Copper-catalyzed intramolecular hydroalkoxylation of α-(1-hydroxy-1- alkyl-and-aryl)methylallenoates by a 5-endo mode for preparation of 2-alkyl- and 2-aryl-2,5-dihydrofurans

Article abstract of DOI:10.1021/jo2018125

Ethyl α-(1-hydroxy-1-alkyl)methylallenoates and α-(1-hydroxy-1- aryl)methylallenoates containing not only electron-donating groups but also an electron-withdrawing group on the aryl group at the α-position have been shown to undergo an efficient and selec

Full text of DOI:10.1021/jo2018125

Article
pubs.acs.org/joc
Copper-Catalyzed Intramolecular Hydroalkoxylation of α-(1-
Hydroxy-1-alkyl- and -aryl)methylallenoates by a 5-Endo Mode for
Preparation of 2-Alkyl- and 2-Aryl-2,5-dihydrofurans
Sanghyuck Kim and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: Ethyl α-(1-hydroxy-1-alkyl)methylallenoates and α-(1-hy-
droxy-1-aryl)methylallenoates containing not only electron-donating groups
but also an electron-withdrawing group on the aryl group at the α-position
have been shown to undergo an efficient and selective copper-catalyzed
intramolecular hydroalkoxylation to give functionalized 3-ethoxycarbonyl-2-
alkyl- and -aryl-2,5-dihydrofurans in good to excellent yields through a 5-
endo mode.
Scheme 1. Cu-Catalyzed Intramolecular Hydroalkoxylation
by a Selective 5-Endo Mode
INTRODUCTION
■
2,5-Dihydrofurans are important heterocycles that are widely
used in pharmaceuticals and as flavor and fragrance
compounds1 and are found in naturally occurring and
biologically important molecules.2 Accordingly, substantial
attention has been given to developing efficient methods for
the synthesis of 2,5-dihydrofurans. Consequently, the develop-
ment of synthetic approaches of functionalized 2,5-dihydrofur-
ans is of major interest.3 Krause et al. reported a highly efficient
and stereoselective synthesis of 2,5-dihydrofurans by gold-
catalyzed intramolecular hydroalkoxylation of α-hydroxyallenes
by a 5-endo mode (Scheme 1, eq 1).4
In contrast with Krause’s results,4 we recently demonstrated
that α-hydroxyallenes possessing electron-donating groups on
the phenyl ring at the α-position were cyclized to produce ethyl
2-naphthoate derivatives through a gold-catalyzed selective
intramolecular hydroarylation by a 6-endo mode followed by
dehydration (eq 2).5 Because the major consideration in
transition metal-catalyzed reactions is selectivity, control of
reaction pathway between 2,5-dihydrofurans and ethyl 2-
naphthoates depending on metal catalyst is of synthetic
importance and is a very challenging problem. Herein, we
report the conversion of functionalized α-hydroxyallenes into
the corresponding 2,5-dihydrofurans in good to excellent yields
through a selective 5-endo mode by using 10 mol % of
copper(II) chloride as the catalyst (eq 3).6
Although the gold-catalyzed intramolecular hydroalkoxyla-
tion is mild and efficient,4,8 a method using a widely available
transition-metal catalyst instead of an expensive catalyst would
be advantageous. Accordingly, intramolecular hydroalkoxylation
of α-hydroxyallenes that selectively produce 2,5-dihydrofurans
with more available copper catalysts was examined. The results
are summarized in Table 1. The treatment of 1a with 10 mol %
RESULTS AND DISCUSSION
■
First, the functionalized α-hydroxyallenes with an electron-
donating group and an electron-withdrawing group on the
aromatic ring at the α-position were selectively prepared by the
treatment of a wide range of aldehydes with organoindium
reagent generated in situ from indium and ethyl 4-
bromobutynoate (Scheme 2).5,7
Received: September 1, 2011
Published: November 21, 2011
© 2011 American Chemical Society
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of 1b with 5 mol % of Ph3PAuCl and 5 mol % of AgOTf
provided ethyl 5-hydroxy- and 7-hydroxy-2-naphthoate (3) in
76% yield (isomeric ratio = 1:3.2) through an intramolecular
hydroarylation by a 6-endo mode followed by dehydration and
2b (21% yield) through an intramolecular hydroalkoxylation by
a 5-endo mode (Scheme 3).
Scheme 2. Preparation of α-Hydroxyallenes
of CuCl and CuI in DMF (110 °C, 2 h) produced 3-
ethoxycarbonyl-2-phenyl-2,5-dihydrofuran (2a) in 32% and
30% yields, respectively, through a selective intramolecular
hydroalkoxylation by a 5-endo mode (entries 1 and 3). The use
of CuBr in DMF increased the product yield to 59% (entry 2).
Addition of triethylamine to reaction mixture as an additive did
not affect the efficiency of the cyclization (entries 2 and 4 and
entries 9 and 11). Although a variety of solvents (CH2Cl2,
THF, and toluene) with triethylamine were examined, none of
these solvents gave the desired cyclized product (entries 6−8).
However, DMA gave similar result (58% yield) to DMF (entry
5). Next, different copper(II) halides were examined. The
desired product 2a was obtained in 74% yield with 10 mol % of
copper(II) bromide and chloride (entries 9 and 10). Of the
reactions screened, the best result was obtained with the
treatment of 1a with 5 mol % of copper(II) chloride in DMF at
110 °C for 2 h under a nitrogen atmosphere, producing
selectively 2a in 82% yield by a 5-endo mode (entry 13). Two
mol % of copper(II) acetate produced 2a in 40% yield (entry
15). When 1a was treated with 5 mol % of CuCl2 (purity
99.999%) in DMF at 110 °C for 2 h, the desired product was
obtained in 71% yield.9 Therefore, the present cyclization
proceeded by the copper salt that is the real catalyst. In the case
of vinyl group instead of ethoxycarbonyl group, 2-phenyl-4-
vinyl-2,5-dihydrofuran was obtained in 44% yield in DMF at
110 °C for 2 h, indicating that ethoxycarbonyl group is
important but it is not necessary in cyclization.
Scheme 3. Cu-Catalyzed Intramolecular Hydroalkoxylation
by Selective 5-Endo Mode
However, surprisingly, reaction of 1b with 5 mol % of
copper(II) chloride selectively produced 2,5-dihydrofuran (2b)
in 85%. Next, α-hydroxyallene 1c and 1d having a 2- and 3-
methoxyphenyl group at the α-position was treated with 5 mol
% of copper(II) chloride, affording selectively 2,5-dihydrofuran
(2c and 2d) in 65% and 80% yields, respectively (Table 2,
entries 1 and 2). Although elimination followed by Michael
reaction of hydroxy group due to instability of 1e gave ethyl 2-
acetyl-3-methoxyphenylpropenoate in 30% yield, intramolecu-
larly hydroalkoxylated product 2e was obtained in 44% yield
without contamination of naphthoate (entry 3). A wide range
of an α-hydroxyallene having phenyl group containing fluoro
and methoxy substituent at the α-position was treated with 5
mol % of CuCl2 in DMF for 110 °C produced selectively 2,5-
dihydrofuran derivatives (2f, 2g, 2h, and 2i) in ca. 60% yields
through 5-endo-dig mode (entries 4−7). In contrast with using
With these results in hand, the intramolecular hydro-
alkoxylation of an α-hydroxyallene tethering oxygen atom
having nonbonding electron such as methoxy or hydroxy on the
phenyl group at the α-position was investigated. The treatment
Table 1. Optimization of Cu-Catalyzed Intramolecular Hydroalkoxylation
entry
cat.
solvent
temp (°C)
time (h)
yield (%)
1
2
10 mol % CuCl
10 mol % CuBr
10 mol % CuI
DMF
DMF
DMF
DMF
DMA
CH2Cl2
THF
110
110
110
110
130
40
2
2
2
2
2
6
6
6
2
2
2
2
2
2
2
32
59
30
3
a
4
10 mol % CuBr
10 mol % CuBr
10 mol % CuBr
10 mol % CuBr
10 mol % CuBr
10 mol % CuBr2
10 mol % CuCl2
10 mol % CuBr2
5 mol % CuBr2
5 mol % CuCl2
2 mol % CuCl2
2 mol % Cu(OAc)2
61
a
5
58
a
6
0
a
7
80
0
a
8
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
110
110
110
0
9
74
74
10
11
12
13
14
15
a
52
63
82
76
40
a
Et3N (20 mol %) was added.
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optimum reaction conditions, a wide range of α-hydroxyallenes
underwent selective intramolecular hydroalkoxylation through a
5-endo mode without any intramolecular hydroarylation by a 6-
endo mode (Table 3). The treatment of the n-propyl-
Table 2. Cu-Catalyzed Intramolecular Hydroalkoxylation of
α-Hydroxyallenes Having Methoxy on the Aryl Group by a
5-Endo Mode
Table 3. Cu-Catalyzed Intramolecular Hydroalkoxylation by
a 5-Endo Mode
substituted α-hydroxyallene 1m with 5 mol % of copper(II)
chloride gave 2,5-dihydrofuran 2m in 78% yield (entry 1).
Phenethyl-substituted α-hydroxyallene 1n and cyclohexyl-
substituted α-hydroxyallene 1o were subjected to a selective
intramolecular hydroalkoxylation under the above conditions,
producing 2n and 2o in 77% and 86% yields, respectively
(entries 2 and 3). We were pleased to obtain halophenyl-3-
ethoxycarbonyl-2,5-dihydrofurans 2p and 2q selectively from
the reaction of 4-chlorophenyl α-hydroxyallene 1p and 2-
iodophenyl α-hydroxyallene 1q with copper catalyst (entries 4
and 5). α-Hydroxyallenes 1r, 1s, and 1t having electron-
withdrawing groups such as 4-acetyl, 4-ethoxycarbonyl, and 4-
nitro on the aryl ring turned out to be compatible with the
reaction conditions (entries 6−8). The present method worked
equally well even with 4-methyl and 2,4,6-trimethyl substituents
on the phenyl ring (entries 9 and 10).
a
b
Ethyl 2-acetyl-4-methoxyphenyl propenoate. Ratio of 2,5-dihydro-
furan and naphthaoate.
gold catalyst, exposure of 1k to 5 mol % of copper(II) chloride
provided 2,5-dihydrofuran 2k as major product (entry 9). We
were pleased to obtain 2l selectively in 72% yield through a 5-
endo mode from α-hydroxyallene 1l, which contains 3,4,5-
trimethoxyphenyl group (entry 10).
Next, the intramolecular hydroalkoxylation of an α-
hydroxyallene having an alkyl group at the α-position and a
wide range of electron-withdrawing or -donating group on the
phenyl ring at the α-position was examined. Under the
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The intramolecular hydroalkoxylation of 1a in DMF and
D2O gave rise to the corresponding deuterated product 2a in
80% yield with 56% d-incorporation, indicating that a
vinylcopper intermediate might be formed (Scheme 4). Based
synthesis of highly functionalized 2,5-dihdrofurans through a 5-
endo mode that eliminates the need to use an expensive catalyst.
In particular, the intramolecular hydroalkoxylation of α-
hydroxyallenes having electron-donating groups such as
methoxy and hydroxy on the aryl ring at the α-position
proceeded smoothly to produce 2,5-dihydrofurans selectively
without contamination of naphthoate through a 6-endo mode.
This method provides a valuable new way to synthesize a wide
range of functionalized 2,5-dihydrofuran derivatives.
Scheme 4. Deuterium Incorporation in Hydroalkoxylation
EXPERIMENTAL SECTION
■
General Methods for the Synthesis of Dihydrofurans. To a
solution of 5 mol % of copper chloride (2.02 mg, 0.015 mmol) in
DMF (1 mL) was added ethyl α-hydroxyallenoate 1 (0.3 mmol) under
nitrogen atmosphere. The reaction mixture was stirred at 110 °C. After
being stirred for 2 h, the reaction mixture was cooled to room
temperature and then filtered and concentrated under reduced
pressure. The residue was subjected to flash column chromatography
on silica gel (ethyl acetate/hexane = 1:10) to give the desired products
2.
on these results, we were also interested in the functionalization
at C-4 and envisioned that this might be possible through an in
situ trapping of the copper intermediate with an α,β-
unsaturated enone. Unfortunately, when the intramolecular
hydroalkoxylation was carried out in the presence of ethyl
acrylate and 5 mol % copper(II) chloride, only protonolysis
product (2a) was observed.
Although the mechanism of the present reaction has not
been established, a possible reaction mechanism for intra-
molecular Cu-catalyzed hydroalkoxylation is shown in Scheme
3-Ethoxycarbonyl-2-phenyl-2,5-dihydrofuran (2a). To a sol-
ution of 5 mol % of copper chloride (2.02 mg, 0.015 mmol) in DMF
(1 mL) under nitrogen atmosphere was added ethyl 2-(1-
hydroxybenzyl)buta-2,3-dienoate (63.0 mg, 0.3 mmol). The reaction
mixture was stirred at 110 °C. After being stirred for 2 h, the reaction
mixture was cooled to room temperature and then filtered and
concentrated under reduced pressure. The residue was subjected to
flash column chromatography on silica gel (ethyl acetate/hexane =
1:10) to give 3-ethoxycarbonyl-2-phenyl-2,5-dihydrofuran (51.0 mg,
1
82%): H NMR (400 MHz, CDCl) δ 7.35−7.27 (m, 5H), 7.01 (s,
1H), 5.94−5.91 (m, 1H), 5.02 (dd, J = 6.20 Hz, J = 6.2 Hz, 1H), 4.88
(d, J = 15.80 Hz, 1H), 4.15−4.06 (m, 2H), 1.16 (t, J = 7.09 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 162.3, 140.9, 138.3, 136.0, 128.3,
Scheme 5. Plausible Mechanism
128.2, 127.2, 87.0, 75.3, 60.6, 14.0; IR (film) 3431, 3054, 2987, 2123,
1716, 1421, 1265, 1108, 1056, 896 cm−1; HRMS (EI) m/z calcd for
C13H14O3 218.0943, found 218.0947.
3-Ethoxycarbonyl-2-(3-hydroxyphenyl)-2,5-dihydrofuran
(2b): 1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.86 Hz, 1H), 7.01
(s, 1H), 6.90 (d, J = 7.86 Hz, 1H), 6.79 (s, 1H), 6.74 (d, J = 7.86 Hz,
1H), 5.88−5.86 (m, 1H), 5.74 (s, 1H), 4.99 (dd, J = 6.05 Hz, J = 6.05
Hz, 1H), 4.86 (d, J = 15.88 Hz, 1H), 4.18−4.04 (m, 2H), 1.78 (s, 1H),
1.18 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9,
156.3, 142.7, 138.9, 136.1, 130.0, 119.8, 115.8, 114.6, 87.1, 75.7, 61.2,
14.4; IR (film) 3433, 2253, 1643, 1265, 907, 728, 650, 494 cm−1;
HRMS (EI) m/z calcd for C13H14O4 234.0892, found 234.0894.
3-Ethoxycarbonyl-2-(2-methoxyphenyl)-2,5-dihydrofuran
(2c): 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.03 Hz, 1H), 7.13
(dd, J = 1.65 Hz, J = 6.25 Hz, 1H), 7.05 (m, 1H), 6.91 (t, J = 7.82 Hz,
2H), 6.37 (m, 1H), 4.87 (dd, J = 15.78 Hz, J = 20.93 Hz, 2H), 4.09
(m, 2H), 3.86 (s, 3H), 1.14 (t, J = 7.06 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.9, 158.0, 139.5, 137.7, 135.4, 128.7, 120.9, 111.4, 81.5,
75.3, 60.9, 56.1, 14.4; IR (film) 2986, 2937, 2839, 1719, 1492, 1260,
1051, 754 cm−1; HRMS (EI) m/z calcd for C14H16O4 248.1049, found
248.1051.
3-Ethoxycarbonyl-2-(3-methoxyphenyl)-2,5-dihydrofuran
(2d): 1H NMR (400 MHz, CDCl3) δ 7.25 (t, J = 7.79 Hz, 1H), 7.00
(s, 1H), 6.94 (d, J = 7.79 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J = 7.79 Hz,
1H), 5.91−5.88 (m, 1H), 5.01 (dd, J = 6.18 Hz, J = 6.18 Hz, 1H), 4.86
(d, J = 15.92 Hz, 1H), 4.18−4.08 (m, 2H), 3.80 (s, 3H), 1.17 (t, J =
7.09 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 160.0, 142.8,
138.8, 136.3, 129.8, 120.0, 114.0, 113.2, 87.2, 75.7, 61.0, 55.6, 14.4; IR
(film) 3422, 2981, 1719, 1645, 1601, 1487, 1373, 1260, 1155, 1106,
1051, 774 cm−1; HRMS (EI) m/z calcd for C14H16O4 248.1049, found
248.1053.
5. The reaction would be initiated by the activation of the
allenyl group by the copper catalyst,5 followed by a 5-endo
cyclization to afford the vinylcopper intermediate 6, which then
gives intermediate 7. Subsequent protonation of the transient
vinylcopper intermediate 7 produces 2 and regenerates copper
to continue the catalytic cycle. In addition, a direct protonation
by HX formed by reduction of CuX2 might explain the result
that the reaction with ethyl acrylate did not proceed.
3-Ethoxycarbonyl-2-(4-methoxyphenyl)-2,5-dihydrofuran
(2e): 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.69 Hz, 2H), 7.00
(s, 1H), 6.87 (d, J = 8.76 Hz, 1H), 5.90−5.87 (m, 1H), 4.99 (dd, J =
6.14 Hz, J = 6.14 Hz, 1H), 4.86 (d, J = 15.81 Hz, 1H), 4.18−4.01 (m,
2H), 3.79 (s, 3H), 1.17 (t, J = 7.14 Hz, 3H); 13C NMR (100 MHz,
CONCLUSION
■
We developed an efficient and selective copper-catalyzed
intramolecular hydroalkoxylation of α-hydroxyallenes for the
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CDCl3) δ 162.4, 159.5, 138.2, 136.0, 133.1, 128.4, 113.7, 86.5,75.0,
60.6, 55.2, 14.0; IR (film) 3422, 2981, 1719, 1645, 1601, 1487, 1373,
1260, 1155, 1106, 1051, 774 cm−1; HRMS (EI) m/z calcd for
C14H16O4 248.1049, found 248.1050.
3-Ethoxycarbonyl-2-(2-fluoro-3-methoxyphenyl)-2,5-dihy-
drofuran (2f): 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1H), 7.04 (t, J
= 7.96, 1H), 6.9 (t, J = 8.08 Hz, 1H), 6.82 (t, J = 6.08 Hz, 1H), 6.21
(m, 1H), 4.93 (dd, J = 6.3 Hz, J = 15.8 Hz, 2H), 4.09 (m, 2H), 3.87 (s,
3H), 1.15 (t, J = 7.08 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.4,
152.4, 149.9, 139.5, 134.9, 129.1, 124.1, 120.6, 113.6, 81.4, 75.8, 61.0,
56.7, 14.3; IR (film) 2982, 2940, 2905, 2845, 1719, 1649, 1619, 1588,
1489, 1271, 1108, 1052, 779 cm−1; HRMS (EI) m/z calcd for
C14H15FO4 266.0954, found 266.0954.
1.31 (t, J = 7.18 Hz, 3H), 0.94 (t, J = 7.35 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 163.2, 138.8, 136.0, 85.2, 74.8, 60.9, 37.0, 18.6, 14.6,
14.5; IR (film) 2959, 1720, 1464, 1374, 1257, 1096, 1044 cm−1;
HRMS (EI) m/z calcd for C10H16O3 184.1099, found 184.1098.
3-Ethoxycarbonyl-2-phenethyl-2,5-dihydrofuran (2n): 1H
NMR (400 MHz, CDCl3) δ 7.29−7.15 (m, 5H), 6.86 (s, 1H),
5.07−5.04 (m, 1H), 4.81 (dd, J = 6.02 Hz, J = 6.02 Hz, 1H), 4.73 (d, J
= 15.82 Hz, 1H), 4.25−4.16 (m, 2H), 2.78−2.66 (m, 2H), 2.25−2.17
(m, 2H), 1.99−1.90 (m, 1H), 1.29 (t, J = 7.12 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.1, 142.5, 139.2, 135.7, 128.9, 128.7, 126.1,
84.7, 74.9, 61.0, 36.5, 31.6, 14.6; IR (film) 3422, 2984, 2252, 1714,
1644, 1455, 1375, 1265, 1240, 1110, 908, 729 cm−1; HRMS (EI) m/z
calcd for C15H18O3 246.1256, found 246.1254 .
2-Cyclohexyl-3-ethoxycarbonyl-2,5-dihydrofuran (2o): 1H
NMR (400 MHz, CDCl3) δ 6.86 (s, 1H), 4.91 (s, 1H), 4.71 (d, J =
4.89 Hz, 2H), 4.29−4.16 (m, 2H), 1.86−1.66 (m, 5H), 1.48−1.03 (m,
6H), 1.31 (t, J = 7.17 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.9,
138.8, 134.2, 89.2, 75.2, 60.5, 41.4, 30.2, 26.7, 26.4, 26.1, 25.4, 14.2; IR
(film) 3423, 3054, 2986, 2929, 2854, 1715, 1265, 1108, 909, 742 cm−1;
HRMS (EI) m/z calcd for C13H20O3 224.1412, found 224.1412.
2-(4-Chlorophenyl)-3-ethoxycarbonyl-2,5-dihydrofuran
(2p): 1H NMR (400 MHz, CDCl3) δ 7.32−7.26 (m, 4H), 7.01 (s,
1H), 5.91−5.88 (m, 1H), 5.01 (dd, J = 6.22 Hz, J = 6.22 Hz, 1H), 4.87
(d, J = 15.93 Hz, 1H), 4.13−4.06 (m, 2H), 1.18 (t, J = 7.13 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 162.5, 139.9, 138.9, 136.1, 134.3,
129.0, 128.9, 86.6, 75.8, 61.1, 14.4; IR (film) 2850, 1720, 1647, 1489,
1373, 1327, 1259, 1236, 1106, 1089, 1060, 1015, 922, 815 cm−1;
HRMS (EI) m/z calcd for C13H13ClO3 252.0553, found 252.0551.
3-Ethoxycarbonyl-2-(2-iodophenyl)-2,5-dihydrofuran
(2q): 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.90 Hz, 1H), 7.31
(t, J = 7.51 Hz, 1H), 7.17−7.13 (m, 2H), 6.98 (t, J = 7.90 Hz, 1H),
6.27−6.24 (m, 1H), 4.95 (dd, J = 6.13 Hz, J = 6.13 Hz, 1H), 4.85 (d, J
= 15.94 Hz, 1H), 4.14−4.05 (m, 2H), 1.14 (t, J = 7.19 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 162.4, 142.6, 140.14, 140.12, 135.9, 130.4,
128.9, 128.5, 100.3, 90.6, 75.6, 61.1, 14.4; IR (film) 3433, 2253, 1643,
1265, 907, 728, 649 cm−1; HRMS (EI) m/z calcd for C13H13IO3
343.9909, found 343.9910.
2-(4-Acetylphenyl)-3-ethoxycarbonyl-2,5-dihydrofuran
(2r): 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.29 Hz, 2H), 7.46
(d, J = 8.29 Hz, 2H), 7.03 (s, 1H), 5.98−5.95 (m, 1H), 5.05 (dd, J =
6.19 Hz, J = 6.19 Hz, 1H), 4.91 (d, J = 15.92 Hz, 1H), 4.16−4.03 (m,
2H), 2.58 (s, 3H), 1.17 (t, J = 7.16 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 198.1, 162.4, 146.5, 139.1, 137.3, 136.0, 128.8, 127.8, 86.8,
76.1, 61.1, 27.0, 14.4; IR (film) 2852, 1719, 1683, 1608, 1415, 1359,
1327, 1266, 1106, 1061, 1016, 826 cm−1; HRMS (EI) m/z calcd for
C15H16O4 260.1049, found 260.1050.
3-Ethoxycarbonyl-2-(4-methoxycarbonylphenyl)-2,5-dihy-
drofuran (2s): 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.26 Hz,
2H), 7.43 (d, J = 8.26 Hz, 2H), 7.02 (s, 1H), 5.98−5.95 (m, 1H), 5.05
(dd, J = 6.24 Hz, J = 6.24 Hz, 1H), 4.90 (d, J = 15.95 Hz, 1H), 4.15−
4.02 (m, 2H), 3.90 (s, 3H), 1.16 (t, J = 7.11 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.2, 162.4, 146.4, 139.1, 136.0, 130.3, 130.0, 127.6,
86.8, 76.0, 61.1, 52.5, 14.4; IR (film) 3405, 1719, 1435, 1280, 1104,
1060, 1018, 760, 435 cm−1; HRMS (EI) m/z calcd for C15H16O5
276.0998, found 276.0998.
3-Ethoxycarbonyl-2-(2-fluoro-4-methoxyphenyl)-2,5-dihy-
drofuran (2g): 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J = 8.53, 1H),
7.03 (s, 1H), 6.66 (dd, J = 2.46 Hz, J = 8.64 Hz, 1H), 6.59 (dd, J =
2.48 Hz, J = 12.12 Hz, 1H), 6.15 (m, 1H), 4.91 (dd, J = 15.73 Hz, J =
38.99 Hz, 2H), 4.09 (m, 2H), 3.78 (s, 3H), 1.17 (t, J = 7.11 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 163.1, 162.6, 160.6, 139.3, 135.1,
130.0, 120.3, 110.3, 102.1, 81.3, 75.5, 60.9, 55.9, 14.3; IR (film) 2982,
2938, 2906, 2854, 1719, 1500, 1263, 1206, 919, 817, 740 cm−1; HRMS
(EI) m/z calcd for C14H15FO4 266.0954, found 266.0953.
3-Ethoxycarbonyl-2-(2-fluoro-5-methoxyphenyl)-2,5-dihy-
drofuran (2h): 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.96 (t,
J = 9.11 Hz, 1H), 6.77 (m, 1H), 6.17 (m, 1H), 4.93 (dd, J = 15.79 Hz,
J = 41.55 Hz, 2H), 4.11 (m, 2H), 3.76 (s, 3H), 1.16 (t, J = 7.16 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.4, 155.9, 154.4, 139.5,
135.1, 128.8, 116.6, 115.1, 114.4, 81.4, 75.8, 61.0, 56.1, 14.3; IR (film)
2981, 2938, 2906, 2848, 1720, 1625, 1465, 1445, 1262, 834 cm−1;
HRMS (EI) m/z calcd for C14H15FO4 266.0954, found 266.0956.
3-Ethoxycarbonyl-2-(2-fluoro-5-methoxyphenyl)-2,5-dihy-
drofuran (2i): 1H NMR (400 MHz, CDCl3) δ 7.20 (q, J = 8.41 Hz
1H), 6.97 (s, 1H), 6.65 (m, 2H), 6.49 (m, 1H), 4.92 (dd, J = 15.17 Hz,
J = 40.85 Hz, 2H), 4.09 (m, 2H), 3.83 (s, 3H), 1.14 (t, J = 7.14 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 162.8, 161.4, 159.6,
138.9, 133.9, 130.1, 116.6, 108.8, 107.1, 75.9, 60.8, 56.5, 14.3; IR (film)
2981, 2938, 2904, 2852, 1719, 1586, 1474, 1264, 1238, 1107, 1084,
782 cm−1; HRMS (EI) m/z calcd for C14H15FO4 266.0954, found
266.0956.
3-Ethoxycarbonyl-2-(2,5-dimethoxyphenyl)-2,5-dihydrofur-
an (2j): 1H NMR (400 MHz, CDCl3) δ 7.05 (s, 1H), 6.86−6.78 (m,
2H), 6.70 (d, J = 2.81, 1H), 6.34 (m, 1H), 4.91 (dd, J = 6.13 Hz, J =
6.13 Hz, 1H), 4.85 (d, J = 15.80 Hz, 1H), 4.15−4.05 (m, 2H), 3.83 (s,
3H), 3.74 (s, 3H), 1.16 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.4, 153.6, 152.0, 139.2, 135.0, 129.6, 114.4, 113.8, 112.4,
80.9, 74.9, 60.5, 56.5, 55.7, 14.0; IR (film) 3627, 2939, 2839, 1717,
1662, 1593, 1506, 1463, 1422, 1329, 1261, 1126, 1008, 831, 772 cm−1;
HRMS (EI) m/z calcd for C15H18O5 278.1154, found 278.1153.
3-Ethoxycarbonyl-2-(3,5-dimthoxyphenyl)-2,5-dihydrofuran
(2k): 1H NMR (400 MHz, CDCl3) δ 7.00 (s, 1H), 6.51 (s, 2H), 6.40
(s, 1H), 5.86 (m, 1H), 5.01 (dd, J = 6.22 Hz, J = 6.22 Hz, 1H), 4.87 (d,
J = 15.80 Hz, 1H), 4.12 (m, 2H), 3.78 (s, 3H), 1.20 (t, J = 7.11 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 160.7, 143.1, 138.4,
135.7, 105.2, 100.2, 75.3, 60.6, 55.3, 53.4, 14.1; IR (film) 3627, 2939,
2839, 1717, 1598, 1463, 1430, 1327, 1261, 1204, 1157, 1106, 1051,
839, 773 cm−1; HRMS (EI) m/z calcd for C15H18O5 278.1154, found
278.1154.
3-Ethoxycarbonyl-2-(4-nitrophenyl)-2,5-dihydrofuran
(2t): 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.63 Hz, 2H), 7.54
(d, J = 8.63 Hz, 2H), 7.04 (s, 1H), 6.00−5.98 (m, 1H), 5.07 (dd, J =
6.19 Hz, J = 6.19 Hz, 1H), 4.92 (d, J = 16.04 Hz, 1H), 4.16−4.03 (m,
2H), 1.18 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8,
147.2, 146.7, 138.0, 134.2, 127.1, 122.5, 84.9, 74.9, 59.9, 13.0; IR (film)
3424, 1714, 1646, 1521, 1465, 1348, 1259, 1106, 1062, 749 cm−1;
HRMS (EI) m/z calcd for C13H13NO5 263.0794, found 263.0796.
3-Ethoxycarbonyl-2-(4-methylphenyl)-2,5-dihydrofuran
(2u): 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.98 Hz, 2H), 7.14
(d, J = 7.98 Hz, 2H), 6.99 (s, 1H), 5.91−5.88 (m, 1H), 4.99 (dd, J =
6.18 Hz, J = 6.18 Hz, 1H), 4.85 (d, J = 15.75 Hz, 1H), 4.16−4.02 (m,
2H), 2.32 (s, 3H), 1.17 (t, J = 7.15 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.8, 138.6, 138.33, 138.28, 136.4, 129.4, 127.5, 87.2, 75.6,
61.0, 21.6, 14.4; IR (film) 2981, 1720, 1372, 1259, 1105, 1058, 1020,
3-Ethoxycarbonyl-2-(3,4,5-trimethoxyphenyl)-2,5-dihydro-
furan (2l): 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 6.57 (s, 2H),
5.88 (m, 1H), 5.01 (dd, J = 6.17 Hz, J = 6.17 Hz, 1H), 4.88 (d, J =
15.85 Hz, 1H), 4.18−4.08 (m, 2H), 3.86 (s, 6H), 3.83 (s, 3H) 0.20 (t,
J = 7.10 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.9, 162.8, 153.7,
153.6, 141.6, 138.9, 138.3, 136.7, 136.1, 128.6, 107.4, 104.5, 87.5, 75.6,
61.2, 61.1, 56.5, 56.4; IR (film) 3627, 2939, 2839, 1717, 1662, 1593,
1506, 1463, 1422, 1329, 1235, 1126, 1008, 921, 831 cm−1; HRMS (EI)
m/z calcd for C16H20O6 308.1260, found 308.1257.
3-Ethoxycarbonyl-2-propyl-2,5-dihydrofuran (2m): 1H NMR
(400 MHz, CDCl3) δ 6.83 (s, 1H), 5.05−5.01 (m, 1H), 4.77 (dd, J =
5.98 Hz, J = 5.98 Hz, 1H), 4.70 (d, J = 15.69 Hz, 1H), 4.27−4.18 (m,
2H), 1.86−1.78 (m, 1H), 1.66−1.57 (m, 1H), 1.46−1.37 (m, 2H),
219
dx.doi.org/10.1021/jo2018125 | J. Org. Chem. 2012, 77, 215−220

The Journal of Organic Chemistry
Article
811, 734 cm−1; HRMS (EI) m/z calcd for C14H16O3 232.1099, found
232.1097.
(d) Poonoth, M.; Krause, N. Adv. Synth. Catal. 2009, 351, 117.
(e) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994.
(5) (a) Park, C.; Lee, P. H. Org. Lett. 2008, 10, 3359. (b) Kong, W.;
Fu, C.; Ma, S. Eur. J. Org. Chem. 2010, 6545.
(6) (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 1995, 34, 1581.
(b) Ma, S.; Yu, Z. Synthesis 2006, 3711. (c) Ma, S.; Wu, S. J. Org.
Chem. 1999, 64, 9314. (d) Ma, S.; Wu, S. Tetrahedron Lett. 2001, 42,
4075. (e) Ma, S.; Wu, S. Chem. Commun. 2001, 441. (f) Ma, S.; Xie, H.
Org. Lett. 2000, 2, 3801. (g) Yu, F.; Lian, X.; Zhao, J.; Yu, Y.; Ma, S. J.
Org. Chem. 2009, 74, 1130.
3-Ethoxycarbonyl-2-(2,4,6-trimethylphenyl)-2,5-dihydrofur-
an (2v): 1H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 6.79 (s, 1H),
6.42 (t, J = 6.25 Hz, 1H), 4.95 (dd, J = 6.65 Hz, J = 6.65 Hz, 1H), 4.87
(dd, J = 5.85 Hz, J = 5.85 Hz, 1H), 4.10−4.02 (m, 2H), 2.36 (s, 6H),
2.23 (s, 3H), 1.13 (t, J = 7.11 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 162.9, 138.6, 138.0, 137.8, 135.3, 132.1, 83.3, 75.0, 60.9, 21.3, 14.3;
IR (film) 3432, 2253, 1714, 1644, 1265, 1108, 1054, 906, 728, 649
cm−1; HRMS (EI) m/z calcd for C16H20O3 260.1412, found 260.1415.
(7) MacInnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987,
1077.
ASSOCIATED CONTENT
■
(8) (a) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489. (b) Aponick,
A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669. (c) Kim, S.; Lee, P.
H. Adv. Synth. Catal. 2008, 350, 547. (d) Tarselli, M. A.; Zuccarello, J.
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
́
L.; Lee, S. J.; Gagne, M. R. Org. Lett. 2009, 11, 3490. (e) Aponick, A.;
Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121. (f) Murai, M.; Uenishi,
J.-i.; Uemura, M. Org. Lett. 2010, 12, 4788. (g) Eom, D.; Kang, D.; Lee,
P. H. J. Org. Chem. 2010, 75, 7447.
AUTHOR INFORMATION
■
Corresponding Author
(9) Larsson, P.; Correa, A.; Carril, M.; Norrby, P.; Bolm, C. Angew.
Chem., Int. Ed. 2009, 48, 5691.
*E-mail: phlee@kangwon.ac.kr.
ACKNOWLEDGMENTS
■
This work was supported by the CRI Program (2011-0009011)
funded by the National Research Foundation of Korea (NRF),
by an NRF grant funded by the Korea government (MEST)
(2009-0087013), and by the second phase of the Brain Korea
21 Program in 2009. Dr. Sung Hong Kim at the KBSI (Daegu)
is thanked for obtaining the HRMS data. The NMR data were
obtained from the central instrumental facility in KNU.
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