Base- and copper-catalyzed intramolecular cyclization for the direct synthesis of dihydrofurans

Article abstract of DOI:10.1002/adsc.201000005

A simple and convenient synthetic approach to dihydrofurans has been developed from the cyclization of 2-propynyl-l,3-dicarbonyl compounds catalyzed by potassium tert-butoxide, copper(II) trifluoromethanesulfonate and triphenylphosphine using methanol/dichloromethane as the solvent under very mild conditions. Moreover, dihydrofurans could be easily transformed into the corresponding furans in the presence of trifluoroacetic acid.

Full text of DOI:10.1002/adsc.201000005

FULL PAPERS
DOI: 10.1002/adsc.201000005
Base- and Copper-Catalyzed Intramolecular Cyclization for the
Direct Synthesis of Dihydrofurans
Yong-Fei Chen,a Hai-Fei Wang,a Ya Wang,a Yong-Chun Luo,a Hai-Liang Zhu,a
and Peng-Fei Xua,*
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-5557; e-mail: xupf@lzu.edu.cn
Received: January 4, 2010; Revised: April 7, 2010; Published online: April 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000005.
Abstract: A simple and convenient synthetic ap- under very mild conditions. Moreover, dihydrofurans
proach to dihydrofurans has been developed from could be easily transformed into the corresponding
the cyclization of 2-propynyl-1,3-dicarbonyl com- furans in the presence of trifluoroacetic acid.
pounds catalyzed by potassium tert-butoxide, cop-
per(II) trifluoromethanesulfonate and triphenylphos- Keywords: alkynes; copper; cyclization; dihydrofur-
phine using methanol/dichloromethane as the solvent ans; furans
Introduction
cy, excellent selectivity and low costs.[4,5] Although
many copper-catalyzed strategies have been success-
Dihydrofurans are an important class of oxygenated fully applied to the preparation of many heterocyclic
heterocycles with widespread occurrence in nature, compounds,[6] few applications in the synthesis of di-
and they are also useful building blocks in organic hydrofurans were reported.[7] Based on our previous
synthesis.[1a–k] Meanwhile, a vast number of bioactive studies,[8] we hypothesize that the direct synthesis of
natural and unnatural products based on the dihydro- 5-methylene-4,5-dihydrofurans could be achieved by
furan ring are very useful in the area of pharmaceuti- using 2-propynyl-1,3-dicarbonyl compounds as start-
cal chemistry.[1l–p] So, the development of efficient ing materials (Scheme 1). It is anticipated that the
synthetic approaches to dihydrofurans has attracted rapid enolization of the dicarbonyl compounds under
tremendous attention.[2,3] Several methods for cyclic base catalysis followed by an intramolecular nucleo-
ethers based on the metal-catalyzed cyclization reac- philic addition of the oxygen anion of an enol to a
tions have been reported.[3] Trost and co-workers re- carbon-carbon triple bond activated by a copper salt
ported the cycloisomerization of 1-alkyn-4-ols to dihy-
drofurans catalyzed by Rh.[3a] McDonald and co-
wokers discovered that acyclic alkynols could be
transformed to cyclic enol ethers promoted by
Mo(CO)5.[3b] The Pd-catalyzed cyclization of allenol
was reported by Ma and Alcaide, respectively.[3c,d] The
conversion of a-hydroxyallenes or (Z)-enynols to 2,5-
dihydrofurans catalyzed by Au has been developed by
Lee, Krause and Liu, respectively.[3e–g] However, few
methodologies were reported for the synthesis of 5-
methylene-4,5-dihydrofurans. Therefore, the investiga-
tion of new synthetic routes which allow the facile
building of 5-methylene-4,5-dihydrofuran rings under
the mild conditions would be a timely endeavor.
In recent years, copper-catalyzed reactions have re-
Scheme 1. The synthesis of dihydrofurans from 2-propynyl-
1,3-dicarbonyl compounds by the intramolecular cyclization
ceived considerable attention owing to their efficien- under the catalysis of base and copper.
Adv. Synth. Catal. 2010, 352, 1163 – 1168
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Yong-Fei Chen et al.
Table 1. Optimization of the catalytic conditions.[a]
FULL PAPERS
might provide a facile route to the construction of
substituted 5-methylene-4,5-dihydrofuran compounds.
To the best of our knowledge, this is the first synthesis
of 5-methylene-4,5-dihydrofurans from 2-propynyl-
1,3-dicarbonyl compounds using the combination of
base and copper salt as catalysts. Herein we present
our findings on this reaction that provides a new ap-
proach to dihydrofurans in a direct, efficient and
facile manner.
Entry [Cu]
Base
Ligand Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
–
Cu
–
KO-t-Bu –
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN
CH2Cl2
benzene
CHCl3
toluene
hexane
EtOH
0
G
trace
0
Results and Discussion
Cu
Cu
Cu
Cu
Cu
CuCl
CuSO4
CuI
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
R
ACHTUNGTRENNUNG
E
T
99[c]
52
The starting 2-propynyl-1,3-dicarbonyl compounds
(2a–s) were easily prepared from 1,3-dicarbonyl com-
pounds (1a–s) (Scheme 2).[9]
PPh3
PPh3
PPh3
97
95
93
24
90
91
51
51
37
79
37
60
77
28
trace
trace
99[d]
N
9
KO-t-Bu PPh3
KO-t-Bu PPh3
KO-t-Bu PPh3
10
11
12
13
14
15
16
17
18
19
20
21
22
N
R
E
G
N
G
G
G
Scheme 2. Synthesis of the substrates.
Et2O
THF
dioxane
MeOH-
CH2Cl2
R
G
AHCTUNGTRENNUNG
Preliminary catalyst screening studies were per-
formed using methyl 2-acetylpent-4-ynoate 2a in
methanol at room temperature as a model reaction
(Table 1). No significant reaction was observed with-
out the addition of either CuACHTNUTRGNEUNG(OTf)2 or PPh3 (Table 1,
entries 1–3). The screenings of various assemblies of
strong bases and copper salts revealed a combination
of potassium tert-butoxide (10 mol%) and CuACTHUNRGTNEUNG(OTf)2
(0.5 mol%) in the presence of triphenylphosphine
(2 mol%) provided the best yield for the reaction
[a]
Reaction conditions: unless otherwise noted, [Cu]
(0.5 mol%), PPh3 (2 mol%), 2a (0.2 mmol) and KO-t-Bu
(10 mol%) stirred in solvent (0.2 mL) at room tempera-
ture for 0.5 h.
Isolated yield after flash column chromatography.
Product easily partly isomerized in MeOH.
MeOH/CH2Cl2 =1/1 (v/v).
[b]
[c]
[d]
(Table 1, entries 4–11). Further examination of vari- forded the corresponding 5-methylene-4,5-dihydrofur-
ous solvents showed that MeOH/CH2Cl2 (1/1 v/v) was ans in high yields. The results indicated that 2-propyn-
the most effective solvent for the reaction (Table 1, yl-1,3-dicarbonyl compounds without substitution or
entries 12–22). Although methanol was also a suitable with para or meta electron-withdrawing groups on the
solvent for the reaction, it was found that the product phenyl ring could be rapidly converted to correspond-
partly isomerized in it (Table 1, entry 4). Thus, the in- ing 5-methylene-4,5-dihydrofurans in excellent yields
tramolecular cyclization reaction of methyl 2-acetyl- (Table 2, entries 3, 6, 7, 8, 11, 12 and 17). The reaction
pent-4-ynoate (2a) could be completed smoothly was also efficient for 2-propynyl-1,3-dicarbonyl com-
within 30 min in the presence of KO-t-Bu (10 mol%), pounds with para or meta electron-donating groups
Cu
MeOH/CH2Cl2 (1/1 v/v) as the solvent at room tem- Meanwhile, substrates possessing ortho groups on the
perature in excellent yield. phenyl ring were also successfully employed to give 5-
ACHTUNGTRENNUNG(OTf)2 (0.5 mol%) and PPh3 (2 mol%) using on the phenyl ring (Table 2, entries 4, 5, 9 and 10).
Under these optimized conditions, the scope of re- methylene-4,5-dihydrofuran compounds in good
action was then explored. Typical results are shown in yields (Table 2, entries 13–16). For the heteroaromatic
Table 2. For the aliphatic 2-propynyl-1,3-dicarbonyl compound 2r, the reaction was effectively carried out
compounds, the reaction gave excellent yields in excellent yield (Table 2, entry 18). However, the re-
(Table 2, entries 1 and 2). In general, the reaction for action of 2s (R1 =R2 =phenyl) provided a complex
all aromatic 2-propynyl-1,3-dicarbonyl compounds af- mixture under the optimized conditions. It was found
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Base- and Copper-Catalyzed Intramolecular Cyclization for the Direct Synthesis of Dihydrofurans
Table 2. The synthesis of 5-methylene-4,5-dihydrofurans
from various 2-propynyl-1,3-dicarbonyl compounds: the
scope of substrates.
Table 3. The synthesis of substituted 5-methylene-4,5-dihy-
drofurans.[a]
Entry
R
2
Time [h]
3
Yield [%]
Entry R1
R2
Time [h]
3
Yield [%][d]
1
2
3
4
5
phenyl
p-CH3CO-C6H5 2u
p-CH3-C6H5
ethyl
2t
6
3
12
3t
3u
3v
84
90
80
1
CH3
OMe
OMe
OMe
OMe
0.5
0.5
0.5
2.0
5.0
0.5
0.5
0.5
2.0
2.0
1.5
1.0
2.0
2.0
1.0
1.5
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
99[a]
99[a]
99[a]
95[b]
83[b]
99[a]
99[a]
99[a]
95[b]
90[b]
99[a]
99[a]
88[b]
85[b]
95[b]
91[b]
99[a]
99[a]
90[c]
2
3
n-C3H7
Ph
2v
2w 12
2x 12
3w trace
2x trace
4
p-CH3-C6H5
n-propyl
5
p-CH3O-C6H5 OMe
[a]
Reaction conditions: CuACHTNUGTRNEUNG(OTf)2 (5 mol%), PPh3 (20
6
p-F-C6H5
OMe
OMe
OMe
OMe
mol%), 2 (0.2 mmol) and KO-tBu (10 mol%) stirred in
MeOH/CH2Cl2 (1/1, 0.2 mL) at room temperature.
7
8
9
p-Cl-C6H5
p-Br-C6H5
m-CH3-C6H5
10
11
12
13
14
15
16
17
18
19
m-CH3O-C6H5 OMe
on the phenyl ring, like a methyl group, could also be
converted into the corresponding dihydrofuran with a
longer time (entry 3, Table 3). However, for 1,3-dicar-
bonyl compounds bearing an internal alkyne with ali-
phatic substituted groups (ethyl and n-propyl), the re-
action could not be carried out effectively under
these catalytic conditions (entries 4 and 5, Table 3).
Referring to the related literature,[8] the proposed
mechanism for the reaction is shown in Figure 1.
First, under base catalysis, the enol anion is rapidly
generated from 2. Meanwhile, the coordination of the
carbon-carbon triple bond of 2 to [Cu]2+ activated by
the ligand (PPh3) enhances the electrophilicity of the
alkyne. Subsequently, the intramolecular cyclization
reaction proceeds through the nucleophilic addition
of the enolate oxygen anion to the electron-deficient
alkyne moiety to form a vinyl-copper adduct. Finally,
the adduct undergoes protodemetallation to give the
observed 5-methylene-4,5-dihydrofuran product 3.
Additionally, in the process of the examination of
m-Cl-C6H5
m-Br-C6H5
o-CH3-C6H5
OMe
OMe
OMe
o-CH3O-C6H5 OMe
o-F-C6H5
o-Cl-C6H5
m-Cl-C6H5
2-furyl
OMe
OMe
OC2H5 1.0
OMe
Ph
1.0
2.0
Ph
s
[a]
[b]
[c]
[d]
CuACHTUNGTRENNUNG(OTf)2 (0.5 mol%), PPh3 (2 mol%), 2 (0.2 mmol) and
KO-t-Bu (10 mol%) stirred in MeOH/CH2Cl2 (1/1, v/v,
0.2 mL) at room temperature.
CuACHTUNGTRENNUNG(OTf)2 (1 mol%), PPh3 (4 mol%), 2 (0.2 mmol) and
KO-t-Bu (10 mol%) stirred in MeOH/CH2Cl2 (1/1, v/v,
0.2 mL) at room temperature.
CuACHTUNGTRENNUNG(OTf)2 (0.5 mol%), PPh3 (2 mol%), 2 (0.2 mmol) and
KO-t-Bu (10 mol%) stirred in MeOH/CH2Cl2 (1/1, v/v,
0.2 mL) at 08C.
Isolated yield after flash column chromatography.
later that the desired product 3s could be obtained in various solvents for the reaction, we found that the
good yield when the reaction temperature was de- product 3a was partly isomerized to the substituted
creased to 08C (Table 2, entry 19).
furan 4a in methanol in a long reaction time. Further-
Next, in order to extend the generality of our more, some substituted furans are also useful and ver-
method, the scope of this cyclization reaction was ex- satile intermediates in synthetic organic chemistry.[10]
plored further with 1,3-dicarbonyl compounds bearing As a consequence, many methodologies have been re-
an internal alkyne. Firstly, the cyclization of methyl 2- ported for the synthesis of furan derivatives.[11] The
acetyl-5-phenylpent-4-ynoate was studied (entry 1, most important strategies involving metal-catalyzed
Table 3). However, under the optimized conditions, cyclization of suitable precursors such as enynols, ep-
the rate of the reaction was very slow. Fortunately, oxyalkynes, ketoalkynes or ketoallenes, and
when the amount of catalysts was increased, the cycli- others.[11a–e] Nishizawa reported the Hg
ACTHUNTRGNE(UGN OTf)2-cata-
zation reaction could be smoothly carried out in good lyzed ketoalkyne cyclization leading to 2-methylfur-
yield. For the 1,3-dicarbonyl compound with para ans.[11x] Wipf, Dixneuf and co-workers reported a Pd-
electron-withdrawing groups on the phenyl ring, like catalyzed cyclization reaction to afford substituted
a CH3CO group, the reaction was effectively per- furans.[11f,i,w] Cadierno found a highly efficient rutheni-
formed in good yield (entry 2, Table 3). The 1,3-dicar- um-catalyzed method for the preparation of substitut-
bonyl compound with a para electron-donating group ed furans from secondary propargylic alcohols and
Adv. Synth. Catal. 2010, 352, 1163 – 1168
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Yong-Fei Chen et al.
FULL PAPERS
Figure 1. Proposed mechanistic pathway.
Table 4. Dihydrofuran isomerisation studies.[a]
pounds), an inexpensive catalyst (Cu2+ salt) and
ligand (PPh3) under very mild basic conditions in
good to excellent yields. Furthermore, the reaction ex-
hibited excellent functional group compatibility. Fur-
thermore, 5-methylene-4,5-dihydrofurans could be
easily converted into the corresponding furans under
acidic conditions. Future studies will focus on the de-
velopment of related transformations, and the appli-
cation of this methodology towards the synthesis of
natural products containing the dihydrofuran or furan
moiety.
Entry
3
4
Yield [%]
1
2
3
4
3b
3c
3d
3g
b
c
d
g
80
85
80
88
Experimental Section
[a]
General Remarks
3 (0.2 mmol) and F3CCOOH (20 mol%) stirred in dry
MeOH (3 mL) at room temperature for 24 h.
All reactions were performed under an air atmosphere
1
unless otherwise stated. All H and 13C NMR spectra were
recorded using Bruker 400 MHz and 75 MHz spectrometers.
Chemical shifts (d) are given in ppm, and coupling constants
(J) are given in Hertz (Hz). HR-MS were performed on a
Bruker Apex II mass instrument (ESI). MS were measured
on a VG-7070E spectrometer (EI at 70 eV); IR spectra
were recorded using a Nicolet NEXUS 670 FT-IR instru-
ment.
1,3-dicarbonyl compounds, etc.[12a] Encouraged by
these results, we tried to transform 5-methylene-4,5-
dihydrofurans into the corresponding furans via the
addition of an acid.[12] To our delight, 5-methylene-
4,5-dihydrofurans could be smoothly converted into
the corresponding furans in the presence of
CF3COOH in dry MeOH at room temperature within
24 h in good yields (Table 4, entries 1–4).
General Procedure for the Synthesis of Starting
Materials 2a–x
Conclusions
Under an argon atmosphere, propargyl bromide (5.1 mmol)
was added to a solution of 1 (5 mmol) and DBU (5.1 mmol)
in benzene (15 mL) and the solution was stirred at room
temperature for 24 h. After filtering off the DBU-HBr salt,
the solvent was evaporated and the residue was purified by
column chromatography (petroleum ether/ethyl acetate=
In summary, a general and highly efficient synthetic
method for substituted 5-methylene-4,5-dihydrofuran
compounds has been developed. This intramolecular
cyclization reaction was performed using readily
available materials (2-propynyl-1,3-dicarbonyl com- 1/20, v/v) to afford the desired products 2.
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Base- and Copper-Catalyzed Intramolecular Cyclization for the Direct Synthesis of Dihydrofurans
The product 2a (70%) was isolated as a colourless oil
after column chromatography. IR (KBr): n=3288, 2957,
m/z (rel. intensity, %)=230 (M+, 5.95), 215 (4.05), 128
(12.43), 105 (21.66); HR-MS (ESI): m/z=253.0833, calcd.
2926, 2122, 1745, 1718, 1435, 1361, 1154, 657 cmÀ1; H NMR
for C14H14O3Na [M+Na]+: 253.0835.
1
(400 MHz, CDCl3): d=3.77 (s, 3H), 3.73 (t, J=7.6 Hz, 1H),
2.72 (m, 2H), 2.31 (s, 3H), 2.02 (t, J=2.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=200.85, 168.47, 80.23,
70.26, 57.97, 52.65, 29.52, 17.38; MS (EI): m/z (rel. intensity,
%)=154 (0.44), 139 (33.80), 123 (1.27), 95 (1.83), 43
(100.00).
General Procedure for the Synthesis of 2,3,5-
Trisubstituted Furan compounds 4b, c, d, g
The compound 3 (0.2 mmol) was dissolved in dry MeOH
(3 mL). F3CCOOH (20 mol%) was added to the solution
and the reaction mixture was stirred at room temperature
for 24 h. The reaction was quenched with saturated aqueous
NaHCO3 solution. The crude product was purified by flash
column chromatography to afford the desired product 4.
The product 4b (yield: 80%) was isolated as a colourless
oil after flash chromatography. IR (KBr): n=2960, 1719,
Compounds 2b–2s could be synthesized via a similar
method. The propargyl bromide was replaced by other sub-
stituted propargyl bromide, and 2t–2x could be obtained.
The product 2t (yield: 63%) was isolated as a colourless
oil after column chromatography. IR (KBr): n=2954, 1745,
1719, 1490, 1437, 1358, 1272, 1224, 1152, 759, 693 cmÀ1
;
1584, 1439, 1386, 1239, 1207, 1094, 1053, 779 cmÀ1; H NMR
1
1H NMR (400 MHz, CDCl3): d=7.37 (m, 2H), 7.29 (m,
3H), 3.81 (t, J=7.6 Hz, 1H), 3.80 (s, 3H), 2.96 (dd, J=7.6,
2.0 Hz, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
201.33, 168.75, 131.60, 128.21, 128.03, 123.07, 85.59, 82.47,
58.28, 52.74, 29.69, 18.53.
(400 MHz, CDCl3): d=6.19 (d, J=0.8 Hz, 1H), 3.79 (s, 3H),
2.91 (t, J=7.6 Hz, 2H), 2.24 (d, J=0.8 Hz, 3H), 1.68 (m,
2H), 0.94 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=164.72, 161.72, 149.96, 113.37, 106.05, 51.11, 29.43, 21.52,
13.73, 23.23; MS (EI): m/z (rel. intensity, %)=182 (M+,
29.79), 167 (9.49), 153 (82.74), 151 (13.39), 123 (23.87), 43
(100.00); HR-MS (ESI): m/z=183.1017, calcd. for C10H15O3
[M+H]+: 183.1021; HR-MS (ESI): m/z=183.1016, calcd. for
C10H15O3 [M+H]+: 183.1017.
General Procedure for the Synthesis of 5-Methylene-
4,5-dihydrofuran Compounds 3a–s
A
mixture of CuACTHUNGTERN(NUG OTf)2 (0.001 mmol) and PPh3
(0.004 mmol) in dry MeOH/CH2Cl2 (1/1, v/v, 0.2 mL) was
stirred for 10 min. Substrate 2 (0.2 mmol) and KO-t-Bu
(0.02 mmol) were added and the reaction mixture was
stirred at room temperature. After the completion of the re-
action (monitored by TLC), the reaction mixture was direct-
ly loaded onto a silica gel column and eluted with petroleum
ether/ethyl acetate/triethylamine (100:2:1) to afford the de-
sired product 3.
Acknowledgements
We are grateful for the financial support of “973” project
from the MOST (2009CB626604), the Foundation (20772051,
20972058) from NSFC, the “111” program from MOE of
P.R. China.
The product 3a (yield: 99%) was isolated as a colourless
oil after flash chromatography. IR (KBr): n=2925, 2855,
1725, 1651, 1438, 1119, 1074, 1026, 723 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=4.63 (dd, J=5.6, 3.2 Hz, 1H), 4.28
(dd, J=5.2, 2.8 Hz, 1H), 3.74 (s, 3H), 3.57 (dt, J=2.8,
2.0 Hz, 2H), 2.27 (t, J=2.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=166.04, 165.15, 159.81, 103.72, 85.95, 51.06,
33.33, 13.60; MS (EI): m/z (rel. intensity, %)=154 (M+,
100.00), 139 (67.14), 123 (62.97), 95 (62.18); HR-MS (ESI):
m/z=155.0703, calcd. for C8H11O3 [M+H]+: 155.0701.
References
[1] For selected examples, see: a) F. M. Dean, in: Advances
in Heterocyclic Chemistry, (Ed.: A. R. Katritzky), Aca-
demic Press, New York, 1982, Vol. 30, pp 167–238;
b) F. M. Dean, M. V. Sargent, in: Comprehensive Heter-
ocyclic Chemistry, (Eds.: C. W. Bird, G. W. H. Cheese-
man), Pergamon Press, New York, 1984, Vol. 4, part 3,
pp 531–598; c) B. H. Lipshutz, Chem. Rev. 1986, 86,
795–819; d) J. Lee, J.-H. Li, S. Oya, J. K. Snyder, J.
Org. Chem. 1992, 57, 5301–5312; e) P. A. Jacobi, H. G.
Selnick, J. Org. Chem. 1990, 55, 202–209; f) S. Schab-
bert, E. Schaumann, Eur. J. Org. Chem. 1998, 1873–
1878; g) P. F. Schuda, Top. Curr. Chem. 1980, 91, 75–
111; h) G. Hoffmann, R. K. Johnson, J. Nat. Prod. 1993,
56, 1500–1505; i) J. P. Michael, Nat. Prod. Rep. 2000,
17, 603–620; j) M. F. Grundon, Nat. Prod. Rep. 1990, 7,
131–138; k) J. P. Michael, Nat. Prod. Rep. 1997, 14,
605–618; l) T. G. Kilroy, T. P. OꢀSullivan, P. J. Guiry,
Eur. J. Org. Chem. 2005, 4929–4949; m) D. A. Evans,
Z. K. Sweeney, T. Rovis, J. S. Tedrow, J. Am. Chem.
Soc. 2001, 123, 12095–12096; n) R. L. Danheiser, E. J.
Stoner, H. Kojama, D. S. Yamashita, C. A. Klade, J.
Am. Chem. Soc. 1989, 111, 4407–4413; o) B. M. Fraga,
Nat. Prod. Rep. 1992, 9, 217–241; p) A. T. Merrit, S. V.
Ley, Nat. Prod. Rep. 1992, 9, 243–287.
Typical Procedure for the Synthesis of Substituted 5-
Methylene-4,5-dihydrofuran Compounds 3t–v
A mixture of CuACHTUNGTRENNUNG(OTf)2 (0.01 mmol) and PPh3 (0.04 mmol)
in dry MeOH/CH2Cl2 (1/1, v/v, 0.2 mL) was stirred for
10 min. Substrate 2t (0.2 mmol) and KO-t-Bu (0.02 mmol)
were added and the reaction mixture was stirred at room
temperature. After the completion of the reaction (moni-
tored by TLC), the reaction mixture was directly loaded
onto a silica gel column and eluted with petroleum ether/
ethyl acetate/triethylamine (100/2/1, v/v) to afford the de-
sired product 3t (yield: 84%) as a white solid. IR (KBr): n=
2952, 2924, 1717, 1695, 1656, 1442, 1232, 1086, 987, 698 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.52 (d, J=7.6 Hz, 2H),
7.31 (dd, J=8.0, 7.2 Hz, 2H), 7.16 (t, J=7.6 Hz, 1H), 5.57
(s, 1H), 3.75 (s, 5H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=165.98, 165.07, 153.11, 134.90, 128.32, 127.72,
125.94, 103.87, 102.59, 51.17, 35.12, 13.81; MS (EI, 70 eV):
Adv. Synth. Catal. 2010, 352, 1163 – 1168
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1167

Yong-Fei Chen et al.
FULL PAPERS
[2] For selected papers, see: a) A. Arcadi, S. D. Giuseppe,
F. Marinelli, E. Rossi, Adv. Synth. Catal. 2001, 343,
443–446; b) X. Du, F. Song, Y. Lu, H. Chen, Y. Liu,
Tetrahedron 2009, 65, 1839–1845; c) C.-P. Chuang, K.-
P. Chen, Y.-L. Hsu, A.-I. Tsai, S.-T. Liu, Tetrahedron
2008, 64, 7511–7516; d) E. V. Burgaz, M. Yılmaz, A. T.
Pekel, A. ꢂktemer, Tetrahedron 2007, 63, 7229–7239.
[3] For selected papers, see: a) B. M. Trost, Y. H. Rhee, J.
Am. Chem. Soc. 2003, 125, 7482–7483; b) F. E. McDo-
nald, C. B. Connolly, M. M. Gleason, T. B. Towne, K. D.
Treiber, J. Org. Chem. 1993, 58, 6952–6953; c) Y.
Deng, J. Li, S. Ma, Chem. Eur. J. 2008, 14, 4263–4266;
d) B. Alcaide, P. Almendros, T. M. del Campo, Angew.
Chem. 2006, 118, 4613–4616; Angew. Chem. Int. Ed.
2006, 45, 4501–4504; e) S. Kima, P. H. Lee, Adv. Synth.
Catal. 2008, 350, 547–551; f) ꢂ. Aksi˛n, N. Krause, Adv.
Synth. Catal. 2008, 350, 1106–1112; g) Y. Liu, F. Song,
M. Liu, B. Yan, Org. Lett. 2005, 7, 5409–5412; h) R. K.
Bowman, J. S. Johnson, Org. Lett. 2006, 8, 573–576;
i) Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. Hidai,
S. Uemura, J. Org. Chem. 2004, 69, 3408–3412.
[7] a) Y. Fang, C. Li, Chem. Commun. 2005, 3574–3576;
b) S. Son, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 1046–
1047.
[8] H.-F. Wang, T. Yang, P.-F. Xu, D. Dixon, Chem.
Commun. 2009, 3916–3918.
[9] N. Ono, T. Yoshimura, R. Tanikaga, A. Kaji, Chem.
Lett. 1977, 6, 871–872.
[10] For selected papers, see: a) X. L. Hou, Z. Yang,
H. N. C. Wong, in: Progress in Heterocyclic Chemistry,
(Eds.: C. W. Gribble, T. L. Gilchrist), Pergamon Press,
Oxford, 2003, Vol. 15, pp 167–205; b) W. Friedrichsen,
in: Comprehensive Heterocyclic Chemistry II, (Eds.:
A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Perga-
mon Press, Oxford, 1996, Vol. 2, pp 351–393; c) R. Be-
nassi, in: Comprehensive Heterocyclic Chemistry II,
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven),
Pergamon Press, Oxford, 1996, Vol. 2, pp 259–295.
[11] For selected papers, see: a) A. S. K. Hashmi, P. Sinha,
Adv. Synth. Catal. 2004, 346, 432–438; b) J. A. Mar-
shall, E. D. Robinson, J. Org. Chem. 1990, 55, 3450–
3451; c) A. S. K. Hashmi, L. Schwarz, J. H. Choi, T. M.
Frost, Angew. Chem. 2000, 112, 2382–2385; Angew.
Chem. Int. Ed. 2000, 39, 2285–2288; d) Y. Fukuda, H.
Shiragami, K. Utimoto, H. Nozaki, J. Org. Chem. 1991,
56, 5816–5819; e) B. Seiller, C. Bruneau, P. H. Dixneuf,
Tetrahedron 1995, 51, 13089–13102; f) P. Wipf, M. J.
Soth, Org. Lett. 2002, 4, 1787–1790; g) J. A. Marshall,
D. Zou, Tetrahedron Lett. 2000, 41, 1347–1350; h) D. I.
MaGee, J. D. Leach, Tetrahedron Lett. 1997, 38, 8129–
8132; i) P. Wipf, L. T. Rahman, S. R. Rector, J. Org.
Chem. 1998, 63, 7132–7133; j) B. Sieller, C. Bruneau,
P. H. Dixneuf, J. Chem. Soc. Chem. Commun. 1994,
493–494; k) B. Gabriele, G. Salerno, F. De Pascali, M.
Costa, G. P. Chiusoli, J. Org. Chem. 1999, 64, 7693–
7699; l) N. Asao, T. Nogami, K. Takahashi, Y. Yama-
moto, J. Am. Chem. Soc. 2002, 124, 764–765; m) A.
Arcadi, S. Cacchi, R. C. Laroek, F. Marinelli, Tetrahe-
dron Lett. 1993, 34, 2813–2816; n) S. Cacchi, G. Fabrizi,
L. Moro, J. Org. Chem. 1997, 62, 5327–5332; o) A.
Arcadi, G. Cerichelli, M. Chiarini, S. D. Giuseppe, F.
Marinelli, Tetrahedron Lett. 2000, 41, 9195–9198; p) A.
Arcadi, G. Cerichelli, M. Chiarini, S. D. Giuseppe, F.
Marinelli, Tetrahedron Lett. 2000, 41, 9195–9198;
q) J. A. Marshall, X.-J. Wang, J. Org. Chem. 1991, 56,
960–969; r) J. A. Marshall, G. S. Bartley, J. Org. Chem.
1994, 59, 7169–7171; s) J. A. Marshall, X.-J. Wang, J.
Org. Chem. 1992, 57, 3387–3396; t) S. M. Ma, J. L.
Zhang, L. H. Lu, Chem. Eur. J. 2003, 9, 2447–2456;
u) J. Tsuji, H. Watanabe, I. Minami, I. Shimizu, J. Am.
Chem. Soc. 1985, 107, 2196–2198; v) X. H. Duan, X.-Y.
Liu, L.-N. Guo, M.-N. Liao, W.-M. Liu, Y.-M. Liang, J.
Org. Chem. 2005, 70, 6980–6983; w) M. Picquet, C.
Bruneau, P. H. Dixneuf, Tetrahedron 1999, 55,3937–
3948; x) H. Imagawa, T. Kurisaki, M. Nishizawa, Org.
Lett. 2004, 6, 3679–3681.
[4] For selected papers, see: a) F. Himo, T. Lovell, R. Hil-
graf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless,
V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210–216;
b) H. Isobe, K. Cho, N. Solin, D. B. Werz, P. H. See-
berger, E. Nakamura, Org. Lett. 2007, 9, 4611–4614;
c) A. Klapars, S. Parris, K. W. Anderson, S. L. Buch-
wald, J. Am. Chem. Soc. 2004, 126, 3529–3533; d) L.
Ackermann, H. K. Potukuchi, D. Landsberg, R. Vice-
nte, Org. Lett. 2008, 10, 3081–3084; e) D. Ma, Q. Cai,
ˇ
Acc. Chem. Res. 2008, 41, 1450–1460; f) A. V. Kelin,
A. W. Sromek, V. Gevorgyan, J. Am. Chem. Soc. 2001,
123, 2074–2075.
[5] For selected papers, see: a) I. P. Beletskaya, A. V. Che-
prakov, Coord. Chem. Rev. 2004, 248, 2337–2364; b) G.
Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108,
3054–3131; c) F. Monnier, M. Taillefer, Angew. Chem.
2008, 120, 3140–3143; Angew. Chem. Int. Ed. 2008, 47,
3096–3099.
[6] For selected papers, see: a) J. Zhu, H. Xie, Z. Chen, S.
Li, Y. Wu, Chem. Commun. 2009, 2338–2340; b) L. Li,
M. Wang, X. Zhang, Y. Jiang, D. Ma, Org. Lett. 2009,
11, 1309–1312; c) A. K. Verma, T. Kesharwani, J.
Singh, V. Tandon, R. C. Larock, Angew. Chem. 2009,
121, 1158–1163; Angew. Chem. Int. Ed. 2009, 48, 1138–
1143; d) Y. Ohta, H. Chiba, S. Oishi, N. Fujii, H. Ohno,
Org. Lett. 2008, 10, 3535–3538; e) Y. , Chen, Y. Wang,
Z. Sun, D. Ma, Org. Lett. 2008, 10, 625–628; f) R. D.
Viirre, G. Evindar, R. A. Batey, J. Org. Chem. 2008, 73,
3452–3459; g) B. Zou, Q. Yuan, D. Ma, Angew. Chem.
2007, 119, 2652–2655; Angew. Chem. Int. Ed. 2007, 46,
2598–2601; h) R. Martin, A. Cuenca, S. L. Buchwald,
Org. Lett. 2007, 9, 5521–5524; i) Zheng, Buchwald,
S. L. , Org. Lett. 2007, 9, 4749–4751; j) N. B. Zou, Q.
Yuan, D. Ma, Org. Lett. 2007, 9, 4291–4294; k) M. R.
Rivero, S. L. Buchwald, Org. Lett. 2007, 9, 973–976;
l) R. Martꢃn, M. R. Rivero, S. L. Buchwald, Angew.
Chem. 2006, 118, 7237–7240; Angew. Chem. Int. Ed.
2006, 45, 7079–7082; m) X. Lv, W. Bao, J. Org. Chem.
2009, 74, 5618–5621.
[12] a) V. Cadierno, J. Gimeno, N. Nebra, Adv. Synth. Catal.
2007, 349, 382–394; b) B. Gabriele, G. Salerno, E.
Lauria, J. Org. Chem. 1999, 64, 7687–7692; c) X. Han,
R. A. Widenhoefer, J. Org. Chem. 2004, 69, 1738–1740.
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1163 – 1168