multicomponent reactions for the synthesis of pyrroles · atorvastatin, one of the top-selling...

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

CRITICAL REVIEW www.rsc.org/csr | Chemical Society Reviews

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http://dx.doi.org/10.1039/B917644F

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.

This journal is �c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4402–4421 | 4403

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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.

Notes and references

1 R. V. A. Orru and M. de Greef, Synthesis, 2003, 1471.2 D. Tejedor, D. Gonzalez-Cruz, A. Santos-Exposito, J. J.Marrero-Tellado, P. de Armas and F. Garcıa-Tellado, Chem.–Eur.J., 2005, 11, 3502.

3 A. Domling, Chem. Rev., 2006, 106, 17.4 G. Guillena, D. J. Ramon and M. Yus, Tetrahedron: Asymmetry,2007, 18, 693.

5 B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109, 4439.6 For a monograph on MCRs, see: Multicomponent Reactions,ed. J. Zhu and H. Bienayme, Wiley-VCH, 2005.

7 For a symposium in print on MCRs, see: Tetrahedron Symposia-in-Print, ed. I. Marek, 2005, vol. 67, p. 11299.

8 D. R. Spring, Org. Biomol. Chem., 2003, 1, 3867.9 M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43,46.

10 R. J. Spandl, A. Bender and D. R. Spring, Org. Biomol. Chem.,2008, 6, 1149.

11 L. Weber, Curr. Med. Chem., 2002, 9, 2085.12 C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51.13 J. Sapi and J.-Y. Laronze, Arkivoc, 2004, (vii), 208.14 D. M. D’Souza and T. J. J. Muller, Chem. Soc. Rev., 2007, 36,

1095.15 N. Isambert and R. Lavilla, Chem.–Eur. J., 2008, 14, 8444.16 J. D. Sunderhaus and S. F. Martin, Chem.–Eur. J., 2009, 15, 1300.17 For a summary of the structures of these alkaloids, see:

D. P. O’Malley, K. Li, M. Maue, A. L. Zografos andP. S. Baran, J. Am. Chem. Soc., 2007, 129, 4762.

18 C. C. Hughes, A. Prieto-Davo, P. R. Jensen and W. Fenical, Org.Lett., 2008, 10, 629.

19 D. L. Boger, C. W. Boyce, M. A. Labroli, C. A. Sehon and Q. Jin,J. Am. Chem. Soc., 1999, 121, 54.

20 C. Avendano and J. C. Menendez, Curr. Med. Chem., 2002, 9, 159.21 C. Avendano and J. C. Menendez, Med. Chem. Rev.–Online, 2004,

1, 419.22 T. J. Raub, Mol. Pharmaceutics, 2006, 3, 3.23 N. R. Williamson, H. T. Simonsen, R. A. Ahmed, G. Goldet,

H. Slater, L. Woodley, F. J. Leeper and G. P. Salmond, Mol.Microbiol., 2005, 56, 971.

24 J. L. Seganish and T. J. Davis, Chem. Commun., 2005, 5781.25 C. Avendano and J. C. Menendez, Medicinal Chemistry of

Anticancer Drugs, Elsevier, 2008, ch. 6.26 C. Teixeira, F. Barbault, J. Rebehmed, K. Liu, L. Xie, H. Lu,

S. Jiang, B. Fan and F. Maurel, Bioorg. Med. Chem., 2008, 16,3039.

27 M. Biava, G. C. Porretta, D. Deidda, R. Pompei, A. Tafic andF. Manettic, Bioorg. Med. Chem., 2004, 12, 1453.

28 M. Protopopova, E. Bogatcheva, B. Nikonenko, S. Hundert,L. Einck and C. A. Nacy, Med. Chem., 2007, 3, 301.

29 C. Jiang and A. J. Frontier, Org. Lett., 2007, 9, 4939.30 Lazerges, K. I. Chane-Ching, S. Aeiyach, S. Chelli, B. Peppin-

Donnat, M. Billon, L. Lombard, F. Maurel and M. Jouini, J. SolidState Electrochem., 2009, 13, 231.

31 A. Kros, S. W. F. M. van Hovel, R. J. M. Nolte and N. A. J. M.Sommerdijk, Sens. Actuators, B, 2001, 80, 229.

32 S. Hamilton, M. J. Hepher and J. Sommerville, Sens. Actuators, B,2005, 107, 424.

33 For a review, see: A. Loudet and K. Burgess, Chem. Rev., 2007,107, 4891.

34 P. W. LeQuesne, Y. Dong and T. A. Blythe, in The Alkaloids:Chemical and Biological Perspectives, ed. S. W. Pelletier, PergamonPress, 1999, vol. 13, p. 238.

35 V. F. Ferreira, M. C. B. V. de Souza, A. C. Cunha, L. O. R. Pereiraand M. L. G. Ferreira, Org. Prep. Proced. Int., 2001, 33, 411.

36 G. Balme, D. Bouyssi and N. Monteiro,Heterocycles, 2007, 73, 87.37 G. Balme, Angew. Chem., Int. Ed., 2004, 43, 6238.38 M. W. Roomi and S. F. MacDonald, Can. J. Chem., 1970, 48,

1689.39 V. Kameswaran and B. Jiang, Synthesis, 1997, 530; G. Kaupp,

J. Schemeyers, A. Kuse and A. Atfeh, Angew. Chem., Int. Ed.,1999, 38, 2896.

40 F. Palacios, D. Aparicio, J. M. de los Santos and J. Vicario,Tetrahedron, 2001, 57, 1961.

41 V. S. Matiychuk, R. L. Martyak, N. D. Obushak, Y. V. Ostapiukand N. I. Pidlypnyi, Chem. Heterocycl. Comp., 2004, 40, 2004.

42 R. C. Cambie, S. C. Moratti, P. S. Ruthledge and P. D. Woodgate,Synth. Commun., 1990, 20, 1923.

43 A. W. Trautwein, R. D. Sussmuth and G. Jung, Bioorg. Med.Chem. Lett., 1998, 8, 2381.

44 S. N. Murthy, B. Madhav, A. V. Kumar, K. R. Rao andY. V. D. Nageswar, Helv. Chim. Acta, 2009, 92, 2118.

45 B. Khalili, P. Jajarmi, B. Eftekhari-Sis and M. M Hashemi, J. Org.Chem., 2008, 73, 2090.

46 G. Dou, C. Shi and D. Shi, J. Comb. Chem., 2008, 10, 810.47 A. Alizadeh, M. Babaki and N. Zohreh, Tetrahedron, 2009, 65, 1704.48 S. Dey, C. Pal, D. Nandi, V. S. Giri, M. Zaidlewicz,

M. Krzeminski, L. Smentek, B. A. Hess, J. Gawronski, M. Kwit,N. J. Babu, A. Nangia and P. Jaisankar, Org. Lett., 2008, 10, 1373.

49 B. Tan, Z. Shi, P. J. Chua, Y. Li and G. Zhong, Angew. Chem., Int.Ed., 2009, 48, 758.

50 Our interpretation of the last steps of this mechanism is slightlydifferent from that of the original authors (see the previousreference).

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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51 V. Cadierno, J. Gimeno and N. Nebra, Chem.–Eur. J., 2007, 13,9973.

52 Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. D. Milton,M. Hidai and S. Uemura, Angew. Chem., Int. Ed., 2003, 42, 2681.

53 X.-T. Lui, L. Huang, F.-J. Zheng and Z. P. Zhan, Adv. Synth.Catal., 2008, 350, 2778.

54 A. Shaabani, M. B. Teimouri and S. Arab-Ameri, TetrahedronLett., 2004, 45, 8409.

55 T. Takizawz, N. Obata, Y. Suzuki and T. Yanagida, TetrahedronLett., 1969, 10, 3407; V. Nair, A. U. Vinod, N. Abhilash,R. S. Menon, V. Santhi, R. L. Varma, S. Viji, S. Matthew andR. Srinivas, Tetrahedron, 2003, 59, 10279.

56 C. Cao, Y. Shi and A. L. Odom, J. Am. Chem. Soc., 2003, 125, 2880.57 E. Barnea, S. Majunder, R. J. Staples and A. L. Odom,

Organometallics, 2009, 28, 3876.58 I. R. Baxendale, C. D. Buckle, S. V. Ley and L. Tamborini,

Synthesis, 2009, 1485.59 S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson,

A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott,R. L. Storer and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1,2000, 3815.

60 A. Solinas and M. Taddei, Synthesis, 2007, 2409.61 H. Shiraishi, T. Nishitani, S. Sakaguchi and Y. Ishii, J. Org.

Chem., 1998, 63, 6234.62 B. C. Ranu, A. Hajra and U. Jana, Synlett, 2000, 75.63 B. C. Ranu and A. Hajra, Tetrahedron, 2001, 57, 4767.64 Y.-S. Xiao and Y.-G. Wang, Chin. J. Chem., 2003, 21, 562.65 H. Meyer, Liebigs Ann. Chem., 1981, 1981, 1534.66 B. C. Ranu and S. S. Dey, Tetrahedron Lett., 2003, 44, 2865.67 A. Alizadeh, A. Rezvanian and H. R. Bijanzadeh, Synthesis, 2008,

725.68 H. Shiraishi, T. Nishitani, T. Nishihara, S. Sakaguchi and Y. Ishii,

Tetrahedron, 1999, 55, 13957.69 T. J. J. Muller, M. Ansorge and D. Aktah, Angew. Chem., Int. Ed.,

2000, 39, 1253.70 R. U. Braun, K. Zeitler and T. J. J. Muller, Org. Lett., 2001, 3,

3297.71 R. U. Braun and T. J. J. Muller, Synthesis, 2004, 14, 2391.72 X. Ping, X. Pan, Z. Li, X. Bi, C. Yan and H. Zhu, Synth. Commun.,

2009, 39, 3833.73 A. R. Bharadwaj and K. A. Scheidt, Org. Lett., 2004, 6, 2465.

74 A. E. Mattson, A. R. Bharadwaj, A. M. Zuhl and K. A. Scheidt,J. Org. Chem., 2006, 71, 5715.

75 M. Avalos, R. Babiano, A. Cabanillas, P. Cintas, J. L. Jimenez andJ. C. Palacios, J. Org. Chem., 1996, 61, 7291.

76 R. Dhawan and B. A. Arndtsen, J. Am. Chem. Soc., 2004, 126, 468.77 B. A. Arndtsen, Chem.–Eur. J., 2009, 15, 302.78 C. A. Merlic, A. Baur and C. C. Aldrich, J. Am. Chem. Soc., 2000,

122, 7398.79 D. J. St Cyr and B. A. Arndtsen, J. Am. Chem. Soc., 2007, 129,

12366.80 D. J. St Cyr, N. Martin and B. A. Arndtsen, Org. Lett., 2007, 9,

449.81 M. S. Novikov, A. F. Khlebnikov, E. S. Sidorina and

R. R. Kostikov, J. Chem. Soc., Perkin Trans. 1, 2000, 231.82 C. V. Galliford and K. A. Scheidt, J. Org. Chem., 2007, 72, 1811.83 K. Kawashima, M. Hiromoto, K. Hayashi, A. Kakehi, M. Shiro

and M. Noguchi, Tetrahedron Lett., 2007, 48, 941.84 V. Nair, A. U. Vinod and C. Rajesh, J. Org. Chem., 2001, 66, 4427.85 D. Tejedor, D. Gonzalez-Cruz, F. Garcıa-Tellado, J. J.

Marrero-Tellado and M. Lopez-Rodrıguez, J. Am. Chem. Soc.,2004, 126, 8390.

86 H. Naka, D. Koseki and Y. Kondo, Adv. Synth. Catal., 2008, 350,1901.

87 X. Chen, L. Hou and X. Li, Synlett, 2009, 828.88 D. Suzuki, Y. Nobe, Y. Watai, R. Tanaka, Y. Takayama, F. Sato

and H. Urabe, J. Am. Chem. Soc., 2005, 127, 7474.89 S. Zhang, X. Sun, W.-X. Zhang and Z. Xi, Chem.–Eur. J., 2009,

15, 12608.90 I. Yavari, M. Adib and L. Hojabri, Tetrahedron, 2002, 58, 7213.91 M. Anary-Abbasinejad, K. Charkhati and H. Anakari-Ardakani,

Synlett, 2009, 1115.92 M. Z. Kassaee, H. Masrouri, F. Movahedi and T. Partovi, Helv.

Chim. Acta, 2008, 91, 227.93 I. Yavari and E. Kowsari, Synlett, 2008, 897.94 E. Merkul, C. Boersch, W. Frank and T. J. J. Muller, Org. Lett.,

2009, 11, 2269.95 B. Gabriele, G. Salerno, A. Fazio and F. B. Campana, Chem.

Commun., 2002, 1408.96 G. P. Chuisoli, M. Costa and S. Reverberi, Synthesis, 1989, 262.97 V. Paganuzzi, P. Guatteri, P. Riccardi, T. Sacchelli, J. Barbera,

M. Costa and E. Dalcanale, Eur. J. Org. Chem., 1999, 1527.


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