Cu-catalyzed consecutive hydroxylation and aerobic oxidative cycloetherification under microwave conditions: Entry to 2-arylbenzofuran-3-carboxylic acids

Article abstract of DOI:10.1021/jo502802k

A convenient one-pot synthesis of 2-arylbenzofuran-3-carboxylic acids from (E)-2-(2-bromophenyl)-3-phenylacrylic acids via Cu-catalyzed consecutive hydroxylation and aerobic oxidative cycloetherification under microwave conditions has been developed. This protocol employed the reagent combination of Cu(OAc)₂, 1,10-phen, and KOH in DMSO/H₂O (1:1), all of which are cost-effective, readily available, and easily removable from the reaction mixture. Utilizing this synthetic protocol, various 2-arylbenzofuran-3-carboxylic acids as well as the natural product moracin M have been synthesized in satisfactory yields under mild conditions.

Full text of DOI:10.1021/jo502802k

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Article
Cu-catalyzed Consecutive Hydroxylation and Aerobic
Oxidative Cycloetherification under Microwave
Conditions: Entry to 2-Arylbenzofuran-3-carboxylic Acids
Tianlong Xu, Ensheng Zhang, Dejian Wang, Yan Wang, and Yong Zou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502802k • Publication Date (Web): 02 Apr 2015
Downloaded from http://pubs.acs.org on April 7, 2015
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The Journal of Organic Chemistry
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Cu-catalyzed Consecutive Hydroxylation and Aerobic Oxida-
tive Cycloetherification under Microwave Conditions: Entry to
2-Arylbenzofuran-3-carboxylic Acids
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†,
†,
§
║
,‡
Tianlong Xu,†, Ensheng Zhang, Dejian Wang, Yan Wang, and Yong Zou*
§
§
†Guangzhou Institute of Chemistry, Chinese Academy of Science, Guangzhou 510650, China
‡School of Pharmaceutical Science, Sun Yat-sun University, Guangzhou 510006, China
§University of Chinese Academy of Sciences, Beijing 100039, China
║New Drug Research and Development Center, School of Pharmacy, Second Military Medical University, Shanghai, China
* E-mail: zou_jinan@163.com
ABSTRACT: A convenient one-pot synthesis of 2-arylbenzofuran-3-carboxylic acids from (E)-2-(2-bromophenyl)-3-phenylacrylic acids via
Cu-catalyzed consecutive hydroxylation and aerobic oxidative cycloetherification under microwave conditions has been developed. This
protocol employed the reagent combination of Cu(OAc)2, 1,10-phen, and KOH in DMSO/H2O (1:1), all of which are cost-effective, readily
available, and easily removable from the reaction mixture. Utilizing this synthetic protocol, various 2-arylbenzofuran-3-carboxylic acids as well
as the natural product Moracin M have been synthesized in satisfactory yields under mild conditions.
INTRODUCTION
3-Substituted 2-arylbenzofurans, especially the 3-carbonyl-derived 2-arylbenzofurans represent an important class of privileged structures
prevalent in natural products and active pharmaceutical ingredients.1 Compounds featuring this scaffold showed great therapeutic potential
for the treatment of various diseases such as cancers,2 infections,3 inflammations,4 immunosuppressions5 and convulsant symptoms.6 For in-
stance, the antitumor agent coumestrol7 and sphenostylisin A,8 the antioxidative natural product iteafuranal B,9 the anticomplement com-
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pound oryzafuran,10 the melanin synthesis inhibitor lespeflorins F211 as well as the transmembrane protein 16A (TMEM16A) inhibitor B1312
are all characterized by the 3-carbonyl-derived 2-arylbenzofuran motif (Fig. 1).
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Figure 1. Bioactive compounds containing 3-carbonyl-derived 2-arylbenzofuran scaffold.
Although the synthesis of specific 3-substituted 2-arylbenzofuran derivatives can be achieved individually, a general and compatible method
has not yet been established. From synthetic chemistry perspective, the 3-substituted 2-arylbenzofurans, especially the 3-carbonyl-derived 2-
arylbenzofurans have a common intermediate, namely, the 2-arylbenzofuran-3-carboxylic acids (2). Therefore, the efficient synthesis of 2 can
pave the way for the assembly of 3-substituted 2-arylbenzofurans as well as the decarboxylated products 2-arylbenzofurans, which were also
found to be an intriguing class of natural compounds.13 Generally, methods to access 2 mainly involved the transition-metal-mediated C-C
and C-O bond formation,14 and the oxidative reaction of 2-hydroxychalcones,15 as well as the rearrangement reactions of ethyl 2-(2-
methoxyphenyl)-3-oxo-3-phenylpropanoate, 5-benzoyl-5H-dibenzo[b, f]azepin-10(11H)-one and 2-benzyloxyaromatic cyanohydrin ester.16
The Zn-catalyzed condensation between benzyolacetates and p-benzoquinone reported by Kumar was also workable in the assembly of 5-
hydroxy-2-arylbenzofuran-3-carboxylic acids.12 Despite the advances in the synthesis of 2 and their derivatives, these reported methods still
suffered from the use of expensive transition-metal catalysts, the need of harsh reaction conditions, the necessity of preformed substrates,
limited structural diversity and functional group tolerability, as well as relatively low yields. Therefore, a facile, versatile and practical approach
for access to 2-arylbenzofuran-3-carboxylic acids (2) is greatly demanded.
Over the past decade, Cu-catalyzed reactions have emerged as powerful tools in organic synthesis.17 Various Cu-containing catalysts en-
able direct generation of structurally diversified compounds through the cleavage of C-X (X = H, C, Cl, Br, I) bonds and the construction of a
range of new carbon–heteroatom (C-N, C-O, C-S, C-P, C-Br, C-F, etc.) and carbon–carbon (C-C) bonds.18 Our group has also recently dis-
closed a Cu-catalyzed decarboxylation of (E)-2,3-diphenylacrylic acids, leading to the facile formation of a wide range of natural stilbenes and
derivatives.19 As part of our ongoing efforts for the development of new protocols in stilbenoid synthesis and biomass conversion,20 we herein
report a practical method for the assembly of 2-arylbenzofuran-3-carboxylic acids (2) from (E)-2-(2-bromophenyl)-3-arylacrylic acids (1)
and its application to the total synthesis of the natural product Moracin M.
RESULTS AND DISCUSSION
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Optimization of Reaction Conditions. At the outset, (E)-2-(2-bromo-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid (1aa)
were selected as a model substrate to screen the optimal reaction conditions (Table 1). To our delight, the corresponding product 2aa was
obtained in 38% yield when the reaction was performed in the presence of catalyst CuSO4 (20 mol %), ligand glycine (20 mol %), and base
NaOH (10 equiv) in H2O at reflux for 1 h under aerobic and microwave conditions (Table 1, entry 1). The structure of 2aa was confirmed by
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the H NMR spectra, in which the signal of vinylic proton disappeared, while both of the carboxylic and the phenolic active hydrogen still
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existed. HRMS (ESI-TOF) spectra of 2aa also confirmed the correctness of the molecular formula C17H14O6 (m/z 337.0678 [M + Na]+, calcd
for C17H14NaO6: 337.0683).
Table 1. Optimization of Reaction Conditionsa
Entry
1
Catalyst
Ligand
Base
Solvent
Yieldb
38
CuSO4
Glycine
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Cs2CO3
K3PO4
KOH
H2O
2
CuO
Glycine
H2O
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3
CuI
Glycine
H2O
22
4
Cu(OH)2
Cu2(OH)2CO3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Glycine
H2O
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5
Glycine
H2O
68
6
Glycine
H2O
70
7
-
H2O
trace
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8
DMAP
H2O
9
TMEDA
oxine
H2O
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23
a
H2O
42
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
1,10-phen
H2O
73
H2O
46
H2O
44
H2O
77
KOH
DMSO
80
KOH
DMF
78
KOH
PEG-400
DMSO-H2O(1:1)
DMSO-H2O(1:1)
DMSO-H2O(1:1)
DMSO-H2O(1:1)
DMSO-H2O(1:1)
DMSO-H2O(1:1)
82
KOH
90
KOH
88c
60d
76e
tracef
65g
KOH
KOH
KOH
KOH
Reaction conditions: 1aa (1.0 mmol), Cu salt (0.2 mmol, 20 mol %), ligand (0.2 mmol, 20 mol %), base (10.0 mmol), solvent (5 ml), in an open
flask, at 110 °C for 1 h under air and microwave irradiation. b Isolated yield. c 50 mol % Cu salt. d 10 mol % Cu salt. e Reaction performed at 100 °C.
f
Under N2 atmosphere. g 6.0 equiv KOH was used.
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To obtain a more satisfactory result, different copper catalysts, ligands, bases, and solvents were used to optimize the reaction conditions
(Table 1). Investigation on various copper catalysts showed that the Cu(OAc)2 (20 mol %) gave the best result, while other copper species
such as CuO, CuI, CuSO4, Cu(OH)2 and Cu2(OH)2CO3 were found to be inferior in this reaction (Table 1, entries 1-6). Moreover, a control
experiment showed that only trace amount of 2aa could be detected (monitored by TLC) in the absence of glycine (Table 1, entry 7), indi-
cating that the addition of a ligand is indispensable in this reaction. Subsequently, various other ligands such as DMAP, TMEDA, 1,10-phen
(1,10-phenanthroline), oxine, were screened, among which 1,10-phen proved to be the most optimal (Table 1, entries 6-11). Investigation of
bases (NaOH, KOH, Cs2CO3, and K3PO4) showed that KOH was most effective, while others were found to be less favorable (Table 1, en-
tries 11-14). Solvent screening showed that reactions performed in DMF, DMSO, and H2O slightly decreased the product yields (Table 1,
entries 14-16). Changing the solvent to the versatile and eco-friendly PEG-400 gave rise to a better yield (82%, Table 1, entry 17). We were
pleased to find that an excellent yield (90%) of 2aa could be obtained when DMSO-H2O (1/1, v/v) was used as the solvent (Table 1, entry
18). Further inspection of the reaction conditions revealed that there was no significant improvement in the yield when the catalyst loading
increased to 50 mol % (Table 1, entry 19), whereas reducing the amount of Cu(OAc)2 to 10 mol % decreased the yield to 60% (entry 20). In
addition, experiment showed that when the temperature dropped from 110 °C to 100 °C, a lower yield was obtained, with the detection
(monitored by TLC) of appreciable amount of unreacted substrate 1aa (Table 1, entry 21). It was worth noting that carrying out the reaction
under nitrogen atmosphere dramatically decreased the yield of 2aa, suggesting that molecular oxygen might play an important role in this
transformation (Table 1, entry 22). Result showed that the yield of 2aa decreased to 65% when reducing the amount of KOH to 6.0 equiv
(Table 1, entry 23). Therefore, the optimal reaction conditions for the synthesis of 2-arylbenzofuran-3-carboxylic acids are established with
Cu(OAc)2 (20 mol %), 1,10-phen (20 mol %), and KOH (10.0 equiv) in DMSO-H2O (1:1) at 110 °C under air and microwave irradiation.
The Scope and Generality of the Substrates. To test the scope and generality of the reaction conditions, a variety of substituted (E)-2-
(2-bromophenyl)-3-phenylacrylic acids (1) were prepared and subjected under our optimized conditions (Table 2). It was worth mentioning
that the substrates 1 were readily obtained in high yields via Perkin condensation between commercially available ortho-bromophenylacetic
acids and benzaldehydes (Scheme 1). In consistent with our previous studies, 20h compounds 1 which possessed an E-configuration (but had a
cis-phenyl relationship) were obtained as the major products through Perkin condensation.
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Scheme 1. Preparation of (E)-2-(2-bromophenyl)-3-phenylacrylic acids (I).
As we expected, these (E)-2-(2-bromophenyl)-3-phenylacrylic acids (1) bearing various substituents were successfully transformed into the
desired 2-arylbenzofuran-3-carboxylic acids (2) in moderate to excellent yields under our typical conditions (Table 2). Unlike previously
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reported methods,14a, c we have found that substrates containing a hydroxyl group were compatible with these conditions, and afforded higher
yields compared to those with a methoxyl or ethoxyl group (Table 2, entries 1, 8 vs. 21, 27). Moreover, substrate bearing two hydroxyl groups
gave higher yield than substrate with only one hydroxyl group. For example, the tandem reaction of (E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-
hydroxy-3,5-dimethoxyphenyl)acrylic acid (1ac) with Cu(OAc)2, 1,10-phen, and KOH in DMSO-H2O (1:1) provided the corresponding
product 2ac in 85% isolated yield (Table 2, entry 3), whereas a lower yield (74%) of product 2be was obtained when (E)-2-(2-
bromophenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylic acid (1be) was
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Table 2. Scope of the Copper-Catalyzed 2-arylbenzofuran-3-carboxylic Acida
entry
substrate
product
yield(%)b
90
entry
16
substrate
product
yield(%)b
NDc
1
2ap
2aq
2aa
2ab
1ap
1aa
2
3
88
85
17
18
80
75
1aq
1ar
1ab
2ar
2ac
1ac
4
5
84
83
19
20
67
64
2ad
2as
2at
1as
1ad
2ae
2af
1at
1ae
6
7
76
98
21
22
70
79
2ba
2bb
1ba
1af
2ag
1bb
1ag
8
95
87
88
23
24
25
72
84
74
2bc
2bd
2ah
2ai
1bc
1ah
9
1bd
1ai
1aj
10
2aj
2be
1be
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Br COOH
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83
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4
2ak
2al
2bf
OH 1bf
OCH3
1ak
12
46
27
5
2bg
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9
1bg
1al
1am
1an
13
14
15
a
42
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66
64
68
2am
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2ca
1ca
1cb
45
2cb
2an
NDc
2ao
2cc
1ao
1cc
Reaction conditions: 1 (1.0 mmol), Cu(OAc)2 (0.2 mmol, 20 mol %), 1,10-phen (0.2 mmol, 20 mol %), KOH (10.0 mmol), DMSO-H2O
(1:1) (5 ml), under air in an open flask, at 110 °C for 1h under microwave irradiation. b Isolated yield. c ND, No desired product.
used as the reactant (Table 2, entry 25). Similarly and remarkably, substrate 1ag which also contained two hydroxyl groups gave 6-hydroxy-2-
(4-hydroxyphenyl)benzofuran-3-carboxylic acid (2ag) quantitatively under typical conditions, which might be at least, due in part to the
unexceptionable solubility in aqueous DMSO (Table 2, entry 7). In addition, the reactivity of 1ah having an ethoxyl group was higher than
1ae bearing a methoxyl group (Table 2, compare entry 5 with 8). This correlation was also reinforced by substrates 1bb and 1bg (Table 2,
entries 22 and 27). It could be concluded from the above results that the ethoxyl group was advantageous over the methoxyl group to give the
corresponding products in this consecutive process. Halogen-substituted reactants were also subjected to our optimal reaction conditions and
were smoothly transformed into the desired 2-arylbenzofuran-3-carboxylic acids (Table 2, entries 9-11). Results showed that chlorine-
substituted compound afforded a comparable yield (87%) in comparison with fluoro-substituted ones (88%) (Table 2, entries 9-10). On the
other hand, (E)-2-(2-bromo-4-hydroxyphenyl)-3-(2,4-dichlorophenyl)acrylic acid (1ak) which contained two chlorine atoms gave rise to 2-
(2,4-dichlorophenyl)-6-hydroxybenzofuran-3-carboxylic acid (2ak) in a satisfactory yield (78%, Table 2, entry 11). To our delight, substrates
bearing electron-withdrawing substituents such as CF3, CN and COOH were also compatible with this methodology, giving the desired
products (2al-2an) in moderate yields (46%, 42% and 45% respectively, entries 12-14). However, substrate 1ao which contained a nitro
group failed to give the corresponding product 2ao under typical reaction conditions (Table 2, entry 15). It was notable that substrates con-
taining a heterocyclic aromatic moiety such as furan (1aq) and thiophene (1ar) were found to be smoothly transformed into the correspond-
ing products in moderate to good yields (80% and 75%, respectively), whereas no desired product was detected when substrate with a pyri-
dine ring (1ap) was used (Table 2, entries 16-18). Interestingly, substrate bearing a naphthalene ring (1as) could also afford 2-
arylbenzofuran-3-carboxylic acid (2as) in 67% yield (Table 2, entry 19). We were pleased to find that substrate (2E,4E)-2-(2-bromo-4-
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hydroxyphenyl)-5-phenylpenta-2,4-dienoic acid (1at) was also amenable for this transformation, generating the corresponding (E)-6-
hydroxy-2-styrylbenzofuran-3-carboxylic acid (2at) in moderate yield (64%, Table 2, entry 20). Moreover, (E)-2-(2-bromophenyl)-3-
phenylacrylic acid (1bc) which contained neither electron-donating nor electron-withdrawing group also gave rise to the corresponding
product 2bc in moderate yield (72%, Table 2, entry 23). It was worth noting that substrates having a methoxyl group adjacent to a bromine
such as 1ca-1cc afforded the desired products 2ca-2cc in slightly lower yields (66%, 64% and 68%, respectively), which might be due to the
steric hindrance of the ortho-methoxyl group (Table 2, entries 28-30).
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Total Synthesis of Natural Product Moracin M. Next, we applied this protocol to the total synthesis of the natural product Moracin M,
which was isolated from the stem bark of Milicia excelsa and was reported to have antimicrobial and anti-inflammatory activity (Scheme 2).21
To our delight, the desired reactions were successfully carried out in gram scale. The Perkin condensation of 2-bromo-4-hydroxyphenylacetic
acid and 3,5-dimethoxybenzaldehyde provided (E)-2-(2-bromo-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid (1aa). Subsequently,
a consecutive hydroxylation and oxidative C-O coupling of 1aa (1.89 g, 5mmol) catalyzed by Cu(OAc)2, 1,10-phen, KOH in DMSO-H2O
(1:1) gave 2aa (1.40 g) in 89% yield. Then, decarboxylation of 2aa promoted by CuI/1,10-phen/PEG-40019 afforded 6-hydroxy-2-(3,5-
dimethoxyphenyl)benzofuran (3). Finally, demethylation of 3 using AlCl3/DCE, afforded Moracin M in 69 % overall yield, whose spectral
data were in good agreement with those reported in literature.21b
Scheme 2. Total synthesis of the natural product Moracin M.
Mechanism Investigations. In order to shed light on the possible mechanism of the cyclization reaction, control experiments were car-
ried out (Scheme 3). It was observed that no desired product 2-phenylbenzofuran-3-carboxylic acid (2bc) was obtained in the absence of
KOH, revealing the necessity of base in this transformation (Scheme 3, eq 1). However, an intermediate (E)-2-(2-hydroxyphenyl)-3-
phenylacrylic acid (4bc) was isolated in 75% yield and only trace amount of desired product 2bc was detected (monitored by TLC) when
7
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this reaction was performed under N2 atmosphere (Scheme 3, eq 2). When 2.0 equiv. TBHP was added into the reaction system under N2
atmosphere, the acid 2bc was achieved in 56% yield (Scheme 3, eq 3), indicating that an oxidative process might exist in this protocol. More-
over, the desired product 2bc was obtained in 48% yield in the presence of 3.0 equiv. Cu(OAc)2 under N2 atmosphere (Scheme 3, eq 4). We
reasoned that the excess amount of Cu(OAc)2 might act as the oxidant in place of air or TBHP, and took part in the oxidative C-O coupling
process. Further investigation showed that the isolated intermediate 4bc could be efficiently transformed into 2bc in 95% yield under
Cu(OAc)2/1,10-phen/air without the use of KOH (Scheme 3, eq 5).
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Scheme 3. Control Experiments.
Based on the above mentioned control experiments and the relevant literatures,17e, 18a, d two plausible pathways for this consecutive process
were proposed (Scheme 4). In path A, the hydroxylated intermediate A was initially formed in the presence of Cu(II) salt and KOH. The
coordination of Cu(II) catalyst with A formed complex B, which is nonplanar between the phenyl rings. 22 Complex B would then undergo a
ligand assisted concerted metalation-deprotonation (CMD)23 to give the complex C in reversed configuration. The decomplexation of com-
plex C produced complex D, followed by reductive elimination to afford the desired product 2 with concomitant formation of Cu(0). The
Cu(0) could then be regenerated to give Cu(II) species under air. Alternatively, coordination of Cu(II) species with A could give the ƞ2 π
complex E,24 thus activating the C=C bond and resulting in the nucleophilic attack by the adjacent phenolic group to afford the complex F in
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reversed configuration. Subsequent β-hydride elimination accompanied by reductive elimination would give 2 and Cu(0), which can be re-
oxidized by air to complete the catalytic circle (path B).
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Scheme 4. Plausible Mechanism.
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CONCLUSIONS
In summary, we have developed a practical and efficient method for the synthesis of 2-arylbenzofuran-3-carboxylic acids from readily
available (E)-2-(2-bromophenyl)-3-arylacrylic acids. This tandem approach involved the copper catalyzed hydroxylation and aerobic oxida-
tive cycloetherification process under microwave irradiation. The consecutive C-Br bond cleavage, C-H functionalization and C-O bond
formation were characteristics of this process. The thus obtained 2-arylbenzofuran-3-carboxylic acids can serve as versatile building blocks for
further synthesis of various heterocyclic molecules. Moreover, the total synthesis of the natural product Moracin M has also been achieved
efficiently under this strategy.
EXPERIMENTAL SECTION
General information. All of the reactions were generally run under air conditions. Unless otherwise noted, materials were obtained com-
mercially and used without further purification. Reactions were monitored by TLC and column chromatography was performed on silica gel
(300-400 mesh) using ethyl acetate/petroleum ether as the eluent (60-90 °C). Microwave reactions were carried out with a scientific WBFY
microwave reactor in a flask connected with a condenser. The reaction temperatures were detected in real time using an infrared thermometer
and the ramp time (approximate 0.5 min) is included as part of the reaction time. All melting points were determined on a Thiele apparatus
without correction. 1H and 13C NMR spectra were recorded on a 400 MHz spectrometer (400 MHz for 1H NMR and 100 MHz for 13C NMR)
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at 295 K using DMSO-d6 as the solvent. Chemical shift values (δ) were given in parts per million (ppm) using tetramethylsilane (TMS) as the
internal standard. HRMS spectra analyses were performed on a LC-Q-TOF (ESI) apparatus.
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Typical procedure for the synthesis of (E)-2-(2-bromo-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid (1aa). 2-Bromo-4-
hydroxyphenylacetic acid (2.31 g, 10 mmol), 3,5-dimethoxylbenzaldehyde (1.66 g, 10 mmol), triethylamine (4.16 ml, 30 mmol), acetic an-
hydride (2.84 ml, 30 mmol) were added to a 25 ml round bottom flask. The flask was then placed into an oil bath and raised the temperature
to 110 °C with stirring for 6 h. After completion of the reaction (monitored by TLC), the mixture was poured into ice-cold water and acidified
with concentrated hydrochloric acid with stirring. A white solid was obtained and collected by filtration. It was dissolved in 10% aq NaOH
and the aqueous solution was decolored by extracting with EtOAc. The organic layers were separated and the aqueous layer was acidified with
concd. HCl to pH 3~4. The precipitated crude product was collected by filtration and recrystallized from EtOH to afford 1aa as a white solid.
Yield: 3.60 g (95%); mp 188-190 °C; 1H NMR (400 MHz, DMSO-d6): δ = 12.64 (s, 1H), 9.99 (s, 1H), 7.69 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H),
6.97 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 6.42 (s, 1H), 6.27 (d, J = 2.0 Hz, 2H), 3.56 (s, 6H); 13C NMR (100 MHz, DMSO-d6):
δ = 167.7, 160.1, 157.9, 139.8, 136.1, 132.9, 131.8, 127.9, 123.7, 119.0, 115.4, 108.0, 101.6, 55.0; IR (KBr, cm-1): 3625, 3476, 1692, 1660,
1592, 1500, 1464, 1285, 1157, 829, 681; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H1579BrNaO5: 400.9995; found: 400.9999.
(E)-2-(2-bromo-4-hydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)acrylic acid (1ab). White solid; yield: 3.50 g (96%); mp > 200
°C; 1H NMR (400 MHz, DMSO-d6): δ = 12.39 (s, 1H), 9.95 (s, 1H), 8.98 (s, 1H), 7.60 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz,
1H), 6.78-6.82 (m, 2H), 6.56 (dd, J = 8.8, 1.6 Hz, 1H), 6.47 (d, J = 1.6 Hz, 1H), 3.73 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 168.0,
157.7, 149.0, 146.0, 140.0, 131.7, 129.5, 128.1, 127.1, 123.8, 122.7, 119.1, 117.0, 115.5, 111.6, 55.5; IR (KBr, cm-1): 3596, 3502, 1673, 1605,
1526, 1494, 1438, 1267, 1133, 880, 763; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1379BrNaO5: 386.9839; found: 386.9845.
(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylic acid (1ac). White solid; yield: 3.79 g (96%); mp 146-
148 °C; 1H NMR (400 MHz, DMSO-d6): δ = 12.40 (s, 1H), 9.96 (s, 1H), 8.93 (s, 1H), 7.68 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 8.0
Hz, 1H), 6.85 (dd, J = 8.4, 2.4 Hz, 1H), 6.39 (s, 2H), 3.50 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 168.0, 157.9, 147.5, 140.6, 137.4,
132.1, 129.1, 128.4, 124.4, 124.1, 119.0, 115.5, 108.1, 55.5; IR (KBr, cm-1):3619, 3501,1690, 1655, 1615, 1513, 1453, 1268, 1115, 878, 837;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H1579BrNaO6: 416.9944; found: 416.9952.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-phenylacrylic acid (1ad). White solid; yield: 2.99 g (94 %); mp > 200 °C; H NMR (400 MHz,
DMSO-d6): δ = 12.62 (s, 1H), 9.99 (s, 1H), 7.76 (s, 1H), 7.22-7.27 (m, 3H), 7.07-7.11 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 8.4,
2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.7, 157.8, 139.7, 134.3, 132.5, 131.7, 129.9, 129.3, 128.5, 127.8, 123.7, 119.0, 115.4; IR
(KBr, cm-1): 3304, 3073, 1681, 1600, 1576, 1493, 1447, 1178, 1041, 877, 783; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H1179BrNaO3:
340.9784; found: 340.9786.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid (1ae). White solid; yield: 3.58 g (98%); mp 186-188
°C; 1H NMR (400 MHz, DMSO-d6): δ = 12.36 (s, 1H), 10.29 (s, 1H), 9.56 (s, 1H), 7.66 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 8.4 Hz,
1H), 6.83 (dd, J = 8.4, 2.4 Hz, 1H), 6.65-6.69 (m, 2H), 6.50 (s, 1H), 3.42 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 168.1, 157.8, 148.4,
147.1, 140.3, 132.1, 128.8, 128.4, 125.7, 125.1, 124.1, 119.1, 115.5, 115.4, 112.9, 54.9; IR (KBr, cm-1): 3383, 3329, 1640, 1597, 1492, 1455,
1261, 1119, 857, 772; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1379BrNaO5: 386.9839; found: 386.9846.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-methoxyphenyl)acrylic acid (1af). White solid; yield: 3.35 g (96%); mp 170-172 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 12.45 (s, 1H), 9.98 (s, 1H), 7.71 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.4
Hz, 1H), 6.79-6.83 (m, 3H), 3.72 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 168.0, 160.2, 157.8, 139.6, 131.8, 131.8, 129.7, 128.1, 126.8,
123.8, 119.1, 115.5, 114.1, 55.2; IR (KBr, cm-1): 3624, 3351, 1651, 1601, 1572, 1510, 1460, 1255, 1173, 882, 830; HRMS (ESI-TOF): m/z
[M + Na]+ calcd for C16H1379BrNaO4: 370.9889; found: 370.9892.
(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-hydroxyphenyl)acrylic acid (1ag). White solid; yield: 3.18 g (95%); mp 126-128 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 12.36 (s, 1H), 9.96 (s, 1H), 9.92 (s, 1H), 7.66 (s, 1H), 7.10 (s, 1H), 6.89-6.97 (m, 3H), 6.80 (d, J = 8.0 Hz,
1H), 6.61 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 168.1, 158.8, 157.7, 140.0, 132.0, 131.8, 128.6, 128.3, 125.3, 123.9, 119.1,
115.5, 115.4; IR (KBr, cm-1): 3586, 3437, 1668, 1604, 1495, 1415, 1254, 1174, 879, 742; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C15H1179BrNaO4: 356.9733; found: 356.9738.
(E)-2-(2-bromo-4-hydroxyphenyl)-3-(3-ethoxy-4-hydroxyphenyl)acrylic acid (1ah). White solid; yield: 3.71 g (98%); mp 180-181
°C; 1H NMR (400 MHz, DMSO-d6): δ = 12.36 (s, 1H), 9.96 (s, 1H), 9.47 (s, 1H), 7.64 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz,
1H), 6.82 (dd, J = 8.4, 2.4 Hz, 1H), 6.66-6.71 (m, 2H), 6.43 (s, 1H), 3.63 (q, J = 8.0 Hz, 2H), 1.15 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6): δ = 168.0, 157.8, 148.6, 146.1, 140.3, 131.9, 128.5, 128.4, 125.6, 125.3, 124.0, 119.0, 115.5, 115.4, 113.7, 63.1, 14.5; IR (KBr, cm-
1): 3634, 3444, 1653, 1596, 1494, 1434, 1284, 1122, 880, 821; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H1579BrNaO5: 400.9995;
found: 401.0002.
(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-chlorophenyl)acrylic acid (1ai). White solid; yield: 3.42 g (97 %); mp 174-176 °C; 1H NMR
(400 MHz, DMSO-d6): δ = 12.74 (s, 1H), 10.03 (s, 1H), 7.76 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 3H), 6.95 (d, J = 8.4 Hz,
1H), 6.79 (dd, J = 8.4, 2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.6, 158.0, 138.4, 133.9, 133.3, 133.2, 131.7, 131.5, 128.6, 127.4,
123.5, 119.1, 115.5; IR (KBr, cm-1): 3626, 3492, 1683, 1600, 1491, 1433, 1409, 1212, 877, 731; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C15H1079Br35ClNaO3: 374.9394; found: 374.9399.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-fluorophenyl)acrylic acid (1aj). White solid; yield: 3.23 g (96%); mp > 200 °C; H NMR
(400 MHz, DMSO-d6): δ = 12.65 (s, 1H), 10.02 (s, 1H), 7.77 (s, 1H), 7.10-7.14 (m, 5H), 6.96 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz,
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1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.8, 162.4 (d, JF-C = 247.2 Hz), 158.0, 138.6, 132.2, 132.1 (d, JF-C = 8.7 Hz), 131.7, 131.0 (d,
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4JF-C = 2.3 Hz), 127.6, 123.7, 119.2, 115.6, 115.6 (d, JF-C = 21.4 Hz); IR (KBr, cm-1): 3635, 3302, 1691, 1597, 1511, 1425, 1322, 1157, 880,
798; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H1079BrFNaO3: 358.9690; found: 358.9692.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(2,4-dichlorophenyl)acrylic acid (1ak). White solid; yield: 3.72 g (96%); mp 180-182 °C; H
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NMR (400 MHz, DMSO-d6): δ = 12.96 (s, 1H), 10.04 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 1.6 Hz, 1H), 7.05 (d, J
= 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.71-6.77 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 167.1, 158.0, 135.9, 134.7, 134.7, 134.1,
132.0, 131.9, 130.9, 129.1, 127.2, 126.4, 123.6, 119.0, 115.2; IR (KBr, cm-1): 3651, 3420, 1666, 1604, 1497, 1463, 1423, 1281, 1104, 861, 777;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H979Br35Cl2NaO3: 408.9004; found: 408.9007.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)acrylic acid (1al). Wite solid; yield: 3.40 g (88%); mp 86-88 °C;
1H NMR (400 MHz, DMSO-d6): δ = 12.88 (s, 1H), 10.06 (s, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.11 (s,
1H), 6.96 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.5, 158.1, 138.6, 138.1, 135.2, 131.7, 130.3,
129.0 (2JF-C = 31.5 Hz), 127.2, 125.3 (3JF-C = 2.3 Hz), 124.0 (1JF-C = 270 Hz), 123.5, 119.2, 115.5; IR (KBr, cm-1): 3629, 3378, 1687, 1610,
1494, 1421, 1278, 1170, 927, 873; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1079BrF3NaO3: 408.9663; found: 408.9665.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-cyanophenyl)acrylic acid (1am). Yellow solid; yield: 2.89 g (84%); mp > 200 °C; H NMR
(400 MHz, DMSO-d6): δ =12.56 (s, 1H), 9.49 (s, 1H), 7.81 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 2.0 Hz,
1H), 6.95 (d, J = 8.4 Hz, 1H), 6.79 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.4, 158.1, 139.3, 137.6, 136.0, 132.3,
131.7, 130.3, 127.1, 123.4, 119.2, 118.5, 115.5, 111.2; IR (KBr, cm-1): 3534, 3448, 1679, 1600, 1492, 1421, 1265, 1037, 831, 761; HRMS
(ESI-TOF): m/z [M + Na]+ calcd for C16H1079BrNaNO3: 365.9742; found: 365.9742.
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(E)-4-(2-(2-bromo-4-hydroxyphenyl)-2-carboxyvinyl)benzoic acid (1an). White solid; yield: 2.72 g (75%); mp > 200 °C; H NMR
(400 MHz, DMSO-d6): δ = 12.91 (s, 2H), 10.03 (s, 1H), 7.81 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 2.4 Hz,
1H), 6.94 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.6, 166.8, 158.1, 138.8, 138.7, 134.7,
131.8, 131.0, 129.9, 129.3, 127.4, 123.6, 119.2, 115.5; IR (KBr, cm-1): 3478, 3074, 1689, 1608, 1492, 1415, 1270, 1120, 865, 783; HRMS
(ESI-TOF): m/z [M + Na]+ calcd for C16H1179BrNaO5: 384.9688; found: 384.9685.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(4-nitrophenyl)acrylic acid (1ao). Gray solid; yield: 2.62 g (72%); mp 114-116 °C; H NMR
(400 MHz, DMSO-d6): δ = 13.34 (s, 1H), 10.08 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.85 (s, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 2.4 Hz,
1H), 6.95 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.5, 158.3, 146.9, 141.4, 137.1, 136.8,
131.7, 130.6, 130.5, 127.1, 123.5, 123.3, 119.2, 115.5; IR (KBr, cm-1): 3648, 3187, 1687, 1625, 1594, 1490, 1419, 1272, 1039, 860, 734;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H1079BrNaNO5: 385.9640; found: 385.9641.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(pyridin-4-yl)acrylic acid (1ap). Yellow solid; yield: 2.62 g (82%); mp > 200 °C; 1H NMR (400
MHz, DMSO-d6): δ = 12.95 (s, 1H), 10.11 (s, 1H), 8.45 (d, J = 6.4 Hz, 2H), 7.73 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.95-7.00 (m, 3H), 6.79
(dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.2, 158.2, 149.9, 141.8, 137.1, 137.0, 131.6, 126.9, 123.6, 123.3, 119.2,
115.5; IR (KBr, cm-1): 3237, 3091, 1668, 1604, 1492, 1421, 1278, 1049, 879, 819; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C14H1079BrNaNO3: 341.9742; found: 341.9742.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(furan-2-yl)acrylic acid (1aq). White solid; yield: 2.41 g (78%); mp > 200 °C; H NMR (400
MHz, DMSO-d6): δ = 12.73 (s, 1H), 10.02 (s, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.84 (dd, J =
8.4, 2.0 Hz, 1H), 6.48 (s, 1H), 5.91 (d, J = 3.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.4, 157.9, 150.4, 145.3, 131.5, 129.6, 127.7,
127.3, 123.1, 119.0, 115.3, 114.5, 112.6; IR (KBr, cm-1): 3270, 3077, 1677, 1612, 1484, 1467, 1421, 1251, 1193, 871, 750; HRMS (ESI-TOF):
m/z [M + Na]+ calcd for C13H979BrNaO4: 330.9582; found: 330.9583.
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(E)-2-(2-bromo-4-hydroxyphenyl)-3-(thiophen-2-yl)acrylic acid (1ar). Yellow solid; yield: 2.43 g (75%); mp > 200 °C; H NMR
(400 MHz, DMSO-d6): δ = 12.53 (s, 1H), 10.06 (s, 1H), 8.03 (s, 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.45 (d, J = 2.8 Hz, 1H), 7.12 (d, J = 2.4 Hz,
1H), 7.03-7.06 (m, 2H), 6.86 (dd, J = 8.4, 2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.5, 158.6, 138.1, 134.2, 133.9, 132.4, 132.0,
128.9, 126.9, 126.7, 124.3, 119.4, 115.8; IR (KBr, cm-1): 3598, 3380, 1662, 1606, 1492, 1419, 1276, 1214, 867, 711; HRMS (ESI-TOF): m/z
[M + Na]+ calcd for C13H979BrNaO3S: 346.9353; found: 346.9353.
(E)-2-(2-bromo-4-hydroxyphenyl)-3-(naphthalen-1-yl)acrylic acid (1as). White solid; yield: 3.06 g (83%); mp 197-199 °C; 1H NMR
(400 MHz, DMSO-d6): δ = 12.82 (s, 1H), 9.90 (s, 1H), 8.38 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4 Hz,
1H), 7.55-7.63 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.01-7.03 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.0, 2.4 Hz, 1H); 13C NMR (100
MHz, DMSO-d6): δ = 167.6, 157.6, 137.8, 135.6, 133.0, 132.2, 131.9, 131.3, 128.9, 128.6, 127.7, 126.8, 126.7, 126.3, 125.2, 124.3, 123.9,
118.8, 114.9; IR (KBr, cm-1): 3655, 3423, 1666, 1604, 1490, 1415, 1268, 1187, 879, 771; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C19H1379BrNaO3: 390.9946; found: 390.9947.
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(2E,4E)-2-(2-bromo-4-hydroxyphenyl)-5-phenylpenta-2,4-dienoic acid (1at). Yellow solid; yield: 2.93 g (85%); mp 134-136 °C; H
NMR (400 MHz, DMSO-d6): δ = 12.50 (s, 1H), 10.00 (s, 1H), 7.53 (d, J = 11.2 Hz, 1H), 7.28-7.41 (m, 5H), 7.17 (d, J = 15.2 Hz, 1H), 7.09
(d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.84 (dd, J = 8.4, 2.4 Hz, 1H), 6.48 (dd, J = 15.6, 11.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
δ = 167.4, 157.8, 140.2, 136.0, 133.0, 132.7, 129.1, 129.0, 129.0, 127.1, 126.9, 124.2, 123.9, 118.9, 114.8; IR (KBr, cm-1): 3620, 3489, 1655,
1608, 1500, 1425, 1278, 1160, 883, 750; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H1379BrNaO3: 366.9940; found: 366.9940.
(E)-2-(2-bromophenyl)-3-(3,5-dimethoxyphenyl)acrylic acid (1ba). White solid; yield: 3.52 g (97%); mp 148-150 °C; 1H NMR (400
MHz, DMSO-d6): δ = 12.78 (s, 1H), 7.73-7.75 (m, 2H), 7.42 (td, J = 7.6, 0.8 Hz, 1H), 7.33 (td, J = 7.6, 1.6 Hz, 1H), 7.21 (dd, J = 7.6, 1.6 Hz,
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1H), 6.41 (t, J = 2.0 Hz, 1H), 6.23 (d, J = 2.4 Hz, 2H), 3.52 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 167.3, 160.2, 139.9, 137.9, 135.8,
132.9, 132.5, 131.3, 129.8, 128.2, 123.7, 108.0, 101.8, 55.0; IR (KBr, cm-1): 3470, 3068, 1667, 1596, 1460, 1428, 1281, 1161, 841, 740; HRMS
(ESI-TOF): m/z [M + Na]+ calcd for C17H1579BrNaO4: 385.0046; found: 385.0048.
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(E)-2-(2-bromophenyl)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid (1bb). White solid; yield: 3.42 g (98%); mp 74-76 °C; 1H NMR
(400 MHz, DMSO-d6): δ = 12.53 (s, 1H), 9.61 (s, 1H), 7.75 (dd, J = 8.0, 0.8 Hz, 1H), 7.71 (s, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.33 (td, J =
7.6, 1.6 Hz, 1H), 7.23 (dd, J = 7.6, 1.6 Hz, 1H), 6.64-6.69 (m, 2H), 6.41 (s, 1H), 3.33(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 167.6,
148.5, 147.2, 140.1, 138.4, 132.6, 131.6, 129.6, 128.9, 128.3, 125.4, 125.3, 124.1, 115.4, 112.7, 54.8; IR (KBr, cm-1): 3565, 3470, 1681, 1594,
1526, 1423, 1249, 1129, 815, 732; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H1379BrNaO4: 370.9889; found: 370.9887.
(E)-2-(2-bromophenyl)-3-phenylacrylic acid (1bc). White solid; yield: 2.91 g (96%); mp 120-122 °C; 1H NMR (400 MHz, DMSO-d6):
δ = 12.77 (s, 1H), 7.82 (s, 1H), 7.73 (dd, J = 7.6, 1.2 Hz, 1H), 7.40 (td, J = 7.6, 1.2 Hz, 1H), 7.34 (td, J = 7.6, 1.6 Hz, 1H), 7.18-7.30 (m, 4H),
7.04 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.3, 139.9, 137.7, 134.1, 132.6, 131.2, 129.9, 129.9, 129.5, 128.6, 128.6,
128.2, 123.7; IR (KBr, cm-1): 3486, 3057, 1685, 1620, 1471, 1420, 1290, 1211, 739, 688; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C15H1179BrNaO2: 324.9835; found: 324.9833.
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(E)-2-(2-bromophenyl)-3-(4-hydroxyphenyl)acrylic acid (1bd). White solid; yield: 3.12 g (98%); mp 182-184 °C; H NMR (400
MHz, DMSO-d6): δ = 12.51 (s, 1H), 9.95 (s, 1H), 7.72-7.74 (m, 2H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.33 (td, J = 7.6, 1.6 Hz, 1H), 7.20 (dd, J
= 7.6, 1.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 167.7, 159.1, 140.1, 138.3, 132.6,
132.1, 131.4, 129.7, 128.8, 128.3, 125.1, 124.0, 115.6; IR (KBr, cm-1): 3585, 3358, 1672, 1602, 1508, 1468, 1423, 1285, 1170, 835, 736;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H1179BrNaO3: 340.9784; found: 340.9787.
(E)-2-(2-bromophenyl)-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylic acid (1be). White solid; yield: 3.64 g (96%); mp 188-190 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 12.52 (s, 1H), 8.96 (s, 1H), 7.75-7.77 (m, 1H), 7.73 (s, 1H), 7.46 (td, J = 7.6, 0.8 Hz, 1H), 7.33 (td, J = 7.6,
1.6 Hz, 1H), 7.25 (dd, J = 7.6, 1.6 Hz, 1H), 6.35 (s, 2H), 3.45 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 167.5, 147.5, 140.5, 138.4, 137.5,
132.6, 131.6, 129.6, 129.2, 128.3, 124.1, 124.1, 108.1, 55.5; IR (KBr, cm-1): 3539, 3510, 1672, 1615, 1589, 1518, 1467, 1269, 1154, 824, 740;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H1579BrNaO5: 400.9995; found: 400.9999.
(E)-2-(2-bromophenyl)-3-(3-hydroxy-4-methoxyphenyl)acrylic acid (1bf). White solid; yield: 3.31 g (95%); mp 176-178 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 12.50 (s, 1H), 8.97 (s, 1H), 7.72 (dd, J = 7.6, 0.8 Hz, 1H), 7.65 (s, 1H), 7.41 (td, J = 7.6, 0.8 Hz, 1H), 7.33
(td, J = 7.6, 1.6 Hz, 1H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 8.4, 2.0 Hz, 1H), 6.41 (d, J = 2.0 Hz, 1H), 3.73
(s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 167.6, 149.2, 146.1, 140.0, 138.1, 132.6, 131.3, 129.8, 129.7, 128.2, 126.8, 123.9, 122.7, 117.0,
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111.7, 55.5; IR (KBr, cm-1): 3492, 3078, 1677, 1610, 1510, 1439, 1266, 1133, 873, 733; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C16H1379BrNaO4: 370.9889; found: 370.9892.
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(E)-2-(2-bromophenyl)-3-(3-ethoxy-4-hydroxyphenyl)acrylic acid (1bg). White solid; yield: 3.52 g (97%); mp 160-162 °C; 1H NMR
(400 MHz, DMSO-d6): δ = 12.51 (s, 1H), 9.52 (s, 1H), 7.75 (dd, J = 8.0, 0.8 Hz, 1H), 7.70 (s, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.33 (td, J =
7.6, 2.0 Hz, 1H), 7.23 (dd, J = 7.6, 2.0 Hz, 1H), 6.66-6.71 (m, 2H), 6.36 (d, J = 1.6 Hz, 1H), 3.51 (q, J = 8.0 Hz, 2H), 1.12 (t, J = 8.0 Hz, 3H);
13C NMR (100 MHz, DMSO-d6): δ = 167.5, 148.8, 146.1, 140.2, 138.3, 132.6, 131.5, 129.6, 128.6, 128.2, 125.4, 125.2, 124.0, 115.4, 113.6,
63.0, 14.4; IR (KBr, cm-1): 3494, 3071, 1672, 1585, 1519, 1473, 1264, 1196, 832, 734; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C17H1579BrNaO4: 385.0046; found: 385.0048.
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(E)-2-(2-bromo-3,5-dimethoxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid (1ca). White solid; yield: 3.80 g (93%); mp
188-190 °C; 1H NMR (400 MHz, DMSO-d6): δ = 12.67 (s, 1H), 7.76 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 2H), 6.71 (d, J =
2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 3H), 3.45 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 167.1, 160.1, 156.9,
150.4, 140.1, 139.4, 138.4, 132.8, 132.6, 123.2, 123.0, 113.6, 107.3, 103.4, 99.2, 56.4, 55.7, 55.1; IR (KBr, cm-1): 3627, 3513, 1700, 1620, 1584,
1511, 1464, 1421, 1264, 1162, 852, 734; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H1779BrNaO6: 431.0101; found: 431.0101.
(E)-2-(2-bromo-3,5-dimethoxyphenyl)-3-(3,4-dimethoxyphenyl)acrylic acid (1cb). White solid; yield: 3.64 g (86%); mp 158-160
°C; 1H NMR (400 MHz, DMSO-d6): δ = 12.49 (s, 1H), 7.70 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.80 (dd, J = 8.4, 2.0 Hz, 1H), 6.70 (d, J = 2.8
Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 2.8 Hz, 1H), 3.87 (s, 3H), 3.72 (s, 6H), 3.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ =
167.3, 160.1, 156.9, 150.1, 148.1, 139.9, 139.3, 129.9, 126.6, 124.5, 112.5, 111.4, 107.4, 103.7, 99.1, 56.5, 55.7, 55.5, 54.7; IR (KBr, cm-1):
3468, 3068, 1674, 1589, 1513, 1456, 1262, 1148, 805, 742; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H1979BrNaO6: 445.0257; found:
445.0253.
(E)-2-(2-bromo-3,5-dimethoxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)acrylic acid (1cc). White solid; yield: 3.27 g (80%); mp
160-162 °C; 1H NMR (400 MHz, DMSO-d6): δ = 12.47 (s, 1H), 9.01 (s, 1H), 7.60 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H),
6.60 (dd, J = 8.4, 2.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): δ = 167.4, 159.9, 156.7, 149.2, 146.0, 139.7, 139.5, 129.6, 126.8, 122.9, 116.9, 111.7, 107.3, 103.6, 99.0, 56.3, 55.6, 55.5; IR (KBr,
cm-1): 3627, 3445, 1667, 1584, 1511, 1447, 1264, 1158, 835, 799; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H1779BrNaO6: 431.0101;
found: 431.0098.
Typical procedure for the synthesis of 2-(3,5-dimethoxyphenyl)-6-hydroxybenzofuran-3-carboxylic acid (2aa). A mixture of (E)-2-
(2-bromo-4-hydroxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid 1aa (0.379 g, 1 mmol), Cu(OAc)2 (36 mg, 0.2 mmol, 20 mol %), 1,10-
phen (36 mg, 0.2 mmol, 20 mol %), KOH (0.56 g, 10.0 mmol, 10.0 equiv), and DMSO-H2O (1:1) (5 ml) was added into a flask equipped
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with a condenser. The flask was then placed into the microwave reactor and the mixture was irradiated (240 W) under air with stirring and
raised the reaction temperature to 110 °C for 1 h. After the reaction was completed (monitored by TLC), the resulting mixture was filtered off
and washed with 10 ml EtOAc for three times. The aqueous layer was separated from the filtrate, and acidified to pH 3~4 with 1 M HCl. The
precipitated crude product was collected by filtration and recrystallized from ethyl acetate or purified by column chromatography on silica gel
with ethyl acetate/petroleum ether (1:2) as an eluent to afford 2aa as pale white crystals. Yield 0.28 g, 90%; mp > 200 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 13.02 (s, 1H), 9.81 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.0 Hz, 2H), 6.99 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.8, 2.0
Hz, 1H), 6.62 (t, J = 2.0 Hz, 1H), 3.79 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 164.7, 160.0, 156.9, 156.4, 154.1, 130.9, 122.6, 118.9,
113.6, 109.8, 106.8, 101.9, 97.3, 55.4; IR (KBr, cm-1): 3469, 3054, 1667, 1603, 1557, 1494, 1443, 1292, 1093, 773, 688; HRMS (ESI-TOF):
m/z [M + Na]+ calcd for C17H14NaO6: 337.0683; found: 337.0678; Anal. Calcd for C17H14O6: C, 64.97; H, 4.49. Found: C, 65.26; H, 4.507.
6-Hydroxy-2-(3-hydroxy-4-methoxyphenyl)benzofuran-3-carboxylic acid (2ab). White acicular crystal; yield: 0.26 g (88%); mp 199-
200 °C; 1H NMR (400 MHz, DMSO-d6): δ = 12.86 (s, 1H), 9.74 (s, 1H), 9.28 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H),
7.45 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.4, 2.0 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): δ = 164.8, 158.0, 155.9, 153.8, 149.1, 145.8, 122.3, 121.8, 120.6, 119.1, 115.7, 113.1, 111.4, 107.8, 97.1, 55.5; IR (KBr, cm-1):
3400, 3086, 1679, 1629, 1557, 1510, 1438, 1264, 1148, 797, 727; HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H13O6: 301.0707; found:
301.0709; Anal. Calcd for C16H12O6: C, 64.00; H, 4.03. Found: C, 64.28; H, 3.889.
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6-Hydroxy-2-(4-hydroxy-3,5-dimethoxyphenyl)benzofuran-3-carboxylic acid (2ac). White solid; yield: 0.28 g (85%); mp > 200 °C;
1H NMR (400 MHz, DMSO-d6): δ = 12.92 (s, 1H), 9.74 (s, 1H), 9.03 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.40 (s, 2H), 6.98 (d, J = 2.0 Hz, 1H),
6.82 (dd, J = 8.4, 2.0 Hz, 1H), 3.82 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 165.1, 158.2, 156.0, 153.8, 147.4, 137.7, 122.4, 119.3, 119.1,
113.2, 107.8, 106.8, 97.2, 56.1; IR (KBr, cm-1): 3633, 3443, 1690, 1620, 1572, 1500, 1433, 1290, 1151, 808, 790; HRMS (ESI-TOF): m/z [M
+ H]+ calcd for C17H15O7: 331.0812; found: 331.0813; Anal. Calcd for C17H14O7: C, 61.82; H, 4.27. Found: C, 62.14; H, 4.401.
6-Hydroxy-2-phenylbenzofuran-3-carboxylic acid (2ad). White solid; yield: 0.21 g (84%); mp > 200 °C; 1H NMR (400 MHz, DMSO-
d6): δ = 13.04 (s, 1H), 9.84 (s, 1H), 7.97-7.99 (m, 2H), 7.81 (d, J = 8.4 Hz, 1H ), 7.51-7.52 (m, 3H), 7.03 (d, J = 1.6 Hz, 1H), 6.90 (dd, J = 8.4,
1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.7, 157.7, 156.3, 154.4, 129.8, 129.5, 128.9, 128.1, 122.6, 118.9, 113.5, 109.3, 97.3; IR
(KBr, cm-1): 3189, 3079, 1688, 1605, 1563, 1492, 1460, 1286, 1071, 820, 760; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H10NaO4:
277.0471; found: 277.0467; Anal. Calcd for C15H10O4: C, 70.86; H, 3.96. Found: C, 71.25; H, 3.915.
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6-Hydroxy-2-(4-hydroxy-3-methoxyphenyl)benzofuran-3-carboxylic acid (2ae). White solid; yield: 0.25 g (83%); mp > 200 °C; H
NMR (400 MHz, DMSO-d6): δ = 12.81 (s, 1H), 9.72 (s, 1H), 9.63 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.4,
2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
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δ = 165.1, 158.4, 155.9, 153.8, 148.5, 146.9, 122.4, 120.4, 119.2, 115.4, 115.1, 113.2, 113.1, 107.5, 97.2, 55.6; IR (KBr, cm-1): 3432, 3090,
1621, 1611, 1572, 1507, 1451, 1307, 1155, 856, 813; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12NaO6: 323.0526; found: 323.0529;
Anal. Calcd for C16H12O6: C, 64.00; H, 4.03. Found: C, 63.64; H, 3.680.
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6-Hydroxy-2-(4-methoxyphenyl)benzofuran-3-carboxylic acid (2af). White solid; yield: 0.22 g (76%); mp > 200 °C; 1H NMR (400
MHz, DMSO-d6): δ = 12.90 (s, 1H), 9.75 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 2.0
Hz, 1H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 164.9, 160.4, 158.1, 156.0, 154.0, 130.5, 122.5,
121.8, 119.1, 113.6, 113.3, 108.0, 97.3, 55.3; IR (KBr, cm-1): 3541, 1677, 1615, 1585, 1507, 1438, 1254, 1121, 840, 753; HRMS (ESI-TOF):
m/z [M + H]+ calcd. for C16H13O5: 285.0757; found: 285.0761; Anal. Calcd for C16H12O5: C, 67.60; H, 4.25. Found: C, 67.82; H, 3.878.
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6-Hydroxy-2-(4-hydroxyphenyl)benzofuran-3-carboxylic acid (2ag). White solid; yield:0.26 g (98%); mp > 200 °C; H NMR (400
MHz, DMSO-d6): δ = 12.83 (s, 1H), 10.02 (s, 1H), 9.72 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H),
6.89 (d, J = 8.8 Hz, 2H), 6.83 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 165.0, 159.0, 158.6, 155.9, 153.9, 130.6, 122.4,
120.2, 119.2, 115.0, 113.1, 107.4, 97.2; IR (KBr, cm-1): 3371, 3244, 1694, 1601, 1557, 1514, 1441, 1284, 1127, 830, 695; HRMS (ESI-TOF):
m/z [M + Na]+ calcd. for C15H10NaO5: 293.0420; found: 293.0425; Anal. Calcd for C15H10O5: C, 66.67; H, 3.73. Found: C, 66.93; H, 4.119.
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2-(3-Ethoxy-4-hydroxyphenyl)-6-hydroxybenzofuran-3-carboxylic acid (2ah). White solid; yield: 0.30 g (95%); mp > 200 °C; H
NMR (400 MHz, DMSO-d6): δ = 12.89 (s, 1H), 9.72 (s, 1H), 9.55 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.4,
1.6 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H), 4.08 (q, J = 8.0 Hz, 2H), 1.37 (t, J = 8.0 Hz, 3H);
13C NMR (100 MHz, DMSO-d6): δ = 165.1, 158.4, 155.9, 153.8, 148.8, 146.0, 122.4, 122.3, 120.4, 119.2, 115.2, 114.5, 113.2, 107.5, 97.2,
64.0, 14.7; IR (KBr, cm-1): 3411, 3268, 1688, 1604, 1561, 1501, 1440, 1276, 1094, 860, 754; HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C17H14NaO6: 337.0683; found: 337.0685; Anal. Calcd for C17H14O6: C, 64.97; H, 4.49. Found: C, 65.13; H, 4.725.
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2-(4-Chlorophenyl)-6-hydroxybenzofuran-3-carboxylic acid (2ai). White solid; yield: 0.25 g (87%); mp > 200 °C; H NMR (400
MHz, DMSO-d6): δ = 13.11 (s, 1H), 9.85 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 2.0
Hz, 1H), 6.87 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.6, 156.5, 156.3, 154.4, 134.5, 130.6, 128.3, 128.3, 122.7,
118.8, 113.7, 109.9, 97.3; IR (KBr, cm-1): 3447, 3244, 1703, 1629, 1489, 1404, 1279, 1219, 824, 720; HRMS (ESI-TOF): m/z [M + Na]+
calcd for C15H935ClNaO4: 311.0082; found: 311.0083; Anal. Calcd for C15H9ClO4: C, 62.41; H, 3.14. Found: C, 62.53; H, 3.408.
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2-(4-Fluorophenyl)-6-hydroxybenzofuran-3-carboxylic acid (2aj). White solid; yield: 0.24 g (88%); mp > 200 °C; H NMR (400
MHz, DMSO-d6): δ = 13.06 (s, 1H), 9.83 (s, 1H), 8.03-8.06 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8.8 Hz, 2H), 7.01 (d, J = 2.0 Hz,
1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.7, 162.8 (d, 1JF-C = 246.6 Hz), 156.8, 156.3, 154.3, 131.4 (d, 3JF-
C = 8.7 Hz), 126.0 (d, 4JF-C = 3.0 Hz), 122.7, 118.8, 115.2 (d, 2JF-C = 21.8 Hz), 113.6, 109.3, 97.3; IR (KBr, cm-1): 3443, 3219, 1705, 1629, 1608,
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1494, 1411, 1285, 1121, 811, 731; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H9FNaO4: 295.0377; found: 295.0377; Anal. Calcd for
C15H9FO4: C, 66.18; H, 3.33. Found: C, 66.25; H, 3.482.
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2-(2,4-Dichlorophenyl)-6-hydroxybenzofuran-3-carboxylic acid (2ak). White solid; yield: 0.25 g (78%); mp > 200 °C; 1H NMR (400
MHz, DMSO-d6): δ = 12.90 (s, 1H), 9.85 (s, 1H), 7.79-7.82 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.01 (d, J = 1.6
Hz, 1H), 6.91 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 163.9, 156.6, 155.1, 154.5, 135.5, 134.4, 133.8, 129.1, 128.5,
127.2, 122.3, 117.6, 113.8, 112.4, 97.6; IR (KBr, cm-1): 3568, 3329, 1688, 1628, 1571, 1494, 1438, 1261, 1148, 869, 806; HRMS (ESI-TOF):
m/z [M + Na]+ calcd for C15H835Cl2NaO4: 344.9692; found: 344.9695; Anal. Calcd for C15H8Cl2O4: C, 55.76; H, 2.50. Found: C, 55.88; H,
2.642.
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6-Hydroxy-2-(4-(trifluoromethyl)phenyl)benzofuran-3-carboxylic acid (2al). White solid; yield: 0.13 g (46%); mp > 200 °C; 1H
NMR (400 MHz, DMSO-d6): δ = 13.27 (s, 1H), 9.95 (s, 1H), 8.20 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4Hz, 1H), 7.05
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(d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.5, 156.9, 155.6, 154.7, 133.3, 129.5 (q, JF-C
=
31.4 Hz), 129.6, 125.1 (d, 3JF-C = 3.1 Hz), 124.1 (q, 1JF-C = 270.6 Hz), 123.0, 118.7, 114.0, 111.0, 97.4; IR (KBr, cm-1): 3285, 3216, 1693, 1623,
1571, 1502, 1444, 1288, 1168, 837, 730; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H9NaF3O4: 345.0351; found: 345.0351; Anal.
Calcd for C16H9F3O4: C, 59.64; H, 2.82. Found: C, 59.83; H, 2.996.
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2-(4-Cyanophenyl)-6-hydroxybenzofuran-3-carboxylic acid (2am). White solid; yield: 0.11 g (42%); mp > 200 °C; H NMR (400
MHz, DMSO-d6): δ = 13.24 (s, 1H), 10.20 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4
Hz, 1H), 6.78 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 166.9, 158.0, 138.6, 138.4, 134.8, 131.7, 131.3, 129.9, 129.7,
129.2, 127.4, 123.5, 119.1, 115.4; IR (KBr, cm-1): 3407, 3197, 1693, 1612, 1500, 1417, 1288, 1147, 799, 729; HRMS (ESI-TOF): m/z [M +
Na]+ calcd for C16H9NNaO4: 302.0429; found: 302.0430; Anal. Calcd for C16H9NO4: C, 68.82; H, 3.25; N, 5.02. Found: C, 68.97; H, 3.413;
N, 5.14.
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2-(4-Carboxyphenyl)-6-hydroxybenzofuran-3-carboxylic acid (2an). Yellow solid; yield: 0.13 g (45%); mp > 200 °C; H NMR (400
MHz, DMSO-d6): δ = 13.03 (s, 2H), 10.05 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.4
Hz, 1H), 6.78 (dd, J = 8.4, 2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 167.7, 164.8, 158.1, 156.8, 154.8, 138.8, 134.8, 133.4, 129.9,
129.0, 123.6, 119.2, 115.5, 97.5; IR (KBr, cm-1): 3413, 3077, 1685, 1612, 1498, 1421, 1280, 1039, 862, 786; HRMS (ESI-TOF): m/z [M +
Na]+ calcd for C16H10NaO6: 321.0375; found: 321.0377; Anal. Calcd for C16H10O6: C, 64.43; H, 3.38. Found: C, 64.72; H, 3.299.
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2-(Furan-2-yl)-6-hydroxybenzofuran-3-carboxylic acid (2aq). White solid; yield: 0.19 g (80%); mp > 200 °C; H NMR (400 MHz,
DMSO-d6): δ = 13.12 (s, 1H), 9.88 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 3.6 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.87 (dd,
J = 8.8, 2.0 Hz, 1H), 6.76 (dd, J = 3.2, 1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.1, 156.4, 154.0, 148.7, 144.8, 143.4, 122.5,
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118.0, 114.9, 113.6, 112.3, 107.7, 97.2; IR (KBr, cm-1): 3639, 3334, 1683, 1623, 1596, 1542, 1494, 1448, 1295, 921, 817; HRMS (ESI-TOF):
m/z [M + Na]+ calcd for C13H8NaO5: 267.0269; found: 267.0271; Anal. Calcd for C13H8O5: C, 63.94; H, 3.30. Found: C, 64.18; H, 3.416.
6-Hydroxy-2-(thiophen-2-yl)benzofuran-3-carboxylic acid (2ar). Yellow solid; yield: 0.20 g (75%); mp > 200 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 13.22 (s, 1H), 9.86 (s, 1H), 8.19 (dd, J = 3.6, 1.2 Hz, 1H), 7.84 (dd, J = 5.2, 1.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.25 (dd, J
= 5.2, 3.6 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 8.8, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.8, 156.5, 153.8, 153.1,
1307, 130.2, 130.1, 127.8, 122.7, 118.6, 113.6, 107.5, 97.2; IR (KBr, cm-1): 3284, 3079, 1672, 1625, 1558, 1498, 1442, 1268, 1054, 821, 711;
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H8NaSO4: 283.0041; found: 283.0041; Anal. Calcd for C13H8SO4: C, 59.99; H, 3.10. Found:
C, 60.23; H, 3.261.
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6-Hydroxy-2-(naphthalen-1-yl)benzofuran-3-carboxylic acid (2as). White solid; yield: 0.20 g (67%); mp 178-180 °C; H NMR (400
MHz, DMSO-d6): δ = 12.69 (s, 1H), 9.84 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.78 (dd, J = 7.2,
1.2 Hz, 1H), 7.62-7.70 (m, 2H), 7.53-7.61 (m, 2H), 7.05 (d, J = 1.6 Hz, 1H), 6.95 (dd, J = 8.4, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
δ = 164.3, 157.9, 156.3, 155.1, 132.9, 131.3, 130.2, 129.6, 128.4, 127.6, 127.0, 126.2, 125.1, 125.0, 122.3, 118.2, 113.6, 111.9, 97.6; IR (KBr,
cm-1): 3438, 3174, 1687, 1602, 1562, 1502, 1436, 1286, 1216, 875, 767; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H12NaO4: 327.0633;
found: 327.0634; Anal. Calcd for C19H12O4: C,74.99; H, 3.97. Found: C, 75.11; H, 4.206.
(E)-6-hydroxy-2-styrylbenzofuran-3-carboxylic acid (2at). White solid; 0.18 g (64%); mp > 200 °C; 1H NMR (400 MHz, DMSO-d6):
δ = 13.04 (s, 1H), 9.89 (s, 1H), 7.81 (d, J = 16.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 16.8 Hz, 1H), 7.43-
7.47(m, 2H), 7.38 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.85 (dd, J = 8.8, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 164.8,
157.1, 156.9, 154.7, 135.8, 133.0, 129.0, 128.9, 127.1, 122.3, 118.4, 115.2, 113.5, 109.7, 97.3; IR (KBr, cm-1): 3524, 3330, 1870, 1610, 1578,
1508, 1438, 1294, 1144, 964, 818; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H12NaO4: 303.0628; found: 303.0629; Anal. Calcd for
C17H12O4: C, 72.85; H, 4.32. Found: C, 72.96; H, 4.335.
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2-(3,5-Dimethoxyphenyl)benzofuran-3-carboxylic acid (2ba). White acicular crystals; yield: 0.21 g (70%); mp 198-200 °C; H NMR
(400 MHz, DMSO-d6): δ = 13.24 (s, 1H), 9.57 (d, J = 8.4 Hz, 1H), 8.73 (dd, J = 8.4, 1.2 Hz, 1H), 8.37 (s, 1H), 7.58-7.67 (m, 2H), 7.31 (d, J
= 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 4.10 (s, 3H), 3.93 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 168.9, 159.0, 158.4, 133.3, 131.0,
130.4, 128.3, 127.9, 127.3, 126.7, 125.7, 125.5, 115.8, 103.0, 101.5, 56.1, 55.5; IR (KBr, cm-1): 3468, 3073, 1679, 1615, 1602, 1580, 1455,
1251, 1147, 914, 749; HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H15O5: 299.0914; found: 299.0906; Anal. Calcd for C17H14O5: C, 68.45;
H, 4.73. Found: C, 68.47; H, 4.738.
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2-(4-Hydroxy-3-methoxyphenyl)benzofuran-3-carboxylic acid (2bb). White solid; yield: 0.22 g (79%); mp 160-161 °C; H NMR
(400 MHz, DMSO-d6): δ = 13.01 (s, 1H), 9.74 (s, 1H), 7.99-8.01 (m, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.65-7.67 (m, 1H), 7.54 (dd, J = 8.0, 2.0
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Hz, 1H), 7.33-7.40 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 164.8, 159.9, 152.6, 148.9, 146.9,
127.3, 124.8, 123.9, 122.8, 122.1, 119.9, 115.1, 113.3, 110.9, 107.4, 55.6; IR (KBr, cm-1): 3466, 3060, 1660, 1600, 1507, 1448, 1271, 1181, 752,
691; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12NaO5: 307.0577; found: 307.0581; Anal. Calcd for C16H12O5: C, 67.60; H, 4.25.
Found: C, 67.32; H, 4.582.
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2-Phenylbenzofuran-3-carboxylic acid (2bc). Gray solid; yield: 0.17 g (72%); mp 178-179 °C; H NMR (400 MHz, DMSO-d6): δ =
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13.15 (s, 1H), 7.99-8.05 (m, 3H), 7.70-7.72 (m, 1H), 7.54-7.56 (m, 3H), 7.38-7.45 (m. 2H); 13C NMR (100 MHz, DMSO-d6): δ = 164.6,
159.5, 153.2, 130.3, 129.3, 129.2, 128.2, 127.0, 125.5, 124.2, 122.4, 111.3, 109.3; IR (KBr, cm-1): 3447, 3084, 1692, 1601, 1571, 1496, 1463,
1279, 1155, 946, 806; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H10NaO3: 261.0522; found: 261.0523; Anal. Calcd for C15H10O3: C,
75.62; H, 4.23. Found: C, 75.94; H, 3.938.
2-(4-Hydroxyphenyl)benzofuran-3-carboxylic acid (2bd). Yellow solid; yield: 0.21 g (84%); mp > 200 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 12.98 (s, 1H), 10.12 (s, 1H), 7.98-8.01 (m, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.64-7.66 (m, 1H), 7.33-7.39 (m, 2H), 6.90 (d, J =
8.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 164.7, 160.2, 159.4, 152.6, 131.0, 127.2, 124.8, 123.9, 122.0, 119.7, 115.0, 110.9, 107.3; IR
(KBr, cm-1): 3450, 3076, 1688, 1608, 1573, 1505, 1443, 1383, 1174, 831, 795; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H10NaO4:
277.0471; found: 277.0477; Anal. Calcd for C15H10O4: C, 70.86; H, 3.96. Found: C, 71.18; H, 4.325.
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2-(4-Hydroxy-3,5-dimethoxyphenyl)benzofuran-3-carboxylic acid (2be). White solid; yield: 0.23 g (74%); mp > 200 °C; H NMR
(400 MHz, DMSO-d6): δ = 13.07 (s, 1H), 9.15 (s, 1H), 7.98-8.01 (m, 1H), 7.67 (dd, J = 6.8, 2.0 Hz, 1H), 7.45 (s, 2H), 7.33-7.40 (m, 2H),
3.83 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 165.0, 159.8, 152.6, 147.5, 138.2, 127.5, 125.1, 124.0, 122.3, 118.7, 111.1, 107.9, 107.2,
56.1; IR (KBr, cm-1):3482, 3000, 1685, 1604, 1513, 1491, 1451, 1284, 1110, 889, 730; HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H15O6:
315.0863; found: 315.0859; Anal. Calcd for C17H14O6: C, 64.97; H, 4.49. Found: C, 65.21; H, 4.199.
2-(3-Hydroxy-4-methoxyphenyl)benzofuran-3-carboxylic acid (2bf). White solid; yield: 0.23 g (81%); mp 189-190 °C; 1H NMR (400
MHz, DMSO-d6): δ = 13.02 (s, 1H), 9.35 (s, 1H), 7.98-8.00 (m, 1H), 7.65-7.67 (m, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz,
1H), 7.35-7.39 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 164.7, 159.5, 152.6, 149.5, 145.9, 127.2,
124.9, 123.9, 122.1, 121.4, 121.1, 116.0, 111.5, 110.9, 107.8, 55.5; IR (KBr, cm-1): 3531, 3426, 1675, 1622, 1564, 1509, 1443, 1258, 1132, 888,
757; HRMS: (ESI-TOF) m/z [M + Na]+ calcd. for C16H12NaO5: 307.0577; found: 307.0582; Anal. Calcd for C16H12O5: C, 67.60; H, 4.25.
Found: C, 67.95; H, 4.566.
2-(3-Ethoxy-4-hydroxyphenyl)benzofuran-3-carboxylic acid (2bg). Yellow solid; 0.25 g (83%); mp 184-186 °C; 1H NMR (400 MHz,
DMSO-d6): δ = 12.97 (s, 1H), 9.66 (s, 1H), 7.96-8.00 (m, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.62-7.67 (m, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H),
7.32-7.39 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 4.09 (q, J = 8.0 Hz, 2H), 1.37 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 164.9,
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160.0, 152.6, 149.3, 146.1, 127.4, 124.9, 123.9, 122.7, 122.1, 119.9, 115.3, 114.7, 111.0, 107.5, 64.0, 14.7; IR (KBr, cm-1): 3537, 3457, 1689,
1602, 1569, 1508, 1455, 1262, 1196, 863, 800; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H14NaO5 : 321.0733; found: 321.0736; Anal.
Calcd for C17H14O5: C, 68.45; H, 4.73. Found: C, 68.81; H, 4.383.
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2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxybenzofuran-3-carboxylic acid (2ca). White acicular crystals; yield: 0.23 g (66%); mp
> 200 °C; 1H NMR (400 MHz, DMSO-d6): δ = 13.00 (s, 1H), 9.72 (s, 1H), 7.65 (d, J = 2.0 Hz,1H), 7.43 (dd, J = 8.0, 2.0 Hz, 1H), 7.03 (d, J =
2.0 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ =
164.9, 160.4, 157.1, 148.8, 146.9, 144.9, 137.2, 128.8, 122.7, 120.1, 115.2, 113.3, 108.1, 97.5, 95.5, 55.9, 55.7, 55.6; IR (KBr, cm-1): 3638, 3511,
1688, 1612, 1569, 1513, 1443, 1287, 1131, 842, 792; HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H17O7: 345.0969; found: 345.0965;
Anal. Calcd for C18H16O7: C, 62.79; H, 4.68. Found: C, 63.18; H, 4.953.
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2-(3,4-Dimethoxyphenyl)-5,7-dimethoxybenzofuran-3-carboxylic acid (2cb). Grey solid; yield: 0.23 g (64%); mp 168-170 °C; H
NMR (400 MHz, DMSO-d6): δ = 12.88 (s, 1H), 7.66 (s, 1H), 7.56 (dd, J = 8.8, 1.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H),
6.61 (d, J = 1.6 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 164.9, 160.0, 157.2,
150.5, 148.0, 144.9, 137.3, 128.7, 122.5, 121.5, 112.6, 111.2, 108.6, 97.6, 95.5, 56.0, 55.6, 55.6, 55.5; IR (KBr, cm-1): 3553, 3436, 1686, 1600,
1514, 1491, 1464, 1272, 1106, 815, 731; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H18NaO7: 381.0945; found: 381.0946; Anal. Calcd
for C19H18O7: C, 63.68; H, 5.06. Found: C, 64.02; H, 5.415.
2-(3-Hydroxy-4-methoxyphenyl)-5,7-dimethoxybenzofuran-3-carboxylic acid (2cc). White solid; yield: 0.23 g (68%); mp > 200 °C;
1H NMR (400 MHz, DMSO-d6): δ = 12.95 (s, 1H), 9.71(s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 7.03 (d, J = 2.0 Hz,
1H), 6.90 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ = 165.0,
160.4, 157.2, 148.8, 146.9, 144.9, 137.2, 128.9, 122.7, 120.1, 115.2, 113.3, 108.1, 97.5, 95.5, 55.9, 55.7, 55.6; IR (KBr, cm-1): 3485, 3055, 1689,
1604, 1569, 1490, 1456, 1282, 1110, 890, 769; HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H17O7: 345.0969; found: 345.0976; Anal.
Calcd for C18H16O7: C, 62.79; H, 4.68. Found: C, 63.14; H, 5.034.
(E)-2-(2-hydroxyphenyl)-3-phenylacrylic acid (4bc). This reaction was running under N2 atmosphere. White solid; 0.18 g (75%); mp
148-149 °C; 1H NMR (400 MHz, DMSO-d6): δ = 12.39 (s, 1H), 9.40 (s, 1H), 7.68 (s, 1H), 7.11-7.23 (m, 6H), 6.86-6.88 (m, 2H), 6.76 (t, J =
7.2 Hz, 1H) ; 13C NMR (100 MHz, DMSO-d6): δ = 168.5, 155.2, 138.8, 134.9, 131.0, 130.4, 129.8, 129.0, 128.8, 128.2, 123.7, 119.0, 115.5;
IR (KBr, cm-1): 3431, 3060, 1689, 1600, 1578, 1513, 1443, 1277, 1167, 849, 735; HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H13O3 :
241.0859; found: 241.0859.
Procedure for the synthesis of 6-hydroxy-2-(3,5-dimethoxyphenyl)benzofuran (3). A stirred solution of 2-(3,5-dimethoxyphenyl)-6-
hydroxybenzofuran-3-carboxylic acid (2aa, 0.628 g, 2 mmol), CuI (38 mg, 0.2 mmol, 10 mol %), 1,10-phen (36 mg, 0.2 mmol, 10 mol %),
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and PEG-400 (20 ml) was heated to 180 °C for 10 min under microwave irradiation (2 min irradiation each time with a 5 min interval be-
tween). After completion of the reaction, the mixture was cooled to room temperature. The resulting reaction solution was added into ethyl
acetate (20 ml) and water (20 ml) and filtered. The filtrate was extracted with ethyl acetate. The combined organic layers were washed with
water, dried over anhydrous MgSO4 and then concentrated under vacuum to afford the crude product, which was further recrystallized from
ethyl acetate/petroleum ether to give yellow pale crystals. Yield 0.52 g (96%); mp 110-112 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.66 (s,
1H), 7.42 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 6.99 (d, J = 2.4 Hz, 2H), 6.97 (s, 1H), 6.76 (dd, J = 8.4, 2.0 Hz, 1H), 6.49 (t, J = 2.4 Hz, 1H), 3.82
(s, 6H); 13C NMR (100 MHz, DMSO-d6): δ = 160.8, 155.9, 155.4, 153.4, 132.0, 121.3, 120.7, 112.6, 102.7, 102.0, 100.3, 97.5, 55.4; IR (KBr,
cm-1): 3436, 3234, 1685, 1600, 1574, 1509, 1442, 1271, 1199, 753, 691; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H14NaO4: 293.0784,
found: 293.0784.
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Procedure for the synthesis of Moracin M. A mixture of 6-hydroxy-2-(3,5-dimethoxyphenyl)benzofuran (3, 0.27 g, 1 mmol), aluminum
chloride (0.40 g, 3 mmol) in 1,2-dichloroethane (20 ml) was stired at 80 °C until the reaction was complete (monitored by TLC). After
cooling, the mixture was subjected to vacuum distillation to recover the 1,2-dichloroethane and poured into hot water (80 °C, 50 ml) with
stirring for 20 min. The mother liquor was obtained after the filtration, and extracted with 10 ml ethyl acetate for three times, dried over
anhydrous MgSO4, then concentrated to afford crude product and further purified by crystallization from ethyl acetate to give white pale
crystals. Yield 0.21 g (86%); mp > 200 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.59 (s, 1H), 9.44 (s, 2H), 7.38 (d, J = 8.4 Hz, 1H), 7.08 (s,
1H), 6.92 (d, J = 1.6 Hz, 1H), 6.74 (dd, J = 8.4, 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 2H), 6.21 (t, J = 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6): δ = 158.8, 155.7, 155.2, 153.9, 131.6, 121.1, 120.7, 112.4, 102.6, 102.3, 101.5, 97.4; IR (KBr, cm-1): 3584, 3468, 1684, 1627, 1554, 1494,
1449, 1260, 1095, 865, 800; HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H11O4: 243.0652, found: 243.0653.
ASSOCIATED CONTENT
Supporting Information.
1H and 13C NMR spectra for the products. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: zou_jinan@163.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This work was supported by the National Natural Science Foundation of China (21272280, 81201716), Science & Technology Program of Guang-
dong Province and Guangzhou City (2011A081401002, 2014J4100224), Guangdong Natural Science Foundation (S2013010014278), Guangdong
Provincial Key Laboratory of Construction Foundation (2011A060901014).
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REFERENCES
8
9
(1) For representative examples of 3-substituted 2-arylbenzofurans, see: (a) Roumeliotis, T. I.; Halabalaki, M.; Alexi, X.; Ankrett, D.; Giannopoulou, E. G.;
Skaltsounis, A. L.; Sayan, B. S.; Alexis, M. N.; Townsend, P. A.; Garbis, S. D. J. Proteome Res. 2013, 12, 1591-1603; (b) Mori-Hongo, M.; Takimoto, H.;
Katagiri, T.; Kimura, M.; Ikeda, Y.; Miyase, T. J. Nat. Prod. 2009, 72, 194-203; (c) Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968-2971; (d)
Kryshchyshyn, A.; Kaminskyy, D.; Grellier, P.; Lesyk, R. Eur. J. Med. Chem. 2014, 85, 51-64; (e) Chiummiento, L.; Funicello, M.; Lopardo, M. T.; Lupattelli,
P.; Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2012, 188-192; (f) Chen, P.-Y.; Wang, T.-P.; Huang, K.-S.; Kao, C.-L.; Tsai, J.-C.; Wang, E.-C. Tetrahedron
2011, 67, 9291-9297; (g) Rizzo, S.; Tarozzi, A.; Bartolini, M.; Costa, D. G.; Bisi, A.; Gobbi, S.; Belluti, F.; Ligresti, A.; Allarà, M.; Monti, J.-P.; Andrisano, V.;
Marzo, D. V.; Hrelia, P.; Rampa, A. Eur. J. Med. Chem. 2012, 58, 519-532.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) (a) Wadood, A.; Jamal, S. B.; Riaz, M.; Mir, A. Pharm. Bio. 2014, 52, 1170-1178; (b) Naidu, C. K.; Suneetha, Y. Med. Chem. Res. 2014, 23, 4724-4748;
(c) Galal, S. A.; El-All, A. S. A.; Abdallah, M. M.; El-Diwani, H. I. Bioorg. Med. Chem. Lett. 2009, 19, 2420-2428.
(3) (a) Samala, G.; Nallangi, R.; Devi, P. B.; Saxena, S.; Yadav, R.; Sridevi, J. P.; Yogeeswari, P.; Sriram, D. Bioorg. Med. Chem. 2014, 22, 4223-4232; (b)
Renuka, J.; Reddy, K. I.; Srihari, K.; Jeankumar, V. U.; Shravan, M.; Sridevi, J. P.; Yogeeswari, P.; Babu, K. S.; Sriram, D. Bioorg. Med. Chem. 2014, 22, 4924-
4934; (c) Abdel-Wahab, B. F.; Abdel-Aziz, H. A.; Ahmed, E. M. Eur. J. Med. Chem. 2009, 44, 2632-2635.
(4) (a) Yadav, P.; Singh, P.; Tewari, A. K. Bioorg. Med. Chem. Lett. 2014, 24, 2251-2255; (b) Rao, M. L. N.; Jadhav, D. N.; Dasgupta, P. Eur. J. Org. Chem.
2013, 781-788; (c) Lee, D. S.; Jeong, G. S. Eur. J. Pharmacol. 2014, 728, 1-8.
(5) (a) Vang, T.; Xie, Y.; Liu, W. H.; Vidovic, D.; Liu, Y.; Wu, S.; Smith, D. H.; Rinderspacher, A.; Chung, C.; Gong, G.; Mustelin, T.; Landry, D. W.; Rick-
ert, R. C.; Schurer, S. C.; Deng, S. X.; Tautz, L. J. Med. Chem. 2011, 54, 562-571; (b) Saha, A. K.; Yu, X.; Lin, J.; Lobera, M.; Sharadendu, A.; Chereku, S.;
Schutz, N.; Segal, D.; Marantz, Y.; McCauley, D.; Middleton, S.; Siu, J.; Burli, R. W.; Buys, J.; Horner, M.; Salyers, K.; Schrag, M.; Vargas, H. M.; Xu, Y.; McEl-
vain, M.; Xu, H. ACS Med. Chem. Lett. 2011, 2, 97-101; (c) Ladurner, A.; Atanasov, A. G.; Heiss, E. H.; Baumgartner, L.; Schwaiger, S.; Rollinger, J. M.;
Stuppner, H.; Dirsch, V. M. Biochem. Pharmacol. 2012, 84, 804-812.
(6) Chong, C.-M.; Shen, M.; Zhou, Z.-Y.; Pan, P.; Hoi, P.-M.; Li, S.; Liang, W.; Ai, N.; Zhang, L.-Q.; Li, C.-W.; Yu, H.; Hou, T.; Lee, S. M.-Y. Free Radical
Biol. Med. 2014, 74, 283-293.
(7) Cho, S. Y.; Cho, S.; Park, E.; Kim, B.; Sohn, E. J.; Oh, B.; Lee, E. O.; Lee, H. J.; Kim, S. H. Bioorg. Med. Chem. Lett. 2014, 24, 2560-2564.
(8) Li, J.; Pan, L.; Deng, Y.; Munoz-Acuna, U.; Yuan, C.; Lai, H.; Chai, H.; Chagwedera, T. E.; Farnsworth, N. R.; Carcache de Blanco, E. J.; Li, C.; Soejarto,
D. D.; Kinghorn, A. D. J. Org. Chem. 2013, 78, 10166-10177.
(9) Luo, G.; Zhou, M.; Liu, Y.; Ye, Q.; Gu, J.; Huang, T.; Zhang, G.; Luo, Y. Phytochem. Lett. 2014, 10, 19-22.
(10) Moon, H. I.; Lee, J. H.; Lee, Y. C.; Kim, S. K. Phytother. Res. 2011, 25, 1418-1420.
(11) Mori-Hongo, M.; Takimoto, H.; Katagiri, T.; Kimura, M.; Ikeda, Y.; Miyase, T. J. Nat. Prod. 2009, 72, 194-203.
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(12) Kumar, S.; Namkung, W.; Verkman, A. S.; Sharma, P. K. Bioorg. Med. Chem. 2012, 20, 4237-4244.
1
2
3
4
5
6
7
8
(13) For selected examples, see: (a) Ni, G.; Zhang, Q.-J.; Zheng, Z.-F.; Chen, R.-Y.; Yu, D.-Q. J. Nat. Prod. 2009, 72, 966-968; (b) Hu, X.; Wu, J.-W.; Wang,
M.; Yu, M.-H.; Zhao, Q.-S.; Wang, H.-Y.; Hou, A.-J. J. Nat. Prod. 2012, 75, 82-87; (c) Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2395-2397; (d)
Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283-10286; (e) Chen, Y.; Wei, X.; Xie, H.; Deng, H. J. Nat. Prod. 2008, 71, 929-932; (f)
Celaje, J. A.; Zhang, D.; Guerrero, A. M.; Selke, M. Org. Lett. 2011, 13, 4846-4849.
9
(14) For selected examples of metal-catalyzed synthesis 3-substituted 2-arylbenzofurans, see: (a) Yuan, H.; Bi, K.-J.; Li, B.; Yue, R.-C.; Ye, J.; Shen, Y.-H.;
Shan, L.; Jin, H.-Z.; Sun, Q.-Y.; Zhang, W.-D. Org. Lett. 2013, 15, 4742-4745; (b) Hiroya, K.; Suzuki, N.; Yasuhara, A.; Egawa, Y.; Kasano, A.; Sakamoto, T., J.
Chem. Soc., Perkin. Trans. 1 2000, 4339-4346; (c) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387-17393.
(15) Cummins, B.; Donnelly, D. M. X.; Philbin, E. M.; Swirski, J.; Wheeler, T. S.; Wilson, R. K. Chem. Ind-London 1960, p 348.
(16) (a) Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.; Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1019-1021; (b) Schulenberg, J. W.; Archer, S. J.
Am. Chem. Soc. 1960, 82, 2035-2038; (c) Chatterjea, J. N. Cell. Mol. Life Sci. 1956, 12, 18-19.
10
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30
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56
57
58
59
60
(17) For examples of copper-catalyzed reactions, see: (a) Yao, B.; Liu, Y.; Zhao, L.; Wang, D. X.; Wang, M. X. J. Org. Chem. 2014, 79, 11139-11145; (b)
Hossain, M. L.; Ye, F.; Liu, Z.; Xia, Y.; Shi, Y.; Zhou, L.; Zhang, Y.; Wang, J. J. Org. Chem. 2014, 79, 8689-8699; (c) Gao, J.; Shao, Y.; Zhu, J.; Zhu, J.; Mao, H.;
Wang, X.; Lv, X. J. Org. Chem. 2014, 79, 9000-9008; (d) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234-6458;
(e) Wang, X.; Jin, Y.; Zhao, Y.; Zhu, L.; Fu, H. Org. Lett. 2012, 14, 452-455.
(18) For selected examples of copper-catalyzed bond cleavage and formation processes, see: (a) Thakur, K. G.; Sekar, G. Chem. Commun. 2011, 47, 6692-
6694; (b) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952-3015; (c) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044-5045;
(d) Liao, Q.; Yang, X.; Xi, C. J. Org. Chem. 2014, 79, 8507-8515.
(19) Zou, Y.; Huang, Q.; Huang, T. K.; Ni, Q. C.; Zhang, E. S.; Xu, T. L.; Yuan, M.; Li, J. Org. Biomol. Chem. 2013, 11, 6967-6974.
(20) (a) Zou, Y.; Zhang, E.; Xu, T.; Wu, W.; Chen, Y.; Yuan, M.; Wei, W.; Zhang, X. RSC Adv. 2013, 3, 6545-6552; (b) Zou, Y.; Zhang, E.; Xu, T.; Wei, W.;
Huang, T.; Yuan, M.; Zeng, W. Synthesis 2014, 46, 1167-1176; (c) Zhang, E.; Zhang, X.; Cai, Y.; Wang, D.; Xu, T.; Li, J.; Yan, M.; Zou, Y. RSC Adv. 2014, 4,
39020-39029; (d) Zhang, E.; Xu, T.; Wang, D.; Huang, T.; Yuan, M.; Li, J.; Zou, Y. RSC Adv. 2014, 4, 10022-10027; (e) Xiao, C. F.; Tao, L. Y.; Sun, H. Y.;
Wei, W.; Chen, Y.; Fu, L. W.; Zou, Y. Chin. Chem. Lett. 2010, 21, 1295-1298; (f) Wu, W.; Zou, Y.; Chen, Y.; Li, J.; Lv, Z.; Wei, W.; Huang, T.; Liu, X. Green
Chem. 2012, 14, 363-370; (g) Li, J.; Zou, Y.; Chen, Y.; Sun, H.-Y.; Liu, X.-K.; Xiao, C.-F.; Sun, J.; He, S.-J. Synthesis 2010, 217-222; (h) Xiao, C.-F.; Zou, Y.;
Du, J.-L.; Sun, H.-Y.; Liu, X.-K. Synth. Commun. 2012, 42, 1243-1258; (i) Sun, H.-Y.; Xiao, C.-F.; Chen, Y.; Cai, Y.-C.; Chen, Y.; Wei, W.; Liu, X.-K.; Lv, Z.-L.;
Zou, Y. Chem. Pharm. Bull. 2010, 58, 1492-1496.
(21) (a) Fukai, T.; Hano, Y.; Hirakura, K.; Nomura, T.; Uzawa, J. Chem. Pharm. Bull. 1984, 32, 808-811; (b) Celaje, J. A.; Zhang, D.; Guerrero, A. M.;
Selke, M. Org. Lett. 2011, 13, 4846-4849; (c) Kapche, G. D. W. F.; Fozing, C. D.; Donfack, J. H.; Fotso, G. W.; Amadou, D.; Tchana, A. N.; Bezabih, M.;
Moundipa, P. F.; Ngadjui, B. T.; Abegaz, B. M. Phytochemistry 2009, 70, 216–221; (d) Chen, S. K.; Zhao, P.; Shao, Y. X.; Li, Z.; Zhang, C.; Liu, P.; He, X.;
Luo, H. B.; Hu, X. Bioorg. Med. Chem. Lett. 2012, 22, 3261-3264.
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(22) (a) Monaco, R. R.; Gardiner, W. C.; Stephen, K. Int. J. Quantum Chem. 1999, 71, 57-62; (b) Pettit, G. R.; Rhodes, M. R.; Herald, D. L.; Hamel, E.;
Schmidt, J. M.; Pettit, R. K. J. Med. Chem. 2005, 48, 4087-4099; (c) Nandy, P.; Banerjee, S.; Gao, H.; Hui, M. B. V.; Lien, E. J. Pharm. Res. 1991, 8, 776-781;
(d) Mcgown, A. T.; Fox, B. W. Anti-cancer Drug Des. 1989, 3, 249-254.
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3
4
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6
(23) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118-1126.
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8
9
(24) (a) Masters, K.-S.; Rauws, T. M.; Yadav, A. K.; Herrebout, W. A.; Van der Veken, B.; Maes, B. U. Chem. ―Eur. J. 2011, 17, 6315-6320; (b) Zhao, J.;
Wang, Y.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2012, 14, 1078-1081.
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