Multicomponent Reactions for the Synthesis of Pyrroles

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

Multicomponent reactions for the synthesis of pyrroles

Vero´nica Este´vez, Mercedes Villacampa and J. Carlos Mene´ndez*

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 For this reason, the creation of molecular diversity and complexity from simple and readily available substrates is one To set the rest of the article in context, we will make in this of the major current challenges of organic synthesis, and hence section some general remarks about multicomponent reactions the development of processes that allow the creation of several and the importance of pyrrole. bonds in a single operation has become one of its more attractive goals. 1–5 1.1 Multicomponent reactions Multicomponent reactions (MCRs) can be defined as convergent chemical processes where three or more reagents Present-day requirements for new synthetic methods go far are combined in such a way that the final product retains beyond the traditional ones of chemo-, regio- and stereo- significant portions of all starting materials. Therefore, they selectivity, and can be summarized as follows: lead to the connection of three or more starting materials in a 1. Use of simple and readily available starting materials. single synthetic operation with high atom economy and 2. Experimental simplicity. bond-forming efficiency, thereby increasing molecular 3. Possibility of automation. diversity and complexity in a fast and often experimentally 4. Favourable economic factors, including the cost of raw simple fashion.6,7 For this reason, multicomponent reactions materials, human resources and energy. are particularly well suited for diversity-oriented synthesis,8–10 5. Low environmental impact: use of environmentally and the exploratory power arising from their conciseness friendly solvents, atom economy. makes them also very powerful for library synthesis aimed at carrying out structure–activity relationship (SAR) studies of Downloaded by University of Oxford on 26 October 2010 drug-like compounds, which are an essential part of the

Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F Departamento de Quı´mica Orga´nica y Farmace´utica, research performed in pharmaceutical and agrochemical Facultad de Farmacia, Universidad Complutense, 28040 Madrid, 11,12 Spain. E-mail: [email protected]; Fax: +34 91 3941822; companies. For all these reasons, the development of Tel: +34 91 3941840 new multicomponent reactions is rapidly becoming one of

Verońica Este´vez was born Mercedes Villacampa was in Madrid, and studied born in Madrid. She studied Pharmacy at Universidad Pharmacy at UCM and then Complutense, Madrid (UCM). Optics at the same University. She has finished a two-year For her PhD thesis, she postgraduate course in worked on the synthesis of Medicinal Chemistry and is natural product-based seroto- currently working on her nin analogues. After posto- PhD thesis at the Department doctoral studies with of Organic and Medicinal Professor Nicholas Bodor at Chemistry at the School of the University of Florida at Pharmacy in UCM, under the Gainesville, she obtained a supervision of Drs Villacampa position of Profesor Titular and Meneńdez. Her research at the Organic and Medicinal Verońica Este´vez topic deals with the develop- Mercedes Villacampa Chemistry Department at ment of new multicomponent UCM. She has also done post- reactions for the synthesis of pyrroles and their application to doctoral work at the laboratory of Professor Kendall N. Houk at the preparation of bioactive compounds. the University of California at Los Angeles (UCLA). Her research interests include computational chemistry and the development of new synthetic methodologies, including multicomponent reactions, for their application to the preparation of bioactive heterocycles.

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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 18 aureus strains. We will finally mention the storniamide Fig. 1 Some pyrrole-containing bioactive natural products. family, isolated from a variety of marine organisms (mollusks, ascidians, sponges) and containing 3,4-diarylpyrrole fragments. A number of O-methylated analogues of storniamide this reason, there is much current interest in the development Downloaded by University of Oxford on 26 October 2010 A have shown potent activity as inhibitors of the multidrug of new MDR modulators.20–22 Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F resistance (MDR) phenomenon,19 which can be considered as (b) One interesting property of natural and unnatural the main obstacle to successful anticancer chemotherapy. For products containing polypyrrole structural fragments is that they are often involved in coordination and molecular recognition phenomena. Besides the classical example of the tetra- pyrrole nucleus of the porphyrins and hemoglobin, we will Jose´ Carlos Meneńdez was also mention the case of the bacterial red pigment prodigiosin, born in Madrid and obtained synthesized by bacteria belonging to the Serratia genus, and degrees in Pharmacy and which has antibiotic properties.23 This compound has been Chemistry, followed by a shown to behave as a transporter of chloride anions and PhD in Pharmacy from UCM. After a postdoctoral protons across phospholipid membranes thanks to the asso- stay at the group of Professor ciation of its protonated form with chloride anion, leading to a 24 Steven Ley at Imperial lipophilic species (Scheme 1). The torsional flexibility asso- College, he returned as a ciated with polypyrrole systems linked by peptide bonds is also Profesor Titular to the key to molecular recognition phenomena involved in the Organic and Medicinal Chem- interaction with DNA of the prototype minor groove natural istry Department at UCM, binders netropsin and distamycin and related drugs.25 where he has pursued his (c) Besides the above mentioned natural products, pyrrole career ever since. His research substructures are present in a large number of bioactive interests deal mostly with 26 J. Carlos Meneńdez compounds including HIV fusion inhibitors and antituber- synthetic work related to the cular compounds,27,28 among many others. As examples of development of new antitumour drugs and ligands of prion protein. Other projects pursued in his group place emphasis on pyrrole derived drugs, we will mention the non-steroidal the development of new synthetic methodology, including work antiinflamatory compound tolmetin, the anticancer drug on CAN as a catalyst for synthesis and on new domino and candidate tallimustine (related to the previously mentioned multicomponent reactions for the preparation of biologically natural product distamycin) and the cholesterol-lowering agent relevant compounds. atorvastatin, one of the top-selling drugs worldwide (Fig. 2).

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Fig. 3 Some pyrrole-containing compounds relevant in materials science.

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 Scheme 1 Transport of HCl across cell membranes by the system (BODIPY) have a strong absorption in the UV and polypyrrole pigment prodigiosin. 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 Downloaded by University of Oxford on 26 October 2010 mention earlier work when relevant. Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F

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 Fig. 2 Some drugs containing pyrrole substructures. 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 (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 Scheme 2 The Hantzsch pyrrole synthesis in its original, two-component Introduction. Among the many possible examples, we will form.

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Scheme 4 Hantzsch-type pyrrole synthesis catalyzed by b-cyclodextrin.

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 components. 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. Scheme 3 Hantzsch pyrrole synthesis on solid support.

2.2 Pyrrole syntheses combining enamine formation and aldol 5 other than methyl and also the case of R = H. The yields for reactions these reactions were normally below 50%, and this problem has also been found by more recent authors using the The coupling of the aldol addition of a b-enaminone with a Hantzsch pyrrole synthesis.39,40 In any case, neither the cyclocondensation step may also be used as the basis for a original Hantzsch nor the Roomi and MacDonald conditions pyrrole multicomponent synthesis. As shown in Scheme 5, the can be considered multicomponent, and only a few true simplest example of this strategy consists of the three- three-component related pyrrole syntheses have been component reaction among b-dicarbonyl compounds, aryl- described, restricted to the case R5 = H and using either glyoxals and ammonium acetate in water, which affords 45 a-chloroaldehydes41 or ethyl 1,2-dibromoacetate42 to generate 4-hydroxy-5-arylpyrroles in variable yields. In most cases, the b-enaminone in situ. b-ketoesters were employed as the dicarbonyl component, In 1998, Jung and coworkers described a thee-component although a few examples used b-diketones. However, the Downloaded by University of Oxford on 26 October 2010 Hantzsch pyrrole synthesis on an acetoacetylated Rink resin as reaction failed for the case of compounds containing phenyl- Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F a solid support. The reaction between this material and ketone structural fragments. primary amines presumably afforded the corresponding The mechanism suggested by the authors is summarized in b-enaminones, which were then treated with a-halocarbonyl Scheme 6, and involves an initial aldol addition to give a compounds, followed by hydrolytic liberation of the reaction 1,4-dicarbonyl intermediate 1, followed by a Paal–Knorr-type products from the solid support (Scheme 3). This protocol cyclization and double dehydration. The fact that the final afforded pyrroles with excellent purities, but unfortunately the pyrroles precipitate from the aqueous reaction medium authors did not describe the yields obtained.43 probably helps to direct other possible equilibria towards the Another modification of the Hantzsch synthesis is based on desired products. the use of b-cyclodextrin as a supramolecular catalyst. This A related protocol, using a low-valent titanium derivative as method lacked generality, as it was restricted to the reaction catalyst, was developed more or less simultaneously and found between phenacyl bromide, acetylacetone and ammonium to be complementary to the previous one in that it works best acetate or a variety of amines, most of which were aromatic for diaryl-1,3-diketones. In this method, dibenzoylmethane and a few were benzylic. When these starting materials and derivatives, aldehydes and amines (mostly aromatic, in both b-cyclodextrin were heated in water at 60–70 1C, the corresponding 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 supramolecular 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 Fig. 4 Proposed activation of phenacyl bromide by b-cyclodextrin in bromide through hydrogen bonding interactions of its the Hantzsch pyrrole synthesis.

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Scheme 5 Three-component pyrrole synthesis from b-dicarbonyl Scheme 8 Three-component pyrrole synthesis from b-ketoesters, compounds, arylglyoxals and ammonium acetate. amines and fumaryl chloride.

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 Scheme 6 Mechanism proposed for the transformation in Scheme 5. a 1,4-dicarbonyl fragment and gives pyrrole 7 through a Paal–Knorr condensation. An example of a compound 7 could cases) were mixed in the presence of titanium tetrachloride and be isolated by stopping the reaction before completion, and samarium powder in THF to give 1,2,3,5-tetrasubstituted this observation was considered as a proof in favour of the pyrroles (Scheme 7). The use of non-symmetric dicarbonyl proposed mechanism. A subsequent second Michael addition starting materials led to the isolation of mixtures of regio- onto the a,b-unsaturated imine fragment of 7 gives 8, again 46 a 1,4-dicarbonyl compound, and this is followed by a

Downloaded by University of Oxford on 26 October 2010 isomers in variable ratios. second Paal–Knorr reaction to give the observed products 4 Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 2.3 Pyrrole syntheses combining enamine formation and (Scheme 11). 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

Scheme 7 Low valent titanium-catalyzed pyrrole synthesis from diaryl 1,3-diketones, amines and aldehydes. Scheme 9 Mechanism proposed for the transformation in Scheme 8.

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Scheme 12 Three-component synthesis of pyrroles from b-dicarbonyl compounds, amines and a,b-unsaturated aldehydes.

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

Scheme 10 Multicomponent synthesis of 3,30-bipyrroles. 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

Downloaded by University of Oxford on 26 October 2010 competitive pathways. In the ﬁrst one, an acid-promoted propar-

Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 Scheme 11 Mechanism proposed for the 3,30-bipyrrole synthesis. the reaction between the starting b-dicarbonyl and primary amine components and which was detected by GC-MS experi- 2.4 Pyrrole syntheses combining Michael and aldol reactions ments. These proposals are summarized in Scheme 15. 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 starting material 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 aldehyde 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, Scheme 13 Mechanistic proposal for the reaction in Scheme 12.

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Scheme 16 Four-component pyrrole synthesis from acetylenedicarboxylates, ﬁve-membered cyclic imides and isonitriles.

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.

Downloaded by University of Oxford on 26 October 2010 Subsequent work by a diﬀerent group proved that the

Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F synthesis of pyrroles from primary amines, b-dicarbonyl compounds 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 Scheme 17 Mechanistic proposal to explain the isolation of pyrroles refluxing dichloromethane was found to afford pyrroles in from acetylenedicarboxylates, five-membered cyclic imides and good to excellent yields, albeit in rather long reaction times isonitriles. (Scheme 16).54 The mechanism proposed for this transformation is summarized in pathway b of Scheme 17 and assumes an The four-component reaction between alkynes, amines and initial addition of the isonitrile to the electron-defficient alkyne isonitriles catalyzed by a variety of titanium catalysts affords to give species 13. Reaction of the latter with a second 4-amino-1-azadienes derived from a formal iminoamination molecule of isonitrile affords bis-ketenimine 14, as previously reaction.56 Replacing these catalysts by the pseudotetrahedral 55 Me2 reported. Its reaction with the imide component followed by Ti(NMe2)2(Ind )2 species, generated from 2,3-dimethylin- cyclization explains the isolation of the observed pyrroles. The dole and Ti(NMe2)4, induced the incorporation of a second use of sterically hindered isonitriles (e.g. tert-butyl isonitrile) molecule of isonitrile, leading to the isolation of pyrrole prevented the generation of 14, probably because of steric products (Scheme 18). This reaction works well only with hindrance. In this case, intermediate 13 deprotonates the imide anilines not bearing an ortho substituent and tert-butyl to give intermediate 15, and this is followed by a Michael isonitrile.57 Other substrates lead preferentially to acyclic addition that leads to the observed products (compounds 16), products derived from the previously mentioned three- as shown in Scheme 17, pathway a. component process. Internal alkynes require higher reaction

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Scheme 18 Titanium-catalyzed four-component synthesis of 4,5- Scheme 20 Three-component synthesis of 4-nitropyrroles from diaminopyrroles. nitrostyrenes, TosMIC and ethyl chloroformate.

temperatures or/and longer reaction times than their terminal nitrostyrenes, toluenesulfonylmethyl isocyanide (TosMIC) counterparts. and ethyl chloroformate under strongly basic conditions The mechanism proposed by the authors to explain the achieved by the addition of BuLi.58 The concentration of the isolation of pyrroles involves the initial generation of a reaction medium was found to play a significant role in the titanium imido intermediate 17, which then undergoes a outcome of the reaction, with high concentrations leading to [2+2] cycloaddition onto the starting alkyne to afford an better yields. Purification of the final products also proved azatitanacyclobutene 18. Incorporation of the first molecule challenging, as conventional workup often provided low yields of isonitrile furnishes a five-membered metallacycle 19, which (method A in Scheme 20). The optimal procedure, which led to reacts with a further molecule of isonitrile, leading to a much improved results, turned out to be one based on the use six-membered titanacycle 20. Protolytic cleavage of this inter- of a polymer-assisted catch-and-release protocol for workup mediate by a new molecule of the amine closes the catalytic and purification by addition of a basic polystyrene resin cycle and releases intermediate 21, which affords the final (method B).59,60 These observations are summarized in products by 5-exo-trig intramolecular nucleophilic attack Scheme 20. followed by tautomerism (Scheme 19). The mechanism for this pyrrole synthesis was proposed to A very efficient route to trisubstituted pyrroles bearing an be initiated by the generation of intermediate 22 from unusual 4-nitro functionality has been developed by the Ley base-promoted condensation between TosMIC and ethyl group, which is based on a three-component reaction between chloroformate followed by deprotonation to give anion 22. Downloaded by University of Oxford on 26 October 2010 Addition of 22 to the starting nitrostyrene affords 23, which Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 tautomerism (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 preparation 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 Scheme 19 Mechanism proposed for the Ti-catalyzed four- aﬀorded tetrasubstituted pyrroles in poor to moderate yields 61 component synthesis of pyrroles from amines, alkynes and isonitriles (Scheme 22). The scope of this reaction did not include the (two molecules). use of ketones as starting materials.

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Scheme 23 Mechanism proposed for the four-component reaction between amines, aldehydes (2 molecules) and nitroalkanes.

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 nitroalkanes 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 subsequently studied in ethanol solution under the influence of ultrasound irradiation, which allowed to bring the Scheme 21 Mechanism proposed for the three-component synthesis reaction to completion in reaction times ranging from 20 to of 4-nitropyrroles. 60 min.64 Downloaded by University of Oxford on 26 October 2010 The first mention of the synthesis of pyrroles through a Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 66 Scheme 22 Synthesis of pyrroles from amines, aldehydes and in molten tetrabutylammonium bromide as an ionic liquid. nitroalkanes. In both cases, the reaction was restricted to the synthesis of 2-unsubstituted pyrroles since open-chain ketones did not give As shown in Scheme 23, the mechanism proposed for this the reaction (Scheme 27). However, conditions involving transformation involves the initial formation of the imine 28 heating in molten tetrabutylammonium bromide gave good from the starting amine and one molecule of aldehyde. A results with cyclic ketones as substrates, furnishing tetra- samarium-catalyzed aldol-type self-condensation of 28 affords hydroindoles as products. 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-unsaturated imine 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- Scheme 24 Three-component reaction between amines, a,b-unsaturated catalyzed experiment. aldehydes or ketones and nitroalkanes.

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Scheme 29 Synthesis of a pyrrole from butylamine and two molecules of 1-nitropentene.

Scheme 25 Microwave-accelerated three-component reaction between base, activates this imine to form the enamine complex 33. The amines, a,b-unsaturated carbonyl compounds and nitroalkanes. 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 Scheme 26 Three-component reaction between amines, ketones and nitrostyrenes. The transformations described in this section can be considered as variations of the classical Paal–Knorr pyrrole A similar transformation could also be achieved through a synthesis where the 1,4-dicarbonyl compound is generated sequential procedure using as starting materials amines, in situ. Unavoidably, there is some overlap with previous nitroalkenes and diketene, a well-known acetoacetylating sections and for instance the reactions summarized in reagent that presumably generates a b-ketoamide by reaction Schemes 5, 6, 10 and 11, which also involve 1,4-dicarbonyl with one molecule of the starting amine. Therefore, the ﬁnal intermediates, might also have been included here. pyrrole contains a 3-carboxamide substituent (Scheme 28).67 5.1 Pyrrole synthesis through a four-component process based A single example of a three-component pyrrole synthesis on a Sonogashira/isomerization/Stetter/Paal–Knorr domino from a primary amine and two molecules of a nitroalkene in sequence the presence of samarium triisopropoxide has been described (Scheme 29). This reaction was developed as a three- The Mu¨ller group discovered a synthesis of chalcones from component variant of a previously known synthesis of propargyl alcohols and electron-poor bromoarenes through a 68

Downloaded by University of Oxford on 26 October 2010 pyrroles from imines and nitroalkenes. The mechanism

Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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

Scheme 27 Three-component reaction between amines, aldehydes and nitroalkenes.

Scheme 28 Synthesis of pyrrole-3-carboxamides from amines Scheme 30 Mechanism proposed for the samarium-catalyzed synthesis (two molecules), diketene and nitrostyrenes. of pyrroles from butylamine and two molecules of 1-nitropentene.

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Scheme 31 Four-component pyrrole synthesis based on a Sonogashira/isomerization/Stetter/Paal–Knorr domino sequence.

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 Scheme 32 Mechanism for the Sonogashira/isomerization/Stetter/ Paal–Knorr sequence. 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- Downloaded by University of Oxford on 26 October 2010 stabilized propargyl-allenyl anion that is protonated to give Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 Scheme 33 Synthesis of pyrroles based on a Stetter/Paal–Knorr to the C-nucleophilic dipolar species 38, which can also be sequence. 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 Paal–Knorr reactions.73,74 In this case, the starting materials the aldehyde, reacts with 37 leading to intermediate 40 and employed were chalcones and acylsilanes instead of aldehydes, then to 1,4-diketone 41, which finally yields the observed and the first reaction requires the addition of isopropyl pyrrole products by reaction with the amine component alcohol. Also, this process differs from the previous through the classical Paal–Knorr mechanism. one in the addition of p-toluensulfonic acid and 4 A˚ molecular A closely related reaction that allows the preparation of sieves in order to facilitate the Paal–Knorr reaction highly complex phenyl- and heterocycle-substituted pyrroles (Scheme 34). was developed by the group of Jing, following the same strategy but starting from pre-synthesized a,b-unsaturated ketones 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 Scheme 34 Synthesis of pyrroles based on a sila-Stetter/Paal–Knorr Scheidt group, is based on the combination of sila-Stetter and sequence.

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Scheme 36 Pd-catalyzed synthesis of pyrroles by three-component coupling of alkynes, imines and acyl chlorides.

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 Mu¨nchnone 52. Finally, the 1,3-dipolar cycloaddition between this Mu¨nchnone 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 Scheme 35 Mechanistic proposal for the sila-Stetter/Paal–Knorr in the presence of alkynes (Scheme 37). sequence. Similarly, Merlic and coworkers developed an entry to Mu¨nchnones via an acylamino chromium carbene The mechanism proposed for the sila-Stetter reaction is complex followed by a 1,3-dipolar cycloaddition with depicted in Scheme 35, and involves the addition of the acetylenedicarboxylates that yields pyrroles. Although this acylsilane to the nucleophile 42, generated by deprotonation was not the procedure normally employed, this reaction could of the thiazole catalyst. Intermediate 43 thus obtained under- be carried out as a one-pot, three-component procedure goes a 1,2-silyl group shift from carbon to oxygen, known as a Brook rearrangement leading to 44, which is desilylated by the

Downloaded by University of Oxford on 26 October 2010 alcohol additive to yield 45. From that point, the reaction

Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 Mu¨nchnones, 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 Mu¨nchnones and their analogues as 1,3-dipoles Arndtsen and Dhawan reported a pyrrole synthesis based on the preparation of Mu¨nchnones in one step by a palladium- catalyzed coupling between imines, acid chlorides and carbon monoxide, and then the corresponding pyrroles by the 76,77 addition of alkynes (Scheme 36). The mechanism Scheme 37 Plausible mechanism for the synthesis of pyrroles from proposed to explain this reaction starts with the generation alkynes, imines and acyl chlorides.

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Scheme 40 Phosphonite-mediated three-component pyrrole synthesis.

a phosphine oxide in the last step leads to the final product. Scheme 38 Three-component pyrrole synthesis from amino chromium The participation of 60 in the 1,3-dipolar cycloaddition was carbene complexes, acyl chlorides and acetylenedicarboxylates. 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 Mu¨nchnone 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 Scheme 39 Mechanistic explanation of the pyrrole synthesis from base leads to the amino analogue of Mu¨nchnone 64, which aminocarbene chromium complexes. undergoes a 1,3-dipolar cycloaddition with the alkyne to form Downloaded by University of Oxford on 26 October 2010 the corresponding cycloadduct, followed by elimination of a Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F (Scheme 38).78 Its mechanism (Scheme 39) begins with the molecule of isocyanate to give the desired pyrrole (Scheme 43). acylation of the starting aminocarbene chromium complex with benzoyl chloride to give an acylaminocarbene complex 6.2 Methods using 1,3-dipoles different from Mu¨nchnones 54. Insertion of carbon monoxide can be achieved in a direct, non-photochemical fashion to give a ketene complex 55. This A multicomponent process that combines imines with step is unusual in that CO insertion in heteroatom-substituted dibromodifluoromethane and alkynes leads to 2-fluoropyrrole 81 chromium complexes is generally considered a photochemical derivatives (Scheme 44). The 1,3-dipole involved in the process. The ketene cyclizes to a metal-free Mu¨nchnone 56, cycloaddtion is a difluorocarbene, generated in situ from that could be isolated if desired, with the demetalation step dibromodifluoromethane using different protocols. The best being probably facilitated by the presence of CO. The results were obtained with active lead, prepared by reduction 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 Mu¨nchnone 79 was replaced with a PPh3 unit. 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 Scheme 41 Wittig-type intermediates in the generation of 1,3-dipoles 1,3-dipole 60. After formation of cycloadduct 61, the release of for pyrrole synthesis.

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Scheme 42 Isonitrile-mediated three-component synthesis of pyrroles.

Scheme 45 Mechanism of a pyrrole synthesis based on 1,3-dipolar cycloadditions of ﬂuorinated azomethine ylides.

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 diazoacetonitrile, 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 Scheme 43 Mechanism of the pyrrole synthesis based on 1,3-dipolar can be found in a sequential multicomponent process that cycloadditions of amino analogues of Mu¨nchnones. uses as starting materials an aldehyde derivative, aminoesters

Downloaded by University of Oxford on 26 October 2010 and acetylenic dipolarophiles for the preparation of of aqueous lead acetate with sodium borohydride, instead of 3,4,5-trisubstituted pyrrole derivatives (Scheme 48). In many Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F the more usual powdered lead or zinc dust. The reaction cases, the use of pyridinium p-toluene sulfonate (PPTS) as an conditions are compatible with a variety of functional groups additive was required for the reaction to achieve completion.83 on the imines, although the structures of the alkyne dipolaro- A plausible mechanism that explains this transformation starts philes are restricted to compounds bearing electron- with the formation of an imine between the heterocyclic withdrawing groups. This one-pot synthesis occurs in four aldehyde and the aminoester. This initial imine undergoes steps. First, difluorocarbene is generated by reduction of a 1,2-shift of the acidic hydrogen to produce the dibromodifluoromethane with active lead in presence of tetra- NH-azomethine ylide 67, which is stabilized by intramolecular butylammonium bromide. Then, the carbene is attacked by hydrogen bonding. The cycloaddition reaction between this the nitrogen lone pair of the imine to form the intermediate 1,3-dipole and the starting alkyne furnishes compound 68 with azomethine ylide 65, which participates in a 1,3-dipolar cyclo- complete regioselectivity in favour of the pyrroline derivative addition with the activated alkynes to give a 2,2-difluoro-3- bearing the ester group at the C-3 position. This intermediate pyrroline. The last step is the dehydrofluorination of the latter is cleaved under the acidic reaction conditions to give compound to give the desired 2-fluoropyrrole (Scheme 45). fragments 69 and 70. The 2H-pyrrole initial products (71) The rhodium-catalyzed multicomponent reaction of aryl are transformed into the finally observed 1H-pyrroles by imines, diazoacetonitrile and acetylenedicarboxylates as the aromatization through a 1,5-ester rearrangement followed by tautomerism (Scheme 49).

Scheme 44 Three-component synthesis of 2-ﬂuoropyrroles from Scheme 46 Rhodium-catalyzed synthesis of pyrroles from imines, dibromodiﬂuoromethane, imines and alkynes. diazo compounds and activated alkynes.

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Scheme 47 Mechanism of the rhodium-catalyzed three-component pyrrole synthesis.

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 Scheme 49 Proposed mechanism of the synthesis of pyrroles from using alkynes as starting materials a-amino esters, acetylenes and a quinazoline-derived aldehyde. 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 Downloaded by University of Oxford on 26 October 2010 shown to slowly rearrange to pyrroles. As depicted in Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 transformation generates two C–C and two C–N bonds and Scheme 50 Synthesis of 2-aminopyrroles by three-component comprises up to nine individual reaction steps. The mechanism reaction between isonitriles, tosylimines and acetylenedicarboxylates. proposed to explain it involves two coupled domino processes. An initial three-component domino reaction between the shift then takes place to afford an enamine, which then aldehyde and two molecules of alkyne affords the enol- undergoes the final cyclization. This hydrogen shift was protected propargyl alcohol 73, which then reacts with the proved by the fact that the reaction starting from amine to give 1,3-oxazolidine 72. Its skeletal rearrangement acetaldehyde-d4 furnished a pyrrole derivative with deuterium starts by ring opening and isomerization to 74. A hydrogen at the methyl position, but not at the ring (Scheme 52).

Scheme 48 Synthesis of pyrroles from a-amino esters, acetylenes and Scheme 51 Four-component synthesis of pyrroles from amines, a quinazoline-derived aldehyde. nitriles (two molecules) and aldehydes.

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Scheme 54 Mechanism of the three-component synthesis of pyrroles from an alkynylsilane, an imine and an aldehyde.

Scheme 52 Mechanism proposed for the four-component pyrrole synthesis, involving the generation and rearrangement of a 1,3-oxazolidine intermediate.

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). Scheme 55 Four-component synthesis of pyrroles from a alkyne However, in most cases this reaction was performed in a two- (two molecules), an imine and a dialkylzinc derivative. component fashion, starting from imines and isolated propargyl silyl ethers.86 The mechanism proposed to explain this transformation involves the initial formation of a propargyl silyl ether 75, followed by a base-promoted generation of allene anion 76 which then adds to the starting imine. The ﬁnal pyrrole productisformedfollowinga5-endo-trig cyclization and

Downloaded by University of Oxford on 26 October 2010 elimination of a molecule of trimethylsilyl alcohol (Scheme 54). As shown in Scheme 55, another multicomponent sequence Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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

Scheme 56 Mechanism of the multicomponent synthesis of pyrroles from alkynes, imines and dialkylzinc compounds.

Scheme 53 Synthesis of a pyrrole derivative from an alkynylsilane, an isopropylmagnesium chloride aﬀords pyrrole-2-carbaldehydes imine and an aldehyde. (Scheme 57). The mechanism involves the titanium-promoted

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initial reaction between the alkyne and the ﬁrst nitrile, leading to the formation of an azatitanacyclopentadiene intermediate 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 Scheme 58 Mechanism of the three-component pyrrole synthesis via mechanism for the triphenylphosphine-mediated pyrrole azatitanacyclopentadiene intermediates. 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 Scheme 59 Zircocene-mediated pyrrole synthesis from bis- and 2,3-butanedione afforded N-unsubstituted pyrroles (arylalkynyl)silanes and nitriles. (Scheme 62).92 Another three-component pyrrole synthesis that includes a Michael addition onto a dialkyl acetylenedicarboxylate is Downloaded by University of Oxford on 26 October 2010 summarized in Scheme 63, which uses acyl chlorides and Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 Scheme 60 Triphenylphosphine-promoted three-component to give an anion 81 that adds onto the acetylenic ester. This synthesis of N-phenylpyrroles from aniline, acetylenedicarboxilates leads to another anion 82 that undergoes an intra- and arylglyoxals. molecular addition onto the amide carbonyl and a final elimination of a molecule of water to furnish the final product 7.4 Methods based on palladium-catalyzed cross-coupling (Scheme 64). 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- Scheme 57 Ti-promoted three-component pyrrole synthesis from molecular Pd-catalyzed oxidative carbonylation reaction of alkynes and nitriles. 2-en-4-ynylamines, providing a new route to pyrrole-2-acetic

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Scheme 65 Three-component coupling-addition-cyclocondensation sequence leading to 4-iodopyrroles and their one-pot sequential Scheme 61 Plausible mechanism for the triphenylphosphine- transformation into 4-alkynylpyrroles. promoted synthesis of pyrroles.

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 Scheme 62 Triphenylphosphine-promoted synthesis of N-unsubstituted the present case owing to the low stability of pyrroles to pyrroles. 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 Downloaded by University of Oxford on 26 October 2010 the synthesis of pyrrole-3,4-diacetic ester derivatives. In this Published on 05 July 2010 http://pubs.rsc.org | doi:10.1039/B917644F 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 Scheme 63 Ionic liquid-promoted synthesis of pyrroles from a-amino 96 acids, aromatic acyl chlorides and acetylenedicarboxylates. compounds 84, 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 64 Mechanism of the ionic liquid-promoted, three- component pyrrole synthesis.

esters.95 This reaction was proposed to take place through the mechanism summarized in Scheme 67. The alkoxycarbonylation Scheme 66 Synthesis of pyrrole-2-acetic esters based on a process involves reduction of PdI2 to Pd(0) and two molecules Pd-catalyzed intramolecular oxidative carbonylation reaction.

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