A mild and efficient dehydrogenation of indolines

Article abstract of DOI:10.1016/S0040-4039(01)00986-8

A new mild and efficient dehydrogenation of indolines to indoles has been developed. For the dehydrogenation trichloroisocyanuric acid is used in combination with DBU. After work-up with sodium hydrogen sulfite it was possible to obtain indole in an almost quantitative yield. The new method is also suitable for indolines bearing electron withdrawing or electron donating groups. Under the reaction conditions no ring chlorination was observed.

Full text of DOI:10.1016/S0040-4039(01)00986-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5385–5387
†
A mild and efficient dehydrogenation of indolines
Ulf Tilstam,* Michael Harre, Thilo Heckrodt and Hilmar Weinmann
Process Research, Schering AG-Berlin, D-13342 Berlin, Germany
Received 10 April 2001; revised 3 May 2001; accepted 8 June 2001
Abstract—A new mild and efficient dehydrogenation of indolines to indoles has been developed. For the dehydrogenation
trichloroisocyanuric acid is used in combination with DBU. After work-up with sodium hydrogen sulfite it was possible to obtain
indole in an almost quantitative yield. The new method is also suitable for indolines bearing electron withdrawing or electron
donating groups. Under the reaction conditions no ring chlorination was observed. © 2001 Elsevier Science Ltd. All rights
reserved.
Indole and it’s myriad of derivatives continue to cap-
ture the attention of organic chemists. Several new
indole ring syntheses have been developed over the
Another method for the dehydrogenation of indolines
to indoles through an azasulfonium salt utilizing
dimethyl sulfide, tert-butyl hypochlorite and a base
such as sodium ethoxide at low temperature (−65°C)
1
years and this trend is still ongoing.
5
has been reported by Kikugawa et al. Utilizing this
Indoles bearing various substituents on the benzene
ring often have potent physiological activities and can
be useful intermediates for the synthesis of indole alka-
loids. Synthetic interconversion of substituted indoles
and the corresponding dihydro derivatives (indolines) is
an important process giving access to uncommonly
method it was possible to obtain indole from indoline
in 74%. Due to the use of dimethyl sulfide and low
temperature (−70°C), allowing various other oxidizable
groups in the molecule, this method is unsuitable for
large scale synthesis. Furthermore tert-butyl hypochlor-
ite is not commercially available in bulk quantities
anymore.
2
substituted indoles. The conversion of the indole ring
to an indoline ring can easily be accomplished by
catalytic hydrogenation or reduction with sodium
cyanoborohydride in acetic acid. For the dehydrogena-
tion of indolines to indoles, although studied exten-
sively there has up to now never been an efficient
general method. Various methods like oxidations (e.g.
The dehydrogenation of indolines to indoles has also
been reported using N-chlorinating agents. The first
6
time by Somei et al. utilizing N-chlorosuccinimide with
triethyl amine as base in methylene chloride at room
temperature. Under the reported conditions low yields
of indole were obtained from indoline (35%) and the
obtained products were contaminated with considerable
amounts of nuclear chlorinated products. Later Kiku-
with MnO2, CuCl –pyridine, DDQ, chloranil,
2
Co(Salen)/O , etc.) or catalytic dehydrogenation over
2
noble metal catalysts (e.g. Pd/C Raney Ni, etc.) at
3
5
elevated temperature have been used. All needing a
gawa et al. found that the yield of indole is greatly
large excess of reagent, producing large amounts of
heavy metal waste and carefully controlled reaction
conditions to control overoxidation precludes them
from large scale synthesis. The use of a catalytic
amount of tetra-n-propylammonium perruthenate in
the presence of N-methylmorpholine N-oxide has also
affected by the used solvent and base. After a detailed
study it was possible to optimize the yield of indole to
84% and to minimize the amount of chlorinated prod-
ucts through change to t-butyl hypochlorite as chlori-
nating agent, with DBU as base and diethyl ether with
some DMF as solvent.
4
been reported to give indole from indoline in 73%.
We now report to the best of our knowledge the first
use of trichloroisocyanuric acid (TCCA) for the de-
hydrogenation of indolines to indoles.
*
Corresponding author. Tel.: +49-30-46812074; e-mail: ulf.tilstam@
schering.de
Dedicated to Professor Jan Bergman on the occasion of his 60th
birthday.
Trichloroisocyanuric acid, 1,3,5,-trichloro-1,3,5-tria-
zine-2,4,6-(1H,3H,5H)-trione, has become increasingly
important as disinfectant being more stable and easier
†
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00986-8

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386
U. Tilstam et al. / Tetrahedron Letters 42 (2001) 5385–5387
1
2
to handle than metal hypochlorites. TCCA is used as
disinfectant for swimming pools, cleaning and steriliz-
ing bathrooms and laundry bleach. TCCA is sparingly
soluble in water but highly soluble in organic solvents.
In comparison, N-chlorosuccinimide is sparingly solu-
ble in most organic solvents. TCCA is cheap and easily
accessible and, even on a large scale, the high solubility
in organic solvents makes it an ideal oxidant for
organic synthesis. The waste cyanuric acid is environ-
tetrahydro-b-carbolines. TCCA was found to be an
extremely efficient N-chlorinating agent, and all three
chlorine atoms are available for the chlorination. The
question about possible nuclear chlorinated derivatives
as possible impurities in the product was studied in
detail. No chlorinated derivatives were ever detected in
the products.
Due to the interesting results obtained with b-carboli-
nes, being aware of the difficulties encountering the
7
mentally non-hazardous.
Up to now TCCA has been mainly used in organic
synthesis for the chlorination of aromatic nucleus and
dehydrogenation of indolines we decided to adopt our
method.
8
,9
ketones and for the oxidation of secondary alcohols
1
0
to ketones with pyridine as base. TCCA has also been
used as a co-oxidant in a TEMPO catalyzed oxidation
The first attempt to dehydrogenate indoline in DMF at
−20°C gave an isolated yield of 58% of indole after
chromatographic purification. TLC monitoring of the
reaction showed a spot to spot reaction. The reaction
was complete after 2 h. A detailed study showed that
no 3-chloro-indole was formed under the reaction con-
11
of primary and secondary alcohols.
We recently published a preliminary study on the use of
TCCA and triethyl amine for the dehydrogenation of
Table 1. Indoles prepared from indolines using TCCA/ DBU

U. Tilstam et al. / Tetrahedron Letters 42 (2001) 5385–5387
5387
ditions, reported by previous groups being the major
impurity utilizing N-chlorosuccinimide or t-butyl
hypochlorite as oxidant.
Acknowledgements
7
,8
The authors gratefully thank the Spectroscopical
Department of Schering AG for the measurement of
the physical data.
References
The use of DMF as solvent led to a tedious work-up as
indole 4a did not precipitate during work-up.
1. Gribble, G. J. Chem Soc., Perkin Trans. 1 2000, 1045.
2. Preobrazhenskaya, M. N. Russ. Chem. Rev. (Engl.
Transl.) 1967, 36, 753.
Due to the high solubility of TCCA in organic solvents
it was possible to change to MtB–ether giving a direct
phase separation after addition of the sodium hydro-
gensulfite solution. The amount of oxidant and base for
a complete conversion of indoline to indole was found
to be a 10% molar excess of TCCA with 2 equiv. of
DBU (Table 1). The reaction time in MtB–ether
remained the same and utilizing these reaction condi-
tions it was possible to obtain indole in 89% after
filtration of the organic phase after work-up through a
silica pad and crystallization from petrol ether.
3
. The Chemistry of Indoles; Sundberg, R. J., Ed.; Aca-
demic Press: New York, 1970.
4
5
. Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567.
. Kawase, M.; Miyake, Y.; Kikugawa, Y. J. Chem. Soc.,
Perkin Trans. 1 1984, 1401.
6
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8
. Somei, M.; Hashiba, K.; Yamada, F.; Maekawa, T.;
Kimata, T.; Kaneko, C. Chem. Lett. 1978, 1245.
. Ullman’s Encyclopedia of Industrial Chemistry, 6th ed.,
1999; Electronic Release (Chloroamines).
. Manchand, P. S.; Coffen, D. L.; Belica, P. S.; Wong,
F.; Wong, H. S.; Berger, L. Heterocycles 1994, 39,
8
33.
. Hiegel, G. A.; Nalbandy, M. Synth. Commun. 1992, 22,
589.
0. Hiegel, G. A.; Nalbandy, M. Synth. Commun. 1992, 22,
589.
To study the scope of the reaction various electron rich
and electron poor indoline derivatives were subjected to
the reaction conditions.
9
1
1
3
1
1
1
1
1
All indoline derivatives except the nitro derivatives were
found to behave in the same manner as indoline 3a
under the standard reaction conditions. For the nitro
substituted indolines the reaction had to be performed
at higher temperature (addition of TCCA at 20°C and
heating to reflux after completion of the addition).
After this reaction some starting material could also be
recovered but the reaction conditions were not further
optimized especially for these substrates.
1. Jenny, C. J.; Lohri, B. Eur. Pat. 775684, 1997, to Hoff-
mann La Roche.
2. Haffer, G.; Nickisch, K.; Tilstam, U. Heterocycles
1
998, 48, 993.
3. Typical procedure: Indoline 3a (6.0 g, 50.4 mmol) was
dissolved in 60 ml MtB–ether, and 17.2 ml (2.3 equiv.)
of DBU were added. The solution was cooled to −30°C
and a solution of 4.55 g TCCA dissolved in a mixture
of 75 ml MtB–ether and 25 ml ethyl acetate was added
while maintaining the temperature below −20°C. After
completion of the addition the mixture was allowed to
warm up slowly over 2 h to 0°C. After completion of
the reaction, 50 ml of a saturated solution of sodium
hydrogen sulfite was added while maintaining the tem-
perature below 9°C. The mixture was stirred overnight
at room temperature prior to separation of the phases.
The precipitated solid was filtered off and washed with
To ascertain a good yield of product it was found
necessary especially for electron rich derivatives to
destroy all remaining oxidants prior to phase separa-
tion. The optimal method was found to stir the reaction
mixture with the sodium sulfite solution for at least 10
h as the remaining N-chloro derivatives from TCCA
slowly react with water and release hypochlorous acid
which readily oxidize the product. Unfortunately, it
was not possible to further reduce the amount of
TCCA as the reaction then stopped before completion.
2
0 ml of MtB–ether. The phases were separated and
the aqueous phase was extracted with 30 ml of MtB–
ether. The combined organic phases were washed twice
with 50 ml of water. The organic solution was filtered
through a pad of silica gel (75 g) and the silica gel pad
was subsequently washed with 100 ml of MtB–ether.
The combined organic phase was stripped to dryness
and the residue was taken up in 100 ml of petroleum
ether and 0.25 g of activated charcoal was added. The
mixture was heated to reflux, filtered hot and the color-
less solution was cooled slowly to −20°C. The obtained
crystalline material was filtered off and dried giving
5.25 g of indole 4a as colorless crystals.
We have shown that the use of trichloroisocyanuric
acid TCCA in combination with DBU as base for the
dehydrogenation of indolines to indoles is a mild and
efficient method for electron rich as well as electron
poor derivatives, making it the first general method for
this conversion. A detailed study showed that indole
was not contaminated with ring chlorinated products
being the major obstacle for other reported methods.
The reaction was found to be very clean giving the
indole derivatives in high yields.
.