Iron-palladium association in the preparation of indoles and one-pot synthesis of bis(indolyl)methanes

Article abstract of DOI:10.1002/ejoc.200700831

Indoles were prepared by annulation of the parent alkynylanilines with the use of a new FeCl₃-PdCl₂ catalytic combination. High yields were obtained by using low loadings of the transition-metal complex (FeCl₃-PdCl₂: 2 and 1 mol-%, respectively). One-pot accesses to bis(indolyl)methanes and trisubstituted indoles through annulation/Friedel-Crafts alkylation and annulation/1,4-Michael addition sequences, in which FeCl₃ acts both as a cooxidant and a Lewis acid are described. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700831

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700831
Iron–Palladium Association in the Preparation of Indoles and One-Pot
Synthesis of Bis(indolyl)methanes
[a]
[b]
[a]
[c]
[a]
Vincent Terrasson, Julien Michaux, Anne Gaucher, Johny Wehbe, Sylvain Marque,
[a]
[b,c]
Damien Prim,* and Jean-Marc Campagne*
Keywords: Iron / Palladium / Indole / Bis(indolyl)methane
Indoles were prepared by annulation of the parent alk-
Crafts alkylation and annulation/1,4-Michael addition se-
ynylanilines with the use of a new FeCl
combination. High yields were obtained by using low load-
ings of the transition-metal complex (FeCl –PdCl : 2 and
mol-%, respectively). One-pot accesses to bis(indolyl)meth-
3
–PdCl
2
catalytic
quences, in which FeCl
acid are described.
3
acts both as a cooxidant and a Lewis
3
2
1
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
anes and trisubstituted indoles through annulation/Friedel–
Introduction
Indoles are ubiquitous substructures of natural or syn-
Usually, activation of carbon–carbon triple bonds to-
thetic biologically active products. It is thus not surprising ward intramolecular nucleophilic attack of proximate nu-
that this benzo-fused heterocycle continuously attracted the cleophiles can be achieved through precoordination to or-
attention of the scientific community from the initial dis- gano–transition-metal complexes. In this context, pro-
[
1]
covery, over 120 years ago, of the Fischer indole synthesis
until the most recent metal-catalyzed alternative pro- particularly versatile in both homo- and heterogeneous
cedures that rely on the use of palladium salts appeared
[
3]
[4]
[
2]
cedures. Among the latter, transition-metal-catalyzed hy- catalysis. This intense research area is not restricted to pal-
droamination of o-alkynylaniline derivatives to 2-substi- ladium chemistry. Indeed, gold, copper, platinum, mo-
tuted indoles is one of the most efficient approaches lybdenum, iridium, indium
Figure 1).
cently proved efficient for the preparation of substituted in-
[
5]
[6]
[7]
[
8]
[9]
[10]
or rhodium,[11] have re-
(
[
12]
doles. Only a few methods dealing with unprotected pri-
mary o-alkynylanilines are described to use expensive metal
[
9]
[5]
sources and/or high catalyst loadings: as Ir-, Au-,
[
10]
[13,14]
[6c]
In-, Pd-
and Cu-based complexes. Therefore, the
development of efficient catalytic systems for the prepara-
tion of indoles from the corresponding primary o-alk-
ynylaniline is still of high interest.
On the basis of our previous experience in indole[ syn-
15]
thesis and our recent interest in iron(III)-catalyzed hydro-
[
16]
amination of vinylarenes, our initial plan was to synthe-
size the indole moiety through iron π activation of the triple
bonds of o-alkynylanilines [Equation (1)]. Moreover, as a
result of the Lewis acidity of the iron complex, further one-
pot transformations might be envisaged such as the one-pot
hydroamination/Friedel–Crafts alkylation sequence towards
bis(indolyl)methanes [Equation (2)].
Figure 1. Transition-metal-catalyzed indol syntheses.
[
a] Institut Lavoisier de Versailles UMR CNRS 8180, Université
de Versailles-Saint-Quentin-en-Yvelines,
45, avenue des Etats-Unis, 78035 Versailles, France
Fax: +33-1-39254452
E-mail: prim@chimie.uvsq.fr
[
[
b] Institut de Chimie des Substances Naturelles,
Avenue de la Terrasse 91198 Gif-sur-Yvette, France
c] Ecole Nationale Supérieure de Chimie,
8
rue de l’Ecole Normale 34296 Montpellier, France
Fax: +33-4-67147212
E-mail: jean-marc.campagne@enscm.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
(
1)
5332
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5332–5335

Preparation of Indoles and One-Pot Synthesis of Bis(indolyl)methanes
showed complete conversion to 2. These results suggest that
two different mechanisms may account for the formation of
the indole nucleus.
(
2)
Results and Discussion
Although the very first experiments with substrate 1 in
the presence of iron chloride (10 mol-%) in dichloroethane
(DCE) at 80 °C were successful, the reaction rapidly ap-
peared to be nonreproducible. After considerable experi-
mentation, it appeared that the success of the annulation
reaction was dependent on the preparation procedure of the
Scheme 1.
Although the π activation of the triple bond by an iron
starting alkynylanilines and their purification.[17] The ques- species could not be totally ruled out, one hypothesis on
tion of traces of palladium or copper in the reaction mix- the role of iron in these cyclizations is that it may facilitate
0
II
ture was then posed. Indeed, when the reaction was carried the in situ reoxidation of Pd to Pd . Indeed, the use of a
out in the presence of PdCl (10 mol-%) and FeCl (10 mol- stoichiometric amount of PdCl led to a quantitative con-
2
3
2
%
), indole 2 was obtained in 89% isolated yield (Table 1, version of the starting alkynylaniline into expected indole 2
Entry 1). In contrast, the same reaction run with CuI (Table 1, Entry 4). Moreover, the use of another cooxidant,
10 mol-%) and FeCl (10 mol-%) did not afford the ex- such as benzoquinone and CuCl (Table 1, Entries 8, 9) in
(
3
2
pected indole nucleus (Table 1, Entry 2). Control experi- association with PdCl evidenced the required presence of
2
ments in the presence of PdCl (10 mol-%), but in the ab- an oxidant to complete the catalytic cycle and confirmed
2
sence of iron, only lead to the formation of trace amounts our hypothesis. Because all reactions were carried out in
of indole 2 (Table 1, Entry 3).
open-air flasks, the presence of oxygen may account for the
II
III
0
II
This first set of experiments clearly evidenced that both cascade reoxidation of Fe to Fe and Pd to Pd , which
Pd and Fe are required for the formation of indole starting allows the use of catalytic amounts of FeCl3.
from alkynylanilines under our conditions (80 °C in DCE).
Thus, the cyclization might proceed along two different
In addition to our results, disparate reports in the literature mechanistic paths depending on the solvent. On the one
deserve some comments: whereas a 52% yield was reported hand, in acetonitrile, palladium might play the role of Lewis
[
13]
by Utimoto when the reaction was carried out in MeCN acid (or more precisely the role of π acid according to
[
18]
in the presence of PdCl (5 mol-%), the same reaction in Fürstner ) without any redox transformation in the cata-
2
[
5d]
EtOH
major role played by the solvent in these cyclizations dium is reduced to Pd in a mechanism related to Wacker
Scheme 1). Our own experiment, performed in ethanol in reactions, thus demanding a reoxidation step to complete
the presence of both FeCl (5 mol-%) and PdCl (5 mol-%), the catalytic cycle.
led to a very low yield (5%), which evidences the lytic cycle. On the other hand, in EtOH or DCE, the palla-
0
(
3
2
Table 1. Optimization of the synthesis of 2-phenylindole.
Entry
Catalytic system
[M]
Time
[h]
Conditions
Conversion [%][a]
(isolated yield,%)
Oxidant
Equiv.
Equiv.
1
2
3
4
5
6
7
8
9
FeCl
FeCl
–
3
0.1
0.1
–
PdCl
CuI
2
0.1
0.1
2
2
4
12
2
2
4
2
4
DCE 80°
DCE 80°
DCE 80°
DCE r.t.
DCE 80°
DCE 80°
DCE 80°
DCE 80°
DCE 80°
quant. (89)
–
traces
quant.
Ͼ95 (88)
60
quant. (88)
48
quant.
3
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
0.05
1
0.01
0.01
0.01
0.01
0.01
–
–
FeCl
FeCl
FeCl
3
3
3
0.05
0.02
0.02
1.5
0.02
benzoquinone
CuCl
2
1
[
a] Determined by H NMR spectroscopic data of the crude reaction mixture.
Eur. J. Org. Chem. 2007, 5332–5335
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5333

D. Prim, J.-M. Campagne et al.
SHORT COMMUNICATION
The present conditions compare favourably with pre-
Keeping in mind the one pot transformation of alk-
viously described conditions in terms of catalyst loading ynylanilines to bis(indolyl)methanes, the use of an iron
1 mol-% PdCl vs. 5 mol-%) and yields (89% vs. 52%). complex could be advantageous and act as both the reoxi-
(
2
Moreover, the presence of a Lewis acid such as FeCl paves dant and the Lewis acid.
3
the way to further one-pot transformations. Consequently,
Further use of the iron–palladium combination in a one-
optimization of the catalytic system, scope and limitations pot, two-step sequence was next investigated. Bis(indolyl)-
[
19]
of this methodology were next examined.
methanes are known bioactive compounds, and they are
II
Optimization of reaction conditions as well as both Pd
usually obtained through Friedel–Crafts alkylation of in-
and Fe sources and loadings were next examined. It is doles under acidic or Lewis acid catalysis.
worth noting that several other Pd and Fe sources as is able to stepwise promote the reoxidation of Pd in the
III
[19a,20]
If FeCl3
II
III
0
well as solvents were tested, such as Na PdCl4 or annulation and catalyze Friedel–Crafts alkylation reactions,
2
PdCl TPP , Fe(acac) or Fe(NO ) and toluene or dioxane. one interesting issue would be the one-pot transformation
2
2
3
3 3
If some combinations gave similar results, the best results of alkynylanilines to substituted bis(indolyl)methanes.
were obtained by using the PdCl /FeCl combination in We first tried to prepare bis(indolyl)methane 10 from in-
DCE. Attempts to decrease Pd and Fe loadings to dole 2 and 4-chlorobenzaldehyde under the aforementioned
.01 equiv. and 0.05–0.02 equiv., respectively, led to promis- conditions (DCE, 2 mol-% FeCl ) at room temperature.
2
3
0
3
ing results, as indole 2 could be obtained in 88% yield Under these conditions, expected compound 10 was iso-
Table 1, compare Entries 5–7). The use of 0.02 equiv. of lated in a fair 50% yield. The one-pot annulation and Frie-
(
FeCl required longer reaction times. Indeed, 4 h at 80 °C del–Crafts alkylation sequence was next examined. When
3
were required to ensure completion of the reaction and al- the appropriate alkynyl starting material was treated with
low the isolation of indole 2 in 88% yield (Table 1, Entry 7). the benzaldehyde derivative (0.5 equiv.) and FeCl (2 mol-
3
The scope of the reaction was then surveyed by using %)–PdCl (1 mol-%) in DCE, bis(indolyl)methanes 10–13
2
various electron-withdrawing and -donating substituents on were obtained in yields ranging from 40 to 59%, thus pro-
the aromatic side and heterocyclic or aliphatic moieties on viding one-pot access to bis(indolyl)methanes (Scheme 2).
the alkyne. Results obtained in these reactions are summa-
rized in Table 2.
3
Table 2. FeCl -catalyzed synthesis of substituted indoles.
Entry
R2
H
5-Cl
5-NO
4-Me
H
H
H
H
R1
Product
Isolated yield (%)[a]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
CO
4-NO
4-MeOPh
2-thienyl
2
3
4
5
6
7
8
9
88
83
82
80
2
[
b]
2
Et
Ph
n.r.[
c]
c]
2
40
76[
50
[
4
a] Unless otherwise stated, FeCl
h at 80 °C. [b] No reaction. [c] 20 h.
3
(2 mol-%) and PdCl
2
(1 mol-%),
Scheme 2.
The reactivities of alkynylanilines substituted by various
functional groups such as Cl, NO and Me (Table 2, En- and dual role of FeCl
Further extension of the iron–palladium combination
is also shown in Scheme 3. In the
tries 2–4) were similar to those of compound 1 and allowed presence of a Michael acceptor such as methyl vinyl ketone
2
3
the formation of the indole nucleus in high yields (80
–83%). The electronic effect of the substituent of the alkyne
moiety was also examined. Electron-rich substituents such
as 4-MeOPh or 2-thienyl (Table 2, Entry 7, 8) fairly yielded
the expected indole under standard reaction conditions
(
(
2 mol-% catalyst). In contrast, electron-poor substituents
4-NO Ph; Table 2, Entry 6) required longer reaction times
2
for lower yields. In addition, substrates with strongly with-
drawing groups such as CO Et did not react even after pro-
2
longed heating times.
Scheme 3.
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Eur. J. Org. Chem. 2007, 5332–5335

Preparation of Indoles and One-Pot Synthesis of Bis(indolyl)methanes
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[
[
3
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6
Supporting Information (see footnote on the first page of this arti-
cle): General procedures for the annulation of alkynylanilines, an-
nulation/Friedel–Crafts alkylation and annulation/1,4-Michael ad-
dition sequences as well as spectroscopic data.
2
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Received: September 5, 2007
Published Online: October 1, 2007
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5335