A facile synthesis of highly functionalized dihydrofurans based on 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed reaction of halides with enones

Article abstract of DOI:10.1016/j.tet.2005.07.009

Treatment of halides 5 with electrophilic alkenes 2 afforded the corresponding dihydrofurans 3 and 4 in the presence of 1, 4-diazabicyclo[2.2.2] octane (DABCO) with good to excellent yields and in a stereoselective manner in most cases. Moreover, the ster

Full text of DOI:10.1016/j.tet.2005.07.009

Tetrahedron 61 (2005) 9140–9146
A facile synthesis of highly functionalized dihydrofurans based on
1
,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed reaction of
halides with enones
a
Zhanjun Yang, Mingjin Fan, Ruizhu Mu, Weimin Liu and Yongmin Liang
a
a
a
a,b,
*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
b
Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou 730000, People’s Republic of China
Received 27 May 2005; accepted 6 July 2005
Available online 3 August 2005
Abstract—Treatment of halides 5 with electrophilic alkenes 2 afforded the corresponding dihydrofurans 3 and 4 in the presence of 1,
-diazabicyclo[2.2.2]octane (DABCO) with good to excellent yields and in a stereoselective manner in most cases. Moreover, the
4
stereoisomers 3 and 4 could be easily transformed each other in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
catalytic process. Surprisingly, there was no report on this
catalytic method for synthesis of dihydrofurans.
Dihydrofurans are among the most important heterocycles
for the construction of a wide range of naturally occurring
substances and possess a multiplicity of biological
1
activities. They are also potentially useful intermediates
in organic synthesis. For these reasons, the development of
2. Results and discussion
2
new and efficient methods for the synthesis of dihydrofurans
remains an area of strong interest.
We began our study by investigating the reactivity of
preformed quaternary ammonium salts 1 with (Z)-ethyl-2-
benzyliden-3-oxobutanoate (2b) under different conditions
(Scheme 1). The preliminary studies demonstrated that the
reaction of the ammonium ylides with the enone in the
3
4
5
Recently, the reactions of sulfonium and arsonium ylides
with enones to afford dihydrofurans have been reported.
However, arsonium compounds are strong hazardous
materials; the reactions of sulfonium ylides gave dihydro-
furans accompanying with cyclopropane byproducts. On the
other hand, in the above processes, the ylide precursor was
usually generated in a separate step.
presence of anhydrous K CO under reflux yielded
2 3
dihydrofurans without the formation of cyclopropane. The
results are presented in Table 1, which show that the R
group of salts 1 played an important role in the
stereoselectivity of the procedure. Generally, when R was
a strong electron-withdrawing group, the trans-isomer was
formed preferentially. As we seen, there is a higher trans-
selectivity in entries 5–8 than in entries 1–4 (Table 1).
In this paper, we report a novel synthetic route to form
6
dihydrofurans via ammonium ylides in one-step based on a
Scheme 1. Reaction of salts 1 with (Z)-ethyl-2-benzyliden-3-oxobutanoate.
Keywords: DABCO; Ylides; Enones; Dihydrofurans; Furans.
*
Corresponding author. Tel.: C86 931 3904776; fax: C86 931 8912582; e-mail: liangym@lzu.edu.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.009

Z. Yang et al. / Tetrahedron 61 (2005) 9140–9146
9141
a
Table 1. Reaction of salts 1 with alkene 2b
b
b
Entry
Salt
X
R
Solvent
Product
Yield %
Product
Yield %
c
c
c
c
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
Cl
Cl
Cl
Cl
Br
Br
Cl
Cl
CN
CN
CO
CO
COPh
COPh
CH
CH
CH
CH
CH
CH
CH
CH
2
3
2
3
2
3
2
3
Cl
CN
Cl
CN
Cl
CN
Cl
CN
2
/DMSO
/DMSO
/DMSO
/DMSO
3b
3b
3e
3e
3h
3h
3k
3k
67
65
46
47
85
76
86
75
4b
4b
4e
4e
4h
4h
None
None
25
24
37
36
7
2
2
Et
Et
2
2
6
Thiophene-2-carbonyl
Thiophene-2-carbonyl
2
a
2 3
Salt 1 (1.5 equiv), enone 2b (1.0 equiv), K CO (2.0 equiv), solvent, reflux.
Isolated yield.
v/vZ4/1.
b
c
whether a pure cis- or trans-isomer was used as the starting
material (Table 3).
1 13
The dihydrofurans structure was identified by H and C
NMR, MS, HRMS and IR spectral data. The five-membered
heterocyclic structures of 3j and 4j were further confirmed
by a single-crystal X-ray diffraction analysis (Figs. 1 and 2).
Scheme 2. DABCO-catalyzed reaction.
7
,8
Encouraged by the above results, we then investigated a
catalytic process utilizing 1,4-diazabicyclo[2.2.2]octane
The mechanism of formation of 3 and 4 could be explained
by the following pathway (Scheme 4), based on the previous
(
DABCO) as the catalyst, in which the ammonium salts 1,
9
mechanism of Moorhoff. A halide source 5 undergoes S 2
and hence, the ylides could be generated in situ from readily
available halides 5. The reaction worked well for a range of
halides and enones (Scheme 2), and the results of which are
summarized in Table 2. Chloroacetonitrile (5a) and ethyl
chloroacetate (5b) gave a separable mixture of trans- and
N
displacement with the tertiary amine 8 to form quaternary
ammonium salt 1. Deprotonation of 1 with a mild base
forms the ylide 6, which undergoes Michael addition with 2
to afford the intermediate 7. The intermediate 7 would
Table 2. Synthesis of dihydrofurans
1
2
R
Entry
Halide
X
R
Enone
R
Conditions Product
Yield
a
%
Product
Yield
a
%
b
1
2
3
4
5
6
7
8
9
5a
5a
5a
5b
5b
5b
5c
5c
5c
5d
5d
5d
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Cl
Cl
Cl
CN
CN
CN
CO
CO
CO
COPh
COPh
COPh
2a
2b
2c
2a
2b
2c
2a
2b
2c
Ph
Ph
4-Cl-C
Ph
COMe
CO Et
COMe
COMe
A
A
A
A
A
A
B
B
B
B
B
B
3a
3b
3c
3d
3e
3f
3g
3h
3i
63
69
64
45
50
48
89
88
85
85
88
80
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
None
None
35
26
29
35
39
34
9
8
9
11
b
b
b
b
b
2
6
6
6
6
H
H
H
H
4
4
4
4
2
Et
2
Et
2
Et
Ph
2
CO Et
4-Cl-C
Ph
Ph
4-Cl-C
Ph
Ph
COMe
COMe
CO Et
c
c
c
c
c
c
2
COMe
COMe
CO Et
1
1
1
0
1
2
Thiophene-2-carbonyl 2a
Thiophene-2-carbonyl 2b
Thiophene-2-carbonyl 2c
3j
3k
3l
2
4-Cl-C
COMe
a
b
c
Isolated yield.
Enone (1.0 equiv), halide (1.0 equiv), DABCO (0.2 equiv), K
Enone (1.0 equiv), halide (1.0 equiv), DABCO (0.2 equiv), Na
2
CO
3
(1.5 equiv), CH
2
Cl
2
/DMSO, reflux.
2
CO
3
(1.5 equiv), CH
3
CN, 80 8C.
cis-dihydrofurans in good yields in CH Cl /DMSO (4:1) in
2
readily undergo ring-closing reaction by internal SN2
displacement of the tertiary amine 8 from the enolate
oxygen to give dihydrofurans 3 and 4. The yield of the trans-
isomer is higher than that of the cis-isomer probably due to
the major thermodynamic stability of the trans-isomer. This
2
the presence of K CO . The a-halo carbonyl compounds 5c
2
3
and 5d gave mostly trans-substituted products in acetonitrile
at 80 8C (Table 2). It is worth noting that no reaction took
place in the absence of DABCO, which suggests that the
tertiary amine is required as the catalyst in these reactions.
1
0
result is different from that of Fan et al.
Although different stereoisomers were obtained in most
cases, 3 and 4 could be separated from one another on silica
gel with petroleum ether–ethyl acetate as eluent and the
isomers pair 3 and 4 could be readily transformed each other
in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
Moreover, the obtained dihydrofurans 3 and 4 could be
further converted into the corresponding furans using mild
3
h
(DBU) in benzene (Scheme 3). The transformation
could eventually reach a thermodynamic equilibrium
Scheme 3. Transformation.

9142
Z. Yang et al. / Tetrahedron 61 (2005) 9140–9146
Table 3. Transformation of either isomer
a
a
Entry
Starting
material
Product
Yield %
Entry
Starting
material
Product
Yield %
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
3a
3b
3c
3d
3e
3f
3g
3h
3i
63
69
67
54
59
53
76
88
82
84
11
12
13
14
15
16
17
18
19
20
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
34
26
29
44
39
41
18
7
14
11
10
4j
3j
3j
4j
a
Isolated yield.
Scheme 4. Formation of dihydrofurans.
Figure 1. Molecular structure of 3j.
Scheme 5. Oxidation.
3. Conclusions
In this work, we have developed a facile and economical
synthetic method of tetrasubstituted dihydrofurans as well
as furans via the reaction of ammonium ylides in a catalytic
process. Moreover, one stereoisomer of the two result
dihydrofurans can be conveniently transformed to the other
as required. We believe that this method would give a new
viable entry to highly functionalized dihydrofurans.
Figure 2. Molecular structure of 4j.
4. Experimental
1
1
oxidant, chemical manganese dioxide (CMD). For
example, a benzene solution of 3h was refluxed for 48 h
or a dichloromethane solution of 4h was refluxed for 12 h in
4
.1. General
the presence of an excess of activated MnO (10–15 equiv),
2
Melting points were determined on a microscopic apparatus
and were uncorrected. Column chromatography was carried
out on silica gel. The H and C NMR spectra were
both affording the tetrasubstituted furan 9h in high yield
Scheme 5).
1
13
(

Z. Yang et al. / Tetrahedron 61 (2005) 9140–9146
9143
recorded at 300 and 75 MHz, respectively. IR spectra were
obtained using an FT-IR spectrometer and only major peaks
are reported in cm . Mass spectra were recorded by the EI
(9.42), 170 (15.78), 43 (100). HRMS: m/z [MCH] calcd for
C H NO : 228.1019; found: 228.1015.
1
4
13
2
K1
method. HRMS spectra were obtained with a Bruker APEX
instrument. All reagents were used directly as obtained
commercially unless otherwise noted. All mixed solvent
systems are reported as v/v solutions. Alkenes 2 (2a, 2b and
4.4.2. cis-4-Acetyl-2-cyano-5-methyl-3-phenyl-2,3-di-
hydrofuran (4a). Oil. H NMR (300 MHz, CDCl ): d
1
3
7
.20–7.42 (m, 5H), 5.44 (d, JZ10.2 Hz, 1H), 4.60 (d, JZ
13
0.2 Hz, 1H), 2.39 (s, 3H), 1.95 (s, 3H). C NMR (75 MHz,
1
CDCl ): d 194.1, 167.5, 137.4, 129.4, 129.1, 128.2, 116.0,
1
2
2
c) were easily prepared using a literature procedure.
3
1
1
7
1
14.6, 74.0, 52.3, 29.8, 14.8. IR (KBr): 3022, 2922, 2218,
K1
676, 1606, 1495, 1381, 1216, 757, 705 cm . MS (EI,
4.2. Typical procedure for the preparation of
ammonium salts 1
1
3
C
0 eV): m/z (%) 227 (M , 28.17), 212 (10.28), 200 (18.46),
70 (30.26), 43 (100). HRMS: m/z [MCH] calcd for
DABCO (1.12 g, 10 mmol) was added to a solution of
chloroacetonitrile (0.755 g, 10 mmol) in THF (50 mL). The
reaction was stirred at room temperature for 1 h. After
evaporating the solvent under reduced pressure, the
resulting solid was washed with petroleum ether and then
dissolved in a mixture of MeOH (5 mL) and PhH (5 mL).
The solvents were removed under reduced pressure to afford
the ammonium salt 1a as a white solid (1.8 g, 96%).
C H NO : 228.1019; found: 228.1012.
1
4
13
2
4
.4.3. trans-5-Cyano-2-methyl-4-phenyl-4,5-dihydro-
1
furan-3-carboxylic acid ethyl ester (3b). Oil. H NMR
300 MHz, CDCl ): d 7.18–7.34 (m, 5H), 5.01 (d, JZ
(
4
2
3
.2 Hz, 1H), 4.60 (d, JZ3.9 Hz, 1H), 4.04 (q, JZ7.2 Hz,
13
H), 2.38 (s, 3H), 1.09 (t, JZ7.2 Hz, 3H). C NMR
(75 MHz, CDCl ): d 166.9, 163.9, 140.0, 128.9, 128.0,
3
1
3
1
26.9, 117.0, 107.4, 74.5, 60.0, 54.3, 13.9, 13.8. IR (KBr):
030, 2983, 2255, 1704, 1658, 1605, 1492, 1453, 1378,
213, 1087, 758, 701 cm . MS (EI, 70 eV): m/z (%) 257
4.3. General procedure for the reaction of ammonium
salts 1 with enone 2b
K1
C
(
M , 24.57), 230 (5.66), 212 (15.06), 211 (19.74), 169
83.64), 43 (100). HRMS: m/z [MCNH ] calcd for
The mixture of 1 (1.5 mmol), 2b (1 mmol) and K CO3
2
(
C H NO : 275.1390; found: 275.1394.
4
(
2 mmol) in CH CN or in CH Cl /DMSO (v/v, 4/1) (10 mL)
3 2 2
1
5
15
3
was stirred vigorously at refluxing temperature. Once the
reaction was completed, checked by TLC analysis, the
reaction was quenched with 15–20 mL of water and
extracted with CH Cl (30 mL). The combined organic
4
3
.4.4. cis-5-Cyano-2-methyl-4-phenyl-4,5-dihydrofuran-
-carboxylic acid ethyl ester (4b). Oil. H NMR
1
2
2
(300 MHz, CDCl ): d 7.19–7.39 (m, 5H), 5.44 (d, JZ
3
extracts were washed with water and brine, and dried
MgSO ). After evaporating the solvent under reduced
1
2
0.2 Hz, 1H), 4.55 (d, JZ10.2 Hz, 1H), 4.03 (q, JZ7.2 Hz,
(
4
13
H), 2.37 (s, 3H), 1.05 (t, JZ7.2 Hz, 3H). C NMR
pressure, the residue was purified on silica gel with
petroleum ether–ethyl acetate (30/1–10/1) as eluent to
give first the trans-isomer 3, while further elution to yield
the cis-isomer 4.
(75 MHz, CDCl ): d 167.4, 164.3, 137.7, 129.0, 128.6,
3
1
2
1
28.0, 114.7, 107.7, 73.8, 60.2, 51.8, 14.2, 14.0. IR (KBr):
983, 2928, 2247, 1703, 1656, 1501, 1452, 1379, 1215,
091, 1021, 755, 702 cm . MS (EI, 70 eV): m/z (%) 257
K1
C
(M , 26.33), 230 (3.75), 215 (14.25), 212 (14.15), 211
4.4. General procedure for DABCO-catalyzed reaction
of halides 5 with enones 2
(18.12), 169 (68.66), 43 (100). HRMS: m/z [MCNH ] calcd
for C H NO : 275.1390; found: 275.1384.
4
1
5
15
3
DABCO (0.2 mmol) was added to a stirred solution of 5
(1 mmol) in CH CN or in CH Cl /DMSO (v/v, 4/1) (10 mL)
3 2 2
at room temperature. After stirred for 30 min, the inorganic
4
.4.5. trans-4-Acetyl-3-(4-chlorophenyl)-2-cyano-5-
1
methyl-2,3-dihydrofuran (3c). Solid; mp 107–109 8C. H
NMR (300 MHz, CDCl ): d 7.35 (d, JZ8.4 Hz, 2H), 7.15
base (1.5 mmol) was added, followed by the enone 2
(
3
(
d, JZ8.4 Hz, 2H), 4.92 (d, JZ4.5 Hz, 1H), 4.64 (d, JZ
1 mmol). The reaction was vigorously stirred at refluxing
1
.5 Hz, 1H), 2.41 (s, 3H), 2.05 (s, 3H). C NMR (75 MHz,
3
4
CDCl ): d 193.2, 167.1, 138.3, 134.5, 129.7, 128.6, 116.8,
temperature. Once completed, checked by TLC analysis, the
reaction was quenched with water (15–20 mL) and
extracted with CH Cl (30 mL). The combined organic
3
1
2
16.1, 74.6, 54.4, 29.8, 14.9. IR (KBr): 3030, 2921, 2844,
263, 1679, 1632, 1608, 1491, 1381, 1216, 1091 cm . MS
2
2
K1
extracts were washed with water and brine, and dried
MgSO ). After evaporating the solvent under reduced
C
(EI, 70 eV): m/z (%) 261 (M , 14.20), 246 (4.79), 234
(16.26), 226 (2.69), 219 (12.15), 204 (12.67), 43 (100).
(
4
pressure, the residue was purified on silica gel with
petroleum ether–ethyl acetate (30/1–10/1) as eluent to
give first the trans-isomer 3, while further elution to yield
the cis-isomer 4.
HRMS: m/z [MCH] calcd for C H ClNO : 262.0629;
2
found: 262.0632.
14 12
4.4.6. cis-4-Acetyl-3-(4-chlorophenyl)-2-cyano-5-methyl-
2,3-dihydrofuran (4c). Solid; mp 134–136 8C. H NMR
1
4.4.1. trans-4-Acetyl-2-cyano-5-methyl-3-phenyl-2,3-di-
hydrofuran (3a). Oil. H NMR (300 MHz, CDCl ): d
1
(300 MHz, CDCl ): d 7.37 (d, JZ8.4 Hz, 2H), 7.15 (d, JZ
3
3
7
4
.19–7.39 (m, 5H), 4.96 (d, JZ4.5 Hz, 1H), 4.66 (d, JZ
.2 Hz, 1H), 2.40 (s, 3H), 2.00 (s, 3H). C NMR (75 MHz,
8.4 Hz, 2H), 5.42 (d, JZ9.9 Hz, 1H), 4.58 (d, JZ9.9 Hz,
1H), 2.38 (s, 3H), 1.99 (s, 3H). C NMR (75 MHz, CDCl3):
1
3
13
CDCl ): d 193.8, 167.2, 139.9, 129.6, 128.7, 127.3, 117.1,
3
d 193.4, 167.5, 135.9, 134.9, 129.6, 129.5, 116.1, 114.3,
73.6, 51.7, 29.7, 14.8. IR (KBr): 2924, 2247, 1677, 1629,
1
2
15.9, 74.9, 55.2, 29.9, 14.9. IR (KBr): 3022, 2922, 2852,
147, 1679, 1608, 1494, 1452, 1379, 1217, 757, 703 cm
K1
K1
1605, 1491, 1381, 1213, 1090 cm . MS (EI, 70 eV): m/z
.
C
C
(%) 261 (M , 15.23), 246 (4.20), 234 (14.25), 226 (2.39),
MS (EI, 70 eV): m/z (%) 227 (M , 8.58), 212 (3.87), 200

9144
Z. Yang et al. / Tetrahedron 61 (2005) 9140–9146
219 (11.39), 204 (10.88), 43 (100). HRMS: m/z [MCH]
calcd for C H ClNO : 262.0629; found: 262.0625.
CDCl ): d 193.9, 169.8, 168.8, 140.9, 133.6, 129.4, 128.7,
3
115.4, 85.8, 62.1, 52.8, 29.7, 15.1, 14.3. IR (KBr): 2985,
2
1
4
12
2
919, 1754, 1675, 1626, 1602, 1490, 1380, 1199, 1092,
K1
C
4.4.7. trans-4-Acetyl-5-methyl-3-phenyl-2,3-dihydro-
furan-2-carboxylic acid ethyl ester (3d). Solid; mp 51–
1039, 832 cm . MS (EI, 70 eV): m/z (%) 308 (M , 10.27),
265 (10.95), 235 (47.84), 43 (100). HRMS: m/z [MCH]
1
3 8C. H NMR (300 MHz, CDCl ): d 7.23–7.38 (m, 5H),
.78 (d, JZ4.8 Hz, 1H), 4.49 (d, JZ4.5 Hz, 1H), 4.29 (q,
5
4
calcd for C16H17ClO : 309.0888; found: 309.0888.
4
3
JZ7.2 Hz, 2H), 2.44 (s, 3H), 1.96 (s, 3H), 1.34 (t, JZ
4.4.12. cis-4-Acetyl-3-(4-chlorophenyl)-5-methyl-2,3-di-
hydrofuran-2-carboxylic acid ethyl ester (4f). Sticky oil.
1
.2 Hz, 3H). C NMR (75 MHz, CDCl ): d 194.5, 170.1,
3
7
1
2
1
3
1
68.8, 142.4, 129.3, 127.9, 127.4, 115.3, 86.2, 62.1, 53.5,
9.9, 15.1, 14.4. IR (KBr): 2983, 1753, 1674, 1604, 1494,
449, 1380, 1197, 1037, 764, 703 cm . MS (EI, 70 eV):
H NMR (300 MHz, CDCl ): d 7.26 (d, JZ8.4 Hz, 2H),
3
7.11 (d, JZ8.4 Hz, 2H), 5.30 (d, JZ10.5 Hz, 1H), 4.61 (d,
K1
JZ10.5 Hz, 1H), 3.69–3.87 (m, 2H), 2.44 (s, 3H), 1.96 (s,
C
13
m/z (%) 274 (M , 5.22), 231 (5.27), 201 (24.20), 43 (100).
HRMS: m/z [MCH] calcd for C H O : 275.1278; found:
3H), 0.92 (t, JZ7.2 Hz, 3H). C NMR (75 MHz, CDCl ): d
3
194.0, 168.9, 167.4, 136.8, 133.9, 130.0, 128.7, 116.2, 83.6,
61.4, 51.4, 29.7, 15.1, 13.8. IR (KBr): 2986, 2936, 1753,
1
6 18 4
2
75.1278.
K1
1
719, 1675, 1599, 1490, 1381, 1210, 1092, 1043, 855 cm
.
C
4
2
.4.8. cis-4-Acetyl-5-methyl-3-phenyl-2,3-dihydrofuran-
-carboxylic acid ethyl ester (4d). Oil. H NMR
MS (EI, 70 eV): m/z (%) 308 (M , 9.99), 293 (2.16), 265
(6.74), 235 (29.83), 43 (100). HRMS: m/z [MCH] calcd for
1
(
300 MHz, CDCl ): d 7.15–7.28 (m, 5H), 5.32 (d, JZ
C H17ClO : 309.0888; found: 309.0886.
16 4
3
1
2
0.2 Hz, 1H), 4.62 (d, JZ10.2 Hz, 1H), 3.62–3.82 (m, 2H),
.45 (s, 3H), 1.91 (s, 3H), 0.86 (t, JZ7.2 Hz, 3H). C NMR
13
4.4.13. trans-4-Acetyl-2-benzoyl-5-methyl-3-phenyl-2,3-
dihydrofuran (3g). Solid; mp 125–127 8C. H NMR
1
(
75 MHz, CDCl ): d 194.6, 168.9, 167.6, 138.1, 128.7,
3
1
(
28.6, 128.1, 116.1, 83.9, 61.3, 52.1, 29.8, 15.1, 13.8. IR
KBr): 2985, 2931, 1752, 1674, 1603, 1494, 1450, 1379,
(300 MHz, CDCl ): d 7.24–7.89 (m, 10H), 5.66 (d, JZ
3
4.5 Hz, 1H), 4.53 (d, JZ4.5 Hz, 1H), 2.47 (s, 3H), 1.94 (s,
K1
210, 1043, 757, 703 cm . MS (EI, 70 eV): m/z (%) 274
13
3H). C NMR (75 MHz, CDCl ): d194.4, 193.5, 168.6,
1
3
C
M , 7.49), 259 (1.53), 231 (3.71), 201 (15.96), 43 (100).
(
HRMS: m/z [MCH] calcd for C H O : 275.1278; found:
142.4, 134.3, 133.7, 129.3, 129.1, 127.9, 127.8, 116.0, 89.7,
52.2, 29.8, 15.2. IR (KBr): 2921, 1693, 1671, 1601, 1490,
1382, 1224, 1069, 1017, 757, 696 cm . MS (EI, 70 eV):
1
6 18 4
K1
2
75.1279.
C
m/z (%) 306 (M , 0.46), 263 (78.90), 201 (13.42), 105
(35.77), 77 (41.48), 43 (100). HRMS: m/z [MCH] calcd for
4
.4.9. trans-5-Methyl-3-phenyl-2,3-dihydrofuran-2,4-di-
1
carboxylic acid diethyl ester (3e). Oil. H NMR
300 MHz, CDCl ): d 7.22–7.34 (m, 5H), 4.83 (d, JZ
C H O : 307.1329; found: 307.1332.
20 18 3
(
3
4
2
7
.8 Hz, 1H), 4.41 (d, JZ4.5 Hz, 1H), 4.26 (q, JZ6.9 Hz,
4.4.14. cis-4-Acetyl-2-benzoyl-5-methyl-3-phenyl-2,3-di-
hydrofuran (4g). Sticky oil. H NMR (300 MHz, CDCl ): d
1
H), 4.09 (q, JZ6.9 Hz, 2H), 2.40 (s, 3H), 1.32 (t, JZ
3
1
3
.2 Hz, 3H), 1.06 (t, JZ6.9 Hz, 3H). C NMR (75 MHz,
6.79–7.56 (m, 10H), 6.23 (d, JZ10.2 Hz, 1H), 4.73 (d, JZ
10.2 Hz, 1H), 2.52 (s, 3H), 1.92 (s, 3H). C NMR (75 MHz,
1
3
CDCl ): d 170.2, 168.5, 165.0, 142.8, 128.8, 127.3, 106.6,
3
8
1
5.9, 61.9, 59.7, 52.9, 14.2. IR (KBr): 2982, 2923, 1755,
702, 1651, 1452, 1379, 1209, 1090, 1034, 759, 700 cm
CDCl ): d 194.5, 193.8, 169.2, 137.4, 135.9, 133.7, 128.8,
3
K1
.
128.4, 127.9, 127.7, 116.8, 87.6, 53.2, 29.8, 15.3. IR (KBr):
2924, 1697, 1667, 1601, 1494, 1446, 1386, 1217, 1071,
C
MS (EI, 70 eV): m/z (%) 304 (M , 23.17), 259 (16.66), 258
28.86), 231 (29.75), 230 (78.31), 202 (27.90), 201 (28.88),
K1
C
(
4
3
1021, 755, 696 cm . MS (EI, 70 eV): m/z (%) 306 (M ,
2.44), 263 (42.31), 201 (18.35), 105 (64.63), 77 (46.59), 43
(100). HRMS: m/z [MCH] calcd for C H O : 307.1329;
3 (100). HRMS: m/z [MCH] calcd for C H O :
17 20 5
05.1384; found: 305.1380.
2
0 18 3
found: 307.1331.
4
.4.10. cis-5-Methyl-3-phenyl-2,3-dihydrofuran-2,4-di-
1
carboxylic acid diethyl ester (4e). Oil. H NMR
300 MHz, CDCl ): d 7.13–7.26 (m, 5H), 5.30 (d, JZ
4.4.15. trans-5-Benzoyl-2-methyl-4-phenyl-4,5-dihydro-
furan-3-carboxylic acid ethyl ester (3h). Oil. H NMR
1
(
3
1
2
3
1
1
1
6
0.5 Hz, 1H), 4.56 (d, JZ10.5 Hz, 1H), 3.99 (q, JZ7.2 Hz,
(300 MHz, CDCl ): d 7.24–7.85 (m, 10H), 5.73 (d, JZ
3
H), 3.64–3.78 (m, 2H), 2.41 (s, 3H), 1.03 (t, JZ7.2 Hz,
4.5 Hz, 1H), 4.40 (d, JZ4.5 Hz, 1H), 3.96 (q, JZ7.2 Hz,
1
3
13
H), 0.83 (t, JZ7.2 Hz, 3H). C NMR (75 MHz, CDCl ): d
2H), 2.44 (s, 3H), 1.04 (t, JZ7.2 Hz, 3H). C NMR
3
68.5, 167.9, 165.0, 138.7, 128.4, 128.2, 127.7, 127.5,
07.5, 83.7, 61.2, 59.7, 51.6, 14.2, 13.7. IR (KBr): 2984,
729, 1662, 1624, 1494, 1448, 1379, 1212, 1095, 1042, 757,
(75 MHz, CDCl ): d 193.7, 168.6, 165.1, 142.8, 134.2,
3
133.7, 129.2, 129.0, 127.8, 127.6, 107.2, 89.5, 59.7, 52.0,
14.3. IR (KBr): 3024, 2924, 2855, 1698, 1651, 1601, 1453,
1380, 1218, 1091, 757, 696 cm . MS (EI, 70 eV): m/z (%)
K1
C
K1
97 cm . MS (EI, 70 eV): m/z (%) 304 (M , 37.41), 259
13.63), 258 (11.54), 231 (43.33), 230 (40.86), 202 (15.30),
01 (11.85), 43 (100). HRMS: m/z [MCH] calcd for
C H O : 305.1384; found: 305.1378.
C
(
2
336 (M , 9.34), 321 (9.59), 293 (17.50), 263 (34.69), 231
(22.87), 105 (100), 77 (70.78), 43 (65.56). HRMS: m/z [MC
H] calcd for C H O : 337.1434; found: 337.1433.
21 20 4
1
7
20
5
4.4.11. trans-4-Acetyl-3-(4-chlorophenyl)-5-methyl-2,3-
dihydrofuran-2-carboxylic acid ethyl ester (3f). Sticky
4.4.16. cis-5-Benzoyl-2-methyl-4-phenyl-4,5-dihydro-
furan-3-carboxylic acid ethyl ester (4h). Solid; mp 110–
1
1
112 8C. H NMR (300 MHz, CDCl ): d 6.81–7.55 (m, 10H),
oil. H NMR (300 MHz, CDCl ): d 7.32 (d, JZ8.1 Hz, 2H),
3
3
7
.18 (d, JZ8.1 Hz, 2H), 4.74 (d, JZ4.8 Hz, 1H), 4.48 (d,
6.20 (d, JZ10.5 Hz, 1H), 4.68 (d, JZ10.2 Hz, 1H), 3.99 (q,
1
3
JZ4.5 Hz, 1H), 4.29 (q, JZ6.9 Hz, 2H), 2.44 (s, 3H), 2.00
JZ6.9 Hz, 2H), 2.49 (s, 3H), 1.03 (t, JZ7.2 Hz, 3H).
C
NMR (75 MHz, CDCl ): d194.1, 168.8, 165.1, 138.0, 135.9,
1
3
(
s, 3H), 1.32 (t, JZ6.9 Hz, 3H). C NMR (75 MHz,
3

Z. Yang et al. / Tetrahedron 61 (2005) 9140–9146
9145
1
1
1
3
33.6, 128.7, 128.0, 127.9, 127.3, 108.0, 87.8, 59.8, 52.8,
4.4, 14.2. IR (KBr): 2927, 1696, 1648, 1600, 1449, 1385,
212, 1096, 1021, 756, 696 cm . MS (EI, 70 eV): m/z (%)
142.7, 140.3, 135.3, 133.6, 128.8, 128.5, 127.6, 127.4,
107.1, 90.0, 59.6, 52.4, 14.2. IR (KBr): 3092, 3024, 2982,
2931, 1694, 1652, 1514, 1452, 1380, 1217, 1090, 1031, 756,
K1
C
36 (M , 12.41), 321 (10.08), 293 (16.07), 263 (15.99), 231
K1
C
702 cm . MS (EI, 70 eV): m/z (%) 342 (M , 10.56), 327
(3.99), 299 (14.18), 269 (24.60), 231 (15.21), 111 (100), 43
(44.77). HRMS: m/z [MCH] calcd for C H O S:
(31.87), 105 (100), 77 (84.08), 43 (79.71). HRMS: m/z [MC
H] calcd for C H O : 337.1434; found: 337.1434.
2
1
20
4
19 18
4
343.0999; found: 343.0995.
4.4.17. trans-4-Acetyl-2-benzoyl-3-(4-chloro-phenyl)-5-
methyl-2,3-dihydrofuran (3i). Sticky oil. H NMR
1
4.4.22. trans-4-Acetyl-3-(4-chloro-phenyl)-5-methyl-2-
(thiophene-2-carbonyl)-2,3-dihydrofuran (3l). Sticky
(
300 MHz, CDCl ): d 7.18–7.86 (m, 9H), 5.61 (d, JZ
3
1
oil. H NMR (300 MHz, CDCl ): d 7.14–7.76 (m, 7H),
4
3
1
1
2
1
.8 Hz, 1H), 4.54 (d, JZ4.5 Hz, 1H), 2.44 (s, 3H), 1.97 (s,
3
13
H). C NMR (75 MHz, CDCl ): d 193.72, 193.14, 168.48,
3
5.36 (d, JZ4.8 Hz, 1H), 4.64 (d, JZ4.8 Hz, 1H), 2.46 (s,
1
H), 1.98 (s, 3H). C NMR (75 MHz, CDCl ): d 194.1,
3
40.92, 134.24, 133.52, 129.37, 129.14, 129.05, 128.99,
16.06, 89.20, 51.37, 29.62, 15.09. IR (KBr): 3067, 3017,
924, 1697, 1672, 1623, 1598, 1490, 1446, 1381, 1223,
3
1
1
3
1
0
3
87.3, 168.4, 141.0, 140.3, 135.8, 134.1, 133.7, 129.5,
29.1, 128.7, 116.0, 90.2, 52.0, 29.8, 15.2. IR (KBr): 3097,
015, 2911, 1672, 1625, 1599, 1514, 1490, 1380, 1228,
K1
093, 830, 756, 694 cm . MS (EI, 70 eV): m/z (%) 340
C
K1
C
(
M , 0.20), 297 (68.54), 235 (13.68), 105 (42.96), 77
090, 1022, 830 cm . MS (EI, 70 eV): m/z (%) 346 (M ,
.55), 303 (76.85), 235 (13.68), 111 (53.83), 43 (100).
(
37.74), 43 (100). HRMS: m/z [MCH] calcd for
C H ClO : 341.0939; found: 341.0943.
2
0
17
3
HRMS: m/z [MCH] calcd for C H ClO S: 347.0503;
18 15 3
found: 347.0505.
4.4.18. cis-4-Acetyl-2-benzoyl-3-(4-chloro-phenyl)-5-
methyl-2,3-dihydrofuran (4i). Solid; mp 125–127 8C. H
1
4.5. General procedure for the transformation of either
stereoisomer
NMR (300 MHz, CDCl ): d 7.35–7.59 (m, 5H), 6.99 (d, JZ
3
8
.1 Hz, 2H), 6.74 (d, JZ8.4 Hz, 2H), 6.20 (d, JZ10.2 Hz,
H), 4.72 (d, JZ10.2 Hz, 1H), 2.52 (s, 3H), 1.97 (s, 3H).
1
1
3
The mixture of the cis-isomer 4 (0.1 mmol) and DBU
(
C NMR (75 MHz, CDCl ): d 193.9, 193.5, 169.2, 136.1,
3
0.01 mmol) in benzene (2 mL) was stirred at room
1
5
1
35.7, 133.9, 133.6, 130.0, 128.9, 128.6, 127.9, 117.0, 87.4,
2.6, 29.7, 15.3. IR (KBr): 3015, 2924, 1698, 1671, 1623,
597, 1489, 1446, 1384, 1214, 1088, 756, 694 cm . MS
temperature for 3 h. After evaporating the solvent under
reduced pressure, the residue was purified on silica gel with
petroleum ether–ethyl acetate (30/1–10/1) as eluent to give
first the trans-isomer 3, while further elution to yield the cis-
isomer 4. When the starting material was a trans-isomer, the
reaction took longer.
K1
C
(EI, 70 eV): m/z (%) 340 (M , 1.67), 297 (26.85), 235
10.66), 105 (69.69), 77 (39.45), 43 (100). HRMS: m/z [MC
(
H] calcd for C H ClO : 341.0939; found: 341.0931.
2
0
17
3
4
2
1
8
.4.19. trans-4-Acetyl-5-methyl-3-phenyl-2-(thiophene-
-carbonyl)-2,3-dihydrofuran (3j). Solid; mp 148–
4.6. Typical procedure for oxidation to tetrasubstituted
furans
1
1b
1
50 8C. H NMR (300 MHz, CDCl ): d 7.12–7.74 (m,
3
H), 5.40 (d, JZ4.8 Hz, 1H), 4.64 (d, JZ4.5 Hz, 1H), 2.46
1
3
To 8 mL benzene solution of dihydrofuran 3h (0.4 mmol)
was added 0.52 g (6 mmol) of CMD, and the suspension
was refluxed for 48 h. After the completion of the reaction,
the solvent was removed under reduced pressure and the
residue was purified on silica gel with petroleum–ethyl
acetate (20/1) as eluent to give 122.9 mg (92%) of
tetrasubstituted furan 9h.
(
s, 3H), 1.93 (s, 3H). C NMR (75 MHz, CDCl ): d 194.6,
3
1
1
1
87.6, 168.4, 142.4, 140.5, 135.6, 134.0, 129.4, 128.6,
27.9, 127.8, 115.8, 90.5, 52.7, 29.9, 15.2. IR (KBr): 2924,
674, 1606, 1382, 1229, 1067, 1028, 758, 703 cm . MS
K1
C
(
EI, 70 eV): m/z (%) 312 (M , 0.92), 269 (100), 201
19.94), 111 (53.90), 43 (89.76). HRMS: m/z [MCH] calcd
(
for C H O S: 313.0893; found: 313.0890.
18 16 3
To 5 mL dichloromethane solution of dihydrofuran 4h
(0.2 mmol) was added 174 mg (2 mmol) of CMD, and the
4.4.20. cis-4-Acetyl-5-methyl-3-phenyl-2-(thiophene-2-
carbonyl)-2,3-dihydrofuran (4j). Solid; mp 79–81 8C. H
1
suspension was refluxed for 12 h. After the completion of
the reaction, the solvent was removed under reduced
pressure and the residue was purified on silica gel with
petroleum ether–ethyl acetate (20/1) as eluent to give
NMR (300 MHz, CDCl ): d 6.93–7.64 (m, 8H), 5.90 (d, JZ
3
1
3
1
1
1
0.5 Hz, 1H), 4.76 (d, JZ10.5 Hz, 1H), 2.53 (s, 3H), 1.92 (s,
13
H). C NMR (75 MHz, CDCl ): d 194.6, 186.9, 169.0,
3
41.7, 137.2, 134.6, 132.8, 128.8, 128.5, 128.0, 127.8,
16.5, 88.4, 53.6, 29.8, 15.2. IR (KBr): 3104, 2924, 1670,
602, 1515, 1383, 1219, 1068, 1031, 754, 704 cm . MS
63.5 mg (95%) of tetrasubstituted furan 9h.
K1
C
(EI, 70 eV): m/z (%) 312 (M , 2.50), 269 (62.00), 201
19.31), 111 (66.74), 43 (100). HRMS: m/z [MCH] calcd
4.6.1. 5-Benzoyl-2-methyl-4-phenylfuran-3-carboxylic
acid ethyl ester (9h). Solid; mp 75–77 8C. H NMR
1
(
for C H O S: 313.0893; found: 313.0894.
18
16
3
(300 MHz, CDCl ): d 7.22–7.71 (m, 10H), 4.12 (q, JZ
3
1
3
7
.2 Hz, 2H), 2.74 (s, 3H), 1.06 (t, JZ7.2 Hz, 3H). C NMR
4.4.21. trans-2-Methyl-4-phenyl-5-(thiophene-2-car-
bonyl)-4,5-dihydrofuran-3-carboxylic acid ethyl ester
(75 MHz, CDCl ): d 183.5, 163.0, 162.0, 146.1, 136.9,
3
135.0, 132.1, 131.3, 129.8, 129.2, 127.7, 127.6, 127.2,
116.0, 60.2, 14.6, 13.6. IR (KBr): 3060, 2983, 2932, 1712,
1648, 1593, 1541, 1487, 1447, 1411, 1246, 1180, 1092,
1
3k). Sticky oil. H NMR (300 MHz, CDCl ): d 7.08–7.71
(
3
(
m, 8H), 5.47 (d, JZ4.8 Hz, 1H), 4.53 (d, JZ4.8 Hz, 1H),
K1
C
3
3
.97 (q, JZ7.2 Hz, 2H), 2.44 (s, 3H), 1.03 (t, JZ7.2 Hz,
1011, 731, 696 cm . MS (EI, 70 eV): m/z (%) 334 (M ,
3.66), 333 (3.09), 305 (2.57), 159 (8.16), 115 (10.39), 105
1
3
H). C NMR (75 MHz, CDCl ): d 187.6, 168.2, 164.9,
3

9146
Z. Yang et al. / Tetrahedron 61 (2005) 9140–9146
˚
(100), 77 (66.74), 43 (45.41). HRMS: m/z [MCH] calcd for
C H O : 335.1278; found: 335.1276.
lZ0.71073 A, monoclinic space group P2(1)/n, aZ
˚
˚
˚
9.804(1) A, bZ10.474(1) A, cZ15.324(2) A, aZ90.008,
2
1 18 4
3
˚
bZ102.860(2)8, gZ90.008, VZ1534.0(3) A , ZZ4, D
c
Z
3
K1
1
.353 mg/m , mZ0.221 mm , F(000)Z656, crystal size
Acknowledgements
0.38!0.29!0.21 mm, independent reflections 2860 [R(int)
Z0.0142], reflections collected 7885, refinement method, full-
2
2
We thank the NSF-20021001, NSF-20172024 and the
Hundred Scientist Program’ from the Chinese Academy
of Sciences for the financial support of this work.
matrix least-squares on F , goodness-of-fit on F 1.105, final R
indices [IO2s(I)] R Z0.0373, wR Z0.1067, R indices (all
‘
1
2
2
data) R1Z0.0427, wR Z0.1092, extinction coefficient
0
.0117(18), largest diff. peak and hole 0.243 and
K3
˚
K0.424 e A . Crystallographic data for 3j have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-268616. Copies of
the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: int.
code C44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk].
References and notes
1
. (a) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. (b) Merritt,
A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243. (c) Schoop, A.;
Greiving, H.; Gohrt, A. Tetrahedron Lett. 2000, 41,
8
. Crystal data for 4j: C18
˚
H
16
O
3
S, M
W
Z312.37, TZ288(2) K,
˚
lZ0.71073 A, triclinic space group P-1, aZ6.407(1) A, bZ
1913–1916. (d) Schabbert, S.; Schaumann, E. Eur. J. Org.
Chem. 1998, 1873–1878.
˚
˚
1
1.386(2) A, cZ11.936(2) A, aZ88.60(1)8, bZ75.35(1)8,
3
3
˚
gZ75.53(1)8, VZ815.05(21) A , ZZ2, D
c
Z1.273 mg/m ,
mZ0.208 mm , F(000)Z328, crystal size 0.46!0.34!
.26 mm, independent reflections 3025 [R(int)Z0.0084],
reflections collected 3432, refinement method, full-matrix
2
3
. (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795–819. (b)
Garzino, F.; M e´ ou, A.; Brun, P. Eur. J. Org. Chem. 2003,
K1
0
1410–1414.
. For recent synthesis of substituted dihydrofurans, see: (a)
Zhang, Y.; Raines, A. J.; Flowers, R. A., II Org. Lett. 2003, 5,
2
2
least-squares on F , goodness-of-fit on F 1.073, final R
indices [IO2s(I)] R Z0.0540, wR Z0.1669, R indices (all
2363–2365. (b) Evans, D. A.; Sweeney, Z. K.; Rovis, T.;
1
2
data)
R
1
Z0.0761, wR
2
Z0.1814, extinction coefficient
Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095–12096. (c)
Hamaguchi, M.; Matsubara, H.; Nagai, T. J. Org. Chem. 2001,
K3
˚
0.013(6), largest diff. peak and hole 0.340 and K0.509 e A
.
Crystallographic data for 4j have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-268617. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: int. code C44 1223 336
033; e-mail: deposit@ccdc.cam.ac.uk].
6
6, 5395–5404. (d) Antonioletti, R.; Righi, G.; Oliveri, L.;
Bovicelli, P. Tetrahedron Lett. 2000, 41, 10127–10130. (e)
Hagiwara, H.; Sato, K.; Suzuki, T.; Ando, M. Tetrahedron
Lett. 1997, 38, 2103–2106. (f) Gais, H.-J.; Reddy, L. R.; Babu,
G. S.; Raabe, G. J. Am. Chem. Soc. 2004, 126, 4859–4864. (g)
Xing, C.; Zhu, S. J. Org. Chem. 2004, 69, 6486–6488. (h) Arai,
S.; Nakayama, K.; Suzuki, Y.; Hatano, K.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 9739–9742. (i) Lee, Y. R.;
Yoon, S. H.; Seo, Y.; Kim, B. S. Synthesis 2004, 17,
9. Moorhoff, C. M. Tetrahedron Lett. 1996, 37, 9349–9352.
10. Fan, M.; Guo, L.; Liu, X.; Liu, W.; Liang, Y. Synthesis 2005,
3, 391.
2
787–2798.
. Jiang, Y.; Ma, D. Tetrahedron: Asymmetry 2002, 13,
033–1038.
11. (a) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama, K.;
Anzai, M.; Ando, A.; Shioiri, T. Synlett 1998, 35–36. (b) Cal o` ,
V.; Scordari, F.; Nacci, A.; Schingaro, E.; D’Accolti, L.;
Monopoli, A. J. Org. Chem. 2003, 68, 4406–4409.
12. Tanikaga, R.; Konya, N.; Hamamura, K.; Kaji, A. Bull. Chem.
Soc. Jpn. 1998, 61, 3211–3216.
4
5
6
7
1
. Cao, W.; Ding, W.; Chen, J.; Chen, Y.; Zhang, Q.; Chen, G.
Synth. Commun. 2004, 34, 1599–1608.
. Landberg, B. E.; Lown, J. W. J. Chem. Soc., Perkin Trans. 1
1975, 1326–1333.
13. Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2003, 42, 828–831.
. Crystal data for 3j: C18
16 3 W
H O S, M Z312.37, TZ291(2) K,