Synthesis of 2-phenylbenzofuran derivatives and selective binding activities on estrogen receptor

Article abstract of DOI:10.1248/cpb.60.270

An improved chemical reaction protocol with short time and easy work-up was described here for 2-phenylbenzofuran derivatives. The final purified products, 2-phenylbenzofuran derivatives 5a-g and the intermediate diols 4a-g, were evaluated for their estrogen receptor (ER) binding affinity and selective activity in vitro. Among these fourteen tested compounds, 4g and 5g showed higher binding affinity on ER subtypes, ERα and ERβ. Compound 4g exhibited preferable ERα binding, while 5g was more estrogen selective for ERβ. The molecular docking was also performed to explore the detailed interactive interface between ER and the compounds.

Full text of DOI:10.1248/cpb.60.270

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270
Note
Chem. Pharm. Bull. 60(2) 270 274 (2012)
Vol. 60, No. 2
Synthesis of 2-Phenylbenzofuran Derivatives and Selective Binding
Activities on Estrogen Receptor
Ping Zhang,a Yewei Yang,a Xiaoliang Zheng,b Wenhai Huang,a,c Zhen Ma,a and
,a
Zhengrong Shen*
a Institute of Materia Medica, Zhejiang Academy of Medical Sciences; b Center for Translational Molecular Medicine,
Zhejiang Academy of Medical Sciences; Hangzhou 310013, China: and c ZJU-ENS Joint Laboratory of Medicinal
Chemistry, Zhejiang University; Zijingang Campus, Hangzhou 310058, China.
Received October 18, 2011; accepted November 25, 2011; published online November 30, 2011
An improved chemical reaction protocol with short time and easy work-up was described here for
—
2-phenylbenzofuran derivatives. The final purified products, 2-phenylbenzofuran derivatives 5a g and the
—
intermediate diols 4a g, were evaluated for their estrogen receptor (ER) binding affinity and selective activ-
ity in vitro. Among these fourteen tested compounds, 4g and 5g showed higher binding affinity on ER sub-
types, ERα and ERβ. Compound 4g exhibited preferable ERα binding, while 5g was more estrogen selective
for ERβ. The molecular docking was also performed to explore the detailed interactive interface between ER
and the compounds.
Key words 2-phenylbenzofuran; diol; estrogen receptor; binding affinity; selectivity
2-Phenylbenzofuran compounds, a very important family pounds with ER.
of heterocycles, are widely found in natural products. Due to
their effective pharmacological activities, these compounds
Results and Discussion
Chemistry As shown in Chart 1, 3-phenylcoumarin 3
—
5)
have been extensively studied.1 A literature survey revealed
that most 2-phenylbenzofurans with hydroxy and methoxy was first synthesized by the Perkin reaction of hydroxyl-
groups demonstrated multi-bioactivities, including antitu- ated benzaldehyde 1 with phenylacatic acid derivative 2,
—
10)
mor,6,7) anti-microbial,8
antivirus,11) adenosine A1 receptor then reduced into 2-(3-hydroxy-propenyl)-phenol 4 with di-
antagonists12,13) and immunosuppressant properties.14) In recent isobutylaluminium hydride (DIBAL-H). Compound 4 was
years, it is found that 2-phenylbenzofurans have significant finally cyclized into 2-phenylbenzofurans 5 in the presence
binding affinity and selectivity on estrogen receptor (ER)β.15) of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) at reflux
Here, we reported an improved synthetic method for 2-phenyl- temperature. Comparing to the method reported,16) the proce-
—
—
benzofurans 5a g from 3-phenylcoumarins 3a g. After dure was modified by using DIBAL-H, a more easily-handled
purification, these compounds were evaluated for ER binding material,17) as the reducing agent in stead of using aluminum
affinity and selectivity in vitro. Moreover, we described the chloride (AlCl3) and lithium aluminium hydride (LiAlH4).
preliminary structure–activity relationship (SAR) and carried In addition, toluene was used as the solvent of cyclization in
out molecular docking study for the interactions of these com- stead of using toxic reagent such as benzene. In this study, the
—
°
—
Reagents and conditions: (a) anhydrous CH3COOK, Ac2O, reflux, 4h, 50 60% yield; (b) DIBAL-H (1.1M solution in cyclohexane), dry CH2Cl2, 20 C, 3h, 67
—
96% yield; (c) DDQ, dry toluene, reflux, 3h, 40 60% yield.
—
—
g
Chart 1. Synthesis of Compounds 4a g and 5a
*To whom correspondence should be addressed. e-mail: shenzr601@163.com
© 2012 The Pharmaceutical Society of Japan

February 2012
271
—
Table 1. Reactions of 3-Phenylcoumarins with DDQ for the Synthesis of 2-Phenylbenzofuran Derivatives 5a
g
Entry
R1
R2
R3
Yield of 4 (%)a)
Yield of 5 (%)a)
1
2
3
4
5
6
7
H
OCH3
H
OCH3
OCH3
OCH3
OCH3
Br
H
H
4a, 96
4b, 89
4c, 71
4d, 67
4e, 93
4f, 87
4g, 79
5a, 60
5b, 65
5c, 40
5d, 58
5e, 57
5f, 48
5g, 54
OCH3
OCH3
H
OCH3
H
OCH3
H
Br
H
OH
H
a) Isolated yields.
Table 2. Relative Binding Affinity and Selectivity of Compounds 4g and 5g for ERα and ERβ
IC50 for ERα
(μM)a)
RBAb) for ERα
IC50 for ERβ
(μM)
RBA for ERβ
Compound
RBA ERα/ERβc)
RBA ERβ/ERαd)
(%)
(%)
17β-Estradiol
0.019 0.007
0.553 0.129
>10.00
>10.00
>10.00
>10.00
>10.00
>10.00
1.351 1.007
100.00
0.004 0.001
0.224 0.072
>10.00
>10.00
>10.00
>10.00
>10.00
>10.00
1.004 0.103
100.00
1.00
2.0
—
—
—
—
—
—
4.7
—
—
—
—
—
—
0.5
1.00
0.5
—
—
—
—
—
—
0.2
—
—
—
—
—
—
2.2
Tamoxifen
3.73 0.51
1.90 0.63
e)
—
—
4a
4b
4c
4d
4e
4f
—
—
—
—
—
—
—
—
—
—
4g
5a
5b
5c
5d
5e
5f
1.86 0.66
0.40 0.08
—
—
>10.00
>10.00
>10.00
>10.00
>10.00
>10.00
2.805 0.280
>10.00
>10.00
>10.00
>10.00
>10.00
>10.00
0.360 0.040
—
—
—
—
—
—
—
—
—
—
5g
0.50 0.06
1.11 0.23
a) The values given are the average S.D. of three experiments. b) RBA (relative binding affinity)=(IC50 17β-estradiol/IC50 test compound)×100. c) RBA ERα/
ERβ=RBAα/RBAβ. d) RBA ERβ/ERα=RBAβ/RBAα. e) Not determined.
lactone ring opening took place in a stereoselective manner, or ERβ with IC50≥10.0μM. Interestingly, we found that both
the diol 4a with a (Z)-configuration was obtained as the only 4g and 5g demonstrated higher binding affinity for ERα and
reaction product confirmed by H–H nuclear Overhauser effect ERβ. Compared to Tamoxifen, 4g showed 5-fold more selec-
spectroscopy (NOESY) spectrum.18) The products 5a g and tivity for ERα while 5g was about 2-fold higher ERβ selectiv-
—
—
the intermediate diols 4a g were characterized by spectro- ity, although the overall binding affinity was decreased.
scopic analyses which were collected in the experimental part. In an attempt to understand the molecular interaction be-
Estrogen Receptor Binding Affinity The binding affin- tween synthesized compounds and ER, the molecular dock-
—
ity of this series of 2-phenylbenzofurans 5a g on ER was ing study was performed using the Discovery Studio 2.1/
determined by fluorescence polarization technology. The bind- Flexible Docking protocol with published crystal structure
ing affinity is normalized as relative binding affinity (RBA) of E2/ERα complex (PDB ID:1A52) or E2/ERβ complex
using estradiol as reference with 100% affinity. We focus on (PDB ID:3OLS), respectively. Based on methods within
the diols 4 that have a stilbene skeleton. Stilbenes, an im- CHARMm to sample side-chain and ligand conformations,
portant phytoestrogen, exhibit estrogen activity. The stilbene the side-chains of amino acids in the ligand-binding domain
skeleton is one of the important structures to construct the (LBD) were allowed to move during docking in an induced-
—
22)
selective estrogen receptor modulators (SERMs).19
For fit model. During the docking and subsequent scoring, all the
example, Tamoxifen and Raloxifen, which are usually applied parameters were remained the default setting except the Best
in clinic as SERMs, have a conjugated stilbene skeleton in Conformation Method for the Generate Ligand Conformations.
their structures. In addition, our previous studies of resvera-
As seen in Fig. 1, the phenolic hydroxy of 4g formed three
trol analogues also indicated that all these compounds with a hydrogen bonds with ERα Glu353 and Arg394 (Fig. 1a). The phe-
conjugated stilbene skeleton possessed a certain estrogen-like nolic hydroxy of 5g formed a hydrogen bonding network with
activity.23) Therefore, in this study we selected seven new diols ERα Glu353, Arg394 and a water molecule (Fig. 1b). In contrast,
—
4a g as the test compounds for ER binding affinity study. 4a or 5a, lacking the phenolic hydroxy, formed only one hy-
Tamoxifen was used as the positive control. As indicated in drogen bond with ERα residues (Figs. 1c, d). This observation
Table 2, 17β-estradiol (E2), the known ER ligand, binds to could explain the significant ER binding affinity for 4g and 5g,
both ERα and ERβ equally well. Tamoxifen is more selective hence elucidate the importance of the phenol functionality in
—
—
binding to ERα. Compounds 4a f and 5a f with methoxy terms of hydrogen bonding. Since the ligand binding pockets
or halogen substituents appeared no binding affinity for ERα of ERα and ERβ are highly conserved,24,25) the binding mode

272
Vol. 60, No. 2
Fig. 1. The Binding Patterns of 4g (a), 5g (b), 4a (c) and 5a (d) into ERα
Only key residues are shown for simplicity. Hydrogen binds to key residues are shown as dotted lines.
of these compounds with ERβ was similar to that of ERα (the two compounds could be served as promising structural leads
docking models of ERβ-ligand were not shown). In addition, for future study of novel ER subtype-selective ligands.
compounds 4g and 5g exhibited similar binding free energy
Δ
Δ
( G4g=−68.59kcal/mol, G5g=−72.86kcal/mol). Replacement
Experimental
General All reactions were carried out using oven-dried
of the phenolic hydroxy by a methoxy group, however, re-
sulted in a significant decrease for 4a and 5a in binding free glassware. The starting materials and reagents were obtained
Δ
Δ
energy ( G4a=−27.91kcal/mol, G5a=−38.96kcal/mol) com- from commercial suppliers without further purification.
Δ
pared to E2 ( GE2=−91.38kcal/mol). This also indicated that Dichloromethane (CH2Cl2) and toluene were distilled from
the phenolic hydroxy groups had a high contribution to the calcium hydride (CaH2) immediately prior to use. All reac-
overall binding.
tions were monitored by TLC with Merck silica gel coated
The study of molecular docking could also provide expla- plates (60F254, Qingdao, China) using UV-light (254nm).
nation of ER subtypes preference for 4g and 5g. The binding Column chromatography was carried out using Silica gel
cavity in ERα-E2 complex had a volume of approximately (HG/T2354-92) purchased from Qingdao. Melting points
255.0Å3 with our docking method. This binding cavity size were determined with an X-4 apparatus and are uncorrected.
was slightly larger than that of ERβ-E2, which had a volume Infrared spectra (IR) were measured on a Bruker Vector22
of 207.1Å3. The result was in accordance with ERβ with a spectrometer. 1H-NMR (400MHz) and 13C-NMR (100MHz)
smaller ligand binding pocket than ERα suggested by Hubbard spectra were recorded on a Bruker Avance spectrometer using
and Katzenellenbogen.24,26,27) The molecule volume of 4g tetramethylsilane (TMS) as internal standard. Chemical shifts
was about 178.0Å3, while 5g was 150.3Å3 by calculation. (δ) are reported in ppm, and coupling constants (J) are in Hz.
Moreover, compound 5g exhibited more planar profile with Mass spectra (electron ionization (EI), 70eV) were recorded
ERβ relative to 4g. These observations could partially explain on an Agilent 5975 inert mass selective detector. High resolu-
that 5g was selective for ERβ while 4g was selective for ERα. tion (HR) mass spectra (EI, 70eV) were obtained by the corre-
sponding service at Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences using a Waters Micromass
In summary, we have developed an efficient and practical GCT apparatus.
Conclusion
protocol for synthesis of 2-phenylbenzofurans from 3-phenyl-
Reduction of 3-Phenylcoumarins to the Corresponding
coumarins, with short reaction time and easy work-up. The ER (Z)-2-(3-Hydroxy-2-phenylpropenyl)phenol
Derivatives
—
binding affinity and selectivity of these synthesized 2-phenyl- (4a g) A solution of 3-phenylcoumarins (2.93mmol) in an-
°
benzofurans and intermediate diols had been evaluated and hydrous CH2Cl2 (8mL) was cooled to −10 C under a nitrogen
a clear SAR was also described. The binding affinities of 4g atmosphere. DIBAL-H (1.1M solution in cyclohexane, 8mL,
and 5g on ER subtypes were significant. While 4g showed a 8.8mmol) was added dropwise over a 40min period, while the
°
preference for ERα, 5g showed a better ERβ selectivity. The reaction temperature was maintained at −10 C. The reaction

February 2012
273
was stirred at 20 C for 3h and checked by TLC. After com- (M++2), 304 (M+), 287, 207, 178, 165, 131, 107. HR-MS (EI)
°
°
pleted, the reaction mixture was allowed to cool to −10 C and Calcd for C15H13O2Br: 304.0099. Found: 304.0100.
quenched by addition of methanol, followed by full quenched
(Z)-2-(2-(4-Bromophenyl)-3-hydroxypropenyl)-5-methoxy-
with dilute hydrochloric acid. The mixture was agitated at phenol (4f): Grayish solid, mp 118 119 C. 1H-NMR
room temperature for 1h and filtered. The filtration was (400MHz, DMSO-d6) δ: 7.53 (4H, s), 7.39 (1H, d, J=8.8Hz),
—
°
—
washed with water and target products were then dried. The 6.94 (1H, s), 6.43 6.41 (2H, m), 4.39 (2H, s), 3.70 (3H, s).
filtrate was extracted with ethyl acetate, and the combined 13C-NMR (100MHz, DMSO-d6) δ: 160.5 (s), 157.2 (s), 141.4
organic phase was washed with water and brine. The solvent (s), 136.9 (s), 131.5 (d), 131.1 (s), 128.7 (d), 126.6 (s), 120.1 (s),
was evaporated in vacuo and separated by column chromatog- 117.0 (s), 104.9 (s), 101.4 (s), 58.8 (s), 55.4 (s). IR (KBr) cm−1:
raphy (petroleum ether/ethyl acetate) on silica gel.
3367, 1610, 1431, 1241, 1074, 1012, 859, 814, 762, 718. MS (EI)
(Z)-2-(3-Hydroxy-2-(4-methoxyphenyl)propenyl)phenol (4a): m/z (%): 336 (M++2), 334 (M+), 317, 161, 137. HR-MS (EI)
1
—
°
White solid, mp 124 125 C. H-NMR (400MHz, DMSO-d6) Calcd for C16H15O3Br: 334.0205. Found: 334.0211.
—
—
δ: 7.57 7.55 (2H, d, J=8.8Hz), 7.46 7.44 (1H, d, J=8.0Hz),
(Z)-2-(2-(4-Hydroxyl)-3-hydroxypropenyl)phenol (4g): Vio-
7.11 (1H, t, J=7.6Hz), 6.94 6.91 (3H, m), 6.87 6.79 (2H, m), lescent solid, mp 161 162 C. 1H-NMR (400MHz, DMSO-
4.42 (2H, s), 3.76 (3H, s). 13C-NMR (100MHz, DMSO-d6) δ: d6) δ: 9.48 (1H, s), 9.42 (1H, s), 7.43 (3H, d, J=8.0Hz), 7.09
—
—
—
°
158.9 (s), 155.8 (s), 139.0 (s), 134.1 (s), 130.4 (s), 128.8 (s), 127.9 (1H, t, J=7.6Hz), 6.84 6.75 (5H, m), 4.38 (2H, s). 13C-NMR
—
(q), 124.6 (s), 119.1 (s), 115.6 (s), 114.0 (d), 58.9 (s), 55.5 (s). IR (100MHz, DMSO-d6) δ: 157.1 (s), 155.8 (s), 139.2 (s), 132.5 (s),
(KBr) cm−1: 3450, 3298, 1602, 1451, 1234, 1002, 827, 757. MS 130.3 (s), 128.7 (s), 127.9 (d), 124.8 (s), 123.8 (s), 119.1 (s), 115.4
(EI) m/z (%): 256 (M+), 237, 225, 165, 121. HR-MS (EI) Calcd (q), 58.9 (s). IR (KBr) cm−1: 3379, 3231, 1608, 1223, 1001, 808,
for C16H16O3: 256.1099. Found: 256.1103.
(Z)-2-(3-Hydroxy-2-(4-methoxyphenyl)propenyl)-5-me- HR-MS (EI) Calcd for C15H14O3: 204.0943. Found: 204.0947.
753. MS (EI) m/z (%): 242 (M+), 223, 165, 131, 107, 73, 57.
thoxyphenol (4b): White solid, mp 128 129 C. 1H-NMR
General Procedure for the Preparation of 2-Phenyl-
—
°
—
(400MHz, DMSO-d6) δ: 7.52 (2H, d, J=8.8Hz), 7.40 (1H, d, benzofurans (5a g) Under a nitrogen atmosphere, a mix-
—
J=8.0Hz), 6.92 (2H, d, J=9.2Hz), 6.84 (1H, s), 6.43 6.41 ture of (Z)-2-(3-hydroxy-2-phenylprop-1-enyl)phenol deriva-
(2H, m), 4.39 (2H, s), 3.75 (3H, s), 3.70 (3H, s). 13C-NMR tives (2mmol), DDQ (3.6mmol) and dry toluene (45mL) was
(100MHz, DMSO-d6) δ: 160.1 (s), 158.7 (s), 156.9 (s), 137.4 refluxed for 3h. The reaction was monitored by TLC. After
(s), 134.5 (s), 1301.0 (s), 127.7 (d), 124.4 (s), 117.5 (s), 114.0 removing the precipitates by filtration, the filtrate was concen-
(d), 104.7 (s), 101.4 (s), 59.1 (s), 55.3 (d). IR (KBr) cm−1: 3494, trated and crystallized from methanol and dried.
3268, 1610, 1432, 1232, 1019, 839, 811. MS (EI) m/z (%): 286
2-(4-Methoxyphenyl)benzofuran (5a): White solid, mp
(M+), 267, 253, 161, 137. HR-MS (EI) Calcd for C17H18O4: 148 149 C. 1H-NMR (400MHz, CDCl3) δ: 7.77 (2H, d,
—
°
— —
J=8.4Hz), 7.54 7.47 (2H, m), 7.23 7.17 (2H, m), 6.95 (2H,
286.1205. Found: 286.1203.
(Z)-2-(2-(3,4-Dimethoxyphenyl)-3-hydroxypropenyl)phenol d, J=8.4Hz), 6.85 (1H, s), 3.82 (3H, s). 13C-NMR (100MHz,
(4c): White solid, mp 154 156 C. 1H-NMR (400MHz, CDCl3) δ: 159.9 (s), 156.0 (s), 154.6 (s), 129.4 (s), 126.3 (d),
—
°
—
DMSO-d6) δ: 7.44 (1H, d, J=7.6Hz), 7.16 7.08 (3H, m), 6.93 123.7 (s), 123.3 (s), 122.7 (s), 120.5 (s), 114.2 (d), 110.9 (s),
(1H, d, J=8.2Hz), 6.88 (1H, s), 6.84 6.78 (2H, m), 4.39 (2H, 99.6 (s), 55.3 (s). IR (KBr) cm−1: 2838, 1608, 1501, 1450, 1245,
—
s), 3.78 (3H, s), 3.75 (3H, s). 13C-NMR (100MHz, DMSO-d6) 1175, 1022, 836, 801, 744. MS (EI) m/z (%): 224 (M+), 209,
δ: 155.8 (s), 148.9 (s), 148.6 (s), 139.2 (s), 134.8 (s), 130.5 (s), 181, 152. HR-MS (EI) Calcd for C15H12O2: 224.0837. Found:
128.9 (s), 125.0 (s), 124.6 (s), 119.2 (s), 119.1 (s), 115.7 (s), 112.0 224.0839.
(s), 110.7 (s), 58.8 (s), 55.9 (d). IR (KBr) cm−1: 3467, 3214,
6-Methoxy-2-(4-methoxyphenyl)benzofuran (5b): White
1598, 1456, 1243, 1004, 897, 860, 803, 762. MS (EI) m/z (%): solid, mp 160 161 C. 1H-NMR (400MHz, CDCl3) δ: 7.74
—
°
286 (M+), 267, 237, 165, 151, 73, 57. HR-MS (EI) Calcd for (2H, d, J=8.8Hz), 7.41 (1H, d, J=8.4Hz), 7.06 (1H, s), 6.96
—
(2H, d, J=8.8Hz), 6.88 6.86 (1H, m), 6.80 (1H, s), 3.86 (3H,
C17H18O4: 286.1205. Found: 286.1207.
(Z)-2-(2-(3,4-Dimethoxyphenyl)-3-hydroxypropenyl)-5- s), 3.84 (3H, s). 13C-NMR (100MHz, CDCl3) δ: 159.6 (s), 157.7
—
°
methoxyphenol (4d): Violescent solid, mp 143 145 C. (s), 155.7 (s), 155.3 (s), 125.9 (d), 123.6 (s), 122.8 (s), 120.6 (s),
1H-NMR (400MHz, DMSO-d6) δ: 7.42 (1H, d, J=8.4Hz), 114.2 (d), 111.6 (s), 99.5 (s), 95.9 (s), 55.7 (s), 55.3 (s). IR (KBr)
cm−1: 2838, 1605, 1505, 1445, 1340, 1250, 1227, 1139, 1019,
—
—
7.17 7.12 (2H, m), 6.95 (1H, d, J=8.4Hz), 6.86 (1H, s), 6.45
6.43 (2H, m), 4.40 (2H, s), 3.80 (3H, s), 3.77 (3H, s), 3.72 (3H, 938, 858, 799, 752. MS (EI) m/z (%): 254 (M+, 100.0), 239
s). 13C-NMR (100MHz, DMSO-d6) δ: 160.1 (s), 156.9 (s), (35.0), 168 (26.7), 139 (28.9). HR-MS (EI) Calcd for C16H14O3:
148.8 (s), 148.5 (s), 137.8 (s), 135.0 (s), 131.0 (s), 124.8 (s), 119.0 254.0943. Found: 254.0946.
(s), 117.5 (s), 112.0 (s), 110.5 (s), 104.8 (s), 101.4 (s), 59.1 (s),
2-(3,4-Dimethoxyphenyl)benzofuran (5c): White solid, mp
1
55.9 (d), 55.3. IR (KBr) cm−1: 3370, 1608, 1458, 1248, 1031, 124 125 C. H-NMR (400MHz, CDCl3) δ: 7.59 7.53 (2H,
—
°
—
849, 814. MS (EI) m/z (%): 316 (M+), 297, 283, 267, 161. HR- m), 7.47 7.44 (1H, m), 7.40 (1H, d, J=1.6Hz), 7.31 7.23 (2H,
MS (EI) Calcd for C18H20O5: 316.1311. Found: 316.1312.
—
—
—
m), 6.96 6.92 (2H, m), 4.01 (3H, s), 3.95 (3H, s). 13C-NMR
(Z)-2-(2-(4-Bromophenyl)-3-hydroxypropenyl)phenol (4e): (100MHz, CDCl3) δ: 155.9 (s), 154.7 (s), 149.6 (s), 149.2 (s),
1
—
°
White solid, mp 135 136 C. H-NMR (400MHz, DMSO-d6) 129.4 (s), 123.8 (s), 123.5 (s), 122.8 (s), 120.6 (s), 117.9 (s), 111.4
δ: 7.57 (4H, s), 7.44 (1H, d, J=7.6Hz), 7.14 (1H, s, J=7.6Hz), (s), 110.9 (s), 108.1 (s), 100.0 (s), 56.0 (s), 55.9 (s). IR (KBr)
7.00 (1H, s), 6.88 6.81 (2H, m), 4.43 (2H, s). 13C-NMR cm−1: 2838, 1605, 1505, 1445, 1340, 1250, 1227, 1139, 1019,
—
(100MHz, DMSO-d6) δ: 155.9 (s), 141.1 (s), 138.6 (s), 131.5 938, 858, 799, 752. MS (EI) m/z (%): 254 (M+), 239, 168, 139.
(d), 130.4 (s), 129.3 (s), 128.9 (d), 126.8 (s), 124.1 (s), 120.5 HR-MS (EI) Calcd for C16H14O3: 254.0943. Found: 254.0947.
(s), 119.1 (s), 115.7 (s), 58.7 (s). IR (KBr) cm−1: 3355, 3053,
1599, 1449, 1246, 1074, 1008, 829, 754. MS (EI) m/z (%): 306 White solid, mp 112 113 C. H-NMR (400MHz, CDCl3) δ:
2-(3,4-Dimethoxyphenyl)-6-methoxy Benzofuran (5d):
1
—
°

274
Vol. 60, No. 2
—
—
7.42 7.36 (2H, m), 7.33 (1H, s), 7.06 (1H, s), 6.93 6.91 (1H, China (No. 81102380).
—
m), 6.87 6.85 (1H, m), 6.82 (1H, s), 3.98 (3H, s), 3.92 (3H, s),
3.86 (3H, s). 13C-NMR (100MHz, CDCl3) δ: 157.7 (s), 155.6 (s),
155.1 (s), 149.1 (s), 123.7 (s), 122.7 (s), 120.6 (s), 117.3 (s), 111.6
(s), 111.3 (s), 107.6 (d), 99.7 (s), 95.8 (s), 55.9 (d), 55.6 (s). IR
(KBr) cm−1: 2838, 1619, 1571, 1504, 1462, 1340, 1268, 1144,
1023, 953, 818, 761. MS (EI) m/z (%): 284 (M+), 269, 254, 142.
HR-MS (EI) Calcd for C17H16O4: 284.1049. Found: 284.1055.
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2-(4-Bromophenyl)benzofuran (5e): White solid, mp 147
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149 C. H-NMR (400MHz, CDCl3) δ: 7.73 (2H, d, J=8.0Hz),
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2-(4-Bromophenyl)-6-methoxy Benzofuran (5f): White sol-
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—
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7.04 (1H, s), 6.93 (1H, s), 6.87 (1H, dd, J=2.4, 2.0Hz), 3.86
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4-(Benzofuranyl)phenol (5g): Yellowish solid, mp 189
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1
191 C. H-NMR (400MHz, DMSO-d6) δ: 10.04 (1H, s), 7.72
—
(2H, d, J=8.8Hz), 7.56 (2H, t, J=7.2Hz), 7.23 7.18 (2H,
—
m), 7.13 (1H, s), 6.92 (2H, d, J=8.8Hz). 13C-NMR (100MHz,
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—
“
”
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—
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Acknowledgments This work was supported by Ministry
of Health of Zhejiang Province (WKJ2010-2-001), the
Health Bureau of Zhejiang Province (XKQ-01001), Zhejiang
Provincial Natural Science Foundation of China (Y2111012),
Science Technology Department of Zhejiang Province
(2011F10015) and National Natural Science Foundation of
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