Published on the web December 1, 2012
1633
Multicomponent Cascade Reactions for the Synthesis
of 2,3-Dihydrobenzofuran Derivatives
Qu-Bo Li and Xiao-Chun Hu*
Department of Chemistry and Life Science, Zhejiang Normal University,
Jinhua 321004, P. R. China
(Received August 29, 2012; CL-120898; E-mail: sky34@zjnu.cn)
A multicomponent cascade reaction for the synthesis of
highly substituted 2,3-dihydrobenzofuran derivatives with
moderate to good yields was developed. The synthetic utilities
of these 2,3-dihydrobenzofurans were also further explored.
Table 1. Reaction of N-phenylsalicylideneamine (1a) to dieth-
yl malonate (2a) under different conditionsa
N
Ph
Ph
HN
Cl
Cl
base, promoter
toluene, r.t., 9 h
+
COOEt
COOEt
EtOOC
COOEt
Ethyl
2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylate
O
OH
and ethyl benzofuran-2-carboxylate were easily obtained from
2,3-dihydrobenzofurans.
2a
1a
3aa
Entry
Base
Promoter
Yield/%b
1
2
3
4
5
6
7
DABCO
DBU
K2CO3
KOH
DBU
DBU
NIS
NIS
NIS
NIS
NBS
NCS
I2
trace
81
trace
36
68
42
Multicomponent cascade reactions have garnered significant
recent attention from the synthetic community as a means to
swiftly assemble complex molecules from simple starting
materials with minimal time, waste, high atom- and step-
economy as well as manipulation of reaction intermediates.1 In
particular, these strategies are powerful in the total synthesis of
natural products and bioactive molecules.2 2,3-Dihydrobenzo-
furans (DHB) are recognized to be very important due to their
biological activities3 and their applications in a wide range
of chemical transformations, and other important targets. The
remarkable significance of the 2,3-dihydrobenzofuran ring
system has motivated chemists to develop various approaches
for the construction of them, such as radical4 and transition-
metal-mediated cyclizations5 and benzyne,6 electrocyclic,7
anionic,8 organocatalytic, and dehydrative techniques.9 Recent-
ly, a novel domino annulation between sulfur ylides and salicyl-
N-thiophosphinylimines was developed by Huang.10 However,
most of the reported methods have one or more of the following
drawbacks: for example, use of rather specific substrates, low
yields of products, complicated reaction assembly, tedious
processes for purification, etc. As such, simple and robust facile
methodologies to provide 2,3-dihydrobenzofuran derivatives
wherein we could vary the different substitutions, represent an
important and attractive objective at the forefront of synthetic
chemistry.
DBU
70
aAll the reactions were performed with 0.2 mmol of 1a,
0.48 mmol of 2a, 0.4 mmol of promoter, and 120 mol % of
base in 1.5 mL toluene at room temperature for 9 h. Isolated
b
yields.
further studies, we found that ¡-monoiodinated 1,3-dicarbonyl
compounds were easily obtained by oxidative iodination of 1,3-
dicarbonyl compounds (eq 2).12 Inspired by the above reports,
we envisioned that the new multicomponent cascade reactions of
1, 1,3-dicarbonyl compounds 2, and iodine or NIS (N-iodosuc-
cinimide) would be possible, as outlined in eq 3, giving a facile
protocol to 2,3-dihydrobenzofuran derivatives with multiple
substitutions.
A series of organic solvents and bases were screened for
multicomponent cascade reactions and representative results are
shown in Table 1. We initiated our investigation by subjecting
5-chloro-N-phenylsalicylideneamine (1a) to diethyl malonate
(2a) in the presence of promoter NIS and DABCO in toluene at
room temperature. However, no product 3aa was obtained
(Table 1, Entry 1). To our delight, the domino reaction
proceeded smoothly to provide desired product 3aa with good
yield when the reaction was carried out in the presence of DBU
[1,8-diazabicyclo(5,4,0)undec-7-ene] in toluene at room temper-
ature for 9 h (Entry 2). Optimization of the reaction conditions
revealed that bases and solvents strongly influenced the yield.
Inorganic base K2CO3 was inert in this reaction (Entry 3). Very
poor results were observed when KOH was applied (Entry 4).
Other halogen sources such as NBS, NCS, and molecular iodine
were also screened. However, all of them gave the final product
in low to moderate yields (Entries 5-7). Screening of the
solvents (such as acetone, DCM, THF, and MeOH) gave toluene
as the solvent of choice. The optimal reaction conditions [DBU
(1.2 equiv), NIS (2.0 equiv), toluene, and room temperature] is
shown in Entry 2. With the best reaction conditions, various
XHR2
O
O
O
120 mol% K2CO3
R4
acetone, r.t.,5 h
XR2
R3
R3
ð1Þ
ð2Þ
R4
+
R1
O
R1
O
OH
LG
LG = Br, Cl
O
O
I2 or NIS
R3
R4
O
O
R4
R3
2
I
XHR2
O
O
O
XR2
R3
I
2 or NIS
R1
R4
+
ð3Þ
R3
R4
R1
O
OH
O
3
1
2
Recently, an efficient, mild, and convenient domino reaction
to synthesize differently substituted 2,3-dihydrobenzofurans in
moderate to excellent yields from readily available starting
materials has been developed in our group (eq 1).11 In our
Chem. Lett. 2012, 41, 1633-1635
© 2012 The Chemical Society of Japan
Li, Qu-Bo
