Microwave-promoted Synthesis of Novel Fused Osthole Analogues

Article abstract of DOI:10.1002/cjoc.201600489

Osthole is a natural coumarin derivative and has a broad scope of biological activities. Two series of novel fused osthole analogues were designed, and synthesized through a highly efficient microwave-promoted synthetic protocol via the reaction of 4-hydroxycoumarins and β-ketoesters. The reaction conditions including solvent, catalyst, microwave power and irradiation time were also optimized. The pyrano[3,2-c]chromene-2,5-diones and furo[3,2-c]coumarins were obtained through two distinct intramolecular cyclization processes, and the proposed mechanism was also discussed.

Full text of DOI:10.1002/cjoc.201600489

FULL PAPER
DOI: 10.1002/cjoc.201600489
Microwave-promoted Synthesis of Novel Fused
Osthole Analogues
Mingzhi Zhang, Rongrong Zhang, Jiaqun Wang, Xiang Yu, Yaling Zhang,
Qingqing Wang, and Weihua Zhang*
Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural
University, Nanjing, Jiangsu 210095, China
Osthole is a natural coumarin derivative and has a broad scope of biological activities. Two series of novel fused
osthole analogues were designed, and synthesized through a highly efficient microwave-promoted synthetic proto-
col via the reaction of 4-hydroxycoumarins and β-ketoesters. The reaction conditions including solvent, catalyst,
microwave power and irradiation time were also optimized. The pyrano[3,2-c]chromene-2,5-diones and furo[3,2-c]-
coumarins were obtained through two distinct intramolecular cyclization processes, and the proposed mechanism
was also discussed.
Keywords osthole, microwave-promoted synthesis, pyrano[3,2-c]chromene-2,5-diones, furo[3,4-c]coumarins,
mechanism
Introduction
phytopathogenic fungi.[6]
As the structural core, coumarin is used regularly as
a scaffold in medicinal and agricultural chemistry.[7-9]
As shown in Figure 1, warfarin, phenprocoumon and
acenocoumarol are coumarin anticoagulant agents,
function as vitamin K antagonists that inhibit coagula-
tion by blocking synthesis of coagulation factors.[10,11]
Methoxsalen is a natural coumarin drug used to treat
psoriasis, eczema and some cutaneous lymphomas in
conjunction with exposing the skin to UVA light from
lamps or sunlight.[12] Dicoumarol is a naturally couma-
rin occurring anticoagulant that functions as a functional
Osthole, a natural occurring coumarin derivative
(Figure 1), is reported as the active ingredient of Cnid-
ium Monnieri, a traditional Chinese herbal medicine.
Osthole chemically known as an O-methylated couma-
rin was also found in many plants and possesses a broad
scope of pharmacological and biochemical activities,[1-4]
including antiarrhythmia, antidiabetic, anticancer, anti-
osteoporosis, antiinflammatory, hepatoprotection and
neuroprotection. It has been widely used as a fungicide
in China for a long history,[5] displaying a range of anti-
fungal activities against Rhizoctonia solani and other
O
O
OH
OH
O
OH
O
OH
OH
O
OH
O
O
O
O
O
NO2
O
Acenocoumarol
Warfarin
Phenprocoumon
Osthole
OH
OH
O
O
O
O
O
O
O
O
O
O
O O
O
OH
N
H
O
H2N
O
OH
Dicoumarol
OH
Methoxsalen
O
Novobiocin
Figure 1 Structures of osthole and coumarin-containing drugs.
*
E-mail: njzhangwh@126.com; Tel.: 0086-025-84395255
Received August 1, 2016; accepted September 27, 2016; published online December 20, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201600489 or from the author.
1344
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Chin. J. Chem. 2016, 34, 1344—1352

Microwave-promoted Synthesis of Novel Fused Osthole Analogues
vitamin K depleter (similar to warfarin).[13] Novobiocin
is an aminocoumarin antibiotic obtained from an acti-
nomycete and used to treat infections by Gram-positive
bacteria.[14]
the natural product osthole as a lead to carry out the
structural modification, to improve the bioactivity by
exploring the chemistry, thus, a highly efficient reaction
protocol e.g. microwave-promoted synthesis is preferred
for building up the compounds library.
As most synthetic procedures are costly, time con-
suming and not environmentally friendly, usually giving
relatively poor yields, the application of microwave ir-
radiation has rapidly gained acceptance as a valuable
tool in modern combinatorial and medicinal chemistry.
Compared with traditional heating for organic reactions,
the main benefits of microwave-promoted organic syn-
thesis are significant enhancements in rate and higher
product yields, representing a very efficient and green
synthetic approach.[25]
The prominence of coumarins in natural products
and biologically active molecules has promoted consid-
erable efforts toward their synthesis,[15,16] while, based
on the chemical structures characteristics of these ap-
proved drugs, and the results of substructure search in
DrugBank database (http://www.drugbank.ca/), we can
notice that the fused coumarin derivatives on C-3 and
C-4 were rarely reported in the research of medicinal
and agricultural chemistry, some related publications
mainly focus on the synthetic approaches to furo[3,2-c]-
coumarin and Furtinone A derivatives.[17-19] Though
Gupta and coworkers[20] have previously described the
synthesis and antifungal activity of some fused couma-
rin compounds, some of which possessed effective con-
trol with EC50 values ranging from 0.2 to 2.5 µg/mL
against five tested phytopathogenic fungi in culture,
other than this, few literatures reported the further
structural modification and antifungal activity of fused
coumarin analogues.
4-Hydroxycoumarins 4b － 4d were synthesized
through the reported synthetic route (Scheme 1),[7]
yields for 4b, 4c, and 4d are 85%, 86%, and 82%, re-
spectively. 4-Hydroxycoumarins (4a) was purchased
from a commercial source.
Scheme 1 Synthetic route for 4-hydroxycoumarins 4b－4d
Osthole was treated as the lead compound to carry
out structural optimization in our previous work,[21-23] as
the 2H-pyran-2-one substructure in osthole can be con-
sidered as configuration ring-closed analogue of
(E)-methyl 3-methoxy-2-phenylacrylate (Figure 2),
which is the pharmacophore of the strobilurin fungi-
cides. Our published data showed that the designed
compounds with coumarin as the scaffold are very po-
tent against the phytopathogenic fungi on which they
were tested.[7,24] As continuation of our studies on natu-
ral product based pesticide discovery, we report our re-
search focused on microwave-promoted synthesis of
novel fused oxygen-bearing osthole analogues.
In our initial study, the reaction of 4-hydroxy-
coumarin (4a) with ethyl 2-methylacetoacetate in the
presence of toluene was chosen as a model to optimize
the reaction conditions (Table 1). As shown in Table 1,
compound 5c could be prepared in a moderate yield
with toluene as the best solvent (Table 1, Entries 3, 5, 6),
using 640 W microwave irradiation (Table 1, Entries 6,
7, 8), and 4-dimethylaminopyridine (DMAP) as the cat-
alyst (Table 1, Entries 4, 6). The yields increased con-
sistently with time, from 34% (10 min) to a maximum
of 69% (15 min) under these conditions, however, when
extending the reaction time longer than 20 min, the
yield did not increase significantly (shown in Table 1,
Entries 5, 6 and 9). Therefore, we can conclude that the
optimal conditions include using toluene as the solvent
in the presence of DMAP under microwave irradia tion
(640 W) for 15 min. This optimized method was used to
synthesize the designed coumarin derivatives. Further-
more, compared with conventional heating (Table 1,
Entries 13, 14), the reaction times for the target com-
pounds can be reduced from about 6 h to 15 min at
minimum (Table 1, Entry 6). We also explored the green
conditions (Table 1, Entries 15, 16), unfortunately, the
reaction was not suitable to conduct under water or sol-
vent-free conditions, duct under water or solvent-free
O
E
Bridge
O
O
O
O
Annulation
O
E
O
Pharmacophore
Strobinrin
4-Methoxyosthole
O
O
R
O
Fused osthole analogue
Figure 2 Design strategies of target molecules.
Results and Discussion
Synthetic chemistry
Aiming to discover synthetic analogues with simpler
chemical structures, our research in this study is to use
Chin. J. Chem. 2016, 34, 1344—1352
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Zhang et al.
FULL PAPER
Table 1 Reaction condition optimization for compound 5c
diones have been designed and synthesized (Schemes 2
and 3). All of the target compounds were characterized
O
1
by H NMR, 13C NMR, IR and HRMS, and the struc-
OH
O
O
O
tures of 5b, 6b, 10b and 12a were further confirmed by
X-ray diffraction crystallography (Figure 3).
solvent , catalyst
O
+
reaction conditions
O
O
O
O
4a
5c
Entry Solvent Catalyst MW/W Temperature Time/min Yielda/%
1
2
3
4
5
6
7
8
9
DMF NH4OAc 640
DMF NH4OAc 640
DMF DMAP 640
Toluene NH4OAc 640
Toluene DMAP 640
Toluene DMAP 640
Toluene DMAP 560
Toluene DMAP 720
Toluene DMAP 640
r.t.
r.t
15
20
45
40
35
45
34
69
55
20
65
48
54
30
40
45
r.t.
15
r.t
15
r.t.
10
r.t.
15
r.t.
15
r.t.
15
r.t.
20
10 Ethanol NH4OAc 640
r.t.
20
Figure 3 X-ray structures of compounds 5b, 6b, 10b and 12a.
11 Ethanol DMAP 640
r.t.
20
b
12 DMF NH4OAc
13 DMF DMAP
14 Toluene DMAP
－
－
－
Reflux
Reflux
Reflux
r.t.
360
360
360
15
Proposed reaction mechanisms
b
b
A plausible reaction pathway is proposed in Scheme
4. Nucleophilic attack of compound 4 on the ketone
carbonyl of β-ketoesters followed by protonation gives
intermediate E, which could undergo two distinct in-
tramolecular cyclization processes (Routes 1 and 2) de-
pending on the R1 substituent. When R1 is H, Me, Et or
F, intermediate E proceeds via dehydration of F and
subsequent intramolecular cyclization of G to afford
six-membered-ring product A (Route 1). Due to their
good leaving ability, Cl or Br-substituted E would un-
dergo an alternative cyclization, in which the intramo-
lecular nucleophilic substitution occurs on the α-site of
the ester, process shown in H, then is the subsequent
dehydration of intermediate I to generate five-mem-
bered ring B (Route 2).
c
15
16
H2O DMAP 640
－
d
c
－
DMAP 640
r.t.
15
－
a Yields after recrystallization from ethanol. b Conventional heat-
ing, no microwave irradiation. c Reaction failed. d Solvent free.
conditions, as the starting materials are insoluble in wa-
ter or conglomerate together under solvent-free condi-
tion.
With this efficient method, a focused compounds li-
brary of pyrano[3,2-c]chromene-2,5-diones (5a－9d)
and furo[3,2-c]coumarins (10a － 13d), including
3-(trifluoro)methyl (5a－5e), 8-alkoxy (6a－6d, 8a－8c)
and 8-allyloxy (7a－7c) pyrano[3,2-c]chromene-2,5-
Scheme 2 Microwave-promoted synthetic route for compounds 5a－9d
Compd.
5a
R
H
R1
H
R2
Yield/%
72
Compd.
7b
R
R1
CH3
Et
R2
Yield/%
66
CH3
CH3
CH3
CH3
CF3
CH3
CH3
CH3
CF3
CH3
Allyloxy
Allyloxy
n-Butoxy
n-Butoxy
n-Butoxy
H
CH3
CH3
CH3
CH3
CH3
5b
H
F
13
7c
69
5c
H
CH3
Et
H
68
8a
H
70
5d
H
64
8b
CH3
Et
62
5e
H
20
8c
64
6a
Methoxy
Methoxy
Methoxy
Methoxy
Allyloxy
H
75
9a
(CH2)4
(CH2)4
(CH2)4
(CH2)4
74
6b
CH3
Et
H
71
9b
Methoxy
Allyloxy
n-Butoxy
H
65
6c
69
9c
67
6d
31
9d
75
7a
H
76
9a
74
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Chin. J. Chem. 2016, 34, 1344—1352

Microwave-promoted Synthesis of Novel Fused Osthole Analogues
Scheme 3 Microwave-promoted synthetic routes for compounds 10a－13d
Compd.
10a
Time/min
10
R
Yield/%
65
Compd.
12a
Time/min
10
R
Yield/%
69
H
H
10b
10c
15
Methoxy
Allyloxy
n-Butoxy
H
77
12b
15
Methoxy
Allyloxy
n-Butoxy
H
73
10
67
12c
15
65
10d
11a
10
63
12d
15
62
10
67
13a
15
67
11b
15
Methoxy
Allyloxy
n-Butoxy
73
13b
15
Methoxy
Allyloxy
n-Butoxy
73
11c
15
65
13c
15
65
11d
15
61
13d
15
61
Scheme 4 Proposed mechanism for the formation of structures A and B
O
EtO O
O
2
OH R2
O
OH
O
R1
R2
R1
R2
OH
R
O
-H2O
R
-H+
OEt
OEt
-EtO-
R
H R1
R1
O
O
R
O
O
R
O
O
O
O
base
E
F
G
Structure A
R1 = H, Me, Et, F
Route 1
OH
2
R2
OH
O
O
O
O
O
O
O
R
OH
-H+
H+
R2
OEt
OEt
OEt
H R1
R1
R1
O
R
O
O
O
R
O
O
R
O
C
O
R
O
O
4
D
E
Route 2
OEt
R1 = X (Cl, Br)
OEt
X
OEt
R2
OEt
OH
R2
X
O
O
O
OH
O
O
-H2O
-H+
OH
R2
OH
R2
-X-
R
O
O
R
O
O
R
O
O
R
O
O
H
I
E
Structure B
ester derivatives of coumarin derivatives were deter-
mined on an X-4 apparatus (uncorrected), which was
purchased from Shanghai Tech. Infrared (IR) spectra
were recorded on a Bruker Tensor 27 spectrometer, and
samples were prepared as KBr plates. H NMR and C
NMR spectra were obtained by using a Bruker Avance
400 MHz spectrometer in CDCl3 solution with TMS as
an internal standard. HR-MS (ESI) spectra were carried
out with a Thermo Exactive spectrometer, and X-rays
were measured at 296 K on a Bruker SMART APEX2
Experimental
Chemicals and instruments
All chemicals were purchased from commercial
sources (e.g., Adamas, Crystal Chemicals) and used
without further purification unless otherwise stated. The
microwave treatment was carried out in a microwave
oven (WBFY-201, Gongyi Yuhua Instrument Co., Ltd.)
with an emission frequency of 2450 MHz and a maxi-
mum output power of 800 W. The melting points of the
1
13
Chin. J. Chem. 2016, 34, 1344—1352
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1347

Zhang et al.
FULL PAPER
CCD area detector diffractometer. Most reaction yields
were not optimized.
Hz, 1H), 7.42 (dd, J＝13.8, 8.0 Hz, 2H), 2.73 (dd, J＝
15.2, 7.7 Hz, 2H), 2.70 (s, 3H), 1.21 (q, J＝7.7 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ: 159.54, 159.13, 158.71,
152.75, 149.08, 133.86, 128.15, 124.88, 123.67, 116.66 ,
113.24, 104.31, 20.76, 17.67, 12.52; IR (KBr) ν: 1715,
1620, 1537, 1449 cm1; HR-MS (ESI) calcd for
C15H12O4 [M＋H]＋ 257.08139, found 257.08069.
Microwave-promoted synthetic procedure for the
preparation of compounds 5a－9d
Take the synthesis of compoubd 5c as an example. To
a stirred solution of 4-hydroxycoumarin (4, 1.62g, 10.0
mmol) and β-ketoester (ethyl 2-methyl-3-oxobutanoate,
1.73 g, 12.0 mmol) in toluene (30 mL) was added
DMAP (1.46 g, 12.0 mmol), and the reaction mixture
was irradiated in a microwave apparatus (640 W) under
room temperature for 15 min. After the reaction mixture
was cooled down to ambient temperature, the mixture
was concentrated, and the crude product was purified by
column chromatography using petroleum ether/acetone
(V∶V, 20∶1 to 10∶1) as eluent to give the title com-
pound 5c (1.67 g) as a white solid, yield 69%.
4-Trifluoromethyl-pyrano[3,2-c]chromene-2,5-dione
(5e): white solid; m.p. 200.5－203.0 ℃; 1H NMR (400
MHz, CDCl3) δ: 8.13 (dd, J＝8.0, 1.4 Hz, 1H), 7.80－
7.72 (m, 1H), 7.49－7.41 (m, 2H), 6.88 (d, J＝0.7 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ: 163.80, 156.30,
154.66, 153.70, 142.35, 141.93, 135.75, 125.38, 124.15,
117.16, 115.97 (q, J＝7.3 Hz, 1C), 112.37, 99.63; IR
(KBr) ν: 1724, 1607, 1530, 1458, 1389, 1099, 833 cm1;
＋
HR-MS (ESI) calcd for C13H5F3O4 [M ＋ H]
283.02182, found 283.02127.
8-Methoxy-4-methyl-pyrano[3,2-c]chromene-2,5-
dione (6a): white solid; m.p. 242.0－242.1 ℃; H
Traditional synthetic procedure for the preparation
of compound 5c
1
NMR (400 MHz,CDCl3) δ: 8.02 (s, 1H), 6.99 (s, 1H),
6.87 (s, 1H), 6.17 (s, 1H), 3.97 (s, 3H), 2.66 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ: 165.13, 162.71, 158.69,
158.18, 156.45, 155.36, 125.40, 113.70, 112.72, 106.30,
101.51, 100.55, 56.04, 22.67; IR (KBr) ν: 1709, 1611,
1541, 1281 cm1; HR-MS (ESI) calcd for C14H10O5
[M＋H]＋ 259.06065, found 259.05988.
4-Hydroxycoumarin 4 (1.62 g, 10.0 mmol), ethyl
2-methyl-3-oxobutanoate (1.73 g, 12.0 mmol) and
DMAP (1.46 g, 12.0 mmol) were dissolved in toluene
(30 mL). The mixture was stirred under conventional
heating reflux for about 6 h till full conversion of the
substrates was indicated by TLC analysis, then cooled to
ambient temperature and concentrated at reduced pres-
sure. The crude product was purified by column chro-
matography to give the title compound 5c (1.09 g) as a
white solid, yield 45%.
8-Methoxy-3,4-dimethyl-pyrano[3,2-c]chromene-
1
2,5-dione (6b): white solid; m.p. 212.3－212.9 ℃; H
NMR (400 MHz, CDCl3) δ: 8.01 (s, 1H), 6.97 (s, 1H),
6.85 (s, 1H), 3.95 (s, 3H), 2.67 (s, 3H), 2.23 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ: 164.54, 159.80, 159.70,
159.01, 154.74, 149.83, 124.85, 120.69, 113.44, 106.33,
101.83, 100.34, 55.98, 18.14, 13.06; IR (KBr) ν: 1702,
1609, 1550, 1275 cm1; HR-MS (ESI) calcd for
C15H12O5 [M＋H]＋ 273.07630, found 273.07553.
4-Methyl-pyrano[3,2-c]chromene-2,5-dione
(5a):
white solid; m.p. 257.6－262.5 ℃; 1H NMR (400 MHz,
CDCl3) δ: 8.16 (s, 1H), 7.71 (s, 1H), 7.44 (s, 2H), 6.27
(s, 1H), 2.69 (s, 3H); 13C NMR (101 MHz, DMSO) δ:
135.09, 125.63, 123.99, 117.14, 114.29, 40.51, 40.40,
40.19, 39.91, 39.78, 39.59, 39.46, 22.31; IR (KBr) ν:
1711, 1623, 1446, 1272 cm1; HR-MS (ESI) calcd for
C13H9O4 [M＋H]＋ 229.05009, found 229.04944.
3-Fluoro-4-methyl-pyrano[3,2-c]chromene-2,5-dione
(5b): white solid; m.p. 247.3－247.5 ℃; 1H NMR (400
MHz, CDCl3) δ: 8.05 (s, 1H), 7.69 (s, 1H), 7.41 (s, 2H),
2.64 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 158.03,
157.69, 152.61, 145.45, 142.95, 134.91, 134.34, 125.30,
123.69, 116.96, 112.73, 103.25, 12.84; IR (KBr) ν: 1695,
1616, 1446, 1268 cm1; HR-MS (ESI) calcd for
C13H9FO4 [M＋H]＋ 247.04066, found 247.03992.
3,4-Dimethyl-pyrano[3,2-c]chromene-2,5-dione (5c):
white solid; m.p. 223.5－223.5 ℃; 1H NMR (400 MHz,
CDCl3) δ: 8.15 (s, 1H), 7.69 (s, 1H), 7.41 (s, 2H), 2.69
(s, 3H), 2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ:
159.52, 159.36, 158.65, 152.73, 149.46, 133.86, 124.90,
123.64, 122.41, 116.67, 113.20, 104.18, 18.18, 13.23;
IR (KBr) ν: 1727, 1660, 1446, 1191 cm1; HR-MS (ESI)
calcd for C14H10O4 [M ＋ H] ＋ 243.06573, found
243.06502.
3-Ethyl-8-methoxy-4-methyl-pyrano[3,2-c]chromene-
1
2,5-dione (6c): white solid; m.p. 143.1－143.3 ℃; H
NMR (400 MHz, CDCl3) δ: 8.01 (dd, J＝18.7, 8.9 Hz,
1H), 7.00－6.94 (m,1H), 6.84 (dd, J＝12.5, 2.2 Hz, 1H),
3.95 (s, 3H), 2.71 (dd, J＝14.6, 7.1 Hz, 2H), 2.68 (s,
3H), 1.18 (t, J＝7.5 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ: 164.56, 160.10, 159.36, 159.12, 154.80,
149.47, 126.48, 124.92, 113.40, 106.41, 101.97, 100.35,
55.97, 20.63, 17.64, 12.60; IR (KBr) ν: 1715, 1607,
1397, 1275, 1022 cm1; HR-MS (ESI) calcd for
C16H13O5 [M＋H]＋ 287.09195, found 287.09115.
8-Methoxy-4-trifluoromethyl-pyrano[3,2-c]chromene-
1
2,5-dione (6d): white solid; m.p. 225.6－225.8 ℃; H
NMR (400 MHz, CDCl3) δ: 8.01 (dd, J＝21.3, 8.4 Hz,
1H), 7.09－6.94 (m, 1H), 6.94－6.74 (m, 2H), 3.98 (d,
J＝8.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 166.08,
164.17, 156.66, 156.05, 155.09,143.37, 142.29, 125.49,
115.09, 114.38－113.99 (m, 1C), 105.54, 100.57, 97.02,
－
1
56.21; IR (KBr) ν: 1765, 1731, 1609, 1376, 1150 cm ;
＋
HR-MS (ESI) calcd for C14H7F3O5 [M ＋ H]
3-Ethyl-4-methyl-pyrano[3,2-c]chromene-2,5-dione
(5d): white solid; m.p. 143.4－144.3 ℃; 1H NMR (400
MHz, CDCl3) δ: 8.14 (d, J＝7.9 Hz, 1H), 7.69 (t, J＝7.8
313.03238, found 313.03183.
8-Allyloxy-4-methyl-pyrano[3,2-c]chromene-2,5-
dione (7a): white solid; m.p. 178.1－178.3 ℃; H
1
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Chin. J. Chem. 2016, 34, 1344—1352

Microwave-promoted Synthesis of Novel Fused Osthole Analogues
NMR (400 MHz, CDCl3) δ: 8.03 (s, 1H), 7.01 (s, 1H),
6.88 (s, 1H), 6.17 (s, 1H), 6.09 (s, 1H), 5.46 (s, 2H),
4.70 (s, 2H), 2.66 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ: 164.02, 162.62, 158.63, 158.12, 156.41, 155.21,
131.70, 125.36, 118.89, 114.14, 112.72, 106.34, 101.51,
101.35, 69.53, 22.65; IR (KBr) ν: 1711, 1609, 1544,
1489, 1279, 1089 cm1; HR-MS (ESI) calcd for
C16H11O5 [M＋H]＋ 285.07630, found 285.07554.
J＝6.4 Hz, 2H), 2.67 (dd, J＝13.2, 5.7 Hz, 2H), 2.63 (s,
3H), 1.88－1.76 (m, 2H), 1.51 (dt, J＝14.9, 7.4 Hz, 2H),
1.26 (s, 1H), 1.14 (t, J＝7.5 Hz, 3H), 1.00 (t, J＝7.4 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ: 164.17, 160.15,
159.38, 159.18, 154.80, 149.51, 126.35, 124.83, 113.83,
106.15, 101.83, 100.74, 68.61, 30.93, 20.61, 19.15,
17.64, 13.77, 12.60; HR-MS (ESI) calcd for C19H20O5
[M＋H]＋ 329.13890, found 329.13809.
8-Allyloxy-3,4-dimethyl-pyrano[3,2-c]chromene-2,5-
dione (7b): white solid; m.p. 192.7－193.3 ℃; H
7,8,9,10-Tetrahydro-5,12-dioxa-chrysene-6,11-dione
(9a): white solid; m.p. 211.2－212.3 ℃; 1H NMR (400
MHz, CDCl3) δ: 8.09 (s, 1H), 7.65 (s, 1H), 7.37 (s, 2H),
3.14 (s, 2H), 2.59 (s, 2H), 1.80 (s, 4H); 13C NMR (101
MHz, CDCl3) δ: 159.29, 159.17, 158.40, 152.73, 150.76,
133.77, 124.87, 123.79, 123.56, 116.67, 113.27, 103.83,
28.55, 24.50, 21.53, 20.84; IR (KBr) ν: 1720, 1620,
1605, 1541, 1189 cm1; HR-MS (ESI) calcd for
C16H12O4 [M＋H]＋ 269.08139, found 269.08072.
2-Methoxy-7,8,9,10-tetrahydro-5,12-dioxa-chrysene-
1
NMR (400 MHz, DMSO) δ: 7.79 (s, 1H), 7.15 (s, 1H),
6.32 (s, 1H), 6.10 (s, 1H), 5.39 (d, J＝40.7 Hz, 2H),
4.78 (s, 2H), 3.33 (s, 3H), 2.21 (s, 3H); 13C NMR (101
MHz, CDCl3) δ: 163.44, 159.77, 159.02, 154.63,
149.81, 131.80, 124.86, 120.72, 118.80, 113.92, 106.41,
101.86, 101.17, 69.45, 18.15, 13.07; IR (KBr) ν: 1718,
1605, 1541, 1489, 1291, 1105 cm1; HR-MS (ESI) calcd
for C17H14O5 [M＋H]＋ 299.09195, found 299.09109.
8-Allyloxy-3-ethyl-4-methyl-pyrano[3,2-c]chromene-
1
6,11-dione (9b): white solid, m.p. 238.2－240.8 ℃; H
1
2,5-dione (7c): white solid; m.p. 143.1－143.3 ℃; H
NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 6.95 (s, 1H),
6.82 (s, 1H), 3.91 (s, 3H), 3.12 (s, 2H), 2.56 (s, 2H),
1.78 (s, 4H); 13C NMR (101 MHz, CDCl3) δ: 164.48,
159.88, 159.42, 158.81, 154.77, 151.13, 124.81, 122.11,
113.41, 106.44, 101.49, 100.39, 55.96, 28.55, 24.37,
21.57, 20.93; IR (KBr) ν: 1702, 1605, 1528, 1275 cm1;
HR-MS (ESI) calcd for C17H14O5 ([M＋H]＋) 299.09195,
found 299.09109.
NMR (400 MHz, CDCl3) δ: 7.98 (d, J＝8.9 Hz, 1H),
7.00－6.88 (m, 1H), 6.82 (d, J＝2.3 Hz, 1H), 6.05 (ddd,
J＝22.5, 10.6, 5.3 Hz, 1H), 5.41 (ddd, J＝13.9, 11.6, 1.1
Hz, 2H), 4.63 (d, J＝5.3 Hz, 2H), 2.67 (dd, J＝14.9, 7.4
Hz, 2H), 2.63 (s, 3H), 1.14 (t, J＝7.5 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ: 163.46, 160.04, 159.31, 159.09,
154.67, 149.43, 131.81, 126.52, 124.90, 118.79, 113.92,
106.47, 101.98, 101.17, 69.46, 20.63, 17.63, 12.59; IR
(KBr) ν: 1704, 1616, 1544, 1503, 1277, 1205 cm1;
HR-MS (ESI) calcd for C18H16O5 [M＋H]＋ 313.10760,
found 313.10669.
8-Butoxy-4-methyl-pyrano[3,2-c]chromene-2,5-dione
(8a): white solid; m.p. 183.0－183.9 ℃; 1H NMR (400
MHz, CDCl3) δ: 8.03 (d, J＝8.9 Hz, 1H), 6.99 (dd, J＝
8.9, 2.2 Hz, 1H), 6.85 (d, J＝2.2 Hz, 1H), 6.17 (d, J＝
1.0 Hz, 1H), 4.11 (t, J＝6.5 Hz, 2H), 2.66 (d, J＝0.9 Hz,
3H), 1.91－1.79 (m, 2H), 1.55 (dt, J＝14.7, 7.4 Hz, 2H),
1.04 (t, J＝7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ:
164.74, 162.73, 158.73, 158.21, 156.48, 155.35, 125.30,
114.07, 112.59, 106.02, 101.36, 100.93, 68.73, 30.90,
22.67, 19.14, 13.77; IR (KBr) ν: 1744, 1627, 1546, 1438,
1276, 1087 cm1; HR-MS (ESI) calcd for C17H16O5 [M
＋H]＋ 301.10760, found 301.10675.
2-Allyloxy-7,8,9,10-tetrahydro-5,12-dioxa-chrysene-
6,11-dione (9c): a white solid, m.p. 206.9－207.3 ℃;
1H NMR (400 MHz, CDCl3) δ: 8.02 (d, J＝8.9 Hz, 1H),
7.07－6.93 (m, 1H), 6.86 (d, J＝2.2 Hz, 1H), 6.09 (ddd,
J＝22.4, 10.6, 5.3 Hz, 1H), 5.45 (dd, J＝36.7, 13.9 Hz,
2H), 4.68 (d, J＝5.3 Hz, 2H), 3.16 (s, 2H), 2.60 (s, 2H),
1.87－1.71 (m, 4H); 13C NMR (101 MHz, CDCl3) δ:
163.40, 159.85, 159.40, 158.81, 154.67, 151.11, 131.83,
124.82, 122.15, 118.78, 113.89, 106.53, 101.53, 101.23,
69.45, 28.54, 24.37, 21.57, 20.92; IR (KBr) ν: 1702,
1611, 1550, 1277, 1110 cm1; HR-MS (ESI) calcd for
C19H16O5 ([M＋H]＋) 325.10760, found 325.10675.
2-Butoxy-7,8,9,10-tetrahydro-5,12-dioxa-chrysene-
1
6,11-dione (9d): white solid; m.p. 146.7－147.1 ℃; H
NMR (400 MHz, CDCl3) δ: 7.97 (d, J＝8.9 Hz, 1H),
6.92 (dd, J＝8.9, 2.3 Hz, 1H), 6.79 (d, J＝2.2 Hz, 1H),
4.05 (t, J＝6.5 Hz, 2H), 3.11 (s, 2H), 2.56 (s, 2H),
1.89－1.69 (m, 6H), 1.60－1.42 (m, 2H), 1.00 (t, J＝7.4
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 162.71,
159.17, 158.84, 158.19, 155.43, 141.00, 130.49, 122.90,
113.44, 109.11, 105.24, 101.85, 68.45, 61.27, 30.98,
29.70, 19.17, 14.24, 13.78, 10.17; HR-MS (ESI) calcd
for C20H20O5 ([M＋H]＋) 341.13890, found 341.13835.
8-Butoxy-3,4-dimethyl-pyrano[3,2-c]chromene-2,5-
1
dione (8b): white solid; m.p. 172.5－172.7 ℃; H
NMR (400 MHz, CDCl3) δ: 7.97 (d, J＝8.9 Hz, 1H),
6.93 (dd, J＝8.9, 2.3 Hz, 1H), 6.79 (d, J＝2.2 Hz, 1H),
4.05 (t, J＝6.5 Hz, 2H), 2.63 (s, 3H), 2.19 (s, 3H),
1.88－1.73 (m, 2H), 1.52 (dq, J＝14.7, 7.4 Hz, 2H),
1.00 (t, J＝7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ:
164.17, 159.98, 159.77, 159.13, 154.78, 149.89, 124.80,
120.56, 113.84, 106.11, 101.73, 100.76, 68.62, 30.92,
19.15, 18.15, 13.77, 13.05; HR-MS (ESI) calcd for
C18H18O5 [M＋H]＋ 315.12325, found 315.12239.
Microwave-promoted synthesis for compounds
10a－13d
Based on the above microwave-promoted method,
α-halo-β-ketoesters e.g. ethyl 2-chloro-3-oxobutanoate
were employed as the starting materials, while, the ob-
tained products were furo[3,2-c]coumarins rather than
pyrano[3,2-c]chromene-2,5-diones, and furo[3,2-c]-
8-Butoxy-3-ethyl-4-methyl-pyrano[3,2-c]chromene-
1
2,5-dione (8c): white solid; m.p. 144.3－144.7 ℃; H
NMR (400 MHz, CDCl3) δ: 7.97 (dd, J＝8.9, 1.3 Hz,
1H), 6.92 (dd, J＝8.9, 2.1 Hz, 1H), 6.79 (s, 1H), 4.05 (t,
Chin. J. Chem. 2016, 34, 1344—1352
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1349

Zhang et al.
FULL PAPER
coumarins 10a－13d could be prepared in moderate
yields with toluene as the solvent, using 640 W micro-
wave irradiation, and DMAP as the catalyst. The yields
vary from 61% to 77% considerably depending upon the
irradiative time.
158.12, 157.72, 153.50, 141.59, 132.16, 130.64, 124.78,
121.85, 117.41, 112.11, 111.49, 52.21, 10.12; IR (KBr) ν:
1700, 1623, 1446, 1325, 1232, 1131, 1083 cm1;
HR-MS (ESI) calcd for C14H10O5 [M＋H]＋ 259.06065,
found 259.06010.
3-Methyl-4-oxo-4H-furo[3,2-c]chromene-2-carbo-
xylic acid ethyl ester (10a): white solid; m.p. 140.2－
140.6 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07 (dd, J＝
7.9, 1.4 Hz, 1H), 7.69－7.58 (m, 1H), 7.56－7.37 (m,
2H), 4.50 (q, J＝7.1 Hz, 2H), 2.75 (s, 3H), 1.50 (t, J＝
7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ: 159.01,
158.07, 157.79, 153.50, 141.85, 132.09, 130.31, 124.74,
121.90, 117.40, 112.18, 111.52, 61.45, 14.36, 10.15; IR
(KBr) ν: 1708, 1631, 1446, 1321, 1139, 1087 cm1;
HR-MS (ESI) calcd for C15H12O5 [M＋H]＋ 273.07630,
found 273.07575.
7-Methoxy-3-methyl-4-oxo-4H-furo[3,2-c]chromene-
2-carboxylic acid methyl ester (11b): white solid; m.p.
216.0 ℃; H NMR (500 MHz, CDCl3) δ: 7.91 (d, J＝
1
8.6 Hz, 1H), 7.31 (t, J＝14.7 Hz, 1H), 6.96 (d, J＝11.6
Hz, 1H), 4.01 (dd, J＝17.9, 11.4 Hz, 3H), 3.95－3.88
(m, 3H), 2.72 (dd, J＝17.9, 11.4 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ: 163.15, 159.51, 158.83, 158.09,
155.45, 140.83, 130.83, 122.95, 113.10, 109.21, 105.41,
101.43, 55.87, 52.12, 10.16; IR (KBr) ν: 1736, 1699,
1617, 1445, 1325, 1235, 1082, 960 cm1; HR-MS (ESI)
calcd for C15H10O5 [M ＋ H] ＋ 289.07122, found
289.07066.
7-Methoxy-3-methyl-4-oxo-4H-furo[3,2-c]chromene-
2-carboxylic acid ethyl ester (10b): white solid; m.p.
7-Allyloxy-3-methyl-4-oxo-4H-furo[3,2-c]chromene-
2-carboxylic acid methyl ester (11c): white solid; m.p.
1
186.4－187.1 ℃; H NMR (400 MHz, CDCl3) δ: 8.07
1
(dd, J＝7.9, 1.4 Hz, 1H), 7.69－7.58 (m, 1H), 7.56－
7.37 (m, 2H), 4.50 (q, J＝7.1 Hz, 2H), 2.75 (s, 3H),
1.50 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ:
163.07, 159.14, 158.71, 158.10, 155.37, 141.03, 130.45,
122.95, 113.03, 109.18, 105.41, 101.37, 61.32, 55.85,
14.37, 10.17; IR (KBr) ν: 1739, 1627, 1442, 1323, 1241,
963 cm1; HR-MS (ESI) calcd for C16H14O6 [M＋H]＋
303.08686, found 303.08631.
151.0－154.9 ℃; H NMR (500 MHz, CDCl3) δ:
7.98－7.85 (m, 1H), 7.04－6.89 (m, 2H), 6.12－5.99
(m, 1H), 5.43 (dd, J＝49.7, 13.8 Hz, 2H), 4.65 (s, 2H),
4.07－3.94 (m, 3H), 2.77－2.65 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ: 162.05, 159.46, 158.73, 158.02,
155.31, 140.82, 132.00, 130.79, 122.91, 118.74, 113.55,
109.22, 105.47, 102.25, 69.46, 52.09, 10.13; IR (KBr) ν:
1732, 1623, 1446, 1333, 1260, 1091, 994 cm1; HR-MS
(ESI) calcd for C17H14O6 [M＋H]＋ 315.08686, found
315.08631.
7-Allyloxy-3-methyl-4-oxo-4H-furo[3,2-c]chromene-
2-carboxylic acid ethyl ester (10c): white solid; m.p.
1
155.5－156.2 ℃; H NMR (400 MHz, CDCl3) δ: 7.95
7-Butoxy-3-methyl-4-oxo-4H-furo[3,2-c]chromene-
2-carboxylic acid methyl ester (11d): white solid; m.p.
(d, J＝8.7 Hz, 1H), 7.00 (dd, J＝12.6, 3.8 Hz, 2H), 6.10
(ddd, J＝16.6, 10.4, 5.2 Hz, 1H), 5.45 (dd, J＝39.7,
13.9 Hz, 2H), 4.67 (d, J＝5.2 Hz, 2H), 4.49 (q, J＝7.1
Hz, 2H), 2.73 (s, 3H), 1.49 (t, J＝7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ: 162.01, 159.14, 158.70, 158.11,
155.30, 141.08, 132.02, 130.45, 122.97, 118.66, 113.57,
109.25, 105.55, 102.25, 69.35, 61.31, 14.37, 10.17; IR
(KBr) ν: 1720, 1607, 1450, 1317, 1244, 1083, 994 cm1;
HR-MS (ESI) calcd for C18H16O6 [M＋H]＋ 329.10252,
found 329.10196.
1
145.9－146.8 ℃; H NMR (500 MHz, CDCl3) δ: 7.90
(dd, J＝8.6, 3.5 Hz, 1H), 6.94 (dd, J＝11.6, 5.9 Hz, 2H),
4.10－4.03 (m, 2H), 4.00 (d, J＝3.5 Hz, 3H), 2.70 (t,
J＝9.4 Hz, 3H), 1.84 (s, 2H), 1.56 (dd, J＝16.8, 5.8 Hz,
3H), 1.10－0.96 (m, 3H); 13C NMR (101 MHz, CDCl3)
δ: 159.34, 158.12, 157.72, 153.50, 141.59, 132.16,
130.64, 124.78, 121.85, 117.41, 112.11, 111.49, 68.46,
52.21, 30.98, 19.18, 13.80, 10.12; IR (KBr) ν: 1758,
1711, 1614, 1453, 1329, 1132, 999 cm1; HR-MS (ESI)
calcd for C18H18O6 [M ＋ H] ＋ 331.11816, found
331.11761.
7-Butoxy-3-methyl-4-oxo-4H-furo[3,2-c]chromene-
2-carboxylic acid ethyl ester (10d): white solid; m.p.
1
189.3－192.3 ℃; H NMR (400 MHz, CDCl3) δ: 8.07
2-Acetyl-furo[3,2-c]chromen-4-one (12a): white
1
(dd, J＝7.9, 1.4 Hz, 1H), 7.69－7.58 (m, 1H), 7.56－
7.37 (m, 2H), 4.50 (q, J＝7.1 Hz, 2H), 2.75 (s, 3H),
1.50 (t, J＝7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ:
173.09, 165.25, 162.73, 155.77, 155.45, 126.39, 122.94,
113.73, 113.48, 108.54, 101.87, 100.77, 68.54, 61.30,
30.95, 19.16, 14.38, 13.78, 10.20; IR (KBr) ν: 1732,
1696, 1623, 1442, 1309, 1135, 962 cm1; HR-MS (ESI)
calcd for C19H20O6 [M ＋ H] ＋ 345.13382, found
345.13331.
solid; m.p. 178.7－179.5 ℃; H NMR (400 MHz,
CDCl3) δ: 7.98 (dd, J＝7.8, 1.2 Hz, 1H), 7.66－7.56 (m,
1H), 7.52－7.35 (m, 2H), 2.75 (s, 3H), 2.65 (s, 3H); 13C
NMR (101 MHz, CDCl3 ) δ: 188.73, 157.79, 157.33,
153.66, 149.14, 132.28, 129.54, 124.84, 121.57, 117.54,
112.12, 112.04, 27.66, 10.24; IR (KBr) ν: 1739, 1683,
1623, 1548, 1442, 1360, 1229, 1185, 994 cm1; HR-MS
(ESI) calcd for C14H10O4 [M＋H]＋ 243.06573, found
243.06519.
3-Methyl-4-oxo-4H-furo[3,2-c]chromene-2-carbo-
xylic acid methyl ester (11a): white solid; m.p. 152.2－
152.4 ℃; H NMR (500 MHz, CDCl3) δ: 8.05 (d, J＝
7.8 Hz, 1H), 7.59 (t, J＝26.3 Hz, 1H), 7.43 (dt, J＝34.3,
17.6 Hz, 2H), 4.04 (t, J＝16.4 Hz, 3H), 2.76 (t, J＝16.6
Hz, 3H); 13C NMR (101 MHz, CDCl3 ) δ: 159.34,
2-Acetyl-7-methoxy-furo[3,2-c]chromen-4-one (12b):
white solid; m.p. 200.9－203.2 ℃; 1H NMR (400 MHz,
CDCl3) δ: 7.87 (d, J＝8.6 Hz, 1H), 7.03－6.90 (m, 2H),
3.96－3.87 (m, 3H), 2.74 (s, 3H), 2.62 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ: 188.56, 163.23, 158.06,
158.03, 155.61, 148.61, 129.77, 122.62, 113.22, 109.69,
1
1350
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 1344—1352

Microwave-promoted Synthesis of Novel Fused Osthole Analogues
105.35, 101.46, 55.95, 27.60, 10.28; IR (KBr) ν: 1744,
1627, 1546, 1438, 1276, 1087 cm1; HR-MS (ESI) calcd
for C15H12O5 [M＋H]＋ 273.07630, found 273.007575.
2-Acetyl-7-allyloxy-furo[3,2-c]chromen-4-one (12c):
white solid; m.p. 146.2－146.3 ℃; 1H NMR (500 MHz,
CDCl3) δ: 7.83 (d, J＝8.7 Hz, 1H), 6.99－6.87 (m, 2H),
4.05 (t, J＝6.5 Hz, 2H), 2.77－2.66 (m, 3H), 2.58 (d,
J＝17.9 Hz, 3H), 1.87－1.76 (m, 2H), 1.52 (dt, J＝14.8,
7.5 Hz, 2H), 1.00 (t, J＝7.4 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ: 188.58, 162.14, 158.10, 158.04, 155.50,
148.61, 131.95, 129.76, 122.63, 118.76, 113.73, 109.72,
105.44, 102.30, 69.39, 27.62, 10.29; IR (KBr) ν: 1736,
1607, 1438, 1333, 1252, 1099, 998 cm1; HR-MS (ESI)
calcd for C17H14O5 [M ＋ H] ＋ 289.09195, found
289.09140.
cm1; HR-MS (ESI) calcd for C20H14O4 [M＋H]＋
319.09704, found 319.09649.
7-Butoxy-3-phenyl-furo[3,2-c]chromen-4-one (13d):
white solid; m.p. 182.0－182.1 ℃; 1H NMR (500 MHz,
CDCl3) δ: 7.84－7.77 (m, 3H), 7.71 (d, J＝1.6 Hz, 1H),
7.51－7.44 (m, 2H), 7.44－7.38 (m, 1H), 6.98－6.94
(m, 2H), 4.06 (t, J＝6.5 Hz, 2H), 1.91－1.79 (m, 2H),
1.55 (td, J＝14.8, 7.3 Hz, 3H), 1.06－0.97 (m, 3H); 13C
NMR (101 MHz, CDCl3) δ: 161.80, 159.56, 158.20,
154.44, 140.30, 132.17, 129.35, 128.62, 128.52, 128.24,
126.49, 121.87, 113.29, 105.97, 101.54, 68.36, 31.04,
19.21, 13.83; IR (KBr) ν: 1728, 1623, 1510, 1446, 1272,
1244 cm1; HR-MS (ESI) calcd for C21H18O4 [M＋H]＋
335.12834, found 335.12779.
X-ray diffraction analysis
2-Acetyl-7-butoxy-furo[3,2-c]chromen-4-one (12d):
1
a white solid; m.p. 149.7 ℃; H NMR (500 MHz,
The crystallographic data have been deposited with
the Cambridge Crystallographic Data Centre (CCDC) as
supplementary publication number: 1047356 (5b),
1419461 (6b), 1055787 (10b), 1417754 (12a). Copies
of the data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/, or on application to CCDC,
12 Union Road, Cambridge CB12 1EZ, UK (Fax＋44
1223 336033 or E-mail: deposit@ccdc.cam.ac.uk).
CDCl3) δ: 7.83 (d, J＝8.7 Hz, 1H), 6.99－6.87 (m, 2H),
4.05 (t, J＝6.5 Hz, 2H), 2.77－2.66 (m, 3H), 2.58 (d,
J＝17.9 Hz, 3H), 1.87－1.76 (m, 2H), 1.52 (dt, J＝14.8,
7.5 Hz, 2H), 1.00 (t, J＝7.4 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ: 188.52, 162.84, 158.12, 158.09, 155.62,
148.56, 129.78, 122.54, 113.59, 109.58, 105.11, 101.89,
68.50, 30.98, 27.58, 19.18, 13.80, 10.28; IR (KBr) ν:
1744, 1667, 1627, 1595, 1458, 1256, 1011 cm1;
HR-MS (ESI) calcd for C18H18O5 [M＋H]＋ 315.12325,
found 315.12270.
Conclusions
3-Phenyl-furo[3,2-c]chromen-4-one (13a): white
solid; m.p. 209.1－210.2 ℃; H NMR (500 MHz,
In summary, a highly efficient microwave-promoted
protocol was developed for the synthesis of two series
of fused osthole analogues, and the optimal reaction
conditions include using toluene as the solvent in the
presence of DMAP under microwave irradiation (640
W). Compared with conventional heating, the isolated
yields of microwave-promoted method can be improved
from 30% to 76% at maximum, and the reaction times
for the target compounds can be even reduced from
about 6 h to 15 min at minimum. The proposed mecha-
nism of the formation of two fused osthole derivatives:
pyrano[3,2-c]chromene-2,5-diones and furo[3,2-c]-
coumarins was also discussed in this study.
1
CDCl3) δ: 7.95 (dd, J＝7.8, 1.2 Hz, 1H), 7.80 (dd, J＝
6.3, 2.0 Hz, 2H), 7.57 (ddd, J＝8.8, 7.3, 1.5 Hz, 1H),
7.51－7.47 (m, 3H), 7.44－7.38 (m, 3H); 13C NMR
(101 MHz, CDCl3) δ: 158.80, 157.86, 152.61, 141.28,
130.97, 129.09, 128.68, 128.59, 128.39, 126.74, 124.51,
120.99, 117.13, 112.77, 108.48; IR (KBr) ν: 1732, 1627,
1490, 1438, 1317, 1079, 962 cm1; HR-MS (ESI) calcd
for C17H10O3 [M＋H]＋ 263.07082, found 263.07027.
7-Methoxy-3-phenyl-furo[3,2-c]chromen-4-one
1
(13b): white solid; m.p. 162.1－162.4 ℃; H NMR
(500 MHz, CDCl3) δ: 7.95 (dd, J＝7.8, 1.2 Hz, 1H),
7.80 (dd, J＝6.3, 2.0 Hz, 2H), 7.57 (ddd, J＝8.8, 7.3,
1.5 Hz, 1H), 7.51－7.47 (m, 3H), 7.44－7.38 (m, 3H);
13C NMR (101 MHz, CDCl3) δ: 162.18, 159.46, 158.17,
154.39, 140.38, 129.29, 128.62, 128.54, 128.27, 126.47,
121.95, 112.88, 106.14, 106.05, 101.04, 55.78; IR (KBr)
ν: 1732, 1627, 1454, 1337, 1236, 1131 cm1; HR-MS
(ESI) calcd for C18H12O4 [M＋H]＋ 293.08139, found
293.08084.
7-Allyloxy-3-phenyl-furo[3,2-c]chromen-4-one (13c):
white solid; m.p. 167.4－168.5 ℃; 1H NMR (500 MHz,
CDCl3) δ: 7.80 (ddd, J＝14.9, 11.1, 6.3 Hz, 3H), 7.72 (d,
J＝1.7 Hz, 1H), 7.53－7.38 (m, 3H), 6.99 (td, J＝4.6,
2.3 Hz, 2H), 6.09 (ddt, J＝17.3, 10.6, 5.3 Hz, 1H),
5.55－5.34 (m, 2H), 4.69－4.62 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ: 161.11, 159.44, 158.14, 154.31,
140.40, 132.22, 129.29, 128.62, 128.54, 128.27, 126.49,
121.95, 118.55, 113.41, 106.29, 106.13, 101.96, 69.29;
IR (KBr) ν: 1739, 1611, 1451, 1232, 1138, 1068, 941
Acknowledgement
The project was supported by the National Natural
Science Foundation of China (No. 21272116) and the
Fundamental Research Funds for the Central Universi-
ties (No. KYTZ201604). We thank Prof. Yingguang Zhu
from College of Sciences at Nanjing Agricultural Uni-
versity for reaction mechanism discussion.
References
[1] Shi, Y.; Zhang, B.; Chen, X. J.; Xu, D. Q.; Wang, Y. X.; Dong, H. Y.;
Ma, S. R.; Sun, R. H.; Hui, Y. P.; Li, Z. C. Eur. J. Pharm. Sci. 2013,
48, 819.
[2] Wu, L.; Huang, X.; Li, J.; Zhang, R.; Hu, H. J. Intercult. Eth-
nopharmacol. 2013, 2, 57.
[3] Liang, H. J.; Suk, F. M.; Wang, C. K.; Hung, L. F.; Liu, D. Z.; Chen,
N. Q.; Chen, Y. C.; Chang, C. C.; Liang, Y. C. Chem. Biol. Interact.
Chin. J. Chem. 2016, 34, 1344—1352
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1351

Zhang et al.
FULL PAPER
2009, 181, 309.
chemistry 1997, 36, 9663.
[4] Liu, Y. W.; Chiu, Y. T.; Fu, S. L.; Huang, Y. T. J. Biomed. Sci. 2015,
22, 63.
[15] Chen, Z.; Bi, J.; Su, W. Chin. J. Chem. 2012, 30, 1.
[16] Karade, N. N.; Gampawar, S. V.; Shinde, S. V.; Jadhav, W. N. Chin.
J. Chem. 2007, 25, 1686.
[17] Kolita, S.; Borah, P.; Naidu, P. S.; Bhuyan, P. J. Tetrahedron 2016,
72, 532.
[18] Yoshida, M.; Saito, K.; Fujino, Y.; Doi, T. Tetrahedron 2014, 70,
3452.
[5] Wei, Y.; Zhang, T.; Ito, Y. J. Chromatogr. A 2004, 1033, 373.
[6] Vogl, S.; Zehl, M.; Picker, P.; Urban, E.; Wawrosch, C.; Reznicek, G.;
Saukel, J.; Kopp, B. J. Agric. Food Chem. 2011, 59, 4371.
[7] Zhang, R. R.; Liu, J.; Zhang, Y.; Hou, M. Q.; Zhang, M. Z.; Zhou, F.;
Zhang, W. H. Eur. J. Med. Chem. 2016, 116, 76.
[8] Zhang, M. Z.; Zhang, R. R.; Wang, J. Q.; Yu, X.; Zhang, Y. L.; Wang,
Q. Q.; Zhang, W. H. Eur. J. Med. Chem. 2016, 124, 10.
[9] Chen, Z.; Bi, J.; Su, W. Chin. J. Chem. 2013, 31, 507.
[10] Holbrook, A. M.; Pereira, J. A.; Labiris, R.; McDonald, H.; Douketis,
J. D.; Crowther, M.; Wells, P. S. Arch. Intern. Med. 2005, 165, 1095.
[11] Cesar, J. M.; Garcia-Avello, A.; Navarro, J. L.; Herraez, M. V. Blood
Coagul. Fibrin. 2004, 15, 673.
[12] Abdel Hafez, O. M.; Amin, K. M.; Abdel-Latif, N. A.; Mohamed, T.
K.; Ahmed, E. Y.; Maher, T. Eur. J. Med. Chem. 2009, 44, 2967.
[13] Hamdi, N.; Puerta, M. C.; Valerga, P. Eur. J. Med. Chem. 2008, 43,
2541.
[19] Shin, Y.; Yoo, C.; Moon, Y.; Lee, Y.; Hong, S. Chem. Asian J. 2015,
10, 878.
[20] Gupta, B. B.; Singh, R. V.; Malika, O. P.; Kataria, H. R. Pestic. Sci.
1987, 21, 51.
[21] Yan, H.; Yin, W.; Liu, P.; Liu, J.; Hu, M. C.; Zhang, W. Appl. Or-
ganomet. Chem. 2014, 28, 747.
[22] Zhang, R.; Xu, Z.; Yin, W.; Liu, P.; Zhang, W. Synth. Commun. 2014,
44, 3257.
[23] Yin, Q.; Yan, H.; Zhang, Y.; Wang, Y.; Zhang, G.; He, Y.; Zhang, W.
Appl. Organomet. Chem. 2013, 27, 85.
[24] Zhang, M. Z.; Zhang, R. R.; Yin, W. Z.; Yu, X.; Zhang, Y. L.; Liu, P.;
Gu, Y. C.; Zhang, W. H. Mol. Divers. 2016, 20, 611.
[25] Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
[14] Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H.; Weston, S. A.; Rosen-
brock, G.; Barth, P. T.; Taylor, I. W.; Pauptit, R. A.; Timms, D. Bio-
(Zhao, C.)
1352
www.cjc.wiley-vch.de
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 1344—1352