One-pot synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones using K10 montmorillonite clay as heterogeneous catalyst

Article abstract of DOI:10.1016/j.tet.2018.07.018

A facile and efficient one-pot synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones was developed. The reaction of ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates and 2,5-dimethoxy-2,5-dihydrofuran were performed in presence of K10 Montmorillonite Clay hete

Full text of DOI:10.1016/j.tet.2018.07.018

Accepted Manuscript
One-pot synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones using K10
montmorillonite clay as heterogeneous catalyst
Jin Zhang, Wenhao Xue, Pei Wang, Tao Wang, Yong Liang, Zunting Zhang
PII:
S0040-4020(18)30839-1
10.1016/j.tet.2018.07.018
TET 29678
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 May 2018
Revised Date: 28 June 2018
Accepted Date: 9 July 2018
Please cite this article as: Zhang J, Xue W, Wang P, Wang T, Liang Y, Zhang Z, One-pot synthesis of 3-
(furan-2-yl)-4-hydroxy-2H-chromen-2-ones using K10 montmorillonite clay as heterogeneous catalyst,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.07.018.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
One-Pot Synthesis of 3-(Furan-2-yl)-4-hydroxy-2H-chromen-2-ones
using K10 Montmorillonite Clay as Heterogeneous Catalyst
Jin Zhang, Wenhao Xue, Pei Wang, Tao Wang, Yong Liang and Zunting Zhang*
The reaction of ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates and 2,5-dimethoxy-2,5-
dihydrofuran was performed in presence of K10 Montmorillonite Clay heterogeneous catalyst
under
the
solvent-free
condition,
and
followed
by
further
converted
to
3
-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones via refluxing in the alkaline EtOH solution.

ACCEPTED MANUSCRIPT
One-pot synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones
using K10 montmorillonite clay as heterogeneous catalyst
†
Jin Zhang, Wenhao Xue, Pei Wang, Tao Wang, Yong Liang and Zunting Zhang*
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry,
National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China,
and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710119, People’s Republic
of China. E-mail: zhangzunting@sina.com; Fax: (+86)-29-81530727; Tel: (+86)-29-85303940.
ABSTRACT:
A
facile
-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones was developed. The reaction of ethyl
-(2-hydroxyphenyl)-3-oxopropanoates and 2,5-dimethoxy-2,5-dihydrofuran were performed in
and
efficient
one-pot
synthesis
of
3
3
presence of K10 Montmorillonite Clay heterogeneous catalyst under the solvent-free condition at
o
8
0 C for 1 h, and followed by further converted to 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones
via refluxing in the alkaline EtOH solution for 0.5 h. The demonstrate method not only avoided
the usage of any expensive transition-metals, but also eliminated the tedious intermediate
purification. Moreover, due to the wide functional group tolerance, it could be applied to various
substrates and gave product in good to excellent yields.
Keywords: Coumarin; K10 Montmorillonite Clay; Solvent-free; Transition-metals
O
O
OH
O
O
MeO
OMe
O
R
O
OEt
o
1
. K10 mont. 80 C, 1 h,
R
OH
solvent-free
2
. C H OH, NaOH, 0.5 h
2 5
Yields up to 93%
R = H, Me, OMe, OEt, OH, F, Cl, Br
1
. Introduction
Coumarin was an important heterocyclic core structure, which was present in a large variety of
natural plants, and constituted a member of significant organic compounds due to their wide
applications. For example, various of biological and pharmaceutical properties have been reported
1
2
3
4
for coumarin analogues, e.g. antimicrobial, anti-inflammatory, anticancer, antihypertensive,
1

ACCEPTED MANUSCRIPT
5
6
7
anti-HIV and anticoagulants. It has also been utilized as corrosion inhibitors and
8
9
urease-inhibitors. Moreover, coumarin could be also found in fluorochrome, cosmetics and
1
0
pigments. The 3-aromatic substituted coumarin analogues exhibited various important potential
11
12
13
biological activities as well, e.g. antileishmanial, antioxidant properties, MAO inhibitors and
1
4
inhibit cell proliferation.
Scheme 1. Preparation of 4-hdroxy-3-(5-methylfuran-2-yl)-2H-chromen-2-one (7).
Although a number of methods for the preparation of 3-aryl substituted coumarin analogues
1
5-18
were known in the last decade,
-furan-4-hydroxycoumarins was disclosed. Palmisano and co-workers reported a [3+2]
cycloaddition of 3-diazo-4-hydroxycoumarin and 2-methylfuran in the presence of Rh (OAc) for
only
a
few reports on the synthesis of
3
2
4
the synthesis of furo[3,2-c]coumarin analogues 5 and 6, along with the formation of
4
1
-hydroxy-3-(5-methylfuran-2-yl)-2H-chromen-2-one 7 in 30% yields as a byproduct (Scheme
19
).
Later on, Zhu's group reported the synthesis of 3-arylcoumarin analogues 9 via Pd-catalyzed
cross-coupling of aryl boronic acids with phenyliodonium zwitterion 8 in 80%-88% yields, which
2
0
were obtained by the iodination of 4-hydroxycoumarin with iodobenzene diacetate (Scheme 2a).
Recently, it was reported that Pd-catalyzed Sukuzi coupling of 3-chloro-4-alkoxy coumarins with
heteroarylboronic acids in the presence of base and SPhos gave 3-(benzo)furyl/thiophenyl
2
1
substituted 4-alkoxycoumarin analogues 10 in 64%-93% yields (Scheme 2b). The reported
methods required both prolonged heating and expensive transition-metal catalysts, which were
difficult to recycle and not environmental friendly.
Montmorillonite K10 clay has been known for its tunable Bronsted and Lewis acidities and
2
2-24
used as an environmental friendly catalyst in synthetic organic chemistry.
The K10 clay
offered several advantages compared with other catalysts, such as non-corrosive properties,
2
5-27
non-toxic, low cost, ease of handling and mild reaction conditions.
Moreover, it could be
2
8-30
easily separated and recycled, which made it an excellent heterogeneous green catalyst.
2

ACCEPTED MANUSCRIPT
Herein, we would like to report a facile and efficient K10 Montmorillonite Clay
heterogeneously catalyzed two-step one-pot synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-
ones 3 from ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates 1 and 2,5-dimethoxy-2,5-dihydrofuran
(DHDMF, 2) (Scheme 2c).
Scheme 2. Synthesis of 3-eteroHcyclicaryl-4-hydroxy-2H-chromen-2-ones.
2
1
. Results and discussion
3
1, 32
On the basis of literature report,
refluxing ethyl 3-(2-hydroxyphenyl)-3-oxopropanoate
33
a
with DHDMF in the presence of K10 montmorillonite Clay in anhydrous dichloromethane
(DCM) for 2 h, ethyl 2-(furan-2-yl)-3-(2-hydroxyphenyl)-3-oxopropanoate 4a was given in 12%
yield (Table 1, Entry 1). Replacement of DCM with hexane, the reaction was heated at a higher
o
temperature (70 C), which led to the formation of 4a in 25% yields (Entry 2). It was interesting to
find out that the yield of 4a was significantly improved when reaction was carried out under
solvent-free condition (86%, Entry3). In order to further optimized the reaction conditions, various
ratios of 1a : DHDMF : K10 were carefully screened (Entries 4-7). The result showed that 4a was
3

ACCEPTED MANUSCRIPT
obtained as high as 96 % yields with 1.5 equiv. of 2 (Entry 4), while the yield was not
significantly affected by the continued increased loading of 2 (Entry 5). Reducing or increasing
the loading of K10 led to the lower yield of 4a (Entries 6-7). Taking into account for the economic
and environmental factors, further temperature optimization was performed with the ratio listed in
Entry 4. Slight adjusting the reaction temperature did not improved the yield of 4a as well (Entries
8
-9). The K10 montmorillonite was recycled and it's reaction activity showed a gradual decrease.
The yields of five recycles were 85%, 82%, 75%, 70% and 64%, respectively.
Table 1
a
Optimization of the synthesis of ethyl 2-(furan-2-yl)-3-(2-hydroxyphenyl)-3-oxopropanoate .
b
c
Entry
Ratio 1a : 2 : K10
T (°C)
Solvent
Yield (%)
1
2
3
1 : 1 : 1
1 : 1 : 1
40 °C
70 °C
80 °C
80 °C
80 °C
80 °C
80 °C
70 °C
90 °C
DCM (1.5 mL)
12
25
86
96
97
63
94
79
95
n-Hex (1.5 mL)
1 : 1 : 1
–
–
–
–
–
–
–
d
4
1 : 1.5 : 1
1 : 2 : 1
5
6
7
8
9
1 : 1.5 : 0.5
1 : 1.5 : 1.5
1 : 1.5 : 1
1 : 1.5 : 1
a
All reactions were carried out on a 0.2 mmol of 1a and the reaction mixture was heated (oil bath) for 2 h (Entries
, 2) and 1 h (Entries 3-9).
1
b
DHDMF and 1a were calculated in molar ratio, K10 mont. and 1a were calculated in weight ratio.
Isolated yields was calculated based on 1a.
c
d
The K10 montmorillonite could be recycled. The yields of five recycles were 85%, 82%, 75%, 70% and 64%,
respectively.
The cyclization of 4a was initially performed in the mixture of hydrochloric acid ethanol
solution for refluxing 0.5 h, which gave corresponding cyclization product
-furan-4-hydroxycoumarin 3a in 22% yields (Table 2, Entry 1). It has been found out that
3
different acids slightly affected the yield of 3a. Product 3a was obtained in higher yield in the
presence of CF COOH (Entry 2), while only trace amount of 3a was detected in the presence of
3
4

ACCEPTED MANUSCRIPT
p-CH C H SO H (Entry 3). Surprisingly, the addition of a base significantly increased the yield of
3
6
4
3
3
a compared with an acid (85%, Entry 4). Further investigation on the loading of base revealed
that 2 equiv. of NaOH gave product 3a in best yield (92%, Entries 4-6). In the end, the optimal
conditions for the generation of 3a was Entry 5.
Table 2
a
Optimization of the synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones .
b
c
Entry
Acid/Base
HCl
4a : Acid/Base
1 : 1
Yield
22
1
2
3
4
5
6
CF COOH
1 : 1
35
3
p-CH C H SO H
1 : 1
trace
85
3
6
4
3
NaOH
NaOH
NaOH
1 : 1
1:2
92
1 : 3
91
a
b
c
Compound 4a (0.2 mmol) was refluxing in the mixture of additives and EtOH (1 mL) for 0.5 h.
Molar ratio.
Isolated yields was calculated based on 4a.
To further simplify the methodology and operation, we attempted to perform the coupling and
cyclization under the optimized conditions without isolation and purification of 4a (Scheme 3).
Treatment of 1a (0.2 mmol) with DHDMF (1.5 equiv, molar ratio to 1a) were performed in the
presence of K10 Montmorillonite Clay (1 equiv, mass ratio to 1a) at 80 °C for 1 h without addition
of any solvent to provide intermediate 4a. Without further purification, EtOH (1 mL) and NaOH
(2.0 equiv, 3 M) were added to the crude reaction mixture refluxing for 0.5 h, and followed by the
cyclization product 3a was given in yield of 86%.
Scheme 3. One-pot synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones (3a).
Our methodology, which not only avoided the usage of any expensive transition-metals but
also eliminated the tedious intermediate purification, was expanded to the synthesis of various
5

ACCEPTED MANUSCRIPT
functional group substituted 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one analogues (Table 3).
Due to the tolerance of various functional groups, presence of either electron donating group
(
EDG) or electron with drawing group (EWG) in the substrate could afford product 3 in good to
excellent yields. Generally, substrates bearing an electron donating group (EDG), such as –Me,
OMe or –OEt give the corresponding products in better yields (87–93%, 3b-3h) comparing to the
yields of those carrying an electron withdrawing group (EWG), including –F, –Br or –Cl (65–78%,
j-3o). The presence of halides in the final cyclization provides possibility for further modification.
–
3
It is note worthy that introducing an additional hydroxyl group on the benzene ring could be also
tolerated and the corresponding cyclization products were obtained in moderate yields (64–76%,
3
i, 3q-3s).
Table 3
a
Synthesis of 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones .
6

ACCEPTED MANUSCRIPT
a
All reactions were carried out on a 0.5 mmol of 1 in the presence of DHDMF (1.5 equiv, molar ratio to 1) and
o
K10 Montmorillonite Clay (1 equiv, mass ratio to 1) at 80 C for 1 h, followed by the addition of EtOH (2 mL)
/
NaOH (2 equiv., 3 M) and the mixture was refluxed for 0.5 h. Isolated yields.
To demonstrate the practicality and scalability of our methodology, the synthesis of 3a in
gram-scale was investigated. Ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates (1a, 1 g, 4.8 mmol),
DHDMF (2, 7.2 mmol) and K10 (1a, 1 g) were stirred without any solvent to obtained 4a at 80 °C
for 1 h, then EtOH (5 mL) and NaOH (2.0 equiv, 3 M) was added. Then the mixture was refluxed
for 0.5 h to produce 3a in 65% isolated yield (0.69 g) by the column chromatography.
In 1999, Zhu's group reported the reaction between 1,3-dicarbonyl compounds and DHDMF,
and found it underwent a fast process of Michael addition and a-alkoxyalkylation, then
2
8, 31
2
-furan-1,3-butane diones were obtained. According to this literature reported,
a plausible
mechanism for the 3-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones 3 was proposed and depicted in
Scheme 4. Initially, treatment of DHDMF with K10 montmorillonite led to a fast and efficient
3
1
formation of intermediate A, which reacted with 1 to give intermediate B along. Intermediate 4a
3
1
was obtained with the release of MeOH. Abstraction of phenolic hydrogen with external base led
to the formation of intermediate C, followed by the intramolecular cyclization and leaving of
alkoxide to produce intermediate E. Then, intermediate E tautomerized to the final product 3a due
to the thermodynamic stability.
Scheme 4. Proposed mechanism for the synthesis of compounds 3.
3
. Conclusion
In summary, we have successfully demonstrated a facile and efficient one-pot synthesis of
3
-(furan-2-yl)-4-hydroxy-2H-chromen-2-ones 3 from ethyl 3-(2-hydroxyphenyl)-3-oxopropanoate
7

ACCEPTED MANUSCRIPT
1
and DHDMF with the presence of K10 Montmorillonite Clay without requirement of any
transition-metal catalyst. Since the isolation of the intermediate was not required, the operation
procedure was simplified and reaction time was dramatically shortened. Notable features of our
strategy include (a) K10 Montmorillonite Clay as the catalyst and could be recycled, (b) good to
excellent yields, (c) excellent functional group tolerance, (d) easy to work-up.
4
. Experimental section
4
.1. General
K10 Montmorillonite Clay was purchased from Energy Chemical, and all reagents were
obtained from commercial sources and used without further purification. Melting points were
measured with a X-5 micro-melting point apparatus and are uncorrected. IR spectra were recorded
with a Nicolet 170SX FT-IR spectrophotometer on KBr pellets. High-resolution mass
spectrometry (HRMS) was performed using electron-spray ionization quadrupole-time of flight
(ESI-Q-TOF) techniques. Thin-layer chromatography was performed on precoated silica gel 60
1
GF254 plates. Silica gel (200−300 mesh) was used for column chromatography. H NMR spectra
were recorded on 400 or 600 MHz spectrometers. Spectra were referenced internally to the
1
3
residual proton resonance in CDCl or DMSO-d . C NMR spectra were recorded on 100 or 150
3
6
MHz spectrometers and the spectra were referenced to CDCl or DMSO-d .
3
6
3
3
4
.2. General Procedures for Syntheses of ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates (1a-1s) .
Under a dry argon atmosphere, lithium bis(trimethylsilyl)amide (1 M, 3 mmol) was cooled -78
o
C and a mixture of 2-hydroxyacetophenone (136 mg, 1 mmol) in dry THF (2 mL) was added
o
dropwise to the above solution in 20 min. The reaction solution was stirred at -78 C for 1 h and in
ice-bath for 2 h, and then a solution of diethyl carbonate (127.4 mg, 1.08 mmol) in dry THF (1 mL)
was rapidly added to the above mixture in ice-bath for 3-4 h. Then, the mixture was stirred at
room temperature. After 2-hydroxyacetophenone had disappeared completely, the reaction
solution poured into a mixture of concentrated HCl (1.5 mL) and ice (20 g). The mixture was
extracted with CHCl . The organic layer was dried over Na SO and concentrated under reduced
3
2
4
pressure. The crude products were purified using column chromatography on silica gel to give 1a
in good yields, and 1b-1s were prepared with the same method.
3
3
4
.2.1. Ethyl 3-(2-hydroxyphenyl)-3-oxopropanoate (1a) .
8

ACCEPTED MANUSCRIPT
1
Yield: 85%, 176.8 mg; colourless oil; H NMR (400 MHz, CDCl ) δ (ppm) 11.85 (s, 1H), 7.67
3
(d, J = 8.0 Hz, 1H), 7.50 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.92 (m, 1H), 4.23 (m, 2H), 4.00 (s,
+
2
H), 1.27 (m, 3H). HRMS (ESI): m/z [M + Na] calculated for C H O Na: 231.0628; found:
11
12
4
2
31.0626.
4
.2.2. Ethyl 3-(2-hydroxy-4-methoxyphenyl)-3-oxopropanoate (1b).
o
1
Yield: 95%, 226.1 mg; white solid; m.p. 28.9-29.6 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
1
1
9
2
2.30 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.46-6.37 (m, 2H), 4.19 (m, 2H), 3.90 (s, 2H), 3.82 (s, 3H),
1
3
.24 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 196.4, 167.2, 166.7, 165.8, 132.1, 113.2,
3
-1
08.2, 101.0, 61.7, 55.7, 45.6, 14.1. IR (KBr), ν (cm ): 3473, 2981, 1745, 1629, 1359, 1213, 1151,
+
58, 794, 576, 514. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 261.0733; found:
11
12
4
61.0732.
4
.2.3. Ethyl 3-(2-hydroxy-6-methoxyphenyl)-3-oxopropanoate (1c).
o
1
Yield: 93%, 221.3 mg; white solid; m.p. 37.4-38.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2.82 (s, 1H), 7.32 (m, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.33 (d, J = 8.4 Hz, 1H), 4.14 (m, 2H), 3.91
1
3
(
s, 2H), 3.80 (s, 3H), 1.20 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 198.8, 167.9, 165.0,
3
-1
1
60.90, 136.9, 110.9, 110.7, 101.1, 61.0, 55.5, 51.8, 14.1. IR (KBr), ν (cm ): 3438, 2989, 1728,
+
1
604, 1467, 1230, 1151, 1004, 786, 729, 611. HRMS (ESI): m/z [M + Na] calculated for
C H O Na: 261.0733; found: 261.0738.
1
2
14
5
4
.2.4. Ethyl 3-(2-hydroxy-3-methylphenyl)-3-oxopropanoate (1d).
1
Yield: 93%, 206.5 mg; colourless oil; H NMR (400 MHz, CDCl ) δ (ppm) 12.15 (s, 1H), 7.51
3
(d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.81 (m, 1H), 4.22 (m, 2H), 3.99 (s, 2H), 2.25 (s, 3H),
1
3
1
.26 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 198.7, 167.2, 161.4, 137.9, 128.0, 127.9,
3
-1
1
18.7, 118.4, 61.8, 46.1, 15.6, 14.2. IR (KBr), ν (cm ): 2930, 1740, 1637, 1429, 1306, 1256, 1151,
+
1
2
030, 750, 665, 438. HRMS (ESI): m/z [M + Na] calculated for C H O Na 245.0784; found:
12 14 4 :
45.0790.
4
.2.5. Ethyl 3-(2-hydroxy-5-methylphenyl)-3-oxopropanoate (1e).
o
1
Yield: 92%, 204.2 mg; white solid; m.p. 43.4-43.8 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2
1
1
1.68 (s, 1H), 7.43 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.23 (m, 2H), 3.99 (s,
1
3
H), 2.30 (s, 3H), 1.27 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 198.4, 167.1, 160.8, 138.4,
3
-1
30.0, 128.5, 118.8, 118.6, 61.8, 45.9, 20.6, 14.2. IR (KBr), ν (cm ): 3417, 2987, 2025, 1741,
+
643, 1488, 1386, 1153, 1035, 775, 611, 513. HRMS (ESI): m/z [M + Na] calculated for
C H O Na: 245.0784; found: 245.0783.
1
2
14
4
4
.2.6. Ethyl 3-(2-hydroxy-4,5-dimethoxyphenyl)-3-oxopropanoate (1f).
9

ACCEPTED MANUSCRIPT
o
1
Yield: 94%, 251.9 mg; white solid; m.p. 76.9-77.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2.18 (s, 1H), 6.95 (s, 1H), 6.38 (s, 1H), 4.15 (m, 2H), 3.85 (m, 5H), 3.78 (s, 3H), 1.20 (m, 3H).
1
3
C NMR (101 MHz, CDCl ) δ (ppm) 195.7, 167.1, 160.6, 157.3, 142.1, 110.9, 110.8, 100.5, 61.6,
3
-
1
5
8
2
6.4, 56.1, 45.9, 14.0. IR (KBr), ν (cm ): 3452, 1739, 1637, 1515, 1394, 1263, 1201, 1155, 1026,
+
65, 765, 678, 568. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 291.0839; found:
1
3
16
6
91.0840.
4
.2.7. Ethyl 3-(2-hydroxy-4,6-dimethoxyphenyl)-3-oxopropanoate (1g).
o
1
Yield: 92%, 246.6 mg; white solid; m.p. 66.9-67.4 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
3.44 (s, 1H), 5.95 (s, 1H), 5.81 (s, 1H), 4.09 (m, 2H), 3.80 (s, 2H), 3.71 (s, 6H), 1.16 (m, 3H).
1
3
C NMR (101 MHz, CDCl ) δ (ppm) 196.5, 168.0, 167.7, 166.7, 162.2, 105.3, 93.6, 90.6, 60.7,
3
-
1
5
8
2
5.3, 51.0, 14.0. IR (KBr), ν (cm ): 3427, 2987, 1731, 1625, 1421, 1307, 1220, 1159, 1026, 964,
+
25, 686, 599. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 291.0839; found:
1
3
16
6
91.0843.
4
.2.8. Ethyl 3-(4-ethoxy-2-hydroxy-3-methylphenyl)-3-oxopropanoate (1h).
o
1
Yield: 90%, 239.4 mg; white solid; m.p. 62.8-63.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2.34 (s, 1H), 7.52 (d, J = 8.7 Hz, 1H), 6.44 (d, J = 8.7 Hz, 1H), 4.21 (m, 2H), 4.12 (m, 2H), 3.93
1
3
(
s, 2H), 2.09 (s, 3H), 1.45 (m, 3H), 1.26 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 196.6,
3
-1
1
67.5, 163.7, 162.6, 129.7, 114.0, 113.4, 103.3, 64.3, 61.7, 45.8, 14.9, 14.2, 7.7. IR (KBr), ν (cm ):
3
431, 2985, 1728, 1633, 1504, 1415, 1284, 1209, 1122, 1028, 796, 636, 545. HRMS (ESI): m/z
+
[
M + Na] calculated for C H O Na: 289.1046; found: 289.1057.
1
4
18
5
4
.2.9. Ethyl 3-(2,3-dihydroxy-4-methoxyphenyl)-3-oxopropanoate (1i).
o
1
Yield: 75%, 190.5 mg; white solid; m.p. 70.3-71.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
11.95 (s, 1H), 7.19 (d, J = 9.0 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 5.77 (s, 1H), 4.14 (m, 2H), 3.87
1
3
(
m, 5H), 1.19 (m, 3H). C NMR (100 MHz, CDCl ) δ (ppm) 197.2, 167.1, 152.6, 150.5, 133.4,
3
-
1
1
1
2
22.6, 114.0, 103.2, 61.6, 56.2, 45.5, 14.0. IR (KBr), ν (cm ): 3462, 2989, 1720, 1637, 1448, 1305,
+
230, 1122, 1062, 892, 786, 686, 509. HRMS (ESI): m/z [M + Na] calculated for C H O Na:
1
2
14
6
77.0682; found: 277.0692.
4
.2.10. Ethyl 3-(4-fluoro-2-hydroxyphenyl)-3-oxopropanoate (1j).
o
1
Yield: 76%, 171.8 mg; white solid; m.p. 39.2-40.1 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
3
1
2.12 (s, 1H), 7.66 (m, 1H), 6.60 (m, 2H), 4.18 (m, 2H), 3.93 (s, 2H), 1.23 (m, 3H). C NMR
1
3
(
(
(
100 MHz, CDCl ) δ (ppm) 197.4, 167.8 (d, J = 256.4 Hz), 166.7, 165.3 (d, J = 14.4 Hz), 132.9
3
3
2
2
d, J = 11.9 Hz), 116.2, 107.7 (d, J = 23.1 Hz), 105.2 (d, J = 23.9 Hz), 61.8, 45.9, 14.0. IR
-1
KBr), ν (cm ): 3658, 2987, 1737, 1631, 1502, 1305, 1159, 1122, 966, 802, 557. HRMS (ESI):
+
m/z [M + Na] calculated for C H FO Na: 249.0534; found: 249.0533.
11
11
4
1
0

ACCEPTED MANUSCRIPT
4
.2.11. Ethyl 3-(5-fluoro-2-hydroxyphenyl)-3-oxopropanoate (1k).
o
1
Yield: 77%, 174 mg; white solid; m.p. 41.5-42.3 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
11.60 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.26 (m, 1H), 6.98 (d, J = 8.7 Hz, 1H), 4.24 (m, 2H), 3.97
1
3
1
(
s, 2H), 1.28 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 197.8, 166.6, 159.1, 154.9 (d, J =
3
2
3
1
2
2
2
8
2
38.0 Hz), 124.9 (d, J = 23.5 Hz), 120.2 (d, J = 7.0 Hz), 118.5 (d, J = 6.1 Hz), 115.2 (d, J =
-1
3.3 Hz), 61.9, 45.9, 14.1. IR (KBr), ν (cm ): 3670, 3205, 2927, 1728, 1490, 1238, 1166, 1035,
+
60, 784, 661, 513. HRMS (ESI): m/z [M + Na] calculated for C H FO Na: 249.0534; found:
11
11
4
49.0530.
4
.2.12. Ethyl 3-(5-chloro-2-hydroxyphenyl)-3-oxopropanoate (1l).
o
1
Yield: 74%, 179.1 mg; white solid; m.p. 67.1-68.6 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
4
1
1
1.74 (s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 8.9, 2.2 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H),
1
3
.23 (m, 2H), 3.97 (s, 2H), 1.28 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 197.8, 166.6,
3
-1
61.4, 137.1, 129.6, 124.1, 120.5, 119.7, 62.0, 45.9, 14.2. IR (KBr), ν (cm ): 3664, 3170, 2983,
+
728, 1479, 1265, 1157, 1031, 879, 744, 613, 511. HRMS (ESI): m/z [M + Na] calculated for
C H ClO Na: 265.0238; found: 265.0237.
11
11
4
4
.2.13. Ethyl 3-(5-bromo-2-hydroxyphenyl)-3-oxopropanoate (1m).
o
1
Yield: 73%, 208.1 mg; white solid; m.p. 67.2-68.4 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
4
1
1
1.77 (s, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 8.9, 2.3 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H),
1
3
.24 (m, 2H), 3.97 (s, 2H), 1.28 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 197.7, 166.6,
3
-1
39.9, 132.7, 120.9, 120.3, 110.9, 62.1, 45.9, 14.2. IR (KBr), ν (cm ): 3645, 3305, 2939, 2017,
+
728, 1475, 1265, 1157, 999, 948, 752, 617, 509. HRMS (ESI): m/z [M + Na] calculated for
C H BrO Na: 308.9733; found: 308.9733.
11
11
4
4
.2.14. Ethyl 3-(2-fluoro-6-hydroxyphenyl)-3-oxopropanoate (1n).
1
Yield: 75%, 169.5 mg; colourless oil. H NMR (400 MHz, CDCl ) δ (ppm) 12.32 (s, 1H),
3
7
.45-7.36 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 4.22 (m, 2H), 3.98 (m, 2H),
1
3
3
1
.26 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 197.3, 167.1, 164.3 (d, J = 8.4 Hz), 163.0 (d,
3
1
3
4
2
2
J = 249.1 Hz), 137.0 (d, J = 8.9 Hz), 114.7 (d, J = 3.1 Hz), 109.7 (d, J = 23.8 Hz), 106.3 (d, J
-1
=
24.2 Hz), 61.6, 50.6, 14.2. IR (KBr), ν (cm ): 3456, 2925, 1741, 1641, 1454, 1342, 1218, 1033,
+
7
2
92, 590, 528. HRMS (ESI): m/z [M + Na] calculated for C H FO Na: 249.0533; found:
1
1
11
4
49.0544.
4
.2.15. Ethyl 3-(3,5-difluoro-2-hydroxyphenyl)-3-oxopropanoate (1o).
o
1
Yield: 71%, 173.2 mg; yellow solid; m.p. 90.2-91.0 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
3
1
1.56 (s, 1H), 7.21-7.05 (m, 2H), 4.23 (m, 2H), 3.96 (s, 2H), 1.27 (m, 3H). C NMR (101 MHz,
3
1
3
1
CDCl ) δ (ppm) 197.8, 166.3, 153.7 (dd, J = 10.1 Hz, J = 240.6 Hz), 151.7 (dd, J = 10.1 Hz, J
3
1
1

ACCEPTED MANUSCRIPT
4
2
3
3
=
251.0 Hz), 148.2 (dd, J = 2.7 Hz, J = 25.4 Hz), 119.6 (dd, J = 7.2 Hz, J = 7.4 Hz), 111.9 (dd,
2
2
4
2
J = 21.0 Hz, J = 21.0 Hz), 110.5 (dd, J = 4.3 Hz, J = 23.2 Hz), 62.2, 46.3, 14.1. IR (KBr), ν
-
1
(
cm ): 3402, 2964, 1726, 1633, 1444, 1369, 1272, 1141, 995, 858, 798, 586. HRMS (ESI): m/z
+
[
M + Na] calculated for C H F O Na: 267.0439; found: 267.0455.
1
1
10
2
4
4
.2.16. Ethyl 3-(5-chloro-2-hydroxy-4-methylphenyl)-3-oxopropanoate (1p).
o
1
Yield: 73%, 186.9 mg; white solid; m.p. 96.3-97.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
3
1
1.65 (s, 1H), 7.58 (s, 1H), 6.84 (s, 1H), 4.21 (m, 2H), 3.92 (s, 2H), 2.33 (s, 3H), 1.25 (m, 3H). C
NMR (101 MHz, CDCl ) δ (ppm) 197.2, 166.7, 161.1, 146.5, 129.9, 124.6, 120.6, 118.0 61.8, 45.7,
3
-
1
2
5
0.9, 14.1. IR (KBr), ν (cm ): 3435, 2983, 1730, 1656, 1357, 1272, 1176, 1031, 939, 879, 752,
+
86. HRMS (ESI): m/z [M + Na] calculated for C H ClO Na: 279.0394; found: 279.0408.
1
2
13
4
4
.2.17. Ethyl 3-(2,4-dihydroxy-3-methylphenyl)-3-oxopropanoate (1q).
o
1
Yield: 72%, 171.4 mg; white solid; m.p. 143.0-144.0 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2.56 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.98 (s, 1H), 4.22 (m, 2H), 3.93
1
3
(
s, 2H), 2.11 (s, 3H), 1.27 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 196.5, 167.8, 163.6,
3
-
1
1
1
2
61.2, 129.6, 113.2, 111.7, 107.7, 62.0, 45.7, 14.2, 7.4. IR (KBr), ν (cm ): 3375, 1695, 1629, 1419,
+
215, 1076, 1018, 802, 678, 553. HRMS (ESI): m/z [M + Na] calculated for C H O Na:
1
2
14
5
61.0733; found: 261.0735.
4
.2.18. Ethyl 3-(2,4-dihydroxyphenyl)-3-oxopropanoate (1r).
o
1
Yield: 60%, 134.4 mg; white solid; m.p. 54.0-55.0 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2.24 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.26 (s, 1H), 6.42-6.31 (m, 2H), 4.23 (m, 2H), 3.93 (s, 2H),
1
3
1
.28 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 196.3, 168.4, 165.5, 164.2, 132.8, 113.3,
3
-
1
1
08.8, 103.7, 62.3, 45.5, 14.1. IR (KBr), ν (cm ): 3317, 2985, 2025, 1631, 1510, 1330, 1168, 1137,
+
1
018, 860, 790, 702, 619, 553. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 247.0577;
1
1
12
5
found: 247.0589.
4
.2.19. Ethyl 3-(2,5-dihydroxyphenyl)-3-oxopropanoate (1s).
o
1
Yield: 63%, 141.1 mg; white solid; m.p. 40.7-41.5 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2
1
1.37 (s, 1H), 7.06 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.36 (s, 1H), 4.22 (m,
1
3
H), 3.94 (s, 2H), 1.26 (m, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 198.1, 167.9, 156.7, 148.2,
3
-1
26.2, 119.6, 118.6, 114.9, 62.2, 46.0, 14.1. IR (KBr), ν (cm ): 3429, 2931, 1633, 1380, 1269,
+
1
153, 999, 918, 788, 698, 617, 514. HRMS (ESI): m/z [M + Na] calculated for C H O Na:
1
1
12
5
2
47.0577; found: 247.0591.
4
.2.20. Ethyl 2-(furan-2-yl)-3-(2-hydroxyphenyl)-3-oxopropanoate (4a).
o
1
Yield: 94%, 157.6 mg; white solid; m.p. 46.3-49.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
2

ACCEPTED MANUSCRIPT
11.74 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.48 (m, 1H), 7.42 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.88
1
3
(
m, 1H), 6.46 (d, J = 3.1 Hz, 1H), 6.39 (s, 1H), 5.73 (s, 1H), 4.26 (m, 2H), 1.26 (m, 3H). C NMR
(
101 MHz, CDCl ) δ (ppm) 196.9, 166.7, 163.4, 146.1, 143.1, 137.3, 130.4, 119.4, 119.0, 118.4,
3
-
1
1
8
2
11.2, 110.3, 62.4, 54.5, 14.1. IR (KBr), ν (cm ): 3375, 2979, 1739, 1637, 1492, 1226, 1188, 1016,
+
81, 748, 603. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 297.0733; found:
1
5
14
5
97.0732.
4
.3. General Procedures for Syntheses of 3-(Furan-2-yl)-4-hydroxy-2H-chromen-2-ones (3a-3s).
The ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates were prepared according to the literature
34
report. The mixture of ethyl 3-(2-hydroxyphenyl)-3-oxopropanoates (0.5mmol), DHDMF (1.5
equiv) and K10 Montmorillonite Clay (1equiv, mass ratio) was stirred at 80 °C under solvent-free
conditions for 1 h. Without further purification, EtOH (1 mL) and NaOH (2 equiv.) were added to
crude reaction mixture and the resulting suspension was refluxed for 0.5 h. After cooled down to
ambient temperature, K10 Montmorillonite Clay was recycled by vacuum filtration and the filtrate
was adjusted to pH 6–7 with 20% HCl. Volatiles were removed under reduced pressure and the
oily residue was column chromatographed (dichloromethane) to give 3 in moderate to excellent
yields.
4
.3.1. 3-(Furan-2-yl)-4-hydroxy-2H-chromen-2-one (3a).
o
1
Yield: 86%, 102.3 mg; white solid; m.p. 152.1-154.6 C. H NMR (600 MHz, CDCl ) δ (ppm)
3
9
.56 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.57 (m, 2H), 7.33 (m, 3H), 6.62 (dd, J = 3.5, 1.8 Hz, 1H).
1
3
C NMR (151 MHz, CDCl ) δ (ppm) 159.7, 158.7, 152.1, 148.6, 140.6, 132.6, 124.4, 123.8,
3
-1
1
16.5, 115.6, 112.4, 111.3, 96.8. IR (KBr), ν (cm ): 3053, 2986, 2854, 2191, 1541, 1398, 1194,
+
1
159, 993, 793, 611. HRMS (ESI): m/z [M + H] calculated for C H O : 229.0495; found:
13 9 4
2
29.0486.
4
.3.2. 3-(Furan-2-yl)-4-hydroxy-7-methoxy-2H-chromen-2-one (3b).
o
1
Yield: 87%, 99.2 mg; white solid; m.p. 200.1-201.3 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.50 (s, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.26 (d, J = 3.2 Hz, 1H), 6.90 (dd, J = 8.9, 2.1
1
3
Hz, 1H), 6.81 (d, J = 1.6 Hz, 1H), 6.60 (dd, J = 3.2, 1.6 Hz, 1H), 3.89 (s, 3H). C NMR (101
MHz, CDCl ) δ (ppm) 163.6, 160.1, 159.4, 154.0, 148.9, 140.2, 124.9, 112.9, 112.3, 110.3, 108.8,
3
-
1
1
7
00.2, 94.6, 55.9. IR (KBr), ν (cm ): 3356, 3088, 2183, 1717, 1609, 1433, 1366, 1205, 1124, 1018,
+
35, 586. HRMS (ESI): m/z [M + H] calculated for C H O : 259.0601; found: 259.0595.
1
4
11
5
4
.3.3. 3-(Furan-2-yl)-4-hydroxy-5-methoxy-2H-chromen-2-one (3c).
o
1
Yield: 90%, 102.6 mg; white solid; m.p. 182.1-184.0 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
3

ACCEPTED MANUSCRIPT
1
0.28 (s, 1H), 7.55 (s, 1H), 7.44 (m, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.78 (m, 1H), 6.51 (s, 1H), 4.06
13
(
s, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 160.6, 160.1, 156.4, 153.3, 146.1, 141.9, 132.4,
3
-
1
1
1
2
12.3, 111.1, 106.0, 105.0, 97.6, 57.3. IR (KBr), ν (cm ): 3425, 3259, 1703, 1633, 1440, 1365,
+
257, 1095, 954, 794, 730, 592. HRMS (ESI): m/z [M + Na] calculated for C H O Na:
1
4
10
5
81.0420; found: 281.0416.
4
.3.4. 3-(Furan-2-yl)-4-hydroxy-8-methyl-2H-chromen-2-one (3d).
o
1
Yield: 88%, 106.5 mg; white solid; m.p. 153.4-155.1 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
1
1
3
.48 (br, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 2.3 Hz,
1
3
H), 7.19 (m, 1H), 6.60 (s, 1H), 2.45 (s, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 159.7, 159.0,
3
-1
50.5, 148.8, 140.5, 133.8, 125.9, 123.8, 121.4, 115.3, 112.3, 111.2, 96.4, 15.7. IR (KBr), ν (cm ):
381, 2921, 1708, 1600, 1481, 1309, 1191, 1128, 1020, 908, 750, 582. HRMS (ESI): m/z [M +
+
Na] calculated for C H O Na: 265.0471; found: 265.0468.
1
4
10
4
4
.3.5. 3-(Furan-2-yl)-4-hydroxy-6-methyl-2H-chromen-2-one (3e).
o
1
Yield: 89%, 107.7 mg; white solid; m.p. 167.6-170.3 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.53 (br 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 3.6 Hz, 1H), 7.23 (d,
1
3
J = 8.6 Hz, 1H), 6.62 (dd, J = 3.5, 1.7 Hz, 1H), 2.44 (s, 3H). C NMR (101 MHz, CDCl ) δ (ppm)
3
1
59.8, 158.8, 150.3, 148.8, 140.5, 134.1, 133.7, 123.4, 116.3, 115.2, 112.4, 111.2, 96.7, 21.1. IR
-1
(
KBr), ν (cm ): 3400, 3082, 2172, 2026, 1688, 1549, 1367, 1271, 1192, 1020, 814, 716, 590.
+
HRMS (ESI): m/z [M + Na] calculated for C H O Na: 265.0471; found: 265.0465.
1
4
10
4
4
.3.6. 3-(Furan-2-yl)-4-hydroxy-6,7-dimethoxy-2H-chromen-2-one (3f).
o
1
Yield: 93%, 133.9 mg; white solid; m.p. 205.2-206.9 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.52 (s, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.31 (s, 1H), 7.27 (d, J = 3.5 Hz, 1H), 6.82 (s, 1H), 6.61 (dd,
1
3
J = 3.4, 1.9 Hz, 1H), 3.97 (m, 6H). C NMR (101 MHz, CDCl ) δ (ppm) 160.2, 159.1, 153.7,
3
-1
1
49.0, 148.2, 146.6, 140.2, 112.3, 110.3, 107.6, 103.6, 99.5, 94.9, 56.5, 56.4. IR (KBr), ν (cm ):
+
3
283, 2097, 1763, 1610, 1514, 1346, 1248, 1036, 818, 669, 554. HRMS (ESI): m/z [M + Na]
calculated for C H O Na: 311.0526; found: 311.0518.
1
5
12
6
4
.3.7. 3-(Furan-2-yl)-4-hydroxy-5,7-dimethoxy-2H-chromen-2-one (3g).
o
1
Yield: 91%, 131 mg; white solid; m.p. 168.2-169.5 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
1
0.03 (s, 1H), 7.52 (s, 1H), 6.91 (d, J = 2.8 Hz, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 6.32 (s, 1H), 3.99
1
3
(
s, 3H), 3.81 (s, 3H). C NMR (101 MHz, CDCl ) δ (ppm) 163.4, 161.3, 160.4, 157.4, 155.1,
3
-1
1
46.4, 141.6, 111.5, 111.0, 98.6, 95.8, 95.1, 94.3, 57.2, 56.0. IR (KBr), ν (cm ): 3423, 3257, 2947,
+
1
610, 1454, 1365, 1149, 1116, 960, 900, 808, 729, 496. HRMS (ESI): m/z [M + Na] calculated
for C H O Na: 311.0526; found: 311.0523.
15
12
6
1
4

ACCEPTED MANUSCRIPT
4
.3.8. 7-Ethoxy-3-(furan-2-yl)-4-hydroxy-8-methyl-2H-chromen-2-one (3h).
o
1
Yield: 89%, 127.3 mg; white solid; m.p. 171.0-172.5 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.46 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 3.7 Hz, 1H), 6.86 (d, J
1
3
=
8.9 Hz, 1H), 6.60 (dd, J = 3.7, 1.8 Hz, 1H), 4.14 (m, 2H), 2.32 (s, 3H), 1.47 (m, 3H). C NMR
(
101 MHz, CDCl ) δ (ppm) 160.7, 160.3, 159.6, 151.5, 149.2, 140.1, 121.9, 113.8, 112.3, 110.2,
3
-1
1
08.8, 108.1, 94.3, 64.5, 15.0, 8.4. IR (KBr), ν (cm ): 3355, 2929, 1703, 1610, 1402, 1276, 1122,
+
1
016, 769, 729, 644, 484. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 309.0733;
1
6
14
5
found: 309.0727.
4
.3.9. 3-(Furan-2-yl)-4,8-dihydroxy-7-methoxy-2H-chromen-2-one (3i).
o
1
Yield: 76%, 104.1 mg; white solid; m.p. 161.7-163.3 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.54 (s, 1H), 7.53 (m, 2H), 7.28 (d, J = 3.1 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.61 (dd, J = 3.1, 1.1
1
3
Hz, 1H), 5.74 (s, 1H), 4.01 (s, 3H). C NMR (101 MHz, DMSO-d ) δ (ppm) 161.4, 160.3, 151.2,
6
-
1
1
2
46.0, 142.1, 141.6, 133.2, 113.8, 111.0, 110.9, 110.1, 108.4, 94.8, 56.3. IR (KBr), ν (cm ): 3390,
+
921, 1676, 1591, 1487, 1330, 1089, 1004, 734, 592. HRMS (ESI): m/z [M + Na] calculated for
C H O Na: 297.0369; found: 297.0364.
1
4
10
6
4
.3.10. 7-Fluoro-3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one (3j).
o
1
Yield: 75%, 92.3 mg; white solid; m.p. 143.2-144.3 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
1
1
.55 (s, 1H), 7.96 (m, 1H), 7.54 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 7.02 (s,
1
3
1
H), 6.60 (s, 1H). C NMR (101 MHz, CDCl ) δ (ppm) 165.1 (d, J = 252.9 Hz), 159.4, 158.3,
3
3
3
2
53.2 (d, J = 12.9 Hz), 148.4, 140.6, 125.7 (d, J = 10.3 Hz), 112.6 (d, J = 22.9 Hz), 112.4, 112.1
4
2
-1
(
d, J = 2.5 Hz), 112.2, 104.5 (d, J = 25.5 Hz), 95.9. IR (KBr), ν (cm ): 3377, 3080, 1712, 1554,
+
1
2
492, 1315, 1188, 1083, 962, 740, 611. HRMS (ESI): m/z [M + Na] calculated for C H FO Na:
1
3
7
4
69.0221; found: 269.0218.
4
.3.11. 6-Fluoro-3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one (3k).
o
1
Yield: 78%, 95.9 mg; white solid; m.p. 173.5-174.4 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.56 (s, 1H), 7.65 (dd, J = 8.4, 2.8 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.31
1
3
1
(
m, 2H), 6.63 (dd, J = 3.4, 1.7 Hz, 1H). C NMR (101 MHz, CDCl ) δ (ppm) 159.3, 159.0 (d, J
3
2
3
=
252.9 Hz), 157.6, 148.3, 148.2, 140.9, 120.1 (d, J = 24.6 Hz), 118.2 (d, J = 8.3 Hz), 116.6 (d,
3
2
-1
J = 9.2 Hz), 112.5, 112.0, 109.4 (d, J = 25.4 Hz), 97.4. IR (KBr), ν (cm ): 3377, 3080, 2183,
+
1
713, 1555, 1493, 1367, 1315, 1188, 1148, 988, 741, 611. HRMS (ESI): m/z [M + Na] calculated
for C H FO Na: 269.0221; found: 269.0215.
13
7
4
4
.3.12. 6-Chloro-3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one (3l).
o
1
Yield: 70%, 91.7 mg; white solid; m.p. 203.8-204.9 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.55 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.36 (d, J = 3.4
1
5

ACCEPTED MANUSCRIPT
1
3
Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.64 (dd, J = 3.6, 2.0 Hz, 1H). C NMR (101 MHz, CDCl ) δ
3
-1
(
ppm) 159.1, 157.3, 141.0, 132.5, 130.0, 123.3, 118.0, 116.8, 112.5, 112.0. IR (KBr), ν (cm ):
+
3
367, 3076, 1722, 1542, 1315, 1120, 1020, 935, 815, 725, 607. HRMS (ESI): m/z [M + Na]
calculated for C H ClO Na: 284.9925; found: 284.9920.
1
3
7
4
4
.3.13. 6-Bromo-3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one (3m).
o
1
Yield: 65%, 99.5 mg; white solid; m.p. 169.1-171.2 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.54 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.36
1
3
(
d, J = 3.6 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.63 (dd, J = 3.6, 1.6 Hz, 1H). C NMR (101 MHz,
CDCl ) δ (ppm) 159.0, 157.2, 150.9, 148.3, 141.0, 135.3, 126.3, 118.3, 117.2, 112.8, 112.5, 112.0,
3
-1
9
7.5. IR (KBr), ν (cm ): 3371, 1718, 1608, 1363, 1313, 1107, 1018, 931, 813, 725, 597. HRMS
+
(
ESI): m/z [M + Na] calculated for C H BrO Na: 328.9420; found: 328.9413.
1
3
7
4
4
.3.14. 5-Fluoro-3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one (3n).
o
1
Yield: 76%, 93.5 mg; white solid; m.p. 181.7-183.6 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
1
1
.75 (s, 1H), 7.56 (s, 1H), 7.50 (m, 1H), 7.34 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.02 (m,
1
3
1
H), 6.63 (dd, J = 3.5, 1.7 Hz, 1H). C NMR (151 MHz, CDCl ) δ (ppm) 159.4 (d, J = 253.7 Hz),
3
2
4
3
58.7 (d, J = 25.6 Hz), 158.52, 153.0 (d, J = 4.2 Hz), 148.2, 140.8, 132.5 (d, J = 10.7 Hz), 112.8
4
2
3
(
(
[
d, J = 4.2 Hz), 112.4, 112.0 (d, J = 21.6 Hz), 111.9, 105.8 (d, J = 11.8 Hz), 97.2. IR (KBr), ν
-
1
cm ): 3352, 3149, 2921, 1942, 1722, 1612, 1481, 1315, 1051, 734, 636, 584. HRMS (ESI): m/z
+
M + Na] calculated for C H FO Na: 269.0220; found: 269.0217.
1
3
7
4
4
.3.15. 6,8-Difluoro-3-(furan-2-yl)-4-hydroxy-2H-chromen-2-one (3o).
o
1
Yield: 68%, 89.8 mg; white solid; m.p. 166.2-167.6 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
1
1
.58 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 2.7 Hz, 1H), 7.12 (m, 1H), 6.63 (s,
13
3
1
H). C NMR (101 MHz, CDCl ) δ (ppm) 158.0 (dd, J = 9.9 Hz, J = 246.8 Hz), 157.9, 156.9,
3
3
1
4
2
49.4 (dd, J = 12.3 Hz, J = 253.2 Hz), 147.8, 141.2, 137.1 (dd, J = 2.9 Hz, J = 22.8 Hz), 117.7
3
3
2
2
4
(
dd, J = 10.1 Hz, J = 10.3 Hz), 112.6, 112.5, 107.7 (dd, J = 20.7 Hz, J = 20.6 Hz), 104.8 (dd, J
2
-1
=
2.1 Hz, J = 25.0 Hz), 98.12. IR (KBr), ν (cm ): 3421, 3342, 1662, 1550, 1375, 1307, 1164, 993,
+
9
14, 763, 742, 634, 509. HRMS (ESI): m/z [M + Na] calculated for C H F O Na: 287.0126;
1
3
6
2
4
found: 287.0124.
4
.3.16. 6-Chloro-3-(furan-2-yl)-4-hydroxy-7-methyl-2H-chromen-2-one (3p).
o
1
Yield: 80%, 110.4 mg; white solid; m.p. 227.8-229.1 C. H NMR (400 MHz, CDCl ) δ (ppm)
3
9
.52 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 7.33 (d, J = 3.5 Hz, 1H), 7.22 (s, 1H), 6.62 (dd, J = 3.1, 1.6
1
3
Hz, 1H), 2.48 (s, 3H). C NMR (101 MHz, DMSO-d ) δ (ppm) 159.7, 159.6, 150.4, 145.6, 142.4,
6
-1
1
40.8, 128.9, 123.2, 118.6, 115.6, 111.6, 111.1, 97.1, 19.9. IR (KBr), ν (cm ): 3382, 2923, 1718,
+
1
616, 1523, 1301, 1141, 1020, 931, 813, 727, 603. HRMS (ESI): m/z [M + Na] calculated for
1
6

ACCEPTED MANUSCRIPT
C H ClO Na: 299.0081; found: 299.0080.
1
4
9
4
4
.3.17. 3-(Furan-2-yl)-4,7-dihydroxy-8-methyl-2H-chromen-2-one (3q).
o
1
Yield: 71%, 91.6 mg; white solid; m.p. 127.8-130.0 C. H NMR (400 MHz, DMSO-d ) δ
6
(ppm) 10.48 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 1.8Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H),
1
3
6
.70 (d, J = 3.3 Hz, 1H), 6.55 (dd, J = 3.3, 1.9 Hz, 1H), 2.16 (s, 3H). C NMR (151 MHz,
DMSO-d ) δ (ppm) 162.6, 160.7, 159.4, 152.0, 146.7, 141.6, 121.9, 111.7, 110.9, 110.2, 108.4,
6
-1
9
3.4, 8.1. IR (KBr), ν (cm ): 3444, 2923, 2850, 1676, 1465, 1276, 1089, 1006, 927, 765, 732, 559.
+
HRMS (ESI): m/z [M + Na] calculated for C H O Na: 281.0420; found: 281.0419.
1
4
10
5
4
.3.18. 3-(Furan-2-yl)-4,7-dihydroxy-2H-chromen-2-one (3r).
o
1
Yield: 66%, 80.5 mg; white solid; m.p. 145.8-147.1 C. H NMR (400 MHz, DMSO-d ) δ
6
(ppm) 10.7 (br, 1H), 7.8 (d, J = 8.8 Hz, 1H), 7.7 (s, 1H), 6.8 (d, J = 8.7 Hz, 1H), 6.70 (s, 2H), 6.56
13
(
s, 1H). C NMR (101 MHz, DMSO-d ) δ (ppm) 161.9, 161.7, 160.5, 154.0, 146.2, 141.9, 125.4,
6
-
1
1
13.0, 111.0, 110.6, 108.0, 101.8, 93.9. IR (KBr), ν (cm ): 3440, 3365, 2921, 2027, 1612, 1460,
+
1
232, 1022, 842, 727, 586. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 267.0264;
13 8 5
found: 267.0264.
4
.3.19. 3-(Furan-2-yl)-4,6-dihydroxy-2H-chromen-2-one (3s).
o
1
Yield: 64%, 78.1 mg; white solid; m.p. 198.2-199.4 C. H NMR (400 MHz, DMSO-d ) 11.50
6
(br, 1H), 9.80 (s, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H),
1
3
7
.08 (dd, J = 8.9, 2.9 Hz, 1H), 6.81 (d, J = 3.2 Hz, 1H), 6.60 (dd, J = 3.3, 1.8 Hz, 1H). C NMR
(
151 MHz, DMSO-d ) δ (ppm) 160.2, 160.1, 153.7, 145.9, 145.3, 142.3, 120.8, 117.2, 116.6, 111.4,
6
-1
1
11.1, 107.8, 97.0. IR (KBr), ν (cm ): 3392, 3288, 2025, 1668, 1550, 1313, 1191, 1020, 918, 829,
+
7
40, 621. HRMS (ESI): m/z [M + Na] calculated for C H O Na: 267.0264; found: 267.0261.
1
3
8
5
Acknowledgements
We are grateful for financial support from the National Natural Science Foundation of China
No: 21672132, 21502110) and the Fundamental Funds Research for the Central Universities (No:
(
GK201503034).
Author Information
Corresponding Author
*Tel.: (+86)-29-85303940. Fax: (+86)-29-81530727. E-mail: zhangzunting@sina.com.
Present address
†
Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte,
1
7

ACCEPTED MANUSCRIPT
California 91010, United States.
Appendix A. Supplementary data
1
13
General experimental procedures of 1, spectroscopic data, H NMR, C NMR and HRMS.
Spectra of all compounds (PDF)
References
1
2
3
4
5
6
7
8
9
1
1
1
1
.Abida MI, Alsalman AJ. Trop. J. Pharm. Res. 2016, 15: 393-404.
. Selim YA, Ouf NH. Org. Med. Chem. Lett. 2012, 2: 1-4.
. Gourdeau H, Leblond L, Hamelin B. Mol. Cancer. Ther. 2004, 3: 1375-1383.
. Venugopala KN, Rashmi, V, Odhav B. Biomed. Res. Int. 2013, 2013: 963248-963262.
. Kirkiacharian S, Thuy DT, Sicsic S. Il Farmaco. 2002, 57: 703-708.
. Marvig C L. Verhoef TI. De BA. Thromb. Res. 2015, 136: 69-75.
. Al-Amiery AA, Al-Majedy YK, Kadhum AAH. Molecules. 2015, 20: 366-383.
. Khan KM, Iqbal S, Lodhi MA. Bioorgan. Med. Chem. 2004, 12: 1963-1968.
. Tang L, Li F, Liu M, Nandhakumar R. B. Korean. Chem. Soc. 2011, 32: 3400-3404.
0. Piltan MJ, Ghomi JS. Bull. Chem. Soc. Ethiop. 2016, 30: 289-296.
1. Zaheer Z, Khan FAK, Sangshetti JN. Chinese. Chem. Lett. 2016, 27: 287-294.
2. Rodriguez SA, Nazareno MA, Baumgartner MT. Bioorgan. Med. Chem. 2011, 19: 6233-6238.
3. Serra S, Ferino G, Matos MJ, Vazquez-Rodriguez S. Bioorgan. Med. Chem. Lett. 2012, 22:
2
58-261.
1
1
1
1
1
1
2
2
2
2
4. Stanchev S, Momekov G, Jensen F. Eur. J. Med. Chem. 2008, 43: 694-706.
5. Kalinin AV, Silva AJMD, Lopes CC. Tetrahedron. Lett. 1998, 39: 4995-4998.
6. Serra S, Chicca A, Delogu G. Bioorgan. Med. Chem. Lett. 2012, 22: 5791-5794.
7. Xi GL, Liu ZQ. J. Agr. Food. Chem. 2014, 62: 5636-5642.
8. Tang L, Pang Y, Yan Q. J. Org. Chem. 2011, 76: 2744-2752.
9. Cenini S, Cravotto G, Giovenzana GB. J. Mol. Catal. A-Chem. 2000, 164: 165-171.
0. Zhu Q, Wu J, Fathi R. Org. Lett. 2002, 4: 3333-3336.
1. Prendergast AM, McGlacken GP. Eur. J. Org. Chem. 2017, 2017: 4827-4835.
2. Bahulayan D, Das SK, Iqbal J. J. Org. Chem. 2003, 68: 5735-5738.
3. Jeganathan M, Dhakshinamoorthy A, Pitchumani K. ACS. Sustain. Chem. Eng. 2014, 2:
7
81-787.
2
2
2
2
2
2
3
3
3
3
3
4. Kannan V, Sreekumar K. Mod. Res. Catal. 2013, 2: 42-46.
5. Kumar BS, Dhakshinamoorthy A, Pitchumani K. Catal. Sci. Technol. 2014, 4: 2378-2396.
6. Marques IJ, Vaz PD, Fernandes AC. Micropor. Mesopor. Mat. 2014, 183: 192-200.
7. Fang Z, Liu B, Luo J. Biomass. Bioenerg. 2014, 60: 171-177.
8. Han J, Wang T, Feng S. Green. Chem. 2016, 18: 4092-4097.
9. Jeganathan M, Pitchumani K. RSC. Adv. 2014, 4: 38491-38497.
0. Jeganathan M, Dhakshinamoorthy A, Pitchumani K. Tetrahedron. Lett. 2014, 55: 1616-1620.
1.Soriente RAA, Rosa MD, Palombi L. Green. Chem. 1999, 1: 157-162.
2. Malanga C, Mannucci S. Tetrahedron. Lett. 2001, 42: 2023-2025.
3. Cushman M, Nagarathnam D, Burg DL. J. Med. Chem. 1991, 34: 798-806.
4. Cushman M, Nagarathnam D, Burg DL. J. Med. Chem. 1991, 34: 798-806.
1
8