Communication
the enantioselective aza-Friedel–Crafts reaction as an atom-
economical synthetic process for the synthesis of the described
compounds is highly desirable. Although there are several re-
ports on the catalytic enantioselective aza-Friedel–Crafts reac-
tions of indoles with various ketimines,[11] only a few challenge
the difficulty of the enantioselective Friedel–Crafts reaction of
ketimines with pyrroles.[12] We recently reported the highly
enantioselective reaction of ketimines with various nucleo-
philes,[13] and we also developed novel 1,1-bi-2-naphthol
(BINOL)-derived phosphoric acid catalysts with chiral imidazo-
line groups.[14,15] Futhermore, we have reported the first orga-
nocatalytic aza-Friedel–Crafts reaction of imines, derived from
aldehydes, with non-protected pyrroles.[16] Herein our ongoing
interest was extended to the enantioselective aza-Friedel–
Crafts reaction of 2-substituted-3H-indol-3-ones as ketimines
with non-protected pyrroles using our original organocatalysts
(Figure 2).
Abstract: Organocatalytic enantioselective aza-Friedel–
Crafts reactions of cyclic ketimines with pyrroles or indoles
were catalyzed by imidazoline/phosphoric acid catalysts.
The reaction was applied to various 3H-indol-3-ones to
afford products in excellent yields and enantioselectivities.
The chiral catalysts can be recovered by a single separa-
tion step using column chromatography and are reusable
without further purification. Based on the experimental in-
vestigations, a possible transition state has been proposed
to explain the origin of the asymmetric induction.
Chiral indoline-3-ones with a quaternary chiral carbon center
at the 2-position are an important class of synthetic targets,
because they are often found in a broad range of biologically
active compounds, such as (À)-trigonoliimine C,[1] (+)-isatisine
A,[2] (À)-brevianamide B,[3] (+)-aristotelone,[4] (+)-austamide,[5]
and other natural compounds (Figure 1).[6] Although many syn-
Figure 2. Enantioselective aza-Friedel–Crafts reaction of 2-substituted 3H-
indol-3-one derivatives with pyrroles.
We first examined the reaction of 2-phenyl-3H-indol-3-one
(1a) with pyrrole (2a) (1.2 equiv) in the presence of 5 mol% of
the chiral organocatalysts 3a–h. The results are shown in
Table 1. To our delight, the reaction of 1a with 2a using the
chiral imidazolinephosphoric acid catalyst 3a proceeded effi-
ciently in less than 1 min to afford product 4 in high yield but
with low enantioselectivity (Table 1, entry 1). We next investi-
gated the effect of the substituent on the imidazoline catalysts.
However, changing the substituent on nitrogen in the imidazo-
line catalysts from a tosyl to a benzoyl or benzyl group could
not improve the enantioselectivity of the product 4 (Table 1,
entries 2 and 3). On the other hand, the reaction using the bi-
s(imidazoline)phosphoric acid 3d afforded product 4 in high
yield and enantioselectivity (Table 1, entry 4).[17] The reaction
using the bis(imidazoline)phosphoric acid 3e, which has the
opposite stereochemistry on the BINOL backbone, gave prod-
uct 4 with low enantioselectivity (Table 1, entry 5). We also ex-
amined the reactions of the chiral phosphoric acid catalysts
3 f,g bearing triphenylsilyl or 3,5-trifluoromethylphenyl groups,
and the 2,2’-diphenyl-[3,3’-biphenanthrene]-4,4’-diol (VAPOL)
derived phosphoric acid 3h that afford 4 with low enantiose-
lectivities (Table 1, entries 6–8). Taken together, 3d emerged as
the most suitable catalyst for this reaction. When the reaction
temperature was lowered from room temperature to À408C,
the enantioselectivity improved (Table 1, entry 9, see Experi-
mental Section for details). The catalyst loading of 3d was suc-
cessfully reduced to 2 mol% without the loss of enantioselec-
tivity, although the reactivity and enantioselectivity were re-
duced in the reaction using 1 mol% of the catalyst 3d (Table 1,
entries 10 and 11). The reaction could be carried out in an
Figure 1. Natural indoline-3-one coumpounds with a quaternary, chiral
carbon center.
thetic strategies towards chiral indoline-3-ones have been re-
ported,[7] only a few examples of the catalytic asymmetric syn-
thesis of optically active indoline-3-ones with a quaternary
carbon center can be found in literature.[8] One of the simplest
ways to construct chiral indoline-3-ones with a quaternary
carbon center at the 2-position are reactions of 2-substituted-
3H-indol-3-one derivatives as cyclic ketimines with nucleo-
philes. In 2011, Rueping and co-workers reported that the
enantioselective reaction of 3H-indol-3-ones with indoles using
chiral phosphoric acid catalysts gave products with good enan-
tioselectivities (79–91% ee).[9] After this pioneering report, sev-
eral enantioselective reactions of 3H-indol-3-ones with different
nucleophiles were reported.[10] On the other hand, utilization of
[a] Prof. Dr. S. Nakamura, N. Matsuda, Dr. M. Ohara
Frontier Research Institute for Material Science
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+81)527355245
Supporting information with experimental details for this article can be
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Chem. Eur. J. 2016, 22, 1 – 6
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ÝÝ These are not the final page numbers!