Pyrrole Products Research Articles

Preparation of substituted pyrroles via Ru(II)-catalyzed coupling of alkynes with enamides

An efficient ruthenium-catalyzed oxidative cyclization of enamides with alkynes in water or dimethoxyethane leading to the pyrrole derivatives is reported. Typically, a mixture of ethyl 2-(acetylamino)acrylate, diphenylacetylene, [Ru(p-cymene)Cl2] (2mol%), KPF6, and Cu(OAc)2 in water was heated under refluxing conditions providing the N-acetylated pyrrole product in 95% yield.

ChemInform Abstract: Synthesis of 5‐Azaspiro[2.4]heptan and Penta‐Substituted Pyrrole Derivatives via Pd‐Catalyzed Intramolecular Cyclization Reaction of Alkynyl Carboxamides.

Abstract Penta-substituted pyrrole derivatives, including a three-membered ring (5-azaspiro[2.4]heptan), were readily prepared in moderate to excellent yields by the Pd-catalyzed intramolecular cyclization reaction of alkynyl carboxamide compounds. When an excess amount of ZnCl2 acted as a Lewis acid and a source of halide, the one-pot bi-metallic system could afford more valuable penta-substituted chloroethyl pyrrole products under similar conditions. This indicates that the present method is a powerful tool for the preparation of a wide range of functionalized and polysubstituted pyrroles.

Synthesis of 5-Azaspiro[2.4]heptan and Penta-Substituted Pyrrole Derivatives via Pd-Catalyzed Intramolecular Cyclization Reaction of Alkynyl Carboxamides

Penta-substituted pyrrole derivatives, including a three-membered ring (5-azaspiro[2.4]heptan), were readily prepared in moderate to excellent yields by the Pd-catalyzed intramolecular cyclization reaction of alkynyl carboxamide compounds. When an excess amount of ZnCl2 acted as a Lewis acid and a source of halide, the one-pot bi-metallic system could afford more valuable penta-substituted chloroethyl pyrrole products under similar conditions. This indicates that the present method is a powerful tool for the preparation of a wide range of functionalized and polysubstituted pyrroles.

ChemInform Abstract: Synthesis of 2‐ and 3‐Indolylpyrroles via 1,3‐Dipolar Cycloadditions of Muenchnones and Nitroalkenes.

Abstract2‐Nitrovinylindoles (I) react smoothly with symmetrical muenchnones, generated in situ, to afford the pyrrole products (III) in very good yields.

ChemInform Abstract: Intramolecular Hydroamination of Conjugated Dienes Catalyzed by Lewis and Broensted Acids.

AbstractIn all cases, the pyrrole products bearing the (E)‐side chain are formed with high selectivity.

ChemInform Abstract: 4‐Isoxazolines and Pyrroles from Allenoates.

AbstractBy choosing the conditions for the reaction of nitrones, generated in situ from allenoates, with alkynes the isoxazoline or pyrrole products are prepared.

Palladium-Catalyzed C−H Arylation of 2,5-Substituted Pyrroles

The palladium-catalyzed direct arylation of 2,5-substituted pyrrole derivatives with diaryliodonium salts to generate tri-, tetra-, and penta-substituted pyrrole products is described. The scope and limitations of these transformations are also reported.

Rhodium(III)-Catalyzed Arene and Alkene C−H Bond Functionalization Leading to Indoles and Pyrroles

Recently, the rhodium(III)-complex [Cp*RhCl(2)](2) 1 has provided exciting opportunities for the efficient synthesis of aromatic heterocycles based on a rhodium-catalyzed C-H bond functionalization event. In the present report, the use of complexes 1 and its dicationic analogue [Cp*Rh(MeCN)(3)][SbF(6)](2) 2 have been employed in the formation of indoles via the oxidative annulation of acetanilides with internal alkynes. The optimized reaction conditions allow for molecular oxygen to be used as the terminal oxidant in this process, and the reaction may be carried out under mild temperatures (60 °C). These conditions have resulted in an expanded compatibility of the reaction to include a range of new internal alkynes bearing synthetically useful functional groups in moderate to excellent yields. The applicability of the method is exemplified in an efficient synthesis of paullone 3, a tetracyclic indole derivative with established biological activity. A mechanistic investigation of the reaction, employing deuterium labeling experiments and kinetic analysis, has provided insight into issues of reactivity for both coupling partners as well as aided in the development of conditions for improved regioselectivity with respect to meta-substituted acetanilides. This reaction class has also been extended to include the synthesis of pyrroles. Catalyst 2 efficiently couples substituted enamides with internal alkynes at room temperature to form trisubstituted pyrroles in good to excellent yields. The high functional group compatibility of this reaction enables the elaboration of the pyrrole products into a variety of differentially substituted pyrroles.

ChemInform Abstract: Synthesis of Pyrroles from Benzyl Isocyanoacetate.

Benzyl esters of 5-unsubstituted pyrrole-2-carboxylic acids were prepared in excellent yields by the base-catalyzed condensation of benzyl isocyanoacetate with α-acetoxynitro compounds, or nitroalkenes, in refluxing tetrahydrofuran. These pyrrolic products are important intermediates in the synthesis of porphyrins and related compounds

ChemInform Abstract: Reduction of the Indole Ring System: Synthesis of 4,5,6,7-Tetrahydroindoles.

Abstract A general two-step procedure for the reduction of indoles to the corresponding 4,5,6,7-tetrahydroindoles has been developed. A regioselective Birch reduction followed by catalytic hydrogenation is employed to accomplish this transformation. Yields for the sensitive pyrrole products are typically between 40 and 50%. This method provides access to complex chiral pyrroles that cannot be readily prepared by other methods.

Development of an In vitro Co-culture Assay for the Investigation of Metabolism-Mediated Toxicity of Pyrrolizidine Alkaloids

Pyrrolizidine alkaloids (PAs) are naturally occurring phytochemicals found in plants worldwide. A number of PAs are known to be hepatoxic to humans and may cause fatalities [1]. Consumers may be exposed to PAs through ingestion of contaminated grains or use of dietary supplements. It has been established that the hepatoxicity of many PAs results from their metabolism by hepatic enzymes, including cytochrome P450, to produce reactive pyrroles [2, 3]. In our investigation, metabolism-mediated toxicity of two PAs, retrorsine and monocrotaline, was studied using a co-culture of human hepatocarcinoma (HepG2/C3A) cells and rat liver microsomes. HepG2/C3A cells were incubated with PAs for 6 hrs in the presence and absence of rat liver microsomes and the toxicity was assessed as lowered mitochondrial activity (i.e. mitochondrial reduction of MTT). We found that both retrorsine and monocrotaline were toxic and the toxicity was dependent on microsome-mediated metabolism. In addition, LC/MS was used to measure microsome-mediated metabolism of the PAs and formation of the glutathione conjugates of the resulting reactive pyrroles. The LC/MS measurements indicated that the PAs were rapidly metabolized by rat liver microsomes with concomitant production of reactive pyrroles. The results of the in vitro assay and LC/MS measurements are consistent with metabolism-mediated toxicity for retrorsine and monocrotaline.

Synthesis of Polysubstituted Pyrroles via PhI(OAc)2-Mediated Oxidative Coupling of Enamine Esters and Ketones

Enamine esters or ketones could undergo homocoupling by the action of (diacetoxyiodo)benzene in the presence of BF 3 -OEt 2 , giving rise to pyrrole products. This reaction could be used to synthesize symmetric polysubstituted pyrroles. Some asymmetric polysubstituted pyrroles could also be prepared using this protocol.

A facile and regioselective synthesis of 2,5-disubstituted pyrroles via gold-catalyzed cycloisomerization of acetylenylaziridines

Gold-catalyzed cycloisomerization reaction of acetylenylaziridines provides 2,5-disubstituted pyrroles in high yields. The presence of protic species accelerates the reaction rate and improves the yields of pyrrole products.

One-Step Route to 2,3-Diaminopyrroles Using a Titanium-Catalyzed Four-Component Coupling

A simple indolyl titanium complex, Ti(NMe2)2(IndMe2)2 (1), can be prepared from commercially available reagents, Ti(NMe2)4 and 2,3-dimethylindole. Indolyl-containing 1 is a catalyst for the selective generation of unusual 2,3-diaminopyrroles from four-component coupling of 2 equiv of an isonitrile, 1 equiv of an arylamine, and 1 equiv of an alkyne in an atom-efficient process. For this study, both terminal and internal alkynes were used with a selection of arylamines to provide 11 examples of 2,3-diaminopyrroles. Yields for terminal alkyne substrates in this reaction were 75−93%. In all cases, terminal alkynes result in one of the α-positions on the pyrrole being unsubstituted. Two reactions with internal alkynes provided pentasubstituted pyrroles in 42% and 88% yield. Catalyst 1, along with six of the pyrrole products, was structurally characterized by single-crystal X-ray diffraction.

Counterion Effects in a Gold-Catalyzed Synthesis of Pyrroles from Alkynyl Aziridines

Aryl-substituted N-tosyl alkynyl aziridines undergo a gold-catalyzed ring expansion to afford 2,5-substituted pyrrole products. Under certain conditions, a ring-expansion and rearrangement leads to 2,4-substituted pyrroles. The reaction pathway is determined by the counterion to the gold catalyst.

Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides

A new thermal ring cleavage of 3-pyridyl nitrenes for the formation of 4-isocyanobut-2-enenitrile products is reported. Thermolysis of 4-(thien-3-yl)-3-pyridyl azide 1 and 3-azido-4-(1-TIPS-1 H-pyrrol-3-yl)pyridine 5 afforded two new isonitrile–nitrile products by ring cleavage; 4-isocyano-2-(thiophen-3-yl)but-2-enenitrile ( 3, 27%) and 4-isocyano-2-(1-TIPS-1 H-pyrrol-3-yl)but-2-enenitrile ( 7, 20%), in addition to our previously reported pyrido[3,4- b]thienopyrrole ( 2, 29%) and pyrido[3,4- b]pyrrolo[3,2- d]pyrrole ( 6, 71%) products. Minor amounts of 2-(thien-3-yl)-1 H-pyrrole-3-carbonitrile ( 4, 6%), formed by ring contraction, were also isolated after thermolysis of azide 1. Isonitriles 3 and 7 underwent degradation into amine 3b and formamide 7a by acidic hydrolysis. The nature and chemistry of compounds 3, 4 and 7 were investigated.

Synthesis of Pyrroles from Allenic Aldehydes and Amines

Sulfanyl-substituted allenic aldehydes undergo acid-catalyzed reaction with amines to afford pyrrole derivatives in modest to good yields. The allenic aldehydes are available in a three-step sequence starting with diazoacetates and propargyl sulfides. Although substituent variation in the allenyl aldehyde was insufficiently explored, the reaction provides considerable scope for the construction of highly substituted pyrroles. Two mechanistic pathways are suggested which differ in the manner of 1,2-migration of the sulfanyl group. Both start with the generation of the imine intermediate which undergoes intramolecular cyclization and elimination of the sulfanyl group. In path A, sequential attack of the released sulfanyl group at the iminium carbon and rearomatization leads to the pyrrole product. Path B involves a nucleophilic attack of the imine by the sulfur group and a simultaneous attack of the allene by the nitrogen atom to generate a thiirenium species which then undergoes ring opening and further deprotonation to afford the product.

Chromatography Paper: A Novel Solid Support

A cellulose-based chromatography paper was used as a solid support for organic transformations as well as extractive purification. N-tosylation, Grubbs’ ring-closing metathesis, and Wadsworth-Emmons olefination were carried out on the chromatography paper support where the substrates and reagents were non-covalently immobilized. For example, as can be seen in the scheme, tosyl chloride was charged on the paper tile as a melt and diallylamine (neat) was added subsequently on to the spot of TsCl. After 10 minutes, the paper reactor was washed with aqueous NaHCO3, water, diluted acid, and water to remove unreacted TsCl and amine. Ionic liquid solution of Grubbs’ catalyst was then loaded onto the reaction spot, and the paper reactor was left for three days in a sealed vial. The paper was extracted with ether to afford a pyrrole product in 29% isolated yield (single extraction) with high purity (NMR analysis).

Direct Synthesis of Pyrroles from Imines, Alkynes, and Acid Chlorides: An Isocyanide-Mediated Reaction

[reaction: see text] A direct synthesis of pyrroles from imines, acid chlorides, and alkynes mediated by isocyanides is reported. This reaction proceeds with a range of each of these three substrates, providing a method to generate families of pyrroles in high yield. Mechanistic studies suggest this process proceeds via the generation of imino analogues of munchnones, which can undergo in situ coupling with alkynes to liberate isocyanate and form the pyrrole product.

4-Alkoxy- and 4-Amino-2,2‘-bipyrrole Synthesis

[Structure: see text] 4-alkoxy-2,2'-bipyrroles and the first examples of 4-amino-2,2'-bipyrroles have been synthesized by a diversity-oriented strategy from 4-hydroxyproline. The bipyrrole products offer interesting potential as building blocks for making pyrrole products, as demonstrated by the first synthesis of an amino prodigiosin analogue.