Water-compatible cascade reaction: An efficient route to substituted 2, 3-dihydrofurans

Article abstract of DOI:10.1246/cl.2012.777

A highly efficient domino Michael additionalkylation reaction of 1, 3-dicarbonyl derivatives with 2-nitroacrylates was developed in water. The procedure tolerates a series of functional groups such as methoxy, bromo, chloro, and heteroaromatic groups, providing three types of 2, 3-dihydrofuran derivatives in moderate to good yields.

Full text of DOI:10.1246/cl.2012.777

doi:10.1246/cl.2012.777
Published on the web July 28, 2012
777
Water-compatible Cascade Reaction: An Efficient Route to Substituted 2,3-Dihydrofurans
Ya-Ru Zhang, Fang Luo,* Xu-Jiao Huang, and Jian-Wu Xie*
Department of Chemistry, Zhejiang Normal University, Jinhua 321004, P. R. China
(Received April 26, 2012; CL-120364; E-mail: luofang19@zjnu.cn, xiejw@zjnu.cn)
A highly efficient domino Michael addition-alkylation
reaction of 1,3-dicarbonyl derivatives with 2-nitroacrylates
was developed in water. The procedure tolerates a series
of functional groups such as methoxy, bromo, chloro, and
heteroaromatic groups, providing three types of 2,3-dihydro-
furan derivatives in moderate to good yields.
dihydrofuran. Herein, we report a domino Michael addition-
alkylation reaction in water for the formation of dihydrofurans
using 1,3-dicarbonyl derivatives and 2-nitroacrylates (Scheme 1,
eq 2).
Shi pointed out 1,3-dicarbonyl compounds could be feasible
dinucleophiles to react with nitro-diene A and give the desired
carbon-substituted dihydrofuran (Scheme 2, I).11 Guided by the
successful results, we postulated that 2,3-dihydrobenzofuran
derivatives 3 could be synthesized from the reaction of 1,3-
dicarbonyl compounds with 2-nitroacrylates 1 via base-pro-
moted two-component condensation (Scheme 2, II). Initially,
we chose ethyl ¡-nitrocinnamate (1a) and 4-hydroxycoumarin
(2a) as the model substrates for surveying the reaction
parameters (Table 1). After careful screening, we found the
choice of base had an important effect on the reaction. Et3N and
DIPEA showed good activity while versatile inorganic bases
Dihydrofurans, a family of five-membered O-heterocycles
in plants, are important building blocks in a large number of
biologically active compounds.1 Functionalized dihydrofurans
such as 2,3-dihydrofurans are central structural cores of a broad
range of natural product and pharmaceutical chemistry.1b,2
Approaches have been developed for the synthesis of these
organic skeletons,3 among which the methods between 1,3-
dicarbonyl compounds and ketones or olefins are particularly
important. A well-known method is the “interrupted Feist-
Benary (IFB) reaction,” which made the condensation of ¢-
dicarbonyl compounds with ¡-haloketones stop at the hydrox-
ydihydrofuran step.4 In addition, the entail ionic5 or radical
reactions2f,6 of 1,3-dicarbonyl compounds with appropriate
olefins have also attracted much attention. Recently, we
developed an efficient method for the preparation of the 2,3-
dihydrobenzofuran derivatives by domino reactions via the
Michael alkylation, the Mannich alkylation, and aldol alkyla-
tion.7
) Shi's proposal in the condensation of 1,3-diketone with diene intermediate A
O
O
NO2
NO2
-NO2
O
O
R
R
R
R
R
base
R
COR
COR
R
diene A
) Our proposal in the condensation of 1,3-diketone with 2-nitroacrylates
O
O
NO2
O
COOEt
Ar
2
O
R
EtO2C
R
EtO2C
-NO2
R
R
O2N
Ar
COR
In recent years, there has been growing attention on water
that is an attractive medium for many organic reactions,8 since it
has several advantages such as low cost, improved safety and
low pollution, and operational simplicity. The use of water as
a solvent in the Michael addition has also attracted much
attention.9 Almost at the same time, Rueping and we developed
the Michael addition-nucleophilic substitution reaction for the
efficient synthesis of dihydrofurans from diketones and (E)-¢,¢-
bromonitrostyrenes using harmful chloroform as solvent10
(Scheme 1, eq 1). Considering the need to develop environ-
mentally acceptable chemical processes, we envisioned this type
reaction could use water as solvent to gain the targeted
base
COR
Ar
1
3
Scheme 2. Synthesis of dihydrofuran from 1,3-diketone addi-
tion to nitro-ene.
Table 1. Screening for the optimum conditionsa
COOEt
OH
O
NO2
base
+
solvent
COOEt
O
O
O
3aa
O
1a
2a
Entry
Base
Solvent
Yield/%b
1
2
3
4
5
6
7
8
9
K2CO3
NaOH
CH3COONa
Et3N
DIPEA
Et3N
Et3N
CH3Cl
CH3Cl
CH3Cl
CH3Cl
CH3Cl
EtOH
H2O
trace
0
trace
90
O
O
Ar
Ar
bifunctional
chiral thiourea catalyst
+
eq 1
O
base, CHCl3
NO2
Br
NO2
O
80
Previous work
Ar
trace
0
44c
95d
O
O
Ar
+
base
Et3N
Et3N
H2O
H2O
eq 2
H2O
O
O2N
CO2Et
COOEt
O
aReaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), base
(200 mol %), rt, 12 h. bIsolated yield. cTetrabutylammonium
bromide (TBAB) (20 mol %), 40 °C, 6 h. TBAB (20 mol %),
This work
d
Scheme 1. Synthetic approach to dihydrofurans via domino
Michael addition-alkylation reaction.
70 °C, 6 h.
Chem. Lett. 2012, 41, 777-779
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

778
Table 3. Reaction between 1,3-dicarbonyl derivatives and
(E)-ethyl 2-nitro-3-phenylacrylatea
COOEt
O
O
O
OH
O
2a: R = H
2b:
O
O
R = 6-Me
2c: R = 6-t-Bu
2d: R = 6-Br
R
O
O
O
O
R
2h: R = OMe
2i: R = Me
2f
2e:
2g
R = 6-Cl
O
O
O
Ph
COOEt
Ph
3aa
Et3N
+
TBAB, H2O
O2N
CO2Et
O
O
Figure 1. X-ray crystal structure of ethyl 4-oxo-3-phenyl-3,4-
dihydro-2H-furo[3,2-c]chromene-2-carboxylate (3aa).
1a
2
3
Entry
Substrate 2
Product 3
COOEt
Yield/%b
Table 2. Reaction between 4-hydroxycoumarin and various
2-nitroacrylatesa
O
1
2
3
4
2a
3aa
3ba
3ca
3da
95
93
94
91
Ph
OH
COOEt
R
O
Et3N
O
O
+
R
COOEt
TBAB, H2O
O2N
CO2Et
1
O
O
2a
O
O
3
O
2b
2c
2d
Ph
Entry
Substrate 1
NO2
Product 3
Yield/%b
95
O
O
(1a)
(1b)
(1c)
1
2
3aa
Ph
CO2Et
NO2
CO2Et
NO2
COOEt
O
Ph
3ab
3ac
75
60
Cl
Br
O
O
3
4
5
COOEt
CO2Et
NO2
CO2Et
NO2
O
Br
Cl
Ph
(1d)
(1e)
3ad
3ae
50
86
O
O
COOEt
O
CO2Et
O
2e
3ea
5
91
Ph
O
aAll reactions were run with 1 (0.1 mmol), 2a (0.2 mmol), Et3N
(200 mol %), TBAB (20 mol %) in 1 mL of H2O under air at
O
b
70 °C for 6 h. Isolated yield.
COOEt
Ph
O
6
7
2f
3fa
85
83
such as K2CO3, NaOH, and CH3COONa had no obvious effect
on the reaction in CHCl3 (Table 1, Entries 1-5). The structures
of ethyl 4-oxo-3-phenyl-3,4-dihydro-2H-furo[3,2-c]chromene-
2-carboxylate (3aa) was established by spectroscopic methods,
and was further confirmed by the determination of single-crystal
X-ray structures (Figure 1). It confirms the trans configuration
as illustrated by the ORTEP diagram depicted in Figure 1.
Considering this transformation would use harmful chloroform,
we tried to use eco-friendly solvents. To our disappointment, no
reaction took place when replacing CHCl3 with other solvents
such as EtOH or H2O (Table 1, Entries 6 and 7). However, the
reaction in water afforded the product 3aa in 95% yield with the
addition of TBAB at 70 °C (Table 1, Entry 9). TBAB is crucial
for this reaction in water and may serve as a phase-transfer
reagent. Thus, the best results were obtained in the presence
of Et3N (200 mol %) in water in combination with TBAB
(20 mol %) at 70 °C for 6 h.
O
COOEt
Ph
O
2g
3ga
O
O
Ph
Ph
MeO
8
9
2h
2i
3ha
3ia
86
88
COOEt
Me
O
O
COOEt
Me
O
aAll reactions were run with 1a (0.1 mmol), 2 (0.2 mmol), Et3N
(200 mol %), TBAB (20 mol %) in 1 mL of H2O under air at
70 °C for 6 h. Isolated yield.
b
With the optimized conditions in hand, we investigated the
scope of 2-nitroacrylates. The reaction is presented in Table 2.
As expected, all the reactions proceeded smoothly with yields
ranging from good to excellent and tolerated various functional
groups such as methyl, bromo, and chloro (Table 2, Entries
2-4). Particularly, halogen-substituted ethyl ¡-nitrocinnamate
worked well with 4-hydroxycoumarin (Table 2, Entries 3 and 4)
and the surviving halogen atom could be valuable for further
manipulation. Heteroaromatic substrates such as (Z)-ethyl
2-nitro-3-(tetrahydrofuran-2-yl)acrylate were also observed to
be suitable acceptors in this Michael addition-alkylation
reaction (Table 2, Entry 5). Unfortunately, the reaction became
complicated when 4-hydroxycoumarin was treated with simple
nitro alkenes without an ester group under the same conditions
as above.
Chem. Lett. 2012, 41, 777-779
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

779
After a broad scope of 2-nitroacrylates was established, we
were particularly interested in extending the 1,3-dicarbonyl
derivatives (Table 3). We first further pursued synthesis of
various 2,3-dihydrofurocoumarins. We found that the 4-hydroxy-
coumarin bearing functional groups on the phenyl ring reacted
smoothly to afford the products in 91-95% yield (Table 3,
Entries 1-5). To explore the generality and scope of this
procedure, the reactivity of simple cyclohexanedione in this
tandem reaction was explored. Cyclohexane-1,3-dione deriva-
tives worked well under the conditions described above
(Table 3, Entries 6 and 7). Fortunately, when the branched
chain 1,3-dicarbonyl derivatives were treated with ethyl
¡-nitrocinnamate, good yields were obtained (Table 3, Entries
8 and 9).
In summary, we have succeeded in performing the reaction
between 1,3-dicarbonyl derivatives and 2-nitroacrylates in water,
avoiding using harmful solvent. This domino Michael addition-
alkylation reaction afforded the 2,3-dihydrofuran products in
moderate to good yields. Three types of 2,3-dihydrofuran
derivatives were prepared: 2,3-dihydrofurocoumarins, 2,3,4,5,6,7-
hexahydrobenzofuran, and 2,3,4,5-tetrasubstituted 2,3-dihydro-
furans. The reaction showed remarkably broad substrate scope
and good functional group tolerance.12
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6
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 20902083), the
Natural Science Foundation of Zhejiang Province (Nos.
R4080084 and LY12B02002), and the Program for Changjiang
Scholars and Innovative Research Team in Chinese Universities
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12 Supporting Information is available electronically on the
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index.html.
Chem. Lett. 2012, 41, 777-779
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/