Knorr Pyrrole Research Articles

Greener Paal–Knorr Pyrrole Synthesis by Mechanical Activation

AbstractA straightforward and solventless synthesis of pyrroles was developed by using mechanochemical activation and a biosourced organic acid as the catalyst. Relative to traditional Paal–Knorr methodologies, various N‐substituted pyrroles were obtained in very short reaction times. By reaction with unreactive diketones, desymmetrized aliphatic and aromatic compounds were also synthesized.

Catalytic activity of the nanoporous MCM-41 surface for the Paal–Knorr pyrrole cyclocondensation

Abstract The investigation of different oxide surfaces revealed that nanoporous silica (MCM-41) had the best catalytic activity for Paal–Knorr pyrrole synthesis. Despite the same composition, MCM-41 proved to be more effective than SiO2 itself, probably due to a significantly higher surface area of the SiO2 nanopores. The important features of this “clean” solvent-free protocol are the ease of recovery and the reuse of the catalyst for several cycles, operational simplicity, and easy product isolation and purification.

L-Tryptophan-catalyzed Paal–Knorr pyrrole cyclocondensation: an efficient, clean and recyclable organocatalyst

A simple, clean, and efficient solvent-free protocol is introduced for Paal–Knorr pyrrole synthesis catalyzed by l-tryptophan as a thermally resistant, natural primary amino acid. The products were obtained mostly in excellent yields through the reaction of hexane-2,5-dione with aromatic primary amines bearing a variety of substituents. The catalyst could be easily isolated from the reaction mixture and recycled at least six times without significant loss of activity. The procedure has an environmentally benign nature in agreement with the concepts of green chemistry.

ChemInform Abstract: Total Synthesis of a Pyrrole Lactone Alkaloid, Longanlactone.

AbstractKey reactions in the first asymmetric total assembly of the natural pyrrole lactone longanlactone (I) are a Barbier propargylation and a Paal—Knorr pyrrole synthesis.

Cyclodextrin-based PNN supramolecular assemblies: a new class of pincer-type ligands for aqueous organometallic catalysis.

Water-soluble cyclodextrins (CDs) bearing two nitrogen atoms as metal coordinating sites have been synthesized. An appropriate phosphane could be included within their cavity through the primary face to form self-assembled PNN supramolecular edifices. Once the PNN ligands were coordinated to platinum, the resulting complexes proved to be very effective as catalysts in a domino reaction, where a Pt-catalyzed reduction of nitrobenzene was followed by a Paal-Knorr pyrrole reaction. In the nitrobenzene reduction, the modified CDs acted both as first- and second-sphere ligands. Contrary to an acyclic glucopyranose-based NN ligand unable to interact with a phosphane ligand, the CD-based PNN ligands stabilized the catalytic species in water by supramolecular means. Interestingly, the product and the water-soluble Pt-catalyst could be recovered in two different phases once the reaction was complete.

ChemInform Abstract: Paal—Knorr Pyrrole Synthesis in Water.

Abstract Water was a suitable medium for Paal–Knorr pyrrole cyclocondensation. Hexa-2,5-dione was reacted with several aliphatic and aromatic primary amines, affording N-substituted 2,5-dimethyl pyrrole derivatives in good to excellent yields. An efficient, green method using water either as environmentally friendly solvent or catalyst was presented.

Total Synthesis of a Pyrrole Lactone Alkaloid, Longanlactone

AbstractThe first asymmetric total synthesis of the natural pyrrole lactone longanlactone has been achieved. The key reactions, a Barbier propargylation and a Paal–Knorr pyrrole synthesis, have provided easy access to the target natural product from L‐aspartic acid in six steps and 31 % overall yield. The C‐4 epimer of the natural product and propionyllonganlactone have also been prepared by this strategy.

Paal–Knorr Pyrrole Synthesis in Water

Water was a suitable medium for Paal–Knorr pyrrole cyclocondensation. Hexa-2,5-dione was reacted with several aliphatic and aromatic primary amines, affording N-substituted 2,5-dimethyl pyrrole derivatives in good to excellent yields. An efficient, green method using water either as environmentally friendly solvent or catalyst was presented.

Nanomagnetically Modified Sulfuric Acid (γ-Fe2O3@SiO2-OSO3H): An Efficient, Fast, and Reusable Catalyst for Greener Paal–Knorr Pyrrole Synthesis

Paal–Knorr pyrrole synthesis was performed in the presence of superparamagnetic nanoparticles of modified sulfuric acid (γ-Fe2O3@SiO2-OSO3H) as an efficient and magnetically separable catalyst. Recovery of the catalyst was simple using a magnet, allowing its reuse without significant loss of its catalytic activity (over five cycles).

Furan ring opening–pyrrole ring closure. A simple route to 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones

We report here an application of a furan ring opening-Paal–Knorr pyrrole synthesis sequence for the transformation of furfurylamines into 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-3-ones.

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.

Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler–Wolff Aromatisation for Synthesis of the Indole-4-amide Core

A safe and efficient synthesis of AZD1981 is described in which the indole 4-amide core is formed by a Semmler–Wolff aromatisation of a cyclohexenone oxime fused to a pyrrole ring. The substrate was obtained via Paal–Knorr pyrrole synthesis, followed by incorporation of the key 3-arylthio substituent by reaction with 4-chlorophenylsulfenyl chloride. In this manner, the 1,2,3,4-substitution pattern of the AZD1981 core was regiospecifically established in a concise and efficient telescoped sequence. Accordingly, AZD1981 was obtained in 40% overall yield in six chemical steps, with two isolated crystalline intermediates.

ChemInform Abstract: Silica‐Supported Bismuth(III) Chloride as a New Recyclable Heterogeneous Catalyst for the Paal—Knorr Pyrrole Synthesis.

AbstractThe catalyst system exhibits a remarkable reusable activity and a higher performance compared to homogeneous BiCl3.

Competing Knorr and Fischer–Fink pathways to pyrroles in neutral aqueous solution

A proposed chemical model for the prebiogenesis of tetrapyrrole macrocycles relies on the condensation of a 3-alkyl-substituted 2,4-diketone and an α-aminoketone to form a pyrrole equipped for subsequent self-condensation leading to porphyrinogens. The condensation of acyclic reactants can proceed via competing Knorr (desired) and Fischer–Fink (undesired) pathways. Here, the Knorr and Fischer–Fink pathways are quantitated using (1) analogues of those in the proposed prebiotic route wherein the resulting pyrroles are blocked from subsequent condensation, and (2) a set of internal standards for quantitation of crude reaction mixtures by 1H NMR spectroscopy following extraction into CS2. The reaction of 1-amino-2-butanone and 3-methyl-2,4-pentanedione at 60 °C in aqueous solution at pH 7 for 24 h afforded the Knorr pyrrole and Fischer–Fink pyrrole in yields of 48% and 7%, respectively. The reaction in hot aqueous acid (pH 4.6, reflux, 30 min) afforded the Knorr pyrrole in diminished yield (22%) relative to that of the Fischer–Fink pyrrole (11%). The Knorr pyrrole (4-ethyl-2,3-dimethylpyrrole) is evanescent whereas the Fischer–Fink pyrrole (2,3,4-trimethyl-5-propanoylpyrrole) is quite stable; hence, rapid analysis of the reaction mixture (vs workup and isolation) is essential for accurate analysis.

Vitamin B1 as a metal-free organocatalyst for greener Paal–Knorr pyrrole synthesis

This investigation discloses a greener reaction to prepare pyrrole derivatives. Metal-free catalysts are greener alternatives to existing metal catalysts in synthetic organic chemistry. Indeed, transition metals are often costly and toxic. They may be found as traces in health reaction products such as pharmaceuticals. Alternatively small organic molecules termed “organocatalysts” allow the synthesis of valuable products without traces of toxic metals. Here, we show for the first time the use of vitamin B1 as new organocatalyst for the Paal–Knorr pyrrole synthesis under ambient conditions. Reaction conditions were optimized for the reaction of hexane-2,5-dione with 4-methoxyaniline. Ethanol was the most effective solvent. The conversion was quantitative using vitamin B1, by comparison with a low yield of 30 % without catalysis. The best conditions were performed in ethanol with 5 mol % of vitamin B1 during 1 h. This reaction was tested using various aromatic amines. To conclude the use of vitamin B1 for the Paal–Knorr pyrrole, cyclocondensation has mild reaction conditions, is simple to perform, and gives moderate to excellent yields. It is therefore a promising reaction for the preparation of various pyrrole derivatives.

Silica-supported bismuth(III) chloride as a new recyclable heterogeneous catalyst for the Paal–Knorr pyrrole synthesis

Silica-supported bismuth(III) chloride (BiCl3/SiO2) acts as as a highly efficient heterogeneous Lewis acid catalyst for the Paal–Knorr pyrrole synthesis in hexane at room temperature. The catalyst exhibited remarkable reusable activity and higher catalytic performance than homogeneous BiCl3. A plausible mechanism for the catalytic action of BiCl3/SiO2 has been introduced.

Flow synthesis using gaseous ammonia in a Teflon AF-2400 tube-in-tube reactor: Paal–Knorr pyrrole formation and gas concentration measurement by inline flow titration

Using a simple and accessible Teflon AF-2400 based tube-in-tube reactor, a series of pyrroles were synthesised in flow using the Paal-Knorr reaction of 1,4-diketones with gaseous ammonia. An inline flow titration technique allowed measurement of the ammonia concentration and its relationship to residence time and temperature.

Mechanistic Investigations of the Cyclocondensation Step of the Knorr Pyrrole Synthesis

Mechanistic Investigations of the Cyclocondensation Step of the Knorr Pyrrole Synthesis

Total synthesis of (−)-funebrine via Au-catalyzed regio- and stereoselective γ-butyrolactonization of allenylsilane

The stereoselective total synthesis of (−)-funebrine from 2-butyn-1-ol was described. The crucial steps in the synthesis involved the stereoselective enolate Claisen rearrangement of the ( S)-α-acyloxy-α-alkynylsilane 8, the Au-catalyzed regio- and stereoselective lactonization of the allenylsilane 7, and the Paal–Knorr pyrrole condensation using an unsymmetrical 1,4-diketone 4b.

Multijet Oscillating Disc Millireactor: A Novel Approach for Continuous Flow Organic Synthesis

This report discloses proof of concept and experimental results from a project involving design, development, and investigation of a novel approach for flow chemistry and the realization of equipment operating according to this new approach. This device is named multijet oscillating disk (MJOD) reactor and is dedicated to continuous flow organic synthesis in milliscale. Characteristics such as the importance of the multijet disk unit, with or without oscillating, and possible limitations, such as back-mixing, have been explored, and the flow system is benchmarked with other technologies. Several well-known reactions and syntheses usefully both in the chemical industry as well as in the research laboratory have been conducted using the new system, which have been benchmarked with batch- and microreactor protocols. In particular the Haloform reaction, the Nef reaction, nucleophilic aromatic substitution, the Paal–Knorr pyrrole synthesis, sodium borohydride reduction, O-allylation, the Suzuki cross-coupling ...