A convergent approach to 2-substituted-5-methoxyindoles. Application to the synthesis of melatonin

Article abstract of DOI:10.1039/b204371h

A convergent, radical based synthesis of 5-methoxyindoles including melatonin is described.

Full text of DOI:10.1039/b204371h

A convergent approach to 2-substituted-5-methoxyindoles. Application to
the synthesis of melatonin†
Béatrice Quiclet-Sire, Benoˆit Sortais* and Samir Z. Zard
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, F-91128 Palaiseau Cedex,
France. E-mail: zard@poly.polytechnique.fr; Fax: +33 (0)1 6933 3851; Tel: +33 (0)1 6933 4872
Received (in Cambridge, UK) 8th May 2002, Accepted 25th June 2002
First published as an Advance Article on the web 8th July 2002
A convergent, radical based synthesis of 5-methoxyindoles
including melatonin is described
of cold concentrated sulfuric acid, a clean reaction ensued but
the product turned out to be indole 6 instead of the expected
tricyclic derivative 5 (Scheme 1).‡
The indole nucleus is a key structural feature in a large number
of alkaloids and related compounds, many of which exhibit a
potent pharmacological activity.1 It is not therefore surprising
that numerous routes have been devised over the years to
construct the indole ring.2 In the present communication, we
describe a simple approach to 2-substituted-5-methoxyindoles
and its application to the synthesis of melatonin, a hormone
mainly secreted by the pineal gland and known to play a key
role in the regulation of sleep and temperature rhythms in
mammals.3
We recently found that a convergent access to indolines (e.g.
4) could be achieved by a combination of an intermolecular
radical addition of a xanthate (e.g. 2) to a suitably protected N-
allylaniline (e.g. 1), followed by radical ring closure to the
aromatic ring.4 The first process in the sequence is a radical
chain, requiring only a small amount of peroxide initiator,
whereas the second is not a radical chain and therefore
stoichiometric in peroxide. In the case of indoline 4, the
presence of the ketone group suggested the possibility of
constructing a third ring by a Friedel–Crafts type reaction.
However, when we subjected an indoline of type 4 to the action
Some examples of this transformation are collected in Table
1. The best conditions we found were 10 equiv. of 95% sulfuric
acid for 30 min. Lower temperatures resulted in long reaction
times and higher temperatures or a longer exposure caused the
formation of unwanted side-products. Various functional
groups capable of resisting cold concentrated sulfuric acid for a
short time such as amides, ketones and, to a lesser extent, esters
are tolerated and the yields are generally good. Moreover, under
such conditions, it is reported that the indole ring is not
sulfonylated.5
It is necessary to have the electron-donating p-methoxy group
for the reaction to occur. In its absence, no reaction took place.
Substituents such as halides or (not surprisingly) a nitro group
were not suitable. This observation is in keeping with the
mechanism shown in the lower part of Scheme 1, where the
Table 1 Synthesis of indolines 4 and indoles 5a
Scheme 1 Synthesis of indoles.
a (X = SCSOEt; Ar = p-methoxyphenyl); yields in parenthesis are based
on recovered starting material.
† Dedicated to the memory of our friend, Dr Jean-Claude Barrière.
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This journal is © The Royal Society of Chemistry 2002

slow step is the cleavage of the nitrogen–sulfur bond, assisted
by an electron push by the lone pair on oxygen. The resulting
intermediate 7 first undergoes tautomerisation to 8, then
aromatisation by a [1,5] sigmatropic rearrangement or an acid
catalysed prototropic shift. Although many reagents are known
to oxidise indolines to indoles,6 there is no need in our case to
use an oxidant since the mesyl group serves both as a protecting
group for the nitrogen and a leaving group allowing the
introduction of the desired unsaturation. It interesting that in one
report,6c a 7-methoxy-N-benzenesulfonylindoline was sub-
jected to a Friedel–Crafts reaction in the presence of tin
tetrachloride as the Lewis acid. The indoline portion of the
molecule remained intact, even though the methoxy group is
also in a favourable position to trigger the expulsion of the
sulfonyl group under the strong acidic conditions typical of a
Friedel–Crafts reaction.
With a good access to 2-substituted-5-methoxyindolines in
hand, we considered applying this sequence to the synthesis of
melatonin. Many syntheses of this molecule have been reported
but none, as far as we are aware, involves free radical
chemistry.7 Our approach is outlined in Scheme 2. Addition of
xanthate 2e, prepared in 93% yield by heating ethyl bromoace-
tate with commercially available potassium O-ethylxanthate, to
olefin 1, mediated by the portion-wise addition of lauroyl
peroxide (0.2 equiv.), provided the corresponding adduct 3e in
79% yield. Exposure of this compound to stoichiometric
amounts of peroxide in refluxing 1,2-dichloroethane promoted
ring closure into indoline 4e in 73% yield.
rearrangement mediated by diphenylphosphoryl azide8 and
capture of the intermediate isocyanate with a 95+5 mixture of
acetic acid and acetic anhydride. The latter reagent was used to
avoid any hydrolysis of the isocyanate by adventitious water in
the medium causing the undesired formation of amine then the
symmetrical urea by reaction of the amine with the isocyanate.
Finally, the crude melatonin thus obtained is treated briefly with
methanolic potassium carbonate to cleave a small amount of the
corresponding diacetylimide, generated through overacetyla-
tion.
The second route was one step longer but gave a slightly
better overall yield. It involved hydrolysing first the ester group
with concentrated HCl, performing the Curtius degradation
under acetylating conditions before finally removing the mesyl
group and concomitant aromatisation by treatment with 95%
sulfuric acid.
In summary, we have found a simple route to indoles
substituted with electron donating groups. This chemistry can in
principle be easily adapted to provide access to various
analogues of melatonin, which may not be readily available
otherwise.9
Notes and references
‡ Typical experimental procedure: ice-cold 95% sulfuric acid (10 equiv.)
was added to the pure indoline and the resulting mixture stirred at 0 °C for
about 30 min, then poured carefully into cold distilled water and extracted
with diethyl ether. The aqueous phase was neutralized with potassium
bicarbonate and extracted with ether. The combined organic layers were
dried over sodium sulfate and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel.
Two variants were used to convert 4e into melatonin. The
first consisted in cleaving both the ester and mesyl groups with
95% sulfuric acid at room temperature followed by a Curtius
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Scheme 2 Synthesis of melatonin.
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