Polysubstituted Pyrroles Research Articles

Cu(II)-Catalyzed Reaction of Ethynyl Methylene Cyclic Carbamates and Amines: Synthesis of Polysubstituted Pyrroles.

A copper-catalyzed efficient, operationally simple, general method for straightforward syntheses of polysubstituted pyrroles employing ethynyl methylene cyclic carbamates as precursors reacting with commercially available amines was first reported. A wide variety of polysubstituted pyrroles were obtained in acceptable to good yields under mild conditions. This protocol features broad substrate scope, high functional group tolerance, and easy operation, therefore enabling late-stage functionalization and rapid synthesis of bioactive compounds, including structurally complex marketed drugs and natural products. In addition, a scale-up experiment further highlighted the synthetic utility.

A new route for the synthesis of multi-substituted pyrrole derivatives containing a sulfonyl scaffold via the chemistry of N-sulfonylketenimine

A rapid practical new synthesis of multi-substituted pyrrole derivatives with high yields through a novel four-component reaction of sulfonyl azides, terminal alkynes, nitro compounds, and trichloroacetonitril is a remarkable achievement in organic chemistry. This strategy offers a direct and efficient route to access complex molecular structures from readily available starting materials. To expand the work, the reaction of the final product with sulfinate salt under simple conditions and room temperature, poly-substituted pyrroles with sulfone functional group are formed. The combination of available starting materials, catalytic systems, mild reaction conditions, and ease of purification procedures contributes to the attractiveness of this method for the synthesis of diverse multi-substituted pyrrole derivatives.

Accessing Polysubstituted NH Pyrroles from Nitroalkenes via [4+2]‐Cycloaddition/Reductive Ring Contraction Strategy

AbstractA novel two‐step access to polysubstituted pyrroles from nitroalkenes was developed. It involves [4+2]‐cycloaddition with enol ethers to give six‐membered cyclic nitronates followed by reductive ring contraction with Ra−Ni/AcOH or Ra−Ni/EtOH systems. The process is applicable to a variety of nitroalkenes and enol ethers bearing electron‐rich and electron‐poor substituents and functional groups. The anti‐inflammatory drug Bimetopyrol and its structural modifications were successfully synthesized by the strategy developed. The key side products were identified that provided an insight into the mechanism of the developed reductive ring contraction to pyrroles.

Nickel-catalyzed cyclization of alkynyl nitriles with isocyanide: An expedient way to the synthesis of polysubstituted pyrroles

We herein describe a nickel-catalyzed cascade cyclization of alkynyl nitriles with tert-butylisocyanide under simple reaction conditions. A couple of polysubstituted pyrroles were obtained in moderate yields and with excellent regioselectivity in some cases. The products from this protocol are synthetically useful since the parent pyrrole ring bears one free amino and two cyano groups which enable diverse late-stage transformations.

Cu(I)‐Catalyzed Coupling Reactions of β‐Nitrostyrene, 1,3‐Dicarbonyl compound & Aryl amine: An Efficient Method For the Synthesis of Polysubstituted Pyrroles

AbstractA convenient Cu(I) Catalyzed three‐component coupling strategy for the synthesis of polysubstituted pyrroles is developed using simple and readily available building blocks like, 1, 3‐dicarbonyl compound, aryl amine, and β‐nitrostyrene. CuI has been rarely explored for the pyrrole ring synthesis and a comparative analysis of our current catalyst with a range of previously reported catalysts suggested that, CuI is one of the best catalysts for the multicomponent synthesis of polysubstituted pyrrole derivatives. Notably, this process has several advantages, including a simple and practical set‐up with hassle free reaction conditions, extensive substrate scope, short reaction time, high atom economy and environmentally favorable approach. This methodology provides an alternative approach to the highly substituted pyrroles and under optimized reaction conditions, polysubstituted pyrroles were formed in good to excellent yields. Cu(I) catalyzed Mannich reactions followed by Michael addition reactions along with subsequent intramolecular cyclization are believed to be the key steps of this reaction process.

Cover Picture: Cu(I)‐Catalyzed Coupling Reactions of β‐Nitrostyrene, 1,3‐Dicarbonyl compound & Aryl amine: An Efficient Method For the Synthesis of Polysubstituted Pyrroles (ChemistrySelect 18/2024)

Cover Picture: Cu(I)‐Catalyzed Coupling Reactions of β‐Nitrostyrene, 1,3‐Dicarbonyl compound & Aryl amine: An Efficient Method For the Synthesis of Polysubstituted Pyrroles (ChemistrySelect 18/2024)

Synthesis, antimicrobial activity, DFT-calculation, and docking of 4-(1,3,4-thiadiazol-2-yl)-containing polysubstituted pyrroles

A series of new 4-(1,3,4-thiadiazol-2-yl)-containing polysubstituted pyrroles 3 a-k has been synthesized by a preparative convenient method from ethyl 5-chloro-4-formyl-1H-pyrrole-3-carboxylates 1 a-e, which were selectively transformed into the corresponding polysubstituted pyrrole-4-carboxylic acids 2 а-е using sodium hypochlorite as an oxidizer. Further, they were transformed into the target compounds with a high yield using the cyclocondensation with N-mono- or N,N-disubstituted thiosemicarbazides in the boiling phosphorus trichloroxide. As seen from the screening of antimicrobial activity, the synthesized compounds exhibit the inhibiting and bactericide activity against some bacteria and fungi. The highest activity has been established for the compounds 3 a, c, e-h, j against the strain Klebsiella pneumoniae (МІС=31.25 µg/mL). The calculated HOMO energy level proves that the compound 3 с is the most reactive ligand for the interaction with a protein receptor. The molecular docking data show that the compound 3 h has the highest affinity to the ThiM Klebsiella pneumoniae kinase.

Visible-light-mediated synthesis of polysubstituted pyrroles via CAr–I reduction triggered 1,5-hydrogen atom transfer process

A novel strategy for the construction of polysubstituted pyrroles has been developed through the visible-light-induced single-electron reduction of CAr–I bonds and the following 1,5-hydrogen atom transfer (HAT) process.

Tandem site-selective bromination and highly regioselective Heck reaction of N-allyl enaminones: chemodivergent synthesis of polysubstituted pyrroles and pyridines

Chemodivergent synthesis of polysubstituted pyrroles and pyridines from N-allyl enaminones via tandem site-selective bromination and the highly regioselective Heck reaction.

Rhodium-catalyzed N-alkenylation of ketimines: one-pot synthesis of polysubstituted pyrroles

Herein, we report a one-pot synthesis of pyrroles via rhodium-catalyzed N-alkenylation of ketimines. This method was also applied to the efficient synthesis of the natural product Lamellarin R.

Brønsted acid-promoted synthesis of polysubstituted pyrroles from enamines/imines and diazopyruvates: A metal-free cascade approach

A Brønsted acid-promoted, metal-free cascade reaction of easily available enamines/imines with diazopyruvates has been demonstrated. With triflic acid as the promoter, the reaction proceeds smoothly at room temperature through sequential diazo protonation, nucleophilic enamine N-addition/C-addition and dehydrative aromatisation in a highly regioselective manner. Interestingly, the regioselectivity of the reaction is governed by the unusual enamine N-nucleophilic addition. The method provides an operationally trivial approach to the synthesis of multisubstituted pyrroles including tri-, tetra-, and penta-substituted derivatives as well as N–H free pyrroles with diverse functionalities in good yields under extraordinarily simple and mild conditions. The utility of the method is illustrated by the rapid assembly of polysubstituted bispyrroles and an array of diversely structured pyrrole derivatives.

Four-component condesation of ethyl acetoacetate, phenylglyoxal hydrate, barbituric acid and primary amines

By four-component condensation of ethyl acetoacetate, phenylglyoxal hydrate, barbituric acid and primary amines, polysubstituted pyrroles containing a barbituric acid fragment were obtained. In some cases, minor products of three-component condensation of phenylglyoxal hydrate, barbituric acid and amines have been isolated.

POCl3/Sulfoxide and AcCl/Sulfoxide Mediated Chlorination of Pyrrolo[2,1-a]isoquinolines.

We have developed an efficient chlorination of pyrrolo[2,1-a]isoquinoline derivatives using POCl3 as the chlorine source and tetramethylene sulfoxide as a promoter. A series of pyrrolo[2,1-a]isoquinolines, polysubstituted pyrroles, and naphthols have been readily chlorinated under mild reaction conditions (26 examples, up to >99% yield). AcCl can also act as the chlorine source competently in this chlorination reaction.

Bromination of Pyrrolo[2,1-a]isoquinolines with Acetyl Bromide and Dimethyl Sulfoxide.

A mild bromination of pyrrolo[2,1-a]isoquinolines has been achieved using acetyl bromide and dimethyl sulfoxide. A series of brominated pyrrolo[2,1-a]isoquinolines could be obtained in moderate to excellent yields (46-99%) at room temperature. This strategy can also be expanded to the facile bromination of polysubstituted pyrroles, indoles, electron-rich phenols, aniline, and 2-naphthol.

Rh-catalysed divergent synthesis of polysubstituted pyrroles from α,β-unsaturated ketones via selective single or double insertion of isocyanides

A novel divergent synthetic method for polysubstituted pyrroles from isocyanides and α,β-unsaturated ketones in the presence of a rhodium catalyst and bis(pinacolato)diboron (B2pin2) is described here.

Pd-catalyzed imine-directed one-pot access to polysubstituted pyrrolesviatandem triple isocyanide insertion/aza-Nazarov cyclization reactions

A novel one-pot method for synthesizing polysubstituted pyrrole derivatives via three-component reactions of alkenyl bromides, amines, and isocyanides is reported by Pd catalysis, without additional ligands, with the orderly insertion of three isocyanide molecules.

Synthesis of 1,2,4-Oxadiazolines through Deoxygenative Cyclization of N-Vinyl-α,β-Unsaturated Nitrones with in Situ Generated Nitrile Oxides from Hydroxamoyl Chlorides

A variety of 1,2,4-oxadiazoline derivatives were synthesized in moderate to good yields through a deoxygenative cyclization cascade reaction of N-vinyl-α,β-unsaturated nitrones and hydroxamoyl chlorides. Mechanistic studies revealed that the reaction underwent double additions of nitrile oxides to N-vinyl-α,β-unsaturated nitrones, sequential elimination, and intramolecular cyclization to afford 1,2,4-oxadiazolines. Alternatively, 1,2,5-oxadiazolines were also obtained as major products in i-PrOH solvent through [3 + 3] cycloaddition and selective [3,3]-rearrangement. Moreover, the prepared 1,2,4-oxadiazolines were easily converted to polysubstituted pyrroles under thermal conditions.

I2/FeCl3-Catalyzed Domino Reaction of Aurones with Enamino Esters for the Synthesis of Highly Functionalized Pyrroles.

A novel and efficient I2/FeCl3-catalyzed domino reaction of aurones with enamino esters via Michael addition, iodination, intramolecular nucleophilic substitution, and spiro ring opening processes has been developed, affording a vast variety of polysubstituted pyrroles in moderate to excellent yields. This protocol features mild reaction conditions, broad substrate scope, high atom economy and efficiency, and feasibility for large-scale synthesis. A plausible mechanism for the pyrrole synthesis is proposed.

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

The objective of this study was to design new polysubstituted pyrrole derivatives as selective acetylcholinesterase (AChE) inhibitors to target Alzheimer's disease. In this context, a highly efficient, one-pot, sequential, multi-component synthesis of a diverse range of polysubstituted pyrroles was developed through a sequential domino strategy by the condensation of amines with 1,1-bis(methylthio)-2-nitroethene (BMTNE), Knovenagle reaction of arylglyoxals with malono derivatives and subsequent Michael addition and intramolecular cyclization reaction in EtOH at reflux. Thirty-nine synthesized compounds were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Among the synthesized compounds, compound 4ad (IC50 = 2.95 ± 1.31 µM) was the most potent and selective AChE inhibitor with no significant inhibition against butyrylcholinesterase BChE. A kinetic study of 4ad revealed that this compound inhibited AChE in an uncompetitive mode. Based on a molecular modeling study, compound 4ad due to its small size properly fitted into the active site of AChE compared to BChE and stabilized by H-bond and hydrophobic interactions with the critical residues of the AChE binding pocket. Consequently, it was proposed that the 4ad derivative can be an ideal lead candidate against AD with a simple and practical operation of synthetic procedures.

Au-catalyzed neighboring hydroxymethyl group directed cycloaddition of alkyne with diazadienes: Synthesis of polysubstituted pyrroles

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.