Synthesis of functionalized furo[3,2-c]coumarins via a one-pot oxidative pseudo three-component reaction in poly(ethylene glycol)

Article abstract of DOI:10.1016/j.tet.2012.05.112

An efficient and straightforward synthesis of functionalized furo[3,2-c]coumarins via a one-pot oxidative pseudo three-component condensation of aldehydes and 4-hydroxycoumarin (2 equiv) in poly(ethylene glycol) (PEG) as solvent is described. A mixture of I₂ and K₂S ₂O₈ in the presence of Na₂CO₃ was used as an oxidative reagent. The structure of the furo[3,2-c]coumarins was established by X-ray single crystal structure analysis.

Full text of DOI:10.1016/j.tet.2012.05.112

Tetrahedron 68 (2012) 6721e6726
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of functionalized furo[3,2-c]coumarins via a one-pot oxidative pseudo
three-component reaction in poly(ethylene glycol)
Zeinab Zareai a, Mehdi Khoobi b, Ali Ramazani a, Alireza Foroumadi b, Ali Souldozi c,
d
d
e,
*
ꢀ
Katarzyna Slepokura , Tadeusz Lis , Abbas Shafiee
a Department of Chemistry, University of Zanjan, PO Box 45195-313, Zanjan, Iran
b Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran
c Department of Chemistry, Urmia Branch, Islamic Azad University, PO Box 969, Urmia, Iran
d Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie St., 50-383 Wrocław, Poland
e Department of Medicinal Chemistry, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward synthesis of functionalized furo[3,2-c]coumarins via a one-pot oxidative
pseudo three-component condensation of aldehydes and 4-hydroxycoumarin (2 equiv) in poly(ethylene
glycol) (PEG) as solvent is described. A mixture of I2 and K2S2O8 in the presence of Na2CO3 was used as an
oxidative reagent. The structure of the furo[3,2-c]coumarins was established by X-ray single crystal
structure analysis.
Received 12 February 2012
Received in revised form 13 May 2012
Accepted 28 May 2012
Available online 7 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Furo[3,2-c]coumarin
4-Hydroxycoumarin
Oxidation
X-ray single crystal structure analysis
Poly(ethylene glycol)
1. Introduction
solvents and complete toxicity profiles are available for a range of
PEG molecular weights; some of them are already approved for
Multicomponent reactions (MCRs) have emerged as a highly
efficient tool in modern synthetic organic chemistry due to features
such as atom economy, straightforward reaction design, and the
opportunity to construct target organic molecules by the in-
troduction of several diverse elements. Typically, purification of
products resulting from MCRs is also fairly simple since all the re-
actants employed are consumed and are incorporated into the
target compound.1 MCRs leading to interesting heterocyclic com-
pounds are particularly important for the preparation of diverse
chemical libraries of ‘drug-like’ molecules.1
The use of an obviously benign and inexpensive solvent like
water and poly(ethylene glycol) (PEG) could yield significant ‘green
chemistry’ benefits. Ionic liquid solvents are also the most popular
solvents but they are very expensive, and their toxicity and envi-
ronmental effect are for the most part unknown.2 PEG is a ther-
mally stable, inexpensive, recoverable, and non-toxic hydrophilic
polymer, which can replace with volatile and hazardous organic
internal consumption by the US FDA. The high solubility of PEGs in
water and several organic solvents including alcohol, acetone,
dichloromethane, and toluene instead of insolubility of them in less
polar solvents such as hexane, cyclohexane, or diethyl ether cause
to easy recovery and high performance of them in organic
reactions.2,3
Furocoumarins are found in many natural products and exhibit
potent biological activity. They are inherently photosensitive and
found to have therapeutic applications.4 The photo chemothera-
peutic effects rely on their ability to intercalate with the pyrimidine
bases of microorganism DNA.5 Neo-tanshinlactone is known as
a furo[3,2-c]coumarin that isolated from the rhizome of Salvia
miltiorrhiza Bunge, which is an anti-breast cancer agent.6 The range
of biological activities of furocoumarins such as insecticidal, anti-
tumor, antioxidant, anticoagulant, antimicrobial, and antifungal has
stimulated interest in the synthetic methods for the construction of
them.4,6 There are several methods for the preparation of furo-
coumarins with most involving a Claisen rearrangement and
a tandem alkylation/intramolecular aldolization reaction.7 Nair and
co-worker reported preparation of furan annulated coumarin in-
volving a [4þ1] cycloaddition with various in situ generated
* Corresponding author. Tel.: þ98 21 66406757; fax: þ98 21 66461178; e-mail
address: ashafiee@ams.ac.ir (A. Shafiee).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.112

6722
Z. Zareai et al. / Tetrahedron 68 (2012) 6721e6726
heterocyclic coumarin methides and isocyanides.8 Also, Pd-
catalyzed heteroannulation of 3-alkynyl-4-methoxycoumarins
with aryl halides resulted in the formation of 3-arylfuro[3,2-c]
coumarins.9 Most synthetic routes have focused on coumestrol,
which is the combination of the benzofuran and coumarin skel-
etons.4b Only a few reports have been described for the synthesis of
substituted furo[3,2-c]coumarins.4,8,9 As our continuous endeavor
dealing with the design and preparation of interesting organic
structures,10 especially coumarin derivatives,11 we wish to describe
herein a simple, inexpensive, and fairly efficient synthesis of
functionalized furo[3,2-c]coumarins via the one-pot oxidative
pseudo three-component condensation of aldehydes and 4-
hydroxycoumarin (2 equiv) in PEG.
Fig. 1. X-ray structure of compound 4a with the atom numbering and the intra-
molecular OeH/O hydrogen bond (dashed line). Displacement ellipsoids are shown at
the 50% probability level.
2. Results and discussion
biscoumarin 3a as substrates using previously reported pro-
cedures.12 Then we examined the reaction of compound 3a in the
presence of several oxidants in different media. A summary of the
reaction conditions optimization are shown in Table 1. Optimiza-
tion revealed that potassium persulfate is the best oxidant for this
reaction by providing a yield of 75% of 4a with the assistance of
Our research originated from an unexpected observation made
during simple preparation of biscoumarins 3 according to a pre-
viously reported procedure.12 In refluxing water, the addition of
4-hydroxycoumarin 1 to formaldehyde 2a in the presence of iodine
yield the expected biscoumarins 3a, in addition to small amount of
unknown side product 4a (5%) (Scheme 1).
HO
O
H
O
OH
O
OH
O
O
H
O
I2
water, reflux
H
+
+
H
HO
O
O
O
O
O
1
2a
3a (85%)
4a (5%)
Scheme 1. Formation of an unknown product during simple preparation of biscoumarins 3a.
Compound 4a was separated and fully characterized by IR, 1H
and 13C NMR spectra, and MS. The mass spectrum of 4a displayed
a molecular ion signal at m/z 306 and an ion signal at m/z 186
indicating the loss of the 2-hydroxybenzoyl group. In the 1H NMR
spectrum of compound 4a, in addition to the aromatic protons of
coumarin ring and those assigned to the benzoyl ring
catalytic amounts of iodine and sodium carbonate (entry 11, Table
1). The yields of the reaction under other conditions, such as dif-
ferent oxidants (entries 1e8 and 16e18, Table 1) as well as other
solvents (entries 13e15, Table 1) were all inferior. The presence of
iodine was the pivotal factor for the reaction to proceed and no
reaction occurred without iodine (entries 16e18 in comparison
with entries 5e7, Table 1). In addition, sodium carbonate (Na2CO3)
as a base, gave optimum yield and it was much more efficient than
1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) (entry 11 in comparison to entries 9 and 10,
Table 1).
The best result was obtained with 2 equiv of potassium per-
sulfate, 10 mol % of iodine and 50 mol % of sodium carbonate with
respect to the biscoumarin, in PEG300 at 120 ꢁC in 10 h (entry 11,
Table 1, yield 75%). No improvements were observed upon chang-
ing the reaction time or temperature. When the reaction was per-
formed in the presence of ethanol or water as solvent, yields were
56% and 62%, respectively (entries 13 and 14, Table 1). The yields
were not improved by extending reaction times and formation of
unidentified side products was observed.
(d
¼7.0e8.1 ppm), a sharp singlet due to hydrogen in the furan ring,
which fused to coumarin moiety (7.82 ppm) was observed. Also
a broad singlet at 11.6 ppm due to exchangeable proton of hydroxyl
group was assigned. The most important absorption band of 4a in
the IR spectrum is detected at 1763 and 1630 cmꢀ1 and it is at-
tributed to the two carbonyl stretching frequency. Absorption
bands at 3367 cmꢀ1 are associated with the hydroxyl group. The 1H
decoupled 13C NMR spectrum of 4a showed 18 distinct signals. In
this spectrum, the methine of the furan moiety resonated at
d
¼111.6 ppm and the signal for the two carbonyls was observed at
d¼163.3 and 184.5 ppm. In addition, eight methines and seven
quaternary carbons, all in the aromatic region were in agreement
with the proposed structure. Finally, the structure of compound 4a
was confirmed by single crystal X-ray diffraction (Fig. 1).
The exclusive formation of the unexpected derivatives
4
To examine the efficiency of this reaction, a series of biscou-
marins (3aej) derived from various aldehydes were employed. As
summarized in Table 2, aldehydes with electron-donating sub-
stituents (entries 5 and 7, Table 2) and electron-withdrawing sub-
stituents (entry 4, Table 2) were well tolerated in the reaction. Also,
this protocol can be applied not only to aliphatic and aromatic al-
dehydes with different substitution, but also to heterocyclic alde-
hydes (entries 7e9, Table 2).
prompted our interest in developing a general route to access this
valuable class of compounds. It was noted that a ring opening and
dehydrogenation process were performed under the reaction.
Therefore, our attention turned toward several catalysts and
dehydrogenative reagents to allow for a more efficient and selective
formation of furocoumarin from their corresponding biscoumarin.
We therefore began our work by preparing the requisite

Z. Zareai et al. / Tetrahedron 68 (2012) 6721e6726
6723
Table 1
potassium persulfate and sodium carbonate under optimum con-
dition. Under this condition, we obtained the corresponding furo-
coumarins without significant loss of yield in comparison with
previous method (Scheme 2).
Screening of some catalysts for model reaction
HO
H
O
A plausible mechanism for this reaction is summarized in
Scheme 3. Compounds 4 could be synthesized via sequential
condensation, addition, cyclization, and oxidation. It is conceiv-
able that initially the condensations between 2 equiv of 4-
hydroxycoumarin 1 with aldehydes 2 could give intermediate 3.
This generated biscoumarin could provide compound 5 via lac-
tone ring opening by nucleophilic attack of water, which then
undergoes a decarboxylation. Similar lactone ring opening and
decarboxylation were previously reported.13 In the next step, the
addition of enolate anion 6 to iodine yields compound 7. In this
reaction potassium persulfate can oxidize iodide ion to iodine
and recycle it in the process.14 Finally, intramolecular nucleo-
philic substitution of hydroxyl group to CeI bond in compound 7
gives compound 8, which was oxidized to afford the fully aro-
matized product 4. This type of dehydrogenation is well
precedented.15
H
O
O
OH
O
cat.
solvent
HO
O
O
O
O
4a
3a
Entry Catalyst
Solvent Time Yielda
(5 cc)
(h)
(%)
1
2
3
4
5
6
7
8
I
2 (1 equiv)
I2 (2 equiv)
I2(10 mol %)/O2
I2 (10 mol %)/K2S2O8 (2 equiv)
I2 (10 mol %)/K2S2O8 (2 equiv)
I2 (10 mol %)/oxone (2 equiv)
I2 (10 mol %)/SeO2 (2 equiv)
H2O
H2O
H2O
H2O
12
12
12
12
35
64
32
33
68
58
42
49
45
38
75
58
62
56
51
0
PEG300 12
PEG300 12
PEG300 12
PEG300 12
I2 (10 mol %)/MnO2 (2 equiv)
3. Conclusions
9
I2 (10 mol %)/K2S2O8(2 equiv)/DABCO (0.5 equiv) PEG300 10
I2 (10 mol %)/K2S2O8(2 equiv)/DBU (0.5 equiv) PEG300 10
I2 (10 mol %)/K2S2O8 (2 equiv)/Na2CO3 (0.5 equiv) PEG300 10
I2 (10 mol %)/K2S2O8 (1 equiv)/Na2CO3 (0.5 equiv) PEG300 12
10
11
12
13
14
15
16
17
18
In this work we have reported a facile one-pot synthesis of
furan annulated coumarins via in situ generated biscoumarins,
which offer a convenient and straightforward route to the syn-
thesis of multisubstituted furocoumarin using PEG as a recyclable
solvent. The notable features of this procedure are the application
of an environmentally benign solvent, the cheap oxidant, its
simplicity, and good yields. Also, we have studied the reusability of
the oxidant as well as the solvent, which showed reusability for
a number of cycles (three times) without significant loss of
activity.
I2 (10 mol %)/K2S2O8 (2 equiv)/Na2CO3 (0.5 equiv) H2O
I2 (10 mol %)/K2S2O8 (2 equiv)/Na2CO3 (0.5 equiv) EtOH
6
5
I
2 (10 mol %)/K2S2O8 (2 equiv)/Na2CO3 (0.5 equiv) CH3CN 12
Oxone (2 equiv)
K2S2O8 (2 equiv)
SeO2(2 equiv)
PEG300 12
PEG300 12
PEG300 12
0
0
a
Isolated yield.
In the next step, we looked into the possibility of condensation
of 2 equiv of 4-hydroxycoumrin and aldehydes followed by furo-
coumarin ring formation, under the one-pot oxidative pseudo
three-component condensation. Therefore, 4-hydroxycoumarin 1
was first treated with benzaldehydes 2 in the presence of iodine
(25 mol %) in PEG300 at 80 ꢁC for 0.5e5 h, to generate the corre-
sponding biscoumarins 3, which was then allowed to react with
4. Experimental section
4.1. General method
All commercially available reagents were used without further
purification. Column chromatography was carried out on silica gel
(70e230 mesh). TLC was conducted on silica gel 250 m, F254
plates. Melting points were measured on a Kofler hot stage ap-
paratus and are uncorrected. The IR spectra were taken using
Nicolet FT-IR Magna 550 spectrographs (KBr disks). The mass
spectra were run on a Finnigan Mat TSQ-70 spectrometer at
70 eV. 1H NMR spectra were recorded on a Bruker 400 or
500 MHz NMR instruments. The atoms numbering of the target
compounds used for 1H NMR data are depicted in Scheme 2. The
Table 2
Synthesis of furocoumarins 4
HO
O
R
O
OH
O
O
chemical shifts (d) and coupling constants (J) are expressed in
R
O
K2S2O8
I2, Na2CO3
parts per million and hertz, respectively. Elemental analyses were
carried out with a PerkineElmer model 240-C apparatus. The
results of elemental analyses (C, H, N) were within ꢂ0.4% of the
calculated values.
HO
O
O
O
3a-j
4a-j
Yielda
(%)
4.2. General procedure for the synthesis of compound 4
Entry Compound
R
Time (h) Mp
To a mixture of 4-hydroxycoumarin (2 mmol) and aldehyde
(1 mmol) in PEG (3 mL), catalytic amount of iodine (25 mol %) was
added in ambient temperature. Reaction mixture was heated to
80 ꢁC for several hours (0.5e5 h), after completion of the reaction
(monitored by TLC) and formation of corresponding biscoumarin,
the mixture was cooled and then potassium persulfate (2 equiv)
and sodium carbonate (50 mol %) were added to the reaction
mixture. The mixture was heated to 120 ꢁC until the biscoumarin
disappeared. After completion of the reaction, the mixture was
cooled to room temperature, diluted with ethyl acetate (5 mL),
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
Me
Ph
10
9
17
7
10
9
6
8
3
2
154e156 75
216e218 56
203e205 50
80e82 51
168e170 47
198e200 62
181e183 42
154e156 56
184e186 49
221e223 58
meta-Nitro phenyl
2,5-Dimethoxy phenyl
2-Methoxy-3-nitro phenyl
3-Bromo-4,5-dimethoxy phenyl
Thiophene-2-yl
5-Chlorofuran-2-yl
5-Nitrofuran-2-yl
4j
a
Isolated yield.

6724
Z. Zareai et al. / Tetrahedron 68 (2012) 6721e6726
Scheme 2. Synthesis of furocoumarins by a one-pot oxidative pseudo three-component condensation.
and stirred for 20 min. This process was repeated twice. The
combined ethyl acetate phase was removed under reduced pres-
sure and the resulting crude product was purified by flash chro-
matography (20% ethyl acetate/petroleum ether) to give
corresponding furocoumarins (4ae4j). The mother liquor (PEG/
oxidants/base) was kept aside for further runs and was reused for
a number of cycles (three times) without significant loss of its
activity.
(C9), 125.1 (C8), 130.8 (C60), 132.8 (C7), 137.1 (C40), 151.9 (C4), 153.8
(C11), 157.2 (C2), 159.8 (C20), 163.3 (C12), 184.5 (C]O benzoyl); m/z
(EI) 306 (Mþ, 36), 246 (12), 186 (92), 121(100), 101 (40), 92 (57), 75
(44), 65 (56%).
4.3. Crystal data and structure refinement details of
compound 4a
Single crystals of 4a were prepared by using the branch tube
method in n-hexane/ethyl acetate (10:1) at 45 ꢁC during one week.
The yellowcrystals were filtered off, washed with cold n-hexane, and
4.2.1. 2-(2-Hydroxybenzoyl)-4H-furo[3,2-c]chromen-4-one
(4a). Yield (0.23 g, 75%) as yellow solid, mp 154e156 ꢁC; [Found: C,
70.23; H, 3.44. C18H10O5 requires C, 70.59; H, 3.29%]; nmax (KBr) 3367
16
dried at rt.
C
H10O5, M¼306.26, yellowish platelike block, crystal
18
(OH),1763 (C]O),1629 (C]O) cmꢀ1
;
dH (400 MHz, CDCl3) 7.00 (1H,
dimensions: 0.34ꢃ0.30ꢃ0.06 mm3; orthorhombic, space group
3
ꢁ
ꢁ
0
0
td, J 8.4,1.2 Hz, H5 ), 7.10 (1H, dd, J 8.4,1.2 Hz, H3 ), 7.50 (1H, t, J 8.0 Hz,
Pbca; a¼7.876(2), b¼14.414(3), c¼23.428(5) A; V¼2659.7(10) A ;
T¼100(2) K; Z¼8; rcalcd¼1.530 g cmꢀ3
;
m
¼0.11 mmꢀ1 (for Mo K
a,
0
H8), 7.52 (1H, d, J 8.0 Hz, H6), 7.57 (1H, t, J 8.4 Hz, H4 ), 7.65 (1H, t, J
ꢁ
0
8.0 Hz, H7), 7.82(1H, s, H3), 8.07(1H, dd, J 8.4,1.2 Hz, H6 ), 8.14(1H, d, J
l
¼0.71073 A); F(000)¼1264; reflections collected¼33,860; re-
8.0 Hz, H9), 11.6 (1H, s, OH); dC (100.6 MHz, CDCl3) 111.6 (C10), 111.8
flections independent¼5769 [Rint¼0.034]; reflections observ-
(C10), 117.7 (C3), 118.2 (C30), 118.4 (C13), 118.9 (C6), 119.5 (C50), 122.1
ed¼4066 [I>2
s
(I)];
q
range 2.83e35.09ꢁ; h, k, l range: ꢀ12ꢄhꢄ11,
HO
R
O
OH
OH
O
+
O
-H2O
H
R
O
O
O
O
1 (2 eq)
2
3
O
H
H
HO
O
HO
HO
O
HO
R
O
OH
O
R
OH
O
R
OH
O
O
OH
-CO2
O
O
O
O
5
H
I I
6
5
-2
S2O8
HO
I
HO
HO
R
O
O
O
H
I
H
R
H
O
O
O
O
R
Ox
aromatization
SNi
5-exo-tet
O
O
O
O
O
7
8
4
Scheme 3. A possible mechanism for the formation of compound 4.

Z. Zareai et al. / Tetrahedron 68 (2012) 6721e6726
6725
ꢀ23ꢄkꢄ15, ꢀ35ꢄlꢄ37; full-matrix least-squares on F2; parame-
m/z (EI) 442 (Mþ, 15), 411 (36), 137 (10), 121 (96), 97 (72), 57(100),
41(50%).
ters¼212; restraints¼0; R1¼0.041; wR2¼0.103 [F2>2
s
(F2)];
GooF¼S¼1.01; largest difference in peak and hole, Drmax and
ꢁꢀ3
Drmin¼0.54 and ꢀ0.29 e A . CCDC 856017 contains supplementary
4.3.5. 2-(2-Hydroxybenzoyl)-3-(3-nitro-2-methoxyphenyl)-4H-furo
[3,2-c]chromen-4-one (4f). Yield (0.28 g, 62%) as yellow solid, mp
198e200 ꢁC; [Found: C, 65.31; H, 3.12; N, 3.32. C25H15NO8 requires
C, 65.65; H, 3.31; N, 3.06%]; nmax (KBr) 3417 (OH), 1744 (C]O), 1622
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif or by e-mailing
deposit@ccdc.cam.ac.uk.
(C]O) cmꢀ1
;
dH (500 MHz, CDCl3) 3.98 (1H, s, MeO), 6.95 (1H, t, J
0
0
7.8 Hz, H5 ), 7.05 (1H, t, J 7.7 Hz, H5 phenyl), 7.20 (1H, d, J 7.8 Hz, H3 ),
0
0
4.3.1. 2-(2-Hydroxybenzoyl)-3-methyl-4H-furo[3,2-c]chromen-4-one
(4b). Yield (0.18 g, 56%) as yellow solid, mp 216e218 ꢁC; [Found: C,
71.52; H, 3.97. C19H12O5 requires C, 71.25; H, 3.78%]; nmax (KBr) 3553
7.46 (1H, t, J 7.8 Hz, H4 ), 7.40e7.44 (4H, m, H6 ,8 and H4,6 phenyl),
7.67 (1H, td, J 7.2, 1.5 Hz, H7), 8.02 (1H, dd, J 7.2, 1.5 Hz, H6), 8.16 (1H,
dd, J 7.2, 1.5 Hz, H9), 11.53 (H, s, OH); dC (125 MHz, CDCl3) 56.5
(OMe), 111.7 (C10), 113.7 (C30), 113.9 (C10), 117.7 (C5 phenyl), 118.6
(C6), 119.2 (C50), 119.9 (C13), 121.7 (C9), 122.2 (C8), 124.7 (C1 phe-
nyl),125.0 (C60),131.6 (C4 phenyl and C7),132.8 (C40 and C3 phenyl),
137.0 (C3 and C6 phenyl), 149.9 (C2), 151.7 (C11), 153.7 (C4 and C2
phenyl), 163.5 (C20 and C12), 185.3 (C]O benzoyl).
(OH),1764 (C]O),1629 (C]O) cmꢀ1
;
dH (400 MHz, CDCl3) 2.79 (3H,
0
0
s, CH3), 7.02 (1H, t, J 8.4 Hz, H5 ), 7.09 (1H, d, J 8.4 Hz, H3 ), 7.42 (1H, t,
0
0
J 8.4 Hz, H4 ), 7.44 (1H, d, J 8.4 Hz, H6 ), 7.50 (1H, t, J 8.0 Hz, H8),
7.61(1H, t, J 8.0 Hz, H7), 7.90 (1H, d, J 8.0 Hz, H6), 8.20 (1H, d, J 8.0 Hz,
H9), 12.02 (1H, s, OH); dC (100.6 MHz, CDCl3) 11.1 (Me), 111.8 (C10),
111.9 (C10), 117.6 (C30), 118.7 (C50), 119.0 (C13), 119.1 (C6), 121.6 (C9),
124.9 (C8), 131.4 (C60), 132.4 (C7), 133.1 (C3), 136.4 (C40), 148.3 (C2),
153.7 (C11), 157.5 (C4), 157.9 (C20), 163.6 (C12), 186.3 (C]O
benzoyl).
4.3.6. 2-(2-Hydroxybenzoyl)-3-(3-bromo-4,5-dimethoxyphenyl)-4H-
furo[3,2-c]chromen-4-one (4g). Yield (0.22 g, 42%) as yellow solid,
mp 181e183 ꢁC; [Found: C, 59.72; H, 3.53. C26H17BrO7 requires C,
59.90; H, 3.29%]; nmax (KBr) 3083 (OH), 1760 (C]O), 1629 (C]O)
4.3.2. 2-(2-Hydroxybenzoyl)-3-(phenyl)-4H-furo[3,2-c]chromen-4-
one (4c). Yield (0.19 g, 50%) as yellow solid, mp 203e205 ꢁC;
[Found: C, 75.12; H, 3.41. C24H14O5 requires C, 75.39; H, 3.69%]; nmax
cmꢀ1
; dH (500 MHz, CDCl3) 3.84 (3H, s, MeO), 3.90 (3H, s, MeO),
0
0
6.80 (1H, t, J 8.5 Hz, H5 ), 7.05 (1H, d, J 8.5 Hz, H3 ), 7.01 (1H, d, J
1.3 Hz, H6 phenyl), 7.33 (1H, d, J 1.3 Hz, H2 phenyl), 7.40e7.44 (m,
(KBr) 2922 (OH), 1742 (C]O), 1622(C]O) cmꢀ1
;
dH (500 MHz,
0
2H, H4 ,6 ), 7.52 (1H, d, J 7.7 Hz, H6), 7.66e7.71 (2H, m, H7,8), 8.04 (1H,
d, J 7.7 Hz, H9), 11.52 (1H, s, OH); dC (125 MHz, CDCl3) 56.1 (OMe),
60.6 (OMe), 111.7 (C3 phenyl), 114.2 (C6 phenyl), 117.2 (C10), 117.4
(C30), 118.4 (C6), 118.6 (C10), 119.1 (C50), 121.8 (C9), 124.6 (C13),
125.0 (C8), 126.7 (C2 phenyl), 131.3 (C1 phenyl), 131.8 (C60), 132.7
(C7), 137.0 (C40), 147.0 (C3), 147.2 (C2), 153.0 (C11 and C4 phenyl),
153.5 (C5 phenyl), 156.6 (C4), 158.7 (C20), 163.1 (C12), 186.9 (C]O
benzoyl); m/z (EI) 523 ([Mþ2]þ, 2), 521 (Mþ, 2), 424 (14), 342 (24),
303 (43), 289 (100), 121 (81%).
0
0
0
CDCl3) 6.75 (1H, t, J 8.2 Hz, H5 ), 7.02 (1H, d, J 8.2 Hz, H3 ), 7.41e7.53
0
0
(8H, m, H4 ,6 ,8 and H2,3,4,5,6 phenyl), 7.65 (1H, t, J 7.8 Hz, H7), 7.74
(1H, d, J 7.8 Hz, H6), 8.04 (1H, d, J 7.8 Hz, H9), 11.62 (1H, s, OH); dC
(125 MHz, CDCl3) 111.4 (C10), 117.0 (C30), 117.8 (C6), 118.4 (C8), 121.3
(C50), 124.4 (C9), 127.5 (C10), 127.7 (2C2 phenyl), 127.9 (C13), 128.8
(C60), 129.7 (2C3 phenyl), 131.5 (C4 phenyl), 132.0 (C7), 136.3 (C40),
138.8 (C3 and C1 phenyl), 153.1 (C2, C11, and C4), 162.7 (C12 and
C20), 186.7 (C]O benzoyl).
4.3.3. 2-(2-Hydroxybenzoyl)-3-(3-(nitro)phenyl)-4H-furo[3,2-c]
chromen-4-one (4d). Yield (0.22 g, 51%) as yellow solid, mp
80e82 ꢁC; [Found: C, 67.12; H, 3.32; N, 3.51. C24H13NO7 requires C,
67.45; H, 3.07; N, 3.28%]; nmax (KBr) 3557 (OH), 1761(C]O),
0
4.3.7. 2-(2-Hydroxybenzoyl)-3-(thiophen-2-yl)-4H-furo[3,2-c]chro-
men-4-one (4h). Yield (0.22 g, 56%) as yellow solid, mp
154e156 ꢁC; [Found: C, 68.36; H, 3.47. C22H12O5S requires C, 68.03;
H, 3.11%]; nmax (KBr) 3414 (OH), 1739 (C]O), 1621 (C]O) cmꢀ1
;
dH
0
1624(C]O) cmꢀ1
;
dH (400 MHz, CDCl3) 6.90 (1H, t, J 8.8 Hz, H5 ),
(500 MHz, CDCl3) 6.81 (1H, t, J 8.8 Hz, H5 ), 7.04 (1H, d, J 8.8 Hz, H3 ),
0
0
0
0
0
7.00 (1H, d, J 8.8 Hz, H3 ), 7.47 (1H, t, J 8.8 Hz, H4 ), 7.50e7.52 (2H, m,
0
7.10 (1H, t, J 8.8 Hz, H4 ), 7.50e7.55 (4H, m, H6 ,8, H3,4 thiophen), 7.62
(1H, d, J 3.7 Hz, H5 thiophen), 7.66 (1H, t, J 8.2 Hz, H7), 7.72 (1H, d, J
8.2 Hz, H6), 8.01 (1H, d, J 8.2 Hz, H9), 11.50 (1H, s, OH); dC (125 MHz,
CDCl3) 108.2 (C30), 110.6 (C5),111.9 (C10), 117.4 (C50), 118.4 (C9), 118.7
(C10), 118.9 (C8), 121.3 (C13), 121.8 (C60), 124.7 (C3 thiophen), 124.9
(C4 thiophen), 132.0 (C5 thiophen), 132.5 (C7), 132.7 (C1 thiophen
and C3), 136.8 (C40), 148.6 (C11 and C2), 153.6 (C4), 163.2 (C20 and
C12), 187.2 (C]O benzoyl).
H6 , H8), 7.63 (1H, t, J 7.6 Hz, H5 phenyl), 7.69 (1H, t, J 8.0 Hz, H7), 7.94
(1H, d, J 7.6 Hz, H6 phenyl), 7.90 (1H, d, J 7.6 Hz, H4 phenyl), 8.05 (1H,
d, J 8.0 Hz, H6), 8.30 (1H, d, J 8.0 Hz, H9), 8.47 (1H, s, H2 phenyl), 11.4
(1H, s, OH); dC (100.6 MHz, CDCl3) 111.6 (C10), 117.7 (C30), 118.5
(C10), 118.8 (C2 phenyl), 119.2 (C6), 121.8 (C4 phenyl), 124.0 (C50),
125.1 (C9), 125.5 (C8), 129.0 (C60), 129.9 (C13), 131.0 (C3 and C1
phenyl), 131.6 (C7), 133.0 (C5 phenyl), 136.2 (C6 phenyl), 137.2 (C40),
147.8 (C3 phenyl), 153.7 (C2 and C11), 156.5 (C4), 158.6 (C20), 163.6
(C12), 186.0 (C]O benzoyl).
4.3.8. 2-(2-Hydroxybenzoyl)-3-(5-chlorofuran-2-yl)-4H-furo[3,2-c]
chromen-4-one (4i). Yield (0.20 g, % 49) as yellow solid, mp
184e186 ꢁC; [Found: C, 64.69; H, 2.55. C22H11 ClO6 requires C,
64.96; H, 2.73%]; nmax (KBr) 3438 (OH), 1737 (C]O), 1626 (C]O)
4.3.4. 2-(2-Hydroxybenzoyl)-3-(2,5-dimethoxyphenyl)-4H-furo[3,2-
c]chromen-4-one (4e). Yield (0.21 g, 47%) as yellow solid, mp
168e170 ꢁC; [Found: C, 70.29; H, 4.32. C26H18O7 requires C, 70.58;
cmꢀ1
; dH (500 MHz, CDCl3) 6.29 (1H, d, J 3.4 Hz, H4 furan), 6.83
H, 4.10%]; nmax (KBr) 3413 (OH), 1763 (C]O), 1627(C]O) cmꢀ1
;
dH
0 0
(1H, t, J 8.0 Hz, H5 ), 7.20 (1H, d, J 8.0 Hz, H3 ), 7.43 (1H, t, J 8.0 Hz,
0
0
(500 MHz, CDCl3) 3.58 (3H, s, MeO), 3.78 (3H, s, MeO), 6.69 (1H, t, J
H4 ), 7.50e7.53 (2H, m, H6,6 ), 7.55 (1H, td, J 7.8, 1.5 Hz, H8), 7.60 (1H,
d, J 3.4 Hz, H3 furan), 7.77 (1H, td, J 7.8, 1.5 Hz, H7), 8.00 (1H, dd, J
7.8, 1.5 Hz, H9), 11.61 (1H, s, OH); dC (125 MHz, CDCl3) 108.8 (C4
furan), 111.6 (C10), 117.4 (C3 furan), 118.0 (C30), 118.4 (C5), 119.0
(C50), 119.4 (C10 and C13), 121.9 (C9), 125.0 (C8), 131.6 (C60), 132.7
(C7), 137.0 (C40), 138.3 (C5 furan), 141.6 (C3), 145.6 (C2), 153.4 (C11),
156.7 (C4 and C2 furan), 158.9 (C20), 163.1 (C12), 187.8 (C]O
benzoyl).
0
8.3 Hz, H5 ), 6.74 (1H, d, J 8.9 Hz, H3 phenyl), 6.89 (1H, dd, J 8.9,
0
3.0 Hz, H4 phenyl), 7.01 (1H, d, J 8.3 Hz, H3 ), 7.05 (1H, d, J 3.0 Hz, H6
0
0
phenyl), 7.40e7.43 (2H, m, H4 ,8), 7.49 (1H, d, J 8.3 Hz, H6 ), 7.61 (1H,
t, J 7.7 Hz, H7), 7.70 (1H, d, J 7.7 Hz, H6), 8.05 (1H, d, J 7.7 Hz, H9),
11.54 (1H, s, OH); dC (125 MHz, CDCl3) 55.4 (OMe), 55.8 (OMe),110.6
(C10), 111.6 (C6 phenyl), 112.1 (C10), 116.2 (C3 phenyl), 117.1 (C4
phenyl), 117.4 (C30), 117.9 (C6), 118.1 (C13), 118.7 (C50), 121.7 (C9),
124.7 (C8), 127.6 (C1 phenyl), 131.8 (C60), 132.0 (C3), 132.2 (C7),
136.5 (C40), 147.6 (C2 phenyl), 150.7 (C2), 153.1 (C11), 153.5 (C5
phenyl), 156.5 (C4), 158.5 (C20), 162.6 (C12), 187.5 (C]O benzoyl);
4.3.9. 2-(2-Hydroxybenzoyl)-3-(5-nitrofuran-2-yl)-4H-furo[3,2-c]
chromen (4j). Yield (0.24 g, 58%) as yellow solid, mp 221e223 ꢁC;

6726
Z. Zareai et al. / Tetrahedron 68 (2012) 6721e6726
[Found: C, 63.04; H, 2.95; N, 3.11C22H11 NO8 requires C, 63.32; H,
Supplementary data
2.66; N, 3.36%]; nmax (KBr) 3570 (OH), 1746 (C]O), 1626 (C]O); dH
0
0
(500 MHz, CDCl3) 6.85 (1H, t, J 8.4 Hz, H5 ), 7.15 (1H, d, J 8.4 Hz, H3 ),
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.05.112.
0
7.36 (1H, d, J 3.3 Hz, H3 furan), 7.47 (1H, t, J 8.4 Hz, H4 ), 7.50e7.56
0
0
(2H, m, H8 6 ), 7.62 (1H, d, J 7.8 Hz, H6), 7.70 (1H, t, J 7.8 Hz, H7), 7.73
(1H, d, J 3.3 Hz, H4 furan), 8.02 (1H, d, J 7.8 Hz, H9), 11.50 (1H, s, OH);
dC (125 MHz, CDCl3) 108.7 (C10), 111.1 (C10), 113.8 (C4 furan), 116.2
(C13), 116.6 (C3 furan), 117.0 (C30), 117.2 (C6), 119.0 (C50), 121.8 (C9),
123.8 (C3), 125.3 (C8), 130.5 (C60), 133.1 (C7), 134.6 (C40), 144.8 (C2),
150.0 (C5 furan), 151.5 (C11), 153.0 (C4), 155.9 (C2 furan), 157.6 (C20),
158.0 (C12), 183.1 (C]O benzoyl); m/z (EI) 417 (Mþ, 28), 386 (36),
371 (100), 342 (50), 327 (68), 315(50), 305 (32), 121 (84), 109 (17),
92 (48), 65 (44%).
References and notes
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4.4. X-raydexperimental details
The crystallographic measurement was performed on a
ometry Xcalibur PX four-circle diffractometer with graphite-
monochromatized Mo K radiation ( and scans). Data were
k-ge-
a
u
4
corrected for Lorentz and polarization effects. Data collection, cell
refinement, and data reduction and analysis were carried out with
the Xcalibur PX software, CRYSALIS CCD and CRYSALIS RED, resp. (Oxford
Diffraction Ltd., Abingdon, England, 2009). Empirical absorption
correction was applied to the data with the use of CRYSALIS RED. The
structure was solved by direct methods with the SHELXS-97 program,
and refined using SHELXL-97 17 with anisotropic thermal parameters
for non-H atoms. All H atoms were found in difference Fourier
maps. In the final refinement cycles, all C-bonded H atoms were
treated as riding atoms in geometrically optimized positions, with
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Acknowledgements
This work was financially supported by grants from Research
Council of Tehran University of Medical Sciences and INSF (Iran
National Science Foundation).
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