A Critical Review on Advances in the Multicomponent Synthesis of Pyrroles

Nitrogen containing heterocyclic compounds are biologically significant molecules. This is especially true for pyrrole a five membered nitrogen containing aromatic molecule, which is present as a key structural motif in a large number of drugs and lead molecules. This review aims to provide an overview of the multi-component reaction (MCR) based methodologies used for the synthesis of pyrrole and its derivatives, focusing particularly on eco-friendly methods that avoid the use of hazardous reagents, solvents and catalysts are deemed especially relevant to the disciplines of medicinal chemistry and drug discovery.


INTROdUCTION
Heterocyclic molecules are a valuable class of organic compounds which show a broad spectrum of application in medicinal chemistry, 1 biochemistry, 2 photochemistry, 3 material science 4 and environmental science. 5With the increasing emphasis on eco-friendly chemical synthesis in recent decades, new breakthroughs are needed in the synthesis of heterocyclic compounds so as to avoid the use of hazardous chemicals, catalyst, solvent and techniques.In this context the concept of green chemistry 6 that encompasses a series of consideration like energy consumption, 7 atom efficiency, 8 atom economy, 9 solvent, catalyst and sustainability of the chemical process 10 has become very relevant.Solvents play a very significant role, in organic synthesis.In addition to their use a reaction media, they are; used in extraction, washing, and separation of the final product.No surprise that volatile organic compounds based solvent is responsible for the major share of the pollution originating from the chemical industry.Consequently, in the past two decades scientists have devoted immense efforts towards the replacement of petroleum based hazardous solvents by green solvents.Biodegradable glycerol, 11 polyethylene glycol (PEG), 12 ionic liquids (ILs), 13 water 14 etc. have been explored extensively as alternative solvents.
Pyrrole and derivatives constitutes one of the most important class of nitrogen containing heterocyclic compounds. 15Pyrrole is a key structural motif in a plethora of natural products such as porphyrins, bacteriochlorins, 16 porphyrinogens 17 chlorophyll, vitamin B12, bile pigments like bilirubin and biliverdin, and alkaloids isolated from marine sources. 18They are an important scaffold in organic synthesis and have immense utility 19 in, medicinal chemistry 20 and pharmacology. 21Many pyrrole derivatives are also found to possess diverse biological activities such as antibacterial, 22 antihyperlipidemic, 23 antioxidant, 24 antitumor, 25 antiinflammatory, 26 antifungal, 27 antiviral, 28 anti-HIV, 29 and analgesic effects. 30There most commonly used are many conventional methods for the synthesis of pyrrole derivatives include the Knorr synthesis, 31 Hantzsh synthesis, 32 Buchwald-Hartwing coupling, 33 and Paal-Knorr condensation reaction. 34However, multi component reactions (MCRs), 35 which is a convergent chemical process wherein three or more reactants are combined in such a way that the final product retains significant portions of all the reactants, 36 have immense advantage over the conventional synthesis in term of flexibility, reduced reaction time, use of less energy, cost effectiveness, variable bond forming efficiency, atom economy, operational simplicity, simple purification of product and eco-friendly nature. 37The current emphasis on green chemistry has only increased the relevance of the MCRs approach in organic synthesis.One pot MCR have been successfully employed for the synthesis of a variant pyrrole derivatives. 38The main objective of this manuscript is to provide a critical review of the various MCR based syntheses of pyrrole derivatives focusing especially on eco-friendly methods.

Fig. 1. Some biologically active pyrrole derivatives
Pyrrole is the main heterocyclic moiety in several drugs (Fig. 1) including Lamellarin O (1), a pyrrole alkaloid characterized as a selective inhibitor of breast cancer resistance protein (BCRP). 45Atorvastatin (AVA) 2, one of the leading pyrrole drug, is an inhibitor of HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase) and widely used as a lipid lowering agent.It also shows good activity against Plasmodium falciparum and is used in the treatment of cerebral malaria. 46t has shown significant neuro-protective and anti-inflammatory activities.Pyrrolnitrin 3 functions as a systemic antifungal agent. 47Licofelone 4 possesses significant analgesic, anti-inflammatory, and antiasthmatic activities. 48Pyrrole-2-carbaldehyde 5 is used as antibacterial and HIV-1 integrase inhibitor. 49Ketorolac 6 is one of the most important non-steroidal anti-inflammatory drug (NSAIDs). 50unitinib 7 is a commercially available pyrrole containing drug and is used for the treatment of renal cancer and acts as a multi-targeted receptor tyrosine kinase inhibitor. 51Diguanidino-1-methyl-2,5-diaryl-1H-pyrrole derivatives 8 have exhibited important antifungal activity against Candida species. 52Tolmetin 9 is an important non-steroidal anti-inflammatory drug (NSAID), it works by reducing hormones that cause inflammation as well as pain in the body. 53nder near-critical and supercritical conditions water behaves as a pseudo-organic solvent because its dielectric constant decreases substantially toward The organic molecules at room temperature compared to common organic solvents, 54 The unique physical and chemical properties of water such as high specific heat, surface tension, dielectric constant, large cohesive energy, density and ability to form hydrogen bonds and its amphoteric nature, coupled with its ability to influence the reactivity and selectivity of chemical reactions 55 have served to make it a solvent of choice in organic synthesis. 56Many organic reactions are greatly facilitated when water is employed as the solvent 57 due to their hydrophobic effects.[60][61][62] One of the main advantages of using water is its ability to form strong hydrogen bonds [63][64][65][66] that gives significant surface tension.One of the most useful conventional methods for the synthesis of pyrrole is the Paal-Knorr cyclization reaction in which a primary amine 11 reacts with 1,4-diketone 12 to furnish the pyrrole derivative 13 (Scheme 1).Recently, H. Veisi et al., reported an eco-friendly version of the classical experimental procedure in the year 2013 for the synthesis of N-substituted pyrrole by using sodium dodecyl sulfate (SDS) in water at room temperature. 67The reactant formed micelle in water due to their hydrophobic nature and were forced inside the hydrophobic core of the micelle, thus permitting the reaction to take place more easily, leading to the formation of the product in excellent yields.

Scheme 1. One pot two component synthesis of N-substituted pyrroles
Li et al., developed an eco-friendly and cost effective simple protocol for the synthesis of pyrrole derivatives. 18He performed the reaction by using 50% gluconic acid in aqueous solution (GAAS) at 100 o C (Scheme 2). 68They observed that ionic liquid is the most promising solvent to obtain the desired product in high yields.The mechanistic pathway for this reaction involved Michael addition and cyclization by the elimination of nitroxyl and water to provide the substituted pyrrole derivatives 18 (Figure 4).An eco-friendly and simple, regio-and stereo-selective protocol for the synthesis of polyfunctionalized pyrrole derivatives 21, in good yield, was reported by the M. Masoudi and co-workers through a novel one-pot two-component reaction of enamines of β-ketoesters 19 and α-oxoaldehydes 20 in the presence of triphenylphosphine (PPh 3 ) (Scheme 3). 69On the basis of the regiochemistry of the addition of enaminones to aryl-glyoxals, it is assumed that condensation of the aryl-glyoxal derivative with the enaminone derivative at the aldehydic carbon, first afforded an intermediate, which was subsequently converted into another intermediate, the phosphonium betaine intermediate, by the conjugate addition of the triphenylphosphine.Elimination of triphenylphosphine oxide from this intermediate ultimately led to the polyfunctionalized pyrrole derivatives 21 (Figure 5).The proposed mechanism for the above method is shown below (Fig. 6).Initially, the nitro compounds 22 on treatment with Indium/HCl, were reduced to amines, which then reacted with dialkyl acetylene dicarboxylate 24 to form the zwitterions which on reaction with phenacyl bromide 23 produced an intermediate which underwent cyclization followed by aromatization to produce the desired polysubstituted pyrroles 25.Hydrochloric acid is widely used in organic reactions such as esterification, 71 Mannich reactions, 72 Nitration, Beckmann rearrangement, Friedlander reaction, Michael addition and many one-pot multi-component reactions. 73metal-free two-component, one-pot regioselective method was developed in 2016 by the W. Senapak, et al., using recyclable1-butylsulfonic-3-methylimidazolium hydrogen sulfate ([bsmim] [HSO 4 ]) as a catalyst for the green synthesis of Rajaguru et al., in 2017 synthesized tetra-substituted pyrrole derivatives 31 from α-azidochalcones 29 with copper β-diketonates 30 in aqueous micellar medium using cetyltrimethyl ammonium chloride (CTAC) as a surfactant, at 100 o C. in the presence of copper (II) acetylacetonate as a catalyst (Scheme 6).75 The mechanistic pathway for the formation of substituted pyrroles 31 is initiated by thermolysis of α-azidochalcone 29 which then undergoes denitrogenative decomposition to form a highly strained three membered cyclic imine, 2H-azirine.The solvolysis of metal β-diketonate 30 followed by the addition of the intermediate results in the aziridine compound, which then undergoes intramolecular nucleophilic addition to the carbonyl group with a nitrogen lone pair to furnish the 2, 5-Dihydro-1H-pyrrole intermediate followed by isomerization to form substituted pyrroles 31.Scheme 6.One pot two component synthesis of tetra-substituted pyrrole derivatives dipyrromethenes 28 using aldehydes 26 and pyrrole 27 in water at room temperature.The mechanism involved Friedel Craft reaction and the final product was obtained with good yields (Scheme 5).74 Substituted functional indoloquinoline derivatives were prepared by Shi et al., in good yield, by a one-pot two component method using substituted indole 32 and benzo[c]isoxazole 33 in the presence of [Cp*RhCl 2 ] 2 , AgSbF 6 and NaOAc at 100°C, in the presence of water.(Scheme 7).76

Scheme 7. Synthesis of substituted functional indoloquinoline derivatives
In recent years, with a growing emphasis on green chemistry, a lot of efforts is being invested towards the development of metal free protocols for the synthesis of biologically important organic moieties. 77 Chen and co-workers for the first time developed a thermodynamically versus kinetically controlled, three component reaction utilizing heterocyclic ketene aminals (HKAs) 39, arylglyoxal monohydrates 40 and cyclohexane-1,3-diones 41 for the synthesis of the highly functionalized bicyclic pyrrole derivatives 42a and 42b. in high yield, using a water based green solvent system (H 2 O:EtOH/ 3:1 ratio), under catalyst free conditions (Scheme 9). 79The mechanism involved dual regioselective pathways as exemplified in Fig.

Synthesis of Pyrrole Compounds Using Ionic Liquid as a Solvent
In 2014, Anamik Shah and co-workers performed a catalyst free, simple synthesis of penta-substituted pyrrole derivatives 54 or 55 via a one pot five component reaction (Scheme 11), 81   Wang et al., have developed a highly efficient, catalyst free green method for the one pot four component syntheses of pyrrole derivatives 60.This method presents a new approach for the synthesis of pyrrole derivatives.They observed the possibility of the reaction of 4-hydroxy-2H-chromen-2-one 56 with phenyl glyoxal monohydrate 56, dialkyl but-2-ynedioate 57 and arylamine 58. 82The protocol proceeded efficiently with high yield without the need for chromatography or recrystallization.This synthetic methodology demostrates that various substituted pyrrole can be designed and constructed through the regulation of the starting materials of 4-hydroxy-2H-chromen-2-one in Scheme 14.In the first step of the reaction, the addition of alkynoate 59 and amine 58 gave the enamine as the first intermediate.Niknam et al., reported a new multicomponent protocol for the synthesis of substituted pyrroles by first refluxing aromatic aldehyde 61, in the presence of ionic 3 mol% ionic liquid and 30 mol%, sodium hydroxide, in absolute ethanol in for 30 min.to form benzoin followed by the addition of the 1, 3-dicarbonyl compound 62 and ammonium acetate 63 (Scheme 13).The reaction mixture was then cooled to room temperature and the precipitate formed was filtered and washed with water in order to remove the IL 4. 83 The resulting solid were recrystallized from ethanol to obtain the pure substituted pyrrole 64 in a metal free, eco-friendly, one pot five component sequential reaction was reported by S. Ambethkar which involved the coupling of acetophenone 65, N,Ndimethylformamide-dimethylacetal 66, substituted amine 67, arylglyoxal 68 and malononitrile 69 in methanol under reflux for 1.5 h to obtained novel pyrrole cyano-acetamides 70 in high yields (Scheme14). 84The experimental result showed that solvent and temperature played significant role in the reaction productivity.
T h e m e c h a n i s t i c p a t h way fo r t h e synthesis of substituted pyrrole 70 is shown in   85 They observed that the three-component reaction with excellent yield.t has been reported that when iodobenzene and oxone react, an active iodine species called hydroxyl (phenyl) iodonium ion is generated in situ.This active iodine species, hydroxyl (phenyl) iodonium ion, is used to catalyze the reaction between amine 88, nitro-compounds 89 and β-diketone 90.A four component reaction is proposed using Huisgen's 1,4-dipole, ethanol is used as a solvent and triethyl amine as a promoter.This reaction was performed for 1-12 h at reflux temperature.The pathway for the synthesis involves a Knoevenagel condensation and intramolecular cyclization leading to the formation of pyrrole derivative.In method-A, they used ethanol as a solvent under reflux which led to the formation of desired product after 5-8 h in excellent yields.On the other hand in method-B, they performed the reaction under microwave heating condition at 80 o C and observed that the final product was obtained within 15 min.with appropriate good yield.
They also reported another one-pot three component reaction in which 2-mercaptopyrimidine 116 was used instead of malononitrile 114.This reaction was performed under microwave irradiation in the presence of an acidic catalyst at 120 o C for 20 min.The mechanistic pathway is thought to involve a regioselective nitroso Diels-Alder cyclization reaction.It is remarkable that no pyrrole formation was observed if the cycloadduct is stable on the way to hydrolysis, as incase for the MIDA derivatives.Hence, tri-coordinated sp 2 boron species are required for ring contraction of the oxazine and the desired N-aryl pyrrole derivatives were obtained with mild to good yields.

Scheme 26. One pot two component synthesis of N-aryl pyrrole derivatives
An efficient, economical, eco-friendly and convenient route had been reported by Dhinakaran et al., for the synthesis of tetrahydro pyridines 129 and polysubstituted pyrroles 128 via a one pot three component reaction of 2,2-dihydroxy-1arylethan-1-one 125, malononitrile 126 and ethyl (E)-3-(4-arylamino) acrylates 127 under catalyst and solvent free conditions by using the grinding method (Scheme 27). 98During their experiment they observed that the chemoselectivity of the reaction depends on the substitution on the N-phenyl ring of ethyl (E)-3-(4-arylamino) acrylates (Figure 13).Tian and co-worker.in 2015 published their work on utilization of isocyanide 150 and methylene indolinone derivatives 151 for the synthesis of complex spiro-oxindole derivatives 154 in the presence of indium trichloride as a catalyst through novel multiple isocyanide insertions, Michael addition, cyclization, and imine-enamine tautomerization reaction (Fig. 16). 104This method can serves as an excellent, atom economical, synthetic route for construction of complex spirooxindole (Scheme 32).In 2016 the same research group reported a new facile route for the synthesis of complex polycyclic derivatives 152 and 153 through a double isocyanide insertion ring opening, cyclization and isomerization sequence, by utilizing isocyanide 150 and methylene indolinone derivatives 151, 105 in the presence of KAuCl 4 (15 mol %) under reflux (scheme 32, Fig. 16).Additionally, they also observed a rare oxygen migration when the reaction was conducted at lower temperature (95 o C).  106 The prominent domino process involved an annulation followed by the reaction between aromatic aldehyde 156, substituted aniline 155 and aceto-acetanilide 157 in ethanol (Scheme 33).They obtained satisfactory results in the presence of bismuth nitrate (10 mol%) at room temperature.After 30 min.the desired product was obtained in good yield.Generally, one-pot synthesis of aldehyde and aniline gives substituted pyrrole derivatives but in this process bicyclo [2.2.2] octane derivatives were obtained due to the presence of bismuth nitrate as a catalyst.Now a days many researchers are working towards the development of multi-targeted drugs.Pyrroles are highly valued scaffolds in the realm of medicinal chemistry and drug discovery.Consequently, a lot of work is being done towards the structural modification as well as the development of efficient new routes for the derivatization of pyrroles.In this context, Wu et al., recently proposed a one-pot synthesis of functionalized pyrrole derivatives, 2,6-disubstituted 9-arylcarbazoles 160 and 1,2,4-triaryl-substituted pyrroles 162 (Scheme 33). 107The repor ted experimental procedure, utilized commercially available low-cost reactant, anilines 155 and cyclohexanones 159 in metal-free conditions leading to the formation of 2,6-disubstituted 9-arylcarbazoles 160 in high yields.For the synthesis of 1,2,4-triaryl-substituted pyrroles 162, acetophenones 161 were used in place of cyclohexanones 159.Both reactions were performed under air in the presence of KI.This new method offers simple, fast and attractive procedure over the previous syntheses.Recently, Fleige and Glorius working for the synthetic precedent of Atorvastatin, published an article on the one-pot three-component synthesis of 1,2,4-trisubstituted pyrroles 165 by using simple starting materials, glycol-aldehyde dimer 164, various chalcones 163 and p-toluidine 155.Satisfactory yield of pyrroles 165 was obtained by using thiazolium salt (20 mol%) and K 3 PO 4 (20 mol%) in methyl cyanide. 108rthermore, this protocol exhibited several benefits like mild reaction condition, operational simplicity, low catalyst loading, chemo, regio, and stereoselectivity in product.Mechanistically this reaction has attracted attention due to the use of Stetter-type hydroformylation/Paal-Knorr synthesis.
Cores et al., standardized an effective and cheap methodology for the synthesis of highly substituted pyrrole 169 with the help of β-dicarbonyl compound 167, amine 166 and α-haloester 168.This reaction uses InCl 3 as a catalyst and was performed at room temperature for the first 30 min.and then in a microwave for 30 min.at 120 o C (Scheme 34). 109A plausible mechanistic pathway for this reaction was proposed wherein 1-phenylpropan-1,2-dione 185 and 4-methoxyaniline 186 led to the in situ formation of iminium intermediate which reacted with benzaldehyde 187 and 4-methoxyaniline 186, followed by the intramolecular nucleophilic attack by the amine to afford the amino-alcohol based intermediate in the presence of an acid catalyst (Fig. 18).The proposed mechanism suggests that the reaction involved a nucleophilic addition, condensation, cyclization and, oxidation sequence to generate the desired products.
Similarly, in 2016, Mariappan and co-workers synthesized poly-substituted pyrrole 200 with the help of substituted monophenacylaniline 199 and dialkyl acetylene dicarboxylate 198 in DMF under microwave irradiation (110 W) at 110°C for 10 min.as shown in scheme 41. 117 In this reaction, α-amino ketone initially reacted with the electron deficient alkynes to afford an intermediate.Nucleophilic attack of this intermediate on the carbonyl group followed by the removal of water resulted in the desired product 200.The main advantages of this protocol were the short reaction times, catalyst free conditions and excellent yield of the products.
Zhao et.al., have reported another interesting, impressive and novel one-pot three-component approach for the synthesis of penta-substituted pyrroles 205 from nitroepoxides 204, primary amines 202 and dialkyl acetylene dicarboxylates 198 (Scheme 41). 118This protocol was performed under mild reaction conditions, without the use of any catalyst and the desired product was obtained in good yield.Gilbert et al., reported an exciting synthetic procedure for the synthesis of pyrrole derivatives 207.During their experiments they used Titanium imido precatalysts.The inter and intramolecular oxidative coupling of alkynes or enynes 206 with diazenes 198 in the presence of the aprotic catalyst (py) 3 TiCl 2 (NPh) led to synthesis of poly-substituted pyrroles 207. 119This reaction is a unique example of catalytic oxidative C-N bond formation with a group 4 transition metal and of catalytic formal [2+2+1] six-electron cyclization with a nitrene feedstock.In the same manner, Saleh and Voituriez proposed a simple and attractive protocol wherein they reacted indolecarbaldehyde 208, phospholene (4-nitrophenyl) phosphate in freshly distilled degassed toluene in a Schlenk tube.Then, the di acetylene dicarboxylate 198 and phenylsilane were added using micro-syringes.The reaction mixture was then heated at 60°C for 16 h as shown in scheme 41. 120 The entire procedure (cyclization /hydrolysis/oxidation) could be accomplished consecutively in a one-pot fashion, with remarkable yields up to 90%.This procedure offers several advantages over the conventional protocols like mild reaction conditions, operational simplicity, minimum environmental impact and, facile product formation.
Panther and Muller reported an efficient four-component Heck isomerization-Fischer indolization-alkylation (HIFIA) synthetic procedure for the synthesis of 1-alkyl-3-benzylindoles derivatives 218 by using easily available starting materials such as hydrazines 214, (hetero) aryl bromides 215, allyl alcohols 217, and alkyl bromides 216 under microwave irradiation (Scheme 43). 122This reaction mechanism offers several advantages over other conventional methods like short reaction times, easy handling, high yields and, chemo, regio-and stereoselectivity in the product.
A one-pot method for the synthesis of 5-aryl-3-methyl-1-phenyl-1,2-dihydro-7aHpyrazolo [3,4- In the presence of the co catalyst, the diols convert into diketone.However, due to the use of the transition metal catalyst, this procedure is considered less eco-friendly. 124 the same year Karami et al., also synthesized pyrrole derivatives 228 by using Paal-Knorr reaction in the presence of a metal based catalyst, molybedate sulfuric acid (MSA) in solvent free conditions, at 60 o C, by using diols 226 and secondary amines 227. 125cently, the syntheses of diversely substituted pyrrolidine-fused heterocycles 232 were reported by Jiang et al., They reported for the first time, a one-pot three component reaction by using n-butyl isocyanides 229, allenoates 230, and imines 231 in water and toluene.In this synthesis, two rings and five chemical bonds were formed.Furthermore, four carbon atoms in allenoate were assimilated into the ring formation, which is quite rare, making this synthesis all the more significant (Scheme 47). 126

CONCLUSION
In this review, we have provided an overview of the different multicomponent reactions (MCRs) based strategies for the synthesis of substituted pyrroles, emphasizing on recently repor ted, eco-friendly protocols.Pyrrole is an important heterocyclic scaffold that has played a significant role in different areas of chemistry, especially medicinal chemistry and drug discovery.Multi-component reactions are versatile and attractive approach in organic synthesis with immense potential for the rapid assembly of complex molecule.More than ninety percent of the MCR protocols published in the last three years are covered in this review.This review particularly covers recent environment friendly protocols for the synthesis of pyrroles which utilize the use of alternate green solvents, green catalysts, catalyst free synthesis or microwave assisted synthesis, the present review will be of immense interest to researchers working on the development of efficient, New, MCR based methodologies for the synthesis of pyrrole compounds.
support and communication number (IU/R&D/2017-MCN00047) for the manuscript.A. G. A-S.Thanks Dean, Scientific Research, King Khalid University, Abha Saudi Arabia for administrative support.

Scheme 4 .
Scheme 4. One pot three component synthesis of poly-substituted pyrrole derivatives

78 Scheme 8 .
Scheme 8.One pot three component synthesis of polysubstituted pyrrole derivatives

Scheme 11 .Fig. 8 .
Scheme 11.Four component synthesis of penta-substituted pyrrole under catalyst free conditions Knoevenagel condensation of 4-hydroxycoumarin 57 with phenylglyoxal 56 gave the second intermediate.Michael addition of first intermediate and second intermediate yielded the third intermediate, which on intramolecular cyclization and dehydration led to the formation of the desired pyrrole derivatives 60.

Fig. 10 .
Fig. 10.Initially the intermediate is formed by the formylation reaction between acetophenone 65 and N, N-dimethylformamaide dimethylacetal 66, which undergoes Michael addition with amine 67 followed by elimination of dimethylamine to form the second intermediate.Knoevenagel condensation reaction between aryl-glyoxal monohydrate 68 and malononitrile 69 forms the third intermediate.Subsequently the Michael addition of the second intermediate to the third intermediate produces iminium ion giving the fourth intermediate, which undergoes an imine-enamine-tautomerization driven intramolecular cyclization leading to the formation of the furano-pyrrole intermediate which undergoes ring opening to form the target pyrrole 70.

Scheme 15 .Fig. 11 .
Scheme 15.One pot three component synthesis of indole-substituted dihydrocoumarin Shi et al., have reported a MCR protocol which involves the reaction of 5-methylindoline-2,3dione 75, sarcosine 76 and methyl 3-phenylpropiolate 77 in isopropanol at reflux for 8 h to furnish the desired spiro[indoline-3,2'-pyrrole] derivatives 78 with excellent yield under metal free conditions (Scheme 16). 86The proposed mechanism for this reaction envisages condensation of isatin 75 with sarcosine 76 to form the corresponding azomethine ylide as the first intermediate, after which the protic solvent of isopropanol is thought to promote the decarboxylation of the initially formed intermediate to form the 1,3-dipolar second intermediate.The 1,3-dipolar cycloaddition of the second intermediate with methyl 3-phenylpropiolate 77 results in the target product spiro[indoline-5 3,2'-pyrrole] 78.

Scheme 20 .
Scheme 20.One pot four component synthesis of pyrano-pyrazoles derivativeRecently, an exclusive one-pot synthesis of fused pyridine and pyrrole derivatives 100 and 102 was developed by the Mishra et al., (Scheme 21).They used very cheap and easily available reactants like arylglyoxal monohydrate 97, 4-hydroxy coumarin 98, 3-amino-5-methylpyrazole 99.92For the synthesis of fused pyridine derivatives 100 and for the synthesis of the pyrrole derivatives 3-amino coumarin 101 was used in the place of 3-amino-5-methylpyrazole 99 in acetic acid, under MW heating for 30 min.at 130 o C (Scheme 21).The mechanistic pathway for this protocol shows that initially, Knoevenagel condensation and isomerization takes place to produce an intermediate which then, undergoes intra molecular cyclization followed by tautomerization to gives the final product.

96 Scheme 23 .
Scheme 23.One pot four component synthesis of penta-substituted Pyrrole derivatives

Scheme 30 .
Scheme 30.One pot three component synthesis of complex spirocyclicoxindole-butenolides An efficient and convenient route developed by K. B. Manjappa et al., has paved the way for the synthesis of multi-functionalized spiro-pyrrolizidines 149 or pyrrolizinones 148 by a one-pot three component reaction of L-proline 145, benzaldehyde 146 and 1,3-indanedione 147 via a catalyst free procedure under microwave irradiation.The reaction gave satisfactory results with various compounds (Scheme 31). 103S piropyrrolizidines 149 or pyrrolizinones 148 formation was proceeds via condensation, Michael addition, and a cyclization sequence.

Scheme 33 .
Scheme 33.One-pot synthesis of substituted bicycle-octane and pyrrole derivatives .112 On the basis of the chemistry of N-heterocyclic nucleophiles, it is assumed that the zwitter ionic intermediate A results from the initial addition of the amino pyridine to the dialkyl acetylene dicarboxylate.The nucleophilic attack of the intermediate A on the halogenated carbon atom of the α-halo ketone generates the salt intermediate B, which subsequently loses a proton to form the next intermediate C.This zwitter ionic intermediate C then undergoes cyclization to give intermediate D, which eliminates HZ to afford the indolizines 184.

Scheme 45 .
Scheme 45.One pot three component synthesis of pyrrole derivatives