Ruthenium-catalyzed synthesis of indoles from anilines and trialkanolammonium chlorides in an aqueous medium

Article abstract of DOI:10.1016/S0040-4039(00)00035-6

Anilines react with trialkanolammonium chlorides in an aqueous medium (H₂O-dioxane) at 180°C in the presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II) chloride dihydrate to afford the corresponding indoles in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00035-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1811–1814
Ruthenium-catalyzed synthesis of indoles from anilines and
trialkanolammonium chlorides in an aqueous medium
Chan Sik Cho, Jin Hwang Kim and Sang Chul Shim ∗
Department of Industrial Chemistry, College of Engineering, Kyungpook National University, Taegu 702-701, South Korea
Received 24 November 1999; revised 22 December 1999; accepted 24 December 1999
Abstract
Anilines react with trialkanolammonium chlorides in an aqueous medium (H2O–dioxane) at 180°C in the
presence of a catalytic amount of ruthenium(III) chloride hydrate and triphenylphosphine together with tin(II)
chloride dihydrate to afford the corresponding indoles in good yields. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: ruthenium; catalyst; cyclization; indoles.
It is well-known that indole skeletons play an important role as an intermediate for the design of many
pharmacologically active compounds.1 The Fischer, Madelung, Bischler, and related syntheses are the
most commonly used routes for the construction of the structural core of indoles and have been exten-
sively reviewed. Recently, in contrast to the conventional synthesis, the formation of indole skeletons has
also been attempted by a remarkable catalytic action of transition metal catalysts such as palladium,2–6
ruthenium,7–12 and rhodium13–15 utilizing various substrates. As part of our continuing studies on
transition metal-catalyzed synthesis of N-heterocyclic compounds, we recently developed and reported
a novel ruthenium-catalyzed synthetic approach for the formation of indoles16–18 and quinolines19,20
from anilines and functionalized aliphatic amines. It was suggested that all reactions proceed via amine
exchange reactions21–24 between anilines and functionalized aliphatic amines. However, a clear-cut
example for the synthesis of N-heterocyclic compounds using amine exchange reactions seems to be
limited to the palladium-catalyzed synthesis of pyrimidines and imidazoles24 and ruthenium-catalyzed
synthesis of indoles16–18 and quinolines.19,20 We now report a first ruthenium-catalyzed approach for
the synthesis of 1,2,3-unsubstituted indoles from primary aromatic amines and trialkanolammonium
chlorides in an aqueous medium via amine exchange reaction.
The several results of the ruthenium-catalyzed heteroannulation between aniline (1) and triethanolam-
monium chloride (2) under various conditions are listed in Table 1. Treatment of 1 with 2 in H2O:dioxane
(1:9) under an argon atmosphere in the presence of a catalytic amount of RuCl3·nH2O/PPh3 together with
∗
Corresponding author. Fax: +82 53 950 6594; e-mail: scshim@kyungpook.ac.kr (S. C. Shim)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00035-6
tetl 16315

1812
SnCl2·2H2O at 180°C for 20 h afforded indole (3) in 63% yield (Eq. (1)). The reaction condition was
eventually revealed to be the best for obtaining 3 (run 1). The yield of 3 was considerably affected by
the molar ratio of 1 to 2, the highest yield of 3 being obtained at the molar ratio of 10 (runs 2–5). The
existence of SnCl2·2H2O was essential for the effective formation of 3 as has been observed in our recent
ruthenium-catalyzed synthesis of indoles18,25 and quinolines,19,20 the yield of 3 being only 32% in the
absence of SnCl2·2H2O (run 6). The use of either dioxane or H2O and reverse amount of H2O/dioxane
stopped the reaction almost completely (runs 7–9).
(1)
Table 1
Ruthenium-catalyzed synthesis of 3 from 1 and 2 under various conditionsa
From other easily available anilines the corresponding indoles were also formed in good yields,
several representative results being summarized in Table 2. The indole yield was considerably affected
by the electronic nature and position of the substituent on aniline. With chloroanilines having electron-
withdrawing Cl substituents, the product yields were generally lower than when anilines having electron-
donating characters were used (runs 2–8). With ortho- and meta-substituted anilines, the indole yields
were higher than when para-substituted anilines were used (runs 2–4, 7, 8). In the case of two-methyl
substituted anilines, the reaction proceeded quite well even with the use of 5 mol% of ruthenium catalyst
when compared to mono-substituted anilines as has been observed in our recent report (runs 9–11).18
The formation of >100% yields of indoles indicates that at least two alkanol groups out of three in 2 are
available for the C2-fragment counterpart.
Interestingly, similar treatment of anilines 4 with triisopropanolammonium chloride (5) under identical
reaction conditions afforded 2-methyl substituted regioisomers almost exclusively, no 3-methyl isomers
being detected on both GLC and 1H NMR (Eq. (2)). As is the case for the reaction with 2, however, in a
different manner, the product yield was also affected by the position of the substituent on aniline.

1813
Table 2
Ruthenium-catalyzed synthesis of indoles from anilines and triethanolammonium chloride (2)a
(2)
The initial formation of 2-anilinoethanols by amine exchange reactions21–24 between anilines and
trialkanolammonium chlorides seems to be a key step as has been observed in our recent ruthenium-
catalyzed synthesis of indoles and quinolines from anilines and functionalized aliphatic amines.16–20
Subsequent steps seem to proceed via a similar catalytic cycle to that which has already been proposed
in ruthenium-catalyzed synthesis of indoles from anilines and ethylene glycols.8
A typical experimental procedure is as follows: A mixture of aniline (1) (10 mmol), triethanolam-

1814
monium chloride (2) (1 mmol), RuCl3·nH2O (n=3, 0.1 mmol), SnCl2·2H2O (1 mmol) and PPh3 (0.3
mmol) in H2O/dioxane (1 mL/9 mL) was placed in a pressure vessel. After the system was flushed with
argon, the mixture was stirred at 180°C for 20 h. The reaction mixture was poured into an aqueous 5%
HCl solution to remove excess aniline, and extracted with chloroform. The organic layer was filtered
through a short silica gel column. Removal of the solvent left an oil which was separated by column
chromatography using an ethyl acetate/hexane mixture as an eluent to give indole (3) in 57% yield.
In summary, we have shown that indoles can be synthesized from anilines and trialkanolammonium
chlorides in the presence of a ruthenium catalyst in an aqueous medium. Although several reports are
known for the synthesis of N-heterocyclic compounds using amine exchange reactions in organic media,
the present aquatic process is a first synthetic approach for N-heterocyclic compounds using an amine
exchange reaction. We believe that this aquatic process combined with a mechanistic amine exchange
reaction will be successfully applied for the synthesis of other N-heterocyclic compounds.
Acknowledgements
This work was supported by the Korea Science and Engineering Foundation (97-05-01-05-01-3), the
Korea Research Foundation (1998-15-D00177), and by a Post-Doc. grant (C.S.C.) Program from the
Kyungpook National University (1999).
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