Active methylenes in the synthesis of a pyrrole motif: an imperative structural unit of pharmaceuticals, natural products and optoelectronic materials

Abstract

Pyrrole is one of the most important azaheterocycles, due to its wide range of applications in pharmaceuticals and optoelectronic materials, coupled with its utility as an intermediate in natural products. For several decades, realisation of the scope and potential of this heterocyclic system in both the pharmaceutical and materials industries, has sparked new efforts in finding more efficient synthetic methods for the preparation of pyrrole compounds. Inspired by the importance of this system, herein, we report a review on pyrrole based pharmaceuticals, natural products and optoelectronic materials. Synthetic approaches to pyrrole from active methylenes are also reviewed together with novel reports from our laboratory recently (till 2015).

---

Rajni Khajuria

Rajni Khajuria received her M.Sc. with specialization in Organic Chemistry from the Department of Chemistry, University of Jammu in 2010. In August 2012, she completed her Master of Philosophy (MPhil) degree for dissertation entitled ‘A multicomponent synthesis of 3-nitro-4,6-diaryl-5,6-dihydro-2(1H)-pyridones under ultrasonic irradiation’ at the same University under the guidance of Prof. Kamal K. Kapoor. Currently, she is pursuing her PhD work in the same laboratory and her research focuses on the synthesis and development of novel heterocyclic compounds, particularly five- and six-membered azaheterocycles as anti-microbial agents.

Sumita Dham

Sumita Dham is an Associate Professor at Government College for Women, Parade, Jammu. She received her MPhil and PhD degrees in Synthetic Organic Chemistry from University of Jammu, Jammu. After teaching at Devi Arya Mahila College Dinanagar, PUNJAB [affiliated to Guru Nanak Dev University, Amritsar] for seven years, she joined as lecturer in Jammu and Kashmir Higher Education Department in January 2001. Her research interests include the synthesis of heterocyclic compounds of biological significance.

Kamal K. Kapoor

Kamal K. Kapoor received PhD degree in Synthetic Organic Chemistry from IIT, Kanpur. Joined University of Jammu as Lecturer in December 1995, where he is Professor at present. His research interests include the synthesis of novel heterocyclic compounds (employing MCR) having significance in scaffold hopping, biology and material science. He was awarded DST-BOYSCAST and INSA-Royal Society Fellowship for visiting Japan and UK respectively. He has also served in Dabur Research Foundation (Oncology Division) Sahibabad (UP) and Sphaera Pharma IMT Manesar (Haryana) in Medicinal Chemistry. He was also Advisor Consultant, Medicinal Chemistry to Curadev Pharma Pvt. Ltd, Noida.

---

Introduction

Pyrrole is one of the most important five-membered azaheterocycles because of its occurrence as a synthon in many bioactive natural products, synthetic pharmaceuticals and various kinds of functional materials with inevitable properties.¹ The existence of pyrrole in nature was first interpreted by Runge in 1934, when he first noticed the formation of a new substance during the destructive distillation of coal tar and bone oil, which turned red upon application to acid-moistened pine splinters.² He called this substance “pyrrole” (Greek meaning red) although he did not know its chemical constitution and assumed it to be a gas. Pyrrole was first isolated, purified, analyzed and characterized in 1857 from the product (bone tar) of bone pyrolysis.³

Biological activities and applications

Pyrrole in pharmaceuticals

Pyrrole exhibits remarkable biological and pharmacological properties such as anti-bacterial,⁴ anti-fungal,⁵ anti-inflammatory,⁶ anti-oxidative,⁷ anti-tumor and ionotropic.⁸ It also acts as retroviral reverse transcriptase [i.e., human immunodeficiency virus type 1 (HIV-1)], poly(ADP-ribose)polymerase,⁹ prolyl-4-hydroxylase,¹⁰ cellular DNA polymerase, glycogen synthase kinase-3 (GSK-3)¹¹ and protein kinase inhibitor.¹² The wide range of biological properties displayed by pyrrole has stimulated its considerable pharmaceutical interest.

Atrovastatin (marketed by Pfizer as Lipitor®)¹³ 1 is a blockbuster drug widely used as a cholesterol-lowering agent and acts by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Lipitor also has certain pleiotropic effects, such as decreasing inflammation and improving the endothelial functions.¹⁴ 4-Sulfamoyl pyrroles¹⁵ 2 are designed as a novel hepatoselective HMG-CoA reductase inhibitors to reduce myalgia (a statin-induced adverse effect) and are found to have greater selectivity for hepatocytes than Lipitor.

2,3,4-Triaryl-1H-pyrrole derivatives 3 are important anti-hyperglycemic agents, reported to have significant hepatic glucose lowering properties by acting as inhibitors of glucagon receptor.¹⁶ Arylpiperazine containing pyrrole-3-carboxamide derivatives 4 have been found to have potential anti-depressant activity (Fig. 1).¹⁷

Fig. 1 Medicinally important pyrroles as anti-hyperlipidemic, anti-hyperglycemic and anti-depressant agents.

Pyrrole ring is considered as an essential core for the design and synthesis of new anti-inflammatory agents due to its presence in the pharmacophore system of a number of non-steroidal anti-inflammatory drugs (NSAIDs).¹⁸ The three well-known pyrrole based NSAIDs available in the market are tolmetin (Rumatol®) 5, zomepirac 6 and ketorolac (Ketolac®) 7.¹⁹ They inhibit the synthesis of prostaglandin by non-selective inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole 8 is a novel COX-2 selective inhibitor and its selectivity is much higher than those of the conventional NSAIDs viz. naproxen, sodium diclofenate and indomethacin.²⁰ Another novel pyrrole based anti-inflammatory agent is a pyrrole-2-carboxamide 9, that exhibits its activity through acting as p38α inhibitor.²¹ The p38α mitogen-activated protein kinase was identified in human monocytes as the target for a class of cytokine suppressive anti-inflammatory compounds. It regulates the expression of many pro-inflammatory cytokines including interleukin (IL-1), IFNα and IFNγ.

2-Methyl-1,3,5-trisubstituted pyrrole derivatives 10 exhibit remarkable anti-bacterial activity against Mycobacterium tuberculosis.²² Diguanidino 1-methyl-2,5-diaryl-1H-pyrrole derivatives 11 have displayed significant anti-fungal activity against Candida species.²³ Their anti-fungal activity has been found to be better than that of fluconazole on C. albicans, C. krusei and C. parapsilosis. BM 212 (1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)methyl-pyrrole) 12 is a promising lead compound for the discovery of more potent agents with both anti-fungal and anti-mycobacterial activities (Fig. 2).²⁴

Fig. 2 Biologically important pyrroles as anti-inflammatory, anti-bacterial and anti-fungal agents.

Sunitinib 13 is a commercially available pyrrole derived drug, used for the oral treatment of renal cancer and acts as a multi-targeted receptor tyrosine kinase inhibitor.²⁵ 3-[1-Methyl-4-phenylacetyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide 14 exhibited excellent anti-proliferative and cyto-differentiating effect in erythro leukemia.²⁶ Tallimustine 15, a synthetic anti-cancer drug is related to natural product distamycin (Fig. 3).²⁷

Fig. 3 Medicinally important pyrroles as anti-cancer agents.

Pyrrole in natural products

The most prominent biological context of pyrrole is the tetrapyrrole scaffold, a key structural unit of heme and related porphinoid co-factors²⁸ such as heme b 16, chlorophyll a 17, vitamin B₁₂ 18 and factor 430 19. Porphobilinogen 20 is a biosynthetic precursor of tetrapyrrole chromophores in heme proteins, photosynthetic antennae proteins, photosynthetic reaction centres and phytochromes.²⁹

The pyrrole ring is well-found in marine natural products such as nakamuric acid³⁰ 21 and axially chiral marinopyrroles 22–23, which showed good activity against metacillin-resistant Staphylococcus aureus strains.³¹ Lamellarins, isolated from prosobranch mollusc Lamellaria sp., display remarkable anti-tumor and anti-HIV activities.³² Lamellarin K 24 and Lamellarin L 25 possess biological activities which include cytotoxicity, HIV-1 integrase inhibition and multidrug-resistance (MDR) reversal.³³ O-Methylated analogues of storniamide A 26, isolated from a variety of marine organisms (ascidians, molluscs and sponges) are potent inhibitors of the multidrug resistance (MDR) phenomenon,³⁴ which can be considered as the main obstruction to successful anti-cancer chemotherapy. For this reason, much interest has been paid in the development of new MDR modulators.³⁵ Verrucarin E 27 is an anti-mitotic 3,4-disubstituted pyrrole isolated from Myrothecium verrucaria.³⁶ Halitulin 28 is a cytotoxic spongian natural product isolated from Haliclona tulearensis (Fig. 4).³⁷

Fig. 4 Natural tetrapyrroles.

Pseudilins 29 are a family of halogenated marine alkaloids that act as allosteric inhibitors of the third enzyme in the non-mevalonate pathway for isoprenoid biosynthesis, which is absent in mammals and is therefore a striking target for the development of therapeutic agents.³⁸ The prodiginines are a family of red-coloured, tripyrrolic alkaloids synthesized by bacteria belonging to the Serratia genus and have anti-bacterial, anti-biotic and anti-cancer properties.³⁹ In particular, prodigiosin 30 (Serratia pigment) is a potent anti-biotic agent and obatoclax 31 (GX-15-070) is a prodiginine analogue that triggers cell death via autophagy and is under phase II clinical studies as an anti-tumor agent. Natural anti-biotics netropsin 32 and distamycin 33 are sequence-selective DNA minor-groove non-covalently binding agents, selective for AT-rich sequences of DNA.⁴⁰ Roseophilin 34, another important natural product bearing pyrrole nucleus is a novel anti-biotic isolated from Streptomyces griseoviridis.⁴¹ Roseophilin possesses a topologically distinctive skeleton combining a strained macrocyclic unit with an extended heterocyclic chromophore. This alkaloid exhibits very promising cytotoxicity in vitro against K562 human erythroid leukemia and KB human epidermoid carcinoma cell lines in the submicromolar range, making it a new lead structure in the search for anti-cancer agents (Fig. 5).

Fig. 5 Some bioactive natural products containing the pyrrole nucleus.

Due to its presence in a large number of natural and synthetic compounds with remarkable biological activities, pyrrole and its derivatives continue to receive much attention in organic synthesis and medicinal chemists often turn to pyrrole based compounds as a target pharmacophore for the development of therapeutic agents.

Pyrrole in optoelectronic materials

Pyrrole and its derivatives have been the focus of attraction of material scientists because of their potential as components of optoelectronic materials⁴² such as polymeric light-emitting diodes (PLED) and organic light-emitting diodes (OLED), thin film transistors, non-linear optical polymers, high performance semiconductors derived from hexa(N-pyrrolyl)benzene,⁴³ glucose sensors based on polypyrrole-latex materials⁴⁴ and polypyrrole materials for the detection and discrimination of volatile organic compounds. Derivatives of the 4,4-difluoro-4-boradipyrrin system (BODIPY) 35 have a strong absorption in the UV and emit very intense fluorescence.⁴⁴

Porphyrins are of immense significance because of their natural role in photosynthesis, their intense absorption in the visible region, high stability and the facile functional groups substitution.⁴⁵ Organic dye sensitizers for dye-sensitized solar cells (DSSCs) are of considerable importance as they offer the possibility of low-cost conversion of photo energy, ease of their synthesis and modification, their large molar extinction coefficients and long-term stability.⁴⁶ β-Pyrrolic functionalized porphyrins with donor–π–acceptor character 37–38 and showing high thermal and electrochemical stability, have been exemplified as excellent dye sensitizers for dye-sensitized solar cells.⁴⁷ Conjugated macrocycles particularly the conjugated oligopyrrolic macrocycles (porphyrinoids) have gained significant attention as interesting supramolecular hosts because of their distinctive physical properties and potential applications.⁴⁸ Oligopyrrolic macrocycles containing 2,3-dimethoxy-1,4-phenylene as a non-pyrrolic bridging linkage 39, synthesized from bis-pyrrolyl benzenes by T. Nabeshima group, have shown good fluorescent property due to their remarkable cationic guest recognition ability and large bathochromic shift upon guest binding.⁴⁹

Electrochromic conductive polymers 40 formed by the electrochemical polymerization of β-linked dipyrrole monomers that involves the electrochemical oxidative incorporation of polycyclic aromatic residues into a polymer backbone, are highly electroactive, stable and robust electrochromic conducting materials.⁵⁰ Their conductive electrochromic versatility is due to the electron-rich nature of pyrrole ring that imparts its polymer with enviable intrinsic redox properties such as high conductivity, low oxidation potential and high redox stability. Organic–inorganic heterojunction nanowire arrays are the materials that combine functional organic molecules and inorganic molecules, and have characteristic semi-conducting properties that were not observed in the individual component on a nanoscale or in the bulk.⁵¹ The end-to-end P–N (PBPB/CdS) heterojunction nanowire arrays combined organic (poly[1,4-bis(pyrrol-2-yl)benzene], PBPB) and inorganic (CdS) molecules have been successfully designed and fabricated by N. Chen et al.⁵² They have displayed perfect light-controlled diode and rectifying effects due to a larger energy level gap between PBPB and CdS (Fig. 6).

Fig. 6 Pyrrole based optoelectronic materials.

Pyrrole syntheses from various active methylenes

The important biological, medicinal and materials science applications of pyrrole, coupled with its utility as an intermediate in natural products synthesis have made pyrrole an important class of molecules in organic research. Therefore, the development of simple and convenient synthetic methods for this heterocycle is important in organic synthesis. A large variety of synthetic pathways exists in the literature¹ and most of the starting materials used in the process are chosen from the pool of compounds comprising of α-hydroxyketones, α-dicarbonyls, 1,4-dicarbonyls, α-diazoketones, isocyanides, nitroalkanes, nitroalkenes, active methylenes and alkynes. Availability and accessibility of architecturally diverse active methylenes have rendered them as versatile precursors for the generation of a variety of pyrroles. Active methylene, depending on the structure, has the capacity to contribute one, two, three or four atoms to the five-atom framework of pyrrole system. Many established traditional approaches for the synthesis of pyrrole using active methylenes are based on the venerable Knorr and Hantzsch reactions which were developed in the late 19^th century.

Even with the substantial work on this heterocycle for several decades, new reports that provide efficient and versatile access to pyrroles continue to appear, reflecting the importance of this heterocycle in various areas of organic science. A review on the syntheses of pyrrole motif from various active methylenes is presented here (Fig. 7).

Fig. 7 Synthesis of pyrrole motif from various active methylenes.

Traditional methods of syntheses

L. Knorr in 1885 reported the formation of diversely substituted pyrroles via cyclocondensation of α-aminoketones with β-ketoesters or β-diketones (Scheme 1).⁵³ Knorr pyrrole synthesis is the most widely applied ring closure reaction in the pyrrole chemistry. But, the applicability of this reaction is limited because of the tendency of α-amino ketones for self condensation to form a pyrazine, especially when the methylene ketone is not sufficiently reactive (Scheme 2).

Scheme 1 The Knorr pyrrole synthesis.

Scheme 2

In 1890, Hantzsch published a short communication reporting the synthesis of a pyrrole derivative by refluxing equimolar mixture of acetoacetic ester and α-chloroacetone in the presence of aqueous ammonia⁵⁴ (Scheme 3). This reaction was named as ‘The Hantzsch Pyrrole synthesis’. The reaction proceeds via stabilized enamine intermediate (ethyl β-aminocrotonate) 42.

Scheme 3 The Hantzsch pyrrole synthesis.

Over the years, various methods have been developed for the synthesis of pyrrole and its derivatives using diverse active methylenes and are illustrated in this review article.

From α-activated nitriles

α-Activated nitriles viz. malononitrile, 2-cyanoacetic acid, 2-cyanoacetamide, ethyl 2-cyanoacetate, 2-nitroacetonitrile, tert-butyl 2-cyanoacetate and diethyl (cyanomethyl)phosphonate are useful active methylenes for the synthesis of pyrrole derivatives.

In 1961, K. Gewald reported a base catalyzed condensation of 3-amino-2-butanone with malononitrile to synthesise 2-amino-3-cyano-4,5-dimethylpyrrole (Scheme 4),⁵⁵ which has been widely exploited as a potential precursor in the preparation of medicinally important substituted pyrrolo[1,2-a]-pyrimidines⁵⁶ and a 2,3,4,5-tetrahydropyrrolo[1,2-a][1,3]-diazepine.⁵⁷ In 1977, the J. W. Sowell, Sr. group expanded the scope of Gewald's method to synthesize 5-substituted analogs of 2-amino-3-cyano-4-methylpyrrole by the reaction between N-acetyl-α-amino ketones and malononitrile (Scheme 5).⁵⁸ The 5-substituted analogs 44 were further hydrolysed into the corresponding N1-deacetylated pyrrole derivatives by heating at 50–60 °C using 50% aqueous KOH solution. N-Acetyl-α-amino ketones 43, in turn, were prepared from L-/DL-α-amino acids using Dakin and West procedure.⁵⁹

Scheme 4

Scheme 5

2-Amino-1H-pyrrole-3-carbonitrile derivatives has been widely explored as key compounds for the preparation of fused pyrrolo[2,3-d]pyrimidines in light of the promising chemical and biological properties of the later.⁶⁰ In this perspective, substituted 1-benzyl-2-amino-3-cyano pyrroles were synthesized by H. J. Roth and K. Eger using malononitrile, α-hydroxy ketones and benzylamine as starting materials in refluxing toluene (Scheme 6).⁶¹ In 2005, M. S. Mohamed and his co-workers synthesized 2-amino-1-(3,4-dichlorophenyl)-4-phenyl-1H-pyrrole-3-carbonitrile in two steps from phenacyl bromide, 3,4-dichloroaniline and malononitrile under thermal conditions (Scheme 6).⁶²

Scheme 6

Townsend and co-workers synthesized 1-substituted 2-amino-pyrrole-3-carbonitriles from N-substituted aminoacetaldehyde dimethyl acetals and malononitrile in the presence of p-toluenesulfonic acid monohydrate (p-TsOH·H₂O) (Scheme 7).⁶³

Scheme 7

In 2008, Ghorab et al. prepared 4-(2-amino-3-cyano-4-phenyl-pyrrol-1-yl)benzenesulfonamide by refluxing a mixture of 4-(2-oxo-2-phenyl ethylamino)-benzene sulfonamide and malononitrile in ethanol containing sodium ethoxide (Scheme 8).⁶⁴ 4-(2-Oxo-2-phenyl-ethylamino)benzene sulfonamide was synthesized from sulfanilamide and phenacyl bromide using Ismail et al.'s method.⁶⁵ Two years later, the same group demonstrated the applicability of the above method to synthesize two N-substituted-4-(2-amino-3-cyano-4-phenyl-pyrrol-1-yl)benzenesulfonamides (Scheme 9).⁶⁶ The later was used for the preparation of a series of potent anti-cancer and radio sensitizing 2-substituted-3-cyano-4-phenyl pyrrole derivatives bearing either sulfathiazole or sulfapyridine moieties.

Scheme 8

Scheme 9

K. Wang and A. Dömling developed a multicomponent method to afford 2-amino-5-ketoaryl-1H-pyrrole derivatives employing aromatic aldehydes, N-protected α-amino acetophenones and α-activated nitrile (malononitrile, 2-cyanoacetic acid derivatives) as reactants in refluxing trifluoroethanol (Scheme 10).⁶⁷ A library of 2-amino-5-ketoaryl-1H-pyrrole derivatives with a broad substrate scope were synthesized in moderate to good yields.

Scheme 10

One year later, Magedov et al. reported the novel use of N-(substituted sulfonamido)acetophenones to obtain tetra- and penta-substituted pyrrole derivatives (Scheme 11).⁶⁸ The Magedov's group utilized this methodology for a short, four-step total synthesis of marine alkaloids rigidins A, B, C and D possessing calmodulin antagonistic and cytotoxic activities. The reaction follows the same mechanism as proposed by Wang and Dömling, forming penta-substituted pyrrolidine intermediate, which underwent DDQ promoted in situ oxidation to penta-substituted 2-amino pyrrole derivatives and the tetra-substituted-1H-pyrroles were obtained via DBU-DMF promoted dehydrosulfinylation of pentasubstituted pyrrolidines. Further, refluxing an ethanolic solution of the three starting materials containing 0.6 equiv K₂CO₃ resulted in tetra-substituted-1H-pyrrole derivatives in moderate to excellent yields. This method was applicable to diversely substituted (aryl-, hetaryl-, alkyl) aldehydes, N-(aryl-, hetaryl-, alkyl-sulfonamido)acetophenones and various α-activated nitriles including cyano, acyl, sulfono, alkoxycarbono and carbamido acetonitriles to generate a library of diversely substituted 2-amino pyrrole derivatives.

Scheme 11

In 2010, T. Takayama and co-workers reported the synthesis and characterization of a novel series of 2,3,4,5-tetrasubstituted pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors through their enzyme inhibitory activity, cellular activity against mixed lymphocyte reaction (MLR14), and structure–activity relationships (SAR) (Scheme 12).⁶⁹ 2,3,4,5-Tetrasubstituted pyrrole derivatives were synthesized from easily available 4-phenoxybenzoic acid. 4-Phenoxybenzoic acid was reacted with thionyl chloride under reflux to give the acid chloride analog, followed by treatment with malononitrile giving compound 45. 45 on methylation of its hydroxyl group and reaction with 4-methoxybenzylamine formed the intermediate 46. The intermediate 46 was then reacted with α-bromoacetophenone in the presence of K₂CO₃ and subsequently with polyphosphoric acid in the presence of thioanisole afforded the corresponding pyrrole derivatives. A library of pyrrole derivatives were synthesized employing diversely substituted α-bromoacetophenones. Compound 4-amino-5-(2,6-difluorobenzoyl)-2-(4-phenoxyphenyl)-1H-pyrrole-3-carboxamide 49 was found as the most potent analog and had shown excellent enzymatic activity against Lck inhibitors (IC₅₀ = 1.3 nM).

Scheme 12

In 2013, C. Mukhopadhyay and his group described a one-pot, organocatalyzed, multicomponent synthesis of 3H-pyrrole derivatives from ketones, malononitrile and thiols in eco-benign solvent (Scheme 13).⁷⁰ This novel 3H-pyrrole synthesis presented an entirely new approach involving the dual role of the cyano moiety acting both as a carbon center nucleophile and an electrophile. This is the first report describing the construction of the aza-ring without starting from any amine moiety. Various aryl/alkyl ketones and aryl/alicyclic/alkyl thiols were used to establish the general applicability of this method. Et₃N was the most efficient catalyst among the bases scanned such as NaOH, K₂CO₃, DBU, guanidine and piperidine for this reaction.

Scheme 13

The Nishida group reported a K₂CO₃ promoted condensation of commercially available α-bromoacetophenone with ethyl 2-cyanoacetate, followed by cyclization under acidic condition using HCl in THF to afford ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (Scheme 14).⁷¹ Ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate has been used as a key intermediate by the same group to synthesize novel pyrrole derivatives as highly selective gastric H⁺,K⁺-ATPase inhibitors.

Scheme 14

Triethylamine catalyzed synthesis of novel 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate from 2-cyanoacetamide has been discussed by P. B. S. Dawadi and J. Lugtenburg (Scheme 15).⁷² The reaction of ethyl 2-chloroacetoacetate with 2-cyanoacetamide in the presence of a non-nucleophilic base, triethylamine in stoichiometric amounts, afforded C-alkylation product ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxylate 48, followed by its p-toluenesulfonic acid-catalyzed dehydration to obtain 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate in 81% yield. This work enables access to libraries of biologically significant pyrrole derivatives from commercially available starting materials. Further, reacting ethyl 4-chloroacetoacetate (the 4-chloro isomer of ethyl 2-chloroacetoacetate) with 2-cyanoacetamide under similar reaction conditions yielded a novel ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate as the only product in high yield (87%).

Scheme 15

Y. Yu and co-workers proposed a simple, novel, catalyst-free approach to polyfunctionalized 2-amino-1H-pyrroles in good yields using vinyl azides and α-cyano derivatives (Scheme 16).⁷³ This method proceeded by the initial formation of 2H-azirine intermediate, thermally generated in situ from vinyl azide. 2H-Azirine is then reacted with α-cyano derivative, followed by a sequential domino cyclization and an intramolecular electronic rearrangement to give the desired 2-amino-1H-pyrrole derivatives. Various α-azidovinylesters, α-azidovinylketones and α-cyano derivatives were scanned to create the substrate scope of the method. A range of additives (Mn(OAc)₂·4H₂O, Ni(OAc)₂·4H₂O, AcOH, K₂CO₃, DBU) were screened but additive-free reaction was favoured. Of the various protic and aprotic solvents screened, ethanol gave the best result and a combination of EtOH : H₂O (1 : 1) as co-solvent system was verified as the best reaction medium at 80 °C. Good yields, operational simplicity, no catalyst loading and wide substrate scope are the significant advantages of this reaction from synthetic viewpoint.

Scheme 16

An efficient, catalyst-free synthesis of polysubstituted pyrroles via novel four-component domino reaction of an arylglyoxal monohydrate, an aniline, a dialkylbut-2-ynedioate and malononitrile has been investigated by D.-Q. Shi et al. (Scheme 17).⁷⁴ Among the various solvents like H₂O, DMF, MeOH, EtOH, MeCN and CHCl₃, refluxing EtOH was the most efficient for the transformation. The arylglyoxal monohydrate and the aniline bearing electron donating as well as electron-withdrawing groups on the aryl ring, and also a heteroarylglyoxal ring were well tolerated to access a diverse collection of polysubstituted pyrroles in good yields. Further, to expand the scope of this method, dialkylbut-2-ynedioate was replaced by alkyl acetoacetate, resulting in the formation of the desired polysubstituted pyrroles in moderate yields. Reaction with ethyl 2-cyanoacetate did not form the desired product.

Scheme 17

From 2-(2-oxo-2-phenylethyl)malononitrile

In context of the versatility of nitriles as reagents in heterocyclic synthesis, Hilmy and Pedersen in 1989 reported the reaction of 2-(2-oxo-2-phenylethyl)malononitrile with primary amines in refluxing EtOH using a catalytic amount of HCl to afford the corresponding N-arylated pyrrole derivatives (Scheme 18).⁷⁵ The reaction was completed in 4–8 days and the corresponding products were obtained in 29–45% yields. Use of primary alkyl amines did not give the desired product and instead, the 2-amino-5-phenyl-3-pyrrolecarbonitrile was formed.

Scheme 18

In 2009, Al-Mousawi et al. synthesized 2-amino-4-benzoyl-1H-pyrrole-3-carbonitrile from 2-(2-oxo-2-phenylethyl)malononitrile (Scheme 19).⁷⁶ The initial reaction of 2-(2-oxo-2-phenylethyl)malononitrile with N,N-dimethylformamide dimethyl acetal (DMFDMA) afforded an enaminone, which upon refluxing in acetic acid in the presence of ammonium acetate gave the corresponding 2-aminopyrrole carbonitrile in 60% yield.

Scheme 19

From α-activated isonitriles

One of the most significant applications of α-activated isonitriles is their utility in the synthesis of pyrrole nucleus. In 1985, Barton and Zard reported an expedient synthesis of pyrroles via guanidine-catalyzed Michael addition of α-isocyanoacetate esters to nitroalkenes or their β-acetoxynitro precursors followed by cyclisation to initially form pyrroline intermediates, which underwent base-promoted nitrous acid elimination to afford 5-unsubstituted pyrroles in high yields (Scheme 20).⁷⁷ This reaction is generally known as ‘The Barton–Zard pyrrole synthesis’ or ‘The Barton–Zard reaction’. Pyrroles unsubstituted at 5-position are significant structural units in the synthesis of porphyrins fused with various aromatic rings or bicyclic frameworks. Replacing guanidine with DBU also resulted in pyrrole formation but in lower yield and in somewhat longer reaction time. Ono and Maruyama used this methodology to prepare pyrroles having long alkyl chains at 3- and/or 4-positions (Scheme 21),⁷⁸ the important precursors for the synthesis of lipophilic polypyrroles and porphyrins. The formed polypyrroles and porphyrins can be applied as functional dyes. The reactions between nitroalkenes bearing long alkyl chains and ethyl 2-isocyanoacetate in the presence of a strong base DBU using THF solvent at room temperature afforded 2-ethoxycarbonyl-3,4-dialkylpyrroles (70–85%) and 2,4-bis(ethoxycarbonyl)-3-alkylpyrroles (5–8%).

Scheme 20

Scheme 21

One year later, the same group reported the preparation of 4-alkyl-3-trifluoromethyl pyrrole-2-carboxylic acid esters by the reaction of trifluoromethylated β-nitroacetates with α-isocyanoacetate esters employing the previously established reaction conditions (Scheme 22).⁷⁹ The requisite starting material viz. trifluoromethylated β-nitroacetates were prepared from trifluoroacetic acid and nitroalkanes. They also demonstrated the conversion of 4-alkyl-3-trifluoromethyl pyrrole-2-carboxylic acid esters to the corresponding porphyrins via tetramerization of their 2-(hydroxymethyl) analogs.

Scheme 22

In 1995, the Artico group reported the synthesis of a new class of potent anti-fungal agents 3-aryl-4-[α-(1H-imidazol-l-yl)arylmethyl]pyrroles from 3-aroyl-4-aryl substituted pyrroles. The starting 3-aroyl-4-aryl substituted pyrrole derivatives were prepared from 1,3-diaryl-2-propen-l-ones and tosylmethylisocyanide (TosMIC) using sodium hydride in anhydrous DMSO–Et₂O solvent system at room temperature (Scheme 23).⁸⁰ Using this protocol, Dannhardt et al. reported the preparation of 3-aroyl-4-aryl substituted pyrroles for their evaluation as a new class of COX-1/COX-2 inhibitors (Scheme 23).⁸¹ 3-Aroyl-4-aryl substituted pyrrole derivatives were synthesized from 1,3-diarylprop-2-en-1-ones and TosMIC in the presence of sodium hydride in THF. A variety of 1,3-diarylprop-2-en-1-ones were used to establish the generality of this method.

Scheme 23

The Murahashi group has described a rhodium-complex catalyzed reaction of ethyl 2-isocyanoacetate with β-dicarbonyls for the regioselective construction of pyrrole-2-carboxylates (Scheme 24).⁸² The low-valent rhodium complex acts as an efficient catalyst for the activation of α-C–H bond of ethyl 2-isocyanoacetate, forming isocyanoalkylrhodium intermediate. Insertion of β-dicarbonyls to the Rh–C bond of this complex, followed by decarbonylation and cyclocondensation gave the corresponding pyrrole derivatives. Acetylacetone afforded 3,5-dimethylpyrrole-2-carboxylate as a sole product in 84% yield whereas asymmetric β-dicarbonyl compounds gave regioselective pyrroles on the basis of either steric effects or electronic effects. When R¹ is an electron-withdrawing group and is larger than R³, selective addition of the bulky isocyanoalkylrhodium intermediate would occur predominantly to the carbonyl group adjacent to R¹ because of its high electrophilicity, giving a pyrrole with R¹ at the 3-postion. On the other hand, when R³ is larger than R¹, the addition occurs at the less hindered carbonyl group adjacent to R¹, giving a pyrrole with bulky R³ at the 5-position.

Scheme 24

A rapid and simple regiocontrolled synthesis of various 2-substituted 3,4-diaryl pyrroles was described by Bullington et al. (Scheme 25).⁸³ The reaction of methyl isocyanoacetate with α,β-unsaturated nitriles in the presence of an excess of potassium tert-butoxide at 0 °C under nitrogen atmosphere afforded the 3,4-diaryl-1H-pyrrole-2-carboxylates in 51–60% yields. Both the electron-withdrawing and electron-donating substitutions on the aryl rings were well tolerated. Also, the synthesized methyl 4-(3,4-dimethoxyphenyl)-3-(2,4,5-trimethoxyphenyl)-1H-pyrrole-2-carboxylate was further used as a robust and versatile building block for the concise total synthesis of Ningalin B 50 (a marine natural product belonging to the tunichrome family).

Scheme 25

The Kamijo group developed an organophosphine-catalyzed regioselective synthesis of trisubstituted pyrroles by the initial 1,4-addition of the nucleophilic phosphine catalyst to the alkynes, followed by a [3 + 2] cycloaddition between the resulting alkenyl phosphine intermediates and a carbanion derived from isocyanides (Scheme 26).⁸⁴ A bidentate phosphine 1,3-bis(diphenylphosphino)propane (dppp) was used as an additive in the reaction. They also prepared the trail pheromone 51 of a leaf-cutting ant (Atta texana) in about 42% yield by using this methodology.

Scheme 26

Inspired by the recent boost in the field of nucleoside mimetics owing to their biological and chemotherapeutic properties, Krishna et al. demonstrated a new and exciting synthesis of pyrrole-2-deoxy-C-ribosides by the TosMIC addition and cyclization on 2-deoxy-D- and L-ribo-1-carboxaldehydes (Scheme 27).⁸⁵ (R) and (S)-2,3-O-isopropylidene glyceraldehydes were employed as the core starting materials and were converted to α,β-unsaturated ester I, III, IV/aryl sulfonyl ester II derivatives through a series of steps. Treatment of I–IV independently with lithium salt of TosMIC afforded the corresponding pyrrole C-nucleosides as α/β anomeric mixtures and isolated by column chromatography purification. They further explored the efficacy of this method to achieve the synthesis of pyrrole-2-deoxy-C-ribosides with easily removable benzoyl (OBn) protecting group at C-3 and C-5 for their impending use in the formation of oligomers.

Scheme 27

In 2007, the group of H. Ila developed a new and highly efficient strategy for the regioselective preparation of 2,3,4-trisubstituted pyrroles via a base-induced [3 + 2] cycloaddition of readily accessible polarized ketene S,S- and N,S-acetals with carbanions derived from activated methylene isocyanides (Scheme 28).⁸⁶ This methodology allowed the precise introduction of various substituents viz. aryl, tosyl, acetyl, carbalkoxy, cyano, nitro, benzoyl, cyclic amines at the 2-, 3- and 4-positions of the pyrrole ring, thus establishing the practicability of this method. Employing nitroketene S,S-acetal and ethyl isocyanoacetate as starting materials, 2,3,4-trisubstituted pyrrole with a nitro group at 4-position was obtained, and this constitutes the first example of the Barton–Zard reaction in which a nitro group is retained in the 4-position of the pyrrole ring.

Scheme 28

The group of M. Terzidis reported the reaction of chromone-3-carboxaldehydes with TosMIC to afford 2-tosyl-4-(2-hydroxybenzoyl)pyrrole derivatives in good yields (Scheme 29).⁸⁷ The reaction was performed in the presence of DBU in a aprotic non-polar solvent THF at room temperature to obtain the 2-tosyl-4-(2-hydroxybenzoyl)pyrroles. The reaction occurs via deformylation of the intermediate generated by the chromone ring opening of the initially formed Michael adduct of nucleophilic TosMIC and chromone-3-carboxaldehydes, since the formyl group leaves preferentially over the tosyl group.

Scheme 29

In 2012, Y. Yu et al. explored the use of TosMIC and ethyl 2-azidoacetate for the synthesis of 2,3,4-trisubstituted pyrrole derivatives (Scheme 30).⁸⁸ They reported a base promoted, two-component synthesis of 2,3,4-trisubstituted pyrroles from TosMIC and vinyl azides (obtained by the Knoevenagel condensation of ethyl 2-azidoacetate and aldehydes). Screening of various bases viz. DBU, K₂CO₃, Cs₂CO₃, t-BuOK and NaH revealed that NaH was the most suitable base for this transformation. The reaction involves the initial formation of vinyl azide, followed by its Michael addition by TosMIC and intramolecular cyclization via nucleophilic substitution. Finally, the loss of hydrogen azide from intermediate and its subsequent [1,3] hydrogen shift leads to the final product.

Scheme 30

In 2013, A. lei et al. reported a silver-catalyzed ‘click’ synthesis of a library of substituted pyrroles by the cycloaddition of terminal alkynes and isocyanides using 10 mol% Ag₂CO₃ as the catalyst in N-methyl-2-pyrrolidone (NMP) at 80 °C (Scheme 31).⁸⁹ Among the various silver and copper salts (Ag₂O, AgNO₃, Cu(OAc)₂, CuI) tested, Ag₂CO₃ was most efficient and 0.1 equiv was the best optimized concentration for this transformation. This method was applicable for a wide range of terminal alkynes and isocyanides. The aryl-substituted terminal alkynes bearing both electron-withdrawing and electron-donating substituents smoothly reacted under the optimized reaction conditions to afford the corresponding pyrrole products in good yields. Various aliphatic terminal alkynes with cyclopropyl, n-butyl, n-amyl and terminal hydroxy groups were well tolerated. This method was also successful for internal alkynes such as ethyl 3-phenylpropiolate and dimethylbut-2-ynedioate. Ethyl 2-isocyanoacetate, methyl 2-isocyanoacetate and diethyl isocyanomethyl phosphonate reacted efficiently to give the pyrroles in high yields.

Scheme 31

A regioselective method for the preparation of a diverse array of trisubstituted pyrroles has been developed by Liu et al., starting from the readily available α-formyl ketene dithioacetals, ethyl isocyanoacetate and TosMIC (Scheme 32).⁹⁰ This method proceeds through the catalyst-controlled regiodivergent heterocyclization of ethyl isocyanoacetate or TosMIC with α-formyl ketene dithioacetals to afford 5-alkylthiopyrroles and 4-alkylthiocarbonylpyrroles in high yields in a single step. 5-Alkylthiopyrroles were obtained as the sole products when DBU–ZnCl₂ was used as a promoter whereas the exclusive formation of 4-alkylthiocarbonyl-pyrrole derivatives occurred in the presence of a DBU–[Cu(OTf)]₂–C₆H₆ catalytic system. α-Formyl ketene dithioacetals bearing alkyl, phenyl, electron-deficient/electron-rich aryl and heteroaryl groups were well tolerated for this regioselective synthetic strategy.

Scheme 32

From α-azidoesters

The Entrena group synthesized a series of new 5-phenyl-1H-pyrrole-2-carboxamide derivatives as neural and inducible nitric oxide synthase (nNOS and iNOS) inhibitors, starting from readily available reactants viz. 2-nitro-5-substituted cinnamaldehydes and ethyl 2-azidoacetate (Scheme 33).⁹¹ These molecules show moderate in vitro nNOS and iNOS inhibition and iNOS selectivity in some cases. The two most potent compounds, 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid methylamide (QFF205) 52 and 5-(2-aminophenyl)-1H-pyrrole-2-carboxylic acid cyclopentylamide (QFF212) 53 have been found to prevent the in vivo NOS activity in both cytosol (iNOS) and mitochondria (i-mtNOS) observed in the MPTP model Parkinson's disease.

Scheme 33

From ethyl 2-aminoacetate hydrochloride

In 1980, Barluenga et al. proposed an expedient regioselective synthesis of 3,5-diarylpyrrole-2-carboxylates and 3-arylpyrrole-2-carboxylates by the reaction of azabutadiene derivatives with ethyl 2-aminoacetate hydrochloride in pyridine at 80 °C (Scheme 34).⁹² The reaction was proposed to start with an exchange reaction between the amino group of the glycine ester and the imino group of one of the tautomeric forms of the 1,3-diimine 54. The resulting azapentadiene anion intermediate undergoes electrocyclic closure, giving 1H-pyrrole-2-carboxylates in good yields.

Scheme 34

In 1990, Hombrecher and Horter developed a practical method of preparation of 2,3,4,5-tetrasubstituted pyrroles from ethyl 2-aminoacetate hydrochloride and β-dicarbonyls in two-steps under base-catalyzed reaction conditions (Scheme 35).⁹³ The reaction of ethyl 2-aminoacetate hydrochloride with β-dicarbonyls in the presence of triethylamine led to the formation of ethyl N-(3-oxo-1-alkenyl)glycinates 55, which were then easily converted into corresponding pyrroles by sodium ethoxide catalyzed intramolecular Knoevenagel condensation.

Scheme 35

In 2014, Opatz and co-workers reported an efficient one-pot method for the synthesis of trisubstituted pyrroles from 1,3-diaryl propen-2-ones and ethyl 2-aminoacetate hydrochloride via initial cyclocondensation, followed by DDQ- or Cu(OAc)₂- or CuCl-assisted oxidation of the dihydropyrrole intermediate generated in situ (Scheme 36).⁹⁴

Scheme 36

From carbethoxyacetamidine

Toja et al. reported a novel method of preparation of pyrrolo[3,2-b]pyridine analogs of nalidixic acid using ethyl 2-amino-1H-pyrrole-3-carboxylates as suitable starting materials, in view of the anti-bacterial activity displayed by pyrrolo[3,2-b]pyridines and high-potency of nalidixic acid for the treatment of urinary tract infections. The required ethyl 2-amino-1H-pyrrole-3-carboxylates were synthesized by the reaction of carbethoxyacetamidine with α-bromoacetone/α-chloroacetaldehyde in ethyl acetate within 0.30 h (66–70% yield) (Scheme 37).⁹⁵

Scheme 37

From alkyl 2-nitroacetate

In 1984, Zard et al. developed a simple and mild synthesis of pyrroles from secondary aliphatic nitro compounds (Scheme 38).⁹⁶ This method proceeds through the tributylphosphine–diphenyldisulphide (Bu₃P–PhSSPh) promoted reductive cyclization of γ-nitroketones 56 in THF at room temperature and involves the initial reduction of nitroalkanes to imine derivatives, followed by their subsequent intramolecular cyclization to obtain the corresponding trisubstituted pyrroles. γ-Nitroketones were prepared by the Michael addition of nitroalkanes to 1,3-disubstituted propen-2-ones following Weller et al.'s method.⁹⁷ After a decade, the same group reported an expedient synthesis of 3,5-disubstituted-1H-pyrrole-2-carboxylates from γ-nitroketones 57 (bearing an electron-withdrawing group such as an ester geminal to the nitro group) in the presence of a reducing agent formamidinesulfinic acid (thiourea S.S-dioxide) in an inert atmosphere (Scheme 38).⁹⁸ This reaction also proceeded through the intermediacy of oxime and imine of γ-nitroketones, followed by their intramolecular cyclization and subsequent dehydration to afford the corresponding 3,4,5-trisubstituted pyrrole derivatives.

Scheme 38

Epitomizing the scope and versatility of Zard et al.'s concept of intramolecular trapping of the imine intermediate to give pyrrole system, Kapoor et al. in 2013 reported the use of triethylphosphite (P{OEt}₃) as a reductive cyclizing agent for the synthesis of 2,3,5-trisubstituted-1H-pyrroles from γ-nitroketones 57 under microwave irradiation (Scheme 38).⁹⁹ They developed an efficient two-step synthesis of ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates that involved microwave-assisted reductive cyclization of ethyl 2-nitro-5-oxo-3,5-disubstituted pentanoates (γ-nitroketones 57) with triethylphosphite, which in turn, were synthesized from 1,3-disubstituted-2-propen-1-ones and ethyl 2-nitroacetate following Davey and Tivey procedure¹⁰⁰ using diethylamine in refluxing EtOH. The integrity of the proposed mechanism was established by ³¹P NMR and EIMS experiments.

Subsequently, the same group developed an efficient one-pot, solvent-free cascade reaction protocol for the preparation of various ethyl 3,5-disubstituted-1H-pyrrole-2-carboxylates in good to excellent yields by a reaction of 1,3-disubstituted propen-2-ones with ethyl 2-nitroacetate in the presence of diethylamine and triethylphosphite under microwave irradiation (Scheme 39).¹⁰¹ Various electron-withdrawing and electron-donating aryl groups as well as heteroaryl groups in 1,3-disubstituted propen-2-ones were well tolerated under the optimized reaction conditions to obtain more diversified 2,3,5-trisubstituted-1H-pyrroles. The highlight of this method is the development of a new process to synthesize pyrrole derivatives from easily accessible 1,3-disubstituted propen-2-ones under solvent-free one-step reaction. Another prominent aspect of this method is an access to 1,4-bis(2-carboethoxy-5-phenylpyrrol-3-yl)benzene derivatives (bispyrrolylbenzenes). Bispyrrolylbenzenes are interesting structural units having applications in the generation of supramolecular host conjugated macrocycles, heterojunction organic–inorganic semiconductor nanowire arrays and conductive electrochromic polymers.^49,51,52 A reaction with (2E,2′E)-3,3′-(1,4-phenylene)bis(1-phenylpropen-2-one), under similar reaction conditions, interestingly, yielded 1,4-bis(2-carboethoxy-5-phenylpyrrol-3-yl)benzene 58 in 63% overall yield.

Scheme 39

In 2010, the Cossio group developed a novel strategy for the synthesis of pyrrol-2(5H)-ones and 2,3,5-trisubstituted-1H-pyrroles from α,β-unsaturated carbonyls and ethyl 2-nitroacetate (Scheme 40).¹⁰² Michael addition of ethyl 2-nitroacetate on α,β-unsaturated ketones followed by Nef oxidation yielded either γ-ketoacids 59 or α,δ-diketoesters 60 depending upon the hydrolytic (H₂O₂/H₂O, K₂CO₃) or non-hydrolytic (NaOMe, H₂SO₄) oxidizing reaction conditions. Cyclization of the obtained γ-ketoacids 59 and α,δ-diketoesters 60 in the presence of primary amines under microwave irradiation led to the formation of 3,5-disubstituted pyrrol-2(5H)-ones and ethyl 3,5-diaryl-1H-pyrrole-2-carboxylates respectively in good yields. The cyclization step did not occur under classical heating.

Scheme 40

S. Batra et al. synthesized 2,3,4-trisubstituted pyrroles by the DABCO-assisted S_N2 nucleophilic substitution of Baylis-Hillman acetates with ethyl 2-nitroacetate in a THF–water system forming the nitroalkanoates, followed by the chemoselective reduction of their nitro group using SnCl₂·2H₂O to furnish the corresponding oximes (Scheme 41).¹⁰³ Oximes were then treated with tosyl chloride in the presence of triethylamine in dichloromethane to yield the corresponding tosyl derivatives which upon with DBU in dichloromethane gave 2,3,4-trisubstituted pyrroles in low yields.

Scheme 41

From β-dicarbonyls

A traditional approach for the synthesis of pyrrole ring is by the reaction of β-dicarbonyls with α-amino ketones⁵³/α-halogenated ketones⁵⁴ (Schemes 1 and 3). Since then, a number of preparations have been known for the synthesis of pyrrole and its derivatives from β-dicarbonyls.

In 1998, Jung et al. reported a three-component synthesis of tetra-substituted pyrroles from α-halocarbonyl compounds, primary amines and acetoacetylated Rink resin as a solid support (Scheme 42).¹⁰⁴ This protocol involved an initial reaction between an acetoacetylated Rink resin and primary amines forming the corresponding β-enaminones 61, which on treatment with α-halocarbonyl compounds, afforded the corresponding polysubstituted pyrroles.

Scheme 42

I. Nakamura and his group reported that methyleneaziridines are efficient substrates for the synthesis of 1,2,3,4-tetrasubstituted pyrroles from β-diketones (Scheme 43).¹⁰⁵ The reaction proceeded through palladium catalyzed addition of C–H bond of a β-diketone to the double bond of a methyleneaziridine, followed by ring opening of the aziridine moiety at the N–C2 bond. 25 mol% Pd(PPh₃)₄ was the best catalyst among the other catalysts used viz. Pd(dba)₃, Pd(OAc)₂, Ni(PPh₃)₄, Pt(PPh₃)₄, RhCl(PPh₃)₃, and benzene was the best solvent for this reaction. This reaction did not proceed at all in the absence of the palladium catalyst. Further, β-ketoesters and β-diesters did not react with methyleneaziridines under the reaction conditions.

Scheme 43

In 2008, S. Chiba et al. proposed two synthetic approaches to access regioisomeric polysubstituted 1H-pyrroles (Scheme 44)¹⁰⁶ that involve (i) the thermal reaction of vinyl azides with β-dicarbonyl compounds via the 1,2-addition of β-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides; and (ii) the Cu(II)-catalyzed reaction of ethyl acetoacetate with α-ethoxycarbonyl vinyl azides through 1,4-addition. Among the various copper salts used, copper(II) bis(trifluoromethanesulfonyl)imide {Cu(NTf₂)₂} was most efficient as the catalyst and the addition of 5.0 equiv of H₂O as an additive led to an appreciable increase in the yields. However, the reaction of vinyl azide bearing an α-phenyl group with ethyl acetoacetate gave the corresponding pyrrole in only 9% yield. By these two methods, 1H-pyrroles with a broad substrate scope were synthesized in moderate to excellent yields from a variety of vinyl azides (electron donating, electron withdrawing and pyridyl substituted 2-azidocinnamates, α-acetyl carbonyl vinyl azides, N,N-dimethyl amino carbonyl vinyl azides, azido acrylates with hydrogen, alkyl and ethoxycarbonyl moieties, β-azido styrene, β-aryl vinyl azide); and β-dicarbonyls viz. acetyl acetone, β-oxoaldehyde and ethyl acetoacetate.

Scheme 44

During the same year, this group reported the use of manganese(III) acetate to obtain polysubstituted pyrroles (Scheme 45).¹⁰⁷ They have synthesized various tri- and tetra-substituted pyrrole derivatives through the reactions of vinyl azides and β-dicarbonyls in the presence of 10 mol% Mn(OAc)₃·2H₂O using 2.0 equivalents of acetic acid as an additive.

Scheme 45

In 2011, the preparation of tri- and tetra-substituted pyrroles have further been widely investigated by the same group, by reacting together a mixture of vinyl azides and β-dicarbonyl compounds, in toluene at 100 °C for 2–24 h (Scheme 46).¹⁰⁸ In this case, no catalyst was required. They synthesized a library of 1H-pyrroles using various vinyl azides (2-azidocinnamates bearing electron donating, electron withdrawing and pyridyl moieties, α-acetyl carbonyl vinyl azides, N,N-dimethyl amino carbonyl vinyl azides, azido acrylates with hydrogen, alkyl and ethoxycarbonyl substitutions, α-alkyl/aryl vinyl azides, 2-azido styrene, trisubstituted vinyl azides) and β-dicarbonyls viz. β-diketones bearing methyl, alkenyl and phenyl moieties, β-oxoaldehyde and ethyl acetoacetate, to establish the general applicability of the method. Further, they observed that the reactions of vinyl azides with β-dicarbonyl compounds in the presence of a catalytic amount of K₂CO₃ in DMF as solvent at 40 °C led to 1-vinyl-1,2,3-triazoles via intermolecular 1,3-dipolar cycloaddition, instead of poly substituted pyrrole derivatives.

Scheme 46

β-Trifluoromethylpyrrole derivatives are important starting materials for the further synthesis of new pyrroles and electron-deficient porphyrins.¹⁰⁹ The usual Knorr condensation utilizing the β-dicarbonyls containing the trifluoromethyl group afforded the β-trifluoromethylpyrroles but in very low yields (<5%). In 1983, the H. Ogoshi group synthesized β-trifluoromethylpyrroles from ethyl trifluoromethylacetoacetate and β-dicarbonyls, in moderate yields (41–47%) by the modified Knorr condensation reaction using strong acidic conditions (Scheme 47).¹¹⁰ The role of strong acid media is to favour the keto tautomer of ethyl trifluoromethylacetoacetate, that results in the higher yield of the desired pyrroles.

Scheme 47

Diversely substituted β-(trifluoromethyl)pyrrole derivatives bearing different electron-withdrawing substituents at the 3-position were synthesized in good yields by Korotaev et al. via one-pot, three-component Grob cyclization of readily available (E)-1,1,1-trifluoro-3-nitrobut-2-ene with β-dicarbonyls (acetyl acetone, benzoyl acetone and ethyl acetoacetate) and primary aliphatic amines in refluxing EtOH (Scheme 48).¹¹¹ In case of benzoyl acetone, the regiochemistry was controlled by the more reactive acetyl group, which underwent preferential attack on the amine. In this process, the nitro group of nitroalkenes acts as both a powerful stabilizer of the intermediate anion as well as a good nucleofuge in the aromatization forming a pyrrole ring. The similar reaction of ammonia (25% aqueous solution) afforded N-unsubstituted pyrrole derivatives, although in lower yields (24–28%). However, this method was ineffective for (E)-3,3,3-trifluoro-1-nitropropene, lacking the methyl group compared to its homologue (E)-1,1,1-trifluoro-3-nitrobut-2-ene, signifying that cyclization in case of a primary nitronate is not efficient.

Scheme 48

In 2013, the groups of Sarkar,¹¹² Silveira¹¹³ and Jadhav¹¹⁴ independently reported the one-pot, three-component synthesis of polysubstituted pyrroles using easily accessible starting materials such as β-dicarbonyls, nitroalkenes and primary amines (Scheme 49). In the three cases, diversely substituted pyrrole derivatives were obtained in good yields. The Sarkar group demonstrated the use of various substituted anilines to obtain N-aryl pyrroles. In case of DIB [(diacetoxyiodo)benzene] catalyzed synthesis, the yield of the reaction was dependent on the reactants ratio and the best result was obtained by carrying out the reaction using acetylacetone, nitroalkenes and primary amines in the ratio of 1.2 : 1 : 2.

Scheme 49

A one-pot synthesis of N-protected pyrrole-2,4-dicarboxylic acid derivatives has been demonstrated by Chen and co-workers (Scheme 50).¹¹⁵ The polysubstituted pyrrole derivatives were synthesized by a multicomponent reaction of β-ketoesters, primary amines and nitroallylic acetates via S_N2′ addition–elimination and aromatization process. The reaction was catalyzed by ceric ammonium acetate (CAN) and gives pyrrole derivatives in good yields. The generality of this methodology was established by using various amines and nitroallylic acetates. When methyl acetoacetate was used, the corresponding pyrrole was obtained in low yield (37% only).

Scheme 50

The group of Tamaddon has explored the use of heterogeneous catalysts for the synthesis of tetrasubstituted pyrroles using β-dicarbonyls, benzoins and ammonium acetate under solventless conditions (Scheme 51).¹¹⁶ They demonstrated the use of molybdate sulfuric acid (MSA) as a reusable solid acid catalyst via a novel [2 + 2 + 1] strategy to obtain 2,3,4,5-tetrasubstituted pyrrole derivatives in high yields.^116a The benzoin derivatives bearing electron-withdrawing groups on the aryl ring reacted faster in comparison to those bearing electron-withdrawing groups. At the same time, they also reported the use of silica sulfuric acid (SSA)^116b as a novel catalyst for the construction of tetrasubstituted NH pyrroles using the same approach. The SSA catalyzed three-component reaction of β-dicarbonyls, benzoins and ammonium acetate afforded pyrroles in excellent yields. The same group later illustrated this three component reaction in a binary solvent system (1 : 1 EtOH : H₂O) under catalyst-free conditions (Scheme 51).¹¹⁷ Using this methodology, anisoin successfully reacted and led to the desired pyrrole derivative in 94% yield. In 2013, Bhat and Trivedi also proposed a facile one-pot, multicomponent regioselective synthesis of tetrasubstituted pyrroles from easily accessible β-dicarbonyls, benzoin derivatives and ammonium acetate under catalyst- and solvent-free conditions (Scheme 51).¹¹⁸ The reaction is dependent on the molar ratio of the starting materials and maximum yields were obtained with a 1.1 : 1 : 1.5 ratio of β-dicarbonyls, benzoins and ammonium acetate. A library of tetrasubstituted pyrrole derivatives were synthesized in high yields employing various β-dicarbonyl and benzoin derivatives within a short reaction time. The reaction with dibenzoylmethane did not occur due to the poor reactivity of carbonyl groups towards benzoin in the presence of adjacent bulky phenyl groups. Cyclic diketones and less reactive benzoins such as anisoin failed to react under the optimized conditions.

Scheme 51

Bhat et al. further expanded their catalyst- and solvent-free one-pot protocol, replacing benzoins with phenylglyoxal to synthesize tetrasubstituted pyrroles bearing hydroxyl substituent at C4 position (Scheme 52).¹¹⁸ During the same year, Eftekhari-Sis et al. developed a multicomponent reaction between β-dicarbonyls, arylglyoxal hydrates and ammonium acetate occurring in aqueous medium without any catalyst and assisted by ultrasound irradiation (Scheme 52).¹¹⁹ The 5-aryl-4-hydroxy-2-methyl-1H-pyrrole-3-carboxylic acid ester derivatives were obtained in high yields within 3–5 minutes.

Scheme 52

The Cadierno group reported that a one-pot, three-component coupling reaction of secondary propargylic alcohols, β-dicarbonyls and primary amines catalyzed by the 16-electron allyl-ruthenium(II) complex [Ru(ƞ₃-2-C₃H₄Me)(CO)(dppf)][SbF₅] 62 (where dppf = 1,1′-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid (TFA) afforded pentasubstituted pyrroles (Scheme 53).¹²⁰ This reaction involved the initial TFA-promoted propargylation of the β-dicarbonyl compound forming γ-keto alkyne, followed by its condensation with the primary amine to form a β-enaminone which underwent a Ru(II)-catalyzed 5-exo-dig annulation to afford the corresponding polysubstituted pyrrole.

Scheme 53

Three years later, the same group reported the applicability of this one-pot method for the preparation of tetrasubstituted NH pyrroles replacing primary amines with tert-butyl carbamate (Scheme 54).¹²¹ Tetrasubstituted NH pyrrole derivatives bearing carbonyl functionality at C3 were prepared by the reaction of propargylic alcohols, β-dicarbonyls (ethyl acetoacetate, methyl acetoacetate and acetyl acetone) and tert-butyl carbamate in the presence of 5 mol% of [Ru(ƞ₃-2-C₃H₄Me)(CO)(dppf)][SbF₅] 62 and (0.5 equiv) TFA in THF at 75 °C.

Scheme 54

Attanasi et al. reported an efficient, multi-component synthesis of novel polysubstituted pyrroles using primary aliphatic amines, active methylenes and 1,2-diaza-1,3-dienes (DDs) under catalyst-free and solvent-free conditions (Scheme 55).¹²² The reaction proceeded through the formation of N-substituted enamines by the condensation of active methylene compounds with amines, followed by an aza-annulation through stepwise C-alkylation (Michael addition) and N-condensation of the enamines with DDs. This method was applicable for various aliphatic amines and 1,2-diaza-1,3-dienes. A range of active methylene compounds were also used to further expand the scope of this process. This methodology provides an access to pyrrole derivatives substituted with EWG-containing functional groups such as carboxylic acid derivatives (both symmetrical and unsymmetrical dicarboxylates, esters, amides, thioesters), sulfone and phosphonate moiety at the C3 and C4 positions of the pyrrole ring.

Scheme 55

In 2010, Herath and Cosford developed a first, one-pot synthesis of pyrrole-3-carboxylic acid derivatives by the reaction between β-dicarbonyls, amines and 2-bromoketones using continuous flow technique in a matter of minutes (Scheme 56).¹²³ The reaction was carried out in the presence of a base and among the bases screened (N-diisopropylethylamine (DIPEA), triethylamine, 2,6-lutidine, pyridine, and 2,6-di-tert-butylpyridine), DIPEA gave the best result. In the presence of 0.5 equiv DIPEA, the HBr generated as a by-product in the reaction hydrolysed the tert-butyl ester, generating in situ the corresponding pyrrole-3-carboxylic acids. The hydrolysis could be prevented by using 1.0 equiv of DIPEA forming pyrrole-3-carboxylic acid esters as the sole product. This method was also extended towards the efficient synthesis of pyrrole-3-carboxamide derivatives, including the two cannabinoid receptor subtype 1 (CB1) inverse antagonists in a single continuous process.

Scheme 56

Nageswar et al. reported a new and eco-benign methodology towards the synthesis of substituted pyrroles using β-cyclodextrin (β-CD) as a supramolecular catalyst in water (Scheme 57).¹²⁴ The reactions were carried out by the initial in situ formation of β-cyclodextrin complex of phenacyl bromide in H₂O, followed by the subsequent addition of acetylacetone and primary amines, forming the corresponding pyrroles in high yields. Electron-donating group bearing primary aromatic amines gave higher yields compared to the primary aromatic amines having an electron-withdrawing group. Aliphatic amines also afforded the products albeit in lower yields.

Scheme 57

Meshram and co-workers reported an efficient synthesis of 1,2,3,5-tetrasubstituted pyrroles via a multicomponent reaction between phenacyl bromides, acetylacetone and primary amines in the presence of 10 mol% DABCO in aqueous medium at 60 °C (Scheme 58).¹²⁵ This reaction is applicable for various aliphatic and aromatic primary amines. Among the solvents used (H₂O, THF, MeOH, DCM), H₂O gave the best result. During the same year, M. Pal et al. described a regioselective synthesis of 1,2,3,4-tetrasubstituted pyrroles by the three-component reaction between phenacyl bromide, acetylacetone and primary amines in a single pot (Scheme 58).¹²⁶ Yb(OTf)₃ was the most efficient catalyst among the catalysts such as p-TSA, I₂, amberlyst-15 and NaHSO₃ (2.5%) absorbed on silica examined for this reaction. This Yb(OTf)₃-catalyzed reaction is applicable for primary alkyl, alkylaryl and aryl amines. A number of tetra-substituted pyrrole derivatives were prepared by using this strategy.

Scheme 58

One year later, the A. R. Das group examined the catalytic activity of alum for the preparation of 1,2,3,5-tetrasubstituted pyrroles linked with a coumarin moiety at C5-position (Scheme 59).¹²⁷ They developed a novel, one-pot strategy for the synthesis of a series of 3-(1-aryl-4-acetyl-5-methyl-1H-pyrrol-2-yl)-2H-chromen-2-ones, a new heterocyclic scaffold containing both the coumarin and pyrrole nuclei in a single molecule by means of three-component condensation reaction of 3-(bromoacetyl)coumarin, acetylacetone and an alkyl/arylamine in the presence of alum catalyst in water–PEG 400 binary solvent system. A wide variety of Lewis acids (ZnCl₂, silica gel, ZnO, MgO, FeCl₃, zeolite, alumina, alum), organo acid catalysts (PTSA, AcOH) and polymer-supported PEG-OSO₃H were used but alum proved to be most efficient catalyst. Further, alum showed moderate catalytic activity in water and PEG 400. The best catalytic activity was observed in the water–PEG 400 (3 : 2) binary solvent system, compared to other organic solvents (THF, toluene, MeCN, MeOH).

Scheme 59

J. C. Menéndez et al. synthesized diversely functionalized, polysubstituted pyrroles using high-speed vibration milling (HSVM) under solvent-free conditions (Scheme 60).¹²⁸ They developed a sequential multicomponent process involving the initial α-iodination of ketones with N-iodosuccinimide in the presence of p-TSA, followed by the addition of a mixture of β-dicarbonyls and primary amines in the presence of 5 mol% cerium(IV) ammonium nitrate (CAN) and silver nitrate. This solvent-free, mechanochemical method is applicable for a wide range of amines (aryl, primary alkyl, secondary alkyl and dialkylamino), β-dicarbonyls (β-diketones, β-ketoesters, β-ketoamides and diethyl 3-oxopentanedioate) and aryl/2-naphthyl/3-indolyl/alkyl ketones. This is the first example of a multicomponent reaction carried out under HSVM conditions.

Scheme 60

The group of Maiti has described a CeCl₃·7H₂O catalyzed three-, four- and seven-component synthesis of diversely functionalized pentasubstituted pyrroles and their analogues from readily available amines, α-diketones and β-ketoesters via intermolecular domino reaction (Scheme 61).¹²⁹ This Ce(III) catalyzed reaction has been carried out in the presence of KI (assisting in deprotonation and protonation steps of the domino cyclization) and MgSO₄ (acting as a drying agent). The environmentally-benign reaction conditions, operational simplicity, robust, good yielding, substrate-specific/selective and cost efficiency features make this approach an interesting alternative to the existing methods. Highly arylsubstituted pyrrole derivatives (bisaminomethylpyrroles) were also synthesised using diaryl-α-diketones, aromatic amines and β-ketoesters via a pseudo seven-component domino reaction under the optimized conditions. Further, a three-component domino reaction between primary alkyl amines, α-diketones and ethyl 3-oxohexanoate afforded pentasubstituted pyrroles with a trans-selective C2-olefinic side chain.

Scheme 61

Zeng and his group synthesized a series of 1,2,3-trisubstituted pyrroles by the one-pot, two-steps reaction between β-dicarbonyls, primary amines and acetaldehyde, using Na₂CO₃, piperidine and I₂ at −15 °C (Scheme 62).¹³⁰ This one-pot, two-steps reaction proceeds through the concomitant iodocyclization of enaminones with elimination of HI and spontaneous aromatization. Various primary alkyl/aralkyl amines were employed to establish the wide scope of this method. Mild reaction conditions, cheaply available reaction substrates, operational simplicity, general applicability and good yields are the significant advantages of this reaction from synthetic viewpoint.

Scheme 62

Maiti et al. demonstrated a simple and convenient one-pot four-component reaction of β-dicarbonyls, aldehydes, amines and nitroalkanes in the presence of 10 mol% Fe(III) chloride for the synthesis of diversely substituted pyrroles (Scheme 63).¹³¹ FeCl₃ was the most suitable catalyst among the other catalysts such as FeCl₃·6H₂O, FeBr₃, Fe(acac)₃, Fe(OTf)₃, InCl₃, Yb(OTf)₃, HCl, PTSA and CF₃SO₃H used for this reaction. A library of pentasubstituted pyrroles were prepared using various β-diketones and β-ketoesters, aryl and alkyl aldehydes, aryl and alkyl amines with nitromethane/nitroethane to establish the general applicability of the method. This is first report of Grob and Cameisch's pyrrole synthesis catalyzed by a Lewis acid via one-pot four component-coupling reactions and employing both aliphatic as well as aromatic amines.

Scheme 63

A sequential (PPh₃)₂PdCl₂-catalyzed four-component reaction followed by Suzuki, Heck and Sonogashira couplings in a single pot has been developed for the preparation of novel 1,2,3,4-tetra substituted pyrrole derivatives by M. Pal and co-workers (Scheme 64).¹³² The synthesized pyrroles were evaluated for phosphodiesterase 4B (PDE4B) inhibitory activity and some derivatives showed promising results, thus led to the recognition of a new class of pyrrole-based inhibitor of PDE4B.

Scheme 64

In 2012, Pal et al. developed an elegant method for the preparation of diversely functionalized pyrrole derivatives by the iodine-catalyzed four-component coupling reaction of β-dicarbonyls, aldehydes, amines and nitromethane (Scheme 65).¹³³ The methodology was applicable to various aldehydes, amines and β-dicarbonyls (acetylacetone and ethylacetoacetate). The synthetic utility of this metal- and solvent-free, four-component coupling has been illustrated by the efficient synthesis of 4-biaryl substituted pyrroles and alkynylaryl substituted pyrroles using Suzuki and Sonogashira couplings respectively. During the same time, Khan and co-workers utilized this approach to synthesize highly substituted pyrrole derivatives using 10 mol% Ni(II) chloride hexahydrate and analysed them for phosphodiesterase 4B (PDE4B) inhibitory activity through docking studies (Scheme 65).¹³⁴

Scheme 65

In 2013, one-pot, four-component synthetic approaches toward diversely functionalized pyrroles employing β-dicarbonyls, aldehydes, nitroalkanes and primary amines as starting materials were proposed by various groups using different catalytic systems (Scheme 66).¹³⁵ The Jeong group demonstrated the use of silica supported tungstic acid (STA, a heterogenized tungsten complex) as a heterogeneous catalyst for the cascade four-component coupling of amines, aldehydes, β-dicarbonyl compounds and nitroalkanes to obtain high yields of diversity-oriented tetra-substituted pyrrole derivatives (Scheme 66).^135a Various aromatic aldehydes (both electron-donating and electron-withdrawing), heteroaromatic aldehydes, amines and β-dicarbonyls were well tolerated to establish the wider substrate scope of the reaction. They also reported the reusability of the catalyst four times without any significant loss in its catalytic activity.

Scheme 66

Subsequently, the gluconic acid aqueous solution (GAAS) was used as a eco-benign, recyclable catalyst and a reusable promoting medium for this multicomponent synthesis of polysubstituted pyrrole derivatives by Zhang et al. (Scheme 66).^135b A library of 1,2,3,4-tetrasubstituted pyrroles were synthesized in moderate to good yields employing different aromatic/heteroaromatic aldehydes, aromatic/aliphatic amines, β-diketones, β-ketoesters and nitromethane. However, this procedure is unsuccessful for the aliphatic aldehydes such as cyclohexanecarbaldehyde, and α,β-unsaturated aldehydes such as cinnamaldehyde. Meshram et al. explored the use of an ionic liquid 1-n-butylimidazolium tetrafluoroborate [Hbim]BF₄ as a reusable reaction medium without using an additional catalyst for the generation of a library of diversely substituted pyrroles via this four-component reaction (Scheme 66).^135c They demonstrated the reusability of [Hbim]BF₄ for three cycles without any substantial loss in its catalytic activity. Bharate et al. synthesized polysubstituted pyrroles in good yields using this multicomponent strategy employing a recyclable montmorillonite clay K10 catalyst (10 mol%) (Scheme 66).^135d The Saeidian group proposed the use of CuO nanoparticles (10 mol%) as an efficient, commercially available and non-toxic nanocatalyst for the facile one-pot synthesis of polysubstituted pyrroles in high yields with easy purification (Scheme 66).^135e

Sekar and coworkers carried out the synthesis of 3-benzyl-2,4-dimethylpyrrole in an appreciable 61% yield from easily available acetyl acetone, benzyl bromide and ethyl acetoacetate in four steps (Scheme 67).¹³⁶ 3-Benzyl substituted 1H-pyrrole was further used to synthesise new photostable and efficient BODIPY dyes.

Scheme 67

Conclusions

Pyrrole and its derivatives have become important compounds because of their applications in medicinal and natural products chemistry as well as in the field of material science. Pyrrole synthesis with the use of active methylenes as one of the key components has become very demanding since it enables the generation of diverse range of libraries of pyrrole derivatives. Efforts have been made to report most of the methods known in the literature for preparation of pyrrole derivatives with active methylenes.

Acknowledgements

Work from our group cited in this review was financially supported by Department of Science and Technology, GOI, New Delhi (Project No. SR/S1/OC-38/2010) and University Grants Commission, New Delhi (SRF to RK). We also gratefully acknowledge the Department of Chemistry, University of Jammu for all necessary facilities provided.

References

1. (a) R. A. Jones and G. P. Bean, The Chemistry of Pyrroles, Academic Press, London, 1977, vol. 34; (b) A. Gossauer, in Methoden der Organichen Chemie (Houben-Weyl), Hetarene I, Teil 1 Pyrrole, Georg Thieme Verlag, Stuttgart, New York, 1994, pp. 556–798; (c) G. W. Gribble, in Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, London, 1996, vol. 2, ch. 4; (d) C. T. Walsh, S. Garneau-Tsodikova and A. R. Howard-Jones, Nat. Prod. Rep., 2006, 23, 517–531; (e) V. Estévez, M. Villacampa and J. C. Menéndez, Chem. Soc. Rev., 2010, 39, 4402–4421; (f) V. Estévez, M. Villacampa and J. C. Menéndez, Chem. Soc. Rev., 2014, 43, 4633–4657.
2. R. Runge, Ann. Phys., 1834, 31, 67.
3. T. Anderson, Annalen, 1858, 105, 349.
4. G. Daidone, B. Maggio and D. Schillaci, Pharmazie, 1990, 45, 441–442.
5. D. G. Kaiser and E. M. Glenn, J. Pharm. Sci., 1972, 61, 1908–1911.
6. C. Battilocchio, G. Poce, S. Alfonso, G. C. Porretta, S. Consalvi, L. Sautebin, S. Pace, A. Rossi, C. Ghelardini, L. D. C. Mannelli, S. Schenone, A. Giordani, L. D. Francesco, P. Patrignani and M. Biava, Bioorg. Med. Chem., 2013, 21, 3695–3701.
7. H. M. Meshram, B. R. V. Prasad and D. A. Kumar, Tetrahedron Lett., 2010, 51, 3477–3480.
8. R. Jonas, M. Klockow, I. Lues, H. Pruecher, H. J. Schliep and H. Wurziger, Eur. J. Med. Chem., 1993, 28, 129–140.
9. D. Ferraris, R. P. Ficco, D. Dain, M. Ginski, S. Lautar, K. Lee-Wisdom, S. Liang, Q. Lin, M. X.-C. Lu, L. Morgan, B. Thomas, L. R. Williams, J. Zhang, Y. Zhou and V. J. Kalish, Bioorg. Med. Chem., 2003, 11, 3695–3708.
10. R. I. Dowell, N. H. Hales and H. Tucker, Eur. J. Med. Chem., 1993, 28, 513–516.
11. D. Cross, R. Alessi, P. Cohen, M. Jelkovich and B. Hemmings, Nature, 1995, 378, 785–789.
12. S. K. Sharma, M. Tandon and J. W. Lown, J. Org. Chem., 2001, 66, 1030–1034.
13. B. D. Roth, Prog. Med. Chem., 2002, 40, 1–22.
14. J. K. Liao and U. Laufs, Annu. Rev. Pharmacol. Toxicol., 2005, 45, 89–118.
15. W. K. C. Park, R. M. Kennedy, S. D. Larsen, S. Miller, B. D. Roth, Y. Song, B. A. Steinbaugh, K. Sun, B. D. Tait, M. C. Kowala, B. K. Trivedi, B. Auerbach, V. Askew, L. Dillon, J. C. Hanselman, Z. Lin, G. H. Lu, A. Robertson and C. Sekerke, Bioorg. Med. Chem. Lett., 2008, 18, 1151–1156.
16. A. Goel, N. Agarwal, F. V. Singh, A. Sharon, P. Tiwari, M. Dixit, R. Pratap, A. K. Srivastava, P. R. Maulik and V. J. Ram, Bioorg. Med. Chem. Lett., 2004, 14, 1089–1092.
17. S. Y. Kang, E. J. Park, W. K. Park, H. J. Kim, G. Choi, M. E. Jung, H. J. Seo, M. J. Kim, A. N. Pae, J. Kim and J. Lee, Bioorg. Med. Chem., 2010, 18, 6156–6169.
18. G. Murineddu, G. Loriga, E. Gavini, A. T. Peana, A. C. Mule and G. A. Pinna, Arch. Pharm., 2001, 334, 393–398.
19. S. B. Etcheverry, D. A. Barrioa, A. M. Cortizoa and P. A. M. Williams, J. Inorg. Biochem., 2002, 88, 94–99.
20. S. Ushiyama, T. Yamada, Y. Murakami, S. Kumakura and T. Kimura, Eur. J. Pharmacol., 2008, 578, 76–82.
21. K. Down, P. Bamborough, C. Alder, A. Campbell, J. A. Christopher, M. Gerelle, S. Ludbrook, D. Mallett, G. Mellor, D. D. Miller, R. Pearson, K. Ray, Y. Solanke and D. Somers, Bioorg. Med. Chem. Lett., 2010, 20, 3936–3940.
22. M. Biava, R. Fioravanti, G. C. Porretta, D. Deidda, C. Maullu and R. Pompei, Bioorg. Med. Chem. Lett., 1999, 9, 2983–2988.
23. G. H. Jana, S. Jain, S. K. Arora and N. Sinha, Bioorg. Med. Chem. Lett., 2005, 15, 3592–3595.
24. M. Biava, G. C. Porretta, D. Deidda, R. Pompei, A. Tafi and F. Manetti, Bioorg. Med. Chem., 2003, 11, 515–520.
25. G. S. Papaetis and K. N. Syrigos, BioDrugs, 2009, 23, 377–389.
26. A. Mai, S. Massa, R. Ragno, I. Cerbara, F. Jesacher and P. Loidl, J. Med. Chem., 2003, 46, 512–517.
27. F. C. Giuliani, B. Berbieri, G. Perroni, E. Lazzari, F. Arcamoni and N. Mongelli, Proc. Am. Assoc. Cancer Res., 1988, 29, 330.
28. P. M. Jordan, Biosynthesis of Tetrapyrroles, in New Comprehensive Biochemistry, Elsevier, Amsterdam, 1991, vol. 19, pp. 1–66.
29. (a) M. J. Warren and A. I. Scott, Trends Biochem. Sci., 1990, 15, 486–491; (b) A. R. Battersby, Nat. Prod. Rep., 2000, 17, 507–526.
30. (a) C. Eder, P. Proksch, V. Wray, R. W. M. van Soest, E. Ferdinandus, L. A. Pattisina and Sudarsono, J. Nat. Prod., 1999, 62, 1295–1297; (b) D. P. O'Malley, K. Li, M. Maue, A. L. Zografos and P. S. Baran, J. Am. Chem. Soc., 2007, 129, 4762–4775.
31. C. C. Hughes, A. Prieto-Davo, P. R. Jensen and W. Fenical, Org. Lett., 2008, 10, 629–631.
32. T. Fukuda, F. Ishibashi and M. Iwao, Heterocycles, 2011, 83, 491–529.
33. (a) J. Ham and H. Kang, Bull. Korean Chem. Soc., 2002, 23, 163–166; (b) S. Urban and R. J. Capon, Aust. J. Chem., 1996, 49, 711–713; (c) M. V. R. Reddy, M. R. Rao, D. Rhodes, M. S. T. Hansen, K. Rubins, F. D. Bushman, Y. Venkateswarlu and D. J. Faulkner, J. Med. Chem., 1999, 42, 1901–1907.
34. D. L. Boger, C. W. Boyce, M. A. Labroli, C. A. Sehon and Q. Jin, J. Am. Chem. Soc., 1999, 121, 54–62.
35. (a) C. Avendano and J. C. Menendez, Curr. Med. Chem., 2002, 9, 159–193; (b) C. Avendano and J. C. Menendez, Med. Chem. Rev.--Online, 2004, 1, 419–444.
36. E. Harri, W. Loeffler, H. P. Sigg, H. Stahelin, C. Stoll, C. Tamm and D. Wiesinger, Helv. Chim. Acta, 1962, 45, 839–853.
37. Y. Kashman, G. Koren-Goldshlager, M. D. Garcia-Gravalos and M. Schleyer, Tetrahedron Lett., 1999, 40, 997–1000.
38. A. Kunfermann, M. Witschel, B. Illarionov, R. Martin, M. Rottmann, H. W. Hoffken, M. Seet, W. Eisenreich, H. J. Knolker, M. Fischer, A. Bacher, M. Groll and F. Diederich, Angew. Chem., Int. Ed., 2014, 53, 2235–2239.
39. 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, 971–989.
40. (a) P. B. Dervan, Bioorg. Med. Chem., 2001, 9, 2215–2235; (b) S. Neidle, Nat. Prod. Rep., 2001, 18, 291–309.
41. Y. Hayakawa, K. Kawakami, H. Seto and K. Furihata, Tetrahedron Lett., 1992, 33, 2701–2704.
42. V. M. Domingo, C. Aleman, E. Brillas and L. Jullia, J. Org. Chem., 2001, 66, 4058–4061.
43. M. Lazerges, K. I. Chane-Ching, S. Aeiyach, S. Chelli, M. Peppin-Donnat, M. Billon, C. Lombard, F. Maurel and M. Jouini, J. Solid State Electrochem., 2009, 13, 231–238.
44. (a) A. Kros, S. W. F. M. van Hovel, R. J. M. Nolte and N. A. J. M. Sommerdijk, Sens. Actuators, B, 2001, 80, 229–233; (b) S. Hamilton, M. J. Hepher and J. Sommerville, Sens. Actuators, B, 2005, 107, 424–432.
45. S. Rai and M. Ravikan, Tetrahedron, 2007, 63, 2455–2465.
46. (a) M. Grätzel, Nature, 2001, 414, 338–344; (b) Y. Ooyama and Y. Harima, Eur. J. Org. Chem., 2009, 2903–2934.
47. K. Sirithip, S. Morada, S. Namuangruk, T. Keawin, S. Jungsuttiwong, T. Sudyoadsuk and V. Promarak, Tetrahedron Lett., 2013, 54, 2435–2439.
48. J. L. Sessler and A. Gebauer, in The Porphyrin Handbook, ed. K. M. Kadish, K. M. Smith and R. Guilard, Vogel, E., Academic Press, San Diego, 1999, vol. 2, ch. 8.
49. C. Ikeda, N. Sakamoto and T. Nabeshima, Org. Lett., 2008, 10, 4601–4604.
50. J. M. Nadeau and T. M. Swager, Tetrahedron, 2004, 60, 7141–7146.
51. (a) W. Jaegermann, A. Klein and T. Mayer, Adv. Mater., 2009, 21, 4196–4206; (b) Y. Leroux, J. Lacroix, C. Fave, G. Trippe, N. Felidj, J. Aubard, A. Hohenau and J. Krenn, ACS Nano, 2008, 2, 728–732; (c) G. Lu, H. Tang, Y. Huan, S. Li, L. Li, Y. Wang and X. Yang, Adv. Funct. Mater., 2010, 20, 1714–1720.
52. N. Chen, X. Qian, H. Lin, H. Liu, Y. Li and Y. Li, Dalton Trans., 2011, 40, 10804–10808.
53. (a) L. Knorr, Chem. Ber., 1884, 17, 1635; (b) J. A. Joule and K. Mills, Heterocyclic Chemistry, Blackwell Publishing, 4th edn, 2004, p. 256.
54. (a) A. Hantzsch, Chem. Ber., 1890, 23, 1474; (b) B. P. Mundy, M. G. Ellerd and F. G. Favaloro Jr, Name Reactions and Reagents in Organic Synthesis, John Wiley and Sons, 2005, 2nd edn, p. 305.
55. K. Gewald, Z. Chem., 1961, 1, 349.
56. J. W. Sowell Sr and C. D. Blanton Jr, J. Heterocycl. Chem., 1973, 10, 287–290.
57. J. W. Sowell Sr and C. D. Blanton Jr, J. Pharm. Sci., 1976, 65, 908–910.
58. R. W. Johnson, R. J. Mattson and J. W. Sowell sr, J. Heterocycl. Chem., 1977, 14, 383–385.
59. H. D. Dakin and R. West, J. Biol. Chem., 1928, 78(91), 745–757.
60. S. Wang, N. C. Wan, J. Harrison, W. Miller, I. Chuckowree, S. Sohal, T. C. Hancox, S. Baker, A. Folkes, F. Wilson, D. Thompson, S. Cocks, h. Farmer, A. Boyce, C. Freathy, J. Broadbridge, J. Scott, P. Depledge, R. Faint, P. Mistry and P. Charlton, J. Med. Chem., 2004, 47, 1339–1350.
61. H. J. Roth and K. Eger, Arch. Pharm., 1975, 308, 179–185.
62. M. A. Mohamed, A. E. Rashad, M. E. A. Zaki and S. S. Fatahala, Acta Pharm., 2005, 55, 237–249.
63. T.-C. Chien, E. A. Meade, J. M. Hinkley and L. B. Townsend, Org. Lett., 2004, 6, 2857–2859.
64. D. A. Abou El Ella, M. M. Ghorab, E. Noaman, H. I. Heiba and A. I. Khalil, Bioorg. Med. Chem., 2008, 16, 2391–2402.
65. M. M. F. Ismail, M. M. Ghorab, E. Noaman, Y. A. Ammar, H. I. Heiba and M. Y. Sayed, Arzneim.-Forsch./Drug Res., 2006, 56, 301–308.
66. M. M. Ghorab, F. A. Ragab, H. I. Heiba, H. A. Youssef and M. G. El-Gazzar, Bioorg. Med. Chem. Lett., 2010, 20, 6316–6320.
67. K. Wang and A. Dömling, Chem. Biol. Drug Des., 2010, 75, 277–283.
68. L. V. Frolova, N. M. Evdokimov, K. Hayden, I. Malik, S. Rogelj, A. Kornienko and I. V. Magedov, Org. Lett., 2011, 13, 1118–1121.
69. T. Takayama, H. Umemiya, H. Amada, T. Yabuuchi, F. Shiozawa, H. Katakai, A. Takaoka, A. Yamaguchi, M. Endo and M. Sato, Bioorg. Med. Chem. Lett., 2010, 20, 108–111.
70. P. Das, S. Ray and C. Mukuhopadhyay, Org. Lett., 2013, 15, 5622–5625.
71. H. Nishida, A. Hasuoka, Y. Arikawa, O. Kurasawa, K. Hirase, N. Inatomi, Y. Hori, F. Sato, N. Tarui, A. Imanishi, M. Kondo, T. Takagi and M. Kajino, Bioorg. Med. Chem., 2012, 20, 3925–3938.
72. P. B. S. Dawadi and J. Lugtenburg, Tetrahedron Lett., 2011, 52, 2508–2510.
73. W. Yu, W. Chen, S. Liu, J. Shao, Z. Shao, H. Lin and Y. Yu, Tetrahedron, 2013, 69, 1953–1957.
74. X. Feng, Q. Wang, W. Lin, G.-L. Dou, Z.-B. Huang and D.-Q. Shi, Org. Lett., 2013, 15, 2542–2545.
75. K. M. H. Hilmy and E. B. Pedersen, Liebigs Ann. Chem., 1989, 1145–1146.
76. S. M. Al-Mousawi, M. S. Moustafa, H. Meier, H. Kolshorn and M. H. Elnagdi, Molecules, 2009, 14, 798–806.
77. D. H. R. Barton and S. Z. Zard, J. Chem. Soc., Chem. Commun., 1985, 1098–1100.
78. N. Ono and K. Maruyama, Bull. Chem. Soc. Jpn., 1988, 61, 4470–4472.
79. N. Ono, H. Kawamura and K. Maruyama, Bull. Chem. Soc. Jpn., 1989, 62, 3386–3388.
80. M. Artico, R. D. Santo, R. Costi, S. Massa, A. Retico, M. Artico, G. Apuzzo, G. Simonetti and V. Strippoli, J. Med. Chem., 1996, 38, 4223–4233.
81. G. Dannhardt, W. Kiefer, G. Krämer, S. Maehrlein, U. Nowe and B. Fiebich, Eur. J. Med. Chem., 2000, 35, 499–510.
82. H. Takaya, S. Kojima and S. I. Murahashi, Org. Lett., 2001, 3, 421–424.
83. J. L. Bullington, R. R. Wolff and P. F. Jackson, J. Org. Chem., 2002, 67, 9439–9442.
84. S. Kamijo, C. Kanazawa and Y. Yamamoto, Tetrahedron Lett., 2005, 46, 2563–2566.
85. P. R. Krishna, V. V. R. Reddy and R. Srinivas, Tetrahedron, 2007, 63, 9871–9880.
86. N. C. Misra, K. Panda, H. Ila and H. Junjappa, J. Org. Chem., 2007, 72, 1246–1251.
87. M. Terzidis, C. A. Tsoleridis and J. S. -Stephanatou, Tetrahedron, 2007, 63, 7828–7832.
88. W. Chen, J. Shao, Z. Li, M. A. Giulianotti and Y. Yu, Can. J. Chem., 2012, 90, 214–221.
89. M. Gao, C. He, H. Chen, R. Bai, B. Cheng and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 1–5.
90. T. Wu, L. Pan, X. Xu and Q. Liu, Chem. Commun., 2014, 50, 1797–1800.
91. L. C. L. Cara, M. E. Camacho, M. D. Carrion, V. Tapias, M. A. Gallo, G. Escames, D. A. Castroviejo, A. Espinosa and A. Entrena, Eur. J. Med. Chem., 2009, 44, 2655–2666.
92. J. Barluenga, V. Rubio and V. Gotor, J. Org. Chem., 1982, 47, 1696–1698.
93. H. K. Hombrecher and G. Horter, Synthesis, 1990, 389–392.
94. D. Imbri, N. Netz, M. Kucukdisli, L. M. Kammer, P. Jung, A. Kretzschmann and T. Opatz, J. Org. Chem., 2014, 79, 11750–11758.
95. E. Toja, G. Tarzia, P. Ferrari and G. Tuan, J. Heterocycl. Chem., 1986, 23, 1555–1560.
96. D. H. R. Barton, W. B. Motherwell and S. Z. Zard, Tetrahedron Lett., 1984, 25, 3707–3710.
97. D. Seebach, E. W. Colvin, F. Lehr and T. Weller, Chimia, 1979, 33, 1–18.
98. B. Quiclet-Sire, I. Thevenot and S. Z. Zard, Tetrahedron Lett., 1995, 36, 9469–9470.
99. R. Khajuria, Y. Saini and K. K. Kapoor, Tetrahedron Lett., 2013, 54, 5699–5702.
100. W. Davey and D. J. Tivey, J. Chem. Soc., 1958, 2276–2282.
101. R. Khajuria and K. K. Kapoor, Curr. Microwave Chem., 2014, 1, 110–118.
102. M. Aginagalde, T. Bello, C. Masdeu, Y. Vara, A. Arrieta and F. P. Cossıo, J. Org. Chem., 2010, 75, 7435–7438.
103. V. Singh, S. Kanojiya and S. Batra, Tetrahedron, 2006, 62, 10100–10110.
104. A. W. Trautwein, R. D. Sussmuth and G. Jung, Bioorg. Med. Chem. Lett., 1998, 8, 2381–2384.
105. K. K. A. D. S. Kathriarachchi, A. I. Siriwardana, I. Nakamura and Y. Yamamoto, Tetrahedron Lett., 2007, 48, 2267–2270.
106. S. Chiba, Y.-F. Wang, G. Lapointe and K. Narasaka, Org. Lett., 2008, 10, 313–316.
107. Y.-F. Wang, K. K. Toh, S. Chiba and K. Narasaka, Org. Lett., 2008, 10, 5019–5022.
108. E. P. J. Ng, Y.-F. Wang, B. W. Q. Hui, G. Lapointe and S. Chiba, Tetrahedron, 2011, 67, 7728–7737.
109. Y. Terazono and D. Dolphin, J. Org. Chem., 2003, 68, 1892–1900.
110. H. Ogoshi, M. Homma, K. Yokota, H. Toi and Y. Aoyama, Tetrahedron Lett., 1983, 24, 929–930.
111. V. Y. Korotaev, A. Barkov, I. V. Kotovich and V. Y. Sosnovskikh, J. Fluorine Chem., 2012, 138, 42–47.
112. S. Sarkar, K. Bera, S. Maiti, S. Biswas and U. Jana, Synth. Commun., 2013, 43, 1563–1570.
113. C. C. Silveira, S. R. Mendes, G. M. Martins, S. C. Schlösser and T. S. Kaufman, Tetrahedron, 2013, 69, 9076–9085.
114. N. C. Jadhav, P. B. Jagadhane, H. V. Patile and V. N. Telvekar, Tetrahedron Lett., 2013, 54, 3019–3021.
115. D. R. Magar, Y. J. Ke and K. Chen, Asian J. Org. Chem., 2013, 2, 330–335.
116. (a) F. Tamaddon, M. Farahi and B. Karami, J. Mol. Catal., 2012, 356, 85–89; (b) F. Tamaddon and M. Farahi, Synlett, 2012, 1379–1383.
117. F. Tamaddon and M. Farahi, Synlett, 2013, 1791–1794.
118. S. I. Bhat and D. R. Trivedi, Tetrahedron Lett., 2013, 54, 5577–5582.
119. B. Eftekhari-Sis and S. Vahdati-Khajeh, Curr. Chem. Lett., 2013, 2, 85–92.
120. V. Cadierno, J. Gimeno and N. Nebra, Chem.–Eur. J., 2007, 13, 9973–9981.
121. V. Cadierno, J. Gimeno and N. Nebra, J. Heterocycl. Chem., 2010, 47, 233–236.
122. O. A. Attanasi, G. Favi, F. Mantellini, G. Moscatelli and S. Santeusanio, J. Org. Chem., 2011, 76, 2860–2866.
123. A. Herath and N. D. P. Cosford, Org. Lett., 2010, 12, 5182–5185.
124. S. N. Murthy, B. Madhav, A. V. Kumar, K. R. Rao and Y. V. D. Nageswar, Helv. Chim. Acta, 2009, 92, 2118–2124.
125. H. M. Meshram, V. M. Bangade, B. C. Reddy, G. S. Kumar and P. B. Thakur, Int. J. Org. Chem., 2012, 2, 159–165.
126. G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy, C. L. T. Meda, A. Kandale, D. Rambabu, G. R. Krishna, C. M. Reddy, K. V. L. Parsa, K. S. Kumar and M. Pal, RSC Adv., 2012, 2, 9142–9150.
127. G. Pal, S. Paul and A. R. Das, Synthesis, 2013, 1191–1200.
128. V. Estévez, M. Villacampa and J. C. Menéndez, Chem. Commun., 2013, 49, 591–593.
129. D. Dhara, K. S. Gayen, S. Khamarui, P. Pandit, S. Ghosh and D. K. Maiti, J. Org. Chem., 2012, 77, 10441–10449.
130. P. Xu, K. Huang, Z. Liu, M. Zhou and W. Zeng, Tetrahedron Lett., 2013, 54, 2929–2933.
131. S. Maiti, S. Biswas and U. Jana, J. Org. Chem., 2010, 75, 1674–1683.
132. G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy, L. S. Reddy, P. M. Kumar, G. R. Krishna, C. M. Reddy, D. Rambabu, R. Kapavarapu, C. Lakshmi, T. Meda, K. K. Priya, K. V. L. Parsa and M. Pal, Chem. Commun., 2011, 47, 7779–7781.
133. G. R. Reddy, T. R. Reddy, S. C. Joseph, K. S. Reddy and M. Pal, RSC Adv., 2012, 2, 3387–3395.
134. A. T. Khan, M. Lal, P. R. Bagdi, R. S. Basha and P. Saravanan, Tetrahedron Lett., 2012, 53, 4145–4150.
135. (a) A. B. Atar and Y. T. Jeong, Tetrahedron Lett., 2013, 54, 5624–5628; (b) B. L. Li, P.-H. Li, X.-N. Fang, C.-X. Li, J.-L. Sun, L.-P. Mo and Z.-H. Zhang, Tetrahedron, 2013, 69, 7011–7018; (c) H. M. Meshram, B. M. Babu, G. S. Kumar, P. B. Thakur and V. M. Bangade, Tetrahedron Lett., 2013, 54, 2296–2302; (d) J. B. Bharate, R. Sharma, S. Aravinda, V. K. Gupta, B. Singh, S. B. Bharate and A. Vishwakarma, RSC Adv., 2013, 3, 21736–21742; (e) H. Saeidian, M. Abdoli and R. Salimi, C. R. Chim., 2013, 16, 1063–1070.
136. K. G. Thorat, P. Kamble, R. Mallah, A. K. Ray and N. Sekar, J. Org. Chem., 2015, 80, 6152–6164.

---