Microwave-assisted, solvent-free Bischler indole synthesis

Article abstract of DOI:10.1055/s-2005-922760

The solid-state reaction between anilines and phenacyl bromides in the presence of an equimolecular amount of sodium bicarbonate gives N-phenacylanilines. Microwave irradiation of mixtures of these compounds with anilinium bromides at 540 W for 45-60 s provides a mild, general, and environmentally friendly method for the synthesis of 2-arylindoles in 50-56% overall yields. A one-pot variation of the method, involving irradiation of 2:1 mixtures of anilines and phenacyl bromides, was also developed, allowing a simplified experimental procedure and leading to improved yields (52-75%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922760

LETTER
91
Microwave-Assisted, Solvent-Free Bischler Indole Synthesis
M
icrowave-Assist
e
e
d, Solvent-
l
Free
B
l
ischler
a
Indole Syn
i
thesis samy Sridharan, Subbu Perumal,1 Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(91)3941822; E-mail: josecm@farm.ucm.es
Received 6 September 2005
obviously unsuitable for base-sensitive substrates. Reduc-
tion of the number of steps of these sequences has been re-
cently achieved by the development of some copper-14 or
palladium15-catalyzed domino protocols for the trans-
formation of N-protected 2-iodoanilines into indoles,
without the need to isolate intermediate o-alkynyl inter-
mediates, but the preparation of the starting materials
from commercially available anilines is still necessary.
Abstract: The solid-state reaction between anilines and phenacyl
bromides in the presence of an equimolecular amount of sodium bi-
carbonate gives N-phenacylanilines. Microwave irradiation of mix-
tures of these compounds with anilinium bromides at 540 W for 45–
60 s provides a mild, general, and environmentally friendly method
for the synthesis of 2-arylindoles in 50–56% overall yields. A one-
pot variation of the method, involving irradiation of 2:1 mixtures of
anilines and phenacyl bromides, was also developed, allowing a
simplified experimental procedure and leading to improved yields
(52–75%).
Several known methods for indole synthesis have the
advantage of avoiding the need to prepare o-substituted
anilines, including the classical Fischer indole synthesis
and the Sommelet rearrangement of arylsulfonium ions,16
but the need to transform the starting aniline into an hy-
drazone or a S-anilinosulfonium derivative, respectively,
renders them less attractive than alternative routes. The
Bartoli indole synthesis,17 which starts from nitrobenzene
derivatives, also belongs to the group of methods that do
not require the introduction of a substituent ortho to a ni-
trogen function prior to the construction of the indole sys-
tem, although its scope is also rather limited because it
only works well with 2-substituted nitrobenzenes and it
requires the use of a large excess of Grignard reagents. On
the other hand, the traditional but relatively unexploited
Bischler indole synthesis,6,18 based on an intramolecular
electrophilic cyclization, appeared to us as ideally suited
as a starting point for the development of a green indole
synthesis, since it does not require the use of nitrogen
protecting groups or metallic reagents or catalysts.
Key words: indole synthesis, aniline monoalkylation, solvent-free
synthesis, microwave-assisted synthesis
One of the main aims of green chemistry is the reduction
of the use of organic solvents because of the economical
and environmental concerns associated with them, and
therefore the development of solvent-free synthetic
methods2 is of the utmost importance. We describe in this
paper a user-friendly, solvent-free protocol for the synthe-
sis of 2-arylindoles under Bischler conditions.
Indole derivatives are of great significance because of
their occurrence in nature as part of the structure of a large
number of alkaloids3 and their wide-ranging biological
avtivity,4 and for this reason indole synthesis is a very
active field.5 Besides the traditional procedures based,
among others, on the Fischer, Reissert and Madelung
reactions,6 modern emphasis is on methods that rely on
the transition metal-catalyzed cyclization of o-alkynyl-
anilines. From the point of view of synthetic efficiency,
these methods have the disadvantage of requiring one or
several steps7 to introduce the ortho side chain prior to the
cyclization, and also that they normally require a nitrogen
protecting group, which adds two more steps to the indole
preparations. Besides the lengthy sequences and the use of
stoichiometric amounts of metals in the side chain intro-
duction, another limitation of these methods from eco-
nomical and environmental perspectives is the need for
the use of toxic and expensive transition metal reagents or
catalysts, normally palladium complexes8,9 or copper(II)
salts,10 in the cyclization stage. The introduction of
gold(III) salts as catalysts represented an improvement,11
as they do not require nitrogen protection, but they are
toxic, their cost is very high and they still require the use
of organic solvents. Cyclizations mediated by metal
alkoxides12 and other bases13 are also known, but they are
The Bischler (or Bischler–Möhlau) indole synthesis in-
volves monoalkylation of anilines with phenacyl bro-
mides to compounds 1, followed by treatment with an
aniline hydrobromide as a catalyst, which forms an imine
2 by reaction with 1. Because of the high temperatures
required, which favor thermodynamic control, the more
stable imine tautomer 3 predominates. Its cyclization
gives 4, which then evolves to the final product 5 by loss
of the initial aniline; the tautomerization of 2 to 3 explains
the apparent migration of the aryl group to the indole C-2
position (Scheme 1). If 1 is N-substituted, this tautomer-
ism is not possible and 3-arylindoles are obtained;19 re-
cently, the development of LiBr-mediated cyclization
conditions has allowed the synthesis of N-unsubstituted 3-
arylindoles from intermediates 1 containing several elec-
tron-releasing groups in the benzene ring that acts as the
nucleophile.20 Variations of the Bischler synthesis that
allow the preparation of 2,3-unsubstituted indoles by
cyclization of acetals are known,21 although they are of
limited scope regarding the type of substituents allowed
on the benzene ring.
SYNLETT 2006, No. 1, pp 0091–0095
0
5.
0
1.
2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922760; Art ID: D26805ST
© Georg Thieme Verlag Stuttgart · New York

92
V. Sridharan et al.
LETTER
R3
tion of 2-phenylindole in 71% yield (56% overall from
aniline). This effect of dimethylformamide is probably
due to its role as an energy transfer agent, related to its
high dipole moment and leading to an increased reaction
temperature,25 although it is interesting to note that some
attempts to carry out the reaction in an alumina bath in or-
der to obtain high temperatures upon microwave irradia-
tion were much less effective. In spite of the very short
reaction times employed, the isolation of a 2-arylindole
suggested that the same thermodynamic mechanism sum-
marized in Scheme 1 was in operation under our micro-
wave-enhanced conditions. Reaction of the remaining
compounds 1 and the suitable anilinium hydrobromide
(i.e. the hydrobromide of the aniline used for preparing 1)
led to isolation of several 2-arylindoles in good yields. As
summarized in Table 1, a variety of substituents, both
electron-withdrawing and electron-releasing, could be ac-
commodated without significant differences in reaction
time or yield.26 Besides the much milder conditions and
shortened reaction times, our method also represents a
considerable improvement in yield in those cases where
the availability of literature data enables a comparison.
For instance, the yield of 2-phenylindole (5a) is 17%
under the conventional conditions.27
R3
R2
O
R2
O
+
N
H
NH2
Br
R1
R1
1
R2
Br
NH3
R2
R1
R2
R1
R3
HN
N
R1
R3
R2
N
R1
N
H
R1
R2
R2
3
2
R1
NH
R2
R3
R2
N
R2
R3
H
R1
N
H
5
R1
R1
The literature contains at least one example where anilin-
ium bromide was employed for catalyzing a Bischler
reaction where the starting compound 1 came from a dif-
ferent, more nucleophilic aniline derivative, namely 3,5-
dimethoxyaniline,35 and it can be assumed that in this case
the reaction was catalyzed by the 3,5-dimethoxyaniline
liberated in the last step. Since the possibility of using the
cheaper anilinium bromide at least for some cases was at-
tractive, we attempted to perform the reaction leading to
4i this way, but in our case the reaction product consisted
of a 1:1 mixture of 4a and 4i, showing that competition
between aniline and 2-methoxyaniline had taken place
and that therefore this procedure must be assumed to be
possible only when very activated anilines are liberated in
the course of the reaction.
4
Br
NH3
Scheme 1
Our first task was to develop a simple protocol that al-
lowed the crucial monoalkylation of anilines with phena-
cyl bromides to give phenacylanilines 1 efficiently and
under solvent-free conditions. We found that by simply
mixing equimolecular amounts of both reagents and
sodium bicarbonate and allowing the reaction to proceed
in the solid state for three hours at room temperature,
followed by washing with water, compounds 1 were
obtained in good yields and adequate purities for the next
stage. The cyclization step of the Bischler synthesis has
been previously carried out under thermal conditions, by
heating mixtures of phenacylanilines and the suitable
aniline hydrobromide at 200–250 °C22 or in a high-boiling
solvent, like silicone oil,23 and therefore we explored the
possibility of improving this reaction by microwave irra-
diation, and particularly in the absence of solvent. Micro-
wave irradiation24 has long been considered as a green
technology because it often allows solvent-free reactions
and its level of energy consumption is low compared with
more traditional methods. Our initial experiments in-
volved N-phenacylaniline and anilinium bromide and, al-
though they were encouraging in that the desired 2-
phenylindole was isolated, the conversions were invari-
ably low, even using reaction times of up to six minutes,
and forcing conditions led to decomposition. Fortunately,
after some experimentation, we eventually found that ad-
dition of three drops of dimethylformamide to the mixture
of N-phenacylaniline and anilinium bromide prior to its
irradiation at 540 watts for one minute allowed the isola-
As a refinement of our method, we next sought to carry
out the transformation of anilines and phenacyl bromides
into indoles in a single operation. When 2:1 mixtures of
the suitable aniline and phenacyl bromide were stirred for
three hours and then irradiated for one minute at 600 watts
in the presence of three drops of dimethylformamide but
with no added sodium bicarbonate, the expected 2-arylin-
doles were obtained in one pot. As shown in Table 2,
these reactions normally proceeded in improved yields
with regard to the two-step method, and with the obvious
advantage of a faster and more convenient operation.36
In conclusion, we describe a general, economically and
environmentally friendly protocol for the preparation of
2-arylindoles from anilines under mild conditions, either
in two steps or in one pot, using solvent-free reactions in
both cases and affording much improved yields in com-
parison with the traditional conditions.
Synlett 2006, No. 1, 91–95 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted, Solvent-Free Bischler Indole Synthesis
93
Table 1 Overall Yields for the Two-Step, Solvent-Free Bischler Indole Synthesis and Characterization Data of 2-Arylindoles Obtained
Compd
R1
H
R2
H
R3
H
Microwave irradiation time (s) Overall yield of 5 (%) Mp of 5 (°C)
5a
60
45
60
60
45
60
45
60
60
56
55
51
53
54
51
50
52
50
190–191
(lit. 189.5–190)28
5b
5c
5d
5e
5f
H
H
Cl
CH3
H
207–208
(lit. 206–207)28
H
H
220–221
(lit. 220.5–221)28
H
CH3
Cl
220–221
(lit. 218–219)29
H
H
200–201
(lit. 197–198)30
CH3
H
H
H
118–119
(lit. 117–118)31
5g
5h
5i
CH3
CH3
H
CH3
Cl
H
238–239
(lit. 239–240)32
H
252–253
(lit. 250.5–251.5)33
OCH3
85–86
(lit. 82–85)34
Table 2 Yields Obtained in the One-Pot Bischler Synthesis of 2-
Arylindoles from 2:1 Mixtures of Anilines and Phenacyl Bromides
(2) Tanaka, K. Solvent-Free Organic Synthesis; Wiley: New
York, 2003.
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Compd
5a
R1
H
R2
H
R3
H
Yield (%)
75
52
54
56
59
67
57
55
56
5b
5c
H
H
Cl
CH3
H
H
H
5d
5e
H
CH3
Cl
H
H
5f
CH3
H
H
H
5g
CH3
CH3
H
CH3
Cl
H
5h
5i
H
OCH3
Acknowledgment
We thank CICYT for financial support. The stay of SP in Madrid
was supported by a fellowship from the Spanish Dirección General
de Universidades (Estancias de Profesores, Investigadores, Docto-
res y Tecnólogos extranjeros en España), which is also gratefully
acknowledged.
References and Notes
(1) Permanent address: Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai
625 021, India
Synlett 2006, No. 1, 91–95 © Thieme Stuttgart · New York

94
V. Sridharan et al.
LETTER
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(26) (a) General Procedure for the Two-Step Method.
N-Alkylation: 2 mmol of the suitable phenacyl bromide
(prepared according ref. 26b) was slowly added to a mixture
of 2 mmol of the suitable arylamine and 300 mg of NaHCO3
(the order of addition of the reagents is not normally of
consequence, but it is important to use the method described
here in the case of the anisidine derivatives, which otherwise
lead to dialkylation products). The reaction mixture was
stirred at r.t. with occasional cooling in tap water, soon
becoming semisolid and finally solid. This solid was kept at
r.t. for 3 h, when completion of the reaction was verified by
TLC. Then, H2O was added to the mixture and the separated
solid was filtered, washed with H2O, and dried, giving
materials with sufficient purity for the next step. If desired,
the N-phenacylanilines can be recrystallized from EtOH.
Cyclization: a mixture of 1 mmol of the suitable N-phen-
acylaniline and 1.5 mmol of the corresponding anilinium
hydrobromide with 3–4 drops of DMF was irradiated in a
domestic microwave oven at 540 W for the time period
specified in Table 1. After completion of the reaction the
mixture was loaded onto a silica gel column and pure 2-
arylindoles were obtained by chromatography, eluting with
a gradient starting from 9:1 PE–EtOAc. Alternatively, the
mixture could also be extracted with EtOAc, washed with
H2O, dried and evaporated before chromatography. All
indole derivatives were previously known, and showed the
expected 1H NMR and 13C NMR spectra, and melting points
very similar to those previously described (Table 1).
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Synlett 2006, No. 1, 91–95 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted, Solvent-Free Bischler Indole Synthesis
(36) General Procedure for the One-Pot Synthesis of 2-
95
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Arylindoles from Phenacyl Bromides and Anilines under
Microwave Irradiation.
Phenacyl bromide (1 mmol) was stirred with aniline (2
mmol) at r.t. without any base to neutralize the liberated
HBr. The mixture was kept at r.t. with occasional stirring for
3 h. To the solid mixture, containing N-phenacyl aniline and
anilinium hydrobromide, was added 3–4 drops of DMF and
the mixture was irradiated in a microwave oven at 600 W for
1 min. After completion of the reaction, the mixture was
treated as described for the two-step method to give the pure
2-arylindoles.
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Synlett 2006, No. 1, 91–95 © Thieme Stuttgart · New York