Efficient and mild synthesis of highly substituted 2,5-dihydrofuran and furan derivatives via stepwise reaction

Article abstract of DOI:10.1016/j.tet.2011.03.038

An efficient and mild synthesis of highly substituted 2,5-dihydrofuran and furan derivatives from a variety of alkylidene malonates and 1,4-butyne-diol via one-pot reaction was applied. With various conditions of base amount, temperature and time applied to the reaction, the 2,5-dihydrofuran and the furan derivatives could be selectively obtained. Moreover, the formation of furan derivatives with 2,5-dihydrofuran derivatives as intermediates was also investigated. Some of these 2,5-dihydrofuran derivatives showed potent in vitro anti-tumor activities against HeLa cells.

Full text of DOI:10.1016/j.tet.2011.03.038

Tetrahedron 67 (2011) 3476e3482
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient and mild synthesis of highly substituted 2,5-dihydrofuran and furan
derivatives via stepwise reaction
*
Tiantian Wang, Jia Liu, Zhiliang Lv, Hanyu Zhong, Huan Chen, Chunjuan Niu, Ke Li
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and mild synthesis of highly substituted 2,5-dihydrofuran and furan derivatives from
a variety of alkylidene malonates and 1,4-butyne-diol via one-pot reaction was applied. With various
conditions of base amount, temperature and time applied to the reaction, the 2,5-dihydrofuran and the
furan derivatives could be selectively obtained. Moreover, the formation of furan derivatives with 2,5-
dihydrofuran derivatives as intermediates was also investigated. Some of these 2,5-dihydrofuran de-
rivatives showed potent in vitro anti-tumor activities against HeLa cells.
Received 6 December 2010
Received in revised form 10 March 2011
Accepted 14 March 2011
Available online 21 March 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Stepwise reaction
Selective synthesis
Anti-tumor
2,5-Dihydrofuran
Furan
1. Introduction
program, we have been recently interested in introducing a wide
range of substituents on the 2-, 3- and 4-positions, especially
Functionalized 2,5-dihydrofuran, an important class of hetero-
cyclic compounds, represents common structural units in many
natural products1 and valuable intermediates for organic synthesis.2
Although unsubstituted dihydrofurans can be straightforwardly
derived from furan, preparation of functionalized 2,5-dihydrofurans
is much more complex and difficult. Recently, several synthetic
strategies for functionalized 2,5-dihydrofurans have been reported,
which include RCM reaction, Ag(I)-catalyzed rearrangementecyc-
lization, Prins reaction, and Au(I)-, Ag(I)-, Hg(II)-, Pd(0)-, Ru(III)-, Au
(III)-catalyzed cyclization reactions.3e16 However, the synthesis is
still sub-optimal because of difficulty in obtaining raw materials,
expensive catalysts, harsh reaction conditions, and multi-step syn-
thesis. As such, novel and more efficient methods for synthesis of
functionalized 2,5-dihydrofurans are much needed.
Metal-catalyzed [3þ2] cycloaddition reactions have been
extensively applied to the synthesis of heterocycle derivatives. Also,
propynol has been frequently used to prepare tetrahydrofuran de-
rivatives.17 In the reactions, both the hetero-atom and the alkyne
moiety in the substrates are responsible for bond formation, thus
producing highly functionalized 3-methylene-tetrahydrofurans.18
The above synthetic strategies have been widely adopted, whereas
only a small portion of studies reported the usage of other ring
systems.19 In the pursuit of an ongoing medicinal chemistry
carboxylic acid group on the 3-position, of 2,5-dihydrofuran. 1,4-
Butyne-diol, with a propargyl alcohol structure but possessing two
active hydroxyl functional groups, is a substrate suitable for pre-
paring [3þ2] cycloadditions. Moreover, it is known that when the
Conia-ene reaction is performed upon the linear compounds in the
presence of an excess of base, the cyclization is often followed by
a decarboxylation reaction. In this respect, we conceive that 1,4-
butyne-diol and alkylidene malonates might be cyclized to produce
functionalized 2,5-dihydrofurans through a cascade reaction. In this
paper, we describe an efficient and mild method for the synthesis of
2-aryl-4-vinyl-2,5-dihydrofuran-3-carboxylic acid (3) from the
reaction of 1,4-butyne-diol (2) with alkylidene malonates (1).
Meanwhile, 2-aryl-4-ethyl-furan-3-carboxylic acid (4) was also
obtained through this reaction. Furthermore, with various condi-
tions of base stoichiometry, temperature and time applied to the
reaction, the 2,5-dihydrofuran and furan derivatives could be
selectively obtained (Scheme 1).
2. Result and discussion
In a previous report we described that several tetrahydrofuran
lignans, which 3,5-dimethoxyphenyl substitution at C-2 position
showed potent anti-tumor activity in vitro.20 Hence, diethyl 2-(3,5-
dimethoxybenzylidene) malonate (compound 1a), which can be
readily prepared through Knoevenagel condensation,21 was used as
the model substrate in this study. Compound 1a (1 equiv) was
* Corresponding author. E-mail address: proflike@sina.com (K. Li).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.038

T. Wang et al. / Tetrahedron 67 (2011) 3476e3482
3477
Table 1
The various reaction conditionsa
Scheme 1. Synthesis of 2,5-dihyodrofynan and furan derivatives.
reacted with 1,4-butyne-diol (1.5 equiv) in the presence of NaH
(1.0 equiv) and CuI (0.1 equiv) at room temperature (25 ꢀC) in THF,
and 12 h later, compound 3a was obtained as a major product (69%)
in the presence of the side product 5a (13%).
Entry NaH equiv Catalyst Temp (ꢀC) Time (h) Productb Yieldc (%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
3.0
3.0
3.0
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
10
20
20
20
40
40
40
60
60
40
60
60
60
24
6
12
24
6
12
24
6
12
24
6
No
5a
No
37
Next, the conditions of base stoichiometry, temperature and time
were optimized for optimal reactions to produce compound 3a. Data
in Table 1 outline both the principle and the optimization of the
reaction conditions. First, 1.2 equiv of NaH was applied to the
reaction. When the reaction was undergone at a low temperature
(10 ꢀC), no valid product was obtained within 24 h (Table 1, entry 1).
When the temperature was elevated to 20 ꢀC, after 6 h, compound
5a was afforded as the only product, while a lot of starting material
1a was not consumed in the reaction (Table 1, entry 2). With a pro-
longed reaction time, however, not only the consumption of com-
pound 1a was completed, but also compound 3a was produced
(Table 1, entry 4). After 24 h, compound 3awas obtainedas the single
product with 87% yield (Table 1, entry 5). Furthermore, with a higher
temperature (40 or 60 ꢀC) applied to the reaction, compound 3a was
easily obtained with good yield (Table 1, entries 5e10). Second,
3.0 equiv of NaH was used in the reaction. When the reaction was
undergone at 40 or 60 ꢀC for 24 or 6 h, respectively, compounds 3a
was obtained as the single product (Table 1, entries 10 and 11).
However, when 3.0 equiv of NaH was used in a reaction at 60 ꢀC for
12 h, compound 3awas obtained in the presence of another product,
which was subsequently identified as compound 4a (Table 1, entry
12). Tomoresurprise, under this condition (3.0 equivNaH, 60 ꢀC, and
24 h), only compound 4a was obtained with a 67% yield (Table 1,
entry 13). The structure of compound 3a was unambiguously con-
firmed by X-ray crystallographic analysis as racemates (Fig. 1).
Although the reactions could directly afford compounds 3a, 4a,
and 5a, considering the relevance among the products obtained
under various conditions (Table 1, entries 3, 4, and 11e13), it is
rational to hypothesize that compound 4a was formed sequentially
after compound 5a with compound 3a as an intermediate. Hereby,
a straightforward validation assay was performed (Scheme 2).
When compound 5a was reacted with NaH (1.1 equiv), however, at
40 ꢀC in THF for 48 h, only a small amount of compound 3a was
produced and the majority of compound 5a was not transformed.
1,4-Butyne-diol (1.1 equiv) was subsequently added, and com-
pound 5a disappeared in 6 h. When the temperature was further
raised to 60 ꢀC, compound 3a was still not transformed to com-
pound 4a. However, when 1.1 equiv of NaH was added, after 12 h,
compound 4a was obtained as the single yielding compound with
75% yield. Furthermore, it was suggested that 1,4-butyne-diol is not
essential in the transformation of compound 3a to compound 4a in
this reaction. Hence, the reaction of compound 3a with NaH
(1.1 equiv) was performed at 60 ꢀC in THF. Obviously, compound 4a
was obtained with the consumption of compound 3a at 12 h. These
observations suggest that compound 5a would be converted to
compound 4a when NaH and 1,4-butyne-diol were presented in the
reaction; while compound 3a was transformed to compound 4a in
this reaction with only NaH needed.
3aþ5a
23þ43
3a
87
3a
3a
3a
3a
3a
3a
3a
Not Cald
83
79
Not Cald
76
9
10
11
12
13
73
Not Cald
57þ11
67
12
24
3aþ4a
4a
a
Unless otherwise specified, the reaction was carried on 2.0 mmol scale in 5 ml of
solvent.
b
c
Monitored by TLC.
Isolated yield.
d
Lots of the starting material not involved in the reaction, the yields were not
calculated.
Fig. 1. X-ray crystal structures of 2-(3,5-dimethoxyphenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxylic acid (3a, ORTEP view, CCDC 756984).
Scheme 2. Validation assay.

3478
T. Wang et al. / Tetrahedron 67 (2011) 3476e3482
Table 3
The results above indicate that compound 5a could be converted
Synthesis of 2,5-dihydrofuran derivativesa
to compound 3a and be further transformed to compound 4a. After-
ward, various solvents and Cu salt catalysts were tested to optimize
the conditions for the synthesis of compound 3a (Table 2). The
reaction proceeded well in 1,4-dioxane or CH2Cl2, however, without
enhanced speed and yield. Instead, when the reactionwas performed
inCH2Cl2, the speed wasslowed down(Table 2, entry1). Although the
reaction could be performed in DMF or DMSO at 20 ꢀC with
the complete consumption of compound 1a at 2 h or 1 h, respectively,
the products were lousy (Table 2, entries 3 and 4). As for the catalysts,
CuCl and CuBr had certain effects. However, the reactions would take
much longer time, and meanwhile, the yield was significantly
decreased (Table 2, entries 8 and 9). Except for Cu(OAc)2, the Cu2þ salt
almost had no effects. No matter CuCl2, CuBr2 CuSO4 or Cu(NO3)2 was
used in the reaction, the starting material compound 1a could not be
initiated to the reaction at 20e60 ꢀC within 48 h (Table 2, entries
8e11). When Cu(OAc)2 was added, an elevated temperature of 60 ꢀC
would be needed, whereas most of the starting material could not be
reacted within 48 h (Table 2, entry 7). As such, CuI and THF were fi-
nally determined as the catalyst and the solvent, respectively.
OH
CO2H
R
NaH, 1.2eq
CuI, 0.1eq
CO2Et
+
CO2Et
THF
HO
O
R
3
2
1
Entry
1
Substrate R¼
Ph
2-FePh
4-FePh
3-ClePh
4-ClePh
4-BrePh
4-OCH3ePh
3,4-(OCH3)2ePh
3,4,5-(OCH3)3ePh
2-Furanyl
2-Pyridyl
CH3(CH2)8
4-NO2ePh
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
40
40
40
40
40
40
40
40
40
40
30
40
30
15
15
15
15
15
15
22
22
22
12
10
22
10
75
73
77
71
75
88
82
87
79
80
80
83
89
9
10
11
12
13
a
Table 2
Unless otherwise specified, the reaction was carried on 20.0 mmol scale in 50 ml
Optimization of the solvent and the catalystsa
of solvent.
b
Isolated yield.
CO2H
R
OH
NaH, 1.2eq
Catalyst
solvent
CO2Et
CO2Et
were needed. Meanwhile, an electron-withdrawing group on the
aryl ring was slightly more favored than an electron-donating
+
HO
O
group. The structure of furan derivatives was determined by 1H, 13
C
3a
R
2
NMR and MS spectra, and further unambiguously conformed by
X-ray crystallographic analysis of compound 4l (Fig. 2).
R=
OMe
OMe
1a
Table 4
Synthesis of furan derivativesa
Entry
Catalyst
Solvent
CH2Cl2
1,4-Dioxane
DMF
DMSO
THF
Temp (ꢀC)
Time (h)
Yieldb (%)
CO2H
R
OH
CO2Et
CO2Et
NaH, 3.0eq
CuI, 0.1eq
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
Reflux
40
20
20
40
48
12
2
40
73
d
d
48
59
10
d
d
d
d
+
THF
O
HO
R
1
4
2
1
CuCl
24
24
48
48
48
48
48
CuBr
THF
40
Entry
1
Substrate R¼
Temp (ꢀC)
Time (h)
Yieldb (%)
Cu(OAc)2
CuCl2
CuBr2
CuSO4
Cu(NO3)2
THF
THF
THF
THF
60
60
60
60
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1o
Ph
2-FePh
4-FePh
50
50
60
50
50
50
60
60
60
40
40
60
20
22
22
22
22
22
22
22
22
22
22
22
28
16
73
70
71
82
71
75
75
68
62
66
57
d
9
10
11
THF
60
3-ClePh
4-ClePh
4-BrePh
4-OCH3ePh
3,4-(OCH3)2ePh
3,4,5-(OCH3)3ePh
2-Furanyl
2-Pyridyl
a
Unless otherwise specified, the reaction was carried on 2.0 mmol scale in 5 ml of
solvent.
b
Isolated yield.
9
Under the optimized reaction conditions, the generality of the
10
11
12
13
reaction was investigated by using 1,4-butyne-diol and a variety of
alkylidene malonates to produce 2,5-dihydrofuran derivatives. The
results are summarized in Table 3. The reaction was speedy with
electron-deficient aryl-substituted substrates (Table 3, entry 12),
while slow with electronrich aryl-substituted ones (Table 3, entries
7e9). Heteroaromatic and alkyl substituents could also be applied
to promote conversions to the substituted 2,5-dihydrofurans (Table
3, entries 10e12).
CH3(CH2)8
4-CF3ePh
85
a
Unless otherwise specified, the reaction was carried on 20.0 mmol scale in 50 ml
of solvent.
b
Isolated yield.
Furans are one of the most important class of compounds in
organic and synthetic chemistry, that exist in numerous natural
products, such as kallolides,22 combranolides,23 pheromones,24 and
polyether antibiotics25 with a variety of biological activities.26
Recently, Zanatta et al. reported that a series of furan-3-carbox-
amides demonstrated potent anti-microbial activities.27 Hence, we
synthesized various 2-aryl-4-ethyl-furan-3-carboxylic acids, which
were summarized in Table 4. The process was similar to the syn-
thesis of 2,5-didydrofuran derivatives. No matter when an electron-
withdrawing group or an electron-donating group on the aryl ring
or heteroaromatic substitution was applied, the reaction could be
smoothly performed, despite higher temperature and excess NaH
Fig. 2. X-ray crystal structures of 4-ethyl-5-(pyridin-2-yl)furan-3-carboxylic acid (4l,
ORTEP views, CCDC 790041).

T. Wang et al. / Tetrahedron 67 (2011) 3476e3482
3479
Based on the above results, a tentative mechanism for the tandem
reaction is proposed in Scheme 3. First, 1,4-butyne-diol was treated
with NaH to produce alcohol sodium. One of the oxygen anion of
1,4-butyne-diol conjugate was then added to the double bond of the
substrate alkynylmalonate to form the intermediate A, followed by
copper-promoted cyclization that yields intermediates B and C.
Subsequently, an intramolecular ester exchange between another
anion of 1,4-butyne-diol and one eater of alkynylmalonate yields in-
termediateD. TheCuatomthendrawsofftoyieldproduct5. Product5
(compound E) is not very stable under this condition, and undergoes
[3, 3]-sigmatropic reactionwhich releases one carbon dioxide to form
intermediate F. Later on,
a basic hydrolysis helps generate
intermediate G. Finally, when the temperature was elevated and the
excess base was used, the intermediate G consecutively undergoes
[1,5] and [1,3] migration to produce the intermediate H and the final
intermediate I, respectively. The intermediates G and I yield products
3 and 4, respectively, through acidification.
Fig. 3. Anti-tumor activity evaluation against HeLa cells in vitro.
derivatives showed potent in vitro anti-tumor activities against
HeLa cells. Ongoing experiments are being carried out to further
address these novel functions.
4. Experimental section
4.1. General
All reactions were carried out in oven-dried glassware. Progress of
reactions was monitored by thin layer chromatography (TLC) while
purification of crude compounds was done by column chromatog-
raphy using silica gel (200e300 mesh). Melting points were recorded
on a YUHUA X-5 melting point apparatus and are uncorrected. Ele-
mental analysis was performed with a Carlo Erba 1106 elemental
analyzer. NMR experiments were performed on Bruke Avance 300
and Bruke Avance 600 instruments and samples were obtained in
CDCl3 (referenced to residual CHCl3 at 7.26 ppm for 1H and 77.0 ppm
for 13C) or DMSO-d6 (referenced to residual DMSO at 2.50 ppm for 1H
and 39.5 ppm for 13C). Coupling constants (J) are in hertz. The mul-
tiplicities of the signals are described using the following abbrevia-
tions: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
br¼broad. Mass spectra were recorded using Finigan LCQ Deca XP
MAX mass spectrometer. IR spectra were recorded on Bruker Vector
22 series FT-IR spectrometer, absorbencies are reported in cmꢁ1
.
Yields refer to quantities obtained after chromatography.
4.2. General experimental procedure for synthesis of highly
substituted 2,5-dihydrofurans (3) and furans (4)
NaH (60% in mineral oil, 24 mmol) was added to a solution of but-
2-yne-1,4-diol (2.58 g, 30 mmol) in THF (50 mL) under nitrogen, and
the solution was stirred for 5 min at room temperature. Alkylidene
malonate (1, 20 mmol) and CuI (0.38 g, 2 mmol) were then added
successively. When consumption of the starting materials was ob-
served by TLC, the reaction mixture was quenched by dropwise ad-
dition of a 20% solution of HCl, immediately cooled to room
temperature. The mixture was further diluted and extracted twice
with CH2Cl2, and the organics washed successively with saturated
solution of brine, and water. The organic extracts were dried over
MgSO4, filtered, concentrated, and the residue purified by flash col-
umn chromatography to afford compound 3. Furthermore, 3.0 equiv
(60 mmol) of NaH was used in the reaction to obtained compound 4.
Scheme 3. Tentative mechanism for final product formation.
All these newly synthesized 2,5-dihydrofuran derivatives were
evaluated for their inhibitory effects against proliferation of human
lung cancer (A549) cells, human hepatoma carcinoma (QGY) cells
and human cervix carcinoma (HeLa) cells by MTT assays.28 As
showed in the Fig. 3, several of these 2,5-dihydrofuran derivatives
showed potent in vitro anti-proliferative activities against HeLa
cells. In particular, compound 3j (IC50¼7.5
mM) exhibited the
highest cytostatic activity again HeLa cells, with IC50 twofold lower
than the control drug 5-fluorouracil (16.1 mM) (Fig. 3).
3. Conclusion
4.2.1. 2-(3,5-Dimethoxyphenyl)-4-vinyl-2,5-dihydrofuran-3-carbox-
ylic acid (3a). Yield: 76%; white solid; mp: 140.5e140.7 ꢀC. IR:
3440, 2986, 2957, 2887, 2847, 2661, 2622, 2580, 2530, 1869, 1681,
1633, 1609, 1593, 1463, 1431, 1408, 1384, 1367, 1344, 1315, 1279,
1198, 1157, 1067, 1014, 993, 930, 858, 820, 788, 741 cmꢁ1. 1H NMR
In summary, we have developed an efficient and mild stepwise
reaction of 1,4-butyne-diol and alkylidene malonates that allows
controlled acquisition of highly substituted 2,5-dihydrofurans and
furans, with good to excellent yields. The furan derivatives obtained
by continuous reactions via intermediates 3, 3a-dihydro-1H-furo
[3,4-c]pyran-4(6H)-one and 2,5-dihydrofuran derivatives were also
functionally characterized. Some of these 2,5-dihydrofuran
(DMSO, 300 MHz):
d
12.78 (br 1H), 7.40 (dd, J¼18, 11.1 Hz, 1H),
6.40e6.42 (m, 3H), 5.79 (dd, J¼5.4, 2.7 Hz, 1H), 5.60 (d, J¼11.1 Hz,
1H), 5.48 (d, J¼18.0 Hz, 1H), 5.11 (dd, J¼14.4, 5.4 Hz, 1H), 5.91 (dd,

3480
T. Wang et al. / Tetrahedron 67 (2011) 3476e3482
J¼14.4, 2.7 Hz, 1H), 3.70 (s, 6H) ppm; 13C NMR (DMSO, 75 MHz):
1488, 1470, 1435, 1414, 1384, 1364, 1311, 1280, 1255, 1124, 1106,
1073, 1009, 945, 860, 840, 811, 745 cmꢁ1 1H NMR (DMSO,
300 MHz): 12.84 (br, 1H), 7.47e7.51 (m, 2H), 7.19e7.31 (m, 3H),
d
163.8, 160.3, 146.2, 143.7, 129.0, 127.6, 123.3, 105.2, 99.3, 88.0, 74.7,
.
55.0 ppm. ESIMS: m/s (%): 275.65 [MꢁH]ꢁ. Anal. Calcd for C15H16O5:
d
C, 65.21; H, 5.84. Found: C, 65.27; H, 5.58%.
5.83 (s, 1H), 5.58 (d, J¼10.8 Hz, 1H), 5.48 (d, J¼18.0 Hz, 1H), 5.14 (dd,
J¼14.4, 5.4 Hz, 1H), 4.95 (dd, J¼14.4, 2.1 Hz, 1H) ppm; 13C NMR
4.2.2. 2-Phenyl-4-vinyl-2,5-dihydrofuran-3-carboxylic acid (3b). Yield:
75%; white solid; mp: 165.7e166.2 ꢀC. IR: 3414, 3027, 2895, 2852,
2618, 1575, 2525, 1999, 1952, 1880, 1666, 1586, 1492, 1442, 1407, 1384,
1321, 1276, 1127, 1083, 1066, 1027, 937, 839, 759, 742 cmꢁ1. 1H NMR
(DMSO, 75 MHz): d 163.7, 146.7, 141.0, 131.1, 129.4, 128.7, 127.7,
123.6, 121.0, 87.6, 74.9 ppm. ESIMS: m/s (%): 293.61 [MꢁH]ꢁ. Anal.
Calcd for C13H11BrO3: C, 52.91; H, 3.76. Found: C, 52.39; H, 3.82%.
(DMSO, 300 MHz):
d
12.76 (br, 1H), 7.19e7.58 (m, 6H), 5.86 (dd, J¼5.4,
4.2.8. 2-(4-Methoxyphenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic
acid (3h). Yield: 82%; white solid; mp: 160.1e160.4 ꢀC. IR: 3446,
3035, 3964, 2889, 2855, 2839, 2670, 2621, 2574, 2360, 2340, 1672,
1612, 1588, 1440, 1384, 1513, 1440, 1384, 1320, 1303, 1273, 1248,
1174, 1125, 1113, 1073, 1034, 1019, 947, 852, 824, 809, 742 cmꢁ1. 1H
3.0 Hz, 1H), 5.60 (d, J¼10.8 Hz, 1H), 5.50 (d, J¼18.0 Hz, 1H), 5.13 (dd,
J¼14.4, 5.4 Hz, 1H), 4.95 (dd, J¼14.4, 3.0 Hz, 1H) ppm; 13C NMR
(DMSO, 75 MHz): d 163.8, 146.3, 141.5, 129.2, 128.2, 127.9, 127.8, 127.2,
123.3, 88.3, 74.8 ppm. ESIMS: m/s (%): 215.53 [MꢁH]ꢁ. Anal. Calcd for
C13H12O3: C, 72.21; H, 5.59. Found: C, 72.27; H, 5.63%.
NMR (DMSO, 300 MHz):
d
12.71 (s, 1H), 7.29 (dd, J¼18.0, 11.1 Hz,
1H), 7.14e7.19 (m, 2H), 6.84e6.89 (m, 2H), 5.82 (dd, J¼5.4, 3.0 Hz,
1H), 5.58 (d, J¼11.1 Hz, 1H), 5.48 (d, J¼18.0 Hz, 1H), 5.07 (dd, J¼14.4,
5.4 Hz, 1H), 4.89 (dd, J¼14.4, 3.0 Hz, 1H), 3.72 (s, 3H) ppm; 13C NMR
4.2.3. 2-(2-Fluorophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic
acid (3c). Yield: 73%; white solid; mp: 154.7e154.9 ꢀC. IR: 3446,
3072, 2927, 2853, 2622, 1670, 1635, 1590, 1558, 1540, 1507, 1491,
1455, 1408, 1384, 1319, 1279, 1227, 1178, 1129, 1101, 1065, 1012, 954,
(DMSO, 75 MHz):
d 163.8, 158.9, 146.0, 133.5, 129.3, 128.3, 127.7,
123.1, 113.5, 87.7, 74.3, 55.0 ppm. ESIMS: m/s (%): 245.7 [Mꢁ1]ꢁ.
934, 838, 805, 759, 745 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d
12.81 (s,
Anal. Calcd for C14H14O4: C, 68.28; H, 5.73. Found: C, 68.46; H, 7.89%.
1H), 7.12e7.39 (m, 5H), 6.12 (dd, J¼5.1, 3.0 Hz, 1H), 5.61 (d,
J¼10.8 Hz, 1H), 5.52 (d, J¼18.0 Hz, 1H), 5.09 (dd, J¼14.4, 5.1 Hz, 1H),
4.96 (dd, J¼14.4, 3.0 Hz, 1H) ppm; 13C NMR (DMSO, 75 MHz):
4.2.9. 2-(3,4-Dimethoxyphenyl)-4-vinyl-2,5-dihydrofuran-3-carbox-
ylic acid (3i). Yield: 87%; white solid; mp: 180.3e180.9 ꢀC. IR: 3446,
3009, 2961, 2946, 2836, 1868, 1072, 1646, 1592, 1558, 1520, 1467,
1423, 1384, 1357, 1310, 1264, 1237, 1193, 1161, 1141, 1114, 1062, 1019,
d
163.6, 161.8, 158.6, 147.4, 130.1, 129.4, 128.2, 127.7, 124.3, 123.6,
115.6, 82.2, 74.8 ppm. ESIMS: m/s (%): 233.53 [MꢁH]ꢁ. Anal. Calcd
for C13H11FO3: C, 66.66; H, 4.73. Found: C, 66.81; H, 4.92%.
932, 871, 807, 795, 768, 705 cmꢁ1 1H NMR (DMSO, 300 MHz):
.
d
12.76 (s, 1H), 7.30 (dd, J¼18.0, 11.1 Hz, 1H), 6.76e6.91 (m, 3H), 5.82
4.2.4. 2-(4-Fluorophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic acid
(3d). Yield: 77%; white solid; mp: 155.1e155.7 ꢀC. IR: 3456, 2860,
2580, 2015, 1671, 1603, 1509, 1450, 1384, 1331, 1282, 1218, 1158, 1132,
(dd, J¼5.4, 3.0 Hz, 1H), 5.60 (d, J¼11.1 Hz, 1H), 5.50 (d, J¼18.0 Hz,
1H), 5.09 (dd, J¼14.4, 5.4 Hz, 1H), 4.90 (dd, J¼14.4, 3.0 Hz, 1H), 3.72
(s, 3H), 3.71 (s, 3H) ppm; 13C NMR (DMSO, 75 MHz):
d 164.0, 152.7,
1099, 1072, 1014, 946, 854, 824, 746 cmꢁ1
300 MHz): d 12.83 (br,1H), 7.24e7.34 (m, 3H), 7.11e7.18 (m, 2H), 5.87
.
1H NMR (DMSO,
146.3, 137.2, 137.0, 129.0, 127.7, 123.3, 104.4, 88.3, 74.6, 59.9,
55.8 ppm. ESIMS: m/s (%): 275.7 [Mꢁ1]ꢁ. Anal. Calcd for C15H16O5:
C, 65.21; H, 5.84. Found: C, 65.31; H, 5.90%.
(dd, J¼5.1, 3.0 Hz, 1H), 5.60 (d, J¼14.4 Hz, 1H), 5.50 (d, J¼18.0 Hz, 1H),
5.13 (dd, J¼14.4, 5.1 Hz, 1H), 4.95 (dd, J¼14.4, 3.0 Hz, 1H) ppm; 13C
NMR (DMSO, 75 MHz):
d
163.8, 163.4, 160.2, 146.5, 137.9, 129.2, 127.7,
4.2.10. 2-(3,4,5-Trimethoxyphenyl)-4-vinyl-2,5-dihydrofuran-3-carbox-
ylic acid (3j). Yield: 79%; white solid; mp: 168.6e170.1 ꢀC. IR: 3581,
3453, 2943, 2843, 2626, 2348, 2284, 1899, 1667, 1637, 1594, 1549,
1508, 1466, 1426, 1383, 1323, 1281, 1236, 1185, 1127, 1074, 1001, 942,
123.5, 115.1, 87.5, 74.8 ppm. ESIMS: m/s (%): 233.42 [MꢁH]ꢁ. Anal.
Calcd for C13H11FO3: C, 66.66; H, 4.73. Found: C, 66.69; H, 4.76%.
4.2.5. 2-(3-Chlorophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic
acid (3e). Yield: 71%; white solid; mp: 158.4e158.7 ꢀC. IR: 3428,
3062, 2941, 2849, 2618, 2519, 2360, 2340, 1903, 1683, 1634, 1588,
1475, 1430, 1404, 1384, 1363, 1317, 1270, 1189, 1131, 1097, 1077, 1010,
993, 932, 867, 849, 786, 744, 704 cmꢁ1. 1H NMR (DMSO, 300 MHz):
827, 799, 776, 747 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.83 (br, 1H),
7.31 (dd, J¼18.0, 11.1 Hz, 1H), 6.55 (s, 2H), 5.85 (dd, J¼5.1, 3.0 Hz, 1H),
5.59 (d, J¼11.1 Hz, 1H), 5.49 (d, J¼18.0 Hz, 1H), 5.13 (dd, J¼14.4, 5.1 Hz,
1H), 4.92 (dd, J¼14.4, 3.0 Hz, 1H), 3.79 (s, 6H), 3.73 (s, 3H) ppm; 13C
NMR (DMSO, 75 MHz):
d 164.0, 152.7, 146.3, 137.2, 129.1, 127.8, 123.3,
d
12.90 (br, 1H), 7.31 (m, 5H), 5.88 (dd, J¼5.1, 3.0 Hz, 1H), 5.60 (d,
104.4, 88.3, 74.6, 59.9, 55.8 ppm. ESIMS: m/s (%): 305.69 [MꢁH]ꢁ.
J¼11.1 Hz, 1H), 5.50 (d, J¼18.0 Hz, 1H), 5.16 (dd, J¼14.4, 5.1 Hz, 1H),
Anal. Calcd for C16H18O6: C, 62.74; H, 5.92. Found: C, 62.81; H, 5.99%.
4.95 (dd, J¼14.4, 3.0 Hz, 1H) ppm; 13C NMR (DMSO, 75 MHz):
d
163.7, 164.8, 144.1, 132.9, 130.1, 128.6, 127.8, 127.6, 127.0, 125.9,
4.2.11. 2-(Furan-2-yl)-4-vinyl-2,5-dihydrofuran-3-carboxylic acid
(3k). Yield: 80%; white solid; mp: 158.5e159.1 ꢀC. IR: 3420, 3123,
2848, 2664, 2620, 2577, 2526, 1672, 1636, 1588, 1558, 1541, 1504,
1432, 1408, 1384, 1364, 1317, 1275, 1227, 1067, 1009, 932, 848, 818,
123.7, 87.5, 75.1 ppm. ESIMS: m/s (%): 249.65 [MꢁH]ꢁ. Anal. Calcd
for C13H11ClO3: C, 62.29; H, 4.42. Found: C, 62.28; H: 4.31%.
4.2.6. 2-(4-Chlorophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic acid
(3f). Yield: 75%, white solid; mp: 160.6e161.2 ꢀC. IR: 3080, 3031,
2861, 2667, 2624, 2576, 2529,1771, 1673,1639,1587, 1558,1541,1521,
1507, 1489, 1472, 1431, 1406, 1384, 1371, 1326, 1313, 1277, 1200, 1128,
1091, 1071, 1012, 999, 946, 918, 844, 810, 741 cmꢁ1. 1H NMR (DMSO,
769, 743 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.85 (s, 1H), 7.58 (dd,
J¼1.8, 0.6 Hz,1H), 7.33 (dd, J¼18.0,11.1 Hz,1H), 6.39 (dd, J¼3.0,1.8 Hz,
1H), 6.32 (dd, J¼3.0, 0.6 Hz, 1H), 5.89 (dd, J¼4.8, 3.0 Hz, 1H), 5.60 (d,
J¼11.1 Hz, 1H), 5.50 (d, J¼18.0 Hz, 1H), 4.95 (dd, J¼14.1, 4.8 Hz, 1H),
4.87 (dd, J¼14.1, 3.0 Hz,1H) ppm; 13C NMR (DMSO, 75 MHz):
d 163.6,
300 MHz):
d
12.86 (s, 1H), 7.26e7.39 (m, 5H), 5.88 (dd, J¼5.1, 3.0 Hz,
153.4, 147.8, 142.7, 127.6, 125.9, 123.7, 110.5, 107.9, 80.5, 74.0 ppm.
ESIMS: m/s (%): 205.77 [MꢁH]ꢁ. Anal. Calcd for C11H10O4: C, 64.07; H,
4.89. Found: C, 64.19; H: 4.97%.
1H), 5.60 (d, J¼11.1 Hz, 1H), 5.51 (d, J¼18.0 Hz, 1H), 5.13 (dd, J¼14.4,
5.1 Hz, 1H), 4.94 (dd, J¼14.4, 3.0 Hz, 1H) ppm; 13C NMR (DMSO,
75 MHz):
d 163.7, 146.7, 140.6, 132.4, 129.1, 128.8, 128.2, 127.7, 123.6,
87.5, 74.9 ppm. ESIMS: m/s (%): 249.20 [MꢁH]ꢁ. Anal. Calcd for
4.2.12. 2-(Pyridin-2-yl)-4-vinyl-2,5-dihydrofuran-3-carboxylic acid
(3l). Yield: 70%; blue solid; mp: 138.8e139.5 ꢀC. IR: 3440, 3090,
2885, 2847, 1361, 2343, 1931, 1690, 1648, 1602, 1477, 1439, 1383,
1371, 1342, 1314, 1287, 1217, 1157, 1101, 1072, 1012, 998, 942, 907,
C13H11ClO3: C, 62.29; H, 4.42. Found: C, 62.33; H: 4.47%.
4.2.7. 2-(4-Bromophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic
acid (3g). Yield: 88%, white solid; mp: 144.7e145.2 ꢀC. IR: 3445,
2894, 2854, 2663, 2615, 2574, 2360, 2340, 1892, 1676, 1636, 1589,
839, 775, 737 cmꢁ1
.
1H NMR (DMSO, 300 MHz):
d
12.80 (br, 1H),
8.50 (d, J¼4.2 Hz, 1H), 7.74e7.80 (m, 1H), 7.28e7.39 (m, 3H), 5.91

T. Wang et al. / Tetrahedron 67 (2011) 3476e3482
3481
(dd, J¼4.8, 2.7 Hz, 1H), 5.60 (d, J¼11.1 Hz, 1H), 5.50 (d, J¼18.0 Hz,
1H), 5.05 (dd, J¼14.1, 4.8 Hz, 1H), 4.95 (dd, J¼14.1, 2.7 Hz, 1H) ppm;
726 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d
12.51 (s, 1H), 7.36e7.63 (m,
5H), 2.59e2.67 (m, 2H), 1.18 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO,
13C NMR (DMSO, 75 MHz):
d
163.8, 159.7, 148.9, 147.5, 136.9, 128.1,
75 MHz): d 164.3, 154.6, 139.9, 133.1, 132.1, 131.0, 130.2, 129.3, 127.9,
127.7, 123.4, 123.2, 122.4, 89.0, 75.1 ppm. ESIMS: m/s (%): 218.30
[MþH]þ. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45 found:
C, 66.42; H, 5.22; N, 6.49%.
126.8, 116.3, 17.6, 13.7 ppm. ESIMS: m/s (%): 265.35 [MþNa]þ. Anal.
Calcd for C13H11FO3: C, 66.66; H, 4.73. Found: C, 66.81; H, 4.92%.
4.2.19. 2-(3-Chlorophenyl)-4-ethylfuran-3-carboxylic acid (4e).
Yield: 82%; white solid; mp: 132.3e133.0 ꢀC. IR: 3069, 2970, 2936,
2882, 2682, 2650, 2617, 2573, 1733, 1681, 1602, 1588, 1574, 1558,
1539, 1478, 1443, 1382, 1330, 1299,1252, 1221, 1146, 1089, 1069, 912,
4.2.13. 2-Nonyl-4-vinyl-2,5-dihydrofuran-3-carboxylic acid (3m).
Yield: 63%; colorless oil. IR: 2927, 2854, 2262, 2130, 1730, 1550,
1506, 1458, 1377, 1244, 1155, 1024, 818, 764, 721 cmꢁ1 1H NMR
.
(DMSO, 300 MHz):
d
12.68e12.79 (br, 1H), 7.24 (q, J¼18.0, 8.1 Hz,
890, 806, 777, 766, 745 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.92 (s,
1H), 5.50 (d, J¼8.1 Hz, 1H), 5.55 (d, J¼18.0 Hz, 1H), 4.87 (dd, J¼9.9,
0.9 Hz,1H), 4.11 (dd, J¼10.2,1.8 Hz,1H),1.40e1.46 (m, 2H),1.42e1.51
(m, 1H), 1.65e1.75 (m, 1H), 1.18e1.22 (m, 14H), 0.79e0.88 (m, 3H)
1H), 7.79 (s,1H), 7.65e0.7.69 (m,1H), 7.62 (s,1H), 7.42e7.48 (m, 2H),
2.58 (q, J¼7.5 Hz, 3H), 1.13 (t, J¼7.5 Hz, 1 h) ppm; 13C NMR (DMSO,
75 MHz): d 164.9, 154.1, 139.6, 132.8, 131.8, 129.9, 128.8, 128.5, 127.3,
ppm; 13C NMR (DMSO, 75 MHz):
d
164.2, 146.1, 129.1, 127.3, 122.5,
126.2, 115.2, 17.6, 13.6 ppm. ESIMS: m/s (%): 249.7 [MꢁH]ꢁ. Anal.
86.2, 73.9, 40.3, 40.0, 31.2, 28.3, 29.5, 24.5, 22.0, 13.9 ppm. ESIMS:
m/s (%): 205.58 [MꢁH]ꢁ. Anal. Calcd for C16H26O3: C, 72.14; H, 9.84.
Found: C, 72.22; H, 9.72%.
Calcd for C13H11ClO3: C, 62.29; H, 4.42. Found: C, 62.17; H, 4.22%.
4.2.20. 2-(4-Chlorophenyl)-4-ethylfuran-3-carboxylic acid (4f).
Yield 71%; white solid; mp: 139.7e141.2 ꢀC. IR: 2965, 2936, 2876,
2633, 2578, 1771, 1733, 1683, 1601, 1570, 1558, 1540, 1507, 1484,
1456, 1436, 1384, 1333, 1307, 1295, 1223, 1136, 1096, 1075, 1014, 929,
4.2.14. 2-(4-Nitrophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic
acid (3n). Yield: 89%; yellow solid; mp: 169.7e169.9 ꢀC. IR: 3440,
3078, 2864, 2575,1912,1677,1606,1587,1519,1445,1415,1384,1346,
928, 801, 775, 747, 715 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.87 (s,
1280, 1126, 1108, 1072, 1011, 955, 824, 745 cmꢁ1
.
1H NMR (DMSO,
1H), 7.76 (d, J¼6.9 Hz, 2H), 7.62 (s, 1H), 7.51 (d, J¼7.5 Hz, 2H), 2.56
300 MHz):
d
12.87 (br, 1H), 8.18 (d, J¼9.0 Hz, 2H), 7.58 (d, J¼9.0 Hz,
(q, J¼7.5 Hz, 2H), 1.14 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO,
2H), 7.32 (dd, J¼18.0,11.1 Hz,1H), 6.02 (dd, J¼5.4, 3.0 Hz,1H), 5.64 (d,
75 MHz): d 165.0, 154.8, 139.5, 133.6, 129.5, 128.8, 123.2, 114.7, 17.6,
J¼11.1 Hz, 1H), 5.54 (d, J¼18.0 Hz, 1H), 5.21 (dd, J¼14.4, 5.4 Hz, 1H),
13.7 ppm. ESIMS: m/s (%): 295.38 [MꢁH]ꢁ. Anal. Calcd for
5.01 (dd, J¼14.4, 3.0 Hz,1H) ppm; 13C NMR (DMSO, 75 MHz):
d
163.6,
C13H11ClO3: C, 62.29; H, 4.42. Found: C, 62.19; H, 4.63%.
149.0, 147.2, 147.1, 128.5, 128.3, 127.5, 124.1, 123.5, 123.4, 87.2,
75.4 ppm. ESIMS:m/s(%):260.09 [MꢁH]ꢁ. Anal. CalcdforC13H11NO5:
C, 59.77; H, 4.24; N, 5.36. Found: C, 59.92; H, 4.27; N: 5.43%.
4.2.21. 2-(4-Bromophenyl)-4-ethylfuran-3-carboxylic acid (4g). Yield
75%; white solid; mp: 139.7e141.2 ꢀC. IR: 2964, 2934, 2875, 2691,
2630, 2575,1670,1598,1567,1538,1507,1479,1436,1384,1332,1305,
1294, 1263, 1220, 1136, 1093, 1070, 1011, 928, 827, 801, 773, 754, 735,
4.2.15. 2-(3,5-Dimethoxyphenyl)-4-ethylfuran-3-carboxylic acid (4a).
Yield: 67%; white solid; mp: 105.3e105.6 ꢀC. IR: 3441, 2996, 2963,
2941, 2833, 2623, 1686, 1610, 1588, 1549, 1481, 1446, 1384, 1344, 1327,
1307, 1261, 1194,1157, 1135, 1094, 1062,1042, 1008, 934, 838, 806, 765,
711 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.84 (s, 1H), 7.38e7.73 (m,
5H), 2.56 (m, 2H), 1.14 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO,
75 MHz): d 165.5, 155.3, 139.9, 131.5, 130.2, 129.6, 129.3, 128.5, 122.7,
703 cmꢁ1
.
1H NMR (DMSO, 300 MHz):
d
12.86 (s,1H), 7.56 (t, J¼2.1,
115.2, 18.1, 14.1 ppm. ESIMS: m/s (%): 293.18 [MꢁH]ꢁ. Anal. Calcd for
1.2 Hz, 1H), 6.91 (d, J¼2.4 Hz, 1H), 6.54 (t, J¼2.4, 2.1 Hz, 1H), 3.76 (s,
C13H11BrO3: C, 52.91; H, 3.76. Found: C, 52.89; H, 3.79%.
6H), 2.54e2.59 (m, 2H), 1.11e1.16 (m, 3H) ppm; 13C NMR (DMSO,
75 MHz):
d
165.3, 160.1, 155.0, 131.5, 128.6, 114.8, 105.7, 100.9, 55.2,
4.2.22. 4-Ethyl-2-(4-methoxyphenyl)furan-3-carboxylic
acid
17.6, 13.8 ppm. ESIMS: m/s (%): 275.68 [MꢁH]ꢁ. Anal. Calcd for
(4h). Yield 75%; white solid; mp: 142.3e142.9 ꢀC. IR:2973, 2918,
2875, 2843, 2681, 2583, 1672, 1611, 1589, 1575, 1543, 1497, 1437,
1384, 1370, 1335, 1305, 1286, 1254, 1220, 1176, 1138, 1080, 1024, 927,
C15H16O5: C, 65.21; H, 5.84. Found: C, 65.07; H, 5.66%.
4.2.16. 4-Ethyl-2-phenylfuran-3-carboxylic acid (4b). Yield: 73%;
white solid; mp: 102.7e103.1 ꢀC. IR: 2957, 2924, 2853, 2575, 1683,
1587, 1558, 1539, 1507, 1457, 1383, 1305, 1219, 1135, 1069, 1011, 928,
837, 805, 759 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.88 (s, 1H), 7.66
(d, J¼6.9 Hz, 2H), 7.58 (s, 1H), 7.52 (d, J¼6.9 Hz, 2H), 2.54 (q,
J¼7.5 Hz, 2H), 1.14 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO,
826, 773, 756, 710 cmꢁ1
.
1H NMR (DMSO, 300 MHz):
d
12.78 (br,
75 MHz):d 162.6, 158.7, 152.3, 143.5, 131.2, 125.8, 123.5, 115.8, 17.6,
1H), 7.38e7.73 (m, 6H), 2.57 (q, J¼7.5 Hz, 2H), 1.15 (t, J¼7.5 Hz, 3H)
13.9 ppm. ESIMS: m/s (%): 285.5 [M]þ. Anal. Calcd for C13H10Cl2O3:
ppm; 13C NMR (DMSO, 75 MHz):
d
165.2, 156.0, 139.2, 134.0, 128.9,
C, 54.76; H, 3.54. Found: C, 54.79; H, 3.58%.
128.6, 128.1, 127.8, 17.6, 13.8 ppm. ESIMS: m/s (%): 215.37 [MꢁH]ꢁ.
Anal. Calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.33; H, 5.67%.
4.2.23. 2-(3,4-Dimethoxyphenyl)-4-ethylfuran-3-carboxylic acid (4i).
Yield: 68%; white solid; mp: 112.7e113.1 ꢀC. IR: 3011, 2966, 2941, 2919,
2880, 2837, 2588, 1683, 1616, 1590, 1558, 1540, 1507, 1455, 1383, 1321,
4.2.17. 4-Ethyl-2-(2-fluorophenyl)furan-3-carboxylic acid (4c).
Yield: 70%; white solid; mp: 105.6e106.1 ꢀC. IR: 2970, 2929,
2878, 2589, 2553, 1682, 1623, 1594, 1556, 1383, 1332, 1311, 1260,
1225, 1155, 1136, 1114, 1095, 1069, 1031, 933, 822, 807, 759,
1258, 1236,1213,1175, 1139, 1118, 1080, 1022, 942, 854, 808, 765 cmꢁ1
.
1H NMR (DMSO, 300 MHz): 12.77 (br,1H), 7.53 (s,1H), 7.38 (d, J¼2.1 Hz,
1H), 7.32 (dd, J¼18.3, 2.1 Hz,1H), 6.92 (d, J¼18.3 Hz, 1H), 3.70e3.79 (m,
6H), 2.57 (q, J¼7.5 Hz, 2H),1.14 (t, J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO,
75 MHz): 163.3,158.7,153.7,153.4,133.7,127.3,125.4,123.7,121.6,118.5,
116.5, 17.6, 14.2 ppm. ESIMS: m/s (%): 275.7 [Mꢁ1]ꢁ. Anal. Calcd for
C15H16O5: C, 65.21; H, 5.84. Found: C, 65.31; H, 5.90%.
704 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.56 (s, 1H), 7.66 (s, 1H),
7.48e7.57 (m, 2H), 7.25e7.32 (m, 2H), 2.59 (q, J¼7.5 Hz, 2H), 1.16
(t, J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO, 75 MHz):
d 164.1, 160.9,
157.6, 151.1, 140.2, 131.5, 130.9, 128.4, 124.2, 119.0, 116.8, 115.9,
17.6, 13.8 ppm. ESIMS: m/s (%): 233.49[MꢁH]ꢁ. Anal. Calcd for
C13H11FO3: C, 66.66; H, 4.73. Found: C, 66.74; H, 4.83%.
4.2.24. 4-Ethyl-2-(3,4,5-trimethoxyphenyl)furan-3-carboxylic acid
(4j). Yield: 62%; white solid; mp: 142.6e143.1 ꢀC. IR: 2963, 2944,
2882, 2838, 2625, 1691, 1588, 1551, 1498, 1471, 1455, 1417, 1384,
1347, 1305, 1260, 1244, 1212, 1178, 1134, 1088, 1003, 930, 853, 835,
4.2.18. 4-Ethyl-2-(4-fluorophenyl)furan-3-carboxylic acid (4d). Yield
71%; white solid; mp: 114.6e116.7 ꢀC. IR: 2971, 2924, 2877, 2691,
2621, 2545, 1676, 1610,1587, 1550,1473, 1445, 1383, 1331, 1304, 1265,
1250, 1223, 1140, 1090, 1063, 1046, 1036, 980, 933, 911, 805, 771,
821, 802, 766, 738, 711 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d
12.80 (s,
1H), 7.55 (s, 1H), 7.11 (s, 2H), 3.79 (s, 6H), 3.71 (s, 3H), 2.55 (q,

3482
T. Wang et al. / Tetrahedron 67 (2011) 3476e3482
J¼7.5 Hz, 2H), 1.15 (t,¼7.5 Hz, 3H) ppm; 13C NMR (DMSO, 75 MHz):
References and notes
d
165.4, 155.6, 152.4, 138.7,138.2,128.7,125.2,114.1,105.5, 60.0, 55.8,
17.6, 13.8 ppm. ESIMS: m/s (%): 305.53 [MꢁH]ꢁ. Anal. Calcd for
1. (a) Marshall, J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180; (b) Marshall, J. A.;
Yu, B. J. Org. Chem. 1994, 59, 324; (c) Yamada, O.; Ogasawara, K. Synlett 1995,
427; (d) Kim, S.; Kim, K. H. J. Chem. Soc., Perkin Trans. 1 1997, 1095; (e) Paolucci,
C.; Musiani, L.; Venturelli, F.; Fava, A. Synthesis 1997, 1415; (f) Shieh, S. J.; Fan, J.
S.; Chandrasekharam, M.; Liao, F. L.; Wang, S. L.; Liu, R. S. Organometallics 1997,
16, 3987; (g) Doyle, M. P.; Forbes, D. C.; Protopopova, M. N.; Stanley, S. A.;
Vasbinder, M. M.; Xavier, K. R. J. Org. Chem. 1997, 62, 7210; (h) Crotti, P.; Bussolo,
V. D.; Favero, L.; Pineschi, M. Tetrahedron 1997, 53, 1417; (i) Bauer, T. Tetrahedron
1997, 53, 4763.
2. (a) Kupchan, S. M.; Davies, V. H.; Fujita, T.; Cox, M. R.; Restivo, R. J.; Bryan, R. F. J.
Org. Chem. 1973, 38, 1853; (b) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joullie, M.
M. J. Am. Chem. Soc. 1980, 102, 7505.
3. Carda, M.; Castillo, E.; Rodriguez, S.; Uriel, S.; Marco, J. A. Synlett 1999, 1639.
4. (a) Shigemasa, Y.; Yasui, M.; Ohrai, S.; Sasaki, M.; Sashiwa, H.; Saimoto, H. J. Org.
Chem. 1991, 56, 910; (b) Saimoto, H.; Yasui, M.; Ohrai, S.; Oikawa, H.; Yokoyama,
K.; Shigemasa, Y. Bull. Chem. Soc. Jpn. 1999, 72, 279.
5. Sato, F.; Kanbara, H.; Tanaka, Y. Tetrahedron Lett. 1984, 25, 5063.
6. Darcel, C.; Bruneau, C.; Albert, M.; Dixneuf, P. H. Chem. Commun. 1996, 919.
7. Talipov, R. F.; Starikov, A. S.; Gorina, I. A.; Akmanova, N. A.; Safarov, M. G. Zh. Org.
Khim. 1993, 29, 1024.
8. Xi, C.; Kotora, M.; Takahashi, T. Tetrahedron Lett. 1999, 40, 2375.
9. Chen, J.; Song, Q.; Li, P.; Guan, H.; Jin, X.; Xi, Z. Org. Lett. 2002, 4, 2269.
10. Shieh, S. J.; Tang, T. C.; Lee, J. S.; Lee, G. H.; Peng, S. M.; Liu, R. S. J. Org. Chem.
1996, 61, 3245.
C16H18O6: C, 62.74; H, 5.92. Found: C, 62.51; H, 5.67%.
4.2.25. 4-Ethyl-2,20-bifuran-3-carboxylic acid (4k). Yield: 66%;
white solid; mp: 136.8e137.1 ꢀC. IR: 3143, 2966, 2938, 2877, 2610,
2580, 1733, 1681, 1599, 1558, 1530, 1489, 1457, 1422, 1384, 1322,
1298, 1268, 1233, 1162, 1140, 1091, 1076, 1022, 987, 937, 886, 809,
769, 751 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.88 (s, 1H), 7.82 (q,
J¼1.8; 0.6 Hz, 1H), 7.58 (s, 1H), 7.26 (t, J¼0.6 Hz, 1H), 6.32 (q,
J¼1.8 Hz, 1H), 2.57 (q, J¼7.5 Hz, 2H), 1.16 (q, J¼7.5 Hz, 3H) ppm; 13C
NMR (DMSO, 75 MHz): d 164.3, 143.9, 139.1, 128.4, 133.1, 112.3,111.8,
59.7, 17.6, 13.8 ppm. ESIMS: m/s (%): 205.29 [MꢁH]ꢁ. Anal. Calcd for
C11H10O4: C, 64.07; H, 4.89. Found: C, 64.15; H: 4.93%.
4.2.26. 4-Ethyl-2-(pyridin-2-yl)furan-3-carboxylic acid (4l). Yield:
57%; white solid; mp: 119.0e119.4 ꢀC. IR: 3159, 3131, 3086, 2966,
2929, 2871, 1360, 2341, 1699, 1652, 1635, 1603, 1575, 1558, 1539,
1507, 1456, 1429, 1382, 1219, 1282, 1260, 1217, 1153, 1080, 1019, 932,
817, 782, 749, 738 cmꢁ1
.
1H NMR (DMSO, 300 MHz):
d
8.69 (d,
11. Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957.
12. (a) Olsson, L. I.; Claesson, A. Synthesis 1979, 743; (b) Nikam, S. S.; Chu, K. H.;
Wang, K. K. J. Org. Chem. 1986, 51, 745; (c) Gelin, R.; Gelin, S.; Albrand, M. Bull.
Soc. Chim. Fr. 1972, 1946; (d) Chilot, J. J.; Doutheau, A.; Gore, J. Tetrahedron Lett.
1982, 23, 4693; (e) Chilot, J.-J.; Doutheau, A.; Gore, J. Bull. Soc. Chim. Fr. 1984, II-
307.
J¼4.8 Hz, 1H), 8.16 (t, J¼7.8 Hz, 1H), 7.99 (d, J¼9.1 Hz, 3H), 7.78 (s,
1H), 7.59 (t, J¼6.0 Hz, 1H), 2.68 (q, J¼7.5 Hz, 2H), 1.14 (t, J¼7.5 Hz,
3H) ppm; 13C NMR (DMSO, 75 MHz):
d 162.4, 150.1, 146.1, 146.0,
141.1, 140.2, 131.4, 124.4, 121.0, 118.3, 17.7, 13.5 ppm. ESIMS: m/s (%):
216.19 [MꢁH]ꢁ. Anal. Calcd for C12H11NO3: C, 66.35; H, 5.10; N, 6.45
found: C, 66.28; H, 5.17; N, 6.41%.
13. (a) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966; (b) Marshall, J. A.;
Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995, 60, 5550.
14. For the Pd-catalyzed coupling-cyclization reaction of allenols with aryl or vinyl
halides, see: (a) Uemura, K.; Shiraishi, D.; Noziri, M.; Inoue, Y. Bull. Chem. Soc.
Jpn. 1999, 72, 1063; (b) Kang, S. K.; Baik, T. G.; Kulak, A. N. Synlett 1999, 324;
(c) Kang, S. K.; Yamaguchi, T.; Pyun, S. J.; Lee, Y. T.; Baik, T. G. Tetrahedron Lett.
1998, 39, 2127; (d) Walkup, R. D.; Guan, L.; Kim, Y. S.; Kim, S. W. Tetrahedron
Lett. 1995, 36, 3805; (e) Walkup, R. D.; Guan, L.; Mosher, M. D.; Kim, Y. S.; Kim,
S. W. Synlett 1993, 88.
15. For the Ru-catalyzed reaction, see: (a) Yoneda, E.; Kaneko, T.; Zhang, S. W.;
Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441; (b) Trost, B. M.; Pinkerton, A.
B. J. Am. Chem. Soc. 1999, 121, 10842.
16. For the Au-catalyzed reaction, see: (a) Hoffmann-Roder, A.; Krause, N. Org. Lett.
2001, 3, 2537; (b) Born, D. H.; Kang, D. J.; Lee, P. H. J. Org. Chem. 2010, 75, 7447.
17. For recent reviews, see: Yamazaki, S. Chem.dEur. J. 2008, 14, 6026.
18. For selected examples see: (a) Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi,
D.; Balme, G. Tetrahedron Lett. 1997, 38, 1763; (b) Marat, X.; Monteiro, N.; Balme,
G. Synlett 1997, 845; (c) Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett.
1997, 40, 130; (d) Monteiro, N.; Balme, G. J. Org. Chem. 2000, 65, 3223; (e)
Bottex, M.; Cavicchioli, M.; Hartmann, B.; Monteiro, N.; Balme, G. J. Org. Chem.
2001, 66, 175; (f) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett. 2004, 6, 2015;
(g) Morikawa, S.; Yamazaki, S.; Furusaki, Y.; Amano, N.; Zenke, K.; Kakiuchi, K. J.
Org. Chem. 2006, 71, 3540; (h) Morikawa, S.; Yamazaki, S.; Tsukada, M.; Izuhara,
S.; Morimoto, T.; Kakiuchi, K. J. Org. Chem. 2007, 72, 6459.
19. For selected examples see: (a) McDonald, F. E.; Bowman, J. L. Tetrahedron Lett.
1996, 27, 4675; (b) Clique, B.; Vassiliou, S.; Monteiro, N.; Balme, G. Eur. J. Org.
Chem. 2002, 1493; (c) Consorti, C. S.; Ebeling, G.; Dupont, J. Tetrahedron Lett.
2002, 5, 753 Gowrisankau, a.; Park, D. Y.; (d) Kim, J. N. Bull. Korean Chem. Soc.
2005, 26, 1826.
4.2.27. 4-Ethyl-2-(4-(trifluoromethyl)phenyl)furan-3-carboxylic acid
(4o). Yield: 85%; white solid; mp: 159.9e161.0 ꢀC. IR: 2974, 2942,
2882, 2678, 2633, 2583, 2526, 1683, 1620, 1594, 1549, 1507, 1449,
1427, 1384, 1322, 1227, 1170, 1132, 1080, 1064, 1017, 931, 847, 805,
763, 713 cmꢁ1. 1H NMR (DMSO, 300 MHz):
d 12.02 (s, 1H), 7.95 (d,
J¼8.7 Hz, 2H), 7.75 (d, J¼8.4 Hz, 2H), 7.63 (s, 1H), 2.57 (q, J¼7.5 Hz,
2H), 1.15 (J¼7.5 Hz, 3H) ppm; 13C NMR (DMSO, 75 MHz):
d 165.3,
159.7, 156.0, 138.5, 129.5, 128.6, 126.6, 113.5, 113.0, 55.2, 17.8,
13.9 ppm. ESIMS: m/s (%): 283.10 [MꢁH]ꢁ. Anal. Calcd for
C12H11NO3: C, 59.16; H, 3.90. Found: C, 59.32; H, 3.73%.
4.2.28. Ethyl 3-(3,5-dimethoxyphenyl)-4-oxo-3,3a,4,6-tetra-hydro-
1H-furo[3,4-c]pyran-3a-carboxylate (5a). Yield: 51%; white solid;
mp: 102.6e102.7 ꢀC. IR: 3464, 3110, 3011, 2965, 2932, 2868, 2839,
1726, 1596, 1469, 1427, 1386, 1355, 1289, 1230, 1182, 1151, 1101, 1052,
974, 962, 913, 866, 851, 836, 813, 796, 778, 726, 700 cmꢁ1. 1H NMR
(CDCl3, 300 MHz): d 6.91e6.92 (m, 2H), 6.37e6.39 (m,1H), 6.04e6.06
(m,1H), 4.97 (d, J¼12.0 Hz,1H), 4.81e4.85 (m, 2H), 4.64 (d, J¼12.0 Hz,
1H), 3.78e3.87 (m, 8H), 0.91 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (CDCl3,
20. Sun, H. L.; Wang, T. T.; Lv, Z. L.; Feng, J. L.; Geng, D. P.; Li, K. Bioorg. Med. Chem.
Lett. 2010, 20, 1961.
21. (a) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazaccani, A.; Sartori, G. Tetrahe-
dron Lett. 2001, 42, 5203; (b) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Gianotti,
M.; Tolomelli, A. Synth. Commun. 2003, 33, 1587.
75 MHz):
d 167.4, 164.8, 160.3, 141.9, 138.7, 115.6, 104.6, 100.7, 83.9,
68.8, 67.5, 64.3, 62.2, 55.3,13.4 ppm. ESIMS:m/s(%):371.93[MþNa]þ.
Anal. Calcd for C18H20O7: C, 62.06; H, 5.79. Found: C, 62.13; H, 5.87%.
22. Look, S. A.; Burch, M. T.; Fenical, W.; Qi-tai, Z.; Clardy, J. J. Org. Chem. 1985, 50,
5741.
23. Fenical, W.; Okeeda, R. K.; Basnadurraga, M. M.; Culver, P.; Jacobs, R. S. Science
1981, 212, 1512.
Acknowledgements
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Financial support form the National Natural Science Foundation
of China (No. 30572238), the Chinese Academy of Sciences.
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.038. This data in-
clude MOL file and InChIKey of the most important compound
described in this article.
28. Furst, R.; Zupk, I.; Berenyi, A.; Ecker, G. F.; Rinner, U. Bioorg. Med. Chem. Lett.
2009, 19, 6948.