Organocatalytic Enantioselective Aza-Friedel–Crafts Reaction of Cyclic Ketimines with Pyrroles using Imidazolinephosphoric Acid Catalysts

Article abstract of DOI:10.1002/chem.201601573

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

Full text of DOI:10.1002/chem.201601573

DOI: 10.1002/chem.201601573
Communication
&
Organocatalysis
Organocatalytic Enantioselective Aza-Friedel–Crafts Reaction of
Cyclic Ketimines with Pyrroles using Imidazolinephosphoric Acid
Catalysts
Shuichi Nakamura,* Nazumi Matsuda, and Mutsuyo Ohara[a]
Chem. Eur. J. 2016, 22, 1 – 6
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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
E-mail: snakamur@nitech.ac.jp
Supporting information with experimental details for this article can be
found under http://dx.doi.org/10.1002/chem.201601573.
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Table 1. Enantioselective aza-Friedel–Crafts reaction of 1a with 2a using
various organocatalysts 3a–h.
Table 2. Enantioselective aza-Friedel–Crafts reaction of various substitut-
ed 3H-indol-3-ones 1a–j with 2a using 3d.
Entry
1a–j
R1
R2
t
Product
Yield
[%]
ee[a]
[%]
[min]
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
H
H
H
H
H
H
H
H
3
3
3
3
3
3
3
40
3
4
5
6
7
8
9
10
11
12
13
99
99
99
99
99
99
99
99
80
99
99
96
96
98
99
99
99
97
98
99
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
2-naphthyl
Ph
8[b]
9
H
6’-Br
10
1j
3
[a] Enantiomeric ratio ee was determined by HPLC analysis. [b] At À788C.
We also examined the reaction of 1a with various arene
compounds using 2 mol% of the catalyst 3d at À788C. The re-
action with 3-bromopyrrole (2b), 3-allylpyrrole (2c), and 3-cro-
tylpyrrole (2d) resulted in the formation of the products 14–16
in good yields with high enantioselectivities (Scheme 1).[18]
Indole (2e) also reacted with 1a in the presence of 3d to
afford the (R)-isomer of the product 17 in excellent yield with
good enantioselectivity (Scheme 1). Furthermore, the reaction
of 1a with N-Cbz tryptamine (2 f) using 2 mol% 3d gave rise
to 18 in high yield and enantioselectivity. The obtained 2-sub-
stituted indole derivative 18 is an important structural motif
analogous to trigonoliimine C (Scheme 2).
Run
3a–h
T
t
Yield
[%]
ee[a,b]
[%]
[oC]
[min]
1
2
3
4
5
6
7
8
9
3a
rt
rt
rt
rt
rt
rt
rt
rt
1
30
1
42
9 (R)
9 (R)
0
3b
3c
3d
3e
3 f
3g
3h
3d
3d
3d
3d
42
26
91
50
31
77
73
99
99
97
99
3
1
1
3
1
3
3
3
96 (R)
33 (R)
10 (S)
41 (S)
8 (R)
99 (R)
99 (R)
95 (R)
99 (R)
À40
À40
À78
À78
10[c]
11[d]
12[c,e]
3
[a] Enantiomeric ratio ee was determined by HPLC analysis. [b] The absolute
configuration of 4 is provided in parentheses. [c] 2 mol% 3d. [d] 1 mol% 3d.
[e] The reaction was carried out in an open flask.
open flask to give product 4 without the loss of enantioselec-
tivity (yield 99% with 99% ee).
Having established optimized conditions for the reaction of
the imine 1a with 2a, the reactions of a series of imines 1b–j
with 2a in the presence of 3d were examined (Table 2). The re-
actions of the imines 1b and c, bearing an electron-donating
methyl or methoxy group in the para position, gave the corre-
sponding products 5 and 6 in high yields with excellent enan-
tioselectivities (Table 2, entries 2 and 3). The electron-deficient
imines 1d–h, with fluoro, chloro, or bromo groups in the para,
meta, or ortho position, were tolerated under these reaction
conditions to give products 7–11 with excellent stereoselectivi-
ties (Table 2, entries 4–8). The imine 1i with a naphthyl group
also afforded the product 12 with high enantioselectivity
(Table 2, entry 9). The reaction of 2a with the imine 1j, with
a bromo group, gave rise to the product 13 in excellent yield
and enantioselectivity (Table 2, entry 10). Chemical yields and
enantioselectivities were excellent in most cases.
Scheme 1. Enantioselective aza-Friedel–Crafts reaction of 2-phenyl-3H-indol-
3-one (1a) with 3-bromopyrrole (2b), 3-allylpyrrole (2c), 3-crotylpyrrole (2d),
and indole (2e).
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Scheme 2. Enantioselective aza-Friedel–Crafts reaction of 1a with N-Cbz-
tryptamine (2 f).
To test the scalability, a gram-scale aza-Friedel–Crafts reac-
tion was performed using 2 mol% of the catalyst 3d
(Scheme 3). The reaction of 2a (0.4 mL; 1.2 equiv) with 1a
(1.0 g; 1.0 equiv) proceeded to give the product 4 in 99% yield
with 99% ee within 3 min. It should be noted that most of 3d
was recovered by a single separation step using column chro-
matography and it was reusable without further purification.
The reaction of 1a with 2a using the recovered catalyst afford-
ed the product 4 in 99% yield with 97% ee.
Figure 3. Proposed transition state for the reaction of 1a with 2a using the
catalyst 3d.
philicity of pyrrole by establishing a hydrogen bond between
the oxygen in the phosphoric acid and the imidazoline group.
Furthermore, the electrophilicity of 2-phenyl-3H-indol-3-one 1a
is also activated through hydrogen-bonding interactions with
the phosphoric acid moiety. Therefore, the chiral imidazoline-
phosphoric acid 3d would act as a dual-activating organocata-
lyst. The reaction of pyrrole with 1a proceeded in the coordi-
nation sphere of the chiral catalyst 3d, and the Si-face of the
ketimine reacts with pyrrole to give the (R)-isomer of the prod-
uct with high enantioselectivity. Further studies are required to
fully elucidate the mechanistic detail of the aza-Friedel–Crafts
reaction of pyrroles with 1a.
On the other hand, the enantioselective aza-Friedel–Crafts
reaction of the imine 1a with N-methylpyrrole (2g) gave the
product 19 in good yield, but with moderate enantioselectivity
(Scheme 4). Furthermore, the reactivity of 1h with N-deuterat-
ed pyrrole ([D]-2a, 100% D) was significantly lower due to the
isotope effect,[19] and the reaction was only completed after
18 h at À788C.
These results imply that hydrogen bonding between pyrrole
and the catalyst 3d plays a key role in the catalytic process.
From this consideration, the assumed transition state for the
enantioselective aza-Friedel–Crafts reaction using 3d is shown
in Figure 3. Catalyst 3d could efficiently enhance the nucleo-
In conclusion, we developed
a highly enantioselective
method for the synthesis of quaternary-carbon-center-contain-
ing compounds by the aza-Friedel–Crafts reaction of cyclic ke-
timines with pyrroles or indoles. We identified bis(imidazoline)-
phosphoric acid catalysts to be privileged organocatalysts for
the described reaction. The catalyst loading was successfully
minimized down to 2 mol% without a significant decrease in
yield and enantioselectivity. Further studies focusing on the
scope of the asymmetric reaction using novel organocatalysts
are currently under investigation and will be reported in due
course.
Scheme 3. Gram-scale experiment for the enantioselective aza-Friedel–Crafts
reaction of 1a and 2a using 3d.
Experimental Section
A solution of the bis(imidazoline)phosphoric acid catalyst 3d
(0.0042 mmol, 5 mol%) and 1a (0.0840 mmol) in toluene (1.68 mL)
was cooled to À408C (Table 1, entry 9). Pyrrole (0.101 mmol) was
added and the reaction mixture was stirred at À408C. After com-
pletion of the reaction monitored by TLC (3 min), the mixture was
concentrated and purified by silica-gel column chromatography
(hexane/ethyl acetate=90:10) yielding indoline-3-one 4. Experi-
mental details for the remaining substrates and catalysts can be
found in the Supporting Information.
Acknowledgements
This work was partly supported by Grants-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transfor-
Scheme 4. Enantioselective aza-Friedel–Crafts reaction of 3H-indol-3-ones
with the N-methyl pyrrole (2g) or the N-deuterated pyrrole [D]-2a.
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under MEXT (Japan) and the Tokuyama Science Foundation.
Keywords: aza-Friedel–Crafts reaction · enantioselectivity ·
imidazoline · ketimine · organocatalysis
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[18] The reaction of 1a and 2b without MS4A afforded the product 14 in
slightly lower yield than that using MS4A.
[19] The reaction mixture was directly purified by silica gel column chroma-
tography but the reaction cannot be stopped completely. Therefore,
enantioselectivity of the product was lower than that from the reaction
with non-deutarated pyrrole 2a.
Received: April 5, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Reusable chiral catalysts: Organocata-
lytic enantioselective aza-Friedel–Crafts
reactions of cyclic ketimines with pyr-
roles or indoles using imidazoline/phos-
phoric acid catalysts were developed.
The reaction was applied to various 3H-
indol-3-ones to give products in excel-
lent yields and enantioselectivities. The
chiral catalysts can be reusable without
further purification.
&
Organocatalysis
S. Nakamura,* N. Matsuda, M. Ohara
&& – &&
Organocatalytic Enantioselective Aza-
Friedel–Crafts Reaction of Cyclic
Ketimines with Pyrroles using
Imidazolinephosphoric Acid Catalysts
Chiral Phosphoric Acid Catalysts
Organocatalytic enantioselective aza-Friedel–Crafts reactions
of cyclic ketimines with pyrroles or indole were catalyzed by
imidazolinephosphoric acid catalysts. The reaction was
applied to various 3H-indol-3-ones to afford products in
excellent yields and enantioselectivities. The graphics shows
origami cranes that fly with expanded wings. The
bis(imidazoline)/phosphoric acid catalysts also expand their
wings like the origami cranes, and form a well-fitting
asymmetric space for substrate binding to let the reaction
“fly”. The full story can be found in the Communication by
S. Nakamura and colleagues on page && ff.
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&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!