Ruthenium-catalysed synthesis of indoles from anilines and trialkanolamines in
the presence of tin(ii) chloride dihydrate
Chan Sik Cho, Hyo Kyun Lim, Sang Chul Shim,*† Tae Jeong Kim and Heung-Jin Choi
Department of Industrial Chemistry, College of Engineering, Kyungpook National University, Taegu 702-701, Korea
Table 1 Ruthenium-catalysed synthesis of indole (3) under various
Anilines react with trialkanolamines in dioxane in the
conditionsa
presence of a catalytic amount of a ruthenium catalyst
together with tin(II) chloride dihydrate to give the
corresponding indoles in moderate to good yields.
Molar
GLC yield
(%)b
ratio (1:2)
Metallic halides (mmol)
Transition metal-catalysed cyclisation reactions have been a
useful and convenient method for the formation of a wide
variety of heterocycles. Thus, the formation of the structural
core of indoles has also been attempted using transition metal
catalysts1 since several naturally occurring indoles exert a broad
spectrum of physiological activities.2 As part of our continuing
studies on transition metal-catalysed synthesis of
N-heterocyclic compounds,3 we have recently developed and
reported a novel ruthenium-catalysed synthesis of N-alkyl-
indoles from N-alkylated anilines and triethanolamine as the
C2-fragment.4 However, aniline did not act as a cyclisation
counterpart in the formation of indole itself under the ruthe-
nium-catalysed system. After numerous attempts were made to
achieve the formation of indoles from the primary aromatic
amines under the reaction system used, eventually, it was found
that the addition of tin(ii) chloride dihydrate allows the
formation of indoles. We now report a facile synthesis of
indoles from readily available primary aromatic amines and
triethanolamine in the presence of a ruthenium catalyst together
with SnCl2·2H2O.
We examined the cyclisation between aniline (1) and
triethanolamine (2) in the presence of SnCl2·2H2O to optimise
the reaction conditions using similar catalytic systems which we
employed for the synthesis of N-alkylindoles. The yield of
indole (3) was considerably affected by the molar ratio of 1 to
2 as has been observed in our recent report (Scheme 1).4 Table
1 shows that the highest yield of 3 was obtained at the molar
ratio of 10. The reaction was also affected by the amount of
SnCl2·2H2O. The use of equimolar amounts of 2 and
SnCl2·2H2O resulted in the best yield of 3. A decrease in the
amount of SnCl2·2H2O afforded 3 in a lower yield, but the yield
of 3 did not change with an increase in the amount of
SnCl2·2H2O employed. However, the reaction did not proceed
at all without SnCl2·2H2O. The effect of several metallic halides
other than SnCl2·2H2O upon this cyclisation was examined. As
shown in Table 1, all the salts except for iron(iii) chloride
examined were moderately effective in the formation of 3, but
FeCl3 exhibited nearly the same activity as SnCl2·H2O under the
reaction conditions employed.
4
6
8
SnCl·2H2O (1)
SnCl·2H2O (1)
SnCl·2H2O (1)
SnCl·2H2O (1)
SnCl·2H2O (0.5)
SnCl·2H2O (2.0)
—
AlCl3 (1)
SbCl3 (1)
BiCl3 (1)
LaCl3 (1)
30
29
30
52
25
51
Trace
20
16
7
10
10
10
10
10
10
10
10
10
10
7
52
15
FeCl3 (1)
ZnCl2 (1)
a
All reactions were carried out with 2 (1 mmol), RuCl3·nH2O (7 mol%
based on 2), and PPh3 (2 mol% based on 2) in dioxane (10 ml) at 180 °C for
20 h. b Based on 2.
character, the product yield was generally higher than that when
chloroanilines having electron-withdrawing Cl substituent were
used (runs 2–8). In the cases of meta-substituted anilines such as
m-toluidine and m-anisidine, the corresponding indoles were
obtained as a regioisomeric mixture in good yields (runs 3 and
5). The enhancement of reactivity of the two-methyl substituted
anilines is interesting when compared to the reactivity of the
mono-substituted anilines (runs 10–12). However, in the case of
2,5-dimethoxyaniline, the corresponding indole was obtained
only in 15% yield (run 13).
Similar treatment of anilines 4 with tri(propan-2-ol)amine (5)
under the above reaction system afforded two regioisomeric
Table 2 Ruthenium-catalysed synthesis of various indolesa
Isolated
Run Anilines
Indoles
yield (%)b
1
2
3
4
5
6
7
8
9
Aniline
o-Toluidine
m-Toluidine
p-Toluidine
m-Anisidine
p-Anisidine
o-Chloroaniline
p-Chloroaniline
p-Isopropylaniline
2,3-Dimethylaniline
2,5-Dimethylaniline
3,5-Dimethylaniline
2,5-Dimethoxyaniline
Indole
46
66
65c
38
7-Methylindole
4- and 6-Methylindole
5-Methylindole
4- and 6-Methoxyindole 47c
5-Methoxyindole
7-Chloroindole
5-Chloroindole
5-Isopropylindole
6,7-Dimethylindole
4,7-Dimethylindole
4,6-Dimethylindole
4,7-Dimethoxyindole
33
9
The present cyclisation could also be applied to many
primary aromatic amines, several representative results being
summarised in Table 2.‡ The product yield was dependent on
the electronic nature of the substituent on anilines. With anilines
such as toluidine and anisidine, having electron-donating
21
56
99
86
90
15
10
11
12
13
i
+
N(CH2CH2OH)3
a
All reactions were carried out with anilines (10 mmol), 2 (1 mmol),
RuCl3·nH2O (7 mol% based on 2), PPh3 (2 mol% based on 2), and
SnCl2·2H2O (1 mmol) in dioxane (10 ml) at 180 °C for 20 h. b Based on 2.
N
H
NH2
1
2
3
c
1
Isomeric molar distributions were determined by H NMR spectroscopy
Scheme 1 Reagents and conditions: i, RuCl3·nH2O, PPh3, SnCl2·2H2O,
dioxane, 180 °C, 20 h
(300 MHz): 4-methylindole:6-methylindole = 1:1; 4-methoxyindole:6-
methoxyindole = 1:2.8.
Chem. Commun., 1998
995