Synthesis Strategies and Biological Value of Pyrrole and Pyrrolopyrimidine

For several decades, interest in the synthesis pyrrole and pyrrolopyrimidine increases due to the importance of these heterocycles both from chemical and biological points of view. They possess several biological activities such as antimicrobial, analgesic, anti-inflammatory, anti-cancer, anti-viral, anti-convulsant, anti-hyperlipidemic, anti-depressant, antidiabetic, anti-allergic activities. These findings motivated us to present this review which highlights different methods of the synthesis of pyrrole and pyrrolopyrimidine derivatives as well as their biological importance from the past to recent years.

Literature survey indicated that pyrroles and pyrrolo [2,3-d]pyrimidines are of considerable interest in drug discovery.Pyrrole is one of the most important simple heterocycles, which is found in a broad range of natural products.It is the key structural fragment of heme and chlorophyll (two pigments essential for life), the chlorins, bacteriochlorins, corrins (vitamin B12) and some bile pigment (biliverdin and bilirubin).Pyrrolo [2,3-d]pyrimidines as 7-deazapurines exhibit remarkable biological activity due to their resemblance to cellular purines.
Owing to the importance of these systems, we introduce here the main aspects of the synthesis and the biological value of these heterocycles from the past to recent years.

Synthesis of pyrroles
Pyrrole derivatives could be synthesized by different methods which can be classified into two main categories: 1.1.Synthesis of pyrrole from non-heterocyclic molecules.1.2.Ring transformation of other heterocyclic rings.

Synthesis of pyrrole from non-heterocyclic molecules
Generally, there are eight important strategies for synthesis pyrrole derivatives from non-heterocyclic starting materials, which can be summarized in the following:
In 1996, McLeod et al. 5 reported the reaction of 1,4-dicabonyl derivatives with hydrazides to afford pyrrole 4 which then treated with nBu4NF to give 1amino-pyrrole 5.
In 2005, Banik et al. 6 modified Paal-Knorr reaction using bismuth nitrate in the presence of dichloromethane with amine and ketone at room temperature to obtain pyrrole 6.
In the same year, Demir et al. 7 reported another Pall-Knorr modification via reaction of chloropentenones with amines, amino alcohols or esters of amino acids in presence of triethylamine.
In 2007, Aydogan et al. 9 carried out the reaction of cis-1,4-dichloro-2-butene with various amines, amino alcohols or amino acid esters without solvent under microwave irradiation on silica gel to give pyrroles 9.
Many authors reported the reaction of acetonyl acetone either with benzoic acid hydrazide derivative 11 affording pyrrole 11 or with certain amines using indium(III) salts 12 under solvent-free conditions, zirconium chloride under ultrasound irradiation 13 or Iodine in tetrahydrofuran 14 affording pyrroles 12.
Acetonyl acetone was also utilized 15 for synthesis of pyrrole derivatives 13, 14 and 15 via reaction with thiourea, glycine or glutamic acid in 2010.
In 2014, Pagadala et al. 17 reported the synthesis of highly substituted pyrrole-N-acetic derivatives 17 through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach.

Reaction of α-aminocarbonyl compound with compound has active methylene group α-to carbonyl. (Knorr pyrrole synthesis)
It is the most widely used method for pyrrole synthesis.α-Aminocarbonyl compounds were readily dimerize to dihydropyrazines, one way to avoid this dimerization is to prepare and use them in the form of salts to be liberated for reaction by the base present in the reaction mixture.An alternative way was reported by L. Knorr 19 where the oximino precursor was converted to amino in-situ.

Reaction of α-halocarbonyl compounds, component with active methylene and ammonia derivatives.
This reaction was first reported by Hantzsch 34 in 1890 followed by Feist and Bénary 35 and then by Roomi and Macdonald 36 in 1970.They reported the reaction of α-haloketones with 1,3-dicarbonyl compounds in the presence of ammonia to give pyrroles 26.
In 2011, Kaspersen et al. 38 reported the synthesis of other 2-amino-pyrrole 28 via the reaction of 4-fluorophenacyl bromide with ethoxycarbonyl acetamidine salt in basic medium.
In the same year Yavari et al. 39 reported the reaction of other phenacyl bromide derivatives with certain enaminones under solvent-free conditions to afford 1,2,3,5-tetrasubstituted-pyrrole derivatives 29.

Reaction of nitroalkenes with carbonyl compounds.
In 2003, Ranu and Dey 50 reported an efficient synthesis of substituted pyrroles 44 through one-pot, three-component condensation of a carbonyl compound, amine and nitroalkene using tetrabutyl-ammonium bromide.
One-pot four-component condensation reaction of nitroalkanes, aromatic aldehydes, β-ketoesters, and amines in the presence of 10 mol % NiCl2.6H2Oafforded substituted pyrrole derivatives 48 in good yields.This reaction was reported 54 by A. T. Khan et al.

Piloty-Robinson pyrrole synthesis
Piloty and Robinson reported 55 the reaction of 2 equivalents of an aldehyde and hydrazine to produce ketazine 49 which by treating with strong acid gives pyrroles 51 through sigmatropic rearrangement of divinyl hydrazine 50.
In 2007, B. C. Milgram et al. 56 reported Microwave-Assisted Piloty-Robinson synthesis of pyrroles 52 by treating aldehyde first with hydrazine and then with aroyl chloride.

Reaction of α-dicarbonyl compound with secondary or tertiary amine having two active methylene groups.
In 1965, Friedman 57 reported the reaction of benzils with dimethyl N-acetyliminodiacetate in the presence of sodium methoxide to afford 3,4-diarylpyrrole 53.
In 2012, S. Auricchio et al. reported 62 the synthesis of pyrrole derivatives 61a,b by reaction of 2Hazirines with enaminones and enaminoesters in the presence of metal salts that act as Lewis acids.
Authors suggested 62 that the azirine complex undergoes nucleophilic attack by the enaminic double bond to give intermediates, which can afford the different products depending upon the different intramolecular linkage with nitrogen (route a) or oxygen (route b).
Analogously, in 2004, Joshi et al. 72 reported the transformation of pyridazine C-nucleoside 72 to the corresponding pyrrole 73.

From oxazole derivatives
Hershenson and Pavia reported 73 75 reported the transformation of oxirane derivatives 78 to pyrroles 81.This transformation was carried out by the reaction of oxirane derivatives with alkyne affording alkynols 79 which then transformed to mesylates followed up by in situ SN 2 reaction with sodium azide forming azides 80 which finally cyclized in the presence of zinc chloride and dichloroethane to pyrroles 81.
In the same year, Williams et al. 84 94,95 the Palladium-catalyzed cross coupling of the pyrimidines 104 with tributyl(2-ethoxyvinyl) stannane giving the corresponding vinyl ether 105, which was cyclized to furnish pyrrolopyrimidines 106 upon treatment with acid.This reaction was also reported 96  Pyrrolo [2,3-d]pyrimidines 109 were prepared by the reaction of pyrimidine-5-carbaldehyde 107 with sarcosine esters followed by base induced cyclization of the resulting aminoaldehydes 108.This reaction was reported 97 by Clark et al. in 2007 and Wang et al. 98
Several pyrroles 155 a-c and pyrrolopyrimidine containing sulfonamide 156 are proved to exhibit a remarkable antifungal activity 141 compared with the standard fungicide mycostatine.
Pyrrolo [2,3-d]pyrimidine 159 is a potent carbocyclic nucleoside adenosine kinase (AK) inhibitor 144 , has analgesic and anti-inflammatory activity.Also pyrrole derivatives 8 were proved to have high analgesic activity 8 .160) is known as selective cyclooxygenase-2 (COX-2) inhibitor 145 .The selectivity ratio of this pyrrole derivative was higher than those of the conventional non-steroidal anti-inflammatory drugs naproxen, indomethacin, and sodium diclofenate.

Anti-cancer activity
Toyocamycin and sangivamycin 152 are reported 147,148 as inhibitors of protein kinase C (PKC) and/or protein kinase A (PKA).
Pyrrole derivatives 25 are reported 33a to possess potent anticancer activity against liver and breast cancer cell lines (HEPG2 and MCF7).

Anti-convulsant activity
V. M. Patil et al. 14 reported that two pyrrole derivatives 12a,b have potential anti-convulsant activity.

Anti-depressant activity
Both pyrrole derivatives 184a,b exhibit favorable in vitro and in vivo antidepressant activities as they are targeting serotonin 5-HT2A, 5-HT2C, and serotonin transporter 172 .

Anti-allergic activity
Pyrrolo [2,3-d]pyrimidine derivative 185 is reported to be a potent Signal Transducers and Activators of Transcription 6 (STAT6) inhibitor 96 .STAT6 is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response.Therefore, STAT6 is considered as an excellent therapeutic target for allergic conditions, including asthma and atopic diseases.
by S. Nagashima et al. in 2009.

pyrroles 31 in acidic medium. 1.1.4. Reaction of tosylmethyl isocyanide with Michael acceptors.
reported the synthesis of pyrroles 45 via reaction of βbromonitrostyrenes with enaminones in water.