1284
Chemistry Letters Vol.37, No.12 (2008)
Catalytic Conjugate Addition of Indoles to 4-Aryl-4-oxobut-2-enoates by FeCl3
Xiaoxia Wang,ꢀ Yaohong Zhang, Xiaohui Xiao, and Xinsheng Li
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences,
Zhejiang Normal University, Jinhua, Zhejiang, 321004, P. R. China
(Received October 6, 2008; CL-080963; E-mail: wangxiaoxia@zjnu.cn)
The conjugate addition of indoles to 4-aryl-4-oxobut-2-
Table 1. The Michael addition of indole 1a to ethyl (E)-4-oxo-
4-phenylbut-2-enoate 2a catalyzed by Lewis acids in various
solvents
enoates was achieved with FeCl3 as a catalyst under mild condi-
tions. The reaction was highly regioselective and afforded a
variety of new 3-substituted indoles in good to excellent yields.
HN
O
OEt
Lewis acid
Solvent
O
OEt
N
O
H
The synthesis of indole derivatives continues to be an intri-
guing subject in organic synthesis since the indole nucleus has
been found in a number of biologically active natural and un-
natural compounds.1 Among a variety of reactions for the deri-
vation of indole, the conjugate addition (the Michael addition)
of indole to electron-deficient olefins provides a straightforward
approach to introduce functionalized substituents at its 3-posi-
tion and has received a great deal of recent attention. Simple
enones or nitroalkenes have been frequently employed2,3 in most
investigation as Michael addition templates for indoles. Besides
developing more efficient, milder, or greener reaction condi-
tions,2 chiral catalysts are continually being sought so as to pro-
mote the reaction in a highly enatioselective way.3
Recently, more and more research focusing on the develop-
ment of alternative Michael acceptors such as acrylate,2f,2h acry-
lonitrile,2f alkylidene malonates,4 ꢀ,ꢁ-unsaturated aldehydes,5
ꢀ,ꢁ-unsaturated acylbenzotriazoles,6 and N-acetylated ꢀ,ꢁ-de-
hydroalanine methyl ester,7 together with more functionalized
4-substituted 2-oxo-3-butenoate esters,8 ꢀ,ꢁ-unsaturated acyl
phosphates,9 ꢀ0-hydroxy enones,10 ꢀ,ꢁ-unsaturated 2-acylimi-
dazoles,11 ꢀ0-phosphoric enones,12 and ethyl 3-nitro-2-alke-
noates,13 has been conducted thus providing a number of meth-
ods for the synthesis of diverse 3-substituted indole derivatives
(although some of the aforementioned Michael acceptors were
designed for chiral metal-catalyzed purposes). In this paper,
we wish to report the first efficient regioselective addition of in-
doles to 4-aryl-4-oxobut-2-enoates, which afforded a new kind
of 3-functionalized indole.
O
3aa
1a
2a
Entry
Catalysta
Solventb
Time/h
Yieldsc/%
1
2
3
4
5
6
7
8
9
SmI3
AlCl3
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
CH3CN
Toluene
C2H5OH
Et2O
14
14
14
14
14
14
14
5
10
10
10
10
60
57
35
55
55
62
70
90
45
85
16
32
ZnCl2
CuCl2
Zn(OTf)2
Cu(OTf)2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
10
11
12
aCatalyst load: 20 mol %. The runs were carried out under
reflux conditions; at room temperature, lower efficiency
was observed. Isolated yields.
b
c
found to undergo conjugate addition to 4-aryl-4-oxobut-2-
enoates smoothly to form a C–C bond exclusively in a highly re-
gioselective way, allowing facile access to a broad range of 2-(3-
indolyl)-substituted 4-aryl-4-oxobutanoates in good to excellent
yields.
To search for highly efficient reaction conditions, a variety
of catalysts and solvents were screened with ester 1a and indole
2a as substrates. It was found that anhydrous FeCl317 in refluxing
CH2Cl2 gave the best result in terms of yield and reaction time
(Table 1, Entry 8).
4-Oxobut-2-enoates (or ꢂ-oxo-ꢀ,ꢁ-(E)-alkenoic acid esters),
particularly those substituted with 4-aryl, are biologically and
medicinally important small molecules.14 The ketonic carbonyl
and the esteric carbonyl group present therein activate both ter-
mini of the carbon–carbon double bond and make them potential
Michael acceptors. The superior electron-withdrawing aptitude
exerted by the ketonic carbonyl group can lead to the attack of
N-nucleophiles at their 2-position. For example, addition of var-
ious amino acids to ethyl ꢁ-benzoylacrylate affords ethyl ꢀ-
amino-ꢂ-oxo-ꢂ-phenylbutyrate derivatives, which are important
intermediates for ACE (I) inhibitor.15 In 2007, Han reported the
conjugate addition reaction of a wide variety of NH-containing
heterocyclic compounds to these compounds with DBU as a cat-
alyst in constructing a C–N bond.16 However, the conjugate ad-
dition of indoles to 4-aryl-4-oxobut-2-enoates forming a C–C
bond was not explored to provide the corresponding 3-function-
alized indoles. Herein, catalyzed with Lewis acid, indoles were
Subsequently, a variety of indoles and ethyl (E)-4-aryl-4-
oxobut-2-enoates were applied as substrates under the optimal
conditions to examine the generality of the reaction, and the
results are listed in Table 2.
Generally, both indole and the substituted indoles under-
went the Michael-addition reaction smoothly to give the corre-
sponding 2-(3-indolyl)-substituted 4-aryl-4-oxobutanoates in
good to excellent yields. The attack of indoles with their 3-posi-
tion on the other termini of the carbon–carbon double bond in
ethyl (E)-4-aryl-4-oxobut-2-enoates was not observed at all,
showing high regioselectivity. Besides indole, the indoles substi-
tuted with 2-methyl, 5-methyl, and 5-bromo all worked well.
However, the presence of a phenyl on the 2-position of indole
required relatively longer time for the reaction to afford compa-
rable yields (Table 2, Entry 10), which may be ascribed to the
Copyright Ó 2008 The Chemical Society of Japan
Wang, Xiaoxia
