Fischer Reaction Research Articles

A regiospecific fischer indole reaction with 3‐oxo‐24‐nor‐allobetulin

AbstractFirst case of regiospecific formation of indole fused with a triterpene scaffold is observed. Starting from 3‐oxo‐24‐nor‐allobetulin Fischer reaction with phenylhydrazine under the influence of weak acid catalyst led to 3H‐indole (indolenine) 4. This process was accompanied by a change in the configuration of the methyl group at C‐4 that was confirmed by x‐ray diffraction method. On the other hand, 3,2‐indole 5 was synthesized under the influence of strong acid catalyst (using phenylhydrazine hydrochloride in AcOH acid or phenylhydrazine in MeOH with a few drops of HCl).

Transesterification reactions as a means to produce esters: A critical review

AbstractEsters are important chemicals used in fine and bulk chemical industry with numerous applications: solvents, paints, varnishes, dyes, and cosmetics. Ester formation is dominated mainly by Fischer esterification and transesterification. Fischer reaction is generally used for ester production, but in certain cases, transesterification can be used with advantage. It is useful when the acid is less soluble in the alcohol or in the solvent used, thus forming two layers. Water formation creates purification problems during esterification reactions due to azeotrope formation and transesterification can be useful in such cases. Commercially, cheaply available methyl and ethyl esters can be conveniently used as raw materials for value added ester production by transesterification. Transesterification is also useful when the parent acids are highly reactive and pose difficulty in separation. Transesterifications are slow reactions and a catalyst is used: acids and bases, ion exchange resins, zeolites, and clays. Homogeneous catalysts were used in the past which are now replaced by their heterogeneous counterparts. Heterogeneous catalysts offer added advantages like reusability, lesser corrosion, and ease of separation. Transesterification can be commercially used to produce a number of esters of industrial importance like acrylics and biodiesel. This review considers all these aspects in considerable detail. A large literature set was scanned and its judicious extract is presented.

Synthesis, modification and biological activity of 2,3-indoles of Glycyrrhetinic acid

The synthesis of 2,3-indoles of Glycyrrhetinic acid (GLA) and its methyl ester was carried out by the Fischer reaction. Reductive transformations of GLA methyl ester 2,3-indole 3a were carried out to obtain 11-deoxo- and 9,12-diene analogs. N-methylation of 2,3-indole 3a gave N-methyl-indole-11-oxo-18β-olean-12-en-30-oic acid. The antiulcer and anti-inflammatory activity of 2,3-indole 3a was studied in rats and mice. It was found, compound 3a exhibied a pronounced antiulcer activity in the indomethacin model of ulcers in rats and anti-inflammatory activity in the carrageenan model of acute edoema in mice, at a dose of 50 mg/kg. This is the first report of anti-ulcer and anti-inflammatory activities of 2,3-indolo-GLA derivatives.

Synthetic studies toward the marine alkaloid convolutindole A, a structurally remarkable derivative of the hallucinogen N,N-Dimethyltryptamine (DMT)

Herein we report the results of a synthetic strategy toward the marine alkaloid convolutindole A, a structurally remarkable derivative of the hallucinogen N,N-dimethyltryptamine (DMT). While attempts to forge an advanced tryptamine intermediate using the Fischer reaction were unsuccessful, an iterative CH functionalisation strategy proved more fruitful. Subjecting 6-bromoindole to an iridium-catalysed triborylation gave a 2,4,7-triborylindole, which underwent selective protodeboronation at C2. The resulting 4,7-diborylindole underwent selective Chan-Evans-Lam and bromodeboronation reactions at C7 and C4 respectively, affording 4,6-dibromo-7-methoxyindole. Installation of the tryptamine side chain was achieved by reductive alkylation (presumably via a β-methoxytryptamine intermediate) to give an advanced tri-substituted tryptamine closely related to convolutindole A. This work showcases the utility of the iridium-catalysed CH borylation methodology to prepare densely functionalised indoles that would traditionally be accessed by heteroannulation, while providing an excellent foundation for ongoing synthetic efforts toward convolutindole A.

Functionalization of tetrahydroindol-4-one derivatives

Available and effective methods of tetrahydroindol-4-one derivatives transformation are described, which include functionalization of the nitrogen atom, carbonyl group, side chains in positions 1,2,3,7 of the bicycle, as well as aromatization of the cyclohexene fragment in the presence of dehydrogenating agents. Original preparative approaches to the synthesis of [4,5]-fused indole derivatives (pyrroles, thiophenes, pyrazoles, isoxazoles, thiazoles, 1,2,3-triazoles, pyridazinones), implemented by introducing functional groups in the α-position to the carbonyl group with subsequent cyclocondensations (Hanch, Paal-Knorr, [4+2] and [3+2]-cyclization reactions) are reviewed. Beckman and Schmidt rearrangements in the chemistry of tetrahydroindolones are accompanied by a cycle expansion with the formation of lactams or their transformation products. The Fischer reaction allows to obtain polyheterocycles with a new indole ring at the same time as the Dimrot rearrangement allows to synthesize pyrroloquinolones. Among the ways of modifying side chains of tetrahydroindolone, the three-component Passerini reaction is the most promising one, which provides quick access to indolone-N-amino acid derivatives.

РАЗРАБОТКА МЕТОДИКИ ОПРЕДЕЛЕНИЯ ВОДЫ МЕТОДОМ КУЛОНОМЕТРИЧЕСКОГО ТИТРОВАНИЯ ПО ФИШЕРУ В ФАРМАЦЕВТИЧЕСКИХ СУБСТАНЦИЯХ ГРУППЫ ФТОРХИНОЛОНОВ

Abstract. A wide spectrum of antibacterial action of fluoroquinolones of the III generation (levofloxacin) and IV generation (moxifloxacin) determines their active use for the treatment of various infectious diseases. The quality of the pharmaceutical substances included in their composition affects the manifestation of the therapeutic effect of drugs. Decomposition of the active substance and the formation of undesirable impurities can occur if storage conditions are violated (high humidity, temperature, light). All these factors can significantly affect the pharmacological activity, up to the manifestation of a toxic effect. The humidity regime is especially important for hygroscopic substances (moxifloxacin) and substances containing water of crystallization in the chemical structure (levofloxacin). Weathering of crystallization water is possible at low humidity; this may affect the weight of the sample of the medicinal substance, which is important in the technological process in the manufacture of dosage forms. As a result, it may affect the quality of the finished product. Therefore, the determination of the water content during the quality control of pharmaceutical substances is mandatory. Coulometric titration at a constant current strength (galvanostatic coulometry) is a promising method for determining water in substances. Titration is carried out with electrogenerated iodine, which is formed during the anodic oxidation of iodide ions contained in the background electrolyte. Further, iodine, oxidizing sulfur (IV) in a sulfur-containing compound in the presence of water according to the Fischer reaction, is reduced to iodide ions, from which iodine can be generated again. The cyclic nature of the process makes it possible to carry out multiple measurements without changing the background electrolyte. The water content is calculated from the amount of electricity used for titration. The advantages of this method are specificity, no need for preliminary standardization of the titrant, rapidity and simplicity of the experiment. A unified method for the determination of water by coulometric Fischer titration in levofloxacin and moxifloxacin substances has been developed. The validation evaluation of the method for determining water in the substance of levofloxacin showed its validity in terms of specificity, linearity (r=0.9977), correctness and precision (RSD 2%). The methods can be used in the practice of control and analytical laboratories to assess the "Water" parameter in these pharmaceutical substances.

Fischer Reaction in the Synthesis of New Triterpene Indoles of the Fusidane Series

Fischer Reaction in the Synthesis of New Triterpene Indoles of the Fusidane Series

Coupling Interrupted Fischer and Multicomponent Joullié-Ugi to Chase Chemical Diversity: from Batch to Sustainable Flow Synthesis of Peptidomimetics.

The generation of peptidomimetic substructures for medicinal chemistry purposes requires effective and divergent synthetic methods. We present in this work an efficient flow process that allows quick modulation of reagents for Joullié‐Ugi multicomponent reaction, using spiroindolenines as core motifs. This sterically hindered imine equivalent could successfully be diversified using various isocyanides and amino acids in generally good space‐time yields. A telescoped flow process combining interrupted Fischer reaction for spiroindolenine synthesis and subsequent Joullié‐Ugi‐type modification resulted in product formation in very good overall yield in less than 2 hours compared to 48 hours required in batch mode. The developed protocol can be seen as a general tool for rapid and facile generation of peptidomimetic compounds. We also showcase preliminary biological assessments for the prepared compounds.

INDOLE DERIVATIVES OF FUSIDANE TRITERPENOIDS: SYNTHESIS AND THE ANTIBACTERIAL ACTIVITY

New indole derivatives of fusidic acid were synthesized by using the Fischer reaction. The obtained compounds were screened in vitro for antibacterial activity and were found to inhibit the growth of Staphylococcus aureus (MRSA, strain ATCC 43300) at concentrations comparable to fusidic acid. The obtained indole derivatives of fusidic acid were also characterized by relatively low cytotoxicity and minimal hemolytic effect at the highest concentration that was tested (32 μg/ml).

Indole Derivatives of Fusidane Triterpenoids: Synthesis and the Antibacterial Activity

New indole derivatives of fusidic acid were synthesized by using the Fischer reaction. The obtained compounds were screened in vitro for antibacterial activity and were found to inhibit the growth of Staphylococcus aureus (MRSA, strain ATCC 43300) at concentrations comparable to fusidic acid. The obtained indole derivatives of fusidic acid were also characterized by relatively low cytotoxicity and minimal hemolytic effect at the highest concentration that was tested (32 μg/ml).

Synthesis of new hexahydro-5H-indolo[3,2-c]acridines and indolylbutanoic acids by Fischer cyclization of arylhydrazones

Arylhydrazones of 2,3,5,6,7,8-hexahydroacridin-4(1H)-ones and 7-amino-6-(arylhydrazono)-7-oxoheptanoic acids were cyclized by Fischer reaction, providing previously unknown polysubstituted indole derivatives. The starting hydrazones were synthesized under Japp–Klingemann reaction conditions by using 1,2,3,4,5,6,7,8-octahydroacridine-4-carboxamide and 2-oxocyclohexanecarboxamide as starting materials. It was established from the spectral data that the obtained 7-amino-6-(arylhydrazono)-7-oxoheptanoic acids existed as mixtures of (Z)- and (E)-isomers, but were converted to an individual (Z)- or (E)-isomer in DMSO solution.

SYNTHESIS OF 5-CHLORO-7-AZAINDOLES BY FISCHER REACTION

A simple and effective method on the basis of Fischer reaction in polyphosphoric acid is proposed for the synthesis of previously unknown heterocyclic structures that contain the 5-chloro-1 Н -pyrrolo[2,3- b ]pyridine system. This method can be used for the synthesis of 3-substituted and 2,3-disubstituted 5-chloro-7-azaindoles with alkyl and aryl substituents. Authors: Roman S. Alekseev*, Sabina R. Amirova, Vladimir I. Terenin

Synthesis of 5-chloro-7-azaindoles by Fischer reaction

A simple and effective method on the basis of Fischer reaction in polyphosphoric acid is proposed for the synthesis of previously unknown heterocyclic structures that contain the 5-chloro-1H-pyrrolo[2,3-b]pyridine system. This method can be used for the synthesis of 3-substituted and 2,3-disubstituted 5-chloro-7-azaindoles with alkyl and aryl substituents.

Synthesis and properties of ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates

Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates reacted with phenylhydrazine to give the corresponding hydrazones, ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates, which were converted to ethyl 1′-aryl-4-formyl-5′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazole-3′-carboxylates by treatment with the Vilsmeier–Haack reagent. No indole derivatives were formed from the same hydrazones under the Fischer reaction conditions, but cyclization to 2-aryl-3,4-dimethyl-6-phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-ones was observed.

Novel and Efficient Heterogeneous 4-Methylbenzenesulfonic Acid-Based Ionic Liquid Supported on Silica Gel for Greener Fischer Indole Synthesis

In this work, a functionalizing active species 4-methylbenzenesulfonic acid-based IL on silica gel (IL-SO3H-SiO2) has been prepared, and characterized by FT-IR, XRD, TGA, SEM and EDX spectra. Then, IL-SO3H-SiO2 was utilized as an efficient and heterogeneous catalyst for the synthesis of indoles via the one-pot Fischer reaction of phenyl hydrazines with ketones or aldehydes at room temperature. The heterogeneous catalyst could be recovered easily by filtration and reused many times without significant loss of its catalytic activity.

ChemInform Abstract: Fischer Reaction with 2‐Perfluoroalkylated Cyclic Imines — An Efficient Route to 2‐Perfluoroalkyl‐Substituted Tryptamines and Their Derivatives and Homologues.

The reaction of 2-perfluoroalkyl-substituted cyclic imines with arylhydrazines was investigated. We found that 2-perfluoroalkylated cyclic imines are highly reactive electrophiles that form, through ring opening, the corresponding hydrazones bearing an amine group at the end of the alkyl chain. Subsequent acidic treatment resulted in a Fischer rearrangement. Thus, a new synthesis of 2-perfluoroalkylated tryptamines and their homologues through a Fischer reaction was developed. The possibility of modification of the indole core of the 2-CF3-substituted tryptamine products was demonstrated, and various 2-trifluoromethylated tryptamines substituted at the 5-position were prepared.

Fischer Reaction with 2‐Perfluoroalkylated Cyclic Imines ― An Efficient Route to 2‐Perfluoroalkyl‐Substituted Tryptamines and Their Derivatives and Homologues

AbstractThe reaction of 2‐perfluoroalkyl‐substituted cyclic imines with arylhydrazines was investigated. We found that 2‐perfluoroalkylated cyclic imines are highly reactive electrophiles that form, through ring opening, the corresponding hydrazones bearing an amine group at the end of the alkyl chain. Subsequent acidic treatment resulted in a Fischer rearrangement. Thus, a new synthesis of 2‐perfluoroalkylated tryptamines and their homologues through a Fischer reaction was developed. The possibility of modification of the indole core of the 2‐CF3‐substituted tryptamine products was demonstrated, and various 2‐trifluoromethylated tryptamines substituted at the 5‐position were prepared.

Reactions of 2-Mono- and 2,6-Disubstituted 4-Pyrones with Phenylhydrazine as General Method for the Synthesis of 3-(N-Phenylpyrazolyl)Indoles

Phenylhydrazine reacted regioselectively with 6-substituted 4-pyrone-2-carboxylic acids (or esters) in protic and aprotic solvents, leading to phenylhydrazones of 3-(3-R-1-phenylpyrazol-5-yl)- or 3-(5-R-1-phenylpyrazol-3-yl)pyruvic acids (or esters), respectively. 6-Di(tri)fluoromethylcomanic acids (or esters) reacted analogously, forming the corresponding phenylhydrazones with RF group in the side chain. The obtained phenylhydrazones underwent Fischer reaction under acidic conditions, forming the respective 3-(N-phenylpyrazolyl)indoles. In contrast to comanic acid and its ester, the reactions of 2-substituted 4-pyrones occurred non-selectively and gave mixtures of regioisomeric pyrazoles with phenylhydrazone group in the side chain or 3-(N-phenylpyrazolyl)indoles. A mechanism was proposed to explain the effect of solvent on the course of reaction.

The Fischer Reaction in the Synthesis of 2,3-Disubstituted 7-Azaindoles*

We present the results of our study towards the synthesis of 2,3-disubstituted 7-azaindoles by cyclization of 2-pyridylhydrazones of aliphatic and alkylaromatic ketones under the conditions of Fischer reaction, catalyzed by polyphosphoric acid.

REACTIONS OF 2-MONO- AND 2,6-DISUBSTITUTED 4-PYRONES WITH PHENYLHYDRAZINE AS GENERAL METHOD FOR THE SYNTHESIS OF 3-( N -PHENYLPYRAZOLYL)INDOLES

Phenylhydrazine reacted regioselectively with 6-substituted 4-pyrone-2-carboxylic acids (or esters) in protic and aprotic solvents, leading to phenylhydrazones of 3-(3-R-1-phenylpyrazol-5-yl)- or 3-(5-R-1‑phenylpyrazol-3-yl)pyruvic acids (or esters), respectively. 6-Di(tri)fluoromethylcomanic acids (or esters) reacted analogously, forming the corresponding phenylhydrazones with R F group in the side chain. The obtained phenylhydrazones underwent Fischer reaction under acidic conditions, forming the respective 3-( N -phenylpyrazolyl)indoles. In contrast to comanic acid and its ester, the reactions of 2‑substituted 4-pyrones occurred non-selectively and gave mixtures of regioisomeric pyrazoles with phenylhydrazone group in the side chain or 3-( N -phenylpyrazolyl)indoles. A mechanism was proposed to explain the effect of solvent on the course of reaction. Obydennov, D. L.; Usachev, B. I.; Sosnovskikh, V. Ya. Chem. Heterocycl. Compd. 201 5 , 50 , 1388. [ Khim. Geterotsikl. Soedin. 2014 , 1510.] For this article in the English edition see DOI 10.1007/s10593-014-1603-3