Synthesis of furo[3,2-c] coumarin derivatives using visible-light-promoted radical alkyne insertion with bromocoumarins

Article abstract of DOI:10.1039/c6ob00768f

The synthesis of privileged structures, which are potent drug candidates, is an impetus for drug discovery. The construction of heterocyclic framework furo[3,2-c]coumarins using a visible-light promoted photoredox neutral coupling of 3-bromo-4-hydroxycoumarins with commercially available alkynes has been reported. These reactions can be carried out at room temperature under visible light irradiation with good chemical yields. This work presents 17 furocoumarins, 12 of which are new. Three of the newly synthesized compounds show potent cytotoxicity, and one shows moderate acetylcholinesterase inhibitory activity with IC₅₀ values of 2.16 ± 0.13 μM.

Full text of DOI:10.1039/c6ob00768f

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Zhou, X. Z.
Deng, Z. Ma, A. H. Zhang, Q. Qixue, R.-X. Tan and S. Yu, Org. Biomol. Chem., 2016, DOI:
10.1039/C6OB00768F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/C6OB00768F
Journal Name
ARTICLE
Synthesis of furo[3,2-c]coumarin derivatives using visible-light-
promoted radical alkyne insertion with bromocoumarins
Hui Zhou,a Xinzhao Deng,a Zhenjun Ma,a Aihua Zhang,a Qixue Qin,b Ren Xiang Tana,* and
Shouyun Yub,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Synthesis of privileged structures, which are potent drug condidates, is one of impetus for drug discovery. The
construction of heterocyclic framework furo[3,2-c]coumarins using a visible-light promoted photoredox neutral coupling
of 3-bromo-4-hydroxycoumarins with commercially available alkynes has been reported. These reactions can be carried
out at room temperature under visible light irradiation with good chemical yields. This work presents 17 furocoumarins
and 12 of which are new. Three of the newly synthesized compounds show potent cytotoxicity, and one shows moderate
acetylcholinesterase inhibitory activity with IC50 values of 2.16 ± 0.13 µM.
www.rsc.org/
been performed to establish new synthetic methods toward this
type of compounds.5 Furo[3,2-c]coumarins are one of the most
common representatives of this class of compounds. The
Introduction
The naturally occurring coumarins represent a large family of
heterocyclic molecules with a benzo-α-pyrone moiety, which might
be considered as a source of potential materials1 and candidates for
drug discovery.2 Coumarin derivatives have driven both chemists
and pharmacologists to orchestrate the strategies for their chemical
synthesis since their broad spectrum of bioactivities, including anti-
inflammatories, anticancer, anti-microbials and antivirals.3
established methods for the synthesis of furo[3,2-c]coumarin are
highly relied on the transition metal-catalyzed coupling of
halocoumarins derivatives with alkynes or alkyl metal reagents and
sequential cyclization in stepwise or one-pot manner (Fig. 1).6
Despite these advances, methods for the rapid preparation of
furo[3,2-c]coumarin derivatives with high reaction efficiency under
mild conditions are still desired. Herein, we would like to report our
efforts on the synthesis of furo[3,2-c]coumarin using visible-light-
promoted radical alkyne insertion with bromocoumarins.
O
O
O
O
O
O
O
O
O
Results and discussion
furo[3,4-c]coumarin
furo[2,3-c]coumarin
furo[3,2-c]coumarin
Recently, we have reported synthesis of polysubstituted furans
using visible-light-promoted radical alkyne insertion with 2-bromo-
1,3-dicarbonyl compounds (Fig. 2A).7 In this work, the bromides
must be derived from cyclohexane-1,3-diones.Thus, only
cyclohexanone-fused furans could be synthesized using this
strategy. In order to expand the synthetic potential of this visible-
light-promoted radical alkyne insertion chemistry, we turned our
attention to synthesis of coumarin-fused furans by coupling of
coumarin-derived bromides with alkynes (Fig. 2B).
M
R
R
M = Znor H
O
OR'
R
+
OR'
X
Cu or Pd
O
O
O
O
O
O
furo[3,2-c]coumarin
X = halide
Fig. 1 Typical furan fused coumarins and established methods for the
synthesis of furo[3,2-c]coumarin.
A. Visible-light-promoted radical alkyne insertion with 2-bromocyclohexane-
1,3-diones: our previous work (ref 7)
Furocoumarins, a class of furan-fused coumarin derivatives, have
attracted great attention of researchers due to their biological
properties and chemosynthesis challenge.4 Thus, more efforts have
O
IrIII
O
Vis
hν
IrIV
Br
+
Ar
Ar
O
O
B. Visible-light-promoted radical alkyne insertion with bromocoumarins:
this work
Ar
O
OH
IrIII
Vis
hν
O
Br
R1
Ar
+
R1
O
O
IrIV
O
1
2
3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
View Article Online
DOI: 10.1039/C6OB00768F
ARTICLE
Journal Name
Fig. 2 Visible-light-promoted radical alkyne insertion with 2-bromo-1,3-
dicarbonyl compounds.
also undergo this transformation smoothly to provide the
desired product 3i in 70 % yield (2j). Internal alkynes and alkyl
This idea was first examined using 3-bromo-4-hydroxycoumarin terminal alkynes were not suitable coupling partners in this
transformation. Coumarin-derived bromides could be also
varied. 7-MeO- substituted coumarin-derived bromide reacted
smoothly with a series of alkynes to give the corresponding
(1a) and 4-ethynylanisole (2a) as model substrates (Table 1). When
a solution of 1a and 2a in DMF was irradiated by 13 W white LEDs in
the presence of photocatalyst Ir(ppy)2(dtbbpy)PF6 (I) and Na2HPO4
for 12 h, it was pleased to find that the desired furocoumarin 3a
was isolated in 78% yield (entry 1). Different solvent was then
tested. It was found that EtOH, CH3CN and CH2Cl2 could not give
improved results (entries 2-4) while 84% isolated yield was achieved
when DMSO was used as the solvent (entry 5). A variety of bases
were examined (entries 6-9) and NaHCO3 proved to be the most
suitable base (entry 6). Other photocatalysts, such as Ir(ppy)3 (II)
and Ru(bpy)3(PF6)2 (III) were not superior to Ir(ppy)2(dtbbpy)PF6(I)
(entries 10-11). Control experiments verified the necessity of the
base, irradiation, and photocatalyst (entries 12–14).
furocoumarins 3j-3o with satisfactory yields (44-85%). 6-
halogen-substituted furocoumarins 3p-3q could be also
prepared using this method.
Table 1 Condition screening a
Entry
Catalyst
Base
Solvent
Yield/%b
1
2
I
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
NaHCO3
K3PO4
DMF
C2H5OH
CH3CN
CH2Cl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
78
59
I
3
I
73
4
I
45
5
I
84
6
I
86
7
I
45
8
I
K2HPO4
Na2CO3
NaHCO3
NaHCO3
none
08
9
I
46
10
11
12
13
14c
II
III
37
33
Fig. 3 Scope of alkynes. Reaction conditions: A solution of 1 (0.2 mmol), 2
(0.1 mmol), NaHCO3 (0.12 mmol) and Ir(ppy)2(dtbbpy) PF6 (I) (0.001 mmol,
1.0 mol %) in dry DMSO (1.5 mL) was irradiated by 13 W white LEDs for 12 h.
Isolated yield.
I
trace
trace
none
Na2HPO4
I
Na2HPO4
DMSO
NR
Based on our previous work and other literature precedents,8 a
possible catalytic cycle is proposed for this transformation (Fig. 4).
First, photocatalyst Ir complex is irradiated to the excited state IrIII*
and oxidatively quenched by coumarin-derived bromide 1a with
generation of IrIV complex and radical species 4 respectively. Radical
4 adds onto alkyne 2a to generate vinyl radical intermediate 5. Then
the vinyl radical 5 attacks the carbonyl group intramolecularly to
give radical intermediate 6, which is oxidized by IrIV to form carbon
cation 7 and regenerate IrIII. Ultimately, furocoumarin 3a is formed
by deprotonation assisted by base.
a Reaction conditions: A solution of 1a (0.2 mmol), 2a (0.1 mmol), base
(0.12 mmol) and photocatalyst (0.001 mmol, 1.0 mol %) in the
indicated solvent (1.5 mL) was irradiated by 13 W white LED at rt for
b
c
12 h. Isolated yield. was performed with no irradiation. NR = no
reaction.
With the optimized conditions in hand, we then turn to
explore the scope of this transformation. First, a set of alkynes
were tested, as shown in Fig. 3. It was found that electron-rich
or neutral phenylacetylenes gave the desired furocoumarins
3a
gave the desired furocoumarin 3h in acceptable yield (60%)
while Cl phenylacetylene was not suitable in this
-3g with decent yields (52-93%). p-F phenylacetylene could
p
-
transformation (22%). 6-Methoxy-2-naphthylacetylene could
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 6
View Article Online
DOI: 10.1039/C6OB00768F
Journal Name
ARTICLE
excellent chemical yields under environmentally friendly
conditions. Easily available starting materials 3 bromo
-
-4-
hydroxycoumarins and alkynes, no external stoichiometric
oxidants also feature the advantages of this methodology.
Preliminary biological evaluation shows some of the resultant
furo[3,2-c]coumarins possess
inhibitory potential against
three human tumor cell lines and acetylcholinesterase.
Experimental
General information
All reagents were used as received without further
purification. The 3-bromo-4-oxycoumarins were known
compounds and prepared according to the literature
procedures.9 Alkynes were commercial available. Thin layer
chromatography (TLC) was performed on precoated plates
(silica gel 60 F254, Art 5715) and visualized by fluorescence
quenching under UV light and by staining with
phosphomolybdic acid or potassium permanganate,
respectively. Column chromatography was performed on Silica
Gel 60 (300–400 Mesh) using a forced flow of 0.5–1.0 bar. 1H
Fig. 4 Proposed mechanism.
All the synthesized compounds were evaluated biologically. We test
their inhibitory potential against three human tumor cell lines
(human lung carcinoma A549, human promyelocytic leukemia HL-
60 and human colon carcinoma SW480) by MTT assay. Some of
compounds show a significant activity (Table 2). More significantly, NMR (400 MHz), 13C NMR (100 MHz) and 19F (376 MHz) were
the compound 3k was found to be a potent inhibitor of HL-60 with
the inhibitory value of IC50 =2.88 ± 0.12 µM compared to the
inhibitory value of other two cell lines. It is suggested that
compounds containing both 2-(4-(tert-butyl)phenyl) and 7-methoxy
showed a higher activity towards many human tumor cell lines and
has a better selectivity. At the same time, all compounds were also
evaluated for the inhibitory effect on acetylcholinesterase, and
measured on a Bruker AVANCE III–400 spectrometer. Chemical
shifts are expressed in parts per million (ppm) with respect to
the residual solvent peak. Coupling constants are reported as
Hertz (Hz), signal shapes and splitting patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet.
General procedures
compound 3g was found to be
a
good inhibitor of
A 10 mL round bottom flask equipped with a rubber septum
acetylcholinesterase with the inhibitory value of IC50 = 2.16 ± 0.13
µM, which is comparable to that (IC50 = 0.161 ± 0.007) of Huperzine
A, a prescribed acetylcholinesterase inhibitor coassessed as a
positive control.
and magnetic stir bar was charged with
1 (0.2 mmol, 2.0
equiv), 2(0.1 mmol, 1.0 equiv), Ir(ppy)2(dtbbpy)PF6 (0.001
mmol, 0.01 equiv) and NaHCO3 (0.12 mmol, 1.2 equiv). The
flask was evacuated and backfilled with N2 for 3 times. DMSO
(1.5 mL, 0.1 M) was added with syringe under N2. The mixture
was then irradiated by a 13W white LED strips. After the
reaction was complete (as judged by TLC analysis), the mixture
was poured into a separatory funnel containing 20 mL of H2O
and 20 mL of EtOAc. The layers were separated and the
aqueous layer was extracted with EtOAc for 3 times. The
combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure after filtration. The
crude product was purified by flash chromatography on silica
Table 2 Inhibition of multiple human tumor cell Lines by the
synthesized compounds and positive control
IC50, a μM
Compounds
SW480
HL-60
A549
> 10
3a
9.57 ± 0.12
8.95 ± 0.21
7.61 ± 0.16
1.17 ± 0.11
9.09 ± 0.26
>10
3i
3k
9.33 ± 0.19
7.10 ± 0.08
1.76 ± 0.13
2.88 ± 0.12
0.87 ± 0.04
Doxorubicinb
gel to afford the desired product 3.
2-(4-methoxyphenyl)-4H-furo[3,2-c]chromen-4-one (3a).10
According to general procedure, 1a (0.2 mmol, 2.0 equiv), 2a
(0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and
a
IC50 represents the concentration of compounds required to
inhibit 50% of the activity of cell proliferative. b Doxorubicin is the
reference standard used in the present study. Data are presented as
the mean ± SD.
Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in
dry DMSO (1.5 mL) afforded 3a (25.1 mg, 86%) as a white solid
after purification on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.91
(dd,
1.5, 1H), 7.41 (d,
7.00 (s, 1H), 6.97(d,
J
= 7.8, 1.4 Hz, 1H), 7.71 (d,
= 8.1 Hz, 1H), 7.33 (td,
= 8.0 Hz, 2H), 3.86 (s, 3H); 13C NMR (100
J
= 8.0 Hz, 2H), 7.47 (td,
J = 7.2,
Conclusions
J
J
= 8.0, 1.1 Hz, 1H),
In summary, we have developed a mild and efficient synthetic
approach to prepare furo[3,2-c]coumarins using photoredox
J
MHz, CDCl3) δ 160.3, 158.3, 156.7, 156.3, 152.4, 130.3, 126.1,
124.5, 121.7, 120.6, 117.3, 114.4, 112.8, 112.6, 100.9, 55.4;
neutral coupling of alkynes with 3-bromo-4-hydroxycoumarins.
These reactions proceeded at room temperature in good to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
View Article Online
DOI: 10.1039/C6OB00768F
ARTICLE
Journal Name
HRMS (ESI) calcd for C18H13O4 [M+H]+: 293.0814, found: CDCl3) δ 7.97 (d, J = 4.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.52-
293.0814. 7.45 (m, 4H), 7.38 (t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 1.37 (s, 1H);
2-(2-methoxyphenyl)-4H-furo[3,2-c]chromen-4-one (3b). 13C NMR (100 MHz, CDCl3) δ 158.5, 157.0, 156.8, 152.7, 152.7,
According to general procedure, 1a (0.2 mmol, 2.0 equiv), 2b 130.6, 126.3, 126.1, 124.7, 124.5, 120.9, 117.5, 112.9, 112.6,
(0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and 102.1, 35.0, 31.3; HRMS (ESI) calcd for C21H18O3Na [M+Na]+:
Ir(ppy)2(dtbbpy)PF6 (
I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in 341.1154, found : 341.1149.
dry DMSO (1.5 mL) afforded 3b (23.0 mg, 79%) as a white solid
2-([1,1'-biphenyl]-4-yl)-4H-furo[3,2-c]chromen-4-one (3g).
1
after purification on silica gel. H NMR (400 MHz, CDCl3) δ 7.99 According to general procedure, 1a (0.2 mmol, 2.0 equiv), 2g
(dd, J = 8.0, 1.7 Hz, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.50 (td, J (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and
= 8.8, 1.6 Hz, 1H), 7.49 (s, 1H), 7.44 (dd, J = 8.4, 0.8 Hz, 1H), Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in
7.37-7.32 (m, 2H), 7.08 (td, J = 8.0, 1.0 Hz, 1H), 7.01 (d, J = 8.3 dry DMSO (1.5 mL) afforded 3g (17.6 mg, 52%) as a white solid
Hz, 1H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.6, 156.2, after purification on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.99
155.9, 153.0, 152.6, 130.4, 129.9, 126.2, 124.5, 120.8, 120.8, (d, J = 7.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.0, 2H),
118.0, 117.4, 112.8, 112.8, 111.2, 107.5, 55.5; HRMS (ESI) calcd 7.65 (d, J = 7.4 Hz, 2H), 7.56-7.46 (m, 4H), 7.39 (t, J = 7.2Hz, 2H),
for C18H13O4 [M+H] + : 293.0814, found : 293.0823.
7.23 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 158.3, 157.0, 156.4,
2-(3-methoxyphenyl)-4H-furo[3,2-c]chromen-4-one
(3c). 152.6, 141.9, 140.1, 130.7, 129.0, 127.8, 127.7, 127.0, 125.0,
According to general procedure, 1a (0.2 mmol, 2.0 equiv), 2c 124.6, 120.9, 117.4, 112.8, 112.6, 102.8; HRMS (ESI) calcd for
(0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and C23H14O3 [M+Na] + : 361.0841, found : 361.0839.
Ir(ppy)2(dtbbpy)PF6 (
I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in
2-(4-fluorophenyl)-4H-furo[3,2-c]chromen-4-one
(3h).10
dry DMSO (1.5 mL) afforded 3c (19.0 mg, 65%) as a white solid According to general procedure, 1a (0.2 mmol, 2.0 equiv), 2h
1
after purification on silica gel. H NMR (400 MHz, CDCl3) δ 7.97 (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and
(dd, J = 7.8, 1.4 Hz, 1H), 7.54 (td, J = 7.2, 1.5 Hz, 1H), 7.47 (d, J = Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in
7.6 Hz, 1H), 7.42-7.34 (m, 4H), 7.18 (s, 1H), 6.95 (m, 1H), 3.90 dry DMSO (1.5 mL) afforded 3h (16.8 mg, 60%) as a white solid
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.1, 158.2, 158.9, 156.4, after purification on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.96
152.7, 130.7, 130.2, 124.6, 120.8, 117.4, 117.1, 114.7, 112.8, (dd, J = 8.0, 4.0 Hz, 1H), 7.82-7.79 (m, 2H), 7.54 (td, J = 8.5, 1.6
112.5, 110.2, 103.0, 55.4; HRMS (ESI) calcd for C18H13O4 [M+H]+: Hz, 1H), 7.47 (dd, J = 8.3, 0.8 Hz, 1H), 7.39 (td, J = 7.8, 1.0 Hz,
293.0814, found: 293.0819.
1H), 7.18 (td, J = 8.6, 2.0 Hz, 1H), 7.13 (s, 1H); 13C NMR (100
2-phenyl-4H-furo[3,2-c]chromen-4-one (3d).10 According to MHz, CDCl3) δ164.2 (d, J = 249 Hz), 158.2, 156.9, 155.7, 152.6,
general procedure, 1a (0.2 mmol, 2.0 equiv), 2d (0.1 mmol, 1.0 130.7, 126.6 (d, J = 9.1 Hz), 125.4 (d, J = 3.0 Hz), 124.6, 120.8,
equiv), NaHCO3 (0.12 mmol, 1.2 equiv) and Ir(ppy)2(dtbbpy)PF6 117.5, 116.3 (d, J = 22.0 Hz), 112.7, 112.6, 102.5; HRMS (ESI)
(I
) (0.001 mmol, 0.01 equiv, 1.0 mol%) in dry DMSO (1.5 mL) calcd for C17H9FO3Na [M+Na]+: 303.0433, found: 303.0435.
afforded 3d (21.2 mg, 81%) as a white solid after purification
2-(6-methoxynaphthalen-2-yl)-4H-furo[3,2-c]chromen-4-
on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 7.9, 1.3 one (3i). According to general procedure, 1a (0.2 mmol, 2.0
Hz, 1H), 7.81 (dd, J = 7.2, 1.4 Hz, 2H), 7.52-7.44 (m, 4H), 7.40- equiv), 2j (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2
7.35 (m, 2H), 7.17 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 158.3, equiv) and Ir(ppy)2(dtbbpy)PF6 (
I) (0.001 mmol, 0.01 equiv, 1.0
156.9, 156.7, 152.7, 130.6, 129.2, 129.1, 129.0, 124.6, 120.8, mol%) in dry DMSO (1.5 mL) afforded 3i (23.9 mg, 70%) as a
1
117.4, 112.8, 112.6, 102.7; HRMS (ESI) calcd for C17H10O3Na white solid after purification on silica gel. H NMR (400 MHz,
[M+Na]+: 285.0528, found : 285.0536.
CDCl3) δ 8.24 (s, 1H), 8.03 (dd, J = 7.8, 1.3 Hz, 1H), 7.83 (m, 3H),
2-(p-tolyl)-4H-furo[3,2-c]chromen-4-one (3e).10 According 7.54 (td, J = 8.8, 1.5 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.40 (td, J
to general procedure, 1a (0.2 mmol, 2.0 equiv), 2e (0.1 mmol, = 8.0, 1.0 Hz, 1H), 7.23 (s, 1H), 7.22 (dd, J = 8.8, 2.5 Hz, 1H),
1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and 7.16 (d, J = 2.3 Hz), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in 158.6, 158.4, 157.1, 156.8, 152.7, 134.9, 130.6, 130.0, 128.8,
dry DMSO (1.5 mL) afforded 3e (21.8 mg, 79%) as a white solid 127.7, 124.7, 124.2, 123.6, 122.8, 120.9, 119.9, 117.5, 112.9,
after purification on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.94 112.7, 106.1, 102.4, 55.5; HRMS (ESI) calcd for C22H15O4 [M+H]+:
(dd, J = 7.8, 1.4 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.51 (td, J = 8.4, 343.0970, found: 343.0966.
1.5 Hz, 1H), 7.44 (d, J = 7.56 Hz, 1H), 7.37 (td, J = 7.4, 1.0 Hz,
7-methoxy-2-phenyl-4H-furo[3,2-c]chromen-4-one
(3j).
1H), 7.27 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 2.40 (s, 1H); 13C NMR According to general procedure, 1b (0.2 mmol, 2.0 equiv), 2d
(100 MHz, CDCl3) δ 158.5, 157.1, 156.8, 152.7, 139.5, 130.6, (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and
129.9, 126.4, 124.7, 120.9, 117.5, 113.0, 112.7, 102.1, 21.6; Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in
HRMS (ESI) calcd for C18H12O3Na [M+Na]+: 299.0684, found: dry DMSO (1.5 mL) afforded 3j (14.0 mg, 48%) as a white solid
299.0692.
2-(4-(tert-butyl)phenyl)-4H-furo[3,2-c]chromen-4-one
after purification on silica gel. 1H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 8.0 Hz, 1H), 7.81 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 7.4 Hz,
(3f).11 According to general procedure, 1a (0.2 mmol, 2.0 2H), 7.40 (t, J = 7.3 Hz, 1H), 7.16 (s, 1H), 7.00-6.98 (m, 2H), 3.92
equiv), 2f (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.2, 158.8, 157.8, 155.9,
equiv) and Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 154.6, 129.3, 129.2, 129.1, 124.6, 122.0, 113.1, 110.0, 106.4,
mol%) in dry DMSO (1.5 mL) afforded 3f (29.6 mg, 93%) as a 102.7, 101.7, 56.0; HRMS (ESI) calcd for C18H15O4 [M+H]+:
1
white solid after purification on silica gel. H NMR (400 MHz, 293.0814, found: 293.0823.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 6
View Article Online
DOI: 10.1039/C6OB00768F
Journal Name
ARTICLE
2-(4-(tert-butyl)phenyl)-7-methoxy-4H-furo[3,2-c]chromen- J = 9.0 Hz, 1H), 7.80 (s, 2H), 7.21 (dd, J = 9.0, 2.5 Hz, 1H), 7.19
4-one (3k). According to general procedure, 1b (0.2 mmol, 2.0 (s, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.97 (s,
equiv), 2f (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 1H), 3.95 (s, 3H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
equiv) and Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 161.8, 158.3, 157.4, 156.0, 154.3, 134.5, 129.7, 128.6, 127.5,
mol%) in dry DMSO (1.5 mL) afforded 3k (15.3 mg, 44%) as a 124.2, 123.2, 122.6 121.7, 119.6, 112.8, 110.1, 106.2, 105.8,
white solid after purification on silica gel. 1H NMR (400 MHz, 102.0, 101.4, 55.7, 55.3; HRMS (ESI) calcd for C23H16O5Na
CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.41 (d, [M+Na]+: 395.0895, found: 395.0894.
J = 8.5 Hz, 2H), 7.01 (s, 1H), 6.88 (dd, J = 8.0, 2.4 Hz, 1H), 6.87
8-bromo-2-(4-fluorophenyl)-4H-furo[3,2-c]chromen-4-one
(s, 1H), 3.82 (s, 3H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (3p). According to general procedure, 1c (0.2 mmol, 2.0 equiv),
160.9, 157.7, 156.5, 155.0, 153.4, 151.3, 125.4, 125.0, 123.3, 2h (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and
120.8, 111.9, 109.1, 105.3, 100.9, 100.5, 54.8, 33.9, 30.3; Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in
HRMS (ESI) calcd for C22H20O4Na [M+Na]+: 371.1259, found: dry DMSO (1.5 mL) afforded 3p (14.7 mg, 41%) as a white solid
371.1265.
7-methoxy-2-(p-tolyl)-4H-furo[3,2-c]chromen-4-one
after purification on silica gel. 1H NMR (400 MHz, CDCl3) δ 8.07
(3l). (d, J = 2.2 Hz, 1H), 7.82-7.79 (m, 2H), 7.61 (dd, J = 8.8, 2.2 Hz,
According to general procedure, 1b (0.2 mmol, 2.0 equiv), 2e 1H), 7.35 (d, J = 8.8, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.6
(0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 equiv) and Hz, 1H), 7.13 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 163.4 (d, J =
Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 mol%) in 250 Hz), 157.6, 156.5, 155.5, 151.4, 133.5, 126.8 (d, J = 8.0 Hz),
dry DMSO (1.5 mL) afforded 3l (19.6 mg, 64%) as a white solid 125.1, 123.4, 119.3, 117.6, 116.5 (d, J = 22 Hz), 114.2, 113.3,
1
+
after purification on silica gel. H NMR (400 MHz, CDCl3) δ 7.74 102.6; HRMS (ESI) calcd for C17H8BrFO3Na [M+Na] : 380.9505,
(d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.18 (J = 8.0 Hz, 2H), found : 380.9503.
6.97 (s, 1H), 6.86 (J = 8.0 Hz, 1H), 6.85 (s, 1H), 3.81 (s, 3H), 2.32
8-chloro-2-(4-methoxyphenyl)-4H-furo[3,2-c]chromen-4-
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 157.4, 156.0, 154.4, one (3q). According to general procedure, 1d (0.2 mmol, 2.0
139.1, 129.7, 126.5, 124.4, 121.8, 112.9, 110.1, 106.3, 101.7, equiv), 2a (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2
101.5, 55.8, 21.4; HRMS (ESI) calcd for C19H15O4 [M+H]+: equiv) and Ir(ppy)2(dtbbpy)PF6 (
I) (0.001 mmol, 0.01 equiv, 1.0
307.0970, found: 307.0975.
mol%) in dry DMSO (1.5 mL) afforded 3q (15.3 mg, 47%) as a
white solid after purification on silica gel. 1H NMR (400 MHz,
7-methoxy-2-(4-methoxyphenyl)-4H-furo[3,2-c]chromen-
4-one (3m). According to general procedure, 1b (0.2 mmol, 2.0 CDCl3) δ 7.91 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.74 (d,
equiv), 2a (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2 J = 1.9 Hz, 1H), 7.45 (dd, J = 8.9 Hz, 2.4 Hz, 1H), 7.39 (d, J = 8.8
equiv) and Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0 Hz, 1H), 7.04 (s, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 2.1 Hz,
mol%) in dry DMSO (1.5 mL) afforded 3m (27.3 mg, 85%) as a 1H), 3.88 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.5, 157.7,
1
white solid after purification on silica gel. H NMR (400 MHz, 157.4, 154.9, 150.6, 130.1, 130.0, 126.2, 121.4, 120.1, 118.7,
CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 114.5, 113.8, 113.3, 100.9, 55.4; HRMS (ESI) calcd for
7.00_6.94 (m, 5H), 3.90 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, C18H11ClO4Na [M+Na]+: 349.0244, found: 349.0249.
CDCl3) δ 161.8, 160.4, 158.9, 157.3, 156.1, 154.4, 126.2, 122.2,
121.8, 114.6, 113.0, 110.3, 106.5, 101.7, 101.0, 56.0, 55.6;
HRMS (ESI) calcd for C19H14O5Na [M+Na]+: 345.0739, found:
345.0743.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21472084, 81421091 and 81530089).
2-(4-fluorophenyl)-7-methoxy-4H-furo[3,2-c]chromen-4-
one (3n). According to general procedure, 1b (0.2 mmol, 2.0
equiv), 2h (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12 mmol, 1.2
Notes and references
equiv) and Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01 equiv, 1.0
mol%) in dry DMSO (1.5 mL) afforded 3n (17.1 mg, 55%) as a
white solid after purification on silica gel. 1H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 9.3 Hz, 1H), 7.79-7.76 (m, 2H), 7.19-7.15
(m, 2H), 7.08 (s, 1H), 6.98-6.95 (m, 2H), 3.90 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ163.1 (d, J = 216 Hz), 158.5, 157.6, 154.8,
154.4, 126.4 (d, J = 8.3 Hz), 125.5, 121.7, 116.2 (d, J = 22.0 Hz),
112.9, 110.1, 106.1, 102.2 (d, J = 1.5 Hz), 101.5, 100.0, 55.8;
HRMS (ESI) calcd for C18H11FO4Na [M+Na]+: 333.0539, found:
333.0542.
1
(a) S. R. Trenor, A. R. Shultz, B. J. Love and T. E. Long, Chem.
Rev., 2004, 104, 3059; (b) B. D. Wagner, Molecules, 2009, 14,
210.
(a) Y. Bansal, P. Sethi and G. Bansal, Med. Chem. Res., 2013,
22, 3049; (b) A. Lacy and R. O'Kennedy, Curr. Pharm. Des.,
2004, 10, 3797; (c) M. E. Riveiro, N. De Kimpe, A. Moglioni, R.
Vazquez, F. Monczor, C. Shayo and C. Davio, Curr. Med.
Chem., 2010, 17, 1325; (d) S. Emami, S. Dadashpour, Eur. J.
Med. Chem., 2015, 102, 611; (e) J. Grover, S. M. Jachak, RSC
Adv., 2015, 5, 38892.
K. C. Fylaktakidou, D. J. Hadjipavlou-Litina, K. E. Litinas and D.
N. Nicolaides, Curr. Pharm. Des., 2004, 10, 3813; (b) F.
Borges, F. Roleira, N. Milhazes, L. Santana and E. Uriarte,
Curr. Med. Chem., 2005, 12, 887.
(a) L. Santana, E. Uriarte, F. Roleirab, N. Milhazesc and F.
Borges, Curr. Med. Chem., 2004, 11, 3239; (b) F. G. Medina, J.
G. Marrero, M Macías-Alonso, M. C. González, I. Córdova-
Guerrero, A. G. T.r Garcíaa and S. Osegueda-Roblesa, Nat.
Prod. Rep., 2015, 32, 1472.
2
3
4
7-methoxy-2-(6-methoxynaphthalen-2-yl)-4H-furo[3,2-
c]chromen-4-one (3o). According to general procedure, 1b
(0.2 mmol, 2.0 equiv), 2j (0.1 mmol, 1.0 equiv ), NaHCO3 (0.12
mmol, 1.2 equiv) and Ir(ppy)2(dtbbpy)PF6 (I) (0.001 mmol, 0.01
equiv, 1.0 mol%) in dry DMSO (1.5 mL) afforded 3o (19.4 mg,
52%) as a white solid after purification on silica gel. 1H NMR
(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.82 (d,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C6OB00768F
ARTICLE
5
Journal Name
For selected examples, see: (a) N. Nebra, A. E. Díaz-Álvarez, J.
Díez and V. Cadierno, Molecules, 2011, 16, 6470; (b) L. Tang,
Y. Pang, Q. Yan, L. Shi, J. Huang, Y. Du and K. Zhao, J. Org.
Chem., 2011, 76, 2744; (c) C. A. James, A. L. Coelho, M.
Gevaert, P. Forgione and V. Snieckus, J. Org. Chem., 2009, 74,
4094; (d) V. Nair, R. S. Menon, A. U. Vinod and S. Viji,
Tetrahedron Lett., 2002, 43, 2293; (e) Y.-J. Jang, S.-e. Syu, Y.-
J. Chen, M.-C. Yang and W. Lin, Org. Biomol. Chem., 2012, 10,
843; (f) A. G. Ai-Sehemi and R. S. Ei- Gogary, Chin. J. Chem.,
2012, 30, 316; (g) F. Risitano, G. Grassi, F. Foti and C. Bilardo,
Tetrahedron Lett., 2001, 42, 3503; (h) W.-Y. Huang, Y.-C.
Chen and K. Chen, Chem.–Asian J., 2012, 7, 688; (i) C. Lee, Y.
Jang, Z. Wu and W. Lin, Org. Lett., 2012, 14, 1906; (j) S.
Protti, M. Fagnoni and A. Albini, J. Org. Chem., 2012, 77,
6473.
6
For selected examples, see: (a) W. Huang, J. Wang, Q. Shen
and X. Zhou, Tetrahedron, 2007, 63, 11636; (b) D. Conreaux,
S. Belot, P. Desbordes, N. Monteiro and G. Balme, J. Org.
Chem., 2008, 73, 8619; (c) L. Chen, Y. Li and M.-H. Xu, Org.
Biomol. Chem., 2010, 8, 3073; (d) G. Cheng, Y. Hu, Chem.
Commun., 2007, 3285; (e) G. Cheng and Y. Hu, J. Org. Chem.,
2008, 73, 4732; (f) Y. Moon, Y. Kim, H. Hong and S. Hong,
Chem. Commun., 2013, 49, 8323; (g) X.-c. Tan, H.-y. Zhao, Y.-
m. Pan, N. Wu, H.-s. Wang and Z.-f. Chen, RSC Adv., 2015, 5,
4972.
7
8
H. Jiang, Y. Cheng, Y. Zhang and S. Yu. Org. Lett., 2013, 15,
4884.
(a) C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem.
Rev., 2013, 113, 5322; (b) J. Xuan and W.-J. Xiao, Angew.
Chem. Int. Ed., 2012, 51, 6828; (c) J. M. R. Narayanam and C.
R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102; (d) T. P.
Yoon, M. A. Ischay and J. Du, Nature Chem., 2010, 2, 527; (e)
K. Zeitler, Angew. Chem. Int. Ed., 2009, 48, 9785; (f) X. Sun
and S. Yu, Chin. J. Org. Chem., 2016, 36, 239.
(a) L. Zhang, T. Meng, R. Fan and J. Wu, J. Org. Chem., 2007,
72, 7279; (b) Z. Wang, B. Wang, and J. Wu, J. Comb. Chem.,
2007, 9, 811.
9
10 X. C. Tan, H. Y. Zhao, Y. M. Pan, N. Wu, H. S. Wang and Z. F.
Chen, RSC Adv., 2015, 5, 4972.
11 L. Chen, Y. Li and M. H. Xu, Org. Biomol. Chem., 2010, 8,
3073.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins