2Ph), 6.48e6.49 (d, 1H, Ar, J ¼ 2.4 Hz),
6.58e6.62 (dd, 1H, ArH, J ¼ 8.7 Hz, 2.7 Hz), 6.988e6.934 (dd, 2H,

884
J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
5.1.4. General procedure for the synthesis of 2-(4-methoxyphenyl)
benzofuran-6-ol (5b)
and methanesulfonyl chloride (0.37 mL, 4.65 mmol) in CH2Cl2 was
added dropwise. The reaction was maintained at r.t for another 1 h
after the addition. The reaction mixture was quenched with 1 N
HCl, extracted with dichloromethane (20 mL ꢂ 3). The combined
organic layer was washed with brine, dried with anhydrous sodium
sulphate, concentrated under vacuum, then purified by flash
chromatography (petroleum ether: ethyl acetate ¼ 3:1) to afford
a colorless solid. Yield 80.2%; m.p.: 86e88 ꢀC; 1H NMR (300 MHz,
6-(benzyloxy)-2-(4-methoxyphenyl)benzofuran (4b) (50 mg,
0.15 mmol) was dissolved in CH2Cl2 (10 mL) and TiCl4 (21.8 uL,
0.20 mmol) was added to the solution slowly at r.t and the mixture
was stirred until 4b was consumed. The reaction mixture was
quenched by methanol and condensed at vacuum, then the residue
was subjected to flash chromatography (petroleum ether: ethyl
acetate ¼ 5:1) to get a colorless solid. Yield 63%; m.p.: 155e157 ꢀC;
CDCl3)
d 2.365 (s, 3H, CH3), 2.935e2.978 (m, 5H, CH2CH2, CH3),
1H NMR (300 MHz, CDCl3)
d
3.968 (s, 3H, OCH3), 4.94 (brs, 1H, OH),
4.509e4.553 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 7.423e7.446 (m, 3H, ArH),
6.854e6.878 (d, 1H, ArH, J ¼ 7.2 Hz), 6.914 (s, 1H, CH), 7.060e7.104
7.957e7.990 (m, 2H, ArH); EI-MS m/z: 282.1.
(m, 3H, ArH), 7.470e7.498 (d, 1H, ArH, J ¼ 8.4 Hz), 7.836e7.864 (d,
2H, ArH, J ¼ 8.4 Hz); 13C NMR (125 MHz, CDCl3)
d
159.6,155.4,153.2,
5.1.8. General procedure for the synthesis of 4-(2-(2-(4-
methoxyphenyl) benzofuran-6-yloxy) ethyl)-5-methyl-2-
phenyloxazole (6b)
128.6, 126.0, 123.5, 120.7, 114.2, 111.8, 99.4, 98.2, 55.3; HRMS [ESI
(þ)-MS]: C15H12O3 [M þ H]þ m/z, calc. 240.1, found 241.1; Anal. Calc.
for C15H12O3 (%): C, 74.99; H, 5.03. Found: C, 75.02; H, 5.01.
To a solution of 2-(5-methyl-2-phenyloxazol-4-yl) ethyl meth-
anesulfonate (11) (690 mg, 2.45 mmol) and 2-(4-methoxyphenyl)
benzofuran-6-ol (5b) (588.2 mg, 2.45 mmol) in acetonitrile (20 mL),
was added K2CO3 (675.8 mg, 4.9 mmol) in portions. The reaction
mixture was refluxed overnight, quenched with 1 N NaOH, extracted
with ethyl acetate. The combined organic layer was washed with
brine, dried with anhydrous sodium sulphate, concentrated under
vacuum, then purified by flash chromatography (petroleum ether:
ethyl acetate ¼ 5:1) to afford a yellow solid. Yield 50%; m.p.:
5.1.4.1. 2-phenylbenzofuran-6-ol (5a). Compound 5a (0.65 g, 90%)
as a red solid; m.p.: 86e88 ꢀC; 1H NMR (300 MHz, CDCl3)
d 4.5e5.0
(brs, 1H, OH), 6.957e7.025 (m, 2H, ArH), 7.269e7.302 (m, 1H, ArH),
7.405e7.441 (m, 5H, ArH), 7.839 (s, 1H, CH); 13C NMR (125 MHz,
CDCl3)
d 157.0, 156.9, 155.0, 130.3, 129.2, 128.7, 125.2, 122.3, 121.9,
112.9, 102.7, 97.9; HRMS [ESI (þ)-MS]: C14H10O2 [M þ H2O]þ m/z,
calc. 210.1, found 229.0; Anal. Calc. for C14H10O2 (%): C, 79.98; H,
4.79. Found: C, 79.94; H, 4.81.
76e78 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.415 (s, 3H, CH3),
3.065e3.021 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 3.852 (s, 3H, OCH3),
4.334e4.292 (t, 2H, CH2CH2, J ¼ 6.3 Hz), 6.802 (s, 1H, CH),
6.830e6.859 (d, 1H, ArH, J ¼ 8.7 Hz), 6.951e6.980 (d, 2H, ArH,
J ¼ 8.7 Hz), 7.065 (s, 1H, ArH), 7.353e7.447 (m, 4H, ArH), 7.723e7.748
(d, 2H, ArH, J ¼ 7.5 Hz), 8.001e8.025 (m, 2H, ArH); 13C NMR (125 MHz,
5.1.4.2. 2-(5-methylfuran-2-yl) benzofuran-6-ol (5c). Compound 5c
(21 mg, 31.8%) as a solid; m.p.: 112e114 ꢀC; 1H NMR (300 MHz,
CDCl3)
d
2.478 (s, 3H, CH3), 6.864e6.893 (d, 1H, CHCH, J ¼ 8.7 Hz),
6.955e6.984 (d,1H, CHCH, J ¼ 8.7 Hz), 7.066 (s,1H, CH), 7.523 (s,1H,
ArH), 7.872e7.892 (m, 2H, ArH), 9.843 (brs, 1H, OH); 13C NMR
CDCl3)
d 159.6, 156.6, 155.6, 128.8, 126.3, 125.9, 120.5, 114.2, 112.0,
(125 MHz, CDCl3)
d
155.3, 153.5, 152.8, 128.6, 126.4, 122.5, 120.9,
99.4, 96.8, 67.1, 55.3, 29.7, 10.3; HRMS [ESI (þ)-MS]: C27H23NO4
[M þ H]þ m/z, calc. 425.2, found 426.1; Anal. Calc. for C27H23NO4 (%):
C, 76.22; H, 5.45; N, 3.29. Found: C, 76.25; H, 5.48; N, 3.32.
112.1, 107.9, 99.9, 98.2, 13.7; HRMS [ESI (þ)-MS]: C13H10O3 [M þ H]þ
m/z, calc. 214.1, found 215.0; Anal. Calc. for C13H10O3 (%): C, 72.89; H,
4.71. Found: C, 72.88; H, 4.75.
5.1.8.1. 5-methyl-2-phenyl-4-(2-(2-phenylbenzofuran-6-yloxy) ethyl)
5.1.5. Methyl 2-(5-methyl-2-phenyloxazol-4-yl) acetate (9)
oxazole (6a). Compound 6a (587 mg, 48.1%) as a yellow solid; 1H
The methyl 4-bromo-3-oxopentanoate (10 g, 45 mmol) was
dissolved in toluene (200 mL), and then benzamide (5.45 g,
45 mmol) was added in portions. The reaction mixture was refluxed
overnight. The resulting solid was filtered off and the filtrate was
concentrated in vacuum and subjected to flash chromatography
(petroleum ether: ethyl acetate ¼ 10:1) to get a yellow oil. Yield
NMR (300 MHz, CDCl3) d 2.420 (s, 3H, CH3), 3.010e3.054 (t, 2H,
CH2CH2, J ¼ 6.6 Hz), 4.277e4.321 (t, 3H, CH2CH2, J ¼ 6.6 Hz), 6.818
(s, 1H, ArH), 6.872e6.890 (m, 2H, ArH), 6.950 (s, 1H, CH),
7.088e7.433 (m, 10H, ArH); 13C NMR (125 MHz, CDCl3)
d 159.5,
157.1, 155.8, 145.1, 139.3, 132.9, 129.8, 128.7, 126.5, 124.4, 120.9,
112.4, 101.1, 96.8, 67.2, 26.3, 10.3; HRMS [ESI (þ)-MS]: C26H21NO3
[M þ H]þ m/z, calc. 395.2, found 396.0; Anal. Calc. for C26H21NO3
(%): C, 78.97; H, 5.35; N, 3.54. Found: C, 78.94; H, 5.37; N, 3.50.
40%; 1H NMR (300 MHz, (CD3)2CO)
d 2.378 (s, 3H, CH3), 3.587 (s, 2H,
CH2), 3.665 (s, 3H, OCH3), 7.473e7.499 (m, 3H, ArH), 7.950e7.982
(m, 2H, ArH); EI-MS m/z: 246.01.
5.1.8.2. 5-methyl-4-(2-(2-(5-methylfuran-2-yl) benzofuran-6-yloxy)
5.1.6. 2-(5-methyl-2-phenyloxazol-4-yl) ethanol (10)
ethyl)-2-phenyl-oxazole (6c). Compound 6c (235 mg, 66.3%) as
A solution of Methyl 2-(5-methyl-2-phenyloxazol-4-yl) acetate
(9) (890 mg, 3.63 mmol) in diethyl ether (15 mL) was added to ice-
cooled suspension of lithium aluminum hydride (207.1 mg,
5.45 mmol) in diethyl ether (20 mL). The mixture was stirred at r.t
for 30 min, and then quenched with water. The resulting solid was
filtered off and the filtrate was concentrated in vacuum to get
a colorless solid. Yield 96%; m.p.: 68e70 ꢀC; 1H NMR (300 MHz,
a yellow solid; m.p.: 90e92 ꢀC; 1H NMR(300 MHz, CDCl3)
d 2.058 (s,
3H, CH3), 2.389 (s, 3H, CH3), 3.014e3.058 (t, 2H, CH2CH2, J ¼ 6.6 Hz),
4.283e4.327 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 6.089e6.097 (d, 1H, CHCH,
J ¼ 2.4 Hz), 6.602e6.613 (d, 1H, CHCH, J ¼ 3.3 Hz), 6.749 (s, 1H, CH),
6.868e6.875 (d, 1H, ArH, J ¼ 2.1 Hz), 7.050e7.054 (d, 1H, ArH,
J ¼ 1.2 Hz), 7.270e7.292 (m, 2H, ArH), 7.431e7.450 (m, 3H, ArH),
7.998e8.030 (m, 2H, ArH); 13C NMR (125 MHz, CDCl3)
d 159.3, 156.1,
CDCl3)
d
2.347 (s, 3H, CH3), 2.754e2.792 (t, 2H, CH2CH2, J ¼ 5.7 Hz),
154.4, 151.4, 138.1, 130.6, 129.2, 125.4, 120.9, 111.4, 102.7, 96.4, 67.1,
24.3, 13.1, 10.5; HRMS [ESI (þ)-MS]: C25H21NO4 [M þ H]þ m/z, calc.
399.2, found 400.1; Anal. Calc. for C25H21NO4 (%): C, 75.17; H, 5.30;
N, 3.51. Found: C, 75.20; H, 5.31; N, 3.47.
3.924e3.963 (t, 2H, CH2CH2, J ¼ 5.8 Hz), 6.0e6.5 (brs, 1H, OH),
7.431e7.450 (m, 3H, ArH), 7.989e8.021 (m, 2H, ArH); EI-MS m/z:
204.1.
5.1.7. 2-(5-methyl-2-phenyloxazol-4-yl) ethyl methanesulfonate
(11)
To a solution of 2-(5-methyl-2-phenyloxazol-4-yl) ethanol (10)
(630 mg, 3.1 mmol) in CH2Cl2 (15 mL), triethylamine (0.64 mL,
4.65 mmol) was added dropwise. The mixture was cooled to 0 ꢀC,
5.1.9. General procedure for the synthesis of 1-(2-(4-
methoxyphenyl)-6-(2-(5-methyl-2-phenyloxazol–4-yl) ethoxy)
benzofuran-3-yl) ethanone (7b)
To a solution of 4-(2-(2-(4-methoxyphenyl) benzofuran-6-
yloxy) ethyl)-5-Methyl-2-phenyloxazole (6b) (50 mg, 0.12 mmol)

J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
885
and acetyl chloride (12.7 uL, 0.18 mmol) in CH2Cl2 (10 mL), was
added SnCl4 (17.1 uL, 0.144 mmol) slowly. The mixture was stirred
at r.t for 12 h, quenched with water, and extracted with ethyl
acetate. The combined organic layer was washed with brine, dried
with anhydrous sodium sulphate, concentrated under vacuum,
then purified by flash chromatography (petroleum ether: ethyl
acetate ¼ 3:1) to afford a yellow solid. Yield 51%; m.p.: 60e62 ꢀC; 1H
6.947e6.658 (d, 1H, CHCH, J ¼ 3.3 Hz), 7.039e7.061 (d, 2H, ArH,
J ¼ 6.6 Hz), 7.137e7.144 (d, 1H, ArH, J ¼ 2.1 Hz), 7.147e7.159 (d, 1H,
ArH, J ¼ 3.6 Hz), 7.393e7.402 (m, 5H, ArH), 7.834 (s, 1H, ArH),
7.997e8.010 (m, 2H, ArH); 13C NMR (125 MHz, CDCl3)
d 190.7, 164.4,
159.3, 155.7, 154.4, 152.2, 138.1, 134.9, 130.6, 127.5, 125.4, 121.5,
109.8, 107.6, 96.4, 67.1, 24.3, 13.1, 10.5; HRMS [ESI (þ)-MS]:
C33H24F3NO5 [M þ H]þ m/z, calc. 571.2, found 572.1; Anal. Calc. for
C33H24F3NO5 (%): C, 69.35; H, 4.23; N, 2.45. Found: C, 69.39; H, 4.25;
N, 2.44.
NMR (300 MHz, CDCl3)
d 2.051 (s, 3H, CH3), 2.415 (s, 3H, CH3),
3.065e3.021 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 3.852 (s, 3H, OCH3),
4.334e4.292 (t, 2H, CH2CH2, J ¼ 6.3 Hz), 6.830e6.859 (d, 1H, ArH,
J ¼ 8.7 Hz), 6.951e6.980 (d, 2H, ArH, J ¼ 8.7 Hz), 7.065 (s, 1H, ArH),
7.353e7.447 (m, 4H, ArH), 7.723e7.748 (d, 2H, ArH, J ¼ 7.5 Hz),
5.1.9.5. (6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-(5-methyl-
furan-2-yl)-benzoFuran-3-yl) (3, 4, 5-trimethoxyphenyl) meth-
anone (7e). Compound 7e (26 mg, 34.9%) as a yellow solid; m.p.:
8.001e8.025 (m, 2H, ArH); 13C NMR (125 MHz, CDCl3)
d 193.9,
159.5, 157.5, 149.7, 145.0, 143.0, 131.1, 128.6, 125.9, 122.4, 114.0, 96.4,
67.2, 55.4, 30.3, 26.3, 10.3; HRMS [ESI (þ)-MS]: C29H25NO5 [M þ H]þ
m/z, calc. 467.2, found 468.1; Anal. Calc. for C29H25NO5 (%): C, 74.50;
H, 5.39; N, 3.00. Found: C, 74.53; H, 5.40; N, 3.01.
92e94 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.056 (s, 3H, CH3), 2.436 (s,
3H, CH3), 3.075e3.119 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 3.993 (s, 9H,
3OCH3), 4.223e4.367 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 6.863e6.874 (d,
1H, CHCH, J ¼ 3.3 Hz), 6.892e6.912 (d, 1H, CHCH, J ¼ 2.4 Hz),
7.102e7.116 (m, 3H, ArH), 7.378e7.462 (m, 3H, ArH), 7.463e7.472
5.1.9.1. 1-(6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-(5-methyl-
furan-2-yl)-benzo-furan-3-yl) ethanone (7a). Compound 7a (18 mg,
32.5%) as a yellow solid; m.p.: 68e70 ꢀC; 1H NMR (300 MHz, CDCl3)
(m, 2H, ArH); 13C NMR (125 MHz, CDCl3)
d 189.9, 170.5, 159.7,
157.5, 154.5, 152.9, 148.9, 142.9, 134.0, 129.0, 128.1, 126.6, 124.1,
121.9, 114.0, 107.4, 96.5, 60.9, 56.2, 29.7, 13.5, 10.3; HRMS [ESI
(þ)-MS]: C35H31NO8 [M þ H]þ m/z, calc. 593.2, found 594.0; Anal.
Calc. for C35H31NO8 (%): C, 70.82; H, 5.26; N, 2.36. Found: C, 70.86;
H, 5.27; N, 2.40.
d
2.413 (s, 3H, CH3), 2.453 (s, 3H, CH3), 2.677 (s, 3H, CH3),
3.029e3.073 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 4.298e4.342 (t, 2H,
CH2CH2, J ¼ 6.6 Hz), 6.213e6.224 (d, 1H, CHCH, J ¼ 3.3 Hz),
6.947e6.658 (d, 1H, CHCH, J ¼ 3.3 Hz), 7.137e7.144 (d, 1H, ArH,
J ¼ 2.1 Hz), 7.147e7.159 (d, 1H, ArH, J ¼ 3.6 Hz), 7.430e7.485 (m, 3H,
ArH),7.834 (s, 1H, ArH), 8.003e8.024 (m, 2H, ArH); 13C NMR
5.1.10. (E)-1-(2-(4-methoxyphenyl)-6-(2-(5-methyl-2-
phenyloxazol-4-yl)ethoxy)-benzo-furan-3-yl)-3-(3, 4, 5-
(125 MHz, CDCl3)
d
193.9, 159.5, 157.6, 155.2, 149.7, 145.0, 143.0,
trimethoxyphenyl) prop-2-en-1-one (13)
132.5, 129.8, 128.6, 125.9, 122.1, 116.5, 113.4, 108.7, 96.6, 67.2, 31.1,
26.3,13.9,10.2; HRMS [ESI (þ)-MS]: C27H23NO5 [M þ H]þ m/z, calc.
441.2, found 442.1; Anal. Calc. for C27H23NO5 (%): C, 73.46; H, 5.25;
N, 3.17. Found: C, 73.50; H, 5.24; N, 3.21.
To a solution of 1-(2-(4-methoxyphenyl)-6-(2-(5-methyl-2-
phenyloxazol-4-yl) ethoxy) benzofuran-3-yl) ethanone (7b)
(28 mg, 0.059 mmol) and 3, 4, 5-trimethoxybenzaldehyde (12 mg,
0.059 mmol) in methanol (15 mL), was added potassium hydroxide
(6.6 mg, 0.118 mmol). The reaction mixture was refluxed for 12 h.
The reaction mixture was quenched with 1 N HCl to PH ¼ 1, then
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried with anhydrous sodium sulphate, concentrated
and purified by flash chromatography (petroleum ether: ethyl
acetate ¼ 3:1) to afford a solid. Yield 25%; m.p.: 62e64 ꢀC; 1H NMR
5.1.9.2. 1-(6-hydroxy-2-(5-methylfuran-2-yl) benzofuran-3-yl) etha-
none (12). Compound 12 (30 mg, 32.5%) as a yellow solid; m.p.:
88e90 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.345 (s, 3H, CH3), 2.468 (s,
3H, CH3), 6.232e6.240 (d, 1H, CHCH, J ¼ 2.4 Hz), 7.068e7.075 (d,
1H, CHCH, J ¼ 2.1 Hz), 7.317e7.324 (d, 1H, ArH, J ¼ 2.1 Hz),
7.510e7.521 (d, 1H, ArH, J ¼ 3.3 Hz), 7.940e7.969 (d, 1H, ArH,
(300 MHz, CDCl3) d 2.586 (s, 3H, CH3), 3.035e3.079 (d, 2H, CH2CH2,
J ¼ 8.7 Hz); 13C NMR (125 MHz, CDCl3)
d
193.7, 169.4, 155.8, 153.3,
J ¼ 6.6 Hz), 3.853 (s, 12H, 4OCH3), 4.428e0.472 (d, 2H, CH2CH2,
J ¼ 6.6 Hz), 6.510 (s, 1H, ArH), 6.809e6.861 (d, 1H, CH ¼ CH,
J ¼ 15.6 Hz), 7.003e7.107 (m, 5H, ArH), 7.429e7.443 (m, 2H, ArH),
7.654e7.743 (m, 4H, ArH), 7.992e8.021 (m, 2H, ArH); 13C NMR
151.1, 148.4, 142.7, 122.1, 118.3, 117.4, 108.8, 105.1, 31.1, 21.1, 13.9;
HRMS [ESI (þ)-MS]: C15H12O4 [M þ H]þ m/z, calc. 256.1, found
257.1; Anal. Calc. for C15H12O4 (%): C, 70.31; H, 4.72. Found: C,
70.27; H, 4.75.
(125 MHz, CDCl3)
d 189.9, 170.5, 159.7, 157.5, 154.5, 148.9, 145.1,
134.0, 129.0, 128.1, 126.6, 124.1, 121.9, 114.0, 107.4, 96.5, 60.9, 56.2,
29.7,10.3; HRMS [ESI (þ)-MS]: C39H35NO8 [M þ H]þ m/z, calc. 645.2,
found 646.1; Anal. Calc. for C39H35NO8 (%): C, 72.54; H, 5.46; N, 2.17.
Found: C, 72.57; H, 5.43; N, 2.20.
5.1.9.3. Furan-2-yl (6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-
(5-methylfuran-2-yl)- - benzofuran-3-yl) methanone (7c). Compound
7c (18 mg, 35.5%) as a yellow solid; m.p.: 72e74 ꢀC; 1H NMR
(300 MHz, CDCl3)
d 2.345 (s, 3H, CH3), 2.436 (s, 3H, CH3),
3.075e3.119 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 4.223e4.367 (t, 2H,
CH2CH2, J ¼ 6.6 Hz), 6.863e6.874 (d, 2H, 2CHCH, J ¼ 3.3 Hz),
6.892e6.912 (d, 2H, 2CHCH, J ¼ 2.4 Hz), 7.102e7.116 (m, 3H, ArH),
7.378e7.462 (m, 3H, ArH), 7.463e7.472 (m, 2H, ArH), 7.86 (s, 1H,
5.1.11. 6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-
phenylbenzofuran-3-carbalde-hyde (14)
Phosphorus oxychloride (94.9 uL, 1.04 mmol) and catalytic
amount DMF (80.8 uL, 1.04 mmol) was added in CH2Cl2 (10 mL),
CH); 13C NMR (125 MHz, CDCl3)
d
164.4, 161.7, 159.3, 155.7, 152.2,
then
5-methyl-2-phenyl-4-(2-(2-phenylbenzofuran-6-yloxy)
147.1, 138.1, 130.6, 129.2, 127.5, 112.6, 109.8, 107.6, 96.4, 67.1, 24.3,
13.1, 10.5; HRMS [ESI (þ)-MS]: C30H23NO6 [M þ H]þ m/z, calc. 493.2,
found 494.2; Anal. Calc. for C30H23NO6 (%): C, 73.01; H, 4.70; N, 2.84.
Found: C, 73.04; H, 4.68; N, 2.85.
ethyl) oxazole (50 mg, 0.13 mmol) in CH2Cl2 were added dropwise.
The resulting mixture was refluxed for 12 h. The mixture was
poured on ice, and then extracted with CH2Cl2. The combined
organic layer was washed with brine and saturated sodium bicar-
bonate solution, dried with anhydrous sodium sulphate. The
mixture was concentrated and purified by flash chromatography
(petroleum ether: ethyl acetate ¼ 5:1) to afford a solid. Yield 37%;
5.1.9.4. (6-(2-(5-methyl-2-phenyloxazol-4-yl) ethoxy)-2-(5-methyl-
furan-2-yl)-benzofuran-3-yl) (4-(trifluoromethyl) phenyl) meth-
anone (7d). Compound 7d (10 mg, 13.9%) as a yellow solid; m.p.:
m.p.: 88e90 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.417 (s, 3H, CH3),
60e62 ꢀC; 1H NMR (300 MHz, CDCl3)
d
2.287 (s, 3H, CH3), 2.265 (s,
3.020e3.064 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 4.317e4.361 (t, 2H,
CH2CH2, J ¼ 6.6 Hz), 7.174e8.137 (m, 13H, ArH), 10.312 (s, 1H, CHO);
EI-MS m/z: 424.0.
3H, CH3), 2.967e3.011 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 4.253e4.297 (t,
2H, CH2CH2, J ¼ 6.6 Hz), 6.213e6.224 (d, 1H, CHCH, J ¼ 3.3 Hz),

886
J. Liu et al. / European Journal of Medicinal Chemistry 54 (2012) 879e886
5.1.12. (E)-3, 4, 5-trimethoxy-N-((6-(2-(5-methyl-2-phenyloxazol-
4-yl) ethoxy)-2-phenyl-benzofuran-3-yl) methylene) aniline (15)
The mixture of 6-(2-(5-methyl-2-phenyloxazol-4-yl) ethoxy)-2-
phenylbenzofuran-3-carbaldehyde (14) (50 mg, 0.118 mmol) and
3,4,5-trimethoxyaniline (21.6 mg, 0.118 mmol) in CH2Cl2 was
refluxed for 12 h. The reaction mixture was concentrated at
vacuum, and purified by flash chromatography (petroleum ether:
ethyl acetate ¼ 5:1) to afford a yellow solid. Yield 33%; m.p.:
Acknowledgments
We thank the National Comprehensive Technology Platforms
for Innovative Drug R&D (2009ZX09301-007) and Special
Research Fund to Doctoral Program of College and University
(20110073120081) for the financial support. We thank Professor
Xiaobo Li’s Laboratory (Shanghai Jiao Tong University) for the bio-
logical support of this research.
108e110 ꢀC; 1H NMR (300 MHz, CDCl3)
d 2.416 (s, 3H, CH3),
3.022e3.067 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 3.906 (s, 9H, 3OCH3),
4.327e4.371 (t, 2H, CH2CH2, J ¼ 6.6 Hz), 6.462e6.497 (d, 2H, ArH,
J ¼ 10.5 Hz), 6.982 (s, 1H, ArH), 6.989e7.145 (m, 2H, ArH),
7.425e7.505 (m, 6H, ArH), 7.751e7.769 (m, 2H, ArH), 7.990e8.011
(m, 2H, ArH), 8.784 (s, 1H, CH ¼ N); 13C NMR (125 MHz, CDCl3)
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d
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(catalytic amount). The reaction mixture was stirred at r.t for 12 h.
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d
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The assay was developed according to our published proce-
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inhibit the visible growth of the organism is considered as MIC80
value.