Efficient and general synthesis of 3-aminoindolines and 3-aminoindoles via copper-catalyzed three-component coupling reaction

Article abstract of DOI:10.1002/adsc.201000015

An efficient three-component coupling (TCC) reaction toward a variety of 3-aminoindoline and 3-aminoindole derivatives has been developed. This cascade transformation proceeds via the copper-catalyzed coupling reaction between 2-aminobenzaldehyde, a secondary amine, and an alkyne leading to a propargylamine intermediate which, under the reaction conditions, undergoes cyclization into the indoline core. The latter, upon treatment with a base, smoothly isomerizes into the indole. Alternatively, the indole can directly be synthesized in a one-pot sequential reaction.

Full text of DOI:10.1002/adsc.201000015

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DOI: 10.1002/adsc.201000015
Efficient and General Synthesis of 3-Aminoindolines and
3-Aminoindoles via Copper-Catalyzed Three-Component
Coupling Reaction
Dmitri Chernyak,a Natalia Chernyak,a and Vladimir Gevorgyana,*
a
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, USA
Fax : (+1)-312-355-0836; phone: (+1)-312-355-3579; e-mail: vlad@uic.edu
Received: January 7, 2010; Revised: March 11, 2010; Published online: April 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000015.
Abstract: An efficient three-component coupling
(TCC) reaction toward a variety of 3-aminoindoline
and 3-aminoindole derivatives has been developed.
This cascade transformation proceeds via the
copper-catalyzed coupling reaction between 2-ami-
nobenzaldehyde, a secondary amine, and an alkyne
leading to a propargylamine intermediate which,
under the reaction conditions, undergoes cyclization
into the indoline core. The latter, upon treatment
with a base, smoothly isomerizes into the indole.
Alternatively, the indole can directly be synthesized
in a one-pot sequential reaction.
preparation of starting materials. Thus, the develop-
ment of a simple and general synthesis of 3-aminoin-
doles and 3-aminoindolines from easily available
starting materials is warranted. One of the reasonable
solutions to this problem would be the assembly of
indole and indoline cores via a multicomponent cou-
pling reaction (MCR).[4]
Herein, we wish to report an efficient Cu-catalyzed
three-component coupling reaction of N-protected 2-
aminobenzaldehydes 1 with secondary amines 2 and
terminal acetylenes 3 into the 3-aminoindolines 5 and
their subsequent isomerization into indoles
6
(Scheme 1). The multicomponent Mannich reaction
between benzaldehydes, secondary amines and acety-
lenes is well-documented.[5] Recently, the synthesis of
benzofurans via a three-component coupling reaction
of o-hydroxybenzaldehydes, acetylenes and secondary
amines catalyzed by copper salts has been reported.[6]
However, analogous multicomponent reactions of 2-
aminobenzaldehydes are unknown. We envisioned
Keywords:
3-aminoindolines;
3-aminoindoles;
copper; synthetic methods; three-component cou-
pling
Indole and indoline structural motifs are ubiquitously that a TCC reaction of N-protected 2-aminobenzalde-
found in a wide range of natural products and phar- hydes 1, secondary amine 2 and terminal alkyne 3
maceuticals.[1] In particular, 3-aminoindoles and indo- would lead to the formation of propargylamine inter-
lines have found a broad application in medicinal mediate 4,[7] which, upon activation of the triple bond
chemistry as effective anticancer agents, compounds with a p-philic metal, would undergo an intramolecu-
with analgesic properties, and agents for prevention lar 5-exo-dig cyclization[8,9,10] into indoline 5. It was ex-
of type II diabetes. However, the reported examples pected that under the reaction conditions, a subse-
on the synthesis of 3-aminoindoles[2] and 3-aminoin- quent isomerization of 5 into 3-aminoindoles 6 would
dolines[3] are limited in scope and require multistep occur (Scheme 1).
Scheme 1. Proposed synthesis of 3-aminoindoles.
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To test this hypothesis, the reaction of N-(2-formyl- aldehyde, such as chloro (entries 18 and 19), bromo
phenyl)-4-methylbenzenesulfonamide, piperidine and (entries 20–23), methyl (entry 24), methoxy
phenylacetylene in the presence of different metal (entry 25), and fluoro (entry 26), were also perfectly
salts has been examined (Table 1). It was found that tolerated. Additionally, we have shown that the N-4-
employment of gold(I) and (III), as well as silver and nitrobenzenesulfonyl group can be tolerated under
copper salts, was not effective resulting in formation our reaction conditions resulting in the formation of
of propargylamine intermediate 4 only (entries 1–6). indoline 5aa in good yield (entry 27). Reaction of N-
The TCC reaction in the presence of CuCl and tosylamino-3-naphtalaldehyde resulted in the forma-
CuACHTUNGTRENNUNG(OTf)2 produced trace amounts of 5 (entry 7). Sub- tion of tricyclic indoline 5ab although in slightly de-
stantial improvement of the yields was achieved in creased yield (entry 28). Employment of 1,2,3,4-tetra-
the presence of stoichiometric amounts of Et3N and hydroquinoline resulted in the formation of the corre-
Cs2CO3 (entries 8 and 9). Furthermore, employment sponding indoline 5ac in 68% isolated yield
of DMAP led to the nearly quantitative formation of (entry 29). Furthermore, by utilizing trimethylsilylace-
indoline 5 (entry 10)! Employment of a sole copper tylene as acetylene surrogate,[12] an exomethylene
source in the presence of DMAP (entries 11 and 12) moiety-possessing indoline 5ad was obtained in 64%
was less efficient as compared to the use of a Cu(I)/ yield (entry 30).
Cu(II) binary system.[11]
Next, conversion of indolines 5 into their more
Surprisingly, no formation of indole 6 was observed stable aromatic isomers, indoles 6, was explored [Eq.
under these reaction conditions. Next, under the opti- (1)]. We reasoned that this isomerization reaction
mized conditions, the scope of this new TCC reaction should occur in the presence of a base.[13] Indeed, it
has been examined (Table 2). Gratifyingly, we found
that this transformation is very general for a wide
range of different acetylenes, aldehydes and secon-
dary amines providing an easy access to densely-sub-
stituted indolines 5. Thus, employment of piperidine,
morpholine, and pyrrolidine produced aminoindolines
in good to excellent yields. Acyclic dibenzyl-, diallyl-,
diethyl- and diisobutylamines were similarly effective.
Different alkynes, bearing alkyl or aryl substituents,
displayed high reactivity in this transformation. A va-
riety of different groups at the aromatic moiety of the
Table 1. Optimization of TCC coupling.[a]
#
Conditions – Catalyst (mol%)
Additive (equiv)
5, Yield [%][b]
1
2
3
4
5
6
7
8
AuCl (5)
AuCl3 (5)
NaAuCl4·2H2O (5)
AgOTf (5)
CuCl (5)
none
none
none
none
none
none
none
NEt3 (1.0)
Cs2CO3 (1.0)
DMAP (1.0)
DMAP (1.0)
DMAP (1.0)
– (83)[c]
– (75)[c]
traces
– (70)[c]
– (60)[c]
– (51)[c]
7 (80)[c]
48
Cu
N
CuCl (5), Cu
CuCl (5), Cu
CuCl (5), Cu
CuCl (5), Cu
CuCl (5)
U
E
N
G
9
51
98
10
11
12
70 (10)[c]
47 (21)[c]
CuACTHNUTRGEN(NUG OTf)2 (5)
[a]
[b]
[c]
All reactions were performed with 1 (0.3 mmol), 2 (0.3 mmol) and 3 (0.45 mmol) in MeCN at 808C.
Yield of the isolated product after flash chromatography on silica gel.
Yield in parentheses given for formation of the corresponding propargylamine 4.
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Efficient and General Synthesis of 3-Aminoindolines and 3-Aminoindoles
Table 2. TCC synthesis of 3-aminoindolines.[a]
Entry Product
Yield[b] Entry Product
[%]
Yield[b] Entry Product
[%]
Yield[b]
[%]
1
5a 98
11
12
5k 75
21
22
5u 80
2
5b 94
5l 77
5v 89
3
4
5
6
5c 78
5d 92
5e 90
5f 61
13
14
15
16
5m 78
5n 70
5o 74
5p 68
23
24
25
26
5w 80
5x 97
5y 34
5z 32
7
8
5g 78
5h 84
17
18
5q 90
27
28
5aa 73
5ab 45
5r 68
Adv. Synth. Catal. 2010, 352, 961 – 966
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Table 2. (Continued)
Entry Product
Yield[b] Entry Product
[%]
Yield[b] Entry Product
[%]
Yield[b]
[%]
9
5i 95
19
5s 57
29
30
5ac 68
10
5j 87
20
5t 82
5ad 64[c]
[a]
All reactions were performed with 1 (0.3 mmol), amine 2 (0.3 mmol), acetylene 3 (0.45 mmol) in MeCN (1M) at 808C for
12–16 h.
Yield of the isolated product after flash chromatography on silica gel.
Reaction was performed with trimethylsilylacetylene (1.5 equiv.).
[b]
[c]
Scheme 2. One-pot TCC synthesis of indoles 6.
was found that heating indolines 5 with cesium car- detosylation, but also highly efficient isomerization
bonate in THF/MeOH mixture at 658C resulted in into indoles 7a, c [Eq. (3)].
formation of the corresponding indoles 6a–c in excel-
lent yields.
With the new efficient methodology for assembly
of the 3-aminoindoline core in hand, we performed
Encouraged by these results, we attempted a three-
component one-pot synthesis of 3-aminoindoles 6
(Scheme 2).
Thus, the Cu-catalyzed TCC reaction of N-(2-for-
mylphenyl)-4-methylbenzenesulfonamide 1, piperi-
dine 2, and acetelynes 3 produced indolines 5. Subse-
quent base-assisted one-pot isomerization of the latter
produced indoles 6a, b, d in good to high yields
(Scheme 2). It deserves mentioning that N-tosylin-
doles 6 upon treatment with magnesium powder[14]
could smoothly be detosylated into the corresponding
À
N H indoles 7a, c [Eq. (2)]. Interestingly, treatment
of N-tosylindolines 5a, c with Mg not only caused N-
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Adv. Synth. Catal. 2010, 352, 961 – 966

Efficient and General Synthesis of 3-Aminoindolines and 3-Aminoindoles
Scheme 3. Enantioselective TCC synthesis of indoline 5*.
initial studies toward an enantioselective version of Experimental Section
this transformation (Scheme 3). It was found that
under a modified Knochelꢁs protocol for enantioselec- General Procedure
tive TCC assembly of propargylamines[15,16] (with
In a dry and argon-flushed Wheaton 1-mLV-vial, equipped
Trostꢁs C2-symmetrical ligand[17]), N-(2-formylphenyl)-
4-methylbenzenesulfonamide 1, piperidine 2, and tri-
methylsilylacetelyne 3 underwent smooth coupling re-
action to produce 4ad in high yield and 93% enantio-
selectivity. Employment of alkyl- and arylacetylenes 3
in the synthesis of propargylamines (4c and 4b) result-
ed in good chemical yields, but moderate enantiose-
lectivity (53 and 52% ee, respectively). Direct cyclo-
with
a
magnetic stirring bar and
a screw cap, CuCl
(0.015 mmol, 5 mol%), CuAHCTUNGTR(EUNNNG OTf)2 (0.015 mmol, 5 mol%),
DMAP (0.3 mmol, 1 equiv.) and aldehyde (0.3 mmol,
1 equiv.) were suspended in dry acetonitrile (0.3 mL). Secon-
dary amine (0.3 mmol, 1 equiv.) and alkyne (0.45 mmol,
1.5 equiv.) were added and the reaction mixture was stirred
at 808C until TLC analysis showed full conversion of an al-
dehyde. The reaction mixture then was filtered through
Celite and washed with dichloromethane. The crude product
was concentrated under vacuum and purified by column
chromatography on silica gel.
ACHTUNGTRENNUNGisomerization of 4ad gave poor yield of the desired in-
doline 5ad* (30%). However, desilylation of 4ad into
4ad’ followed by its cyclization under standard condi-
tions produced enantioenriched indoline 5ad* in good
yield with virtually complete preservation of enantio-
selectivity (Scheme 3).
In summary, we have developed a novel highly effi-
cient and general copper-catalyzed three component
coupling reaction of N-protected 2-aminobenzalde-
hydes with secondary amines and terminal acetylenes
into 3-aminoindolines. It was shown that the 3-amino-
indolines, under basic conditions, could highly effi-
ciently be transformed into the isomeric 3-aminoin-
doles. Alternatively, the latter can be obtained via a
one-pot TCC procedure. In addition, we have demon-
strated that the optically active indoline could be syn-
thesized via a stepwise enantioselective version of this
novel TCC protocol.
Acknowledgements
We gratefully acknowledge the financial support of the Na-
tional Institute of Health (1P50 GM-086145).
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