Novel synthesis of substituted furo[3,2- c ]chromen-4-ones via four-component reaction from substituted nitrostyrenes, aromatic aldehydes, coumarins, and ammonium acetate

Article abstract of DOI:10.1021/co4000419

An efficient and direct synthesis of 2-arylideneamino-3-aryl-4H-furo[3,2-c] chromen-4-ones has been developed via four-component reaction from substituted nitrostyrenes, aromatic aldehydes, coumarins, and ammonium acetate under very mild conditions, which involves sequentially a Michael addition, an aza-nucleophilic addition, of the imine to the double bond, an intermolecular nucleophilic addition and a dehydration reaction. The resulting biologically intriguing structures could have broad applications in related biomedical-program structures.

Full text of DOI:10.1021/co4000419

Research Article
pubs.acs.org/acscombsci
Novel Synthesis of Substituted Furo[3,2‑c]chromen-4-ones via Four-
component Reaction from Substituted Nitrostyrenes, Aromatic
Aldehydes, Coumarins, and Ammonium Acetate
Zhengquan Zhou, Hui Liu, Yun Li, Juanjuan Liu, Yan Li, Jinliang Liu, Juan Yao, and Cunde Wang*
School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou 225002, Jiangsu, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and direct synthesis of 2-
arylideneamino-3-aryl-4H-furo[3,2-c]chromen-4-ones has
been developed via four-component reaction from substituted
nitrostyrenes, aromatic aldehydes, coumarins, and ammonium
acetate under very mild conditions, which involves sequentially
a Michael addition, an aza-nucleophilic addition, of the imine
to the double bond, an intermolecular nucleophilic addition and a dehydration reaction. The resulting biologically intriguing
structures could have broad applications in related biomedical-program structures.
KEYWORDS: furo[3,2-c]chromenes, substituted nitrostyrenes, multicomponent reactions, Michael reaction, cyclizations, heterocycles,
Schiff base
particular interest since they exhibit potent biological and
pharmacological activity.7
In addition, Schiff bases are important class of compounds
that show vast biological applications.8 Also the combination of
several heterocycles with Schiff base moieties has been
reported.9
INTRODUCTION
■
The coumarin ring is a key structural unit for numerous natural
products, synthetic pharmaceuticals, and a wide variety of
biologically active compounds.1 Many synthetical coumarin
compounds with the π-conjugated lactone−(hetero)aryl motifs
as the fluorescent core objects have been frequently used in
molecular materials such as optical brightening agents,3
dispersed fluorescent and laser dyes.2 Coumarin derivatives
have also been used as food additives and perfumes.3 Recently,
coumarins fused with (hetero)aryl frameworks as candidates
with potential pharmaceutical activity have attracted consid-
erable attention. Studies have revealed that a number of
biologically important properties of the coumarins fused with
(hetero)aryl frameworks are dependent upon structural features
of the (hetero)aryl framework. Chemical modification of the
(hetero)aryl framework provides a way to alter the functional
groups, sizes, and stereochemistry of the coumarin derivatives,
and numerous structure−activity relationships have been
established by such synthetic alterations. For example, modified
coumarin deriviatives have exhibited a broad range of biological
activities as potent anti-HIV agents and anticancer agents.4
Similarly, the furan ring also is a common structural motif in
many biologically active molecules and natural products, furans
being widely employed as versatile building blocks in synthetic
organic chemistry.5 The important role played by these five-
membered heterocycles in the field of flavors and fragrances
should also be highlighted.6 Furan derivatives on the other
hand are known to have wide applications as drugs and
pharmaceuticals. A combination of chromene with a furan
moiety in a single molecule has also been explored for the
identification of promising bioactive molecules. Among them,
furochromen-4-ones (furocoumarins), tricyclic systems in
which a furan ring is fused to the chromen-2-one unit, are of
The development of efficient syntheses of these bioactive
heterocycles bearing Schiff base moieties has thus attracted
organic and medicinal chemists for decades. Although several
general approaches are presently available, such as the classical
name reaction, Paal−Knorr synthesis, the search for new
methodologies proceeding more efficiently and involving
readily available starting materials still remains an active area
of research. During the past decade, many efficiently synthetic
routes to furochromen-4-ones have been developed. Among
others, relevant contributions to this field have recently
emerged with the aid of transition-metal catalysts, such as
CAN, rhodium, or palladium catalysts because they allow the
construction of complex furochromen-4-ones from readily
available chromenes with terminal alkynes under mild
conditions.10 More recently, Lin and co-workers reported that
furo[3,2-c]coumarin derivatives were synthesized starting from
highly functional phosphorus zwitterions as synthetic reagents
with commercially available acid chlorides in a one-step
procedure.11 Nair and co-workers reported a novel procedure
for the synthesis of furocoumarin via a three-component
reaction of 4-hydroxycoumarin with aryl aldehydes and
cyclohexyl isocyanide in refluxing benzene.12 Afterward, Wu
developed the reaction of aryl isocyanides and aldehydes with
Received: April 12, 2013
Revised: June 8, 2013
© XXXX American Chemical Society
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common 4-hydroxycoumarin as a starting material to furnish
functionalized furo[3,2-c]chromen-4-ones in excellent yields
under microwave irradiation.13
RESULTS AND DISCUSSION
■
Our initial test reaction was run by mixing 1-nitro-2-(p-
fluorophenyl)ethane{1}, p-methoxybenzaldehyde{1}, 4-
hydroxycoumarin{1}, and ammonium acetate together without
any catalyst or promoter in methanol at room temperature for
24 h, but no reaction occurred (Table 1, entry 1). It is known
that bases can promote the Michael-type reaction, but both
inorganic weak base K2CO3 and Cs2CO3, strong base NaOH
did not afford the desired reaction. Piperidine was also used in
the same reaction to no avail even though the reaction was
carried out under reflux. Reconsidering the possible mechanism
of our expected one-pot reaction, we knew that the Michael
addition of 4-hydroxycoumarin{1} to α,β-nitroalkenes is a key
step. However, the reported studies showed the Michael
addition adducts easily cyclized to form a dihydrofuran ring in
the presence of an inorganic base, thus the C2-substitution
failed. The experimental procedure was improved by mixing
equimolecular amounts of 1-nitro-2-(p-fluorophenyl)ethane{1}
and 4-hydroxycoumarin{1} together with the catalyst piper-
idine. The resultant mixture was stirred for 12 h at room
temperature followed by the addition of p-
methoxybenzaldehyde{1}and ammonium acetate with stirring
for 12 h at room temperature. The final mixture was refluxed
for 2h. This modified method gave better results to the one-pot
reaction (Table 1, entry 8). Interestingly, no reaction was
observed without ammonium acetate (Table 1, entry 9),
suggesting it was integral to the reaction. Encouraged by these
results, the reaction conditions were then screened with the aim
of optimizing the yield of 4a. It was observed that 4a could be
obtained in 46% yield when piperidine (50 mol %) and
ammonium acetate (1.0 equiv.) were subjected to the reaction
at room temperature for 24 h and then refluxed for 2 h (Table
1, entry 10). 1.5 Equiv. of ammonium acetate accelerated the
reaction and improved the yield (Table 1, entry 11). Further
increase of the amount of piperidine and ammonium acetate
had no significant beneficial effect on the reaction. Extending
the reflux time to 3 h resulted in a slightly higher yield (Table 1,
entry 12). Triethylamine was also examined as a basic additive
in the reaction, but was less effective than piperidine (Table 1,
entry 14). The reaction of 1-nitro-2-(p-fluorophenyl)ethane
{1}, p-methoxybenzaldehyde {1}, 4-hydroxy coumarin {1}, and
ammonium acetate could proceed in other solvents, such as
ethanol, acetonitrile and DMF (Table 1, entries 15−17).
Among those tested, methanol proved to be the best. The use
of ethanol is similarly effective as methanol.
In the same way, using 4-hydroxycoumarin as a starting
material, heating a mixture of 4-hydroxycoumarin, an
isocyanide, and an aldehyde at high temperature (180 °C)
under an argon atmosphere and solvent-free conditions also
afforded furo[3,2-c]chromen-4-ones.14 Additionally, Shafiee
and co-workers also described an appealing strategy to directly
construct furo[3,2-c ]coumarin core via a one-pot oxidative
pseudo three-component condensation of aldehydes and 4-
hydroxycoumarin (2 equiv) in poly(ethyleneglycol) (PEG) as
solvent using a mixture of I2 and K2S2O8 as an oxidative
reagent.15 It is known that multicomponent reactions as an
efficient synthetic strategy have drawn considerable attention
over the past decades, because complex products are formed in
a one-pot reaction and diversity can be simply attained by
relatively simple starting materials.16 However there are only a
few one-pot multicomponent reactions for the construction of
structurally and stereochemically diverse 2-alkylamino-3-aryl-
furo[3,2-c]chromen-4-ones.12−14 Recently, as a useful building
block for the formation of carbon−carbon bond, α,β-nitro-
alkenes were employed in synthesis of many important
heterocyclic compounds.17 The Michael addition of activated
methylenes to α,β-nitroalkenes is an efficient synthetic tool for
the formation of C−C bonds, which provides easy access to
synthetically important nitroalkanes.18 The transformation of
the corresponding adducts could yield a variety of useful
synthetic intermediates. Recently, we reported a straightforward
one-pot, multicomponent synthesis of polysubstituted piper-
idines using nitrostyrenes as essential building blocks with
aromatic aldehydes, dialkyl malonates, and ammonium
acetate.19 However, to our knowledge, there is no direct
method available for one-pot synthesis of 2-alkylamino-3-
arylfuro[3,2-c]chromen- 4-ones using nitrostyrenes as a
building block with commercially available 4-hydroxycoumarin.
It is known that 4-hydroxy coumarins, because of their
tautomeric existence, act as cyclic β-keto esters. The active
methylene group of such cyclic β-keto esters could be used for
the Michael addition of nitro-alkenes as Michael acceptors.20
Hence, we envisioned the Michael addition of 4-hydroxycou-
marins to α,β-nitroalkenes, keto−enol tautomerism, an intra-
molecular cyclization and aromatization in a single operation.
As a part of our continuous interest directed toward the
development of new methodologies using nitrostyrenes as
essential building blocks for the synthesis of 2-alkylamino-3-
arylfuro[3,2-c]chromen-4-ones, we report the results of our
recent efforts devoted to efficient one-pot, multicomponent
reactions from substituted nitrostyrenes 1 (Figure 1), aromatic
aldehydes 2 (Figure 2), 4-hydroxycoumarin 3 (Figure 3), and
ammonium acetate for the direct formation of substituted
furo[3,2-c]chromene ring bearing Schiff base moiety.
A series of experiments revealed that the optimal results were
obtained when the reaction of 1-nitro-2-(p-fluorophenyl)-
ethane{1}(1.0 equiv) and 4-hydroxy coumarin{1} (1.0 equiv)
together with 50 mol % piperidine was mixed, the resultant
mixture was stirred for 12 h at room temperature, followed by
addition of p-methoxybenzaldehyde{1}(1.0 equiv) and ammo-
nium acetate (1.0 equiv), then stirring for 12 h at room
temperature, the final mixture was refluxed for 3h, whereby the
yield of 4a{1,1,1} reached 62% (Table 1, entry 12).
Having established the optimal conditions for the synthesis
of 4a {1,1,1}, to determine the scope of the protocol, a number
of commercially available aldehydes 2{1−9} and substituted
nitrostyrenes 1{1−6} generated from aromatic aldehydes and
nitromethane were condensed with 4-hydroxy-2H-chromen-2-
one 3{1}, and ammonium acetate under optimized reaction
condition. The results are summarized in Table 2. Both
electron-deficient and electron-rich aromatic aldehydes were
Figure 1. Diversity of substituted nitrostyrenes 1{1−6}.
B
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Figure 2. Diversity of aromatic aldehydes 2{1−9}.
intramolecular nucleophilic addition in 2-azaallene cation gave
dihydrofuro[3,2-c]chromen-4-one (Scheme 1, F), further
aromatization afforded the title 2-alkylamino-3-aryl-4H-furo-
[3,2-c]chromen-4-ones. These title compounds with an imine
are stable in the reaction process and post treatment because
the electron-rich furan ring stables a carbon−nitrogen double
bond of the imine. We tested two-component reaction of m-
methoxynitrostyrene and 4-hydroxycoumarin in the above same
conditions. 2,3-Dihydro-2-(hydroxyimino)-3-(3-
methoxyphenyl)furo [3,2-c]chromen- 4-one (5) was obtained
in low yield of 45% (Scheme 2), which was mixed with
ammonium acetate and p-methoxybenzaldehyde. Then the
reaction was carried out again in the presence of piperidine
using methanol as solvent, but no reaction occurred. Obviously,
this result indicated the four-component reaction from
substituted nitrostyrenes, aromatic aldehydes, coumarins, and
ammonium acetate did not give dihydro-2-(hydroxyimino)-
furo[3,2-c]chromen-4-one first, followed by the reaction with
ammonium acetate and aryl aldehyde to form the desirable
products.
Figure 3. 4-Hydroxy-2H-chromen-2-one 3{1}.
similarly viable affording the products in moderate to good
yields. The structures of all compounds were elucidated with
1
the aid of H and 13C NMR. The structure of compound
4r{6,2,1} was determined by X-ray crystallographic analysis
(Figure 4).22
The reaction mechanism shown in Scheme 1 is proposed.
First, the Michael addition of 4-hydroxycoumarin to the
substituted nitrostyrene formed 3-(1-aryl-2-nitroethyl) 4-
hydroxycoumarin (Scheme 1, A), which is followed by base-
promoting deprotonation to form a resonance-stabilized N-
oxide oxime (Scheme 1, B). Next, intermediate arylimine
nucleophilic addition to N-oxide oxime (Scheme 1, B) gave an
intermediate N-oxide hydroxyamine (Scheme 1, C), following
dehydration yielded 2-nitroso Schiff base (Scheme 1, D). Then
removal of nitroso group formed a key intermediate
accumulated 2-azaallene cation (Scheme 1, E). Finally,
a
Table 1. Optimization of Promoters, Solvents and Time in the Synthesis of 4a{1,1,1}
b
entry
base (mol %)/AcONH4(equiv)/solvent/T (°C)/time (h)
yield (%) no wa
1
(-)/(1 equiv)/MeOH/rt/24 h
0
0
2
Na2CO3(20)/1 equiv/MeOH/rt/24 h
3
Cs2CO3(20)/1 equiv/MeOH/rt/24 h
0
4
NaOH(20)/1 equiv /MeOH/rt/24 h
0
5
piperidine(20)/1 equiv/MeOH/rt/24 h
0
6
piperidine(20)/1 equiv/MeOH/reflux/24 h
0
7
piperidine(20)/1 equiv/MeOH/rt−reflux/12−12 h
piperidine(20)/1 equiv/MeOH/rt−rt−reflux/12−12−2 h
piperidine(20)/0 equiv/MeOH/rt−rt−reflux/12−12−2 h
piperidine(50)/1 equiv/MeOH/rt−rt−reflux/12−12−2 h
piperidine(50)/1.5 equiv/MeOH/rt−rt−reflux/12−12−2 h
piperidine(50)/1.5 equiv/MeOH/rt−rt−reflux/12−12−3 h
piperidine(100)/1.5 equiv/MeOH/rt−rt−reflux/12−12−3 h
Et3N(50)/1.5 equiv/MeOH/rt−rt−reflux/12−12−3 h
piperidine(50)/1.5 equiv/EtOH/rt−rt−reflux/12−12−3 h
piperidine(50)/1.5 equiv/MeCN/rt−rt−reflux/12−12−3 h
piperidine(50)/1.5 equiv/DMF/rt−rt−reflux/12−12−3 h
0
8
35
0
9
10
11
12
13
14
15
16
17
46
57
62
62
24
58
42
12
a
Reaction condition: 1-Nitro-2-(p-fluorophenyl)ethene/p-methoxybenzaldehyde/4-hydroxycoumarin/ammonium acetate = 1/1/1/1.5 (mol).
Isolated yields.
b
C
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Research Article
imine to the double bond, intermolecular nucleophilic addition,
and dehydration reactions. This protocol, combining con-
struction and modification of the furo[3,2-c]chromene skeleton,
increases the structural diversity of final products from readily
available starting materials. We expect that the resulting
biologically intriguing structures will have broad applications
in our related biomedical program.
Table 2. Preparation of 2-Arylideneamino-3-aryl-4H-
furo[3,2-c]chromen-4-ones
a
b
entry
Ar1
Ar2
product
yield (%)
EXPERIMENTAL PROCEDURES
■
1
p-FC6H4
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
4a{1,1,1}
4b{2,1,1}
4c{3,2,1}
4d{3,1,1}
4e{3,3,1}
4f{1,4,1}
4g{1,5,1}
4h{1,6,1}
4i{1,7,1}
4j{3,4,1}
4k{4,6,1}
4l{4,1,1}
4m{4,2,1}
4n{4,4,1}
4o{5,6,1}
4p{5,8,1}
4q{5,1,1}
4r{6,2,1}
4s{5,9,1}
62
57
73
72
64
67
56
72
66
68
57
62
53
64
58
58
63
52
60
General. All melting points were determined in a Yanaco
melting point apparatus and are uncorrected. IR spectra were
recorded in a Nicolet FT-IR 5DX spectrometer. The 1H NMR
(600 MHz) and 13C NMR (150 MHz) spectra were recorded
in a Bruker AV-600 spectrometer with TMS as internal
reference in CDCl3 solutions. The J values are given in hertz.
2
C6H5
3
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-FC6H4
4
p-MeOC6H4
o-MeOC6H4
p-(CH3)2NC6H4
p-FC6H4
5
6
1
7
p-FC6H4
Only discrete or characteristic signals for the H NMR are
8
p-FC6H4
p-MeC6H4
reported. The MS spectra were obtained on a ZAB-HS mass
spectrometer with 70 eV. The elemental analyses were
performed in a Perkin-Elmer 240C instrument. X-ray crystallo-
graphic analysis was performed with a Smart-1000 CCD
diffractometer. Flash chromatography was performed on silica
gel (230−400 mesh) eluting with ethyl acetate−hexanes
mixture. All reactions were monitored by thin layer
chromatography (TLC). All reagents and solvents were
purchased from commercial sources and purified commonly
before used.
General Procedure for Preparation of 2-Arylidenea-
mino-3-aryl-4H-furo[3,2-c]chromen-4-ones. The 4-hy-
droxycoumarin (324 mg, 2 mmol), appropriate 2-aryl-1-
nitroethene (2 mmol) and piperidine (85 mg, 1 mmol) were
dissolved in 10 mL of methanol at room temperature and the
resultant mixture was stirred at room temperature for 12 h.
Then, to the resultant solution appropriate aromatic aldehyde
(2 mmol) and ammonium acetate (230 mg, 3 mmol) were
added at room temperature. The reaction mixture was stirred at
room temperature for 12 h and under reflux for 3 h, and the
completion of reaction was confirmed by TLC (EtOAc/
methanol 10:1). Subsequently, the precipitated product was
filtered off and the solid washed with methanol and diethyl
ether two times to give a product 4a{1,1,1}−4s{5,9,1}. The
filtrate was purified by flash chromatography (silica gel, EtOAc/
CH2Cl2, 10/1) to give other product 4a{1,1,1}−4s{5,9,1}. The
merged crude product was purified ulteriorly by crystallization
from hot ethanol−ethyl acetate or ethyl acetate-dichloro-
methane to yield pure 4a{1,1,1}−4s{5,9,1}. The air-dried
product showed a single spot on TLC and was pure enough for
all analytical purposes.
9
p-FC6H4
3-thiophenyl
p-(CH3)2NC6H4
p-MeC6H4
10
11
12
13
14
15
16
17
18
19
p-MeOC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
p-BrC6H4
o-MeOC6H4
p-BrC6H4
p-MeOC6H4
p-ClC6H4
p-(CH3)2NC6H4
p-MeC6H4
p-BrC6H4
p-MeOC6H4
p-ClC6H4
m-MeOC6H4
a
Reaction condition: Substituted nitrostyrene/aromatic aldehyde/4-
hydroxycoumarin/ammonium acetate = 1/1/1/1.5 (mol), 50 mol %
piperidine, rt, 24 h, and reflux, 3 h, solvent = MeOH. Isolated yields.
b
2-(4-Methoxybenzylideneamino)-3-(4-fluorophenyl)-
4H-furo[3,2-c]chromen-4-one (4a): mp 218−219 °C
1
(MeOH/CH2Cl2); H NMR (CDCl3, 600 MHz) δ (ppm)
8.78 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H),
7.76 (d, J = 7.8 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.38 (t, J =
8.4 Hz, 3H), 7.31 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H),
3.82 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 162.20 (J
= 242 Hz), 158.76, 156.40 153.49, 152.97, 150.54, 136.73,
133.65, 131.20 (J = 7.8 Hz), 130.14, 129.10, 128.22, 123.48 (J =
3.2 Hz), 120.46, 117.74, 116.26, 113.80 (J = 21 Hz), 112.45,
111.23, 109.46, 54.31; IR (KBr, cm−1) 2963, 2855, 1727, 1609,
1556, 1422, 1384, 1161, 1074, 804; MS (EI) (M + 1) 414.55
(78%); Anal. Calcd. for C25H16FNO4 (%) C 72.63, H 3.90, N
3.39; Found C 72.82, H 4.06, N 3.40.
Figure 4. Molecular structure of compound 4r{6,2,1}.
CONCLUSION
■
In summary, we have demonstrated an efficient, one-pot
method for the expeditious synthesis of 2-alkylamino-3-aryl-
4H-furo[3,2-c]chromen-4-ones via a one-pot, multicomponent
reaction from substituted nitrostyrenes, aromatic aldehydes, 4-
hydroxycoumarin, and ammonium acetate which involves
sequential Michael addition, aza-nucleophilic addition of
2-(4-Methoxybenzylideneamino)-3-phenyl-4H-furo-
[3,2-c]chromen-4-one (4b): mp 223−225 °C (MeOH/
D
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Scheme 1. Possible Mechanism for the Formation of Products 4a{1,1,1}−4s{5,9,1}
Scheme 2. Two-Component Reaction of Nitrostyrene and 4-
Hydroxycoumarin
REFERENCES
■
(1) (a) Murray, R. D. H.; Mendey, J.; Brown, S. A. The Natural
Coumarins; Wiley: New York, 1982, 147; (b) Valencia, E.; Patra, A.;
Freyer, A. J.; Shamma, M.; Fajardo, V. Santiagonamine: A new
aporphinoid alkaloid incorporating a phenanthridine skeleton.
Tetrahedron Lett. 1984, 25, 3163−3166. (c) Lewis, W. H.; Stonard,
R. J.; Porras-Reyes, B.; Mustoe, T. A.; Thomas, A. Wound-healing
Compostion. U.S. Patent 5156847, 1992.
(2) (a) Zahradink, M. The Production and Application of Fluorescent
Brightening Agents; Wiley: New York, 1992, 284. (b) Maeda, M. Laser
Dyes; Academic Press: New York, 1984, 19.
(3) Kennedy, R. O.; Tharnes, R. D. Coumarins: Biology, Application
and Mode of Action; Wiley: Chichester, U.K., 1997, 1.
CH2Cl2); 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.80 (s, 1H),
7.89 (d, J = 6.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.79 (d, J =
9.0 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H),
7.38 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.31 (t, J =
7.8 Hz, 1H), 6.90 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 161.84, 156.43, 154.88, 153.02,
151.96, 151.80, 130.06, 129.90, 129.80, 128.41, 128.11, 126.92,
126.77, 123.40, 119.92, 116.22, 115.82, 113.41, 111.37, 109.52,
54.48; IR (KBr, cm−1) 2984, 2851, 1731, 1594, 1515, 1489,
1383, 1095, 1027, 901, 845, 739; MS(EI) (M + 1) 396.44
(100%); Anal. Calcd. for C25H17NO4 (%) C 75.94, H 4.33, N
3.54; Found C 76.18, H 4.49, N 3.47.
(4) (a) Thaisrivongs, S.; Janakiraman, M. N.; Chong, K. T.; Tomich,
P. K.; Dolack, L. A.; Turner, S. R.; Strohbach, J. W.; Lynn, J. C.;
Horng, M. M.; Hinshaw, R. R.; Watenpugh, K. D. Structure-based
design of novel HIV protease inhibitors: Sulfonamide-containing 4-
hydroxycoumarins and 4-hydroxy-2-pyrones as potent non-peptidic
inhibitors. J. Med. Chem. 1996, 39, 2400−2410. (b) Rappa, G.; Shyam,
K.; Lorico, A.; Fodstad, O.; Sartorelli, A. C. Structure−activity studies
of novobiocin analogs as modulators of the cytotoxicity of etoposide
(VP-16). Oncol. Res. 2000, 12, 113−119. (c) Yang, E. D.; Zhao, Y. N.;
Zhang, K.; Mack, P. Daphnetin, one of coumarin derivatives, is a
protein kinase inhibitor. Biochem. Biophys. Res. Commun. 1999, 260,
682−685.
(5) (a) Lipshutz, B. H. Five-membered heteroaromatic rings as
intermediates in organic synthesis. Chem. Rev. 1986, 86, 795−819.
(b) Heaney, H.; Ahn, J. S. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Elsevier: Oxford,
U.K., 1996; 2, 297; (c) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky,
A. R. In Heterocycles in Life and Society; John Wiley & Sons: Chichester,
1997; (d) Wong, H. N. C.; Yu, P.; Yick, C.-Y. The use of furans in
natural product syntheses. Pure Appl. Chem. 1999, 71, 1041−1044.
(e) Lee, H.-K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-W.;
Wong, H. N. C. Use of furans in synthesis of bioactive compounds.
Pure Appl. Chem. 2005, 77, 139−143.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Additional experimental details, general information, and H
and 13C NMR spectra for all products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +86-514-8797-5568. Fax: +86-514-8797-5244. E-mail:
wangcd@yzu.edu.cn.
■
(6) (a) Bauer, K.; Garbe, D.; Surburg, H. In Common Fragrance and
Flavor Materials; Wiley-VCH: Weinheim, Germany, 2001; (b) Ash,
M.; Ash, I. In Handbook of Flavors and Fragrances; Synapse
Information Resources, Inc.: New York, 2006.
Funding
Financial support of this research by the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by authors. A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions.
(7) (a) Gambari, R.; Lampronti, I.; Bianchi, N.; Zuccato, C.; Viola,
́
G.; Vedaldi, D.; DallAcqua, F. Structure and biological activity of
furocoumarins. Top. Heterocycl. Chem. 2007, 9, 265−276. (b) Conforti,
F.; Marrelli, M.; Menichini, F.; Bonesi, M.; Statti, G.; Provenzano, E.;
Menichini, F. Natural and synthetic furanocoumarins as treatment for
Notes
The authors declare no competing financial interest.
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ACS Combinatorial Science
Research Article
vitiligo and psoriasis. Curr. Drug Ther. 2009, 4, 38−58. (c) Santana, L.;
Uriarte, E.; Roleira, F.; Milhazes, N.; Borges, F. Furocoumarins in
medicinal chemistry. Synthesis, applications, and biological activity.
Curr. Med. Chem. 2004, 11, 3239−3261. (d) Traven, V. F. New
synthetic routes to furocoumarins and their analogs: A review.
Molecules 2004, 9, 50−66. (e) Ryu, Y. B.; Kim, J. H.; Park, S.-J.; Chang,
J. S.; Rho, M.-C.; Bae, K.-H.; Park, K. H.; Lee, W. S. Inhibition of
neuraminidase activity by polyphenol compounds isolated from the
roots of Glycyrrhiza uralensis. Bioorg. Med. Chem. Lett. 2010, 20, 971−
974. (f) Dong, Y.; Shi, Q.; Pai, H.-C.; Peng, C.-Y.; Pan, S.-L.; Teng, C.-
M.; Nakagawa-Goto, K.; Yu, D.; Liu, Y.-N.; Wu, P.-C.; Bastow, K. F.;
Morris-Natschke, S. L.; Brossi, A.; Lang, J.-Y.; Hsu, J. L.; Hung, M.-C.;
Lee, E. Y.-H. P.; Lee, K.-H. Antitumor agents. 272. Structure−activity
relationships and in vivo selective anti-breast cancer activity of novel
neo-tans hinlactone analogues. J. Med. Chem. 2010, 53, 2299−2308.
(8) (a) Mladenova, R.; Ignatova, M.; Manolova, N.; Petrova, T.;
Rashkov, I. Preparation, characterization and biological activity of
Schiff base compounds derived from 8-hydroxyquinoline-2-carbox-
aldehyde and Jeffamines ED. Eur. Polym. J. 2002, 38, 989−999.
(b) Walsh, O. M.; Meegan, M. J.; Prendergast, R. M.; Nakib, T. A.
Synthesis of 3-acetoxyazetidin-2-ones and 3-hydroxyazetidin-2-ones
with antifugal and antifungal and antibacterial activity. Eur. J. Med.
pot synthesis of furocoumarins via sequential Pd/Cu-catalyzed
alkynylation and intramolecular hydroalkoxylation. Org. Biomol.
́
Chem. 2010, 8, 3073−3077. (j) Nebra, N.; Díaz-Alvarez, A. E.; Díez,
J.; Cadierno, V. Expeditious entry to novel 2-methylene-2,3-
dihydrofuro[3,2-c]chromen-2-ones from 6-chloro-4-hydroxychromen-
2-one and propargylic alcohols. Molecules 2011, 16, 6470−6480.
(11) Lee, C.-J.; Jang, Y.-J.; Wu, Z.-Z.; Lin, W. Preparation of
functional phosphorus zwitterions from activated alkanes, aldehydes,
and tributylphosphine: Synthesis of polysubstituted furo[3,2-c]-
coumarins. Org. Lett. 2012, 14, 1906−1909.
(12) Nair, V.; Menon, R. S.; Vinod, A. U.; Viji, S. A facile three-
component reaction involving [4 + 1] cycloaddition leading to furan
annulated heterocycles. Tetrahedron Lett. 2002, 43, 2293−2295.
(13) Wu, J. General microwave-assisted protocols for the expedient
synthesis of furo[3,2-c]chromen-4-ones. Chem. Lett. 2006, 35, 118−
119.
(14) Adib, M.; Mahdavi, M.; Bagherzadeh, S.; Bijanzadeh, H. R. An
efficient and direct solvent-free synthesis of naphtho[1,2-b]furans,
naphtho[2,1-b]furans, and furo[3,2-c]chromenes. Synlett 2009, 15,
2542−2544.
(15) Zareai, Z.; Khoobi, M.; Ramazani, A.; Foroumadi, A.; Souldozi,
A.; Slepokura, K.; Lis, T.; Shafiee, A. Synthesis of func tionalized
furo[3,2-c]coumarins via a one-pot oxidative pseudo three-compone nt
reaction in poly(ethylene glycol). Tetrahedron 2012, 68, 6721−6726.
(16) (a) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Multicomponent
reaction design in the quest for molecular complexity and diversity.
Angew. Chem., Int. Ed. 2011, 50, 6234−6246. (b) Tejedor, D.; Garcia-
Tellado, F. Chemo-differentiating ABB′ multicomponent reactions.
Privileged building blocks. Chem. Soc. Rev. 2007, 36, 484−491.
(c) Zhu, J., Bienayme, H., Eds. Multicomponent Reactions; Wiley-VCH:
̈
Chem. 1996, 31, 989−1000. (c) Odabasoglu, M.; Arslan, F.; Olmez,
H.; Buyukgungor, O. Synthesis, crystal structures and spectral
̈
̈
̈
̈
characterization of trans-bisaquabis(o-vanillinato) copper(II), cis-
aquabis (o-vanillinato)copper(II), and aqua[bis(o-vanillinato)-1,2-
ethylenediimin] copper(II). Dyes Pigm. 2007, 75, 507−515.
(d) Samadhiya, S.; Halve, A. Synthetic utility of Schiff bases as
potential herbicidal agents. Orient. J. Chem. 2001, 17, 119−122.
(e) Pandeya, S. N.; Sriram, D.; Nath, G.; DeClercq, E. Synthesis,
antibacterial, antifungal and anti-HIV activities of Schiff and Mannich
bases derived from isatin derivatives and N-[4-(4′-chlorophenyl)-
thiazol-2-yl] thiosemicarbazide. Eur. J. Pharm. Sci. 1999, 9, 25−31.
(f) Singh, N. K.; Singh, S. B. Synthesis, characterization and biological
properties of manganese(II), cobalt(II), nickel(II), copper(II), zinc-
(II), chromium(III), and iron(III) complexes with a new thiosemi-
carbazide derivative. Indian J. Chem. 2001, 40, 1070−1075. (g) Vicini,
P.; Geronikaki, A.; Incerti, M.; Busonera, B.; Poni, G.; Cabras, C. A.;
Colla, P. L. Synthesis and biological evaluation of benzo[d]isothiazole,
benzothiazole, and thiazole Schiff bases. Bioorg. Med. Chem. 2003, 11,
4785−4788.
Weinheim, Germany, 2005. (d) Domling, A. Recent developments in
̈
isocyanide based multicomponent reactions in applied chemistry.
Chem. Rev. 2006, 106, 17−35. (e) Wang, K.; Nguyen, K.; Huang, Y. J.;
Domling, A. Cyanoacetamide multicomponent reaction (I): Parallel
synthesis of cyanoacetamides. J. Comb. Chem. 2009, 11, 920−927.
(f) Toure, B. B.; Hall, D. G. Natural product synthesis using
multicomponent reaction strategies. Chem. Rev. 2009, 109, 4439−
4486. (g) Candeias, N. R.; Montalbano, F.; Cal, P. M.; Gois, P. M. P.
Boronic acids and esters in the Petasis−Borono Mannich multi-
component reaction. Chem. Rev. 2010, 110, 6169−6193. (h) Nanda-
luru, P. R.; Bodwell, G. J. Multicomponent synthesis of 6H-
dibenzo[b,d]pyran-6-ones and a total synthesis of cannabinol. Org.
Lett. 2012, 14, 310−313. (i) Jiang, B.; Rajale, T.; Wever, W.; Tu, S.; Li,
G. Multicomponent reactions for the synthesis of heterocycles. Chem.
Asian J. 2010, 5, 2318−2335. (j) Sunderhaus, J. D.; Martin, S. F.
Applications of multicomponent reactions to the synthesis of diverse
heterocyclic scaffolds. Chem.Eur. J. 2009, 15, 1300−1308.
(9) Ghorab, M. M.; Shaaban, M. A.; Refaat, H. M.; Heiba, H. I.;
Ibrahim, S. S. Anticancer and radiosensitizing evaluation of some new
pyranothiazole−Schiff bases bearing the biologically active sulfona-
mide moiety. Eur. J. Med. Chem. 2012, 53, 403−407.
(10) (a) Lee, Y. R.; Byun, M. W.; Kim, B. S. Efficient one-step
synthesis of 2-arylfurans by ceric ammonium nitrate (CAN)-mediated
cycloaddition of 1,3-dicarbonyl compounds to alkynes. Bull. Korean
Chem. Soc. 1998, 19, 1080−1083. (b) Kobayashi, K.; Sakashita, K.;
Akamatsu, H.; Tanaka, K.; Uchida, M.; Uneda, T.; Kitamura, T.;
Morikawa, O.; Konishi, H. CAN-mediated formation of furopyranones
and furoquinolinones. Heterocycles 1999, 51, 2881−2892. (c) Lee, Y.
R.; Suk, J. Y.; Kim, B. S. Rhodium(II)-catalyzed reactions of 3-diazo-
2,4-chromenediones. First one-step synthesis of pterophyllin 2.
Tetrahedron Lett. 1999, 40, 6603−6607. (d) Tollari, S.; Palmisano,
G.; Cenini, S.; Crovotto, G.; Giovenzana, G. B.; Penoni, A. Synthesis
of furocoumarins via rhodium(II)-catalysed heterocyclisation of 3-
diazobenzopyran-2,4(3H)-dione with terminal alkynes. Synthesis 2001,
735−740. (e) Cheng, G.; Hu, Y. One-pot synthesis of furocoumarins
through cascade addition-cyclization-oxidation. Chem. Commun. 2007,
3285−3287. (f) Cheng, G.; Hu, Y. Two efficient cascade reactions to
synthesize substituted furocoumarins. J. Org. Chem. 2008, 73, 4732−
4735. (g) Conreaux, D.; Belot, S.; Desbordes, P.; Monteiro, N.; Balme,
G. Et3N-induced demethylation-annulation of 3-alkynyl-4-methoxy-2-
pyridonas and structurally related compounds in the synthesis of
furan-fused heterocycles. J. Org. Chem. 2008, 73, 8619−8622.
(h) Raffa, G.; Rusch, M.; Balme, G.; Monteiro, N. A Pd-catalyzed
heteroannulation approach to 2,3-disubstituted furo[3,2-c]coumarins.
Org. Lett. 2009, 11, 5254−5257. (i) Chen, L.; Li, Y.; Xu, M.-H. One-
(17) (a) Tietze, L. F.; Dietz, S.; Boehnke, N.; Duefert, M. A.;
Objartel, I.; Stalke, D. Three-component domino Knoevenagel/
hetero-Diels−Alder reaction for the synthesis of the amino sugars 2-
acetoxyforosamine and 2-acetoxyossamineExperimental and the-
oretical results. Eur. J. Org. Chem. 2011, 32, 6574−6580. (b) Xiong, G.;
Wei, M.; Zhou, Y.; Li, Y.; Zhang, F.; Gong, Y. A multicomponent
reaction between alpha-substituted acroleins, nitroalkanes and
paraformaldehyde: Efficient construction of nitro delta-lactol. Synthesis
2011, 3439−3446. (c) Das, B.; Shinde, D. B.; Kanth, B. S.;
Satyalakshmi, G. An efficient multicomponent synthesis of polysub-
stituted pyrrolidines and tetrahydropyrimidines starting directly from
nitro compounds in water. Synthesis 2010, 2823−2827. (d) Song, W.;
Lu, W.; Wang, J.; Lu, P.; Wang, Y. A facile route to gamma-nitro
imidates via four-component reaction of alkynes with sulfonyl azides,
alcohols, and nitroolefins. J. Org. Chem. 2010, 75, 3481−3483.
(18) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Tsogoeva, S. B. Recent advances in asymmetric
organocatalytic 1,4-conjugate additions. Eur. J. Org. Chem. 2007,
1701−1716. (c) Almasi, D.; Alonso, D. A.; Jera, C. N. Organocatalytic
asymmetric conjugate additions. Tetrahedron: Asymmetry 2007, 18,
299−365. (d) Zhang, Z. H.; Dong, X. Q.; Chen, D.; Wang, C. J. Fine-
tunable organocatalysts bearing multiple hydrogen bonding donors for
F
dx.doi.org/10.1021/co4000419 | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
construction of adjacent quaternary and tertiary stereocenters via a
Michael reaction. Chem.; Eur. J. 2008, 14, 8780−8783. (e) Yu, Z. P.;
Liu, X. H.; Zhou, L.; Lin, L. L.; Feng, X. M. Bifunctional guanidine via
an amino amide skeleton for asymmetric Michael reactions of β-
ketoesters with nitroolefins: A concise synthesis of bicyclic β-amino
acids. Angew. Chem., Int. Ed. 2009, 48, 5195−5198. (f) Berner, O. M.;
Tedeschi, L.; Enders, D. Asymmetric Michael additions to nitro-
alkenes. Eur. J. Org. Chem. 2002, 1877−1894. (g) Almas-i, D.; Alonso,
D. A.; Gomez-Bengoa, E.; Najera, C. Chiral 2-aminobenzimidazoles as
recoverable organocatalysts for the addition of 1,3-dicarbonyl
compounds to nitroalkenes. J. Org. Chem. 2009, 74, 6163−6168.
(19) (a) Liu, H.; Zhou, Z.; Sun, Q.; Li, Y.; Li, Y.; Liu, J.; Yan, P.;
Wang, D.; Wang, C. Synthesis of polysubstituted 2-piperidinones via a
Michael addition/nitro-Mannich/lactamization cascade. ACS Comb.
Sci. 2012, 14, 366−371. (b) Zhou, Z.; Liu, H.; Sun, Q.; Li, Y.; Yang, J.;
Liu, J.; Yan, P.; Wang, C. Novel synthesis of trans-4,6-diaryl-5-
nitropiperidin-2-ones via four-component reaction from substituted
nitrostyrenes, aromatic aldehydes, dimethyl malonate, and formamide.
Synlett 2012, 2255−2260.
(20) (a) Tu, Z.; Raju, B. R.; Liou, T.-R.; Kavala, V.; Kuo, C.-W.; Jang,
Y.; Shih, Y.-H.; Yao, C.-F. An efficient method for the synthesis of α-
arylated nitroalkanes and α-arylated hydroximoyl chlorides mediated
by AlCl3. Tetrahedron 2009, 65, 2436−2442. (b) Gao, S.; Tu, Z.; Kuo,
C.-W.; Liu, J.-T.; Chu, C.-M.; Yao, C.-F. Efficient conversion of
nitronate into nitrile oxide using cyanuric chloride. One-pot synthesis
of bicyclic isoxazolines and isoxazoles from nitroalkenes. Org. Biomol.
Chem. 2006, 4, 2851−2857. (c) Barange, D. K.; Raju, B. R.; Kavala, V.;
Kuo, C.-W.; Tu, Y.-C.; Yao, C.-F. A mild and convenient one-pot two-
step synthesis of hydroxy-iminodihydrobenzofurans mediated by silica
gel under microwave activation conditions. Tetrahedron 2010, 66,
3754−3760. (d) Barange, D. K.; Kavala, V.; Kuo, C.-W.; Lei, P.-M.;
Yao, C.-F. Synthesis of C3-nitroalkylated-4-hydroxycoumarin and
hydroxyimin odihydrofuroquinolinone derivatives via the Michael
addition of cyclic 1,3-dicarbonyl compounds to β-nitrostyrenes.
Tetrahedron 2011, 67, 2870−2877.
(21) Wu, M. Y.; Wang, M. Q.; Li, K.; Feng, X. W.; He, T.; Wang, N.;
Yu, X. Q. An efficient, transition-metal-free process for the synthesis of
substituted dihydrofurans via a Michael/cyclization tandem reaction.
Tetrahedron Lett. 2011, 52, 679−683.
(22) Crystallographic data for 4r{6,2,1} have been deposited with the
Cambridge Crystallographic Data Centre with the deposition number
CCDC 937473. These data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [fax
(+44) 1223 336033, e-mail deposit@ccdc.cam.ac.uk].
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dx.doi.org/10.1021/co4000419 | ACS Comb. Sci. XXXX, XXX, XXX−XXX