[Cp?IrCl2]2-catalysed cyclization of 2-alkynylanilines into indoles

Article abstract of DOI:10.1016/j.tetlet.2014.08.053

[Cp?IrCl₂]₂ catalyses the cyclization of 2-alkynylanilines into indoles. A wide variety of substrates is tolerated. A reaction pathway involving intramolecular hydroamination is proposed.

Full text of DOI:10.1016/j.tetlet.2014.08.053

Tetrahedron Letters 55 (2014) 5495–5498
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[Cp⁄IrCl2]2-catalysed cyclization of 2-alkynylanilines into indoles
⇑
Elumalai Kumaran, Weng Kee Leong
Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
[Cp⁄IrCl2]2 catalyses the cyclization of 2-alkynylanilines into indoles. A wide variety of substrates is
tolerated. A reaction pathway involving intramolecular hydroamination is proposed.
Ó 2014 Elsevier Ltd. All rights reserved.
Article history:
Received 2 June 2014
Revised 18 July 2014
Accepted 13 August 2014
Available online 19 August 2014
Keywords:
Catalytic hydroamination
Indole
2-Alkynylaniline
Iridium
On binding to transition metals, alkynes are activated towards
nucleophilic attack. This has been demonstrated with a variety of
nucleophiles, including amines,1 imines,2 water,3 alcohols,4 phe-
nols,5 halides,6 carboxylic acids,7 nitro groups,8 carbonyl groups9
and enol ethers.10 Catalytic transformations of alkynes based on
such activation have been studied with a number of different met-
als, and intramolecular versions are very useful in providing het-
erocyclic compounds. In particular, inter- and intramolecular
alkyne hydroamination reactions have been extensively explored
because the resulting N-heterocycles have broad synthetic interest
and applications.11
Complex 1 catalysed the cyclization of 2-(2-phenylethynyl)ani-
line (2a) to afford 2-phenylindole (3a) in 76% yield (Scheme 1).
An optimization study (Table 1) showed that the reaction was
more effective in higher polarity solvents such as methanol or ace-
tonitrile (entries 2–6). The catalyst loading could be lowered from
5 to 2 mol % without detriment, but further lowering to 1 mol % led
to a significantly lower yield (entries 2, 7 and 8). Although a num-
ber of salt additives (NaPF6, NaBF4, NH4BF4 or NH4PF6) were effec-
tive (entries 9–12), NaBF4 showed the best catalytic activity; NaBF4
itself was not catalytically active (entry 13).
Similar cyclization reactions have been studied with a number
of transition metals including Au,17 Pd,18 Rh19 and others,20
although some of them have disadvantages such as higher catalyst
loading,20a high temperature,18b,c,17d,19,20 or the need for protection
of the amino group.20a Several iridium complexes have also been
examined,1a,19a,21 but the functional group tolerance was tested
with only two catalytic systems,1a,21b both of which showed very
limited functional group compatibility. For example, Liu et al.
reported the iridium-catalysed intramolecular cyclization of amin-
oalkynes,1a but their catalyst failed with alkynylanilines containing
We have previously reported that [Cp⁄IrCl2]2 (1) can activate
the C„C bond for transformations that include hydrosilylation,12
dimerization,13 and C„C bond cleavage.14 This catalyst was also
found to lead to the formation of a variety of iridium amino-car-
bene derivatives in the presence of an alkyne and an arylamine.15
Quite surprisingly, it also catalysed the formation of 2,20-biindoles
from 2-ethynylanilines under similar reaction conditions.16 These
reactions all involved terminal alkynes or alkynyl moieties, and
they were proposed to proceed via initial coordination of the
alkyne moiety followed by rearrangement into a vinylidene. As
expected, internal 2-alkynylanilines cannot undergo rearrange-
ment into a vinylidene and hence cannot form 2,20-biindoles. We
have found, instead, that these undergo cyclization to form indoles.
Ph
Cp*IrCl2 2 (1)
salt additive
solvent
N
H
Ph
NH2
3a
2a
⇑
Corresponding author. Tel.: +65 6592 7577.
E-mail address: chml2k@ntu.edu.sg (W.K. Leong).
Scheme 1.
http://dx.doi.org/10.1016/j.tetlet.2014.08.053
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5496
E. Kumaran, W.K. Leong / Tetrahedron Letters 55 (2014) 5495–5498
Table 1
Optimization of the intramolecular cyclization of 2a to give 3a catalysed by [Cp⁄IrCl2]2 (1)
Entry
Catalyst (mol %)
Additive (mol %)
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (2)
1 (1)
1 (2)
1 (2)
1 (2)
1 (2)
—
—
Acetonitrile-d3
Acetonitrile-d3
Toluene-d8
Chloroform-d3
THF-d8
Methanol-d4
Acetonitrile-d3
Acetonitrile-d3
Acetonitrile-d3
Acetonitrile-d3
Acetonitrile-d3
Acetonitrile-d3
Acetonitrile-d3
60
60
60
60
60
60
60
60
40
40
40
40
40
12
4
18
30
24
4
8
8
8
8
76
95
89
30
76
95
93
59
96
78
83
67
—
NaBF4 (10)
NaBF4 (10)
NaBF4 (10)
NaBF4 (10)
NaBF4 (10)
NaBF4 (4)
NaBF4 (2)
NaBF4 (4)
NH4PF6 (4)
NH4BF4 (4)
NaPF6 (4)
NaBF4 (4)
8
8
8
a
Yield determined by NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.
As a demonstration of the utility of this reaction for the con-
struction of more complex N-heterocycles, we also synthesized
2,20-biindole (3q), 1,4-diindolylbenzene (3r) and 1,3,5-triindolyl-
benzene (3s) in good yields using this methodology (Scheme 2).
The reaction presumably involves initial binding of the alkyne
moiety, in a similar manner to that proposed earlier for the forma-
tion of biindoles from 2-ethynylanilines,16 but with the loss of a
chloride to form a cationic intermediate A (Scheme 3). Formation
of a cationic species is favoured by a polar environment—in the
presence of a salt or in a polar solvent. Such a cationic species
has been proposed earlier for a related rhodium catalytic system,1b
and similarly, the alkyne is asymmetrically bound (Fig. S1). The
third ligand L is presumably a solvent molecule or, more likely, a
second N-bound alkynylaniline. Intramolecular nucleophilic attack
by the aniline moiety onto the coordinated alkyne would form B.
Loss of a proton from the aniline moiety and protonolysis at the
alkenylAiridium bond would give the indole, and recoordination
of the alkynylaniline would regenerate A. We have examined this
pathway computationally at the B3LYP/LanL2DZ level using den-
Table 2
A substrate scope study for the intramolecular cyclization catalysed by 1
R'
1 (2 mol%)
NaBF4 (4 mol%)
N
R''
R'
MeCN, 40 o
C
R
R
NHR''
3
2
Entry
Ra
R0
R00
Yieldb (%)
1
2
3
4
5
6
7
8
H
4-CH3
4-C(CH3)3
4-Cl
4-NO2
4-CO2Et
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-n-BuC6H5
4-ClC6H5
n-Bu
Si(CH3)3
Si(CH3)3
Si(CH3)3
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
3a, 90
3b, 92
3c, 93
3d, 91
3e, 89
3f, 92
3g, 85
3h, 87
3i, 81
3j, 91
3k, 86
3l, 76
3m, 78
3n, 83
3o, 85
3p, 82
4-CO2Et, 6-C2Ph
H
H
H
H
9
10
11c
12c
13c
14
15
16
sity functional theory (DFT); the free energy changes (in kJ molꢀ1
)
4-NO2
4-CO2Me
H
H
H
from A are also shown in Scheme 3, and are reasonable.
In conclusion, we have found that complex 1, in the presence of
a salt additive, acts as an effective catalyst for the intramolecular
hydroamination of internal alkynylanilines 2 to afford indoles 3.
A wide variety of substrates was tolerated. The reaction pathway
proposed involved initial coordination of the alkynylaniline via
the alkyne moiety to a cationic intermediate, which subsequently
underwent intramolecular attack by the aniline to form the indole.
CH2Ph
SO2Me
a
b
c
Designations refer to the ethynylanilines.
Isolated yield.
No salt additive, with DCE as the solvent.
Acknowledgments
This work was supported by Nanyang Technological University
and the Ministry of Education (Research Grant No. M4011017).
One of us (E.K.) thanks the Nanyang Technological University for
a Research Scholarship.
electron-withdrawing substituents on the aniline moiety. Simi-
larly, the catalyst reported by Fukuzawa was not effective for alk-
ynylanilines with an electron-withdrawing substituent on the
alkyne moiety.21b Unlike these iridium-based catalytic sys-
tems,1a,21b however, complex 1 showed good catalytic performance
with a wide range of substrates; electron-donating and electron-
withdrawing substituents on either the aniline or the alkyne moi-
ety were tolerated, as were secondary (entries 14 and 15) and ste-
rically crowded (entry 7) 2-alkynylanilines and N-protected (entry
16) alkynylanilines (Table 2). Formation of 2-trimethylsilylindole
using the optimized conditions failed; this problem has been
reported with some of the other catalytic systems.18c,20a,b In our
case, however, the reaction could be made to work with a slight
modification of the conditions (no salt additive and with DCE as
the solvent).
Supplementary data
Experimental procedures and characterization data for all sub-
strates, computationally optimized structures of intermediates A
and B, and 1H NMR and 13C NMR spectra for new compounds. This
material is available free of charge via the internet at http://
dx.doi.org/1.1016/j.tetlet.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.08.
053.

E. Kumaran, W.K. Leong / Tetrahedron Letters 55 (2014) 5495–5498
H2N
5497
1 (4 mol%)
NaBF4 (8 mol%)
MeCN, 40 o
H
N
N
H
C
3q, 84%
NH2
1 (4 mol%)
NaBF4 (8 mol%)
MeCN, 40 o
N
H
H
N
NH2
C
NH2
3r, 78%
H2N
HN
1 (5 mol%)
NaBF4 (10 mol%)
MeCN, 40 o
N
H
NH2
C
NH
3s, 71%
NH2
Scheme 2.
R
NaCl
Ir
Cp*IrCl2 2
Cl
Cl
Ir
Cl
L
NH2
R
NH2
NH2
4
L, Na+
R
A
N
H
R
-119
-15
3
R=CH3
R
L
L =
NH2
Ir
Cl
L
N
R
H2
B
Scheme 3.
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