Enantioselective Michael-type Friedel-Crafts reactions of indoles to enones catalyzed by a chiral camphor-based Bronsted acid

Article abstract of DOI:10.1002/ejoc.200600646

Chiral Bronsted acid, D-camphorsulfonic acid, was found to be practical and efficient in the catalysis of the enantioselec-tive Michael-type Friedel-Crafts reactions of indoles with aromatic enones to afford the corresponding β-indolyl ketones in excellen

Full text of DOI:10.1002/ejoc.200600646

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600646
Enantioselective Michael-Type Friedel–Crafts Reactions of Indoles to Enones
Catalyzed by a Chiral Camphor-Based Brønsted Acid
[a]
[a]
[a]
[a]
[a]
Wei Zhou, Li-Wen Xu,* Lyi Li, Lei Yang, and Chun-Gu Xia*
Keywords: Michael addition / Friedel–Crafts Reaction / Indoles / Enones / Asymmetry / Dual Activation
Chiral Brønsted acid,
D-camphorsulfonic acid, was found to
BmimBr and D-CSA which leads to active catalytic systems
be practical and efficient in the catalysis of the enantioselec-
tive Michael-type Friedel–Crafts reactions of indoles with
aromatic enones to afford the corresponding β-indolyl
ketones in excellent yields and moderate enantioselectivit-
ies. A surprising synergistic effect was discovered between
for the Friedel–Crafts reaction. The efficiency of these sys-
tems might result from the catalytic Lewis acid activation of
the Brønsted acids.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
The addition of aromatic substrates to electron-deficient Ronchi have reported the enantioselective Al(Salen)Cl-cata-
alkenes, such as enones, is an important type of reaction in lyzed conjugate addition of indoles to simple alkyl α,β-un-
synthetic organic chemistry for the formation of new C–C saturated ketones with moderate-to-high enantioselectivi-
[
6]
bonds, which may be considered a Friedel–Crafts (FC) type ties.
alkylation or a Michael-type FC reaction in many re-
Previously, we reported an efficient organic Brønsted
spects. Among the FC reactions, the Michael-type FC re- acid (2,6-pyridinedicarboxylic acid) which catalyzed
[
1]
[
7]
action of indoles is a widely investigated process because it Michael-type FC reactions of indoles. As a part of our
is involved in the total synthesis of a class of bioactive in- ongoing research on organic Brønsted acid controlled reac-
dole alkaloids, for example the hapalindoles and other 3- tions of appropriately functionalized heteroatom-contain-
substituted indoles, which are significant substructures and ing compounds, we report here our new results of enantio-
building blocks for the synthesis of natural products and selective Michael-type FC additions of indoles to aromatic
[
2]
therapeutic agents.
enones catalyzed by easily available -camphorsulfonic acid
Since the pioneering study published by Casnati and Ca- (-CSA) and its derived BmimBr–CSA complex. Although
[
3]
siraghi on the enantioselective orthohydroxy alkylation of -CSA has been recognized as an excellent catalyst in vari-
phenol with aldehydes catalyzed by stoichiometric amounts ous organic transformations, such as Diels–Alder reactions
[
8]
of chiral aluminum complexes, many efforts have been de- and the oxidation of sulfides, there is no report about its
voted to the exploitation of new catalytic stereocontrolled stereoselectivity in previous studies.
FC procedures.[ Although numerous and significant ad-
4]
Initially, we aimed to examine the asymmetric-induced
vances have been achieved,[ the asymmetric conjugate ad- effect of a chiral Brønsted acid in the promotion of this
5]
dition of aromatic compounds to simple α,β-unsaturated Michael-type FC reaction (Scheme 1). Interestingly, in
ketones (FC-type reactions) under efficient catalytic condi- CH CN the reaction was found to proceed spontaneously
3
tions is still a considerable challenge. In FC reactions, en- in the presence of a catalytic amount of -CSA to give the
ones are particularly attractive and are widely used as corresponding product with excellent yield. -CSA dis-
Michael acceptors because their ketone moieties are strong played a moderate but promising asymmetric induction
electron-withdrawing groups that can be readily trans- (18% ee; Table 1, Entry 1) to the products. We also found
formed into a range of different functionalities. Up to now, that aprotic solvents, such as CH Cl or toluene, had a
2
2
with the best of our knowledge, only Bandini and Umani- negative influence on the enantioselectivity, as well as ethe-
real solvents such as THF on the catalytic activity to give
product 3a. As predicted, the reactions in water or CH OH
gave a much poorer conversion or a lower enantio-
selectivity, respectively (Table 1, Entries 5,7). By lowering to
3
[
a] State Key Laboratory for Oxo Synthesis and Selective Oxi-
dation, Lanzhou Institute of Chemical Physics, Chinese Acad-
emy of Sciences,
7
30000, Lanzhou, P. R. China
0
°C, we found that the temperature had a negative effect
Graduate School of the Chinese Academy of Sciences,
Beijing, P. R. China
on the conversion, whereas a slight improvement in the
enantioselectivity of the reaction was observed (Table 1, En-
try 8). The absolute stereochemistry was assigned as the
(S)-stereoisomer by comparison of the optical rotation with
Fax: +86-931-8277088
E-mail: lwxu@lzb.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 5225–5227
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5225

W. Zhou, L.-W. Xu, L. Li, L. Yang, C.-G. Xia
SHORT COMMUNICATION
the reported values.[6] It is no doubt that the present com- In our successive work, a novel chiral Brønsted acidic
mercial Brønsted acid is a powerful catalyst for the acti- BmimBr–CSA complex was prepared according to a litera-
[
12]
vation of carbonyl groups in this Michael-type FC reaction ture procedure. The obtained pale yellow liquid was not
of indole with chalcone.
soluble in ether. Its catalytic activity in the Michael-type
FC reactions of indole with chalcone was then investigated.
We were pleased to find that the BmimBr–CSA complex
was also an efficient catalyst and provided a better yield
(96%) than that observed(78%) by using only -CSA as a
catalyst and a moderate level of stereoselectivity (19% ee)
was obtained. However, if BmimBr was added to the mix-
ture of indole, chalcone, and -CSA catalyst in CH CN di-
3
rectly, there was no improvement in the conversion or the
stereoselectivity of the reaction. Furthermore, the combina-
tion of -CSA with inorganic salts such as KBr and NaBr,
or an organic base such as phosphane did not lead to active
catalytic systems.
Scheme 1. Addition of indole 2a to enone 1a to give access to op-
tically active 2-indole-1-ketone derivative 3a.
Table 1. Solvent effect on the -CSA-catalyzed Michael-type Frie-
del–Crafts reaction of indole with chalcone.
From a mechanistic point of view, we believe that the
observed synergistic effects might proceed: (1) by a purely
Brønsted acid catalysis, (2) by a molecular interaction be-
tween CSA and BmimBr, which generates a stable molecu-
lar complex, (3) by a Lewis acid promoted Brønsted acid
Entry[a] Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CH
THF
toluene
3
CN
78
60
33
88
18
19
11
10
–
–
0
[13]
catalysis (LBA), which results in the double-activation of
CH
2
Cl
2
the enone and indole.
H
H
2
O
trace
2
O/THF (1:10) trace
Next, we expanded the range of substrates by using two
different Brønsted acids, -CSA and its derived BmimBr–
CSA complex, as catalysts under the optimized reaction
CH
CH
3
OH
CN
98
60
[
d]
3
24
[
a] Experimental conditions: To a solution of enone (0.5 mmol) and conditions. Table 2 summarizes the chemical and optical re-
indole (0.55 mmol) in solvent (3 mL), catalyst (0.05 mmol) was
added. All the reactions were carried out at room temp. for 12 h
except Entry 8. [b] Isolated yields. [c] Determined by chiral station-
ary phase HPLC. [d] The reaction was carried out at 0 °C for 24 h.
sults for the 1,4-addition of indoles to enones. Except for
Entries 3–4 and 7–8, substrates gave nearly the same levels
of enantioselectivity. In Entries 7–8, although indole 2a af-
forded corresponding product 3d in good yields, the
In the last decades, room temperature ionic liquids have enantioselectivities contrasted greatly. -CSA gave no
been described as one of the most promising new reaction enantioselectivity whereas the BmimBr–CSA complex gave
[
9]
mediums. Ionic liquids are being used as green solvents a moderate ee of 29%. Similarly, in Entries 3–4, the ee im-
because of their unique properties, for example wide liquid proved remarkably from 37 to 58% when the BmimBr–CSA
range, good dissolubility, tunable polarity, and high thermal complex was used as the catalyst. At the same time, the
stability, etc. Attractively, their properties can be regulated yields of all entries suggested that the BmimBr–CSA com-
to satisfy specific chemical tasks. As a result of their green plex had a slightly better catalytic activity than that of -
credentials and potential to enhance rates and selectivities, CSA. So, it is worthy to note that the BmimBr–CSA com-
ionic liquids, which are used as dual solvent–catalysts, are plex showed better catalytic activity in both the conversion
[
10]
finding increased application in organic synthesis.
Re- and stereochemistry than -CSA. We also tested the reac-
cently, the studies on ionic liquids used as catalysts in or- tions of 2-cyclohexen-1-one and 2-cyclopenten-1-one cata-
ganic reactions have attracted more and more chemists. lyzed by BmimBr–CSA. The yields were 15 and 88%,
Moreover, Brønsted acidic ionic liquids are specially allur- respectively. Unfortunately, no ee was observed in the prod-
ing because they behave as dual solvent–catalysts in some uct of the reaction of 2-cyclopenten-1-one. Although the
reactions and display excellent catalytic activities in the es- novel catalyst system (BmimBr–CSA) is not soluble in
terification of acids, carbonylation of toluene, Mannich re- ether, the recovery and reuse of the catalyst is difficult.
[
11]
actions, etc.
In fact, these ionic liquids are special When the ionic liquid BmimBr–CSA was recovered and re-
Brønsted acids that can be reused several times. With the used once the corresponding yield and ee was 55% and
consideration that various Brønsted acids have proven to 25%, respectively (Table 2, Entry 15).
be effective catalysts similar to CSA in the Michael-type FC
In summary, we have found that chiral Brønsted acids,
reactions of indoles, we wish to investigate the combination commercial -CSA and its derived BmimBr–CSA complex,
of an ionic liquid with a chiral Brønsted acid and investi- are effective catalysts in the enantioselective Michael-type
gate its catalytic activity and its asymmetric induction effect Friedel–Crafts reactions of indoles with enones. By mixing
in Michael-type FC reactions of indoles.
a Brønsted acid with BmimBr a new set of active catalysts
[
13]
Further investigation allowed us to find that the ionic (LBA)
for this reaction are generated. This simple pro-
liquid (molten salt) 1-butyl-3-methyl-1H-imidazolium bro- cess provides easy access to a large library of highly func-
mide (BmimBr) was an effective promoter in this reaction. tionalized β-indolyl ketones containing a stereocenter in the
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Eur. J. Org. Chem. 2006, 5225–5227

Enantioselective Michael-Type Friedel–Crafts Reactions of Indoles
SHORT COMMUNICATION
Table 2. Michael-type Friedel–Crafts reactions of indoles with en-
ones catalyzed by -CSA and its acidic BmimBr–CSA complex.
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Enones
Indoles
Yield
[
ee
[%]
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%][
b]
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1
3
1
2
3
4
5
6
7
8
9
-CSA
R = H;
R = H
3a: 78
18
19
37
58
21
26
0
2
R = H
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3
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R = H
3a: 96
3b: 92
3b: 90
3c: 75
3c: 85
3d: 96
3d: 92
3e: 96
2
R = H
1
3
-CSA
R = H;
R = H
2
R = p-Cl
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3
BmimBr–CSA R = H;
R = H
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R = p-Cl
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-CSA
R = p-OCH
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R = H
2
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R = H
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3
BmimBr–CSA R = H;
R = H
29
22
2
R = o-Cl
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3
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R = 5-
Br
2
R = H
1
3
10
11
12
BmimBr–CSA R = H;
R = 5-
3e: 96
3f: 77
3f: 76
24
25
21
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8
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[
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[a] Experimental conditions: To a solution of enone (0.5 mmol) and
indole (0.55 mmol) in solvent (3 mL), catalyst (0.05 mmol of -
CSA or 0.12 mmol of BmimBr–CSA complex) was added. All reac-
tions were carried out at room temp. for 12 h. [b] Isolated yields.
[
c] Determined by chiral stationary phase HPLC. [d] The catalyst
was recovered and used for a second time.
β-position in excellent yields and moderate enantiomeric
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Acknowledgments
1
924, and references cited therein.
This work was supported by the National Nature Science Founda-
tion of China (Project No. 20572114 and 20533080).
Received: July 26, 2006
Published Online: October 12, 2006
Eur. J. Org. Chem. 2006, 5225–5227
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5227