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Multicomponent reactions and ionic liquids: a perfect
synergy for eco-compatible heterocyclic synthesis
Nicolas Isambert, Maria del Mar Sanchez Duque, Jean-Christophe
Plaquevent, Yves Génisson, Jean Rodriguez, Thierry Constantieux
To cite this version:
Nicolas Isambert, Maria del Mar Sanchez Duque, Jean-Christophe Plaquevent, Yves Génisson, Jean
Rodriguez, et al.. Multicomponent reactions and ionic liquids: a perfect synergy for eco-compatible
heterocyclic synthesis. Chemical Society Reviews, Royal Society of Chemistry, 2011, 40, pp.1347-1357.
�10.1039/c0cs00013b�. �hal-00681335�
This journal is
c
The Royal Society of Chemistry 2011 Chem. Soc. Rev., 2011, 40,1347–1357 1347
Multicomponent reactions and ionic liquids: a perfect synergy
for eco-compatible heterocyclic synthesis
Nicolas Isambert,
a
Maria del Mar Sanchez Duque,
a
Jean-Christophe Plaquevent,
b
Yves Ge
´
nisson,
b
Jean Rodriguez*
a
and Thierry Constantieux*
a
Received 18th June 2010
DOI: 10.1039/c0cs00013b
The efficiency of a chemical synthesis can be nowadays measured, not only by parameters
like selectivity and overall yield, but also by its raw material, time, human resources and
energy requirements, as well as the toxicity and hazard of the chemicals and the protocols
involved. The development of multicomponent reactions (MCRs) in the presence of
task-specific ionic liquids (ILs), used not only as environmentally benign reaction media,
but also as catalysts, is a new approach that meet with the requirements of sustainable
chemistry. The aim of this tutorial review is to highlight the synergistic effect of the
combined use of MCRs and ILs for the development of new eco-compatible
methodologies for heterocyclic chemistry.
Introduction
In the context of sustainable chemistry,
1
the design and
development of sequences allowing highly selective access to
elaborated molecular scaffolds while combining structural
diversity
2
with eco-compatibility,
3
are great challenges for
organic chemists. Thanks to their ability to build one product
in a single operation from three or more reactant molecules
with high atom-economy
4
and multiple-bond-forming efficiency,
5
multicomponent reactions (MCRs),
6
are now well-established
approaches to reach this near ideal goal.
7
Due to these
environmental concerns, investigation of alternatives to con-
ventional organic solvents resulted in a considerably growing
interest in the use of room temperature ionic liquids
(RTILs).
8,9
Furthermore, thanks to their user-friendly and
adjustable physico-chemical properties, RTILs have found
numerous applications not only as environmentally benign
reaction media, but also as catalysts and reagents.
10
From this
perspective, combining synthetic potentialities of MCRs with
the dual properties of RTILs as solvents and promoters results
in the emergence of promising strategies for the development
of valuable eco-compatible organic synthesis procedures.
11
This review aims at illustrating this concept through recent
selected examples and to highlight the synergistic use of
MCRs and RTILs for an eco-compatible heterocyclic
chemistry.
12
This article will be divided in four sections.
a
Aix-Marseille Universite
´
– Institut des Sciences Mole
´
culaires de
Marseille-UMR CNRS 6263 iSm2, Centre Saint Je
´
ro
ˆ
me,
Service 531, 13397, Marseille Cedex 20, France.
E-mail: thierry.constantieux@univ-cezanne.fr;
Fax: +33-(0)491-289-187; Tel: +33-(0)491-282-874
b
Universite
´
Paul Sabatier Toulouse III-LSPCMIB,
UMR CNRS 5068, 31062 Toulouse 9, France.
E-mail: plaquevent@chimie.ups-tlse.fr; Fax: +33-(0)561-556-011;
Tel: +33-(0)561-556-511
Nicolas Isambert
Nicolas Isambert was born in
Albi (France) on 22nd August
1978. After studying chemis-
try at the University of
Montpellier, he completed his
PhD under the supervision of
Dr N. J. Westwood at St
Andrews University, Scotland.
After a postdoctoral position
in Barcelona under the super-
vision of Professor Rodolfo
Lavilla where he was investi-
gating development of multi-
component reactions, he moved
back to France in Professor
J. Rodriguez lab to develop
multicomponent reactions in ionic liquids. He is currently at
the University of Orle
´
ans in a collaboration with Servier. His
research interest includes multicomponent reaction, heterocyclic
chemistry, medicinal chemistry and green chemistry.
Maria del Mar Sanchez
Duque
Maria del Mar Sanchez Duque
was born in Cali, Colombia, in
August 1985. She obtained her
BSc in chemistry in 2006 and
her MSc in 2008 both from the
University of Montpellier
(France). Currently, she is
pursuing her PhD under the
supervision of professors
Thierry Constantieux and
Jean Rodriguez at the Univer-
sity Paul Ce
´
zanne in Marseille
(France). Her research focuses
on multicomponent reactions
and asymmetric synthesis.
TUTORIAL REVIEW www.rsc.org/csr | Chemic al Society Reviews
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1348 Chem. Soc. Rev., 2011, 40,1347–1357 This journal is
c
The Royal Society of Chemistry 2011
The first one concerns the use of ionic liquids as alternative
solvents for organic transformations, the second one presents
the use of ionic liquids as catalysts in organic chemistry, and
the third one deals with ionic liquids as immobilizing phases.
Finally, the last part of this review discusses the challenge of
relative and absolute stereochemical control in the combined
use of MCR and RTILs.
Ionic liquids as alternative solvents for MCRs
This section deals with MCRs performed in ionic liquid
solutions. The capacity of ionic environments to generate
internal pressure and to promote the association of reactants
in solvent cavities render them excellent media for multiple
bond-forming transformations. Their wide solvating capacity
and liquid range also clearly render them suitable solvents for
multicomponent processes.
Condensations with functionalized carbonyl compounds
The synthesis of imidazoles via MCRs involving an aldehyde,
a source of ammonia and a 1,2-dicarbonyl reactant is a useful
process. However, harsh conditions such as several hours of
reflux in AcOH or H
2
SO
4
are usually applied in standard
methods that suffer from low yields. The use of additional
acidic catalysts is also required under solvent-free conditions.
Interestingly, the combined use of microwave irradiation and
Scheme 1 Microwave-assisted three-component synthesis of 2,4,5-
trisubstituted imidazoles.
Jean-Christophe Plaquevent
Jean-Christophe Plaquevent
was born in 1953 in Normandy,
France. In 1977 he joined the
CNRS at Rouen University,
where he completed his thesis
in 1980 in the laboratory of
Professor P. Duhamel. He
had postdoctoral experiences
as a research associate with
Professor A. Eschenmoser at
ETH Zu
¨
rich and at Rouen
University where he studied
molecular biology with
Dr H. Vaudry. In 2007, he
moved to Toulouse University,
where he is still employed by
CNRS as research director. His research interests focus on
asymmetric synthesis, pharmaceutical compounds, amino acid
and peptide chemistry, and ionic liquid methodologies.
Yves Ge
´
nisson
Yves Ge
´
nisson was born in
Boulogne sur Seine, France,
in 1963. He completed his
PhD in 1992 at the ICSN in
Gif sur Yvette under the super-
vision of Dr C. Marazano.
After working for two years
at the Merck-Frosst Centre
of Therapeutic Research in
Montre
´
al, Canada, he joined
the CNRS as a researcher in
the group of Dr A. E. Greene
in Grenoble, France. In 1998,
he moved to the Universite
´
Paul Sabatier of Toulouse
where he completed his Habili-
tation in 2003. He is currently working both in the field of chiral
ionic liquids and asymmetric synthesis of bioactive compounds.
Jean Rodriguez
Jean Rodriguez was born in
Cieza (Spain) in 1958 and in
1959 his family emigrated to
France. After studying
chemistry at the University
Paul Ce
´
zanne in Marseille
(France), he completed his
PhD as a CNRS researcher
with Prof. B. Waegell and
Prof. P. Brun in 1987. He
completed his Habilitation in
1992, also at Marseille, where
he is currently Professor and
Director of the UMR-CNRS-
6263-iSm2. His research
interests include the develop-
ment of domino and multicomponent reactions, and their appli-
cation in stereoselective synthesis. In 1998 he was awarded the
ACROS prize in Organic Chemistry, and in 2009 he was
awarded the prize of the Division of Organic Chemistry from
the French Chemical Society.
Thierry Constantieux
Thierry Constantieux was
born in Pau, France, on 6
May 1968. After studying
chemistry at the University
Bordeaux I, he completed
his PhD under the supervision
of Dr J.-P. Picard and
Dr J. Dunoguez in 1994. He
completed his Habilitation in
2004, at the University Paul
Ce
´
zanne, in Marseille, where
he is currently Professor of
Organic Chemistry. His main
research interest is focused on
the development of new eco-
compatible synthetic methodo-
logies, especially domino multicomponent reactions from
1,3-dicarbonyl compounds, and their applications in heterocyclic
chemistry.
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protonated 1-alkylimidazoles, referred to as Brønsted acidic
ionic liquids, in the one-pot condensation with alkyl, aryl
aldehydes and ammonium acetate in refluxing ethanol allowed
Xia et al. to improve the synthesis of 2,4,5-trisubstituted
imidazoles in significantly reduced reaction times without
additional acidic catalysts (Scheme 1).
13
The recyclability of [C
7
mim]BF
4
as the reaction medium
was demonstrated by systematically studying reactions
involving four different aldehydes. After four consecutive
cycles, the authors observed that the products of interest were
still obtained in efficient synthetic yields. Alternatively, an
eco-friendly procedure for the same reaction, using tetra-
butylammonium bromide as a neutral ionic liquid catalyst,
has been reported.
14
Benzimidazole and benzothiazole derivatives are important
classes of heterocyclic compounds exhibiting a wide spectrum
of pharmacological properties. Among the numerous synthetic
approaches, an efficient multicomponent sequence in ionic liquids
has been developed for the synthesis of new 2,3-dihydro-
quinazolin-4(1H)-ones.
15
Indeed, the reaction of 2-amino-
benzothiazole with isatoic anhydride and various aldehydes
was studied in various ionic solvents, and [bmim]Br revealed
most appropriate (Scheme 2). The reaction proceeds well with
a wide variety of aldehydes, and the desired products are
formed in 0.5 h with yields ranging from 73 to 93%. Even
when the reaction medium is recycled up to five times, the
heterocycles are obtained in comparable yields. It is important
to note that the reaction yielded only traces of the desired
product in absence of the ionic liquid, even at high
temperatures.
Isatoic anhydride was also recently involved in a three-
component reaction carried out in the presence of an acidic ionic
liquid, allowing the first direct access to 2-styryl quinazo-
linones under environmentally benign conditions.
16
Thus,
the one-pot condensation of isatoic anhydride with triethyl
orthoacetate and various primary amines in 1-methylimida-
zolium trifluoroacetate ([Hmim]TFA) led to the formation of
the corresponding 2-methylquinazolinones. Subsequent addi-
tion of one equivalent of an aromatic aldehyde resulted in
the one-pot formation of the expected 2-styryl substituted
products in good overall yields (Scheme 3). The success of
this one-pot process confirmed that the acidic ionic liquid
[Hmim]TFA could act as an efficient reaction medium for
heterocyclic synthesis
17
as well as an efficient promoter of
Knoevenagel condensation of C–H acid compounds with
aromatic aldehydes.
18
Another important class of biologically relevant hetero-
cycles has been efficiently synthesized in ionic liquids.
1-Pyridylimidazo[1,5-a]pyridines are usually generated in classical
organic solvents and the synthetic protocols necessitate harsh
conditions, long reaction times, and low conversions are observed.
It was reported that these heterocycles can be accessed through
a one-pot condensation of 1,2-dipyridylketone, aromatic
aldehydes and ammonium acetate in various ionic liquids, in
the absence of any added catalyst (Scheme 4).
19
The Brønsted
acidic ionic liquid 1-butylimidazolium tetrafluoroborate,
[Hbim]BF
4
, was found to be the medium of choice, and
under the optimized conditions, the reaction was driven to
completion after a couple of hours at 100 1C. Moreover, yields
are dramatically increased compared to similar reactions run
in conventional organic solvents. Interestingly enough, the
authors observed a good correlation between the basicity of
the anion of the ionic liquid and the efficiency of the trans-
formation. As the same phenomenon was observed with
increasing polarity of the medium, the authors concluded that
ionic liquid both acts as a reaction medium and as a promoter.
Due to their interesting biological properties, a-carbolines,
i.e. pyrido[2,3-b]indoles have attracted considerable interest.
A green and efficient four-component synthesis of a-carboline
derivatives in ionic liquids has been recently reported
(Scheme 5).
20
Among the different advantages related to the
use of ionic liquids, it is important to note that a similar
reaction conducted in organic solvents only afforded traces of
the desired products.
Condensations with 1,3-dicarbonyl compounds and analogues
The Biginelli reaction is one of the fundamental MCRs yielding
dihydropyrimidines (DHPMs) from ureas, aldehydes and
1,3-dicarbonyls. It is often catalyzed by Brønsted acids, and
such activation is also necessary when ionic liquids are used as
reaction media. For example, it was reported that quinazolin-
2,5-dione derivatives may be efficiently accessed via the
reaction between dimedone, aldehydes and urea or thiourea
Scheme 2 Three-component synthesis of 2,3-dihydroquinazolin-
4(1H)-ones in [bmim]Br.
Scheme 3 One-pot synthesis of 2-styryl quinazolinones in acidic ionic
liquid.
Scheme 4 Ionic liquid promoted one-pot synthesis of 1-Pyridyl-
imidazo[1,5-a]pyridines.
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The Royal Society of Chemistry 2011
using a combination of [bmim]Br and silica sulfuric acid (SSA)
as a solid acid catalyst (Scheme 6).
21
Products were obtained in moderate to good yields within
short reaction times under conventional heating conditions.
Comparing their results with that of similar reactions ran in
ethanol,
22
the authors showed that yields were considerably
increased with the new protocol, the reaction times being also
dramatically reduced. Moreover, the reaction medium could
be recycled four times keeping yields around 70%.
The use of additional acid catalyst for activation of the
Biginelli reaction is obviated when the MCR is conducted in a
Brønsted acidic ionic liquid. DHPMs have been synthesized in
[Hbim]BF
4
under ultrasound irradiation with excellent yields
and short reaction times at ambient temperature (Scheme 7).
23
On the basis of NMR and IR analyses, the authors demon-
strated that the –NH proton, associated with the Brønsted
acidity of the ionic liquid, was able to bond with the carbonyl
oxygen of the aldehyde as well as that of the b-keto ester, thus
activating both partners. Thereby, the IL not only acts as a
favourable reaction medium but also as a promoter of the
MCR. It is important to note that the combined synergistic
effects of acidic IL and ultrasound activation account for the
reaction reaching completion at room temperature in
short times.
Another well-established MCR is the Hantzsch reaction
involving 1,3-dicarbonyl compounds, aldehydes and primary
amines, leading to dihydropyridines (DHPs). In 2006, Fan
et al. reported the sequential synthesis of DHPs through a
four-component reaction in ionic solvents (Scheme 8).
24
This
method describes the use of [bmim]BF
4
for the quantitative
pre-formation of the enaminoketone on which the other
partners of the MCR are added. After several hours at
80 1C, the nitrogen containing heterocycle was isolated in
moderate to excellent yields. Due to the specific role of
Meldrum’s acid and ammonium acetate, only the variation
on the aldehyde and the 1,3-diketone has been investigated.
The reaction was run in a successful manner with either cyclic
or acyclic b-dicarbonyl partners, the latter giving the lowest
yields. This ionic liquid method improves the synthesis of
DHP derivatives otherwise facing unsatisfactory yields and
long reaction times. The important issue of recycling the
reaction media is demonstrated in this work as the recovery
of the IL allowed the synthesis of DHPs after four cycles
without a drop in efficiency.
A related three-component reaction involving a preformed
cyclic b-enaminocarbonyl in various ionic liquids can also give
access to polycyclic compounds in high yields, overcoming
some problems previously faced with classical volatile organic
solvents. Thus, the reaction between 6-aminopyrimidine-2,4-
dione, dimedone and various aromatic aldehydes in [bmim]Br
delivered in less than 5 h the corresponding pyrimido-
[4,5-b]quinolines easily isolated in high yields (Scheme 9).
25
Interestingly enough, when phenylacetaldehyde was used in
this sequence, the corresponding oxidized product was isolated
after elimination of toluene and formation of the pyridine
moiety.
Scheme 5 Ionic liquid promoted four-component synthesis of
a-carbolines.
Scheme 6 Combination of an ionic liquid and an acid solid catalyst
for the one-pot synthesis of Biginelli-type scaffolds.
Scheme 7 Synergistic effect of the use of acidic IL under ultrasound
irradiation for the free-acidic catalyst Biginelli reaction.
Scheme 8 Hantzsch-type reaction in ionic liquid.
Scheme 9 Three-component synthesis of pyrimido[4,5-b]quinolines.
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