A novel route to 2,3-disubstituted indoles via palladium-catalyzed three-component coupling of aryl iodide, o-alkenylphenyl isocyanide and amine

Article abstract of DOI:10.1016/S0040-4039(02)01316-3

Three-component coupling reactions of aryl iodide, o-alkenylphenyl isocyanide and amine in the presence of palladium catalysts produced 2,3-substituted indoles in moderate yields.

Full text of DOI:10.1016/S0040-4039(02)01316-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6197–6199
A novel route to 2,3-disubstituted indoles via palladium-catalyzed
three-component coupling of aryl iodide, o-alkenylphenyl
isocyanide and amine
Kiyotaka Onitsuka, Shinobu Suzuki and Shigetoshi Takahashi*
The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan
Received 24 May 2002; revised 19 June 2002; accepted 28 June 2002
Abstract—Three-component coupling reactions of aryl iodide, o-alkenylphenyl isocyanide and amine in the presence of palladium
catalysts produced 2,3-substituted indoles in moderate yields. © 2002 Elsevier Science Ltd. All rights reserved.
Since an indole nucleus is found in a wide variety of
biologically active natural products, considerable atten-
tion has been directed toward the synthesis of indole
derivatives.1 Although many procedures have been
developed for the synthesis of indoles,2,3 annulation
mediated by palladium catalysts is one of the most
powerful tools.4 On the other hand, ortho-functional-
ized aryl isocyanides are fascinating substrates for syn-
thesis of the indole framework due to the high
reactivity of isocyanides.5,6 Although an efficient route
from o-alkenylphenyl isocyanides via radical cyclization
has been developed,7 there are few reports on
approaches to indole synthesis using transition metal
mediators.5,8 We recently showed the formation of
indole derivatives from o-alkenylphenyl isocyanide
through the use of a stoichiometric amount of an
organopalladium complex.9 We extended this finding to
a catalytic process. We report here a novel catalytic
synthesis of 2,3-disubstituted indoles by the three-com-
ponent coupling of aryl iodide, o-alkenylphenyl isocya-
nide and amine (Scheme 1).
1.2:1:18 in THF was stirred at 40°C for 10 h in the
presence of 5 mol% of Pd(OAc)2 and 10 mol% of dppp,
3-(diethylamino)methyl-2-phenylindole
(4a)
was
obtained in 32% yield (Table 1, entry 1).11 An increase
in the ratio of 1a:2a led to a slight increase in the yield
of 4a (entries 2 and 3). Although the reaction using 6
equiv. of 3 relative to 2a gave 4a in a yield similar to
that using 18 equiv. of 3 (entry 4), a further decrease in
the amount of 1 decreased the yield of 4a (entry 5). At
60°C, no considerable difference in the yield of 4a was
observed (entry 6), while the reaction at 25°C hardly
proceeded and 4a was obtained in only 8% yield (entry
7).
Addition of PPh3 to the reaction mixture instead of
dppp remarkably decreased the yield of 4a (entry 8).
This phenomenon is likely due to the lower reactivity of
the intramolecular successive insertion of 2a toward
organopalladium complexes with PPh3 compared to
those with dppp.8 The length of the alkyl chain of
diphosphine also affected the reactivity of palladium
catalysts. Thus, the use of dppe or dppb as a ligand
decreased the yield of 4a (entries 9 and 10). Although
Pd2(dba)3 could be used as a catalyst precursor (entry
When a mixture of phenyl iodide (1a), o-vinylphenyl
isocyanide (2a)10 and diethylamine (3) in a ratio of
NEt2
Pd cat. (5 mol%)
L (10 mol%)
+
+
HNEt2
I
NC
THF
N
H
3
1a
2a
4a
Scheme 1.
Keywords: indole; cyclization; isocyanide; palladium catalyst.
* Corresponding author. Tel.: +81-6-6879-8457; fax: +81-6-6879-8459; e-mail: takahashi@sanken.osaka-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01316-3

6198
K. Onitsuka et al. / Tetrahedron Letters 43 (2002) 6197–6199
Table 1. Three-component coupling reaction under several conditions
Entry
1a (equiv.)a
3a (equiv.)a
Pd cat.b
Ligandc
Temp. (°C)
Time (h)
Yield of 4ad (%)e
1
2
3
4
5
6
7
8
1.2
2.4
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
3.6
18
18
18
6
2.5
18
18
18
18
18
18
18
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
dppp
dppp
dppp
dppp
dppp
dppp
dppp
PPh3
dppe
dppb
dppp
bpy
40
40
40
40
40
60
25
40
40
40
40
40
10
9
3.5
5.5
6
32
36
42
43
21
44
8
6
18
9
1
3.5
33
33
7
9
26
9
10
11
12
36
3
a Based on 2.
b 5 mol%.
c 10 mol%.
d Compound 4a isolated was characterized by spectral analyses.
e Determined by 1H NMR.
hydrogen to give (h3-indolylmethyl)palladium complex
(7). Nucleophilic attack by diethylamine produces 2,3-
disubstituted indoles along with palladium hydride
complex 8, which is converted into Pd(0) species 5 by
the reaction with amine.
11), 2,2%-bipyridine was not suitable as a ligand (entry
12).
This reaction could be applied to a substituted aryl
iodide, as summarized in Table 2. p-Methoxyphenyl
iodide 1b and p-nitrophenyl iodide 1c also produced
2,3-substituted indole derivatives 4b and 4c, respectively
(entries 2 and 3). However, the reaction using phenyl
triflate 1d gave 4a in 10% yield (entry 4). When o-
(methoxycarbonylethenyl)phenyl isocyanide (2b)8 was
used instead of 2a, the corresponding indole derivative
was not formed.
In summary, we have demonstrated a new route to
2,3-disubstituted indoles through the three-component
coupling of aryl iodide, o-alkenylphenyl isocyanide and
amine using palladium catalysts. Further studies on the
scope and limitations of this catalytic reaction are now
in progress.
Based on our previous results on the stoichiometric
reaction of palladium complexes with o-alkenylphenyl
isocyanide,8 the catalytic cycle that may be responsible
for the formation of 4 is illustrated in Scheme 2.
Phenylpalladium complex 6 generated by the oxidative
addition of aryl iodide to Pd(0) species 5 reacts with 2
to induce the successive insertion of the alkenyl and
isocyano groups followed by the 1,3-migration of
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports and Culture. We thank The Material Analysis
Center, ISIR, Osaka University, for supporting our
study with spectral measurements.
Table 2. Three-component coupling reactiona
Entry
Aryl halide
o-Alkenylphenyl isocyanide
Time (h)
Yield (%)b
1
2
3
4
5
1a (Y=H, X=I)
2a (R=H)
2a (R=H)
2a (R=H)
2a (R=H)
3.5
21
2
27
30
42 (4a)
39c (4b)
24c (4c)
10 (4a)
–
1b (Y=OMe, X=I)
1c (Y=NO2, X=I)
1d (Y=H, X=OTf)
1a (Y=H, X=I)
2b (R=CO2Me)
a 1/2/3=3.6/1/18.
b Determined by 1H NMR.
c Isolated yield.

K. Onitsuka et al. / Tetrahedron Letters 43 (2002) 6197–6199
6199
3•HI
1
P
Pd
P
5
3
Y
P
P
H
I
P
P
Pd
Pd
8
I
6
NEt2
P
Pd
I
P
2a
N
H
Y
3
N
H
Y
4
Scheme 2.
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