multicomponent reactions for the synthesis of pyrroles · atorvastatin, one of the top-selling...
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Multicomponent reactions for the synthesis of pyrroles
Veronica Estevez, Mercedes Villacampa and J. Carlos Menendez*
Received 26th February 2010
DOI: 10.1039/b917644f
Multicomponent reactions are one of the most interesting concepts in modern synthetic chemistry
and, as shown in this critical review, they provide an attractive entry into pyrrole derivatives,
which are very important heterocycles from many points of view including medicinal and
pharmaceutical chemistry and materials science (97 references).
1. Introduction
To set the rest of the article in context, we will make in this
section some general remarks about multicomponent reactions
and the importance of pyrrole.
1.1 Multicomponent reactions
Present-day requirements for new synthetic methods go far
beyond the traditional ones of chemo-, regio- and stereo-
selectivity, and can be summarized as follows:
1. Use of simple and readily available starting materials.
2. Experimental simplicity.
3. Possibility of automation.
4. Favourable economic factors, including the cost of raw
materials, human resources and energy.
5. Low environmental impact: use of environmentally
friendly solvents, atom economy.
For this reason, the creation of molecular diversity and
complexity from simple and readily available substrates is one
of the major current challenges of organic synthesis, and hence
the development of processes that allow the creation of several
bonds in a single operation has become one of its more
attractive goals.
Multicomponent reactions (MCRs)1–5 can be defined as
convergent chemical processes where three or more reagents
are combined in such a way that the final product retains
significant portions of all starting materials. Therefore, they
lead to the connection of three or more starting materials in a
single synthetic operation with high atom economy and
bond-forming efficiency, thereby increasing molecular
diversity and complexity in a fast and often experimentally
simple fashion.6,7 For this reason, multicomponent reactions
are particularly well suited for diversity-oriented synthesis,8–10
and the exploratory power arising from their conciseness
makes them also very powerful for library synthesis aimed at
carrying out structure–activity relationship (SAR) studies of
drug-like compounds, which are an essential part of the
research performed in pharmaceutical and agrochemical
companies.11,12 For all these reasons, the development of
new multicomponent reactions is rapidly becoming one of
Departamento de Quımica Organica y Farmaceutica,Facultad de Farmacia, Universidad Complutense, 28040 Madrid,Spain. E-mail: [email protected]; Fax: +34 91 3941822;Tel: +34 91 3941840
Veronica Estevez
Veronica Estevez was bornin Madrid, and studiedPharmacy at UniversidadComplutense, Madrid (UCM).She has finished a two-yearpostgraduate course inMedicinal Chemistry and iscurrently working on herPhD thesis at the Departmentof Organic and MedicinalChemistry at the School ofPharmacy in UCM, under thesupervision of Drs Villacampaand Menendez. Her researchtopic deals with the develop-ment of new multicomponent
reactions for the synthesis of pyrroles and their application tothe preparation of bioactive compounds.
Mercedes Villacampa
Mercedes Villacampa wasborn in Madrid. She studiedPharmacy at UCM and thenOptics at the same University.For her PhD thesis, sheworked on the synthesis ofnatural product-based seroto-nin analogues. After posto-doctoral studies withProfessor Nicholas Bodor atthe University of Florida atGainesville, she obtained aposition of Profesor Titularat the Organic and MedicinalChemistry Department atUCM. She has also done post-
doctoral work at the laboratory of Professor Kendall N. Houk atthe University of California at Los Angeles (UCLA). Herresearch interests include computational chemistry and thedevelopment of new synthetic methodologies, including multi-component reactions, for their application to the preparation ofbioactive heterocycles.
4402 | Chem. Soc. Rev., 2010, 39, 4402–4421 This journal is �c The Royal Society of Chemistry 2010
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the frontiers of organic synthesis. While a large part of the
work developed in this field is focused on reactions using
isonitriles as one of the starting materials and leading to
peptide-like structures, recent years have witnessed a steady
growth in the development of MCRs that lead directly
to heterocycles,13–16 the most important single class of
compounds in the development of bioactive substances.
1.2 Importance of pyrrole
Pyrrole is one of the most important simple heterocycles,
which is found in a broad range of natural products and drug
molecules, and is also of growing relevance in materials
science. It was first isolated in 1857 from the products of bone
pyrolysis, and identified as biologically relevant when it was
recognized as a structural fragment of heme and chlorophyll.
The current importance of pyrrole can be summarized in the
points that are detailed below.
(a) The pyrrole nucleus is widespread in nature, and, as
previously mentioned, is the key structural fragment of heme
and chlorophyll, two pigments essential for life. Some
representative examples of pyrrole-containing secondary
metabolites are summarized in Fig. 1. They include some
antibacterial 3-halopyrroles such as pentabromopseudodiline
and pioluteorine, both isolated from bacterial sources. Pyrrole
moieties are particularly prominent in marine natural
products, including dimeric structures such as nakamuric
acid17 and the axially chiral marinopyrroles, which showed
good activity against metacillin-resistant Staphylococcus
aureus strains.18 We will finally mention the storniamide
family, isolated from a variety of marine organisms (mollusks,
ascidians, sponges) and containing 3,4-diarylpyrrole frag-
ments. A number of O-methylated analogues of storniamide
A have shown potent activity as inhibitors of the multidrug
resistance (MDR) phenomenon,19 which can be considered as
the main obstacle to successful anticancer chemotherapy. For
this reason, there is much current interest in the development
of new MDR modulators.20–22
(b) One interesting property of natural and unnatural
products containing polypyrrole structural fragments is that
they are often involved in coordination and molecular recog-
nition phenomena. Besides the classical example of the tetra-
pyrrole nucleus of the porphyrins and hemoglobin, we will
also mention the case of the bacterial red pigment prodigiosin,
synthesized by bacteria belonging to the Serratia genus, and
which has antibiotic properties.23 This compound has been
shown to behave as a transporter of chloride anions and
protons across phospholipid membranes thanks to the asso-
ciation of its protonated form with chloride anion, leading to a
lipophilic species (Scheme 1).24 The torsional flexibility asso-
ciated with polypyrrole systems linked by peptide bonds is also
key to molecular recognition phenomena involved in the
interaction with DNA of the prototype minor groove natural
binders netropsin and distamycin and related drugs.25
(c) Besides the above mentioned natural products, pyrrole
substructures are present in a large number of bioactive
compounds including HIV fusion inhibitors26 and antituber-
cular compounds,27,28 among many others. As examples of
pyrrole derived drugs, we will mention the non-steroidal
antiinflamatory compound tolmetin, the anticancer drug
candidate tallimustine (related to the previously mentioned
natural product distamycin) and the cholesterol-lowering agent
atorvastatin, one of the top-selling drugs worldwide (Fig. 2).
Fig. 1 Some pyrrole-containing bioactive natural products.
J. Carlos Menendez
Jose Carlos Menendez wasborn in Madrid and obtaineddegrees in Pharmacy andChemistry, followed by aPhD in Pharmacy fromUCM. After a postdoctoralstay at the group of ProfessorSteven Ley at ImperialCollege, he returned as aProfesor Titular to theOrganic and Medicinal Chem-istry Department at UCM,where he has pursued hiscareer ever since. His researchinterests deal mostly withsynthetic work related to the
development of new antitumour drugs and ligands of prionprotein. Other projects pursued in his group place emphasis onthe development of new synthetic methodology, including workon CAN as a catalyst for synthesis and on new domino andmulticomponent reactions for the preparation of biologicallyrelevant compounds.
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(d) Pyrrole derivatives are versatile synthetic intermediates,
and can be transformed into many other heterocyclic systems.
As an example, we will mention the transformation of a type
of fused pyrroles into chiral indolizidines.29
(e) Pyrrole derivatives are particularly important in
materials science (Fig. 3). This is a very extensive field, which
cannot be adequately summarized in the context of this
Introduction. Among the many possible examples, we will
mention the existence of semiconducting materials derived
from hexa(N-pirrolyl)benzene,30 glucose sensors based on
polypyrrole-latex materials31 and polypyrrole materials for
the detection and discrimination of volatile organic
compounds.32 Derivatives of the 4,4-difluoro-4-boradipyrrin
system (BODIPY) have a strong absorption in the UV and
emit very intense fluorescence. These compounds have many
applications as chemosensors, for laser manufacture, image
diagnosis, etc.33
In this context, the present critical review aims to provide an
in-depth account of the use of multicomponent reactions for
the synthesis of pyrroles. While a considerable amount of
review literature on classical pyrrole synthesis exists,34,35 to
our knowledge there are only two articles related to the present
contribution. One of them deals specifically with MCRs
leading to furans and pyrroles that use acetylenes as starting
materials,36 and the other is a 2004 ‘‘Highlight’’ in Angewandte
Chemie, International Edition that essentially summarizes the
content of four papers.37 In the present article we have placed
particular emphasis on discussing the developments of the
subject from 2000 to the end of 2009, although we occasionally
mention earlier work when relevant.
2. Multicomponent pyrrole syntheses based on
condensation reactions of 1,3-dicarbonyl compounds
2.1 The three-component Hantzsch pyrrole synthesis
The Hantzsch pyrrole synthesis, in its traditional form, is based
on the reaction between a b-enaminone and a a-haloketone(Scheme 2).
In spite of its named reaction status, the Hantzsch synthesis
has received little attention in the literature. Thus, a study by
Roomi and MacDonald published in 197038 concluded that
only nine pyrrole derivatives had been prepared by this
method in the 80 years elapsed since the initial Hantzsch
publication. While the original Hantzsch method was
restricted to the use of ethyl b-aminocrotonate, Roomi and
MacDonald extended its scope to include R2 substituents
Scheme 1 Transport of HCl across cell membranes by the
polypyrrole pigment prodigiosin.
Fig. 2 Some drugs containing pyrrole substructures.
Fig. 3 Some pyrrole-containing compounds relevant in materials
science.
Scheme 2 The Hantzsch pyrrole synthesis in its original, two-component
form.
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other than methyl and also the case of R5 = H. The yields for
these reactions were normally below 50%, and this problem
has also been found by more recent authors using the
Hantzsch pyrrole synthesis.39,40 In any case, neither the
original Hantzsch nor the Roomi and MacDonald conditions
can be considered multicomponent, and only a few true
three-component related pyrrole syntheses have been
described, restricted to the case R5 = H and using either
a-chloroaldehydes41 or ethyl 1,2-dibromoacetate42 to generate
the b-enaminone in situ.
In 1998, Jung and coworkers described a thee-component
Hantzsch pyrrole synthesis on an acetoacetylated Rink resin as
a solid support. The reaction between this material and
primary amines presumably afforded the corresponding
b-enaminones, which were then treated with a-halocarbonylcompounds, followed by hydrolytic liberation of the reaction
products from the solid support (Scheme 3). This protocol
afforded pyrroles with excellent purities, but unfortunately the
authors did not describe the yields obtained.43
Another modification of the Hantzsch synthesis is based on
the use of b-cyclodextrin as a supramolecular catalyst. This
method lacked generality, as it was restricted to the reaction
between phenacyl bromide, acetylacetone and ammonium
acetate or a variety of amines, most of which were aromatic
and a few were benzylic. When these starting materials and
b-cyclodextrin were heated in water at 60–70 1C, the corres-
ponding 1,5-diarylpyrroles were obtained in good to excellent
yields (Scheme 4).44 This transformation is unusual in that
arylamines are not normally good Hantzsch substrates,
but it may follow a mechanism different from the usual one
(see below).
Experimentally, the reaction involved generating the supra-
molecular inclusion complex between b-cyclodextrin and
phenacyl bromide in water at 50 1C, followed by addition of
the other reagents and stirring at 60–70 1C. Therefore, the role
of cyclodextrin was assumed to be the activation of phenacyl
bromide through hydrogen bonding interactions of its
bromine atom with hydroxy substituents in the cyclodextrin
rim, as shown in Fig. 4, and hence the reaction does not follow
the usual Hantzsch mechanism, in which a b-enaminone is first
formed by reaction of the b-dicarbonyl and amine compo-
nents. A control experiment showed no reaction in the absence
of b-cyclodextrin, both in water and in polyethyleneglycol
(PEG-400), although pyrroles were obtained in low yields
when bases were added to the PEG-400 reaction media.
2.2 Pyrrole syntheses combining enamine formation and aldol
reactions
The coupling of the aldol addition of a b-enaminone with a
cyclocondensation step may also be used as the basis for a
pyrrole multicomponent synthesis. As shown in Scheme 5, the
simplest example of this strategy consists of the three-
component reaction among b-dicarbonyl compounds, aryl-
glyoxals and ammonium acetate in water, which affords
4-hydroxy-5-arylpyrroles in variable yields.45 In most cases,
b-ketoesters were employed as the dicarbonyl component,
although a few examples used b-diketones. However, the
reaction failed for the case of compounds containing phenyl-
ketone structural fragments.
The mechanism suggested by the authors is summarized in
Scheme 6, and involves an initial aldol addition to give a
1,4-dicarbonyl intermediate 1, followed by a Paal–Knorr-type
cyclization and double dehydration. The fact that the final
pyrroles precipitate from the aqueous reaction medium
probably helps to direct other possible equilibria towards the
desired products.
A related protocol, using a low-valent titanium derivative as
catalyst, was developed more or less simultaneously and found
to be complementary to the previous one in that it works best
for diaryl-1,3-diketones. In this method, dibenzoylmethane
derivatives, aldehydes and amines (mostly aromatic, in both
Scheme 3 Hantzsch pyrrole synthesis on solid support.
Scheme 4 Hantzsch-type pyrrole synthesis catalyzed by b-cyclodextrin.
Fig. 4 Proposed activation of phenacyl bromide by b-cyclodextrin in
the Hantzsch pyrrole synthesis.
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cases) were mixed in the presence of titanium tetrachloride and
samarium powder in THF to give 1,2,3,5-tetrasubstituted
pyrroles (Scheme 7). The use of non-symmetric dicarbonyl
starting materials led to the isolation of mixtures of regio-
isomers in variable ratios.46
2.3 Pyrrole syntheses combining enamine formation and
Michael additions
A solvent- and catalyst-free synthesis of pentasubstituted,
functionalized pyrrole systems has been developed recently,
based on the three-component reaction between primary
amines, alkyl acetoacetates and fumaryl chloride. The pyrrole
derivatives thus obtained contain a 5-chloro substituent,
together with carboxylic ester and carboxymethyl functional
groups (Scheme 8).47
The proposed mechanism is initiated by the formation of
b-enaminone 2, followed by its Michael addition onto a
molecule of fumaryl chloride to afford 3. The intramolecular
attack of the enamine nitrogen onto the acyl chloride function
leading to the generation of the five-membered ring did not
follow the expected pathway with elimination of HCl, but
instead involved the loss of a molecule of water with retention
of the chlorine substituent (Scheme 9).
A double enaminone formation-Michael addition sequence
can be used as the basis for a 3,30-bipyrrole synthesis. Thus,
the reaction between b-ketoesters or symmetrical b-diketones,diaroylacetylenes and ammonium acetate in the presence of
indium trichloride afforded compounds 4, which turned out to
exhibit axial chirality (Scheme 10).48
The mechanism proposed for this transformation starts with
coordination of the indium catalyst to one of the ketone
carbonyls, followed by the Michael addition of the enol
tautomer of the dicarbonyl compound onto the conjugated
triple bond of the acetylene substrate to give intermediate 5.
This is then tautomerized into compound 6, which contains
a 1,4-dicarbonyl fragment and gives pyrrole 7 through a
Paal–Knorr condensation. An example of a compound 7 could
be isolated by stopping the reaction before completion, and
this observation was considered as a proof in favour of the
proposed mechanism. A subsequent second Michael addition
onto the a,b-unsaturated imine fragment of 7 gives 8, again
a 1,4-dicarbonyl compound, and this is followed by a
second Paal–Knorr reaction to give the observed products 4
(Scheme 11).
Scheme 5 Three-component pyrrole synthesis from b-dicarbonylcompounds, arylglyoxals and ammonium acetate.
Scheme 6 Mechanism proposed for the transformation in Scheme 5.
Scheme 7 Low valent titanium-catalyzed pyrrole synthesis from
diaryl 1,3-diketones, amines and aldehydes.
Scheme 8 Three-component pyrrole synthesis from b-ketoesters,amines and fumaryl chloride.
Scheme 9 Mechanism proposed for the transformation in Scheme 8.
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2.4 Pyrrole syntheses combining Michael and aldol reactions
A three-component reaction starting from b-ketoesters or
symmetrical b-diketones, 2-hexenal and sodium nitrite
provides access to 1-hydroxypyrrole derivatives. In contrast
to other reactions mentioned in this section, in this case the
carbonyl function remaining from the b-dicarbonyl startingmaterial is at the C-2 position of the final product rather than
at C-3 (Scheme 12).49
Regarding the mechanism of this transformation, the
authors propose that it starts with the nitrosation of the
b-dicarbonyl substrate to give the corresponding oxime 9,
whose nitrogen atom then adds to the a,b-unsaturated alde-
hyde in a conjugate fashion. The complete chemoselectivity of
this Michael addition in favour of the oxime nitrogen was
explained by the stabilization of the hydroxy group by
intramolecular hydrogen bonding with the adjacent carbonyl,
which would prevent its participation in a similar Michael
addition. The five-membered ring would then be generated by
an intramolecular aldol condensation, followed by aromatization
through a 1,7-hydrogen shift (Scheme 13).50
2.5 Pyrrole syntheses combining nucleophilic substitution,
enamine formation and 5-exo-dig cycloisomerization reactions
A one-pot, three-component reaction between primary
amines, b-ketoesters or b-diketones and propargyl alcohols
provided an efficient entry into pyrroles, as shown by Gimeno
and coworkers. This transformation was carried out in sealed
vessels using tetrahydrofuran containing trifluoroacetic
acid as the reaction medium and in the presence of the
[Ru(Z3-2-C3H4Me)(CO)(dppf)][SbF5] system, where dppf is
1,10-bis(diphenylphosphanyl)ferrocene, and afforded fully
substituted derivatives of the pyrrole system in good to
excellent yields (Scheme 14).51 This reaction is related to, but
much more general than, a previously published platinum-
catalyzed pyrrole synthesis based on a three-component
reaction between anilines, ketones and propargyl alcohols.52
Mechanistically, this transformation was explained by two
competitive pathways. In the first one, an acid-promoted propar-
gylation of the b-dicarbonyl substrate affords a g-ketoalkyne 10,which could be isolated in a separate experiment.
Intermediate 10 then reacts with the primary amine to give
the propargylated b-enaminone 11, which undergoes a final
Ru-catalyzed 5-exo-dig annulation leading to the observed
pyrrole final products. Alternatively, intermediate 11 can be
reached by propargylation of b-enaminone 12, arising from
the reaction between the starting b-dicarbonyl and primary
amine components and which was detected by GC-MS experi-
ments. These proposals are summarized in Scheme 15.
Scheme 10 Multicomponent synthesis of 3,30-bipyrroles.
Scheme 11 Mechanism proposed for the 3,30-bipyrrole synthesis.
Scheme 12 Three-component synthesis of pyrroles from b-dicarbonylcompounds, amines and a,b-unsaturated aldehydes.
Scheme 13 Mechanistic proposal for the reaction in Scheme 12.
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Subsequent work by a different group proved that the
synthesis of pyrroles from primary amines, b-dicarbonylcompounds and propargyl alcohols can also be carried out
under experimentally simpler conditions in the presence of
indium trichloride, using toluene as solvent.53
3. Multicomponent synthesis of pyrroles using
isonitriles as starting materials
A four-component reaction between acetylenedicarboxylates,
succinimide or maleimide and two molecules of an isonitrile in
refluxing dichloromethane was found to afford pyrroles in
good to excellent yields, albeit in rather long reaction times
(Scheme 16).54 The mechanism proposed for this transforma-
tion is summarized in pathway b of Scheme 17 and assumes an
initial addition of the isonitrile to the electron-defficient alkyne
to give species 13. Reaction of the latter with a second
molecule of isonitrile affords bis-ketenimine 14, as previously
reported.55 Its reaction with the imide component followed by
cyclization explains the isolation of the observed pyrroles. The
use of sterically hindered isonitriles (e.g. tert-butyl isonitrile)
prevented the generation of 14, probably because of steric
hindrance. In this case, intermediate 13 deprotonates the imide
to give intermediate 15, and this is followed by a Michael
addition that leads to the observed products (compounds 16),
as shown in Scheme 17, pathway a.
The four-component reaction between alkynes, amines and
isonitriles catalyzed by a variety of titanium catalysts affords
4-amino-1-azadienes derived from a formal iminoamination
reaction.56 Replacing these catalysts by the pseudotetrahedral
Ti(NMe2)2(IndMe2)2 species, generated from 2,3-dimethylin-
dole and Ti(NMe2)4, induced the incorporation of a second
molecule of isonitrile, leading to the isolation of pyrrole
products (Scheme 18). This reaction works well only with
anilines not bearing an ortho substituent and tert-butyl
isonitrile.57 Other substrates lead preferentially to acyclic
products derived from the previously mentioned three-
component process. Internal alkynes require higher reaction
Scheme 14 Ruthenium-catalyzed, three-component synthesis of
pyrroles from primary amines, b-dicarbonyl compounds and
propargyl alcohols.
Scheme 15 Mechanistic rationale for the synthesis of pyrroles from
primary amines, b-dicarbonyl compounds and propargyl alcohols.
Scheme 16 Four-component pyrrole synthesis from acetylene-
dicarboxylates, five-membered cyclic imides and isonitriles.
Scheme 17 Mechanistic proposal to explain the isolation of pyrroles
from acetylenedicarboxylates, five-membered cyclic imides and
isonitriles.
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temperatures or/and longer reaction times than their terminal
counterparts.
The mechanism proposed by the authors to explain the
isolation of pyrroles involves the initial generation of a
titanium imido intermediate 17, which then undergoes a
[2+2] cycloaddition onto the starting alkyne to afford an
azatitanacyclobutene 18. Incorporation of the first molecule
of isonitrile furnishes a five-membered metallacycle 19, which
reacts with a further molecule of isonitrile, leading to a
six-membered titanacycle 20. Protolytic cleavage of this inter-
mediate by a new molecule of the amine closes the catalytic
cycle and releases intermediate 21, which affords the final
products by 5-exo-trig intramolecular nucleophilic attack
followed by tautomerism (Scheme 19).
A very efficient route to trisubstituted pyrroles bearing an
unusual 4-nitro functionality has been developed by the Ley
group, which is based on a three-component reaction between
nitrostyrenes, toluenesulfonylmethyl isocyanide (TosMIC)
and ethyl chloroformate under strongly basic conditions
achieved by the addition of BuLi.58 The concentration of the
reaction medium was found to play a significant role in the
outcome of the reaction, with high concentrations leading to
better yields. Purification of the final products also proved
challenging, as conventional workup often provided low yields
(method A in Scheme 20). The optimal procedure, which led to
much improved results, turned out to be one based on the use
of a polymer-assisted catch-and-release protocol for workup
and purification by addition of a basic polystyrene resin
(method B).59,60 These observations are summarized in
Scheme 20.
The mechanism for this pyrrole synthesis was proposed to
be initiated by the generation of intermediate 22 from
base-promoted condensation between TosMIC and ethyl
chloroformate followed by deprotonation to give anion 22.
Addition of 22 to the starting nitrostyrene affords 23, which
yields the observed major product by 5-endo-trig cyclization
onto the isonitrile group, followed by a 1,2-hydrogen shift and
a final elimination with loss of the tosyl group and tauto-
merism (pathway a in Scheme 21). In some cases, the reaction
led to minor amounts of pyrroles 25, whose formation was
explained by an intramolecular attack of the nitroalkane anion
onto the ester group, leading to its rearrangement and
affording intermediate 26, which then evolves to 25 by the
usual route (pathway b). Neither the sequence following
cyclization in pathway a nor the one following ester transfer
in pathway b seem to be reversible. The mechanism proposed
for the isolation of 25 was confirmed by independent prepara-
tion of alkene 27, which afforded 25 in excellent yield upon
treatment with TosMIC in the presence of BuLi (reaction c).
4. Multicomponent synthesis of pyrroles using
nitroalkanes and nitroalkenes as starting materials
The Ranu group developed a four-component coupling of
aldehydes, amines and nitroalkanes in the presence of a
catalytic amount of samarium trichloride at 60 1C, which
afforded tetrasubstituted pyrroles in poor to moderate yields
(Scheme 22).61 The scope of this reaction did not include the
use of ketones as starting materials.
Scheme 18 Titanium-catalyzed four-component synthesis of 4,5-
diaminopyrroles.
Scheme 19 Mechanism proposed for the Ti-catalyzed four-
component synthesis of pyrroles from amines, alkynes and isonitriles
(two molecules).
Scheme 20 Three-component synthesis of 4-nitropyrroles from
nitrostyrenes, TosMIC and ethyl chloroformate.
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As shown in Scheme 23, the mechanism proposed for this
transformation involves the initial formation of the imine 28
from the starting amine and one molecule of aldehyde. A
samarium-catalyzed aldol-type self-condensation of 28 affords
the a,b-unsaturated imine 29, which is attacked by the
nitroalkane in a conjugate fashion to yield intermediate 30.
An intramolecular proton transfer followed by a 5-exo-dig
cyclization affords a new intermediate 31, which then evolves
to the final aromatic pyrrole following loss of water and HNO.
The sequence of reactions starting from the a,b-unsaturatedimine 29 is not catalyzed by the samarium species, as proved
by an independent experiment that showed that the
uncatalyzed reaction of 29 and nitroalkanes led to pyrroles
in yields similar to those of the corresponding samarium-
catalyzed experiment.
As shown in Scheme 24, the same group subsequently
noticed that a related three-component reaction between
amines, a,b-unsaturated aldehydes or ketones and nitro-
alkanes did not require any catalyst, presumably owing to
the enhanced stability of the initial imine due to its
conjugation. The use of unsaturated ketones allowed access
to compounds bearing a substituent at C-2 and hence
to pentasubstituted pyrroles.61 Subsequent work, again by
the Ranu group, proved that this transformation could be
performed in the solid state by supporting the reactants
on silica gel. This transformation was accelerated by
microwave irradiation, which also afforded greatly improved
yields (Scheme 25).62,63 The same reaction was also sub-
sequently studied in ethanol solution under the influence
of ultrasound irradiation, which allowed to bring the
reaction to completion in reaction times ranging from 20 to
60 min.64
The first mention of the synthesis of pyrroles through a
three-component reaction between an amine, a ketone and a
nitroalkene can be found in a 1981 paper by Meyer,65
although only two low-yielding examples were described
(Scheme 26). Ranu and coworkers showed subsequently that
this method for pyrrole synthesis was much improved in terms
of yield when the reaction was irradiated with microwaves in
the solid state, with all substrates adsorbed onto alumina63 or
in molten tetrabutylammonium bromide as an ionic liquid.66
In both cases, the reaction was restricted to the synthesis of
2-unsubstituted pyrroles since open-chain ketones did not give
the reaction (Scheme 27). However, conditions involving
heating in molten tetrabutylammonium bromide gave good
results with cyclic ketones as substrates, furnishing tetra-
hydroindoles as products.
Scheme 21 Mechanism proposed for the three-component synthesis
of 4-nitropyrroles.
Scheme 22 Synthesis of pyrroles from amines, aldehydes and
nitroalkanes.
Scheme 23 Mechanism proposed for the four-component reaction
between amines, aldehydes (2 molecules) and nitroalkanes.
Scheme 24 Three-component reaction between amines, a,b-unsaturatedaldehydes or ketones and nitroalkanes.
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A similar transformation could also be achieved through a
sequential procedure using as starting materials amines,
nitroalkenes and diketene, a well-known acetoacetylating
reagent that presumably generates a b-ketoamide by reaction
with one molecule of the starting amine. Therefore, the final
pyrrole contains a 3-carboxamide substituent (Scheme 28).67
A single example of a three-component pyrrole synthesis
from a primary amine and two molecules of a nitroalkene in
the presence of samarium triisopropoxide has been described
(Scheme 29). This reaction was developed as a three-
component variant of a previously known synthesis of
pyrroles from imines and nitroalkenes.68 The mechanism
proposed to explain this transformation starts with the
formation of imine 32 from the amine and a molecule of
nitroalkene, with nitromethane acting as a leaving group.
Samarium triisopropoxide, which in this case behaves as a
base, activates this imine to form the enamine complex 33. The
reaction of 33 with a second molecule of the nitroalkene gives
adduct 34, which cyclizes to a pyrroline derivative that evolves
to the final product and a new samarium species that evolves
by loss of water and HNO, with concomitant activation of a
new molecule of imine 32 that thus becomes 33 and is able to
enter the catalytic cycle (Scheme 30).
5. Multicomponent pyrrole syntheses based
on the generation and subsequent reactions
of 1,4-dicarbonyl compounds
The transformations described in this section can be
considered as variations of the classical Paal–Knorr pyrrole
synthesis where the 1,4-dicarbonyl compound is generated
in situ. Unavoidably, there is some overlap with previous
sections and for instance the reactions summarized in
Schemes 5, 6, 10 and 11, which also involve 1,4-dicarbonyl
intermediates, might also have been included here.
5.1 Pyrrole synthesis through a four-component process based
on a Sonogashira/isomerization/Stetter/Paal–Knorr domino
sequence
The Muller group discovered a synthesis of chalcones from
propargyl alcohols and electron-poor bromoarenes through a
Scheme 26 Three-component reaction between amines, ketones and
nitrostyrenes.
Scheme 27 Three-component reaction between amines, aldehydes
and nitroalkenes.
Scheme 28 Synthesis of pyrrole-3-carboxamides from amines
(two molecules), diketene and nitrostyrenes.
Scheme 29 Synthesis of a pyrrole from butylamine and two
molecules of 1-nitropentene.
Scheme 30 Mechanism proposed for the samarium-catalyzed synthesis
of pyrroles from butylamine and two molecules of 1-nitropentene.
Scheme 25 Microwave-accelerated three-component reaction between
amines, a,b-unsaturated carbonyl compounds and nitroalkanes.
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Sonogashira cross-coupling/base-promoted isomerization
sequence, which was considered to have some advantages over
the traditional aldol-based protocols.69 On this basis, they
subsequently developed a sophisticated one-pot method for
pyrrole synthesis involving a sequential procedure that starts
by generation of a chalcone using the above mentioned
Sonogashira/isomerization, followed by the in situ preparation
of a 1,4-dicarbonyl compound via the Stetter reaction and a
final Paal–Knorr pyrrole synthesis (Scheme 31).70 The pyrrole
derivatives thus obtained, which show aryl substituents on at
least two positions, exhibited a strong blue fluorescence.71
The mechanistic course of this reaction sequence is shown in
Scheme 32, and starts with the Sonogashira coupling of the
propargyl alcohol and the aryl bromide, which requires that
the latter bears a sufficiently electron-withdrawing substituent
and results in the formation of 35. Deprotonation of the
propargyl C–H bond by triethylamine yields a resonance-
stabilized propargyl-allenyl anion that is protonated to give
hydroxyallene 36, which then tautomerizes to chalcone 37.
This compound enters the catalytic cycle of a Stetter reaction.
Thus, the thiazolium catalyst is deprotonated by triethylamine
to the C-nucleophilic dipolar species 38, which can also be
viewed as a N-heterocyclic carbene and traps the aldehyde
component to furnish 39 after a hydrogen-shift step. This
intermediate, whose polarity is inverted with regard to that of
the aldehyde, reacts with 37 leading to intermediate 40 and
then to 1,4-diketone 41, which finally yields the observed
pyrrole products by reaction with the amine component
through the classical Paal–Knorr mechanism.
A closely related reaction that allows the preparation of
highly complex phenyl- and heterocycle-substituted pyrroles
was developed by the group of Jing, following the same
strategy but starting from pre-synthesized a,b-unsaturatedketones and using DBU as base. Thiazolium-catalyzed Stetter
reaction of the latter with aldehydes generates 1,4-diketone
intermediates, and the sequential addition of primary amines
leads to the desired pyrrole products (Scheme 33).72
5.2 Three-component pyrrole synthesis based on a
sila-Stetter/Paal–Knorr sequence
Another variant of the previous sequence, reported by the
Scheidt group, is based on the combination of sila-Stetter and
Paal–Knorr reactions.73,74 In this case, the starting materials
employed were chalcones and acylsilanes instead of aldehydes,
and the first reaction requires the addition of isopropyl
alcohol. Also, this process differs from the previous
one in the addition of p-toluensulfonic acid and 4 A molecular
sieves in order to facilitate the Paal–Knorr reaction
(Scheme 34).
Scheme 31 Four-component pyrrole synthesis based on a
Sonogashira/isomerization/Stetter/Paal–Knorr domino sequence.
Scheme 32 Mechanism for the Sonogashira/isomerization/Stetter/
Paal–Knorr sequence.
Scheme 33 Synthesis of pyrroles based on a Stetter/Paal–Knorr
sequence.
Scheme 34 Synthesis of pyrroles based on a sila-Stetter/Paal–Knorr
sequence.
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The mechanism proposed for the sila-Stetter reaction is
depicted in Scheme 35, and involves the addition of the
acylsilane to the nucleophile 42, generated by deprotonation
of the thiazole catalyst. Intermediate 43 thus obtained under-
goes a 1,2-silyl group shift from carbon to oxygen, known as a
Brook rearrangement leading to 44, which is desilylated by the
alcohol additive to yield 45. From that point, the reaction
follows the usual Stetter mechanism and affords 1,4-diketone
46, the direct precursor to the pyrrole final products.
Intermediate 44, obtained independently, was shown to afford
1,4-dicarbonyl compounds upon reaction with a chalcone,
which can be considered as proof for the proposed mechanism.
6. Pyrrole syntheses based on 1,3-dipolar
cycloadditions
1,3-Dipolar cycloadditions are one of the most useful
approaches to five-membered heterocycles. One of the most
versatile substrates employed as masked 1,3-dipoles are
1,3-oxazolium-5-oxides, commonly known as Munchnones,
which contain a mesoionic ring that can react with a wide
variety of double and triple-bond dipolarophiles.75 For this
reason, we will organize this section according to their use.
6.1 Methods based on the use of Munchnones and their
analogues as 1,3-dipoles
Arndtsen and Dhawan reported a pyrrole synthesis based on
the preparation of Munchnones in one step by a palladium-
catalyzed coupling between imines, acid chlorides and carbon
monoxide, and then the corresponding pyrroles by the
addition of alkynes (Scheme 36).76,77 The mechanism
proposed to explain this reaction starts with the generation
of the N-acyliminium salt 47, and continues with its oxidative
addition to Pd(0) to give 48. In the next step, coordination of
CO generates the palladium complex 49 followed by migratory
carbon monoxide insertion leading to 50. Next, the base
promotes elimination of chloride as a salt to give ketene 51
that is in equilibrium with Munchnone 52. Finally, the
1,3-dipolar cycloaddition between this Munchnone and the
starting alkyne takes place, to form a cycloadduct 53 that
releases a molecule of CO2 and leads to the desired pyrrole.
After a study of ligand (L) influence, the authors observed that
the more favorable scenario involves a donor ligand, the best
one being P(o-tolyl)3 due to its high reactivity during catalyst
generation and its capability of promoting the catalytic cycle
in the presence of alkynes (Scheme 37).
Similarly, Merlic and coworkers developed an entry to
Munchnones via an acylamino chromium carbene
complex followed by a 1,3-dipolar cycloaddition with
acetylenedicarboxylates that yields pyrroles. Although this
was not the procedure normally employed, this reaction could
be carried out as a one-pot, three-component procedure
Scheme 35 Mechanistic proposal for the sila-Stetter/Paal–Knorr
sequence.
Scheme 36 Pd-catalyzed synthesis of pyrroles by three-component
coupling of alkynes, imines and acyl chlorides.
Scheme 37 Plausible mechanism for the synthesis of pyrroles from
alkynes, imines and acyl chlorides.
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(Scheme 38).78 Its mechanism (Scheme 39) begins with the
acylation of the starting aminocarbene chromium complex
with benzoyl chloride to give an acylaminocarbene complex
54. Insertion of carbon monoxide can be achieved in a direct,
non-photochemical fashion to give a ketene complex 55. This
step is unusual in that CO insertion in heteroatom-substituted
chromium complexes is generally considered a photochemical
process. The ketene cyclizes to a metal-free Munchnone 56,
that could be isolated if desired, with the demetalation step
being probably facilitated by the presence of CO. The
1,3-dipolar cycloaddition to the alkyne is followed by loss of
a molecule of carbon dioxide, yielding the final pyrrole.
More recently, the Arndtsen group developed a 1,3-dipolar
cycloaddition where the carbonyl group of the Munchnone
was replaced with a PPh3 unit.79 This phosphorus-based
1,3-dipolar substrate can be generated by the one-pot reaction
of phosphines, imines and acid chlorides and undergoes a
cycloaddition leading to pyrroles in a similar fashion to classic
1,3-dipoles (Scheme 40). The first reaction of the mechanism
proposed for this transformation consists of the reaction
between the starting imine and acyl chloride to give
acyliminium species 57, which is then attacked by the
phosphine and leads to the phosphonium salt 58. Deprotona-
tion of 58 generates the phosphorous ylide 59 and then the
1,3-dipole 60. After formation of cycloadduct 61, the release of
a phosphine oxide in the last step leads to the final product.
The participation of 60 in the 1,3-dipolar cycloaddition was
found to be possible only when using electron-poor phosphites
or phosphonites in order to allow chelation of the amide
oxygen with the relatively electron-rich phosphorus center.
PhP(catechyl) was found to give both steps in good yields due
to its suitable balance between a nucleophilicity sufficient for
the reaction with the acyl iminium salt and an acceptable
chelation ability of the amide oxygen to form a five-membered
ring (Scheme 41).
Another analogue of Munchnone was developed by using a
molecule of isocyanide instead of a molecule of carbon
monoxide or a phosphine group.80 The dipolar cycloaddition
of these intermediates onto electron-defficient alkynes
provides pyrrole derivatives under mild conditions, and this
process was compatible with a diverse range of imine and acid
chloride substrates. It was found that the yields improved
when the addition of the isocyanide, and then the base, was
carried out sequentially (Scheme 42). In these reactions, the
in situ generated N-acyliminium salt is attacked by isocyanide
to give 62, which then cyclizes to 63. Subsequent addition of
base leads to the amino analogue of Munchnone 64, which
undergoes a 1,3-dipolar cycloaddition with the alkyne to form
the corresponding cycloadduct, followed by elimination of a
molecule of isocyanate to give the desired pyrrole (Scheme 43).
6.2 Methods using 1,3-dipoles different from Munchnones
A multicomponent process that combines imines with
dibromodifluoromethane and alkynes leads to 2-fluoropyrrole
derivatives (Scheme 44).81 The 1,3-dipole involved in the
cycloaddtion is a difluorocarbene, generated in situ from
dibromodifluoromethane using different protocols. The best
results were obtained with active lead, prepared by reduction
Scheme 38 Three-component pyrrole synthesis from amino chromium
carbene complexes, acyl chlorides and acetylenedicarboxylates.
Scheme 39 Mechanistic explanation of the pyrrole synthesis from
aminocarbene chromium complexes.
Scheme 40 Phosphonite-mediated three-component pyrrole synthesis.
Scheme 41 Wittig-type intermediates in the generation of 1,3-dipoles
for pyrrole synthesis.
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of aqueous lead acetate with sodium borohydride, instead of
the more usual powdered lead or zinc dust. The reaction
conditions are compatible with a variety of functional groups
on the imines, although the structures of the alkyne dipolaro-
philes are restricted to compounds bearing electron-
withdrawing groups. This one-pot synthesis occurs in four
steps. First, difluorocarbene is generated by reduction of
dibromodifluoromethane with active lead in presence of tetra-
butylammonium bromide. Then, the carbene is attacked by
the nitrogen lone pair of the imine to form the intermediate
azomethine ylide 65, which participates in a 1,3-dipolar cyclo-
addition with the activated alkynes to give a 2,2-difluoro-3-
pyrroline. The last step is the dehydrofluorination of the latter
compound to give the desired 2-fluoropyrrole (Scheme 45).
The rhodium-catalyzed multicomponent reaction of aryl
imines, diazoacetonitrile and acetylenedicarboxylates as the
dipolarophile partner provides ready access to 1,2-diarylpyrroles
(Scheme 46).82 The mechanism proposed for this reaction starts
with the combination of the rhodium acetate and diazoaceto-
nitrile, affording the corresponding metallocarbenoid. Addition
of the latter to the starting imine leads to the formation of the
azomethine ylide intermediate 66, although the authors did not
discard an alternative mechanism via an aziridine intermediate.
The 1,3-dipolar cycloaddition of 66 with the activated alkyne
affords a pyrroline adduct that undergoes elimination of
hydrogen cyanide to form the aromatic pyrrole (Scheme 47).
Among the transition metal salts studied, the best results were
provided by rhodium acetate in just 1 mol% catalyst loading.
Another case where the formation of NH-azomethine ylide
as an intermediate is the key step in a pyrrole synthesis
can be found in a sequential multicomponent process that
uses as starting materials an aldehyde derivative, aminoesters
and acetylenic dipolarophiles for the preparation of
3,4,5-trisubstituted pyrrole derivatives (Scheme 48). In many
cases, the use of pyridinium p-toluene sulfonate (PPTS) as an
additive was required for the reaction to achieve completion.83
A plausible mechanism that explains this transformation starts
with the formation of an imine between the heterocyclic
aldehyde and the aminoester. This initial imine undergoes
a 1,2-shift of the acidic hydrogen to produce the
NH-azomethine ylide 67, which is stabilized by intramolecular
hydrogen bonding. The cycloaddition reaction between this
1,3-dipole and the starting alkyne furnishes compound 68 with
complete regioselectivity in favour of the pyrroline derivative
bearing the ester group at the C-3 position. This intermediate
is cleaved under the acidic reaction conditions to give
fragments 69 and 70. The 2H-pyrrole initial products (71)
are transformed into the finally observed 1H-pyrroles by
aromatization through a 1,5-ester rearrangement followed by
tautomerism (Scheme 49).
Scheme 42 Isonitrile-mediated three-component synthesis of pyrroles.
Scheme 43 Mechanism of the pyrrole synthesis based on 1,3-dipolar
cycloadditions of amino analogues of Munchnones.
Scheme 44 Three-component synthesis of 2-fluoropyrroles from
dibromodifluoromethane, imines and alkynes.
Scheme 45 Mechanism of a pyrrole synthesis based on 1,3-dipolar
cycloadditions of fluorinated azomethine ylides.
Scheme 46 Rhodium-catalyzed synthesis of pyrroles from imines,
diazo compounds and activated alkynes.
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A three-component reaction between isonitriles, tosylimines
and acetylenedicarboxylates was found to provide a very
efficient access to 2-aminopyrroles, again having a 1,3-dipolar
cycloaddition reaction of an azomethine ylide as the key step
(Scheme 50).84
7. Miscellanous multicomponent pyrrole syntheses
using alkynes as starting materials
We will describe here some reactions that have in common the
use of alkynes as starting materials and that have not been
covered in previous sections.
7.1 Methods based on nucleophilic additions onto carbonyl and
imino groups
The reaction of alkynes, aldehydes and amines in the presence
of ytterbium triflate afforded 1,3-oxazines 72. The reaction can
be stopped at this stage, and compounds 72 thus isolated were
shown to slowly rearrange to pyrroles. As depicted in
Scheme 51, it was subsequently proved that by carrying out
the whole process under solvent-free conditions in the presence
of triethylamine, with the reagents supported on silica gel and
under microwave irradiation, pyrroles were obtained directly
from the acyclic starting materials.85 Overall, this trans-
formation generates two C–C and two C–N bonds and
comprises up to nine individual reaction steps. The mechanism
proposed to explain it involves two coupled domino processes.
An initial three-component domino reaction between the
aldehyde and two molecules of alkyne affords the enol-
protected propargyl alcohol 73, which then reacts with the
amine to give 1,3-oxazolidine 72. Its skeletal rearrangement
starts by ring opening and isomerization to 74. A hydrogen
shift then takes place to afford an enamine, which then
undergoes the final cyclization. This hydrogen shift was
proved by the fact that the reaction starting from
acetaldehyde-d4 furnished a pyrrole derivative with deuterium
at the methyl position, but not at the ring (Scheme 52).
Scheme 47 Mechanism of the rhodium-catalyzed three-component
pyrrole synthesis.
Scheme 48 Synthesis of pyrroles from a-amino esters, acetylenes and
a quinazoline-derived aldehyde.
Scheme 50 Synthesis of 2-aminopyrroles by three-component
reaction between isonitriles, tosylimines and acetylenedicarboxylates.
Scheme 51 Four-component synthesis of pyrroles from amines,
nitriles (two molecules) and aldehydes.
Scheme 49 Proposed mechanism of the synthesis of pyrroles from
a-amino esters, acetylenes and a quinazoline-derived aldehyde.
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The reaction between an alkynylsilane, an imine and an
aldehyde in the presence of a catalytic amount of a phosphazene
base (tBu-P4) afforded the corresponding pyrrole (Scheme 53).
However, in most cases this reaction was performed in a two-
component fashion, starting from imines and isolated propargyl
silyl ethers.86 The mechanism proposed to explain this trans-
formation involves the initial formation of a propargyl silyl
ether 75, followed by a base-promoted generation of allene
anion 76which then adds to the starting imine. The final pyrrole
product is formed following a 5-endo-trig cyclization and
elimination of a molecule of trimethylsilyl alcohol (Scheme 54).
As shown in Scheme 55, another multicomponent sequence
that leads to pyrrole products involves the reaction between
phenylacetylene, imines derived from ethyl glyoxylate and
dialkylzinc derivatives.87 Mechanistically, this reaction was
proposed to be initiated by the addition of a molecule of the
dialkylzinc reagent to the starting imine to give a N-zinc-a-aminoester intermediate, followed by reaction of a molecule of
the C1-zinc-derivative of the starting terminal alkyne to the
ester group, with elimination of R2ZnOEt, addition of a
second molecule of the same alkynylzinc reagent, cyclization
and a final elimination step (Scheme 56).
7.2 Methods based on nucleophilic additions onto nitrile groups
Coupling of an acetylene, two a-alkoxynitriles and a titanium
reagent generated from titanium tetraisopropoxide and
isopropylmagnesium chloride affords pyrrole-2-carbaldehydes
(Scheme 57). The mechanism involves the titanium-promoted
Scheme 52 Mechanism proposed for the four-component
pyrrole synthesis, involving the generation and rearrangement of a
1,3-oxazolidine intermediate.
Scheme 53 Synthesis of a pyrrole derivative from an alkynylsilane, an
imine and an aldehyde.
Scheme 54 Mechanism of the three-component synthesis of pyrroles
from an alkynylsilane, an imine and an aldehyde.
Scheme 55 Four-component synthesis of pyrroles from a alkyne
(two molecules), an imine and a dialkylzinc derivative.
Scheme 56 Mechanism of the multicomponent synthesis of pyrroles
from alkynes, imines and dialkylzinc compounds.
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initial reaction between the alkyne and the first nitrile,
leading to the formation of an azatitanacyclopentadiene inter-
mediate 77, which can trap in situ another nitrile
molecule to give diazatitana-cycloheptatriene 78, the
precursor to the tetrasubstituted pyrrole final products
(Scheme 58).88
In a related procedure, the zircocene-mediated reaction
between bis(arylalkynyl)silanes and nitriles was found to yield
pyrroles in moderate yields (Scheme 59).89
7.3 Methods based on Michael additions
The reaction between triphenylphosphine, dimethyl
acetylenedicarboxylate and amines was known to lead to
b-aminophosphoranes.90 On this basis, a new synthesis of
N-phenylpyrroles was developed, based on the treatment of
aniline, acetylenedicarboxylates and arylglyoxals in the
presence of triphenylphosphine (Scheme 60).91 A plausible
mechanism for the triphenylphosphine-mediated pyrrole
synthesis starts with an initial Michael addition of the
phosphine onto the conjugated triple bond that affords the
dipolar intermediate 79, which then undergoes a proton
exchange with the amine followed by a second Michael
addition having as nucleophile the anion derived from the
latter to give the b-aminophosphorane 80. A domino
sequence comprising a chemoselective Wittig reaction and a
final cyclocondensation affords the observed pyrrole
product (Scheme 61). A similar transformation starting
from ammonium acetate, dialkyl acetylenedicarboxylates
and 2,3-butanedione afforded N-unsubstituted pyrroles
(Scheme 62).92
Another three-component pyrrole synthesis that includes a
Michael addition onto a dialkyl acetylenedicarboxylate is
summarized in Scheme 63, which uses acyl chlorides and
a-amino acids as the two additional components and was
performed in an aqueous solution containing 1-butyl-3-methyl-
imidazolium hydroxide ([bmim]OH), an ionic liquid.93
Mechanistically, this transformation was assumed to start
by acylation of the amino acid, followed by decarboxylation
to give an anion 81 that adds onto the acetylenic ester. This
leads to another anion 82 that undergoes an intra-
molecular addition onto the amide carbonyl and a final
elimination of a molecule of water to furnish the final product
(Scheme 64).7.4 Methods based on palladium-catalyzed cross-coupling
reactions
The reaction between acyl chlorides, N-Boc protected
propargylamines and sodium iodide in the presence of copper
iodide and a catalytic amount of PdCl2(PPh3)2 afforded
2-substituted N-Boc-4-iodopyrroles through a coupling/
addition/cyclocondensation sequence having the N-acylated
compound 83 as an intermediate. It was subsequently found
that these 4-iodopyrroles, upon addition of a further molecule
of alkyne, underwent an in situ Sonogashira coupling to yield
2-substituted-4-alkynyl-N-Boc pyrroles (Scheme 65).94
In Scheme 66 another example is summarized of a
palladium-catalyzed multicomponent pyrrole synthesis, in
which carbon dioxide was found to promote the intra-
molecular Pd-catalyzed oxidative carbonylation reaction of
2-en-4-ynylamines, providing a new route to pyrrole-2-aceticScheme 57 Ti-promoted three-component pyrrole synthesis from
alkynes and nitriles.
Scheme 58 Mechanism of the three-component pyrrole synthesis via
azatitanacyclopentadiene intermediates.
Scheme 59 Zircocene-mediated pyrrole synthesis from bis-
(arylalkynyl)silanes and nitriles.
Scheme 60 Triphenylphosphine-promoted three-component
synthesis of N-phenylpyrroles from aniline, acetylenedicarboxilates
and arylglyoxals.
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esters.95 This reaction was proposed to take place through the
mechanism summarized in Scheme 67. The alkoxycarbonylation
process involves reduction of PdI2 to Pd(0) and two molecules
of HI. Pd(0) is subsequently back-transformed into the active
species PdI2 by I2 generated from HI and oxygen. The amine
that serves as the substrate for this reaction is sufficiently basic
to trap HI and can therefore inhibit the reoxidation of Pd(0).
While this problem can often be solved by running the reaction
in the presence of a large excess of oxygen, which favours the
oxidation of HI to I2, this approach could not be employed in
the present case owing to the low stability of pyrroles to
oxidation. The authors found that carbon dioxide provided
an efficient method for freeing HI by reversibly binding to the
amino group, generating a carbamate that, after serving its
purpose as a protecting group, underwent decarboxylation
during the final cyclization process.
The use of double oxidative carboxylation reactions allowed
the synthesis of pyrrole-3,4-diacetic ester derivatives. In this
case, the use of CO2 as a temporary protection was not
necessary because the starting material was an amide derived
from dipropargylamine. The initial experiments afforded
compounds 84,96 but it was later found that they could be
isomerized in situ to the corresponding pyrroles by using
dimethylacetamide (DMA) as cosolvent (Scheme 68).97
Conclusions
Pyrrole derivatives have great relevance in many fields of
chemistry, and we hope to have shown that multicomponent
reactions are an excellent, multipurpose approach to their
synthesis. Besides the development of new reactions or
improved conditions for the classical ones, future
Scheme 61 Plausible mechanism for the triphenylphosphine-
promoted synthesis of pyrroles.
Scheme 62 Triphenylphosphine-promoted synthesis ofN-unsubstituted
pyrroles.
Scheme 63 Ionic liquid-promoted synthesis of pyrroles from a-amino
acids, aromatic acyl chlorides and acetylenedicarboxylates.
Scheme 64 Mechanism of the ionic liquid-promoted, three-
component pyrrole synthesis.
Scheme 65 Three-component coupling-addition-cyclocondensation
sequence leading to 4-iodopyrroles and their one-pot sequential
transformation into 4-alkynylpyrroles.
Scheme 66 Synthesis of pyrrole-2-acetic esters based on a
Pd-catalyzed intramolecular oxidative carbonylation reaction.
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developments in this field will probably involve the application
of multicomponent-based strategies to target-oriented
synthesis. We hope that this review will serve to stimulate
research in this fascinating and very useful area of organic
synthesis.
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Scheme 68 Pd-catalyzed double oxidative carbonylation, leading to
pyrrole-3,4-diacetic esters.
Scheme 67 Mechanism of the carbon-dioxide promoted, Pd-catalyzed
synthesis of pyrrole-2-acetic esters.
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