COMMUNICATION
DOI: 10.1002/chem.201100576
An Enantioselective Approach to 2,3-Disubstituted Indolines through
Consecutive Brønsted Acid/Pd-Complex-Promoted Tandem Reactions
Ying Duan, Mu-Wang Chen, Zhi-Shi Ye, Duo-Sheng Wang, Qing-An Chen, and
Yong-Gui Zhou*[a]
Tandem reactions and consecutive catalysis (or relay cat-
alysis) have been receiving considerable attention in organic
synthesis due to their abilities of constructing multiple new
chemical bonds to build complex chiral molecules in a single
operation.[1,2] Transition-metal-catalyzed asymmetric hydro-
genation is one of the most widely used and reliable catalyt-
ic methods for preparation of chiral molecules.[3] The combi-
nation of Brønsted acid/transition-metal-catalyzed tandem
reactions involving asymmetric hydrogenation as key step
remains rare,[4] although Krische and co-workers reported
2,3-disubstituted indolines (Scheme 1).[12] Herein, we de-
scribe the enantioselective access to chiral 2,3-disubstituted
indolines through consecutive Brønsted acid/Pd-complex-
À
the C C bond formation with metal hydride as the catalytic
species.[2c,5]
Chiral 2,3-disubstituted indolines are significant building
blocks in biologically active natural products and pharma-
ceutically active compounds.[6] Generally, these compounds
are synthesized from either dynamic resolution or multiple-
step reactions.[7] The most straightforward and atom eco-
nomic means towards chiral indolines may be the asymmet-
ric hydrogenation of substituted indole derivatives. Recently,
some significant progress has been achieved by us and other
groups for the highly enantioselective hydrogenation of sub-
stituted indoles using chiral Pd, Rh, Ru, and Ir complexes as
catalysts.[8] Very recently, we developed a facile approach to
chiral 2,3-disubstituted indolines through dehydration-trig-
gered asymmetric hydrogenation of 3-(a-hydroxyalkyl)in-
doles.[9] Despite these contributions, the tedious procedure
for the preparation of the substrates limits its synthetic ap-
plications. So, the search for a rapid, simple, and divergent
method for synthesizing chiral 2,3-disubstituted indolines is
still highly desirable.
Scheme 1. The process for synthesis of 2,3-disubstituted indolines Brøn-
sted acid (HX)-promoted three-step reaction and Pd-catalyzed two-step
reaction.
promoted reductive alkylation/hydrogenation reactions with
up to 98% ee (Scheme 1). Three steps are promoted by a
Brønsted acid and two hydrogenation steps are catalyzed by
a Pd complex. Furthermore, the asymmetric hydrogenation
should drive the equilibrium of the Friedel–Crafts reaction
by converting the Friedel–Crafts product into a hydrogena-
tion product.
The reaction process was proposed as shown in Scheme 1.
The Brønsted-acid-promoted Friedel–Crafts reaction of 2-
methylindole and aldehyde afforded 3-(a-hydroxyalkyl)in-
dole 4; then, 4 was dehydrated to give the important inter-
mediate vinylogous iminium I,[13] followed by two asymmet-
ric hydrogenation steps to accomplish this process. For the
above process, several issues should be addressed. Firstly, 2-
substituted indole 1a might be preferentially hydrogenated
(Scheme 2, reaction 1).[8e] Secondly, bisindoles 6 is always
the byproduct of indole and aldehyde with Brønsted acid as
the catalyst (Scheme 2, reaction 2).[10e,14] Thirdly, both strong
Brønsted acid and water existed in the reaction, so the rele-
vant hydrogenation catalyst must be compatible with them.
Therefore, several experiments were designed to assess the
feasibility of this process. To our delight, after mixing 2-
methylindole, benzaldehyde, and para-toluenesulfonic acid
monohydrate (TsOH·H2O) in CDCl3 and stirring for 5 min,
the peaks of 2-methylindole and benzaldehyde almost disap-
peared, as observed by 1H NMR analysis. This result sug-
gested that the Friedel–Crafts reaction between 2-methyl
Considering reductive alkylation (Friedel–Crafts/dehydra-
tion/reduction) of 2-substituted indoles and aldehydes can
rapidly lead to 2,3-disubstituted indoles,[10] we envisioned
that combination of reductive alkylation of 2-substituted in-
doles and asymmetric hydrogenation[11] of 2,3-disubstituted
indoles can lead to a rapid and divergent approach to chiral
[a] Y. Duan, M.-W. Chen, Z.-S. Ye, D.-S. Wang, Q.-A. Chen,
Prof. Y.-G. Zhou
Dalian Institute of Chemical Physics
Chinese Academy of Sciences (CAS)
457 Zhongshan Road, Dalian 116023 (P.R. China)
Fax : (+86)411-84379220
Supporting information for this article is available on the WWW
Chem. Eur. J. 2011, 17, 7193 – 7197
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