Acid-mediated aryl migration reaction of C-3 aryl substituted pyrrolidinoindolines

Article abstract of DOI:10.1016/j.tetlet.2016.11.069

Aryl migration reactions of C-3 aryl substituted pyrrolidinoindoline compounds to provide highly conjugated C-2 aryl indole compounds have been discovered. The developed reactions have a wide substrate scope and proceed in high yield under simple acidic c

Full text of DOI:10.1016/j.tetlet.2016.11.069

Accepted Manuscript
Acid-Mediated Aryl Migration Reaction of C-3 Aryl Substituted Pyrrolidinoin-
dolines
Shinji Tadano, Hayato Ishikawa
PII:
S0040-4039(16)31537-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.069
TETL 48355
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 October 2016
10 November 2016
16 November 2016
Please cite this article as: Tadano, S., Ishikawa, H., Acid-Mediated Aryl Migration Reaction of C-3 Aryl Substituted
Pyrrolidinoindolines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.069
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Acid-Mediated Aryl Migration Reaction of
C-3 Aryl Substituted Pyrrolidinoindolines
Leave this area blank for abstract info.
Shinji Tadano, Hayato Ishikawa*
aryl or heteroaryl
group
R
R
CO2Me
NH2
MsOH
CO2Me
C2
C3
CO2Me
NH3
N
H
NH
R
N
H
N
H
H

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Acid-Mediated Aryl Migration Reaction of C-3 Aryl Substituted Pyrrolidinoindolines
Shinji Tadanoa and Hayato Ishikawaa, ∗
a Department of Chemistry, Graduate School of Science and Technology, Kumamoto University, 2-39-1, Kurokami, Chuo-ku, Kumamoto 860-8555 (Japan)
ARTICLE INFO
ABSTRACT
Article history:
Received
Aryl migration reactions of C-3 aryl substituted pyrrolidinoindoline compounds to provide
highly conjugated C-2 aryl indole compounds have been discovered. The developed reactions
have a wide substrate scope and proceed in high yield under simple acidic conditions. A unique
cationic cyclopropane intermediate as the transition state is proposed.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aryl migration
pyrrolidinoindoline
indolenine
indole
Introduction
derivative 5 under acidic conditions to promote aryl migration
from C-3 to C-2 toward thermodynamically stable indole 6.
The indole architecture, which is composed of benzene and
pyrrole rings, exhibits a specific reactivity derived from its
unique electron states. A wide variety of indole alkaloids that
come from tryptophan have been isolated as natural products.
In biosynthesis, the diversity of indole alkaloid compounds
stems from the specific reactivities of indole; reactions can be
induced by both nucleophilicity and electrophilicity, and the
structure can undergo migration processes1. Recently, the
specific reactivity of indole and its derivatives have been
widely applied in the fields of chemical biology and material
chemistry2. Although
a large number of specific indole
reactions have been reported, it remains a developing area.
Therefore, expanding the range of indole reactions is an
important topic in current organic chemistry.
Whereas several oxidative migration reactions of aryl groups
from the C-2 to the C-3 position to form oxindole core or alkyl
group migration reactions from the C-3 to the C-2 position to
form pseudoindoxyl core have been documented3, to our
knowledge, only two examples of an aryl migration reaction
from the C-3 position of indolenine to the C-2 position of the
pseudoindoxyl core has been reported (Schmidt and Beitzke;
Scheme 1)3h, 4. Therefore, thermolysis of aniline derivative 1
induced aryl migration via iminium ion intermediate A (C-2 to
C-3) to provide C-3 diaryl compound 3 as a major component.
The minor rearrangement product was the C-2 diaryl product,
which was formed via cationic indolenine intermediate B (C-3
Scheme 1. Migration of aryl group on indole related molecules.
Herein, we report the acid-mediated aryl migration reactions
of an aryl group on the C-3 position of pyrrolidinoindoline to
the C-2 position of indoles via
intermediate.
a cationic indolenine
4
Result and discussion
to C-2) . We envisioned that a similar cationic indolenine
intermediate C could be generated from pyrrolidinoindoline
To investigate the proposed aryl migration reaction,
pyrrolidinoindoline derivatives were prepared using Qin’s
———
∗ Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
protocol5 followed by removal of the Boc group (see details in
the Supporting Information). The migration of C-3 tolyl
derivative 5a was used to screen a selection of acids with a
range of pKa values (Table 1).
Me
Me
Me
CO2Me
NH3
H+
CO2Me
A
C
X
CO2Me
NH
B
NH
N
H
Table 1. The effect of acid on the migration reaction of 5a.[a]
N
H
N
H
H
3 X
5a
7
8
Me
CO2Me
CO2Me
NH2
CO2Me
X
NH3
acid
NH2
CO2Me
N
H
N
H
CH2Cl2, 23 °C
H
Me
Me
N
H
NH
Me
N
H
6a
9
H
6a
5a
Scheme 2. Proposed reaction pathway.
Entry
1
Acid [equiv.]
pKa in H2O
Time [h]
Yield [%][b]
N. R.
CH3CO2H
4.76
24
24
[30.0 equiv.]
Next, the substrate scope of the reaction was investigated.
Compounds 5b–h and 5j were prepared using the procedure
described for 5a. Compound 5i was prepared using our
previously developed dimerization reaction of tryptophan
derivatives6.
2
3
CH2ClCO2H
[30.0 equiv.]
2.86
1.29
N. R.
trace
CHCl2CO2H
[30.0 equiv.]
24
Table 2. Scope of the reaction.[a]
4
5
6
7
8
CCl3CO2H
0.65
–0.25
–2.6
24
24
1
45
(quant.) [c]
[30.0 equiv.]
CO2R
NH2
Ar
CO2R
CH3SO3H (10.0 equiv.)
solvent, conditions
CF3CO2H
85
(99) [c]
NH
Ar
[30.0 equiv.]
N
H
N
H
H
5a-j
6a-j
CH3SO3H
quant.
99
[30.0 equiv.]
Entry
1
Ar
R
solvent
CH2Cl2
Temp.
[°C]
Time
[h]
Yield
[%][b]
CF3SO3H
–14.0
–2.6
0.25
2
[30.0 equiv.]
Me
23
2
quant.
CH3SO3H
quant.
Me
[10.0 equiv.]
5a
5b
[a] Reaction conditions: 5a (0.05 mmol), CH2Cl2 (0.5 mL, 0.1 M). [b] Yield of
2
3
Me
Me
CH2Cl2
CH2Cl2
23
2
99
the isolated product. [c] Base on recovered starting material.
OMe
When weaker acids such as dichloroacetic acid,
monochloroacetic acid, or acetic acid (30 equiv., CH2Cl2, 23
°C) were employed, the desired migrated product was not
observed (pKa > 1.29; Table 1, entries 1–3). In contrast, the use
of either trichloroacetic acid (pKa 0.65) or trifluoroacetic acid
(pKa –0.25) led to the desired rearrangement reaction to give C-
2 tolyl indole 6a, although the reaction was not complete after
24 h (entries 4 and 5). Finally, methanesulfonic acid (MsOH,
pKa –2.6) and trifluoromethanesulfonic acid (TfOH, pKa –14)
were both found to be suitable for promotion of the aryl
migration reaction. Therefore, when 30 equivalents of either
MsOH or TfOH were added to 5a in CH2Cl2, 6a was obtained
in quantitative yield (MsOH, 1 h; TfOH, 15 min; entries 6 and
7). The amount of acid could be reduced to 10 equivalents,
although longer reaction times were required (MsOH, 2 h; entry
8).
The proposed reaction mechanism is shown in Scheme 2.
Under acidic conditions, the secondary amine on ring C was
converted into the salt; this ring was then opened to generate
cationic indolenine intermediate 7. Subsequently, the tolyl
group migrated from the C-3 to the C-2 position to afford
intermediate 9 via cationic cyclopropane intermediate 8. This
was followed by tautomerization to provide the highly
conjugated thermodynamically stable indole compound 6a.
23
23
2
2
95
96
MeO
5c
4
Me
CH2Cl2
5d
5e
5
6
7
Me
Me
Me
CH2Cl2
CH2Cl2
23
23
80
2
4
2
quant.
23 [c]
93
NH2
5f
5f
(ClCH2)2
73 [d]
NHAc
8
Me
(ClCH2)2
80
2
5g

3
dimeric compound 11 to the salt form of 6j and cationic
indolenine intermediate 12 (Scheme 3).
9
Me
CH2Cl2
23
23
2
2
96
93
CO2Me
S
N
Me
CO2Me
NH2
NH2
CH3SO3H (20.0 equiv.)
CO2Me
NH2
5h
(ClCH2)2, 80 °C, 2 h
72%
N
H
N
H
S
S
10
Et
CH2Cl2
CO2Et
NH2
6j
11
HN
migration
process
H
N
H
CO2Me
S
5i
CO2Me
NH3
CO2Me
S
X
NH3
CO2Me
11
12
Me
Me
CH2Cl2
23
80
2
2
36 [e]
X
NH3
X
N
H
NH
3X
S
H
S
N
H
N
S
6j (salt form)
HN
12
5j
5j
Scheme 3. Retro reaction and migration of dimeric thiophen derivative 11.
(ClCH2)2
88
Scheme 3. Retro reaction and migration of dimeric thiophen
derivative 11.
[a] Reaction conditions: 5 (0.1 mmol), solvent (1 mL, 0.1 M). [b] Yield of the
isolated product. [c] Starting material 5f was recovered in 73% yield. [d]
Deacetyl rearrangement compound 6f was obtained in 13% yield. [e]
Dimeric compound 11 was obtained in 63 % yield.
If these equilibrium conditions were established in situ,
thermodynamically stable 6j would be obtained selectively.
Therefore, isolated dimeric compound 11 in 1, 2-
dicholoroethane was treated with MsOH at 80 °C for 2 h. As a
result, the desired monomer 6j was obtained in good yield
(72%). The optimized reaction conditions were then directly
applied to 5j. In this case, the yield of 6j improved dramatically
without any production of 11 (88% yield; Table 2, entry 12).
The discovered equilibrium reaction suggested that C-2
thiophene adducts such as 11 could be employed as a cationic
indolenine equivalent.
When 5b was used as substrate under the optimized reaction
conditions (10 equiv. MsOH, CH2Cl2, 23 °C), rearrangement
compound 6b was obtained in 99% yield (Table 2, entry 2). o-
methoxybenzene derivative 5c was transformed to 6c ragio-
selectivily in superb yeild (95%, Table 2, entry 3). Naphthalene
derivatives 5d and 5e were also suitable substrates, giving 6d
and 6e in 96% and quantitative yield, respectively (entries 4
and 5). On the other hand, aniline derivative 5f was less
reactive under the established conditions (MsOH 10.0 equiv.,
23 °C); in this case, the reaction gave 6f in reaction to the
iminium ion might be inhibited. After optimization, a higher
reaction temperature was identified as being required to obtain
excellent conversion (MsOH 10.0 equiv., 1, 2-dichloroethane,
80 °C, 93%; entry 7). When the reaction with acetylated 5g was
carried out under the heating conditions described for 5f (entry
7), 6g was obtained in 73% yield along with deacetylated 6f in
13% (entry 8). C3-indole derivatives 5h7 and 5i also provided
migrated products 6h and 6i in excellent yield (96% and 93%,
respectively; entries 9 and 10). In addition, the relative
stereochemistry of the ethoxycarbonyl group did not have any
effect on the migration reaction (Eq. 1). Therefore, tryptophan
dimeric derivative 106, which is the diastereomer of 5i, was
converted into 6i in excellent yield under same reaction
Conclusions
We have developed aryl migration reactions of C-3 aryl
substituted pyrrolidinoindoline compounds to provide highly
conjugated C-2 aryl indole compounds via a cationic indolenine
intermediate. The developed reactions proceed in high yield
under simple acidic conditions and show excellent substrate
generality. Therefore, the novel reaction mode of indole-related
compounds has been expanded to further enhance the field of
indole chemistry. Applications of the migration reaction to π-
conjugated compounds for use in chemical biological studies
and material chemistry are underway.
conditions (91%).
NH2
Acknowledgements
EtO2C
CO2Et
NH2
NH
CH3SO3H
(10.0 equiv.)
We gratefully acknowledge financial support through a Grant-
in-Aid for Scientific Research (B) (Grant Number 25288050)
and Exploratory Research (Grant Number 25670005) from
JSPS, and a JSPS Research Fellowship for Young Scientists to
S. T. We would also like to thank Prof. Hiromitsu Takayama
(Chiba University) and members of his laboratory for their
support and guidance.
(1)
CO2Et
N
H
CH2Cl2, 23 °C, 2 h
CO2Et
NH2
NH
91%
N
HN
6i
H
H
10
Interestingly, the migration reaction of thiophene derivative
5j gave dimeric compound 11, which was formed by Friedel–
Crafts addition of the desired product 6j to the cationic
indolenine intermediate; compound 11 was obtained in 63%
yield as the major product (desired 6j was obtained in 36%
yield as the minor compound; entry 11). This unexpected side
reaction derived from the high nucleophilicity of the thiophene
moiety. Therefore, we considered the retro reaction from
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Supplementary Material
Supplementary data associated with this article can be found, in
the online version, at http://

*Highlights
The novel reaction mode of indole-related compounds has been discovered.
A unique cationic cyclopropane intermediate as the transition state is proposed.
The developed aryl migration reactions have a wide substrate scope.
The developed reactions proceeded in high yield under simple acidic condition.