Communications
DOI: 10.1002/anie.201003919
Asymmetric Catalysis
Enantioselective Intramolecular Aza-Michael Additions of Indoles
Catalyzed by Chiral Phosphoric Acids**
Quan Cai, Chao Zheng, and Shu-Li You*
Chiral indole frameworks are widely distributed throughout
natural products and pharmaceuticals.[1] In this scenario,
enormous efforts have been devoted to the development of
efficient syntheses of enantioenriched indole derivatives.[2] It
has been well documented that the C3-position of an indole is
the most reactive of the three reactive positions (N1, C2, C3).
Therefore, considerable attention has been paid to the
asymmetric C3 alkylation of indole.[3] Recently, the enantio-
selective C2 alkylation of indole was realized through an
asymmetric Pictet–Spengler reaction,[4] alkylation of 2-indolyl
trifluoroborate salts,[5] and Friedel–Crafts alkylation of 4,7-
dihydroindoles.[6] However, the enantioselective N alkylation
of an indole has rarely been explored,[7] despite the fact that
the products are privileged structural motifs in natural
alkaloids and biologically active compounds.[8]
indole could increase the nucleophilicity of the indolyl
nitrogen atom. However, this approach would have to avoid
the C3 alkylation of the 3-substituted indoles to produce the
indolenines, a strategy that has been demonstrated by several
groups that employed transition-metal catalysis or organo-
catalysis.[9] For the initial investigation, the indolenine prod-
uct was obtained from the tetrahydrocarbazole and enone in
the presence of chiral phosphoric acid; the N-alkylation
product was not observed [Eq. (3)]. Interestingly, when the
Upon introduction of an electron-withdrawing group
(EWG) on the indole core, the proton on the nitrogen atom
becomes more acidic, therefore making the N position prone
to alkylation under basic reaction conditions [Eq. (1), E =
intramolecular reaction was tested, the N-alkylation product
was obtained chemoselectively [Eq. (4)], providing facile
electrophile]. In taking advantage of this strategy, several
groups have successfully realized the enantioselective N al-
kylation of indoles.[7] However, in most of the reported
catalytic systems, indoles without electron-withdrawing
groups were not tolerated, the only exception being in the
work by Chen et al.[7c]
As part of our ongoing program on the asymmetric
Friedel–Crafts alkylation of indoles,[2e] we recently explored
the N alkylation of indoles by using chiral phosphoric acid
catalysts [Eq. (2)]. We envisaged that installation of an
electron-donating group (EDG) at the C3-position of the
access to enantioenriched polycyclic indoles.[10] Herein we
communicate our study on the chiral phosphoric acid
catalyzed asymmetric, intramolecular Friedel–Crafts-type
aza-Michael reaction of indoles and the preliminary mecha-
nistic investigation.
We first studied the cyclization of a,b-unsaturated ketone
4a with various chiral phosphoric acids (entries 1–7, Table 1).
To our delight, the aza-Michael addition product was
obtained with promising chemoselectivity and enantioselec-
tivity. Chiral phosphoric acid 1g bearing triphenylsilyl groups
proved to be the optimal catalyst, affording product 5a in
96% yield and 89% ee (entry 7, Table 1). Additional screen-
ing of solvents (entries 7–9, Table 1) revealed that toluene
was the best. When 4 ꢀ molecular sieves (M.S.) were used as
[*] Q. Cai, C. Zheng, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-5492-5087
E-mail: slyou@mail.sioc.ac.cn
[**] We thank the National Natural Science Foundation of China
(20732006, 20821002), the National Basic Research Program of
China (973 Program 2010CB833300), and the Chinese Academy of
Sciences for generous financial support.
Supporting information for this article is available on the WWW
8666
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8666 –8669