Synthesis of furo[3,2-c]coumarins via I2/TBHP-mediated reaction of 4-hydroxycoumarins with terminal alkynes

Article abstract of DOI:10.1016/j.tet.2018.01.012

An efficient I₂/TBHP-mediated process for the formation of furo[3,2-c]coumarins from readily available materials has been developed. This process for the formation of furo[3,2-c]coumarins is quite environmental friendly and atom-economical.

Full text of DOI:10.1016/j.tet.2018.01.012

Accepted Manuscript
Synthesis of furo[3,2-c]coumarins via I /TBHP-mediated reaction of 4-
2
hydroxycoumarins with terminal alkynes
Xianglong Chu, Ziqiang Tang, Jiangshan Ma, Libowen He, Lei Feng, Chen Ma
PII:
S0040-4020(18)30034-6
10.1016/j.tet.2018.01.012
TET 29227
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 December 2017
Revised Date: 8 January 2018
Accepted Date: 9 January 2018
Please cite this article as: Chu X, Tang Z, Ma J, He L, Feng L, Ma C, Synthesis of furo[3,2-c]coumarins
via I /TBHP-mediated reaction of 4-hydroxycoumarins with terminal alkynes, Tetrahedron (2018), doi:
2
10.1016/j.tet.2018.01.012.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of Furo[3,2-c]coumarins via I2/TBHP-mediated Reaction of 4-
Hydroxycoumarins with Terminal Alkynes
Xianglong Chu,[a] Ziqiang Tang,[a] Jiangshan Ma,[a] Libowen He,[a] Lei Feng,*[a]and Chen Ma [a], [b]
a school of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P R China.
b State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, P. R. China.
An efficient I2/TBHP-mediated process for the formation of furo[3,2-c]coumarins has been developed. This process for the
formation of furo[3,2-c]coumarins is quite environmental friendly and atom-economical.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of Furo[3,2-c]coumarins via I2/TBHP-mediated Reaction of 4-Hydroxycoumarins
with Terminal Alkynes
Xianglong Chu,[a] Ziqiang Tang,[a] Jiangshan Ma,[a] Libowen He,[a] Lei Feng,*[a]and Chen Ma [a], [b]
a
school of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P R China.
b State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and
Peking Union Medical College, Beijing, 100050, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient I2/TBHP-mediated process for the formation of furo[3,2-c]coumarins from readily
available materials has been developed. This process for the formation of furo[3,2-c]coumarins
is quite environmental friendly and atom-economical.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
I2/TBHP
transition-metal free
furo[3,2-c]coumarins
coupling/cyclization
with 3-halo-4-hydroxycoumarins.5 Lin et al.6 reported the
synthesis of polysubstituted furo[3,2-c]coumarins from
phosphorus zwitterions and acid chlorides. Foti and Cristina7
reported the formation of furo[3,2-c]coumarins from 4-
hydroxycoumarins and double electrophile α-haloketones
(Scheme 1a). Recently, Chen and co-workers8 developed a
palladium catalyzed C–H functionalization strategy for the
construction of furo[3,2-c]coumarins. (Scheme 1b). However,
these methods suffered from metal contamination, harsh reaction
conditions and prefunctionalization of starting materials. Very
recently, Hajra and Dey9 employed 4-hydroxycoumarins with
alkynes catalyzed by FeCl3/ZnI2 to furnish furo[3,2-c]coumarins
in a convenient and direct synthesis method (Scheme 1b). Herein,
we reported a transition-metal free strategy for the synthesis of
furo[3,2-c]coumarins from 4-hydroxycoumarins and terminal
alkynes using I2/TBHP under aerobic conditions (Scheme 1c).
Advantages of this process include the better atom-economy and
commercial availability of the starting materials. Futhermore,
molecular iodine is an environmental friendly, cheap and easy
storage solid reagent. It has been proved that iodine could be a
substitute for transtion-metal to catalyze some organic reactions.10
1. Introduction
The furocoumarin core is characterized as a significant structure
that widely exists in many biologically active natural products,1
such as pterophyllin, wedelactone, neo-tanshinlactone (Figure 1).
Furocoumarin derivatives have been found to possess great
interesting biological activities including anti-neurodegenerative
diseases, antitumor, anticancer, Na+, K+-ATPase inhibitors.2
Figure 1. Representative furocoumarin molecules.
Due to its great value, much effort has been devoted to the
synthesis of furocoumarin derivatives. The cyclization of
alkynylcoumarins catalyzed by transition-metal3 or iodine4 is one
of the most efficient among these methods. Another alternative
approach is sequential coupling/cyclization of terminal alkynes
———
Corresponding author. e-mail: chenma@sdu.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1. Optimizing the conditions for the formation of 3a.a
Scheme 1. Representative approaches for synthesis of
furo[3,2-c]coumarins
entry
1
[I]
–
[O]
AgF
base
Cs2CO3
solvent
DMF
DMF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
yield, %b
trace
7
2
–
Ag2CO3
TBHP
TBHP
TBHP
TBHP
–
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2NH4
K3PO4
3
NH4I
ZnI2
NIS
I2
–
4
21
trace
73
trace
–
5
6
7
I2
8
I2
BQ
9
I2
BPO
62
–
10
11
12
13
14
15
I2
O2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
47
–
I2
I2
t-BuOK
49
8
I2
K2CO3
I2
NEt3
60
2. Results and Discussion
16
I2
TBHP
DBU
DCE
68
We began to study the reaction utilizing 4-hydroxycoumarin
(1a) and phenylacetylene (2a) as model substrates to screen the
reaction conditions (Table 1). When the reaction was performed
at silver/base system,12e the target molecule furo[3,2-c]coumarin
(3a) was obtained in a low yield (Table 1, entries 1-2).
Gratifyingly, the reaction proceeded smoothly to get the 3a when
[I] (iodine source) was added to the reaction system (Table 1,
entries 3-5) and molecule I2 was the best iodine source affording
the compound 3a in a yield of 73% (Table 1, entry 6).
Encouraged by this result, we studied the effect of equivalent of
I2. Regretfully, catalytic amount of I2 only afforded 3a in 23%
yield and the best equivalent of I2 was 0.8 equiv (see Supporting
Information Table 1, entries 1-6). A series of oxidants were then
examined for the reaction, including BQ (benzoquinone), BPO
(dibenzoyl peroxide) and O2. Trace amount of target compound
was obtained in the absence of oxidant and TBHP was still the
best choice (Table 1, entries 6-10). A screening of base, such as
CH3COONH4, K3PO4, t-BuOK, K2CO3, Et3N, DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), proved that CH3COOK was the
optimal base to give 3a in a yield of 73% (Table 1, entries 11-17).
Further switching solvent like DMSO, H2O, MeCN, dioxane
found that the yield of 3a was slightly improved with the dioxane
(Table 1, entries 18-22). Increasing or reducing the temperature
had a negative influence on this transformation (see Supporting
Information Table 1, entries 7-8). Finally, the optimized reaction
conditions were 2a (0.5 mmol), 3 equiv of 1a, 0.8 equiv of I2, 3
equiv of TBHP and 1 equiv of CH3COOK in 4 mL dioxane at 90
oC for 8 h under air atmosphere.
17
18
19
20
21
I2
I2
I2
I2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
–
DCE
H2O
30
20
–
CH3CO2K
CH3CO2K
CH3CO2K
CH3CO2K
DMSO
MeCN
19
15
H2O/DCE
1:1
Dioxane
22
I2
TBHP
CH3CO2K
77
aReaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), [I] (0.4 mmol),
[O] (1.5 mmol), base (0.5 mmol) and solvent (4 mL), 90 oC, air, 8 h.
bIsolated yield.
the yield (compared 3c, f to 3g, i). Notably, halogen moieties,
such as fluorophenylacetylene, chlorophenylacetylene and
bromophenylacetylene were tolerated well with good yield
(Scheme 2, 3g-3i), providing the possibilities for further coupling
reaction. Steric hindrance had little effect on this transformation
(compared 3b, g to 3j, k). It was found that the heterocyclic
derived substrates were also compatible under the optimal
conditions (Scheme 2, 3m-3n). The aliphatic terminal alkyne
(hexyne) was also found to be suitable for this reaction but in a
low yield (Scheme 2, 3o). The reaction of various 4-
hydroxycoumarin derivatives with phenylacetylene were also
summarized in Scheme 2. Both electron-donating groups (4-Me,
3-OMe and 4-OMe) and electron-withdrawing groups (4-F, Cl
and Br) could smoothly afford target molecules. Generally,
electron-withdrawing groups gave higher yields than those with
electron-donating groups (Scheme 2, 3p-3w).
With the scope of the reaction established, some control
With the optimized conditions in hand, the substrate scope was
then examined. The results are summarized in Scheme 2. A series
of terminal alkynes with different electronic properties smoothly
underwent the reaction, the corresponding compounds were
obtained in 30-88% yields (Scheme 2, 3a-n). Generally, electron-
donating substituents on the aromatic ring have positive effect on
experiments were carried out. When
4 equiv of 1,1-
diphenylethylene or BHT (2,6-di-tert-butyl-4-methylphenol) was
added to the reaction system under the standard conditions, no
desired compound was obtained and radical addition product was
detected by HRMS (Scheme 3). These phenomena indicated that
the reaction possibly underwent a radical pathway.

3
Scheme 2. Scope of terminal alkynes and 4-
Scheme 4. Proposed mechanism.
ACCEPTED MANUSCRIPT
hydroxycoumarins.a, b
O
O
O
O
O
O
O
O
O
O
O
O
3a, 77%
3c, 83%
3b, 77%
3d, 79%
O
O
O
O
O
O
O
O
O
O
O
O
O
3h, 30%
3g, 45%
3f, 88%
3e, 74%
3. Conclusions
O
Br
F
O
O
O
O
O
O
In summary, we have developed a transition-metal free and
simple strategy for the construction of a series of furo[3,2-
c]coumarins from readily available 4-hydroxycoumarins and
terminal alkynes using I2/TBHP system under a mild air
conditions. This method provided an atom-economical,
transition-metal free and operationally simple access to the
furo[3,2-c]coumarins.
O
O
F
O
O
O
O
O
3i, 32%
3l, 64%
3j, 81%
3k, 48%
Cl
F
O
O
O
O
O
O
O
O
S
O
O
O
O
O
F
S
3m, 49%
3n, 61%
3o, 17%
3p, 60%
O
O
O
O
O
O
O
O
O
4. Experimental section
O
O
O
O
3t, 74%
3r, 66%
3s, 75%
3q, 61%
4.1. General remarks
O
O
O
O
O
O
O
Substituted substrates 1 were obtained according to the
literature reports.13 Other reagents and solvents were obtained
from commercial available and used directly without further
purification. All the reactions were monitored by thin-layer
F
O
O
O
Cl
Br
3u, 72%
3w, 61%
3v, 85%
aReaction conditions: 1a (1.5 mmol), 2a (0.5 mmol), I2 (0.4 mmol),
TBHP (1.5 mmol), CH3COOK (0.5 mmol) and dioxane (4 mL), 90
oC, air, 8 h. bIsolated yield.
1
chromatography. H NMR spectra were recorded on a Bruker
Avance 500 spectrometer at 500 MHz using CDCl3 as solvent and
tetramethylsilane (TMS) as internal standard. 13C NMR spectra
were run in the same instrument at 125 MHz. HRMS spectra
were measured on a Q-TOF instrument in positive-ion mode with
an ESI ion source. Melting points were recorded on an XD-4
digital micro melting point apparatus.
Scheme 3. Control Experiments for Mechanism
4.2. General procedure
4.2.1. Typical Procedure for the Synthesis of 11 3
In a 250 mL two-neck round-bottom flask, 9 mmol of o-
hydroxyacetophenone in 15 mL toluene was slowly added to
sodium hydride (60% w/w suspension, 5 equiv, 45 mmol, 1.8 g)
o
in toluene (10 mL) under N2 atmosphere at 0 C. After 15 min,
Based on the above results and other literature reports,11, 12
a
13.5 mmol of diethyl carbonate in 10 mL toluene was added
dropwise, and the mixture was stirred at room temperature for 30
min and refluxed until the reaction finished (monitored by TLC
(Thin Layer Chromatography)). After the mixture cooled to room
temperature, the reaction was quenched by slowly addition of 2 N
hydrochloric acid. The resulting precipitate was further purified
by a short silica gel column chromatography to give a white solid.
possible mechanism is proposed for this transformation in
Scheme 4. First, D was formed by the oxidation of 1a’ by I+
12a
which was generated in situ by TBHP and I..11,
Then D
generated radical intermidiate E. Next, the addition of E with
alkyne generated vinyl radical intermediate F. F attacked
carbonyl group to give G, which was oxidized by TBHP to form
target molecule 3a
.
4.2.2. General procedure for preparation of 3 (3a as an example)
A sealed tube was charged with 4-hydroxycoumarin (1a
)
(1.5 mmol, 0.243 g), phenylacetylene (2a) (0.5 mmol, 0.051
g), TBHP (1.5 mmol, 0.193 g), I2 (0.4 mmol, 0.102 g), CH-
3COOK (0.5 mmol, 0.049 g) and dioxane (4 mL). Then, the
o
mixture was stirred at 90 C under air until the reaction was

4
Tetrahedron
ACCEPTED MANUSCRIPT
completed (monitored by TLC). The cooled reaction
1H), 7.43-7.41 (m, 1H), 7.37-7.34 (m, 1H), 7.29-7.27 (m, 2H),
mixture was diluted with brine and saturated Na2S2O3 (20
mL) and extracted with ethyl acetate (20 mL×3). The
combined organic layers were dried with Na2SO4 and
evaporated under vacuum to afford the residue. The residue
was purified by column chromatography (silica gel) with
petroleum ether/ethyl acetate (50: 1) to obtain pure product 3a
as a yellow solid (77% yield).
7.09-7.08 (m, 1H), 2.71 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 158.31, 156.91, 156.59,
152.51, 145.67, 130.44, 128.52, 126.43, 124.60, 124.54, 120.74,
117.33, 112.80, 112.52, 101.89, 28.76, 15.39; HRMS (ESI)
calculated for C19H14O3 (M+H)+ 291.1016; found: 291.1002.
4.2.9. 2-(4-Fluorophenyl)-4H-furo[3,2-c]chromen-4-one (3g).
Yellow solid (45%), M.P.: 216-218 oC; 1H NMR (500 MHz,
CDCl3): δ 7.95 (dd, J = 8.0, 1.0 Hz, 1H), 7.81-7.79 (m, 2H), 7.55-
7.52 (m, 1H), 7.47-7.45 (m, 1H), 7.40-7.37 (m, 1H), 7.19-7.16 (m,
2H), 7.12 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 164.16 (d, J =
248.8 Hz), 158.16, 156.90, 155.73, 152.64, 130.71, 126.58 (d, J =
7.5 Hz), 125.35 (d, J = 2.5 Hz), 124.64, 120.76, 117.45, 116.35 (d,
J = 22.5 Hz), 112.70, 112.55, 102.43; HRMS (ESI) calculated for
C17H9FO3 (M+H)+ 281.0608; found: 281.0608.
4.2.3. 2-Phenyl-4H-furo[3,2-c]chromen-4-one (3a). Yellow
solid (77%), M.P.: 164-166 oC; 1H NMR (500 MHz, CDCl3):
δ
7.97 (dd,
7.45 (m, 4H), 7.41-7.36 (m, 2H), 7.18 (s, 1H); 13C NMR
(125 MHz, CDCl3): 158.37, 157.02, 156.76, 152.76,
J = 10.0, 1.5 Hz, 1H), 7.82-7.80 (m, 2H), 7.55-
δ
130.76, 129.30, 129.17, 129.10, 124.73, 124.71, 120.94,
117.54, 112.91, 112.66, 102.83; HRMS (ESI) calculated for
C17H10O3 (M+H)+ 263.0703; found: 263.0699.
4.2.10. 2-(4-Bromophenyl)-4H-furo[3,2-c]chromen-4-one (3h).
White solid (30%), M.P.: 260-262 oC; 1H NMR (500 MHz,
CDCl3): δ 7.92 (dd, J = 7.5, 1.5 Hz, 1H), 7.69-7.68 (m, 2H), 7.62-
7.61 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.46 (m, 1H), 7.41-7.38 (m,
1H), 7.20 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 150.09, 157.09,
155.51, 152.71, 135.08, 130.85, 129.35, 127.47, 125.81, 124.67,
120.84, 117.49, 112.65, 112.55, 103.20; HRMS (ESI) calculated
for C17H9BrO3 (M+H)+ 340.9808; found: 340.9816.
4.2.4. 2-(p-Tolyl)-4H-furo[3,2-c]chromen-4-one (3b). Yellow
o
1
solid (77%), M.P.: 176-178 C; H NMR (500 MHz, CDCl3): δ
7.91 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.51-7.48 (m,
1H), 7.43-7.42 (m, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.00-6.94 (m,
3H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 160.50, 158.44,
156.88, 156.46, 152.56, 130.41, 126.23, 124.62, 121.89, 120.75,
117.43, 114.58, 112.94, 112.71, 101.02, 55.52; HRMS (ESI)
calculated for C18H12O4 (M+H)+ 293.0808; found: 293.0794.
4.2.11. 2-(4-Chlorophenyl)-4H-furo[3,2-c]chromen-4-one (3i).
White solid (32%), M.P.: 270-272 oC; 1H NMR (500 MHz,
CDCl3): δ 7.97-7.95 (m, 1H), 7.76-7.74 (m, 2H), 7.57-7.53 (m,
1H), 7.48-7.45 (m, 3H), 7.41-7.38 (m, 1H), 7.18 (s, 1H); 13C
NMR (125 MHz, CDCl3): δ 158.09, 157.09, 155.51, 152.71,
135.08, 130.85, 129.35, 127.47, 125.81, 124.67, 120.84, 117.49,
112.65, 112.55, 103.20; HRMS (ESI) calculated for C17H9ClO3
(M+H)+ 297.0313; found: 297.0300.
4.2.5. 2-(p-Tolyl)-4H-furo[3,2-c]chromen-4-one (3c). White
solid (83%), M.P.: 198-200 oC; 1H NMR (500 MHz, CDCl3):
δ
7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H),
7.52-7.49 (m, 1H), 7.44-7.42 (m, 1H), 7.38-7.34 (m, 1H),
7.26-7.25 (m, 2H), 7.08 (s, 1H), 2.40 (s, 3H); 13C NMR (125
MHz, CDCl3):
δ 158.29, 156.89, 156.58, 152.54, 139.35,
130.44, 129.70, 126.23, 124.54, 124.51, 120.74, 117.35,
112.82, 112.49, 101.88, 21.26; HRMS (ESI) calculated for
C18H12O3 (M+H)+ 277.0859; found: 277.0843.
4.2.12. 2-(3-Methoxyphenyl)-4H-furo[3,2-c]chromen-4-one
o
1
(3j). White solid (81%), M.P.: 180-182 C; H NMR (500
MHz, CDCl3): 7.96 (dd, = 7.5, 1.5 Hz, 1H), 7.54-7.51
δ
J
(m, 1H), 7.45-7.44 (m, 1H), 7.39-7.36 (m, 3H), 7.320-7.317
(m, 1H), 7.16 (s, 1H), 6.94-6.92 (m, 1H), 3.89 (s, 3H); 13C
4.2.6. 2-(4-Pentylphenyl)-4H-furo[3,2-c]chromen-4-one (3d).
Yellow solid (79%), M.P.: 156-158 oC; 1H NMR (500 MHz,
CDCl3): δ 7.94-7.92 (m, 1H), 7.72-7.68 (m, 2H), 7.50-7.34 (m,
3H), 7.28-7.26 (m, 2H), 7.09-7.06 (m, 1H), 2.66-2.63 (m, 2H),
1.67-1.63 (m, 2H), 1.38-1.34 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3): δ 158.30, 156.96, 156.60, 152.54,
144.33, 130.44, 129.07, 126.43, 124.56, 124.54, 120.74, 117.35,
112.83, 112.55, 101.86, 35.80, 31.47, 30.98, 22.55, 14.04; HRMS
(ESI) calculated for C22H20O3 (M+H)+ 333.1485; found: 333.1488.
NMR (125 MHz, CDCl3):
δ 160.04, 158.20, 156.86, 156.41,
152.63, 130.65, 130.17, 130.16, 124.59, 120.83, 117.39,
117.11, 114.65, 112.73, 112.48, 110.14, 103.01, 55.42;
HRMS (ESI) calculated for C18H12O4 (M+H)+ 293.0808;
found: 293.0813.
4.2.13. 2-(2-Fluorophenyl)-4H-furo[3,2-c]chromen-4-one (3k).
White solid (48%), M.P.: 158-460 oC; 1H NMR (500 MHz,
CDCl3): δ 7.93-7.89 (m, 2H), 7.52-7.49 (m, 1H), 7.41-7.39 (m,
1H), 7.37-7.31 (m, 3H), 7.25-7.24 (m, 1H), 7.17-7.13 (m, 1H);
13C NMR (125 MHz, CDCl3): δ 160.08 (d, J = 251.4 Hz), 158.00,
156.47, 152.67, 150.58 (d, J = 3.1 Hz), 130.83, 130.26 (d, J = 8.5
Hz), 126.25, 124.60, 124.57 (d, J = 3.5 Hz), 120.85, 117.36,
117.26, 116.37 (d, J = 21.1 Hz), 112.59, 112.47, 107.67 (d, J =
12.9 Hz); HRMS (ESI) calculated for C17H9FO3 (M+H)+
281.0608; found: 281.0615.
4.2.7. 2-(4-Ethoxyphenyl)-4H-furo[3,2-c]chromen-4-one (3e).
Yellow solid (74%), M.P.: 176-178 oC; 1H NMR (500 MHz,
CDCl3): δ 7.92 (dd, J = 8.0, 1.5 Hz, 1H), 7.71-7.69 (m, 2H), 7.51-
7.47 (m, 1H), 7.43-7.42 (m, 1H), 7.37-7.34 (m, 1H), 6.99 (s, 1H),
6.98-6.95 (m, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ 159.80, 158.36, 156.86,
156.33, 152.44, 130.28, 126.11, 124.51, 121.61, 120.63, 117.32,
114.96, 112.85, 112.61, 100.82, 63.66, 14.78; HRMS (ESI)
calculated for C19H14O4 (M+H)+ 307.0965; found: 307.0970.
4.2.14. 2-(3-Fluorophenyl)-4H-furo[3,2-c]chromen-4-one (3l).
Yellow solid (64%), M.P.: 176-178 oC; 1H NMR (500 MHz,
CDCl3): δ 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.56-7.51 (m, 2H), 7.49-
7.36 (m, 4H), 7.17 (s, 1H), 7.09-7.06 (m, 1H); 13C NMR (125
MHz, CDCl3): δ 164.11 (d, J = 245.3 Hz), 157.97, 157.11, 155.19
4.2.8. 2-(4-Ethylphenyl)-4H-furo[3,2-c]chromen-4-one (3f).
White solid (88%), M.P.: 148-150 oC; 1H NMR (500 MHz,
CDCl3): δ 7.93-7.91 (m, 1H), 7.70-7.68 (m, 2H), 7.51-7.48 (m,

5
(d, J = 3.0 Hz), 152.71, 130.93, 130.85, 130.81 (d, J = 8.4 Hz),
20.95; HRMS (ESI) calculated for C H O (M+H)+ 307.0965;
found: 307.0964.
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124.69, 120.86, 120.25 (d, J = 3.0 Hz), 117.44, 116.10 (d, J =
21.3 Hz), 112.53, 112.44, 111.56 (d, J = 23.8 Hz), 103.76; HRMS
(ESI) calculated for C17H9FO3 (M+H)+ 281.0608; found:
281.0627.
4.2.15. 2-(Thiophen-2-yl)-4H-furo[3,2-c]chromen-4-one (3m).
Yellow solid (49%), M.P.: 160-162 oC; 1H NMR (500 MHz,
CDCl3): δ 7.91 (dd, J = 8.0, 1.5 Hz, 1H), 7.52-7.48 (m, 1H), 7.46-
7.45 (m, 1H), 7.43-7.41 (m, 1H), 7.38-7.33 (m, 2H), 7.12-7.10 (m,
1H), 6.98 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 157.96, 156.41,
152.57, 151.92, 131.38, 130.63, 128.07, 126.52, 125.12, 124.60,
120.80, 117.33, 112.55, 112.48, 102.35; HRMS (ESI) calculated
for C15H8O3S (M+H)+ 269.0267; found: 269.0276.
4.2.16. 2-(Thiophen-3-yl)-4H-furo[3,2-c]chromen-4-one (3n).
Yellow solid (61%), M.P.: 142-144 oC; 1H NMR (500 MHz,
CDCl3): δ 7.86-7.85 (m, 1H), 7.671-7.665 (m, 1H), 7.49-7.46 (m,
1H), 7.40-7.31 (m, 4H), 6.93-6.92 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 158.10, 156.32, 153.32, 152.52, 130.51, 130.50, 127.12,
124.67, 124.53, 121.74, 120.68, 117.29, 112.63, 112.27, 102.21;
HRMS (ESI) calculated for C15H8O3S (M+H)+ 269.0267; found:
269.0275.
4.2.22. 8-Fluoro-2-phenyl-4H-furo[3,2-c]chromen-4-one (3t).
Yellow solid (74%), M.P.: 218-220 oC; 1H NMR (500 MHz,
CDCl3): δ 7.81-7.80 (m, 2H), 7.63-7.60 (m, 1H), 7.50-7.47 (m,
2H), 7.44-7.40 (m, 2H), 7.25-7.21 (m, 1H), 7.18 (s, 1H); 13C
NMR (125 MHz, CDCl3): δ 160.00 (d, J = 243.6 Hz), 157.80,
157.24, 155.95 (d, J = 2.9 Hz), 148.70, 129.43, 129.10, 128.75,
124.68, 119.15 (d, J = 8.5 Hz), 118.08 (d, J = 24.5 Hz), 113.53 (d,
J = 9.6 Hz), 113.25, 106.75 (d, J = 25.8 Hz), 102.78; HRMS (ESI)
calculated for C17H9FO3 (M+H)+ 281.0608; found: 281.0620.
4.2.23. 7-Fluoro-2-phenyl-4H-furo[3,2-c]chromen-4-one (3u).
White solid (72%), M.P.: 176-178 oC; 1H NMR (500 MHz,
CDCl3): δ 7.92-7.90 (m, 1H), 7.77-7.75 (m, 2H), 7.47-7.44 (m,
2H), 7.40-7.37 (m, 1H), 7.16-7.10 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ 164.73 (d, J = 251.3 Hz), 157.80, 156.57, 156.44,
153.66 (d, J = 13.75 Hz), 129.23, 129.05, 128.77, 124.51, 122.31
(d, J = 10.0 Hz), 112.86 (d, J = 22.5 Hz), 111.42, 109.52 (d, J =
2.5 Hz), 105.22 (d, J = 25.0 Hz), 102.50; HRMS (ESI) calculated
for C17H9FO3 (M+H)+ 281.0608; found: 281.0605.
4.2.24. 8-Chloro-2-phenyl-4H-furo[3,2-c]chromen-4-one (3v).
Yellow solid (85%), M.P.: 212-214 oC; 1H NMR (500 MHz,
CDCl3): δ 7.92 (d, J = 2.5 Hz, 1H), 7.82-7.80 (m, 2H), 7.50-7.45
(m, 3H), 7.43-7.38 (m, 2H), 7.18 (s, 1H); 13C NMR (125 MHz,
CDCl3): δ 157.60, 157.31, 155.50, 150.88, 130.52, 130.19, 129.46,
129.11, 128.67, 124.68, 120.32, 118.84, 113.80, 113.26, 102.76;
HRMS (ESI) calculated for C17H9ClO3 (M+H)+ 297.0313; found:
297.0325.
4.2.17. 2-Butyl-4H-furo[3,2-c]chromen-4-one (3o). Yellow liquid
1
(17%); H NMR (500 MHz, CDCl3): δ 7.85 (d, J = 7.5 Hz, 1H),
7.50-7.42 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 6.58 (s, 1H), 2.82 (t, J
= 7.5 Hz, 2H), 1.77 (quint, J = 7.5 Hz, 2H), 1.48 (sext, J = 7.5 Hz,
2H), 0.99 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ
160.12, 158.50, 156.56, 152.35, 130.09, 124.37, 120.59, 117.28,
113.03, 111.50, 103.35, 29.74, 27.78, 22.15, 13.72; HRMS (ESI)
calculated for C15H14O3 (M+H)+ 243.1016; found: 243.1005.
4.2.18. 8-Methoxy-2-phenyl-4H-furo[3,2-c]chromen-4-one (3p).
Yellow solid (60%), M.P.: 162-164 oC; 1H NMR (500 MHz,
CDCl3): δ 7.78-7.76 (m, 2H), 7.47-7.44 (m, 2H), 7.39-7.36 (m,
1H), 7.33 (d, J = 9.5 Hz, 1H), 7.28-7.27 (m, 1H), 7.11 (s, 1H),
7.06 (dd, J = 9.0, 4.0 Hz, 1H), 3.91 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 158.28, 156.69, 156.55, 156.33, 147.09, 129.14, 129.00,
128.91, 124.54, 118.55, 118.51, 112.92, 112.67, 102.77, 55.95;
HRMS (ESI) calculated for C18H12O4 (M+H)+ 293.0808; found:
293.0806.
4.2.25. 8-Bromo-2-phenyl-4H-furo[3,2-c]chromen-4-one (3w).
White solid (61%), M.P.: 204-206 oC; 1H NMR (500 MHz,
CDCl3): δ 8.053-8.049 (m, 1H), 7.80-7.79 (m, 2H), 7.60 (dd, J =
9.0, 2.5 Hz, 1H), 7.49-7.46 (m, 2H), 7.42-7.39 (m, 1H), 7.33 (d, J
= 8.5 Hz, 1H), 7.16 (s, 1H); 13C NMR (125 MHz, CDCl3): δ
157.51, 157.30, 155.31, 151.33, 133.39, 129.46, 129.10, 128.63,
124.67, 123.30, 119.10, 117.47, 114.25, 113.25, 102.74; HRMS
(ESI) calculated for C17H9BrO3 (M+H)+ 340.9808; found:
340.9817.
Acknowledgments
4.2.19. 7-Methoxy-2-phenyl-4H-furo[3,2-c]chromen-4-one (3q).
Yellow solid (61%), M.P.: 198-200 oC; 1H NMR (500 MHz,
CDCl3): δ 7.84 (d, J = 8.5 Hz, 1H), 7.79-7.77 (m, 2H), 7.48-7.44
(m, 2H), 7.39-7.36 (m, 1H), 7.12 (s, 1H), 6.96-6.94 (m, 2H), 3.89
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 162.00, 158.56, 157.60,
155.71, 154.41, 129.13, 128.99, 128.88, 124.39, 121.78, 112.89,
110.03, 106.18, 102.50, 101.49, 56.06; HRMS (ESI) calculated
for C18H12O4 (M+H)+ 293.0808; found: 293.0821.
We are grateful to the National Science Foundation of China (No.
21572117) and State Key Laboratory of Bioactive Substance and
Function of Natural Medicines, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union
Medical College (No. GTZK201707) for their financial support.
Appendix A. Supplementary data
4.2.20. 8-Methyl-2-phenyl-4H-furo[3,2-c]chromen-4-one (3r).
Yellow solid (66%), M.P.: 148-150 oC; 1H NMR (500 MHz,
CDCl3): δ 7.79-7.73 (m, 2H), 7.69 (s, 1H), 7.47-7.44 (m, 2H),
7.39-7.36 (m, 1H), 7.32-7.28 (m, 2H), 7.13 (s, 1H), 2.46 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 158.38, 156.89, 156.41, 150.84,
134.44, 131.66, 129.07, 129.00, 124.51, 120.48, 117.08, 112.40,
112.39, 102.67, 20.96; HRMS (ESI) calculated for C18H12O3
(M+H)+ 277.0859; found: 277.0849.
Supplementary data related to this article can be found at t
http:// dx.doi.org/
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