Pyrrolic Intermediates Research Articles

Synthesis, Thermal Stability and Antifungal Evaluation of Two New Pyrrole Esters.

To develop new chemicals that are stable at high temperatures with biological activity, a pyrrole intermediate was firstly synthesized using glucosamine hydrochloride as raw materials through cyclization and oxidation. Further, two novel pyrrole ester derivatives were prepared via Steglich esterification from pyrrole intermediate with vanillin and ethyl maltol, respectively. Nuclear magnetic resonance (1 H-NMR, 13 C NMR), infrared spectroscopy (IR) and high resolution mass spectrometry (HRMS) were used to confirm the target compounds. Thermal behavior of the compounds was investigated by thermogravimetry (TG), differential scanning calorimeter (DSC) and the pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) methods. The plausible pyrolytic mechanism was proposed. Additionally, their biological activities against the pathogens Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Phytophthora nicotianae, and Rhizoctonia solani were assessed. These target compounds showed outstanding antifungal activities and the highest inhibitor rates of 62.50 % and 68.75 % against R. solani with EC50 values of 0.0296 and 0.0200 mg mL-1 , respectively. SDHI protein sequence was molecularly docked to identify the binding mechanisms in the active pocket and examine the interactions between both the molecules and the SDHI protein.

Physiologically based kinetic modeling of senecionine N-oxide in rats as a new approach methodology to define the effects of dose and endpoint used on relative potency values of pyrrolizidine alkaloid N-oxides.

Over 1,000 pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) occur in 3% of all flowering plants. PA-N-oxides are toxic when reduced to their parent PAs, which are bioactivated into pyrrole intermediates that generate protein- and DNA-adducts resulting in liver toxicity and carcinogenicity. Literature data for senecionine N-oxide in rats indicate that the relative potency (REP) value of this PA-N-oxide compared to its parent PA senecionine varies with the endpoint used. The first endpoint was the ratio between the area under the concentration-time curve (AUC) for senecionine upon dosing senecionine N-oxide or an equimolar dose of senecionine, while the second endpoint was the ratio between the amount for pyrrole-protein adducts formed under these conditions. This study aimed to investigate the mode of action underlying this endpoint dependent REP value for senecionine N-oxide with physiologically based kinetic (PBK) modeling. Results obtained reveal that limitation of 7-GS-DHP adduct formation due to GSH depletion, resulting in increased pyrrole-protein adduct formation, occurs more likely upon high dose oral PA administration than upon an equimolar dose of PA-N-oxide. At high dose levels, this results in a lower REP value when based on pyrrole-protein adduct levels than when based on PA concentrations. At low dose levels, the difference no longer exists. Altogether, the results of the study show how the REP value for senecionine N-oxide depends on dose and endpoint used, and that PBK modeling provides a way to characterize REP values for PA-N-oxides at realistic low dietary exposure levels, thus reducing the need for animal experiments.

ACID-CATALYZED REARRANGEMENT OF 1-ACYL-2-AZABUTA-1,3-DIENES TO 4-PYRROLIN-2-ONES

1-Acyl-2-azabuta-1,3-dienes underwent rearrangement to 4-pyrrolin-2-ones in the presence of acidic catalysts (silica gel or ZnCl 2 ) and water. The reaction proceeded via the formation of 2,3-dihydroxy-3,4-dihydropyrrole and 2-hydroxy-2 Н -pyrrole intermediates, the latter of which was transformed by [1,5]-sigmatropic shift of carbonyl substituent and prototropic isomerization. 4-Chloro-substituted 1-acetyl-2-azabuta-1,3-dienes were stable toward rearrangement, while brominated analogs rearranged into 4-pyrrolin-2-ones, probably as a result of the initial radical hydrodebromination. According to calculations performed at the DFT level, two steps of the reaction were catalyzed by acid: the cyclization of 2-azabutadiene and the sigmatropic shift in the 2-hydroxy-2 Н -pyrrole intermediate. Authors: Nikolai V. Rostovskii, Ilia A. Smetanin, Alexander N. Koronatov, Anastasiya V. Agafonova, Vasilii V. Potapenkov, Alexander F. Khlebnikov, Mikhail S. Novikov*

Electrochemical Polymerization of Pyrrole–Perimidine Hybrids: Low-Band-Gap Materials with High n-Doping Activity

Conductive π-conjugated polymers were electrochemically generated from a variety of donor–acceptor pyrroles containing fused perimidine subunits. Alternating oxidative and reductive polarization of these precursors induces multidirectional coupling involving both perimidine and acenaphtho[1,2-c]pyrrole moieties, producing cross-linked polymeric structures. Chemical oxidation experiments and computational analyses of spin densities in the charged pyrrole intermediates indicate that the formation of inter-perimidine linkages occurs prior to pyrrole–pyrrole couplings. In the resulting polymers, a very stable dication state is achievable with the positive charge located on the bis-perimidine linker. These polymers do not show any stable neutral state and can be easily reduced. Cationic and anionic states of these electrogenerated films were investigated in the solid state by UV–vis–NIR and EPR spectroelectrochemistry, assisted by DFT calculations.

Cascade Synthesis of Benzothieno[3,2- b]indoles under Oxidative Conditions Mediated by CuBr and tert-Butyl Hydroperoxide.

A series of biologically relevant compounds of benzothieno[3,2- b]indole derivatives were conveniently synthesized from reactions of N-protected 2-((2-bromophenyl)ethynyl)anilines and potassium ethylxanthate, mediated by cuprous bromide/ tert-butyl hydroperoxide. The method features the construction of the pyrrole and thiophene rings in a cascade sequence with the pyrrole ring being formed prior to the thiophene ring via a possible reactive Cu(III)-pyrrole intermediate.

Comparative triad of routes to an alkyne-BF2 azadipyrromethene near-infrared fluorochrome

A series of three inter-related synthetic routes to a water soluble alkyne substituted BF2-azadipyrromethene fluorochrome is described. Each route allows for the introduction of the required reactive alkynyl group and water solubilizing propane-sulfonic acid through either more advanced pyrrole intermediates or through their earlier synthetic precursors. The advantages and disadvantages of each route lie in the number of synthetic steps required versus the formation of undesired azadipyrromethene by-products. Upon its synthesis, the alkyne-bearing fluorochrome was shown to efficiently participate in CuACC reactions with a series of azido substrates in water at room temperature and 37 °C. NIR-photophysical properties of the fluorochrome and its conjugates were similar, showing strong potential for in vitro and in vivo imaging applications.

Synthesis of (±)-γ-Lycorane by Using an Intramolecular Friedel–Crafts Reaction

A total synthesis of γ-lycorane has been achieved by employing N-tosylpyrrole as a key building block. The synthesis employs both an intermolecular and an intramolecular Friedel–Crafts reaction, as well as a completely diastereoselective hydrogenation of a late-stage pyrrole intermediate.

Synthesis of 2H-pyrrolo[3,4-C]quinoline via an Aldol/Van Leusen/Staudinger/aza-Wittig sequence

ABSTRACTAn aldol/van Leusen/Staudinger/aza-Wittig reaction for the preparation of the derivatives of 2H-pyrrolo[3,4-c]quinolines from 2-azidobenzaldehyde, acetyl compounds, and tosylmethyl isocyanide was developed. The process involves an aldol condensation of 2-azidobenzaldehyde with acetyl compound in base, a van Leusen reaction to form the key pyrrole intermediates, and then a Staudinger and intramolecular aza-Wittig reaction occurred with the addition of triphenylphosphine to complete the formation of pyrrolo[3,4-c]quinoline ring in high yields.

Total syntheses of codonopsinine and 4-epi-codonopsinine via gold-mediated tandem-catalyzed pyrrole synthesis.

The total syntheses of codonopsinine (1) and 4-epi-codonopsinine (2) were accomplished. The key substituted pyrrole intermediate was constructed via gold-catalyzed addition-cyclization cascade of an aminoacetaldehyde acetal derivative and a terminal alkyne. After diastereoselective reduction of the pyrrole intermediate to the corresponding 3-pyrroline derivative with zinc dust and sulfonic acid, the total synthesis of 4-epi-codonopsinine (2) was achieved via stereoselective construction of the diol by dihydroxylation. In addition, the total synthesis of codonopsinine (1) was completed through stereochemical inversion of the hydroxyl group via epoxide and subsequent ring cleavage under the acidic aqueous condition.

オリゴピロール誘導体のらせん構造制御

Unique cyclooligopyrroles with figure of 8 conformation were prepared from useful pyrrole intermediates such as bis(azafulvene)s and 2-borylpyrrole. [32]Octaphyrin-(1.0.1.0.1.0.1.0) 1 with 32π-cycloconjugation exists in a P,P- and a M,M-helical form, which are rapidly interchanged by the stretching-compressing mechanism. Cyclooctapyrrole 1 was successfully applied to a chirality sensor for determining absolute configuration of chiral carboxylic acids taking advantage of the unique chiroptical property. Calix[8]phyrin 2 having interrupted π-conjugation also undergoes rapid conformational change in solution, but its dinuclear CuII complex 2Cu2 was resolved into enantiomers by HPLC on chiral phase. Metal insertion into 2 in the presence of (R)-(+)-1-(phenyl)ethylamine caused helix sense bias to the P,P-helicity. Cyclotetrapyrroletetrapyridine 3 composed of eight heterocycles also takes helical conformation and provides dual monoanionic tridentate coordination environment. Its dinuclear CoII complexes 3Co2L2 with an amino acid anion (L−) at each metal site could be isolated to show full helix sense bias in the case of Thr, Phe, Tyr, and Trp. An open chain oligopyrrole was also studied to generate helix sense bias. Dinuclear PdII complex 4Pd2 of hexapyrrole-α,ω-dialdehyde was reacted with (R)-(−)-1-cyclohexylethylamine to give the corresponding α,ω-diimines with 85% diastereoselectivity in favor of the P helical conformation, the chiroptical property of which could be tuned by redox.

ChemInform Abstract: Helical Chirality Induction of Expanded Porphyrin Analogues

AbstractReview: 47 refs.

Helical chirality induction of expanded porphyrin analogues

Expanded porphyrin analogues with unique figure-eight conformation were prepared by way of useful pyrrole intermediates such as bis(azafulvene)s and 2-borylpyrrole. Supramolecular chirogenesis of cyclooctapyrrole O1 with 32π-cycloconjugation was successfully applied to determine absolute configuration of chiral carboxylic acids. Dinuclear CuII complex of cyclooctapyrrole O2 with interrupted π-conjugation was resolved by HPLC into enantiomers and their helical handedness was determined by theoretical simulation of their CD spectral pattern. Enantioselective induction of helicity in the metal helicate formation in the presence of a chiral promoter was demonstrated by using (R)-(+)-1-(1-phenyl)ethylamine that favoured P, P helicity. Dinuclear CoII complexes of cyclotetrapyrroletetrapyridine O3 were found to be substitution labile and pick up amino acid anions in water. Those amino acid complexes of O3Co 2 were rendered to adopt a particular unidirectional helical conformation preferentially depending on the ligated amino acid anion.

Study of Catalytic Sites on Ruthenium For Hydrogenation of N-ethylcarbazole: Implications of Hydrogen Storage via Reversible Catalytic Hydrogenation

Hydrogen storage is a significant challenge for the development and viability of hydrogen-powered vehicles. Storage of molecular hydrogen in nitrogen-substituted polyunsaturated aromatic organic molecules through reversible catalytic hydrogenation and dehydrogenation is a promising approach. The success of developing a catalytic hydrogen storage concept is highly dependent on finding an efficient catalyst; however, understanding how molecules interact with metal catalytic sites is, at present, rather limited. In this work, a combined experimental and theoretical study is conducted to identify efficient catalytic sites on metallic surfaces and to understand the reaction mechanism for the forward hydrogenation reaction. It is clearly revealed from experimentation that hydrogenation of N-ethylcarbazole, a typical nitrogen-substituted polyunsaturated aromatic organic molecule, is taking place in a stepwise manner over metal catalysts. Because of steric constraints at terrace sites, the kinetically stable pyrrole intermediate, formed by partial hydrogenation of N-ethylcarbazole, cannot be readsorbed once desorbed into solution. Therefore further hydrogenation occurs at the low coordinated sites where no similar steric hindrance is encountered. Thus, the mechanism for hydrogenation involves an unusual shuttling of partially hydrogenated intermediates from terrace sites to higher indexed sites via solution. First-principles calculations confirm that the pyrrole intermediate can strongly adsorb to various low coordination sites, typically steps on the vicinal (109) surface, while the adsorption is extremely weak on flat (001) terraces. This work is the first example of catalytic site analysis to account for observed activity, selectivity and recyclability of a typical metal catalyst for catalytic hydrogen storage, which could lead to rational design of superior materials.

Preparation of Sulfenyl Pyrroles

Sulfenyl groups are attracting interest as masking/protecting groups for pyrroles. A facile one-step synthesis of sulfenyl pyrroles, involving the reaction of pyrroles with N-(aryl- and alkyl­thio)phthalimides in the presence of MgBr2, is reported and the methodology extends to include sulfinyl pyrroles. The one-step procedure gives good yields and is more efficient and practical than current multistep protocols to sulfenyl pyrroles that involve thio­cyanato pyrrolic intermediates. A convenient procedure for the synthesis of N-(aryl- and alkylthio)phthalimides is also reported.

Porphyrins with Exocyclic Rings. Part 20. Synthesis and Spectroscopic Characterization of Porphyrins with Fused 2,1,3‐Benzoxadiazole and 2,1,3‐Benzoselenadiazole Moieties.

Abstract Porphyrins with fused 2,1,3-benzoxadiazole and 2,1,3-benzoselenadiazole units were prepared by the ‘3+1’ MacDonald-type methodology. 4-Nitro-2,1,3-benzoxadiazole, 6-chloro-4-nitro-2,1,3-benzoxadiazole and 4-nitro-2,1,3-benzoselenadiazole condensed with isocyanoacetates in the presence of the non-nucleophilic base DBU to give tricyclic pyrrole derivatives in excellent yields. Further cleavage of the ester moieties and decarboxylation afforded α-unsubstituted pyrroles and these were further condensed with 2 equiv of an acetoxymethylpyrrole tert -butyl ester to give crude preparations of tripyrranes. The tert -butyl ester protective groups were cleaved with TFA and following dilution with dichloromethane, ‘3+1’ condensation with a pyrrole dialdehyde, and oxidation with ferric chloride, the heterocyclic ring fused porphyrins were obtained in moderate yields. The yields were lower than expected because of difficulties in preparing required tripyrranes due to the reduced reactivity of the pyrrolic intermediates. The UV–vis spectra of these new porphyrin systems were highly modified showing broadened split Soret bands. In addition, the nickel(II), copper(II) and zinc complexes gave unusual UV–vis spectra with weakened split Soret bands and strong Q-type absorptions above 600 nm. These modified structures show some potential for applications as photosensitizers in photodynamic therapy.

Porphyrins with exocyclic rings. Part 20: Synthesis and spectroscopic characterization of porphyrins with fused 2,1,3-benzoxadiazole and 2,1,3-benzoselenadiazole moieties

Porphyrins with fused 2,1,3-benzoxadiazole and 2,1,3-benzoselenadiazole units were prepared by the ‘3+1’ MacDonald-type methodology. 4-Nitro-2,1,3-benzoxadiazole, 6-chloro-4-nitro-2,1,3-benzoxadiazole and 4-nitro-2,1,3-benzoselenadiazole condensed with isocyanoacetates in the presence of the non-nucleophilic base DBU to give tricyclic pyrrole derivatives in excellent yields. Further cleavage of the ester moieties and decarboxylation afforded α-unsubstituted pyrroles and these were further condensed with 2equiv of an acetoxymethylpyrrole tert-butyl ester to give crude preparations of tripyrranes. The tert-butyl ester protective groups were cleaved with TFA and following dilution with dichloromethane, ‘3+1’ condensation with a pyrrole dialdehyde, and oxidation with ferric chloride, the heterocyclic ring fused porphyrins were obtained in moderate yields. The yields were lower than expected because of difficulties in preparing required tripyrranes due to the reduced reactivity of the pyrrolic intermediates. The UV–vis spectra of these new porphyrin systems were highly modified showing broadened split Soret bands. In addition, the nickel(II), copper(II) and zinc complexes gave unusual UV–vis spectra with weakened split Soret bands and strong Q-type absorptions above 600nm. These modified structures show some potential for applications as photosensitizers in photodynamic therapy.

Monocrotaline Pyrrole Interacts with Actin and Increases Thrombin-Mediated Permeability in Pulmonary Artery Endothelial Cells

One of the earliest morphologic changes evident in the monocrotaline (MCT) model of pulmonary hypertension in rats is microvascular leak. Whether this represents a direct effect of MCT metabolites or is secondary to inflammatory and thrombotic changes remains uncertain. To determine whether MCT directly affects endothelial cell permeability barrier function, we characterized the interaction of the reactive pyrrole intermediate of MCT (MCTP) with endothelial cell actin and characterized its effects on thrombin-mediated signal transduction and monolayer permeability. Bovine pulmonary endothelial cells (BPAEC) treated with MCTP had altered distribution of filamentous actin evident by fluorescence microscopy. Correlative Western blots and autoradiography of actin isolated from BPAEC treated with14C-MCTP showed comigration of actin and MCTP-derived14C. MCTP treatment did not alter cellular free Ca2+concentrations nor did it interfere with thrombin-mediated intracellular Ca2+signal. Pretreatment with MCTP significantly augmented the thrombin-mediated transudation of Evan's blue albumin in BPAEC monolayers apparently by increasing the size of intercellular gaps. We conclude that MCTP directly interacts with actin to alter its polymerization state but does not significantly affect endothelial cell response to contractile stimulus. Our results suggest that MCTP may affect endothelial cell barrier function through alterations in intracellular junctions.

Synthesis of novel porphyrin chromophores from nitroarenes: Further applications of the Barton-Zard pyrrole condensation

Porphyrins with fused nitronaphthalene and benzothiadiazole subunits have been synthesized by the “2 + 2” and “3 + 1” methodologies; the key pyrrolic intermediates were prepared by the base catalyzed condensation of dinitronaphthalenes or 4-nitro-2,1,3-benzothiadiazole with isocyanoacetates.

The synthesis and chemistry of azolenines. Part 18. Preparation of 3-ethoxycarbonyl-3 [formula omitted]-pyrroles [formula omitted] the paal-knorr reaction, and sigmatropic rearrangements involving competitive ester migrations to c-2, c-4 and n.

3 H -Pyrrole-3-carboxylic esters ( 4 ) have been prepared, in some cases together with isomers ( 5 ) and ( 6 ) having exocyclic double bonds, by cyclization of suitably substituted 2-ethoxycarbonyl-1,4-diketones ( 1 ) with liquid ammonia, followed by dehydration of the isolable 2-hydroxy-3,4-dihydro-2 H -pyrrole intermediates ( 2 ) and ( 3 ) with aluminia in boiling solvents. Prolonged heating in toluene or p-xylene coverts the 3H pyrroles ( 4 ) quantitatively into isomeric 4-esters ( 11 ) and N -esters ( 13 ) of 1 H -pyrroles via competitive [1,5]sigmatropic rearrangements. Isolable intermediate 2 H -pyrrole-2-carboxylic esters ( l2 ) are converted similarly into the same products, under the same conditions. Detection of 3 H -pyrroles ( 4 ) as intermediates in the latter reaction demonstrates for the first time the reversibility of the thermal 2 H -pyrrole to 3 H -pyrrole interconversion.

Polypyrrole intermediates in porphyrin biosynthesis. Studies with Euglena gracilis

1. 1. Evidence for the formation of pyrrolic intermediates resulting from the action of a whole enzyme system and deaminase preparations from Euglena gracilis on porphobilinogen, under normal anaerobic conditions is reported. 2. 2. It was found that the activity of Euglena gracilis pellet was not affected by the presence of air; the yield of porphyrinogens being the same under anaerobiosis and aerobiosis. Both with pellet and deaminase preparations, two phases in porphyrinogen synthesis were observed, a slow and a rapid one, suggesting that some intermediates in the reaction were formed. 3. 3. The nature of these intermediates was investigated by incubating them with different enzyme preparations and PBG. Results obtained suggested that the polypyrroles formed from the whole system and deaminase were different. They did not behave as substrates but as intermediates m the reaction and significantly inhibited total porphyrinogen formation. It is proposed that these intermediates could be in high percentage larger polypyrrylmethanes.