An efficient, transition-metal-free process for the synthesis of substituted dihydrofurans via a Michael/cyclization tandem reaction

Article abstract of DOI:10.1016/j.tetlet.2010.11.151

An efficient green route for the synthesis of substituted dihydrofurans was developed through a simple base-catalyzed, tandem reaction of nitrostyrene with 1,3-dicarbonyl compounds. The desired products were prepared with a large substrate scope and in excellent yields (up to 95%).

Full text of DOI:10.1016/j.tetlet.2010.11.151

Tetrahedron Letters 52 (2011) 679–683
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Tetrahedron Letters
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An efficient, transition-metal-free process for the synthesis of substituted
dihydrofurans via a Michael/cyclization tandem reaction
⇑
⇑
Ming-Yu Wu, Ming-Qi Wang, Kun Li , Xing-Wen Feng, Ting He, Na Wang, Xiao-Qi Yu
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, 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 green route for the synthesis of substituted dihydrofurans was developed through a simple
base-catalyzed, tandem reaction of nitrostyrene with 1,3-dicarbonyl compounds. The desired products
were prepared with a large substrate scope and in excellent yields (up to 95%).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 September 2010
Revised 19 November 2010
Accepted 30 November 2010
Available online 4 December 2010
Keywords:
Dihydrofuran
Tandem reaction
Nitrostyrene
1,3-Dicarbonyl compounds
Substituted dihydrofurans are widely present in numerous
natural products, show important biological activities, and are
widely applied in the pharmaceutical industry.1 Due to their
important applications in organic synthesis, synthetic methodolo-
gies for the synthesis of dihydrofurans have been studied for many
years, and many synthetic routes for their access have been re-
ported.2–4 Among them, radicals, carbenoids, ylides, and heavy or
precious metal complexes have been frequently explored;
however, these compounds are harmful to human health, and
product purification typically is difficult. In recent years, research
involving green chemical protocols for accessing heterocyclic
compounds has received much attention from chemists because
green methodologies can provide substrate conservation in
environmentally benign systems.5 Recently, Chuang reported a
base-catalyzed method for the synthesis of 2,3-dihydrofurans uti-
reported for the synthesis of 3-acetyl-4-aryl-2-methyl-dihydrofu-
rans, and most of them required heavy metal complexes, such as
TI(IV), Pb(IV) or Mn(III), or involved complicated substrates.8
In this work, we report an efficient, transition-metal-free
process for the synthesis of 3-acetyl-4-aryl-2-methyl-dihydrofu-
rans via base-catalyzed, tandem condensation of nitrostyrene and
pentane-2,4-dione or cyclohexane-1,3-dione (Scheme 1).
Table 1
Base-mediated synthesis of 4-aryl-dihydrofuransa
O
NO2
Ph
O
O
K2CO3
DMSO 50 ºC
lizing enones and a
-nitro carbonyl compounds,6 and Shi reported
Ph
O
3a
2
1
a one-pot synthesis of substituted dihydrofurans using nitroal-
kenes, aldehydes, and 1,3-dicarbonyl compounds with the assis-
tance of proline and a base.7 However, few examples have been
Entry
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
Et3N
Pyridine
Ethylenediamine
Piperidine
Na2CO3
K2CO3
KOH
NaOCH3
NaOt-Bu
26
9
33
25
81
85
76
47
34
Scheme 1. Base-catalyzed synthesis of substituted dihydrofurans.
a
Reaction conditions: Nitrostyrene (0.1 mmol), pentane-2,4-dione (0.2 mmol),
base (10 mg), and DMSO (1 mL) were added to a 10 mL test-tube, which was then
⇑
Corresponding authors. Tel.: +86 28 85460576.
E-mail address: xqyu@tfol.com (X.-Q. Yu).
shaken at 200 rpm in a shaking incubator at 50 °C for 2 h.
b
Yield was determined by HPLC analysis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.151

680
M.-Y. Wu et al. / Tetrahedron Letters 52 (2011) 679–683
Table 2
Table 3 (continued)
Effect of solvent in the synthesis of 4-aryl-dihydrofuransa
Entry
8
Ar
n
Compound
Yieldb (%)
Entry
Solvent
Yieldb (%)
O
1
2
3
4
5
6
7
8
9
DMSO
DMF
CH3CN
Pyridine
Dioxane
THF
Toluene
n-Butyl alcohol
Ethanol
85
64
18
14
14
13
11
2
O
2-ClC6H4
0
50
3h
Cl
O
<1
O
a
9
3-ClC6H4
0
0
95
52
Reaction conditions: Nitrostyrene (0.1 mmol), pentane-2,4-dione (0.2 mmol),
K2CO3 (10 mg), and solvent (1 mL) were added to a 10 mL test-tube, which was then
shaken at 200 rpm in a shaking incubator at 50 °C for 2 h.
3i
b
Yield was determined by HPLC.
Cl
O
Table 3
Base-mediated tandem Michael/cyclization reactiona
O
10
2-BrC6H4
O
NO2
O
O
Ar
K2CO3
DMSO 50ºC
n
3j
Br
O
n
O
Ar
n = 0,1
3
2
1
11
12
C4H3O
0
1
61
88
O
Entry
1
Ar
n
Compound
Yieldb (%)
O
O
3k
O
C6H5
0
0
O
87
C6H5
O
3a
3l
O
O
O
2
4-CH3C6H4
81
O
13
4-CH3C6H4
1
76
3b
H3C
3m
H3C
O
O
O
3
4
5
6
7
4-OCH3C6H4
0
0
0
0
0
92
86
83
86
93
O
14
15
16
17
18
4-OCH3C6H4
1
1
1
1
1
87
92
91
92
89
H3CO
3c
3n
H3CO
O
O
O
4-FC6H4
O
4-FC6H4
3d
F
3o
F
O
O
O
O
4-ClC6H4
4-BrC6H4
4-CF3C6H4
O
4-ClC6H4
4-BrC6H4
4-CF3C6H4
Cl
3e
3f
3p
3q
Cl
O
O
O
Br
Br
O
O
O
O
3g
F3C
3r
F3C

M.-Y. Wu et al. / Tetrahedron Letters 52 (2011) 679–683
681
Initially, we investigated the reactivity of various bases in
DMSO at 50 °C. As shown in Table 1, organic bases showed poor
reactivity (entries 1–4), whereas inorganic bases exhibited mild
to good yields of dihydrofuran with short reaction time. It appears
that the yield of the target compound is closely related to the ba-
sicity of the catalysts; mild basicity is beneficial to the reaction
(entries 5 and 6), whereas strong basicity reduced the yield of
the substituted dihydrofuran product (entries 7–9). Therefore,
K2CO3 was chosen to be used as the catalyst in the following
experiments.
Table 3 (continued)
Entry
Ar
n
Compound
Yieldb (%)
O
O
19
2-ClC6H4
1
51
3s
Cl
O
We next surveyed the base-catalyzed reaction in various sol-
vents. As shown in Table 2, the reaction did not proceed in protic
solvents (entries 8 and 9), and poor yields were obtained in aprotic,
non-polar solvents (entries 4–7), although some aprotic, polar sol-
vents were favorable for the desired reaction (entries 1 and 2).
DMSO was found to be the most suitable solvent out of those
examined.
O
20
3-ClC6H4
1
94
3t
Cl
O
To determine the scope of this transition-metal-free process
and to test the generality of our protocol, a range of nitrostyrenes
and pentane-2,4-dione or cyclohexane-1,3-dione were surveyed
(Table 3). A wide range of nitrostyrenes can effectively participate
in the reaction with good yields (up to 95%).9 Pentane-2,4-dione is
much more reactive (2 h) than cyclohexane-1,3-dione (6 h) in the
reaction. The structure of 3t was characterized by X-ray diffraction
(Fig. 1). Several dicarbonyl compounds were investigated; how-
ever, the results indicated that ethyl acetoacetate and diethylmal-
onate were not suitable in the reaction under such basic conditions
because they hydrolyzed.
O
21
22
2-BrC6H4
1
1
44
65
3u
Br
O
C4H3O
O
3v
O
a
2 mmol of nitrostyrene, 4 mmol of pentane-2,4-dione (n = 0) or 1,3-cyclohex-
anedione (n = 1), 1.2 mmol K2CO3 (166 mg), and 20 mL DMSO were stirred vigor-
ously at 50 °C for 2 h (3a–k) or 6 h (3l–v).
The mechanism of the dihydrofuran-forming reaction was not
clear. To gain more information about dihydrofuran formation,
b
Isolated yield.
Figure 1. X-ray crystal structure of 3t.10

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M.-Y. Wu et al. / Tetrahedron Letters 52 (2011) 679–683
Figure 2. 1H NMR spectroscopy of this tandem reaction at different times.
the reaction mixture was analyzed by 1H NMR spectroscopy at
different times (5 min, 2, and 6 h, Fig. 2). The proton shift of a
and b in the Michael adduct as well as c and d in the dihydrofuran
product were compared to determine their content in the reaction
medium. Only the Michael adduct was detected at the first stage;
however, both dihydrofurans and Michael adduct were found in
the reaction after 2 h, although the Michael adduct converted to
the dihydrofuran product after 6 h. The results indicated that the
Michael adduct was the intermediate, which was quickly gener-
ated at the initial stage of the reaction. On the other hand, the
Michael adduct could be transformed to 4-aryl-dihydrofurans un-
der the same conditions. Based on these results, we summarized
our proposed mechanism in Scheme 2. Initially, nitrostyrene and
cyclohexane-1,3-dione react to form I in the presence of a base.
Tautomerization of I leads to generation of II, followed by intermo-
lecular cyclization of intermediate II and elimination of the
nitro group resulting in dihydrofuran product formation.
inexpensive starting materials in a safe reaction medium. This
Michael/cyclization tandem reaction exhibited wide generality; a
series of substituted nitrostyrenes reacted with pentane-2,4-dione
or 1,3-cyclohexanedione to generate 3-acetyl-4-aryl-2-methyl-
dihydrofurans with high yields (up to 95%). Importantly, this tan-
dem procedure does not involve precious or heavy metals or the
isolation of intermediate products and can be considered a green
protocol for substituted dihydrofuran synthesis.
Acknowledgments
We gratefully acknowledge the National Natural Science Foun-
dation of China (Nos. 20725206, 20732004 and 21001077) and the
Program for Changjiang Scholars and Innovative Research Team in
University (IRT0846) for financial support. M.Y.W. thanks the sup-
port of the Student Innovation Fund of Sichuan University (No.
091061005). We also thank the Sichuan University Analytical &
Testing Center for NMR analysis.
In summary, we have developed a simple, efficient, and transi-
tion-metal-free protocol for the synthesis of 4-aryl substituted
dihydrofurans. The base-mediated reaction is performed using
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.151.
References and notes
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9. Typical experimental procedure for synthesis of 4-aryl substituted
dihydrofurans: Nitrostyrene (2 mmol), 1,3-dicarbonyl compounds (4 mmol),
166 mg K2CO3 (1.2 mmol), and 20 mL DMSO were added to a 50 mL round-
bottom flask. The mixture was vigorously stirred at 50 °C for 2 or 6 h, filtered to
get rid of the solid, then 20 mL 0.1 N HCl was added, and the solution was
extracted three times with ethyl acetate (50 mL). The organic phase was
combined and washed with saturated NaHCO3 (30 mL) and brine (30 mL), then
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography from 5:1 to 2:1 (petroleum ether/ethyl acetate).
The amount of K2CO3 necessary in the reaction was also investigated
(Supplementary data, Table S1).
10. CCDC 779824 contains the supplementary Crystallographic data for this paper.
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Centre via www.ccdc.cam.ac.uk/data_request/cif.