Enatioselective Synthesis of Tetrahydrocarbazoles via Chiral Phosphoric
Acid Promoted Domino Friedel–Crafts-type Reaction of Indole-3-butanal
and Xiaomei Zhang
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
University of Chinese Academy of Sciences, Beijing 100049, China
Received July 25, 2017
Published online 10 January 2018 in Wiley Online Library (wileyonlinelibrary.com).
By employing a chiral phosphoric acid as a catalyst, enantioselective domino Friedel–Crafts-type reaction
of indole-3-butanal with indoles was realized. This transformation allowed for the synthesis of a wide variety
of enantioenriched 1-indolyl-tetrahydrocarbazoles with good yields (up to 99%) in moderate enantio-
selectivities (up to 81% ee).
J. Heterocyclic Chem., 55, 619 (2018).
Tetrahydrocarbazoles are important structural motifs
that widely exist in natural products and pharma-
ceutical substances . Therefore, preparation of
tetrahydrocarbazoles has attracted much attention and
many efﬁcient strategies have been well established to
construct structurally diverse tetrahydrocarbazoles [2,3].
Recently, Nielsen et al. disclosed a catalytic
enantioselective synthesis of tetrahydrocarbazoles via
domino Friedel–Crafts-type reaction of indole-3-butanals
with various nucleophiles including indoles, 1H-1,2,4-
triazole and thiols [3d]. However, in their study on
reaction of indole-3-butanals with indoles, only 2-tert-
butylindole and 2-TMS-indoles were used in reaction
with indole-3-butanal. Other 2-substituted-indoles have
not been investigated.
In this paper, we demonstrated an enantioselective
domino Friedel–Crafts-type of indole-3-butanal with a
wide variety of indoles including a series of 2-aryl-
indoles promoted by a chiral phosphoric acid.
This transformation enables easy access to a wide variety
of 1-indolyl-tetrahydrocarbazoles with good yields (up to
99%) in moderate enantioselectivities (up to 81% ee) and
we found that many 2-aryl-indoles delivered obviously
superior enantioselection to 2-unsubstituted-indoles in the
reaction with indole-3-butanal.
RESULTS AND DISCUSSION
We initiated the investigation with the reaction of indole-
3-butanal 1 with indole 2a in dichloromethane at 0°C.
First, various chiral phosphoric acids were evaluated. As
shown in Table 1, chiral phosphoric acids (R)-PA4 that
has bulky groups in the 3,3
positions of BINOL
produced good yield of 1-indolyl-tetrahydrocarbazole 3a
with the best ee value (Table 1, entry 4). Therefore, PA4
was determined as the optimal catalyst and was used
throughout our study. Subsequently, several solvents were
screened. Among the chlorinated solvents, reaction in 1,2-
dichloroethane was found to provide the product in good
yield with the best enantioselection (Table 1, entry 7).
Reaction in acetonitrile resulted in obvious decrease
in yield and ee value (Table 1, entry 9), meanwhile,
no desired product was generated in tetrahydrofuran
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