Paal-Knorr Reaction Research Articles

ChemInform Abstract: The Paal—Knorr Reaction Revisited. A Catalyst and Solvent‐Free Synthesis of Underivatized and N‐Substituted Pyrroles.

AbstractA new, modified synthesis of pyrroles via reaction of 1,4‐diketones with a variety of amines under the ultimate green conditions is developed.

Mechanism of the Paal–Knorr reaction: the importance of water mediated hemialcohol pathway

The mechanism of the Paal–Knorr reaction was explored using quantum chemical methods. Hydronium ion catalysed hemialcohol pathway has been established as the preferred mechanistic route for the Paal–Knorr formation of furan, pyrrole and thiophene.

The Paal–Knorr reaction revisited. A catalyst and solvent-free synthesis of underivatized and N-substituted pyrroles

A catalyst and solvent-free room temperature synthesis of pyrroles is described.

A facile and convenient synthesis and photovoltaic characterization of novel thieno[2,3-b]indole dyes for dye-sensitized solar cells

Two novel dyes IK-1,2 bearing the 8-alkyl-8H-thieno[2,3-b]indole unit as an electron-donating part of the push–pull system have been designed and prepared, as promising sensitizers for solar cells. The key steps of the synthesis involve the crotonic condensation of 1-alkylisatins with 2-acetylthiophene, followed by reduction of the CC double bond and further cyclization through the Paal–Knorr reaction with the Lawesson reagent, thus leading to the formation of 2-(thien-2-yl) substituted thieno[2,3-b]indole derivatives. The optical and electrochemical properties of these dyes have been investigated by using spectrophotometry and cyclic voltammetry respectively, while their photovoltaic performance was evaluated by a device fabrication study. The DSSCs based on IK-1 and IK-2 have demonstrated an efficiency of η=0.37% (FF=73%) and η=0.79% (FF=69%) under 100mWcm−2 simulated AM 1.5G solar irradiation, respectively.

Direct oxidative coupling of enamides and 1,3-dicarbonyl compounds: a facile and versatile approach to dihydrofurans, furans, pyrroles, and dicarbonyl enamides.

An efficient manganese(III)-mediated oxidative coupling reaction between α-aryl enamides and 1,3-dicarbonyl compounds has been developed. A series of dihydrofurans and dicarbonyl enamides were synthesized in moderate to good yields. Moreover, these dihydrofurans could be readily transformed into the corresponding furans and pyrroles via the Paal-Knorr reaction.

ChemInform Abstract: An Approach to the Paal—Knorr Pyrroles Synthesis in the Presence of β‐Cyclodextrin in Aqueous Media.

Abstract An efficient and facile method for the synthesis of N-substituted pyrroles in moderate to good yields by the Paal–Knorr reaction of γ-diketones with amines in the presence of β-cyclodextrin in aqueous media has been developed. Moreover, this process tolerated diamines (e.g., para-, meta- or ortho-phenylenediamine) to construct bis-pyrrole or mono-pyrrole derivates. β-Cyclodextrin can be recovered easily after the reactions and reused without evident loss in activity.

A General Route to 1,3′-Bipyrroles

A general method is described for the synthesis of 1,3'-bipyrroles. The route involves constructing a pyrrole ring on the nitrogen of a substituted 1H-pyrrole, so as to generate the 1,3'-bipyrrole. In this approach the nitrogen of the starting pyrrole was alkylated with a special Michael acceptor having an allylic leaving group, and the product was then modified in such a way that the second pyrrole ring could be formed by a Paal-Knorr reaction. Two variants of this sequence were examined, one of which led to formation of a 3-hydroxypyridine instead of the second pyrrole ring; the other variant used phenacyl bromide instead of the special Michael acceptor.

An approach to the Paal–Knorr pyrroles synthesis in the presence of β-cyclodextrin in aqueous media

Abstract An efficient and facile method for the synthesis of N-substituted pyrroles in moderate to good yields by the Paal–Knorr reaction of γ-diketones with amines in the presence of β-cyclodextrin in aqueous media has been developed. Moreover, this process tolerated diamines (e.g., para-, meta- or ortho-phenylenediamine) to construct bis-pyrrole or mono-pyrrole derivates. β-Cyclodextrin can be recovered easily after the reactions and reused without evident loss in activity.

Convenient synthesis of substituted pyrroles via a cerium (IV) ammonium nitrate (CAN)-catalyzed Paal–Knorr reaction

A screening of various cerium salts for promoting the Paal–Knorr pyrrole synthesis revealed the superiority of cerium (IV) ammonium nitrate (CAN) as a catalyst. Excellent yields of substituted pyrroles were obtained in CAN-catalyzed Paal–Knorr reactions of 1,4-diketones with various amines. The protocol is noteworthy for the mild reaction condition, short reaction times, scalability and easy isolation of products and high yields of the products.

A novel enzyme-catalyzed synthesis of N-substituted pyrrole derivatives

A novel method for the synthesis of substituted pyrroles catalyzed by α-amylase from hog pancreas via Paal-Knorr reaction was developed. A series of pyrrole derivatives were synthesized under mild conditions and the products were obtained with good to excellent yields (60-99 %). The impact of factors, such as solvents, enzyme amount, and temperature, on the reaction were investigated. This study reports an efficient route for the synthesis of N-substituted pyrrole derivatives.

Controlling the aggregation of 5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrin by the use of polycations derived from polyketones bearing charged aromatic groups

The interaction between 5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrin and different polycations is studied by UV–vis spectroscopy. Two polycations containing charged aromatic residues (imidazolium and pyridinium) have been easily synthesized by Paal–Knorr reaction of alternating aliphatic polyketones with histamine and 4-picolylamine. It was found that these polymers stabilize the tetra-anionic form of the porphyrin at acidic conditions, and avoid the formation of H- and J-type self-aggregates. Other polycations such as poly(allylamine) and poly(decylviologen) enhance porphyrin self-aggregation. As the latter polymer has also aromatic charged groups, the influence of the polymer structure as a whole in the behavior of the porphyrin/polycation system is highlighted. In this context, similar but not equal results have been found comparing the influence of the polyketone derivative containing pyridinium groups and the polycation poly(4-vinylpyridine) on the porphyrin self-aggregation and acid–base behavior. ► Polycations bearing pyridinium, imidazolium , and viologen units influence the aggregation of the tetrakis-(4-sulfonatophenyl)porphyrin. ► The cations also produce changes on the acid–base and luminescent properties of the porphyrin. ► The aggregation state of the porphyrin has been described in the presence of every polycation and as a function of pH. ► The aggregation interactions are based on hydrophobic, aromatic–aromatic, and electrostatic interactions. ► Competition reactions have been evaluated to highlight the strength of the interactions.

Racemic marinopyrrole B by total synthesis

The first synthesis of marinopyrrole B, which is highly active against methicillin-resistant Staphylococcus aureus, is described. The route involved constructing a pyrrole ring on the nitrogen of a 3-bromo-4,5-dichloropyrrole by N-alkylation with a special Michael acceptor having an allylic leaving group; the second pyrrole ring was then formed by a Paal-Knorr reaction.

A green, chemoselective, and practical approach toward N-(2-azetidinonyl) 2,5-disubstituted pyrroles

Pyrrole and 2-azetidinone are two essential heterocyclic scaffolds, which are being broadly used in medicinal chemistry and drug discovery field. A green and practical method to synthesize novel N-(2-azetidinonyl) 2,5-disubstituted pyrroles, which are comprised of both pyrrole and 2-azetidinone moieties, has been developed. The classical Paal–Knorr reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful pyrrole derivatives. The present procedure for the synthesis of N-(2-azetidinonyl) 2,5-disubstituted pyrroles (1,2,5-trisubstituted pyrroles) has been accomplished by reacting 3-amino β-lactams and 2,5-hexanedione in the presence of bismuth nitrate pentahydrate as an ecofriendly catalyst using microwave irradiation under solvent free condition. A comparison has also been made between the efficiency of microwave-assisted condition and the classical method (stirring at room temperature). The present method is equally effective for N-polyaromatic substituted β-lactams and optically pure β-lactams with chemically sensitive functionalities. The structure and stereochemistry of the products have been confirmed by extensive spectroscopic and X-ray crystallographic analyses. The present procedure for synthesizing N-(2-azetidinonyl) 2,5-disubstituted pyrroles may find application in the development of potent pharmacologically active molecules.

Organic synthesis via magnetic attraction: benign and sustainable protocols using magnetic nanoferrites

Magnetic nano-catalysts have been prepared using simple modification of iron ferrites. The nm size range of these particles facilitates the catalysis process, as an increased surface area is available for the reaction; the easy separation of the catalysts by an external magnet and their recovery and reuse are additional beneficial attributes. Glutathione bearing nano-ferrites have been used as organocatalysts for the Paal–Knorr reaction and homocoupling of boronic acids. Nanoferrites, post-synthetically modified by ligands, were used to immobilize nanometals (Cu, Pd, Ru, etc.) which enabled the development of efficient, sustainable and green procedures for azide–alkynes-cycloaddition (AAC) reactions, C–S coupling, O-allylation of phenol, Heck-type reactions and hydration of nitriles.

Room temperature aqueous Paal–Knorr pyrrole synthesis catalyzed by aluminum tris(dodecyl sulfate)trihydrate

This article reports a novel procedure to prepare pyrroles using a modification of the Paal–Knorr reaction. Water is a safe solvent meeting environmental considerations, but most organic substrates are not soluble in water. A possible solution to improve the solubility of substrates is the use of surface-active reagents that can form micelles. For instance, combined Lewis acid–surfactant catalyst acts both as a Lewis acid to activate the substrate molecules and as a surfactant to form emulsions in water. Here, we prepared and used aluminum tris(dodecyl sulfate)trihydrate to condense various amines to 2,5-hexadione at room temperature. The sole solid pyrrole was separated by a simple filtration. Our findings thus show a novel and improved modification of the Paal–Knorr reaction in terms of mild reaction conditions and clean reaction profiles, using a simple workup procedure and improved yields with excellent chemo-selectivity.

Synthesis of highly substituted pyrroles using ultrasound in aqueous media

A two-step protocol for the synthesis of highly substituted pyrroles in aqueous media and without catalyst is described. The first step is the dimerization of a 1,3-dicarbonyl compound by ceric ammonium nitrate/ultrasound to produce a tetracarbonyl derivative. This derivative is then combined with an amine in the absence of any catalysts to obtain the pyrrole via a Paal–Knorr reaction. This route is an improvement when compared with classical methodologies toward Green Chemistry objectives.

Synthesis of Atorvastatin Lactone Linker Constructs for Target Fishing

AbstractWith the aim of connecting atorvastatin lactone 9 to a linker for affinity‐based target fishing, a concise route to the pyrrolecarboxylic acid 8 was developed. Key features of the synthesis of the diol‐containing side‐chain were a catalytic enantioselective vinylogous aldol reaction resulting in 5‐hydroxy‐enoate 14 (88 % ee). Subsequent intramolecular oxa‐Michael addition and amide reduction furnished key building block 5. As we have described previously, Paal–Knorr reaction of amine 5 with diketone 6 led to pyrrole 7, which – after carboxylation – provided acid 8. Since atorvastatin lactone is an aniline derivative of acid 7, we prepared two linkers having an aniline terminus. For this purpose ethylene glycol based allyl ethers 20 and 27 were combined with nitrostyrene 22 by cross‐metathesis. After hydrogenation of the nitro group and the double bond, anilines 25 and 29, respectively, were obtained. The anilines were condensed with carboxylic acid 8 to afford the corresponding amides 30 and 35. Elaboration of the side‐chain then provided atorvastatin lactone linker constructs 34 and 39, respectively.

Automated Multitrajectory Method for Reaction Optimization in a Microfluidic System using Online IR Analysis

An automated multitrajectory optimization platform with continuous online infrared (IR) monitoring is presented. The production rate of a Paal–Knorr reaction is maximized within a constrained temperature and residence time design space. The automated platform utilizes a microreactor system to carry out optimizations with low material requirements and implements a micro IR flow cell for continuous online monitoring of reaction conversion. The approach to steady state at each set of reaction conditions is assessed continuously before the objective function is evaluated and reactor conditions move to the next set point. Several optimization algorithms are tested for their performance on a complex objective terrain. Each function comes to agreement on the optimal conditions but requires a significantly different number of experiments to reach the final conditions. Additionally, multiple objective functions are compared to analyze the trade-off between production rate and conversion.

Paal–Knorr reaction catalyzed by metal–organic framework IRMOF-3 as an efficient and reusable heterogeneous catalyst

A highly porous metal–organic framework (IRMOF-3) was synthesized from the reaction of zinc nitrate hexahydrate and 2-amino-1,4-benzenedicarboxylic acid by solvothermal method. Physical characterizations of the material were achieved by using a variety of different techniques, including X-ray powder diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR), atomic absorption spectrophotometry (AAS), and nitrogen physisorption measurements. The IRMOF-3 was used as an efficient heterogeneous catalyst for the Paal–Knorr reaction of benzyl amine with 2,5-hexanedione. Excellent conversions were obtained under mild conditions in the presence of 3mol% catalyst. The IRMOF-3 catalyst could be reused several times without a significant degradation in catalytic activity.

Polystyrenesulfonate-catalyzed synthesis of novel pyrroles through Paal-Knorr reaction

BackgroundThe classical Paal-Knorr reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful pyrrole derivatives.ResultsPolystyrenesulfonate-catalyzed simple synthesis of substituted pyrroles following Paal-Knorr reaction has been accomplished with an excellent yield in aqueous solution. This method also produces pyrroles with multicyclic polyaromatic amines.ConclusionsThe present procedure for the synthesis of N-polyaromatic substituted pyrroles will find application in the synthesis of potent biologically active molecules.