Synthesis and antimicrobial evaluation of 3-substituted-imine-6-hydroxy-benzofuran derivatives

Article abstract of DOI:10.1007/s00044-016-1694-8

A series of 3-substituted-imine-6-hydroxy-benzofuran derivatives were chemically synthesized and biologically evaluated as antibacterial and antifungal agents against Candida albicans, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and Bacillus subtilis. Most compounds showed a selective antibacterial activity to gram-positive bacteria and four compounds revealed great antibacterial activities against methicillin-resistant Staphylococcus aureus comparing to the positive control (Ceftazidime) with MIC₈₀ = 12.5–25 μg/mL. Structure-activity relationship studies demonstrated that the free hydroxy group at the C-6 position is essential to the antibacterial activity, and the aromatic imine fragment at the C-3 position also greatly increases antibacterial activity.

Full text of DOI:10.1007/s00044-016-1694-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1694-8
ORIGINAL RESEARCH
Synthesis and antimicrobial evaluation of 3-substituted-imine-6-hydroxy-
benzofuran derivatives
Wan He1 Buzhe Xu1 Jian Bao1 Xinxian Deng1 Wenlu Liu1 Yong Zhang1
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Faqin Jiang1 Lei Fu1
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Received: 7 January 2016 / Accepted: 16 July 2016
© Springer Science+Business Media New York 2016
Abstract A series of 3-substituted-imine-6-hydroxy-ben-
zofuran derivatives were chemically synthesized and bio-
logically evaluated as antibacterial and antifungal agents
against Candida albicans, Escherichia coli, Staphylococcus
aureus, methicillin-resistant Staphylococcus aureus and
Bacillus subtilis. Most compounds showed a selective
antibacterial activity to gram-positive bacteria and four
compounds revealed great antibacterial activities against
methicillin-resistant Staphylococcus aureus comparing to
the positive control (Ceftazidime) with MIC80 = 12.5–25
μg/mL. Structure-activity relationship studies demonstrated
that the free hydroxy group at the C-6 position is essential to
the antibacterial activity, and the aromatic imine fragment at
the C-3 position also greatly increases antibacterial activity.
pipeline of antibiotics (McPhillie et al., 2015; Rachakonda
and Cartee, 2004). Benzofuran derivatives have drawn
considerable attention over the last few years due to their
valuable biological activities including anticancer (Kau et
al., 2003; Rizzo et al., 2008; Salomé et al., 2014; Xie et al.,
2015), antimicrobial (Koca et al.,2005; Jiang et al., 2011),
antihyperglycemic (Cottineau et al., 2002), analgesic (Xie et
al., 2014), antiparasitic (Thévenin et al., 2013), and anti-
inflammatory properties (Manna and Agrawal, 2009;
Hayakawa et al., 2004; Gündoğdu-Karaburun et al., 2006).
Especially, benzofuran derivatives containing substituents
at the C-2 and/or C-3 positions have been extensively stu-
died for their biological activities (Rizzo et al., 2008; Abdel-
Aziz and Mekawey, 2009; Kirilmis et al., 2008; Guo et al.,
2010). For example, moracin and viniferin (Fig. 1), show
promising biological activities, such as antibacterial (Naik
et al., 2015; Yim et al., 2010), antioxidant (Kapche et al.,
2009), and cytotoxic effects (Yang et al., 2010; Zelová et al.,
2014; Pryce and Langcake, 1977; Chen et al., 2002; Jordan,
2006; Vogel et al., 2006; Zheng et al., 2010).
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Keywords Benzofuran derivatives Synthesis
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Antibacterial activity SAR
Introduction
Our previous studies have reported the synthesis and
antibacterial activity of a series of 6-substituted benzofuran
derivatives. We discovered two compounds, 6-hydro-
xybenzofuran (Fig. 2a) and 3-imine-6-substituted-benzo-
furan (Fig. 2b) with excellent antibacterial activities. The
individual structure-activity relationship (SAR) analysis of
compounds A and B demonstrated that the hydroxy group
at the C-6 position of benzofuran is essential to antibacterial
activity for the compounds with no imine linker at the C-3
position (i.e., Fig. 2a), while the imine linker at the C-3
position plays important role in the antibacterial activity and
selectivity for the compounds with the hydroxyl group
blocked at the C-6 (i.e., Fig. 2b).
The rapid evolution of bacterial resistance to the current
spectrum of antibacterial agents constantly requires a new
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1694-8) contains supplementary material,
which is available to authorized users.
Wan He and Buzhe Xu contributed equally to this work
* Lei Fu
leifu@sjtu.edu.cn
1
Herein, we further explored the synthesis and anti-
bacterial activities of compounds that collectively have the
School of Pharmacy, Shanghai Jiao Tong University, No. 800
Dongchuan Rd., Shanghai 200240, P.R. China

Med Chem Res
Fig. 1 Structures of moracin
and viniferin
Fig. 2 Design of 3-imine-6-
hydroxy-benzofuran derivatives
(c) based on our published
results (a and b)
A
B
C
C-3 and the C-6 substitutions. Specifically, we designed a
series of 3-imine-6-hydroxylbenzofuran derivatives to study
the effect of electron densities, substituent bulkiness and
substituent position on the antibacterial activity and selec-
tivity (Fig. 2c).
Microbiological Culture Collection Center. Cefradine,
Ceftazidime, Cefotaxime, Sodium penicillin, and Ketoco-
nazole were used as control drugs. The assay was conducted
according to the procedures previously reported (Jiang
et al., 2011; Zhang et al., 2011). The MIC is defined as the
lowest antibiotic concentration of the test compound that
resulted in 480 % inhibition of bacterial growth after
incubation at 37 °C for 24 h. The antimicrobial activity data
of the compounds and the control drugs as MIC (μg/mL)
values are given in Table 1.
Evaluation of antimicrobial activity
The minimum inhibitory concentration (MIC) assays of the
synthesized compounds were conducted against a fungus
Candida albicans (ATCC10231), Gram-negative bacteria
Escherichia coli (ATCC11303), Gram-positive bacteria
Staphylococcus aureus (ATCC10832), methicillin-resistant
Staphylococcus aureus (ATCC700699), and Bacillus sub-
tilis (ATCC33712) by the two-fold serial dilution technique
in accordance with National Committee for Clinical
Laboratory Standards for susceptibility testing (CLSI, 1998,
2003). All the strians were purchased from American Type
Culture Collection and maintained in China General
Result and discussion
Chemistry
The benzofuran derivatives described in this paper were
prepared according to the synthetic route in Schemes 1–3.
The conventional and classical approach were used in the

Med Chem Res

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Scheme 1 Reagents and conditions a KI, NaHCO3, CH3CN, reflux b R1PPh3Cl, KOH, toluene, r.t. c K2CO3, I2, THF d POCl3, DMF, (CH2Cl)2,
reflux e RNH2, toluene, reflux
Scheme 2 Synthesis of compounds 7, reagents and conditions: a TiCl4, CH2Cl2 b RNH2, toluene, reflux
the synthesis of target compounds. According to Scheme 1,
coupling of 2,4-dihydroxybenzaldehyde with benzyl chlor-
ides in K2CO3 and KI gave the compound 1, which upon
treatment with substituted triphenyl phosphonium chloride
(R1PPh3Cl) via Wittig reaction yielded intermediate 2. Then
compound 2 underwent intra-molecular cyclization in
K2CO3 and I2 to furnish benzofuran 3, which was treated
with POCl3 via Vilsmeier reaction to produce compound 4.
Sequentially, treatment of substituted aromatic amine with
compound 4 yielded compound 5. Deprotection of benzyl
group from compounds 4 with TiCl4 produced compound
6a and 6b, which condensed with substituted aromatic
amine to afford compound 7 in Scheme 2. Via acetylization
and deprotection of benzyl group of compound 3 in
Scheme 3, compounds (6c, 6d, and 6e) were obtained. Here,
most of compounds were synthesized for the first time,
excluding compounds 6d and 6e (Harris et al., 2000;
Kiyonaga et al., 2012). All the previously and newly syn-
thesized benzofuran derivatives were evaluated for their in
vitro antimicrobial activities against human pathogenic
microbes.
The newly synthesized compounds were supported by
spectral data. The IR, 1H NMR, 13C NMR, and mass spectra
results are consistent with the proposed structures.
According to the spectroscopic data of the compounds
5a–6c, 7a–7k, the IR spectra showed that characteristic

Med Chem Res
Scheme 3 Synthesis of
compound 6c, 6d, and 6e,
reagents and conditions: a
RCOCl, TiCl4, CH2Cl2, b TiCl4,
CH2Cl2
C=N or C=O stretching bands were in the 1625–1582 cm−1
five tested strains. The results are in accordance with that of
our previously reported (Liu et al., 2012).
1
and 1754–1620 cm−1 regions, respectively. In the H NMR
spectra of the compounds 5a–5f and 7a–7k, the signal of
CH=N proton was observed at 8.689–8.831 ppm as a
singlet band. The signals of CH=O proton of the com-
pounds 6a and 6b were observed at 10.221 and 10.228 ppm.
Besides, benzylic CH2 and aromatic OH protons appeared
at 5.185–5.215 ppm and 9.092–10.188 ppm as a singlet,
respectively. Moreover, all the aromatic protons were
observed at 6.587–8.419 ppm. 13C NMR spectra of the
compounds were appropriate to their formulas. For mass
spectra of the compounds, the [M+H]+ peaks were con-
sistent with their formulas, since the electrospray ionization
method was employed.
Compounds 6a and 6b with formyl group alone at the C-
3 revealed potent activity against gram-positive bacteria,
while compounds 6c and 6d almost lost their antibacterial
activity with benzoyl group and acetyl group at the C-3,
respectively, which was similar to our findings with 3-
methanone-6-substituted-benzofuran derivatives. In add-
tion, the strain-specific was not observed when the C-3
position was fixed with the imine group and the C-6 posi-
tion was occupied by the free hydroxyl group (7a and 7i), as
compared to the compound B (Fig. 2b) previously reported
(Liu et al., 2012), indicating that the strain-specific may be
owe to the joint action of 5-methyl-2-phenyloxazole-4-
ethyloxy group and the imine linker.
The substitution of R1 had little impact on the anti-
microbial activity. Antimicrobial activity of substituted
benzofuran analogs are similar to those without any sub-
stitution on the R1 position in most cases (6a vs. 6b, 7a vs.
7g, 7b vs. 7h, 7d vs. 7i, 7e vs. 7j). To our surprise, com-
pound 6e, which was fixed an additional hydroxy group at
the R1, was revealed to have less potent antibacterial
activity than that of the lead compound A (Fig. 2a, Liu
et al., 2012). The substitution of R2 had positive effect on
the antimicrobial activity. Compound 7f, with R2 sub-
stituted by the –Cl at the meta position and the –OH at the
para position, displayed the most excellent antibacterial
activity against S. aureus, B. subtilis and MRSA with
MIC80 values of 12.5 μg/mL. Its activities against MRSA
(Table 1) are comparable to that of Ceftazidime (the posi-
tive control drug). In contrast, when the R2 was repalaced
by the –OH and –OCH3 at the meta and/or a para positions
(7b, 7c, 7d, 7h, 7i) caused reduction in antibacterial activity
with MIC80 values of 25–50 μg/mL. Meanwhile, we noted
that compound 7g with three methoxy groups, had similar
activities against all three bacteria as compound 7h
(MIC80 = 25–50 μg/mL) with single one. On the other hand,
Antimicrobial activity
The results revealed that most of the compounds were
active against gram-positive bacteria (S. aureus, B. subtilis
and MRSA) with MIC80 = 12.5–50 μg/mL. Compounds
showed differentiated antibacterial activity and selectivity
for tested bacteria. The synthesized benzofuran derivatives
seem to be effective to inhibit the growth of gram-positive
bacteria: S. aurus, B. subtili and MRSA. Only three com-
pounds, 7i, 7j, and 7k display weak antifungal activity
against C. albicans with a MIC80 value of 100 μg/mL.
Compounds 7h–7k showed obvious antimicrobial activity
with MIC80 value from 12.5 to 50 μg/mL, respectively, at
the same level with compounds 6a and 6e. Compounds with
a BnO-substitution on R3 position (5a–5f) almost lose their
antibacterial activity. Otherwise, compounds (7a–7k) with
the free hydroxyl group have good antibacterial activity up
to 12.5 μg/mL. It suggests that the free hydroxyl group at
the C-6 position of benzofuran plays a significant role for
antibacterial activity, once the free hydroxyl group was
obstructed, the compounds will show no potency to all the

Med Chem Res
Fig. 3 Numbering for 13C NMR
spectra
compounds with the methylation of the hydroxyl group
would reduce the solubility and decrease their antimicrobial
abilities, such as compounds 7b vs. 7c. All of the tested
compounds showed no activity against E. coli.
mass spectra were obtained on an Agilent Technologies
Q-TOF 6230 (Fig. 3).
Synthesis procedures and analytical data
4-benzyloxy-2-hydroxybenzaldehyde (1) To a solution of
2,4-dihydroxybenzaldehyde (5.00 g, 36 mmol) and benzyl
chloride (5.50 g, 43.5 mmol) in CH3CN (50 mL), KI (5.50
g, 54 mmol) and NaHCO3 (4.50 g, 54 mmol) were added.
The mixture was refluxed overnight and cooled to room
temperature. The reaction was quenched with water and
extracted by ethyl acetate. The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4,
concentrated and purified over silica gel column (elution:
10/1 petroleum ether/ethyl acetate) to give compound 1
(5.25 g, 64 %) as white solid. 1H NMR (CDCl3, 300 MHz):
δ = 5.11 (s, 2H, OCH2Ph), 6.51–6.52 (d, 1H, J = 3.0 Hz,
ArH), 6.60–6.63 (dd, 1H, J = 1.5 Hz, 7.5 Hz ArH), 7.36–
7.46 (m, 6H, ArH), 9.72 (s, 1H, OH), 11.48 (s, 1H, OH).
Conclusions
In summary, we have presented an efficient method for the
synthesis of benzofuran derivatives containing three-sub-
stituted aromatic imides and evaluated their in vitro anti-
bacterial activities. Surveying the data presented in Table 1,
some compounds showed selective antibacterial activity
against S. aurus, B. subtilis and MRSA with moderate
antibacterial activity. The preliminary SAR demonstrated
that the free hydroxyl group at the 6-C position is essential
to the antibacterial activity. Meanwhile, the aromatic imine
fragment at the C-3 position also greatly increases anti-
bacterial activity, especially, for C. albicans. The results
obtained in this study may provide useful clues for the
design and discovery of new antibacterial inhibitors. More
research in this direction is under progress and results will
be published in due course.
(E)-5-(benzyloxy)-2-styrylphenol (2a) Step 1 The mixture
of benzyl chloride (11.8 g, 50.70 mmol) and triphenylpho-
sphine (13.70 g, 52.22 mmol) in CH3CN (100 mL) was
refluxed overnight, cooled to room temperature, filtered and
washed with ether to afford benzyl(triphenyl)phosphonium
chloride (20.8 g, 83 %). 1H NMR (DMSO-d6, 300 MHz): δ
= 5.04 (s, 2H, OCH2Ph), 5.11–5.16 (d, 2H, J = 15 Hz,
CH2P), 6.88 (s, 4H, ArH), 7.36–7.40 (m, 5H, ArH), 7.63–
7.77 (m, 12H, ArH), 7.87–7.90 (m, 3H, ArH). Step 2 To a
solution of compound 1 (1.70 g, 7.45 mmol) and benzyl
(triphenyl)phosphonium chloride (2.89 g, 7.45 mmol) in
CH3CN (30 mL), 1,8-Diazabicyclo[5.4.0]undec-7-ene
(1.17 mL, 7.7 mmol) was added dropwise. The mixture was
refluxed overnight and was then concentrated. The residue
was dissolved in CH2Cl2, washed with water and acidified
with 1 M HCl to pH 7.0. The organic layer was dried over
anhydrous Na2SO4, concentrated and purified by chroma-
tographer (elution: 10/1 petroleum ether/ethyl acetate) to
give compound 2a (1.78 g, 79 %) as a white solid. 1H NMR
(DMSO-d6, 300 MHz): δ = 5.07(s, 2H, OCH2Ph), 6.51–
6.53 (m, 2H, ArH), 7.04–7.09 (d, 1H, J = 15 Hz, CH=CH),
Experimental section
General methods
The moisture sensitive reactions were carried out under
nitrogen atmosphere with the solvents distilled from
appropriate drying agents prior to use. Other solvents and
commercial chemicals were purchased and used directly
without purification. Reactions were monitored with thin
layer chromatograph plates under 254 nm UV light. The
melting points were measured with a capillary melting point
apparatus (Mettler MP50) and were uncorrected. The NMR
spectra were gotten from a Bruker AvanceIII 300 spectro-
meter (1H NMR at 300 MHz; 13C NMR at 101 MHz).
Chemical shifts were designated as follows in ppm from the
internal standard (chemical shift in δ, ppm). High resolution

Med Chem Res
7.181–7.245 (q, 1H, J = 7.5 Hz, J = 4.5 Hz, ArH), 7.299–
6-benzyloxy-2-(4-benzyl-oxyphenyl)benzofuran
(3b)
7.51 (m, 11H, ArH), 9.829 (s, 1H, OH).
according to the procedure for the synthesis of compound
4a as yellow solid (54 % yield); H NMR (DMSO-d6, 300
1
(E)-5-benzyloxy-2-(4-benzyloxystyryl) phenol (2b) Com-
pound 2b was prepared from 4-(benzyloxy)-2-Hydro-
xybenzaldehyde and 4-(benzyloxy)ben-zylchloride (4.36 g,
8.77 mmol) according to the procedure described in synth-
esis of compound 2a. It was obtained as white solid (2.02 g,
MHz): δ = 5.176 (s, 2H, OCH2Ph), 5.214 (s, 2H, OCH2Ph),
7.066–7.102 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz, ArH), 7.210–
7.239 (d, 2H, J = 8.7 Hz, ArH), 7.322–7.457 (m, 11H,
ArH), 7.891–7.92 (d, 2H, J = 8.7 Hz, ArH), 7.959–7.988 (d,
1H, J = 8.7 Hz, ArH), 10.182 (s, 1H, CHO).
1
56.4 % yield). H NMR (DMSO-d6, 300 MHz): δ = 5.063
(s, 2H, OCH2Ph), 5.11 (s, 2H, OCH2Ph), 6.491–6.509 (m,
2H, ArH), 6.977–7.021 (m, 3H, ArH), 7.144–7.199 (d, 1H,
J = 16.5 Hz, CH=CH), 7.327–7.468 (m, 13H, ArH), 9.736
(s, 1H, OH).
General synthesis of compounds (5a–5f) Compound 4a
(50 mg, 0.152 mmol) and anilines (0.152 mmol) were dis-
solved in toluene (10 mL) and refluxed for 12 h. The mix-
ture was concentrated, then the residue was redissolved in
ethyl acetate, washed with water and brine, dried over
anhydrous Na2SO4, concentrated, and purifyed over silica
gel column with petroleum ether/ethyl acetate to give
compounds 5a–5f.
6-benzyloxy-2-phenylbenzofuran (3a) Compound 2a
(1.00 g, 3.31 mmol) and anhydrous K2CO3 (2.55 g, 19.85
mmol) were dissolved in THF (20 mL) and stirred for 30
min, then I2 (5.04 g, 19.85 mmol) was added and stirred for
2 h at room temperature. The reaction was quenched with
saturated NaHSO3 to remove residual I2, extracted with
ethyl acetate, washed with brine, dried over anhydrous
Na2SO4, concentrated and purified over chromatographic
column to afford compound 3a as yellow solid (0.18 g,
18 % yield). 1H NMR (CDCl3, 300 MHz): δ = 5.137 (s, 2H,
OCH2Ph), 6.94–6.974 (m, 2H, ArH), 7.138–7.143 (d, 1H, J
= 1.5 Hz, ArH), 7.318–7.493 (m, 9H, ArH), 7.799–7.824
(d, 2H, J = 7.5 Hz, ArH).
(E)-N-((6-(benzyloxy)-2-phenylbenzofuran-3-yl)methy-
lene)-3, 4, 5-trimethoxyaniline (5a) Compound 5a as
yellow solid (60 % yield). m.p.: 138–140 °C; IR (KBr) νmax
:
1
2937, 1582 (C=N), 1494, 1149, 1127, 819, 694 cm−1; H
NMR (CDCl3, 300 MHz): δ = 3.892 (s, 3H, OCH3), 3.919
(s, 6H, OCH3, OCH3), 5.185 (s, 2H, OCH2Ph), 6.514 (s,
2H, ArH), 7.083–7.12 (dd, 1H, J = 8.7 Hz, 2.4 Hz, ArH),
7.173–7.18 (d, 1H, J = 2.1 Hz, ArH), 7.361–7.578 (m, 8H,
ArH), 7.786–7.818 (dd, 2H, J = 8.4 Hz, 1.8 Hz, ArH), 8.39–
8.419 (d, 1H, J = 8.7 Hz, ArH), 8.801 (s, 1H, CH=N); 13C
NMR (DMSO-d6, 101 MHz): δ = 158.9 (C, C-1), 158.0 (C,
C-15), 155.2 (C, C-6), 153.7 (C, C-8), 153.5 (C, C-18, C-
20), 148.6 (C, C-16), 137.2 (C, C-23), 136.2 (C, C-19),
130.4 (C, C-11, C-13), 129.7 (C, C-25, C-27), 129.5 (C, C-
12), 128.9 (C, C-26), 128.6 (C, C-24, C-28), 128.4 (C, C-9),
128.3 (C, C-10, C-14), 124.0 (C, C-4), 119.9 (C, C-3),
115.2 (C, C-5), 114.1 (C, C-2), 99.0 (C, C-17, C-21), 97.3
(C, C-7), 70.2 (CH2, C-22), 60.5 (OCH3, C-19 OCH3), 56.4
(OCH3, C-18 OCH3, C-20 OCH3); HRMS [ESI(+)-MS]:
C31H27NO5 [M+H]+ m/z, calc. 494.1962, found 494.1967.
6-benzyloxy-2-(4-benzyloxyphenyl)benzofuran (3b) Com-
pound 3b was prepared according to the procedure descri-
bed in synthesis of compound 3a as yellow solid (22.5 %
1
yield); H NMR (DMSO-d6, 300 MHz): δ = 5.152 (s, 4H,
OCH2Ph, OCH2Ph), 6.915–6.95 (dd, 1H, J = 8.4 Hz, J =
2.1 Hz, ArH), 7.095–7.158 (t, 3H, J = 9.3 Hz, ArH), 7.288–
7.486 (m, 12H, ArH), 7.754–7.783 (d, 2H, J = 8.7 Hz,
ArH).
6-benzyloxy-2-phenyl-benzofuran-3-formaldehy-de (4a)
To a solution of DMF (1.3 mL, 16.0 mmol) and CH2Cl2 (20
mL), POCl3 (1.5 mL, 16.0 mmol) was added dropwise at 0–
5 °C. After being stirred for 30 min at room temperature,
compound 3a (0.6 g, 2.0 mmol) was added and refluxed
overnight and cooled. The mixture was poured onto ice
water and stirring for 1 h, then extracted with CH2Cl2,
washed with saturated Na2CO3 solution and brine, and then
dried over anhydrous Na2SO4, concentrated and purified
over silica gel column to give compound 4a (0.45 g, 69 %
yield). 1H NMR (CDCl3, 300 MHz): δ = 5.149 (s, 2H,
OCH2Ph), 7.074–7.109 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz,
ArH), 7.141–7.147 (d, 1H, J = 1.8 Hz, ArH), 7.343–7.565
(m, 8H, ArH), 7.809–7.840 (m, 2H, ArH), 8.128–8.157 (d,
1H, J = 8.7 Hz, ArH), 10.310 (s, 1H, CHO).
(E)-N-((6-(benzyloxy)-2-phenylbenzofuran-3-yl)methy-
lene)-4-methoxyaniline (5b) Compound 5b as yellow
solid (69 % yield). m.p.: 137–138 °C; IR (KBr) νmax: 2914,
1
1615 (C=N), 1495, 1243, 1130, 1074, 697 cm−1; H NMR
(DMSO-d6, 300 MHz): δ = 3.78 (s, 3H, OCH3), 5.21 (s, 2H,
OCH2Ph), 6.971–7.00 (d, 2H, J = 8.7 Hz, ArH), 7.087–
7.123 (dd, 1H, J = 8.7 Hz, J = 2.4 Hz, ArH), 7.329–7.628
(m, 11H, ArH), 7.869–7.896 (m, 2H, ArH), 8.329–8.358 (d,
1H, J = 8.7 Hz, ArH), 8.831 (s, 1H, CH=N). 13C NMR
(DMSO-d6, 101 MHz), δ = 158.4 (C, C-1), 158.3 (C, C-19),
157.9 (C, C-15), 155.2 (C, C-6), 151.7 (C, C-8), 145.3 (C,
C-16), 137.3 (C, C-23), 130.3 (C, C-11, C-13), 129.7 (C, C-
25, C-27), 129.6 (C, C-12), 128.9 (C, C-26), 128.6 (C, C-
24, C-28), 128.3 (C, C-10, C-14), 128.3 (C, C-9), 124.1 (C,
C-4), 122.8 (C, C-17, C-21), 120.0 (C, C-3), 115.4
6-benzyloxy-2-(4-benzyloxyphenyl)benzofuran-3-for-
maldehyde (4b) Compound 4b was obtained from

Med Chem Res
(C, C-18, C-20), 114.9 (C, C-5), 114.0 (C, C-2), 97.3 (C, C-
7), 70.2 (CH2, C-22), 55.7 (CH3, OCH3); HRMS [ESI
(+)-MS]: C29H23NO3 [M+H]+ m/z, calc. 434.1751, found
434.1748.
CH=N). 13C NMR (DMSO-d6, 101 MHz): δ = 159.1 (C,
C-1), 158.0 (C, C-15), 155.2 (C, C-6), 154.0 (C, C-8), 148.8
(C, C-16), 137.3 (C, C-23), 130.4 (C, C-11, C-13), 129.7
(C, C-25, C-27), 129.4 (C, C-12), 128.9 (C, C-26), 128.7
(C, C-24, C-28), 128.3 (C, C-9), 128.3 (C, C-10, C-14),
124.0 (C, C-4), 123.3 (C, C-17), 123.2 (C, C-21), 119.8 (C,
C-3), 116.4 (C, C-18), 116.2 (C, C-20), 115.2 (C, C-5),
114.1 (C, C-2), 97.4 (C, C-7), 70.2 (C, C-22); HRMS [ESI
(+)-MS]: C28H20FN O2 [M+H]+ m/z, calc. 422.1551, found
422.1541.
(E)-4-(((6-(benzyloxy)-2-phenylbenzofuran-3-yl)methy-
lene)amino)phenol (5c) Compound 5c as yellow solid
(58 % yield). m.p.: 202–204 °C; IR (KBr) νmax: 3486–3385
(O–H), 1619 (C=N), 1493, 1301, 1266, 695 cm−1; 1H NMR
(DMSO-d6, 300 MHz): δ = 5.209 (s, 2H, OCH2Ph), 6.802–
6.831 (d, 2H, J = 8.7 Hz, ArH), 7.082–7.118 (dd, 1H, J =
8.7 Hz, J = 2.1 Hz, ArH), 7.234–7.263 (d, 2H, J = 8.7 Hz,
ArH), 7.345–7.627 (m, 9H, ArH), 7.86–7.888 (m, 2H,
ArH), 8.327–8.356 (d, 1H, J = 8.7 Hz, ArH), 8.822 (s, 1H,
CH=N), 9.486 (s, 1H, OH). 13C NMR (DMSO-d6, 101
MHz): δ = 158.0 (C, C-1), 157.9 (C, C-15), 156.7 (C, C-
19), 155.2 (C, C-6), 150.5 (C, C-8), 143.7 (C, C-16), 137.3
(C, C-23), 130.2 (C, C-11, C-13), 129.7 (C, C-25, C-27),
129.6 (C, C-12), 128.9 (C, C-26), 128.5 (C, C-24, C-28),
128.4 (C, C-10, C-14), 128.3 (C, C-9), 124.1 (C, C-4),
122.8 (C, C-17, C-21), 120.1 (C, C-3), 116.2 (C, C-18, C-
20), 115.5 (C, C-5), 113.9 (C, C-2), 97.3 (C, C-7), 70.2
(CH2, C-22); HRMS [ESI(+)-MS]: C28H21NO3 [M+H]+
m/z, calc. 420.1594, found 420.1576.
(E)-4-(((6-(benzyloxy)-2-phenylbenzofuran-3-yl)methyl-
ene)amino)-2-chlorophenol (5f) Compound 5f as yellow
solid (52 % yield). m.p.: 134–136 °C; IR (KBr) νmax: 3104–
3063 (O-H), 1617 (C=N), 1580, 1285, 1150, 1078, 818,
1
695 cm−1; H NMR (DMSO-d6, 300 MHz): δ = 5.206 (s,
2H, OCH2Ph), 6.996–7.024 (d, 1H, J = 8.4 Hz, ArH),
7.077–7.113 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz, ArH), 7.209–
7.246 (dd, 1H, J = 8.7 Hz, J = 2.7 Hz, ArH), 7.343–7.623
(m, 10H, ArH), 7.88–7.903 (d, 2H, J = 6.9 Hz, ArH),
8.309–8.337(d, 1H, J = 8.4 Hz, ArH), 8.811 (s, 1H,
CH=N), 10.209 (s, 1H, OH). 13C NMR (DMSO-d6, 101
MHz): δ = 158.6 (C, C-1), 157.9 (C, C-15), 155.2 (C, C-6),
152.1 (C, C-8), 152.1 (C, C-19), 144.4 (C, C-16), 137.3 (C,
C-23), 130.3 (C, C-11, C-13), 129.7 (C, C-25, C-27), 129.5
(C, C-12), 128.9 (C, C-26), 128.6 (C, C-24, C-28), 128.4
(C, C-10, C-14), 128.3 (C, C-9), 124.1 (C, C-4), 122.8 (C,
C-20), 121.8 (C, C-21), 120.5 (C, C-17), 120.0 (C, C-3),
117.2 (C, C-18), 115.3 (C, C-5), 114.0 (C, C-2), 97.3 (C, C-
7), 70.2 (C, C-22); HRMS [ESI(+)-MS]: C28H20ClNO3
[M+H]+ m/z, calc. 454.1204, found 454.1212.
(E)-5-(((6-(benzyloxy)-2-phenylbenzofuran-3-yl)methy-
lene)amino)-2-methoxyphenol (5d) Compound 5d as yel-
low solid (65 % yield). m.p.: 140–142 °C; IR (KBr) νmax
:
3429–3301 (O–H), 2914, 1623 (C=N), 1493, 1273, 1143,
1069, 823, 695 cm−1; 1H NMR (DMSO-d6, 300 MHz): δ =
3.789 (s, 3H, OCH3), 5.215 (s, 2H, OCH2Ph), 6.783–6.84
(m, 2H, ArH), 6.94–6.968 (d, 1H, J = 8.4 Hz, ArH), 7.093–
7.129 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz, ArH), 7.347–7.635
(m, 9H, ArH), 7.857–7.884 (m, 2H, ArH), 8.303–8.332 (d,
1H, J = 8.7 Hz, ArH), 8.776 (s, 1H, CH=N), 9.103 (s, 1H,
OH). 13C NMR (DMSO-d6, 101 MHz): δ = 158.4 (C, C-1),
157.9 (C, C-15), 155.2 (C, C-6), 151.3 (C, C-8), 147.5 (C,
C-19), 147.0 (C, C-20), 145.7 (C, C-16), 137.3 (C, C-23),
130.3 (C, C-11, C-13), 129.7 (C, C-25, C-27), 129.6 (C, C-
12), 128.9 (C, C-26), 128.6 (C, C-24, C-28), 128.3 (C, C-9),
128.3 (C, C-10, C-14), 124.0 (C, C-4), 120.0 (C, C-3),
115.4 (C, C-5), 114.0 (C, C-2), 113.0 (C, C-18), 112.7 (C,
C-21), 108.6 (C, C-17), 97.4 (C, C-7), 70.2 (CH2, C-22),
56.3 (C, C-19 OCH3); HRMS [ESI(+)-MS]: C29H23NO4
[M+H]+ m/z, calc. 450.1700, found 450.1797.
2-phenyl-6-hydroxylbenzofuran-3-formaldehyde
TiCl4 (47 μL, 0.43 mmol) was dropped into the solution of
6-benzyloxy-2-phenyl-benzofuran-3-formaldehyde (4a)
(6a)
(100 mg, 0.31 mmol) in CH2Cl2 (10 mL). The reaction
mixture was stirred for 30 min at room temperature and
quenched with methanol. Then the solvent was removed in
vacuum and purified over silica gel column eluting with
petroleum ether/ethyl acetate=5:1 to give compound 6a (65
mg, 90 %) as yellow solid. m.p.: 170–171 °C; IR (KBr)
νmax: 3247–3120 (O-H), 2918, 2848, 1620 (C=O), 1499,
1278, 1071, 898, 771, 702 cm−1; 1H NMR (DMSO-d6, 101
MHz): δ = 6.887–6.922 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz,
ArH), 7.065–7.072 (d, 1H, J = 2.1 Hz, ArH), 7.60–7.621
(m, 3H, ArH), 7.913–7.964 (m, 3H, ArH), 9.920 (s, 1H,
OH), 10.221 (s, 1H, CHO). 13C NMR (DMSO-d6, 101
MHz): δ = 187.2 (CHO, C-15), 163.6 (C, C-1), 157.4 (C, C-
8), 155.2 (C, C-6), 131.3 (C, C-2), 129.7 (C, C-11, C-13),
129.2 (C, C-12), 128.6 (C, C-10, C-11), 122.6 (C, C-9),
117.3 (C, C-4), 117.2 (C, C-5), 114.6 (C, C-3), 98.1 (C, C-
7); HRMS [ESI(+)-MS]: C15H10O3 [M+H]+ m/z, calc.
239.0703, found 239.0750.
(E)-N-((6-(benzyloxy)-2-phenylbenzofuran-3-yl)methy-
lene)-4-fluoroaniline (5e) Compound 5e as white solid (55
% yield). m.p.: 128–130 °C; IR (KBr) νmax: 1618 (C=N),
1
1494, 1198, 1078, 823, 696 cm−1; H NMR (DMSO-d6,
300 MHz): δ = 5.196 (s, 2H, OCH2Ph), 7.076–7.113 (dd,
1H, J = 8.7 Hz, J = 2.4 Hz, ArH), 7.197–7.256 (m, 2H,
ArH), 7.328–7.613 (m, 11H, ArH), 7.865–7.896 (m, 2H,
ArH), 8.29–8.318 (d, 1H, J = 8.4 Hz, ArH), 8.792 (s, 1H,

Med Chem Res
2-(4-hydroxyphenzyl)-6-hydroxybenzofuran-3-for-
C-16); HRMS [ESI(+)-MS]: C16H12O3 [M+H]+ m/z, calc.
maldehyde (6b) 6-benzyloxy-2-(4-benzyloxyphenyl)Ben-
zofuran-3-formaldehyde (4b) with TiCl4 according to the
procedure for the synthesis of compound 6c. It was obtained
as white solid (61.4 mg, 78 % yield). m.p.: 238–239 °C; IR
(KBr) νmax: 3320–3110 (O-H), 1620 (C=O), 1498, 1285,
1069, 902, 842, 696 cm−1; 1H NMR (DMSO-d6, 300 MHz):
δ = 6.826–6.861 (dd, 1H, J = 8.4 Hz, J = 2.1 Hz, ArH),
6.94–6.969 (d, 2H, J = 8.7 Hz, ArH), 7.000–7.006 (d, 1H, J
= 1.8 Hz, ArH), 7.757–7.786 (d, 2H, J = 8.7 Hz, ArH),
7.847–7.876 (d, 1H, J = 8.7 Hz, ArH), 9.802 (s, 1H, OH),
10.15 (s, 1H, OH), 10.228 (s, 1H, CHO). 13C NMR
(DMSO-d6, 101 MHz): δ = 186.9 (C, C-15), 164.6 (C, C-1),
160.6 (C, C-12), 156.9 (C, C-8), 154.8 (C, C-6), 131.0 (C,
C-2), 122.3 (C, C-10, C-14), 119.4 (C, C-4), 117.4 (C, C-9),
116.6 (C, C-11, C-13), 115.9 (C, C-5), 114.2 (C, C-3), 98.1
(C, C-7); HRMS [ESI(+)-MS]: C15H10O4 [M+H]+ m/z, calc.
255.0652, found 255.0615.
253.0859, found 253.0822.
2-(4-hydroxyphenzyl)-benzofuran-6-ol (6e) Compound 6e
was prepared by reaction of 6-benzyloxy-2-(4-benzyloxy)
phenylbenzofuran (3b) with TiCl4 according to the proce-
dure for the synthesis of compound 6a. It was obtained as
white solid (65 % yield). m.p.: 243–244 °C; IR (KBr) νmax
:
3320–3110 (O–H), 1498, 1285, 1069 cm−1; 1H NMR
(DMSO-d6, 300 MHz): δ = 6.72 (d, 1H, J = 8.22 Hz, ArH),
6.93 (br. s., 1 H, ArH), 7.23 (s, 1 H, OH), 7.26–7.33 (m, 1
H, ArH), 7.36 (br. s., 1 H, ArH), 7.39–7.49 (m, 2 H, ArH),
7.78 (d, 2 H, J = 7.8 Hz, ArH), 9.60 (s, 1 H, OH); 13C NMR
(DMSO-d6, 101 MHz): δ = 158.8 (C, C-12), 156.3 (C, C-1),
155.9 (C, C-8), 154.0 (C, C-6), 130.6 (C. C-10, C-14),
129.4 (C, C-4), 128.5 (C, C-3), 124.4 (C, C-9), 121.7 (C, C-
11), 121.2 (C, C-13), 113.0 (C, C-5), 102.4 (C, C-2), 98.0
(C, C-7); HRMS [ESI(+)-MS]: C14H10O3 [M+H]+ m/z, calc.
227.0703, found 227.0712.
(6-hydroxy-2-phenylbenzofuran-3-yl)(phenyl)methanone
(6c) Compound 6c was prepared by reaction of 6-benzy-
loxy-2-phenylbenzofuran (3a) with benzoyl chloride
according to the procedure for the synthesis of compound
6a. It was obtained as white solid (41 % yield). m.p.: 148–
149 °C; IR (KBr) νmax: 3055 (O-H), 1735 (C=O), 1267,
1246, 1134, 913, 705 cm−1; 1H NMR (DMSO-d6, 300
MHz): δ = 7.185–7.219 (dd, 1H, J = 8.4 Hz, J = 1.8 Hz,
ArH), 7.41–7.434 (d, 1H, J = 8.4 Hz, ArH), 7.482–7.534
(m, 3H, ArH), 7.594–7.783 (m, 5H, ArH, OH), 7.905–7.929
(d, 2H, J = 8.4 Hz, ArH), 8.150–8.174 (d, 2H, J = 8.4 Hz,
ArH). 13C NMR (DMSO-d6, 101 MHz): δ = 165.3 (C=O,
C-15), 156.7 (C, C-1), 154.5 (C, C-8), 148.4 (C, C-6), 134.5
(C, C-16), 130.3 (C, C-19), 130.2 (C, C-17, C-21), 130.0
(C, C-2), 129.5 (C, C-11, C-13), 129.4 (C, C-18, C-20),
129.4 (C, C-12), 127.2 (C, C-10, C-11), 125.1 (C, C-9),
121.6 (C, C-4), 118.2 (C, C-5), 106.0 (C, C-3), 102.3 (C, C-
7); HRMS [ESI(+)-MS]: C21H14O3 [M+H]+ m/z, calc.
315.1016, found 315.1087.
General experimental procedure of preparing compounds
(7a–7k) The mixture of compound 6a or 6b (0.21 mmol,
1.0 equiv) and anilines (0.21 mmol, 1.0 equiv) in toluene
(10 mL) was refluxed overnight, then the solvent was
removed and purified over silica gel column eluting with
10/1 petroleum ether/ethyl acetate to give compounds
7a–7k.
(E)-3,4,5-trimethoxy-N-((6-hydroxy-2-(phenyl)benzofuran-
3-yl)methylene)aniline (7a) Compound 7a as yellow solid
(52 % yield). m.p.: 156–157 °C; IR (KBr) νmax: 3551–3328
1
(O–H), 1585 (C=N), 1123, 1067, 992, 829, 696 cm−1; H
NMR (DMSO-d6, 300 MHz): δ = 3.666 (s, 3H, OCH3),
3.819 (s, 6H, 2OCH3), 6.637 (s, 2H, ArH), 6.873–6.918 (m,
1H, ArH), 7.038–7.045 (d, 1H, J = 2.1 Hz, ArH), 7.554–
7.591 (m, 3H, ArH), 7.864–7.892 (m, 2H, ArH), 8.199–
8.228 (d, 1H, J = 8.7 Hz, ArH), 8.804 (s, 1H, CH=N),
9.819 (s, 1H, OH). 13C NMR (DMSO-d6, 101 MHz): δ =
158.3 (C, C-1), 157.1 (C, C-15), 155.4 (C, C-6), 153.7 (C,
C-8), 153.6 (C, C-18, C-20), 148.7 (C, C-16), 136.2 (C, C-
19), 130.2 (C, C-11, C-13), 129.6 (C, C-12), 129.6 (C, C-9),
128.5 (C, C-10, C-14), 124.0 (C, C-4), 118.5 (C, C-3),
115.3 (C, C-5), 113.7 (C, C-2), 99.0 (C, C-17, C-21), 97.9
(C, C-7), 60.5 (CH3O, C-19 CH3O), 56.4 (CH3O, C-18
CH3O, C-20 CH3O); HRMS [ESI(+)-MS]: C24H21NO5
[M+H]+ m/z, calc. 404.1492, found 404.1494.
6-hydroxy-2-phenylbenzofuran-3-yl)ethanone (6d) Com-
pound 6d was prepared by reaction of 6-benzyloxy-2-phe-
nylbenzofuran (3a) with acetyl chloride according to the
procedure for the synthesis of compound 6a. It was
obtained as yellow solid (88 % yield). m.p.: 159–160 °C; IR
(KBr) νmax: 3082–2912 (O–H), 1754 (C=O), 1484, 1277,
1
903, 761, 687 cm−1; H NMR (DMSO-d6, 300 MHz): δ =
2.289 (s, 3H, O=CH3), 7.018–7.052 (dd, 1H, J = 8.4 Hz, J
= 1.8 Hz, ArH), 7.376–7.523 (m, 5H, ArH, OH), 7.634–
7.662 (d, 1H, J = 8.4 Hz, ArH), 7.885–7.91 (d, 2H, J = 7.5
Hz, ArH). 13C NMR (DMSO-d6, 101 MHz): δ = 169.9
(C=O, C-15), 156.5 (C, C-1), 154.5 (C, C-8), 148.3 (C, C-
6), 130.0 (C, C-2), 129.5 (C, C-11, C-13), 129.1 (C, C-12),
128.4 (C, C-10, C-11), 125.0 (C, C-9), 121.6 (C, C-4),
118.2 (C, C-5), 105.8 (C, C-3), 102.3 (C, C-7), 21.3 (CH3,
(E)-3-(((4-methoxyphenyl)imino)methyl)-2-phenylbenzo-
furan-6-ol (7b) Compound 7b as yellow solid (60 %
yield). m.p.: 139–140 °C; IR (KBr) νmax: 3489–3348 (O–
H), 1619 (C=N), 1504, 1250, 1143, 1072, 831, 693 cm−1;
1H NMR (DMSO-d6, 300 MHz): δ = 3.781 (s, 3H, OCH3),
6.872–6.906 (m, 1H, ArH), 6.97–7.032 (m, 3H, ArH),
7.316–7.345 (d, 2H, J = 8.7 Hz, ArH), 7.525–7.611 (m, 3H,
ArH), 7.853–7.877 (d, 2H, J = 7.2 Hz, ArH), 8.232–8.26 (d,

Med Chem Res
1H, J = 8.4 Hz, ArH), 8.815 (s, 1H, CH=N), 9.796 (s, 1 H,
OH). 13C NMR (DMSO-d6, 101 MHz): δ = 158.3 (C, C-1),
157.8 (C, C-19), 157.1 (C, C-15), 155.4 (C, C-6), 151.8 (C,
C-8), 145.4 (C, C-16), 130.1 (C, C-11, C-13), 129.7 (C, C-
12), 129.6 (C, C-9), 128.5 (C, C-10, C-14), 124.0 (C, C-4),
122.7 (C, C-17, C-21), 118.6 (C, C-3), 115.5 (C, C-18, C-
20), 114.9 (C, C-5), 113.7 (C, C-2), 97.9 (C, C-7), 55.7
(CH3, CH3O); HRMS [ESI(+)-MS]: C22H17NO3 [M+H]+
m/z, calc. 344.1281, found 344.1258.
J = 2.1 Hz, ArH), 7.022–7.028 (d, 1H, J = 1.8 Hz, ArH),
7.193–7.252 (m, 2H, ArH), 7.343–7.39 (m, 2H, ArH),
7.514–7.60 (m, 3H, ArH), 7.847–7.878 (dd, 2H, J = 7.8 Hz,
J = 1.8 Hz, ArH), 8.192–8.22 (d, 1H, J = 8.4 Hz, ArH),
8.772 (s, 1H, CH=N), 9.804 (s, 1H, OH); 13C NMR
(DMSO-d6, 101 MHz): δ = 158.6 (C, C-1), 157.1 (C, C-15),
155.4 (C, C-6), 154.1 (C, C-19), 148.9 (C, C-8), 130.3 (C,
C-11, C-13), 129.6 (C, C-12), 129.6 (C, C-9), 128.6 (C, C-
10, C-14), 124.0 (C, C-4), 123.2 (C, C-17), 123.2 (C, C-21),
118.4 (C, C-3), 116.4 (C, C-18), 116.2 (C, C-20), 115.3 (C,
C-5), 113.8 (C, C-2), 97.9 (C, C-7); HRMS [ESI(+)-MS]:
C21H14FNO2 [M+H]+ m/z, calc. 332.1081, found 332.1057.
(E)-3-(((4-hydroxyphenyl)imino)methyl)-2-phenylbenzo-
furan-6-ol (7c) Compound 7c as yellow solid (80 % yield).
m.p.: 193–194 °C; IR(KBr) νmax: 3416–3350 (O–H), 1622
1
(C=N), 1449, 1137, 837, 697 cm−1; H NMR (DMSO-d6,
(E)-3-(((3-chloro-4-hydroxyphenyl)imino)methyl)-2-phe-
nylbenzofuran-6-ol (7f) Compound 7f as yellow solid (67
% yield). m.p.: 178–179 °C; IR (KBr) νmax: 3354–3145 (O–
H), 1612 (C=N), 1498, 1279, 1137, 1078, 882, 811, 765,
694 cm−1; 1H NMR (DMSO-d6, 300 MHz): δ = 6.857–
6.892 (dd, 1H, J = 8.4 Hz, J = 2.1 Hz, ArH), 6.992–7.021
(d, 2H, J = 8.7 Hz, ArH), 7.193–7.23 (dd, 1H, J = 8.7 Hz, J
= 2.4 Hz, ArH), 7.409–7.417 (d, 1H, J = 2.4 Hz, ArH),
7.501–7.616 (m, 3H, ArH), 7.861–7.883 (d, 2H, J = 6.6 Hz,
ArH), 8.209–8.237 (d, 1H, J = 8.4 Hz, ArH), 8.791 (s, 1H,
CH=N), 9.797 (s, 1H, OH), 10.188 (s, 1H, OH). 13C NMR
(DMSO-d6, 101 MHz): δ = 158.0 (C, C-1), 157.1 (C, C-15),
155.4 (C, C-6), 152.3 (C, C-8), 152.0 (C, C-19), 144.6 (C,
C-16), 130.1 (C, C-11, C-13), 129.7 (C, C-12), 129.6 (C, C-
9), 128.5 (C, C-10, C-14), 124.1 (C, C-4), 122.8 (C, C-18),
121.7 (C, C-21), 120.5 (C, C-17), 118.5 (C, C-3), 117.3 (C,
C-20), 115.4 (C, C-5), 113.7 (C, C-2), 97.8 (C, C-7);
HRMS [ESI(+)-MS]: C21H14ClNO3 [M+H]+ m/z, calc.
364.0735, found 364.0715.
300 MHz): δ = 6.79–6.82 (d, 2H, J = 9.0 Hz, ArH), 6.861–
6.896 (dd, 1H, J = 8.7 Hz, J = 2.1 Hz, ArH), 7.02–7.026 (d,
1H, J = 1.8 Hz, ArH), 7.217–7.246 (d, 2H, J = 8.7 Hz,
ArH), 7.521–7.615 (m, 3H, ArH), 7.837–7.87 (dd, 2H, J =
8.4 Hz, J = 1.5 Hz, ArH), 8.226–8.255 (d, 1H, J = 8.7 Hz,
ArH), 8.803 (s, 1H, CH=N), 9.465 (s, 1H, OH), 9.779 (s,
1H, OH). 13C NMR (DMSO-d6, 101 MHz): δ = 157.5 (C,
C-1), 157.0 (C, C-15), 156.6 (C, C-19), 155.4 (C, C-6),
150.6 (C, C-8), 143.9 (C, C-16), 130.0 (C, C-11, C-13),
129.8 (C, C-12), 129.6 (C, C-9), 128.4 (C, C-10, C-14),
124.1 (C, C-4), 122.8 (C, C-17, C-21), 118.7 (C, C-3),
116.2 (C, C-18, C-20), 115.6 (C, C-5), 113.6 (C, C-2), 97.8
(C, C-7); HRMS [ESI(+)-MS]: C21H15NO3 [M+H]+ m/z,
calc. 330.1125, found 330.1190.
(E)-3-(((3-hydroxy-4-methoxyphenyl)imino)methyl)-2-phe-
nylbenzofuran-6-ol (7d) Compound 7d as yellow solid
(80 % yield). m.p.: 204–205 °C; IR (KBr) νmax: 3530–3476
(O–H), 1625 (C=N), 1496, 1277, 1143, 1074, 781, 770
1
cm−1; H NMR (DMSO-d6, 300 MHz): δ = 3.387 (s, 3H,
OCH3), 6.764–6.822 (m, 2H, ArH), 6.867–6.902 (dd, 1H, J
= 8.4 Hz, J = 1.8 Hz, ArH), 6.936–6.964 (d, 1H, J = 8.4 Hz,
ArH), 7.025–7.031 (d, 1H, J = 1.8 Hz, ArH), 7.53–7.623
(m, 3H, ArH), 7.837–7.864 (m, 2H, ArH), 8.201–8.23 (d,
1H, J = 8.7 Hz, ArH), 8.754 (s, 1H, CH=N), 9.095 (s, 1H,
OH), 9.794 (s, 1H, OH). 13C NMR (DMSO-d6, 101 MHz):
δ = 157.8 (C, C-1), 157.1 (C, C-15), 155.4 (C, C-6), 151.5
(C, C-8), 147.4 (C, C-19), 147.0 (C, C-20), 145.8 (C, C-16),
130.1 (C, C-11, C-13), 129.7 (C, C-12), 129.6 (C, C-9),
128.5 (C, C-10, C-14), 124.0 (C, C-4), 118.6 (C, C-3),
115.5 (C, C-5), 113.7 (C, C-2), 113.0 (C, C-18), 112.6 (C,
C-17), 108.6 (C, C-21), 97.9 (C, C-7), 56.3 (CH3, CH3O);
HRMS [ESI(+)-MS]: C22H17NO4 [M+H]+ m/z, calc.
360.1230, found 360.1206.
(E)-2-(4-hydroxyphenyl)-3-(((3,4,5-trimethoxyphenyl)
imino)methyl)benzofuran-6-ol (7g) Compound 7g as yel-
low solid (61 % yield). m.p.: 128–129 °C; IR (KBr) νmax
:
3348–3148 (O–H), 1589 (C=N), 1465, 1235, 1126, 1070,
1
991, 838, 696 cm−1; H NMR (DMSO-d6, 300 MHz): δ =
3.647 (s, 3H, OCH3), 3.801 (s, 6H, 2OCH3), 6.587 (s, 2H,
ArH), 6.824–6.852 (d, 1H, J = 8.4 Hz, ArH), 6.928–6.977
(m, 3H, ArH), 7.667–7.694 (d, 2H, J = 8.1 Hz, ArH), 8.13–
8.158 (d, 1H, J = 8.4 Hz, ArH), 8.719 (s, 1H, CH=N), 9.7–
9.74 (brs, 1H, OH), 10.02–10.08 (brs, 1H, OH). 13C NMR
(DMSO-d6, 101 MHz): δ = 159.6 (C, C-1), 159.3 (C, C-15),
156.6 (C, C-12), 155.0 (C, C-6), 153.8 (C, C-8), 153.7 (C,
C-18, C-20), 148.9 (C, C-16), 136.0 (C, C-19), 130.3 (C, C-
11, C-13), 123.6 (C, C-4), 120.5 (C, C-10, C-14), 118.7 (C,
C-3), 116.5 (C, C-5), 113.6 (C, C-2), 113.4 (C, C-9), 98.9
(C, C-17, C-21), 97.8 (C, C-7), 60.5 (OCH3, C-19 OCH3),
56.3 (OCH3, C-18 OCH3, C-20 OCH3); HRMS [ESI
(+)-MS]: C24H21NO6 [M+H]+ m/z, calc. 420.1442, found
420.1431.
(E)-3-(((4-fluorophenyl)imino)methyl)-2-phenylbenzo-
furan-6-ol (7e) Compound 7e as yellow solid (53 % yield).
m.p.: 195–196 °C; IR(KBr) νmax: 3148–2993 (O–H), 1619
(C=N), 1582, 1197, 1071, 838, 697 cm−1; 1H NMR
(DMSO; 300 MHz): δ = 6.857–6.892 (dd, 1H, J = 8.4 Hz,

Med Chem Res
(E)-2-(4-hydroxyphenyl)-3-(((4-methoxyphenyl)imino)
methyl)benzofuran-6-ol (7h) Compound 7h as yellow
solid (70 % yield). m.p.: 126–127 °C; IR(KBr) νmax: 2916–
2849 (O–H), 1610 (C=N), 1497, 1244, 1141, 833 cm−1; 1H
NMR (DMSO-d6, 300 MHz): δ = 3.76 (s, 3H, OCH3),
6.814–6.849 (dd, 1H, J = 8.7 Hz, J = 1.8 Hz, ArH), 6.929–
6.972 (m, 5H, ArH), 7.271–7.30 (d, 2H, J = 8.7 Hz, ArH),
7.657–7.685 (d, 2H, J = 8.4 Hz, ArH), 8.162–8.19 (d, 1H, J
= 8.4 Hz, ArH), 8.732 (s, 1H, CH=N), 9.691 (s, 1H, OH),
10.042 (s, 1H, OH); 13C NMR (DMSO-d6, 101 MHz): δ =
159.5 (C, C-1), 158.9 (C, C-15) 158.1 (C, C-19), 156.6 (C,
C-12), 155.0 (C, C-6), 152.1 (C, C-8), 145.6 (C, C-16),
130.2 (C, C-11, C-13), 123.7 (C, C-4), 122.6 (C, C-18, C-
20), 120.6 (C, C-10, C-14), 118.8 (C, C-3), 116.5 (C, C-5),
114.8 (C, C-17, C-21), 113.9 (C, C-2), 113.3 (C, C-9), 97.8
(C, C-7), 55.7 (CH3, CH3O); HRMS [ESI(+)-MS]:
C22H17NO4 [M+H]+ m/z, calc. 360.1230, found 360.1208.
(+)-MS]: C21H14FNO 3 [M+H]+ m/z, calc. 348.1030, found
348.1004.
(E)-3-(((3-chloro-4-hydroxyphenyl)imino)methyl)-2-(4-
hydroxyphenyl)benzofuran-6-ol (7k) Compound 7k as
yellow solid (68 % yield). m.p.: 190–191 °C; IR (KBr) νmax
:
3334–3134 (O–H), 1610 (C=N), 1491, 1275, 1144, 1073,
824 cm−1; 1H NMR (DMSO-d6, 300 MHz): δ = 6.805–
6.839 (dd, 1H, J = 8.7 Hz, J = 1.8 Hz, ArH), 6.93–7.00 (m,
4H, ArH), 7.152–7.186 (dd, 1H, J = 8.4 Hz, J = 1.8 Hz,
ArH), 7.358–7.365 (d, 1H, J = 2.1 Hz, ArH), 7.667–7.696
(d, 2H, J = 8.7 Hz, ArH), 8.142–8.171 (d, 1H, J = 8.7 Hz,
ArH), 8.71 (s, 1H, CH=N), 9.687 (s, 1H, OH), 10.045 (s,
1H, OH), 10.134 (s, 1H, OH). 13C NMR (DMSO-d6, 101
MHz): δ = 159.5 (C, C-1), 159.1 (C, C-19), 156.6 (C, C-
15), 155.0 (C, C-6), 152.6 (C, C-12), 151.8 (C, C-8), 144.8
(C, C-16), 130.3 (C, C-4), 123.7 (C, C-11, C-13), 122.7 (C,
C-18), 121.5 (C, C-17), 120.5 (C, C-20), 120.4 (C, C-10, C-
14), 118.7 (C, C-3), 117.3 (C, C-21), 116.5 (C, C-5), 113.8
(C, C-2), 113.3 (C, C-9), 97.8 (C, C-7); HRMS [ESI
(+)-MS]: C21H14ClNO4 [M+H]+ m/z, calc. 380.0684, found
380.0665.
(E)-3-(((3-hydroxy-4-methoxyphenyl)imino)methyl)-2-(4-
hydroxyphenyl)benzofuran-6-ol (7i) Compound 7i as
yellow solid (50 % yield). m.p.: 110–111 °C; IR (KBr) νmax
:
3017–2910 (O–H), 1609 (C=N), 1589, 1493, 1273, 837
cm−1; 1H NMR (DMSO; 300 MHz): δ = 3.783 (s, 3H,
OCH3), 6.74–6.767 (dd, 1H, J = 6.3 Hz, J = 1.8 Hz, ArH),
6.786–6.792 (d, 1H, J = 1.8 Hz, ArH), 6.832–6.858 (dd,
1H, J = 8.7 Hz, J = 1.5 Hz, ArH), 6.93–6.986 (m, 4H, ArH),
7.658–7.68 (d, 2H, J = 6.6 Hz, ArH), 8.151–8.172 (d, 1H, J
= 6.3 Hz, ArH), 8.689 (s, 1H, CH=N), 9.092 (s, 1H, OH),
9.71 (s, 1H, OH), 10.071 (s, 1H, OH). 13C NMR (DMSO-
d6, 101 MHz): δ = 159.5 (C, C-1), 158.9 (C, C-15), 156.6
(C, C-12), 155.1 (C, C-6), 151.8 (C, C-8), 147.5 (C, C-19),
146.8 (C, C-20), 146.1 (C, C-16), 131.0 (C, C-10, C-14),
130.2 (C, C-4), 123.6 (C, C-11, C-13), 120.6 (C, C-18),
118.8 (C, C-3), 116.5 (C, C-5), 113.3 (C, C-2), 113.2 (C, C-
9), 112.5 (C, C-17), 108.6 (C, C-21), 97.8 (C, C-7), 56.4
(CH3, CH3O); HRMS [ESI(+)-MS]: C22H17NO5 [M+H]+
m/z, calc. 376.1179, found 376.1165.
Acknowledgments This research was supported by the National
Natural Science Foundation, Beijing, China (to Dr. Jiang, No:
81202397; to Dr. Zhang, No: 31200597), the Shanghai Natural Sci-
ence Foundation Project, Shanghai, China (to Dr. Jiang, No:
12ZR1415300), and the International S&T Cooperation Program of
China (to Dr. Fu, No: 2014DFA41360)
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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