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The Hantzsch pyrrole synthesis
Abstract and Figures
Ethyl esters of 2-alkyl- and 2,4-dialkylpyrrole-3-carboxylic acids are obtained generally by extensions of the Hantzsch synthesis, benzyl and t-butyl esters when the 2-alkyl group is methyl. Hemopyrrole is obtained from butanal and ethyl acetoacetate in three steps. Pyrroles bearing higher alkyl groups or carbobenzoxy groups are reductively alkylated like the corresponding methylpyrroles and carbethoxy derivatives; t-butyl esters do not survive.
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Pyrrole is a versatile heterocyclic moiety exhibiting a wide range of pharmacological actions with high therapeutic value. The importance of pyrrole in the pharmaceutical field lies in its versatility, selectivity, and biocompatibility, and these properties make it a valuable tool for drug design and development. The pyrrole moiety is a fundamental building block for many biologically active molecules and has gathered significant attention in the fields of medicinal and organic chemistry; hence, its synthesis has been a crucial area for research. There are various conventional as well as modern approaches to acquiring a series of pyrrole scaffolds, with a wide range of attractive features and drawbacks pertaining to each approach. An extensive amount of literature must be studied to compare the best synthetic routes. This article highlights the applications of pyrrole derivatives in various fields, such as drug discovery, material science, and catalysis, and provides an overview of modern synthetic pathways that include metals, nanomaterials, and complex heterogeneous catalysed methods for pyrrole derivatives. Special emphasis is given to the use of green chemistry principles like green solvent-based methods, microwave-aided methods, and solvent-free methods in the synthesis of pyrroles, with the recent developments and prospects in the synthetic and organic chemistry fields. Overall, this review article provides a comprehensive overview of the synthesis of pyrroles and complies with all the possible developments in the synthetic routes for pyrroles within 2015– 2022. Among all, the reactions catalysed by proline, copper oxides, and oxones have been shown to be the most effective synthetic route for pyrrole derivatives at mild reaction conditions and with excellent yields. This information will be helpful for researchers interested in the development of new pyrrole-based compounds. The categorization in this review provides an easy means for the reader to rationally select the best possible synthetic method for pyrrole derivatives.
Heterocycles are organic compounds, the most important pharmaceutical skeleton widely distributed in nature. Many of them possess medicinal as well as pharmacological activities. Pyrroles are well-known five-member-privileged scaffolds with pharmaceutical potential. Pyrrole is the component of complex macrocycles, including porphyrins of heme and chlorophylls. Nowadays, the development of microwave-supported synthetic strategies for such biologically relevant heterocycles is an important objective. Microwave-induced pyrrole synthesis has become an environmentally benign route in organic transformation with reduced reaction time and high yields. This mini-review focuses on the eco-friendly microwaveinduced synthesis of pyrroles, their derivatives, and their potential pharmacological applications, covering literature up to 2022.
The treatment of advanced non‐small cell lung cancer (NSCLC) has made substantial progress due to the rapid development of small molecule targeted therapy, with dramatically prolonged survival. As an effective drug for the treatment of NSCLC, epidermal growth factor receptor (EGFR) inhibitors are currently experiencing issues like severe adverse events and drug resistance. It is urgent to develop novel types of EGFR inhibitors to overcome the abovementioned limitations. Pyrrole always works well as a probe for the creation of novel medication candidates for hard‐to‐treat conditions like lung cancer. Although the design, synthesis, and biological assays of pyrrole derivatives have been reported, their inhibitory actions against the receptor tyrosine kinase (RTK) EGFR have not been in‐depthly studied. This review highlights the small molecule EGFR inhibitors containing pyrrole heterocyclic pharmacophores in recent years, and the research on their mechanism, biological activity, and structure–activity relationship (SAR). In this review, EGFR inhibitors containing pyrrole structures were studied and classified by structure into phenylpyrroles, pyrroles, pyrrolopyridines, and other classes. The structure–activity relationships and cytotoxicity of these derivatives were also analyzed.
Polysubstituted pyrroles are very important scaffolds in many bioactive natural products and synthetic pharmaceuticals. Here, a new gold-catalyzed cycloaddition of alkynes with azadienes to access tetrasubstituted pyrroles is demonstrated. The neighboring hydroxylmethyl group serves a very important directing group through an addition/cycloaddition/elimination cascade. Diverse polysubstituted pyrroles were synthesized in good yields under mild conditions in one step, and tricyclic pyrrole containing heterocycles were easily obtained through derivatization.
A fast and convenient method for synthesis of some new functionalized pyrrole derivatives have been described via a three-component reaction between arylglyoxals, Meldrum’s acid and ethyl 2-chloro-3-(arylamino)but-2-enoate derivatives in excellent yields. When a mixture of arylglyoxal, Meldrum’s acid and ethyl 2-chloro-3-(arylamino)but-2-enoats were stirred in ethanol as a green solvent at room temperature, after one hour a solid product was separated from the reaction mixture. Simple filtration of this solid and its washing with ethanol afforded pure products. The structure of the products was proved by elemental analysis and IR and NMR apectral data.Graphical abstract
An expeditious green method for the synthesis of diverse valued substituted pyrroles through a Paal-Knorr condensation reaction, using a variety of amines and 2,5-hexanedione/2,5-dimethoxytetrahydrofuran in the presence of a low melting mixture of N,N'-dimethylurea and L-(+)-tartaric acid (which acts as a dual catalyst/solvent system), has fruitfully been revealed. Herein, we have disclosed the applicability of this simple yet effective strategy for the generation of mono- and dipyrroles in good to excellent yields. Moreover, C3-symmetric tripyrrolo-truxene derivatives have also been assembled by means of cyclotrimerization, Paal-Knorr and Clauson-Kaas reactions as crucial steps. Interestingly, the melting mixture was recovered and reused with only a gradual decrease in the catalytic activity (over four cycles) without any significant drop in the yield of the product. This particular methodology is simple, rapid, environmental friendly, and high yielding for the generation of a variety of pyrroles. To the best of our knowledge, the present work reveals the fastest greener method reported up to this date for the construction of substituted pyrroles by utilizing the Paal-Knorr synthetic protocol, achieving impressive yields under operationally simple reaction conditions without involving any precarious/dangerous catalysts or unsafe volatile organic solvents.
One-pot conversion of sustainable d-ribose with l-amino acid, methyl esters produced pyrrole-2-carbaldehydes 5 in reasonable yields (32-63%) under pressurized conditions of 2.5 atm at 80 °C. The value-added pyrraline compounds 5 as platform chemicals were utilized for quick installation of poly-heterocyclic cores for the development of pyrrole-motif natural and artificial therapeutic agents. A pyrrole-fused piperazin-2-one scaffold 6 was prepared by reductive amination of pyrralines 5 with benzylamine. While further cyclization of pyrralines 5 with ethane-1,2-diamine produced pyrrolo-piperazin-2-ones 7 with an extra imidazolidine ring, the reaction with 2-amino alcohols derived from natural l-amino acids, alanine, valine, and phenylalanine, respectively provided pyrrolo-piperazin-2-ones 8, 9, and 10 with oxazolidine as the third structural core. Cell viability and an anti-inflammatory effect of the synthesized compounds were briefly tested by the MTT method and the Griess assay, among which 8h and 10g exhibited significant anti-inflammatory effects with negligible cell toxicity.
This review aims to present a comprehensive overview of the catalytic asymmetric C−H as well as N−H functionalization of pyrroles reported from 2010 to now. Pyrroles have unique reactivity and tremendous efforts have been made not only for their synthesis but also for the development of reactions using them as the synthons and their utilization in the stereocontrolled synthesis of complex molecules.
Abstract
The wide occurrence of pyrroles in natural products and pharmaceuticals calls for novel synthetic methodologies for the efficient synthesis of enantiopure pyrroles. Owing to their highly reactive nature and wide-ranging chemical landscape, enormous efforts have been dedicated not only to their synthesis but also to the development of reactions using them as a platform and their utilization in the stereocontrolled synthesis of diverse molecules. In sharp contrast to the extensive studies devoted toward indoles, the asymmetric functionalization of pyrroles was less explored. Nevertheless, the attractiveness of pyrroles for their selective functionalization to access natural product analogy, and medicinally useful architectures have witnessed tremendous growth in the last few years. Their effectiveness under both metal- and organocatalytic conditions currently encompasses a vast majority of enantioselective transformations. This review article aims to present a comprehensive overview of the catalytic asymmetric C−H as well as N−H functionalization of pyrroles reported from 2010 to now.
As solvent-free synthesis becomes an extensively explored area of synthetic chemistry and as pyrrole is a potent synthon in natural product biosynthesis, a review on solvent-free pyrrole synthesis possesses great significance in the current scenario of environmentally friendly organic synthesis. This review provides an overview of the recent advances in sustainable and solvent-free synthesis of pyrrole derivatives.
Abstract
Pyrroles are well known scaffolds having wide applications in biological and pharmaceutical field. It is a privileged heterocyclic scaffold present in many natural products, drug molecules, agrochemicals and has shown applications in material science. Solvent-free synthesis of pyrroles became an emerging area in organic synthesis. This review focuses on the solvent-free synthesis of pyrroles covering literature up to 2021.
Acetessigsäure-tert.-butylester läßt sich allgemein für Pyrrol-Synthesen verwenden. Die tert.-Butylestergruppe zerfällt katalytisch unter Bildung der entsprechenden Pyrrolcarbonsäuren, die thermisch decarboxyliert werden können.
Methylpyrrole carboxylic esters generally are reductively methylated at 25–45°. Some are also reductively alkylated by aliphatic aldehydes generally to give, for example, 2,3(or 2,4)-dimethyl-4(or 3)-alkyl-5-carbethoxypyrroles, using hydriodic acid or HCl/AcOH–Zn/Hg respectively. An analogous alkylation by glyoxylic acid gave 5-carbethoxyhemopyrrole-dicarboxylic ester. Using HI, paraldehyde at 100° gave diethyl derivatives of dimethylpyrroles, and aminoacetal at 35° converted 2,4-dimethyl-3-acetylpyrrole into its 5-(2-amino-ethyl)-derivative. Reductive alkylations have been most useful with pyrroles but HI converted 2-biphenylcarbaldehyde into fluorene.
The proofs of the structures proposed for the Chlorobium pheophorbides 650, fractions 1–5, and for the Chlorobium pheophorbides 660, fractions 5 and 6, are completed and the degradational evidence, where parallel, confirmed through the synthesis of derived porphyrins.
Convenient syntheses have been devised for all the C-methylpyrroles with the exception of 3-methylpyrrole. Lithium aluminum hydride reduction of a C-acyl to a C-alkyl group was the key step in most of the syntheses. Attempts to use this method for the preparation of N-methylpyrroles were unsuccessful because reduction of C-acyl-N-methylpyrroles stopped at the hydroxymethyl stage, regardless of whether the acyl group was at the 2-or the 3-position. 1,2-Dimethylpyrrole and 1,2,3,5-tetramethylpyrrole were prepared, however, by methylation of the potassium salts of the required C-methyl derivatives. Infrared, ultraviolet, and proton magnetic resonance spectra are tabulated for pyrrole and fourteen N- and C-methylpyrroles.
05 g) was 10. A. TREIBS
Methyl-4-ethyl-3-carbethoxypyrrole (9.05 g) was 10. A. TREIBS. Ann. Chem. 524, 285 (1936).
Chem. 533, Knorr. Ring Synthesis of 7
- H Fischer
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H. FISCHER and H. HOFELMANN. Ann. Chem. 533,
Knorr. Ring Synthesis of 7.7 cf. (3r)
216 (1938).
then twice from n-pentane as long colorless needles (25 %), 22. H. PAULI
then twice from n-pentane as long colorless needles (25 %), 22. H. PAULI. Chem. Ber. 34, 1771 (1901).