One-pot synthesis of furocoumarins via sequential Pd/Cu-catalyzed alkynylation and intramolecular hydroalkoxylation

Article abstract of DOI:10.1039/c004233a

A novel and rapid assembly of an interesting class of furocoumarins-4H- furo[3,2-c]chromen-4-ones has been successfully achieved using one-pot sequential coupling/cyclization strategy with easily available starting materials 3-bromo-4-acetoxycoumarins and

Full text of DOI:10.1039/c004233a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
One-pot synthesis of furocoumarins via sequential Pd/Cu-catalyzed
alkynylation and intramolecular hydroalkoxylation†
Lei Chen, Yi Li and Ming-Hua Xu*
Received 16th March 2010, Accepted 26th April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c004233a
A novel and rapid assembly of an interesting class of furocoumarins-4H-furo[3,2-c]chromen-4-ones has
been successfully achieved using one-pot sequential coupling/cyclization strategy with easily available
starting materials 3-bromo-4-acetoxycoumarins and terminal alkynes. The key synthesis involves
Pd/Cu-catalyzed alkynylation with in situ prepared dialkynylzincs followed by intramolecular
hydroalkoxylation.
achieved in one-pot via intramolecular hydroalkoxylation7 after
the corresponding alkynylation of 3-halo-4-hydroxycoumarin in
the presence of same transition-metal catalyst such as palladium
or copper (Scheme 1).
Introduction
Coumarins are an extremely important family of heterocyclic
compounds owing to their presence in a large variety of
biologically active substances and their use as valuable agents
for pharmaceuticals and fine chemicals.1 Over the past several
decades, synthesis and screening of coumarin compounds for
drug discovery has been a vital subject of constant interest
in organic and medicinal chemistry.2 Furocoumarins that
contain
a
common 4H-furo[3,2-c]chromen-4-one scaffold
represent a promising class of synthetic targets because of
their noticeable biological properties.3 In the last few years,
there have been many efforts to develop new approaches for
synthesis of the related scaffolds.4,5 Among them, one-pot
synthesis of furocoumarins has proved to be one of the most
attractive methods, however, only a limited number of reports
are currently known.5 Successful examples including cascade
Scheme 1 New strategy for synthesis of 4H-furo[3,2-c]chromen-4-one.
Results and discussion
addition/cyclization/oxidation
of
3-alkynyl-chromones,5a,b
propargylation/cyclization of 4-hydroxycoumarins,5c,d and
Sonogashira-acetylide coupling/demethylation/cyclization of 3-
iodo-4-methoxy-coumarin,5e but some of these syntheses suffered
from low overall yields or relatively poorer substrate availability.
Methods for the rapid preparation of furocoumarin derivatives
with high reaction efficiency and broad generality are still desired.
Herein, we wish to report our efforts on the development of a
new and efficient synthetic approach for one-pot synthesis of
substituted furocoumarins.
To begin addressing the above hypothesis, we first sought to find
a mild reaction which would allow the easy preparation of key
intermediate 3-halo-4-hydroxycoumarins. It has been reported
that 3-bromo-4-hydroxycoumarin could be generated by treatment
of commercially available 4-hydroxycoumarin with NBS using
Mg(ClO4)2 as a Lewis acid.8 However, perchlorate salts are
potentially explosive and need to be handled with great care. For
safety concern, we turned our attention to other Lewis acids which
might catalyze the C-3 bromination of 4-hydroxycoumarins in a
mild and practical way. Fortunately, after several attempts, when
ZnCl2 combined with NBS in EtOAc was employed, the reaction
underwent smoothly and gave the desired product 3-bromo-4-
hydroxycoumarin 3a with a satisfactory yield of 81% (Scheme 2).
Previously, we have succeeded on straightforward syntheses of
chromeno[3,4-b]pyrrol-4(3H)-one derivatives (pyrrolocoumarins)
by
palladium-catalyzed
sequential
coupling/cyclization
reactions.6 The key strategy relies on creation of a pyrrole
ring through palladium-catalyzed intramolecular hydroamination
of related acetylenic aminocoumarins. In considering the 4H-
furo[3,2-c]chromen-4-one (1) framework, we envisioned that
the similar construction of a furan ring might be subsequently
State key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai
201203, People’s Republic of China. E-mail: xumh@mail.shcnc.ac.cn;
Fax: +86 21 5080 7388; Tel: +86 21 5080 7388
Scheme 2 Improved synthesis of 3-bromo-4-hydroxycoumarins and their
derivatives.
† Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra of compounds 4a–d, 1a–m, and 5. See DOI:
10.1039/c004233a
With the key intermediate 3-bromo-4-hydroxycoumarin 3a
in hand, we then investigated the potential of cascade
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Table 1 Attempts on using alkynylzinc reagents for cross-couplinga
coupling/cyclization, as proposed in Scheme 1, to construct the
designed furocoumarins (4H-furo[3,2-c]chromen-4-ones). Cross-
coupling of 3-bromo-4-hydroxycoumarin 3a with phenylacetylene
was initially examined under Sonogashira9 conditions (Pd(PPh3)4,
◦
CuI, Et3N, THF, 60 C). However, the result was disappointing.
Considerable amount of the debromo coumarin formation was
found, and neither the desired cross-coupling product nor furo-
coumarin was isolated. It appeared that the unprotected electron-
rich hydroxy group at the neighboring C-4 position is responsible
for this undesired C-3 debromination. To address the issue, we
decided to introduce an electron-withdrawing acetyl group to the
hydroxy oxygen. The advantages of this introduction could be
considered as follows: 1) the electron density on the oxygen can
be largely lowered; 2) further activation of the C–Br bond by two
electron-withdrawing groups ortho-acetoxy and -ester carbonyl to
enable smooth alkynylation might be expected; 3) removal of the
acetyl should be easily accomplished in base conditions, making
it feasible to proceed intramolecular alkyne hydroalkoxylation.
Accordingly, the 3-bromo-4-acetoxycoumarins were readily pro-
duced by further treatment of the C-3 bromination products
3-bromo-4-hydroxycoumarins 3 with Ac2O in the presence of
pyridine in one-pot (Scheme 2).
Next, the reaction of 3-bromo-4-acetoxycoumarin 4a with
phenylacetylene was examined. In contrast to the case of 3-
bromo-4-hydroxycoumarin, the expected furocoumarin product
1a was observed, however, the yield was low (8%). To our
delight, the use of 1,1¢-bis(diphenylphosphino)ferrocene (dppf) as
additive was found to be helpful, the reaction gave the desired
furocoumarin in 29% yield together with 14% of cross-coupling
product in 5 h. These results indicate that the expected cascade
coupling/cyclization process occurs and its incompletion may
account for the rather difficult hydrolysis of the acetyl under mild
Sonogashira conditions. Indeed, when an additional hydrolysis
procedure (K2CO3, H2O) was employed in one-pot, a much higher
yield (51%) of furocoumarin 1a was obtained (Scheme 3). Despite
this improvement, the Sonogashira alkynylation appeared to not
be satisfactory.
Pd(PPh3)4- CuI
(mol%)
Entry
1
(mol%) Ligand Yield (%)b
15
15
15
15
dppf
dppf
dppf
trace
15
2
3
15
15
25
4
5
6
7
15
10
15
15
15
10
15
—
dppf
dppf
None
dppf
81
75
38
19
a The cross-coupling reaction was carried out with 4a (0.2 mmol), indicated
phenylethynylzinc reagent (0.3 mmol) in the presence of Pd(PPh3)4
(0.03 mmol), CuI (0.03 mmol), and indicated ligand (0.03 mmol) in distilled
THF (5 mL). b Isolated yield.
can be prepared in situ by direct metallation of 1-alkynes with
Me2Zn.13 To our knowledge, their reactivity in cross-coupling
reactions has been far less explored.14 In 2000, efficient cross-
couplings of corresponding alkynylzinc reagents with unsaturated
organotellurium compounds were described.14c In our case,
when methyl(phenylethynyl)zinc was employed by the catalysis
of Pd(PPh3)4/CuI/dppf, the reaction afforded 1a in 25% yield
(entry 3) together with 34% yield of competitive methylation
product. Gratifyingly, di(phenylethynyl)zinc was found very
effective in the related transformation, generating the cascade
coupling/cyclization product 1a in good yield (81%) under
the same one-pot conditions (entry 4). When the reaction was
carried out in the absence of dppf, only 38% yield was afforded
(entry 6). Our further efforts on ligand screening using (o-tolyl)3P,
1,3-bis(diphenylphosphino)propane (dppp), Xanphos and
(R)-BINAP did not gave better results (< 50% yield). A slight
decrease of the reaction yield (75%) was observed with lowered
catalyst loading of Pd(PPh3)4 and CuI (entry 5). Notably,
the reaction catalyzed without CuI only provided 19% of 1a,
suggesting its important role in the process (entry 7).
Scheme 3 Synthesis of furocoumarin via Sonogashira coupling approach.
In order to achieve better efficiency in the reaction of cross-
coupling step, we envisioned to investigate other alternative
strategies such as Negishi cross-coupling.10 Recently, the use of
preformed metallated alkynes especially alkynylzincs for efficient
alkynylation has proved promising.11 Unfortunately, when the
routine made phenylethynylzinc chloride and bromide were
attempted to react with 3-bromo-4-acetoxycoumarin 4a under
the above same reaction conditions, the desired furocoumarin
1a was not obtained in more than 15% yield (Table 1, entries 1
and 2). In conjunction with our recent interests in asymmetric
alkynylzinc addition to aldehydes,12 we were curious as to whether
the reactive species methylalkynylzinc and dialkynylzinc could
be applied to the expected alkynylation. These zinc acetylides
Consequently, the one-pot cascade coupling/cyclization pro-
cedure for the synthesis of diverse substituted furocoumarins
was examined with 3-bromo-4-acetoxycoumarins 4 and a range
of dialkynylzincs prepared from the corresponding 1-alkynes
using the optimal conditions in Table 1, entry 4, the results are
summarized in Table 2. It was found that both aromatic and
aliphatic alkynes could be typically employed in the reaction
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Table 2 Synthesis of diverse substituted furocoumarins
CuI. Interestingly, InCl3 is also capable of catalyzing the reaction,
but was less effective (entry 5).
Conclusion
In summary, a novel and rapid assembly of an interesting class
of furocoumarins-4H-furo[3,2-c]chromen-4-ones has been suc-
cessfully achieved using one-pot sequential coupling/cyclization
strategy with easily available starting materials 3-bromo-4-
acetoxycoumarins and 1-alkynes. The cascade transformation re-
lies on palladium/copper-catalyzed alkynylation and intramolec-
ular hydroalkoxylation. The use of in situ prepared dialkynylzincs
as reactive acetylides in transition-metal catalyzed cross-coupling
reactions was rarely reported, our current study provides an
important alternative route to form C(sp2)-C(sp) bond. We
anticipate that this approach would be useful for providing a
valuable source of new physiologically active coumarin agents.
Further research to investigate the utility of current methodology
is underway.
Entrya
R1
R2
1
Yield (%)b
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
6-Me
7-BnO
6-BnO
6-Me
7-BnO
C6H5
1a
1b
1c
1d
1e
1f
1g
1h
1i
81
66
91
76
54
65
64
53
96
88
67
60
51
4-t-BuC6H4
4-MeOC6H4
3,5-(MeO)2C6H3
3,4,5-(MeO)3C6H2
t-Bu
n-Bu
1-Cyclohexenyl
C6H5
9
10
11
12
13
C6H5
1j
1k
1l
4-t-BuC6H4
4-t-BuC6H4
4-FC6H4
1m
a The cross-coupling reaction was carried out with alkyne (0.6 mmol),
ZnMe2 (1.2 M in toluene, 0.25 mL, 0.3 mmol), and 4 (0.2 mmol) in the
presence of Pd(PPh3)4 (0.03 mmol), CuI (0.03 mmol), dppf (0.03 mmol) in
distilled THF (5 mL). b Isolated yield.
Experimental
General procedure for synthesis of 3-bromo-4-acetoxycoumarins
(4)
A mixture of 4-hydroxycoumarin compound 2 (1 mmol), NBS
(1.1mmol) and ZnCl2 (0.5–1 mmol) in EtOAc (5 mL) was stirred
at room temperature until TLC indicated consumption of the
starting material 2. The reaction solution was cooled to 0 ◦C,
then pyridine (1.5 mmol) and acetic anhydride (1.2 mmol) were
added, and the stirring was maintained for another 0.5 h. The
mixture was diluted with EtOAc, filtered through a short silica gel
layer and concentrated under vacuum. The residue was purified by
column chromatography (petroleum ether/CH2Cl2, 1/1) on silica
gel to afford product 4 as white solid.
Table 3 Cyclization of coupling intermediate
Entrya Conditions
Time/h Yieldb
1
2
3
4
5
K2CO3/H2O, THF, reflux
15 mol% Pd(PPh3)4, K2CO3/H2O, THF, reflux 18
15 mol% CuI, K2CO3/H2O, THF, reflux
5 mol% CuI, K2CO3/H2O, THF, reflux
15% InCl3, K2CO3/H2O, THF, reflux
24
0
45
91
46
39
3-Bromo-4-acetoxycoumarin (4a). 0.5 mmol ZnCl2 was used.
18
36
36
1
75% yield. H NMR (300 MHz, CDCl3) d 2.50 (s, 3H), 7.31–
7.65 (m, 4H); 13C NMR (100 MHz, CDCl3) d 20.5, 104.7,
115.9, 116.7, 122.6, 124.9, 133.0, 151.7, 157.6, 157.7, 165.3. MS
(ESI) m/z: 305/307 [M+Na]+/[M+2+Na]+. ESI-HRMS calcd for
C11H7BrNaO4 [M+Na]+ 304.9425, found 304.9432.
a Reaction was performed with 5 in 0.1 mmol scale in distilled THF (5 mL).
b Isolated yield.
3-Bromo-4-acetoxy-6-methylcoumarin (4b). 0.5 mmol ZnCl2
was used. 77% yield. 1H NMR (300 MHz, CDCl3) d 2.41 (s, 3H),
2.50 (S, 3H), 7.23–7.41 (m, 3H); 13C NMR (100 MHz, CDCl3) d
20.5, 20.9, 104.8, 115.8, 116.7, 122.2, 134.1, 135.0, 150.1, 157.6,
158.0, 165.5. IR (KBr): n 1790, 1726, 1618, 1570, 1163, 1078, 997,
824 cm-1. MS (ESI) m/z: 319/321 [M+Na]+/[M+2+Na]+.
sequence. Regardless of the substituent pattern and the electronic
property of R2, the desired furocoumarin products could be
obtained in moderate to good yields (entries 1–8). Moreover, the
reactions with 6- and 7-substituted coumarins were also feasible
(entries 9–13).
To gain some preliminary understanding of the step of
hydroalkoxylation, we further investigated the cyclization of
coupling product 5 under several different reaction conditions
(Table 3). A control experiment was performed by treatment with
K2CO3/H2O in THF at 60 ◦C, demonstrating that in the absence
of transition-metal catalyst no furocoumarin product 1i could be
observed (entry 1). Indeed, the use of catalytic amount of either
Pd(PPh3)4, or CuI assisted the hydroalkoxylation (entries 2–4).
As indicated, CuI appeared to have superior catalytic efficiency,
affording the desired product in high yield (91%, entry 3).
Thus, we assume at present the actual transformation in the
cascade procedure was cooperatively catalyzed by Pd(PPh3)4 and
3-Bromo-4-acetoxy-6-benzyloxycoumarin (4c). 1.0 mmol
1
ZnCl2 was used. 58% yield. H NMR (300 MHz, CDCl3) d 2.46
(s, 3H), 5.09 (s, 2H), 6.95 (d, J = 3.0 Hz, 1H), 7.22–7.44 (m, 7H);
13C NMR (100 MHz, CDCl3) d 20.6, 70.9, 105.5, 106.8, 116.6,
118.1, 120.9, 127.5, 128.4, 128.7, 135.9, 146.4, 155.6, 157.3, 157.9,
165.2. IR (KBr): n 1792, 1728, 1570, 1441, 1275, 1165, 1022 cm-1.
MS (ESI) m/z: 411/413 [M+Na]+/[M+2+Na]+.
3-Bromo-4-acetoxy-7-benzyloxycoumarin (4d). 1.0 mmol
ZnCl2 was used. 60% yield. 1H NMR (300 MHz, CDCl3) d
2.47 (s, 3H), 5.13 (s, 2H), 6.92–6.97 (m, 2H), 7.37–7.42 (m, 6H);
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13C NMR (100 MHz, CDCl3) d 20.6, 70.7, 101.2, 101.8, 109.7,
114.0, 123.9, 127.5, 128.5, 128.7, 135.3, 153.7, 157.9, 158.3, 162.7,
165.4. IR (KBr): n 1774, 1716, 1606, 1367, 1184, 1086 cm-1. MS
(ESI) m/z: 411/413 [M+Na]+/[M+2+Na]+.
3H), 3.95 (s, 6H), 6.99 (s, 2H), 7.09 (s, 1H), 7.34–7.97 (m, 4H);
13C NMR (100 MHz, CDCl3) d 56.3, 61.0, 101.9, 102.4, 112.5,
112.6, 117.4, 120.7, 124.4, 124.5, 130.5, 139.1, 152.5, 153.7, 156.4,
156.6, 158.1. IR (KBr): n 2943, 1743, 1591, 1497, 1413, 1242,
1126, 754 cm-1. MS (ESI) m/z: 353 [M+H]+. ESI-HRMS calcd for
C20H16NaO6 [M+Na]+ 375.0844, found 375.0856.
General procedure for synthesis of furocoumarins (1)
2-tert-Butyl-4H-furo[3,2-c]chromen-4-one (1f). 65% Yield,
Under nitrogen atmosphere, alkyne (0.6 mmol), freshly distilled
THF (5 mL) and ZnMe2 (1.2 M in toluene, 0.25 mL, 0.3 mmol)
were successively added into a dry flask. The reaction mixture was
stirred at 60 ◦C for 4 h and then cooled to room temperature. The
solution was transferred by cannula under nitrogen into another
dry flask charged with 3-bromo-4-acetoxycoumarin 4 (0.2 mmol),
Pd(PPh3)4 (0.03 mmol), dppf (0.03 mmol), CuI (0.03 mmol). The
mixture was heated at 60 ◦C for 6 h. 0.5 mL of degassed saturated
aqueous solution of K2CO3 was subsequently added and the
1
white solid. H NMR (300 MHz, CDCl3) d 1.39 (s, 9H), 6.56 (s,
1H), 7.33–7.87 (m, 4H); 13C NMR (100 MHz, CDCl3) d 28.8, 33.1,
100.7, 111,2, 113.0, 117.2, 120.6, 124.3, 130.1, 152.3, 156.5, 158.6,
167.7. IR (KBr): n 2966, 2872, 1741, 1633, 1576, 1502, 1363, 1059,
966, 746 cm-1. MS (ESI) m/z: 243 [M+H]+. ESI-HRMS calcd for
C15H14NaO3 [M+Na]+ 265.0840, found 265.0846.
2-Butyl-4H-furo[3,2-c]chromen-4-one (1g). 64% Yield, brown
1
gum. H NMR (300 MHz, CDCl3) d 0.96 (t, J = 7.5 Hz, 3H),
◦
reaction was stirred at 60 C overnight. The mixture was cooled
1.37.1.77 (m, 4H), 2.79 (t, J = 7.5 Hz, 2H), 6.57 (s, 1H), 7.29–7.84
(m, 4H); 13C NMR (100 MHz, CDCl3) d 13.7, 22.1, 27.7, 29.6,
103.2, 111.3, 112.9, 117.1, 120.5, 124.3, 130.0, 152.2, 156.4, 158.4,
160.0. IR (KBr): n 3118, 2953, 2868, 1734, 1628, 1587, 1500, 1161,
966, 756 cm-1. MS (ESI) m/z: 243 [M+H]+. ESI-HRMS calcd for
C15H14NaO3 [M+Na]+ 265.0840, found 265.0845.
to room temperature and diluted with EtOAc, washed with water.
The organic layer was filtered through a short silica gel layer, dried
over Na2SO4 and concentrated under vacuum. The residue was
purified by column chromatography (petroleum ether/EtOAc) on
silica gel to afford product 1.
2-Phenyl-4H-furo[3,2-c]chromen-4-one (1a). 81% Yield, yel-
low solid. 1H NMR (300 MHz, CDCl3) d 7.16 (s, 1H), 7.34–7.95
(m, 9H); 13C NMR (100 MHz, CDCl3) d 102.5, 112.3, 112.5, 117.2,
120.6, 124.4, 124.5, 128.7, 128.9, 129.0, 130.5, 152.4, 156.4, 156.6,
158.1. IR (KBr): n 3107, 1736, 1633, 1487, 1425, 1186, 1057,962,
748, 690 cm-1. MS (ESI) m/z: 263 [M+H]+. ESI-HRMS calcd for
C17H10NaO3 [M+Na]+ 285.0527, found 285.0533.
2-Cyclohexenyl-4H-furo[3,2-c]chromen-4-one (1h). 53% Yield,
white solid. H NMR (300 MHz, CDCl3) d 1.64–1.84 (m, 4H),
1
2.25–2.35 (m, 4H), 6.57–6.60 (m, 1H), 6.64 (s, 1H), 7.29–7.86 (m,
4H); 13C NMR (100 MHz, CDCl3) d 21.8, 22.0, 24.6, 25.2, 100.9,
111.8, 112.7, 117.1, 120.6, 124.4, 126.0, 126.6, 130.2, 152.4, 156.1,
157.9, 158.4. IR (KBr): n 2926, 2852, 1743, 1645, 1630, 1498, 1059,
966, 754 cm-1. MS (ESI) m/z: 267 [M+H]+. ESI-HRMS calcd for
C17H14NaO3 [M+Na]+ 289.0840, found 289.0845.
2-(4-tert-Butylphenyl)-4H-furo[3,2-c]chromen-4-one (1b). 66%
1
Yield, yellow solid. H NMR (300 MHz, CDCl3) d 1.36 (s, 9H),
8-Methyl-2-phenyl-4H-furo[3,2-c]chromen-4-one
(1i). 96%
7.13 (s, 1H), 7.34–7.97 (m, 8H); 13C NMR (100 MHz, CDCl3) d
31.2, 34.8, 102.0, 112.5, 112.8, 117.3, 120.8, 124.4, 124.5, 125.96
(2C), 126.2, 130.5, 152.5, 156.7, 156.9, 158.4. IR (KBr): n 3113,
2964, 1743, 1626, 1184, 1068, 968, 752 cm-1. MS (ESI) m/z: 319
[M+H]+. ESI-HRMS calcd for C21H19O3 [M+H]+ 319.1334, found
319.1339.
1
Yield, yellow solid. H NMR (300 MHz, CDCl3) d 2.44 (s, 3H),
7.08 (s, 1H), 7.26–7.45 (m, 5H), 7.64 (s, 1H), 7.73–7.75 (m, 2H);
13C NMR (100 MHz, CDCl3) d 20.9, 102.5, 112.25 (2C), 117.0,
120.4, 124.4, 128.8, 128.9, 129.0, 131.6, 134.4, 150.7, 156.3, 156.8,
158.3. IR (KBr): n 1738, 1637, 1570, 1506, 1488, 1428, 979,
755 cm-1. MS (ESI) m/z: 277 [M+H]+. ESI-HRMS calcd for
C18H13O3 [M+H]+ 277.0864, found 277.0866.
2-(4-Methoxyphenyl)-4H-furo[3,2-c]chromen-4-one (1c). 91%
1
Yield, yellow solid. H NMR (300 MHz, CDCl3) d 3.87 (s, 3H),
7-(Benzyloxy)-2-phenyl-4H-furo[3,2-c]chromen-4-one
(1j).
6.98 (d, J = 8.7 Hz, 2H), 7.02 (s, 1H), 7.33–7.53 (m, 3H), 7.76
(d, J = 8.7 Hz, 2H), 7.91–7.94 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 55.4, 100.9, 112.5, 112.8, 114.4, 117.3, 120.6, 121.7,
124.5, 126.1, 130.3, 152.4, 156.3, 156.7, 158.4, 160.3. IR (KBr):
n 2955, 1747, 1612, 1495, 1265, 1178, 1072, 972, 824, 748 cm-1.
MS (ESI) m/z: 263 [M+Na]+. ESI-HRMS calcd for C18H12NaO4
[M+Na]+ 315.0633, found 315.0640.
1
88% Yield, yellow solid. H NMR (300 MHz, CDCl3) d 5.13
(s, 2H), 7.00–7.04 (m, 2H), 7.11 (s, 1H), 7.33–7.84 (m, 11H);
13C NMR (100 MHz, CDCl3) d 70.4, 102.4, 106.2, 110.0, 113.4,
121.7, 124.3, 127.5, 128.31 (2C), 128.7, 128.8, 128.9, 128.9, 135.7,
154.1, 155.6, 157.4, 158.5, 160.9. IR (KBr): n 3099, 2924, 1736,
1628, 1608, 1510, 1439, 1256, 1157, 1105, 1013, 760, 694 cm-1.
MS (ESI) m/z: 369 [M+H]+. ESI-HRMS calcd for C24H16NaO4
[M+Na]+ 391.0946, found 391.0947.
2-(3,5-Dimethoxyphenyl)-4H-furo[3,2-c]chromen-4-one
(1d).
1
76% Yield, yellow solid. H NMR (300 MHz, CDCl3) d 3.83
(s, 6H), 6.43 (s, 1H), 6.86 (s, 1H), 6.87 (s, 1H), 7.08 (s, 1H),
7.31–7.90 (m, 4H); 13C NMR (100 MHz, CDCl3) d 55.4, 101.0,
102.6, 103.0, 112.3, 112.5, 117.2, 120.7, 124.5, 130.4, 130.5,
152.5, 156.2, 156.6, 158.0, 161.1. IR (KBr): n 2922, 1738, 1633,
1597, 1568, 1452, 1205, 1159, 1068, 750 cm-1. MS (ESI) m/z:
323 [M+H]+. ESI-HRMS calcd for C19H15O5 [M+H]+ 323.0919,
found 323.0928.
8-(Benzyloxy)-2-(4-tert-butylphenyl)-4H-furo[3,2-c]chromen-4-
one (1k). 67% Yield, yellow solid. 1H NMR (300 MHz, CDCl3)
d 1.37 (s, 9H), 5.18 (s, 2H), 7.12 (s, 1H), 7.13 (d, J = 3.0 Hz,
1H), 7.16 (d, J = 3.0 Hz, 1H), 7.36–7.52 (m, 8H), 7.74 (d, J =
8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 31.2, 34.8, 70.8,
102.1, 104.2, 112.7, 113.1, 118.5, 118.9, 124.4, 126.0, 126.2, 127.6,
128.3, 128.7, 136.3, 147.1, 152.5, 155.4, 156.5, 156.9, 158.4. IR
(KBr): n 2960, 1728, 1568, 1495, 1211, 1057, 995, 758, 700 cm-1.
MS (ESI) m/z: 425 [M+H]+. ESI-HRMS calcd for C28H24NaO4
[M+Na]+ 447.1572, found 447.1585.
2-(3,4 5-Trimethoxyphenyl)-4H-furo[3,2-c]chromen-4-one (1e).
1
54% Yield, yellow solid. H NMR (300 MHz, CDCl3) d 3.90 (s,
3076 | Org. Biomol. Chem., 2010, 8, 3073–3077
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2-(4-tert-Butylphenyl)-8-methyl-4H-furo[3,2-c]chromen-4-one
(1l). 60% Yield, yellow solid. 1H NMR (300 MHz, CDCl3)
d 1.36 (s, 9H), 2.48 (S, 3H), 7.12 (s, 1H), 7.32–7.76 (m, 7H);
13C NMR (100 MHz, CDCl3) d 21.0, 31.2, 34.8, 102.0, 112.4,
112.5, 117.1, 120.5, 124.4, 125.93 (2C), 126.2, 131.5, 134.4, 150.7,
152.4, 156.7, 158.6. IR (KBr): n 3109, 2962, 1736, 1633, 1570,
1493, 1182, 980, 916, 822, 768, 555 cm-1. MS (ESI) m/z: 333
[M+H]+. ESI-HRMS calcd for C22H21O3 [M+H]+ 333.1490, found
333.1496.
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7-(Benzyloxy)-2-(4-fluorophenyl)-4H-furo[3,2-c]chromen-4-one
1
(1m). 51% Yield, yellow solid. H NMR (300 MHz, CDCl3) d
5.13 (s, 2H), 6.99–7.82 (m, 13H); 13C NMR (100 MHz, CDCl3)
d 70.4, 102.1, 102.4, 106.2, 110.0, 113.5, 116.1 (d, J = 22.0 Hz),
121.7, 125.4, 126.2 (d, J = 8.1 Hz), 127.5, 128.4, 128.7, 135.7,
154.2, 154.7, 157.4, 158.4, 161.0, 162.9 (d, J = 248.5 Hz). IR
(KBr): n 3111, 2929, 1736, 1628, 1605, 1512, 1497, 1448, 1256,
1232, 1155, 1105, 1011, 833, 700 cm-1. MS (ESI) m/z: 387
[M+H]+. ESI-HRMS calcd for C24H16FO4 [M+H]+ 387.1032,
found 387.1039.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (20721003), the Shanghai Rising-Star Program
(08QH14027), the Chinese Academy of Sciences, State key
Laboratory of Drug Research, SIMM and National Science &
Technology Major Project (2009ZX09301-001) is acknowledged.
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The Royal Society of Chemistry 2010
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