Facile ionic liquid-mediated,three-component sequential reactions for the green,regio- and diastereoselective synthesis of furocoumarins

An environmentally friendly approach to the diastereoselective synthesis of trans-4-oxo-3-aryl-3,4-dihydro-2H-furo[3,2-c]coumarin-2-carbonitriles, trans-2-benzoyl-3-(aryl)-2H-furo[3,2-c]chromen-4(3H)-ones and trans-ethyl-4-oxo-3-(aryl)-3,4-dihydro-2H-furo[3,2-c]chromene-2-carboxylates in good yields is described. The method is based on the sequential multicomponent reactions of 4-hydroxycoumarin, aromatic aldehydes and in situ generated cyanomethylpyridinium, phenacylpyridinium/(2-ethoxy-2-oxoethyl)pyridinium ylides, in the presence of the ionic liquid [BMIm]OH, which functions both as a catalyst and the reaction medium.     

Facile rearrangement of 2-amino-3-carbethoxy-4-ethylfuro[3,2-b]pyridinium cation to 2-oxo-3-cyano-4-ethyl-4H-furo[3,2-b]pyridine

The rearrangement of 2-amino-3-carbethoxy-4-ethylfuro[3,2-b]pyridinium iodide in basic solution was studied. The reaction product is 2-oxo-3-cyano-4-ethyl-4H-furo[3,2-b]pyridine which was obtained also by alkylation with ethyl iodide and sodium hydride in dimethylformamide of 2-oxo-3-cyano-3H-furo[3,2-b]-pyridine or of p-nitrophenyl-3-acetoxypyridine-2-cyanacetate.     

Synthesis of thio- and furan-fused heterocycles: furopyranone,furopyrrolone, and thienopyrrolone derivatives

We report herein the synthesis of a novel class of compounds, ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl carbonate, (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-c]pyran-4,6(7H)-dione, 5-oxo-N-phenyl-2,5-dihydro-4H-furo[3,2-b]pyrrole-4-carboxamide, and 5-oxo-N-phenyl-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxamide starting from the corresponding acid derivatives. Intramolecular cyclization in the presence of thionyl chloride formed the target fused ring systems. Additional transformation was seen in the cyclization of furan-fused heterocycle. A mechanism was proposed based on experimental and computational findings.     

Reaction of 4-hydroxycoumarin with 2-acetyloxiranes

The reaction of 4-hydroxycoumarin with 2-acetyloxiranes in dimethylformamide in the presence of triethylamine gave 2,3-dihydro-4H-furo[3,2-c]chromen-4-ones which were converted into 4H-furo[3,2-c]-chromen-4-one derivatives as a result of dehydration or fragmentation.     

Synthesis of 4H-furo[3,2-b]indole derivatives. III. Preparation of 4H-furo[3,2-b]indole-2-carboxylic acid derivatives

Methyl or ethyl 4H-furo[3,2-b]indole-2-carboxylates (Va,b) were prepared from deoxygenation of methyl or ethyl 5-(2-nitrophenyl)-2-furoates (IIIa,b) and thermolysis of methyl or ethyl 5-(2-azidophenyl)-2-furoates (VIIIa,b). 4H-Furo[3,2-b]indole-2-carboxylic acid amides (XIa-h) were obtained by the reaction of 4H-furo[3,2-b]indole-2-carboxyl chloride (X) with the appropriate amines.     

Synthesis of novel 4<Emphasis Type="Italic">H</Emphasis>-furo[3,2-c]pyran-4-ones and 4<Emphasis Type="Italic">H</Emphasis>-furo[3,2-<Emphasis Type="Italic">c</Emphasis>]chromen-4-ones

It was found that the condensation of two equivalents of 4-hydroxy-6-methyl-2H-pyran-2-one or 4-hydroxycoumarin with arylglyoxals in boiling formic acid leads to 4H-furo[3,2-c]-pyran-4-ones or 4H-furo[3,2-c]chromen-4-ones, respectively.     

Highly regio- and diastereoselective three-component reaction of acyclic/cyclic donor–acceptor carbenoids for the synthesis of angularly fused furocoumarins and spirooxindolylfurocoumarins

A highly regio- and stereoselective method has been developed for the synthesis of spiro[furo[3,4-c]chromene-1,3′-indoline]-2′,4(9bH)-dione derivatives via a three component reaction of cyclic diazoamide and aldehyde with methyl 2-oxo-2H-chromene-3-carboxylate, 3-acetyl-2H-chromen-2-one and 3-benzoyl-2H-chromen-2-one using 3 mol % of Rh₂(OAc)₄. Similarly, acyclic diazoesters also undergo smooth coupling with carbonyl compounds and 3-substituted coumarin in the presence of 1 mol % of Rh₂(OAc)₄ to afford a novel series of tetrahydro-1H-furo[3,4-c]chromene-1-carboxylates in 78–88% yield with high regio- and stereo-selectivity for the first time.     

Heterocycles [h]-fused onto 4-oxoquinoline-3-carboxylic acid, Part VI [1]. Synthesis and X-ray structure of model indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylic esters

Cyclocondensation reaction of ethyl 7,8-diamino-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate with 1-methylisatin produced a separable mixture of the corresponding indolo[3,2-b]- and [2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates, of which the latter isomer predominates. On the other hand, interaction with 1H-isatin or 5-chloroisatin gave the respective indolo[2,3-b]pyrido[2,3-f]quinoxaline-3-carboxylates as the sole regiospecific products. The structures of these new pentacyclic derivatives are based on microanalytical, spectral (IR, MS, and NMR) and X-ray crystal structure data.     

An expedient cyclization of polyfunctional (aryl)(pyrimidinyl)(pyranyl)methanes into spiro[furo[3,2-c]pyran-2,5’-pyrimidine] scaffold

Spirocyclization of morpholinium 3-[(aryl)(1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)methyl]-6-methyl-2-oxo-2H-pyran-4-olate by the action of sodium acetate-N-bromosuccinimide system in ethanol at room temperature results in spiro[furo[3,2-c]pyran-2,5’-pyrimidine] derivatives in 92–98% yields, the protocol allowing to avoid column chromatography purification. This new highly efficient and facile procedure is a convenient way to substituted unsymmetrical spiro scaffold containing pyrimidine-2,4,6-trione and 2,3-dihydro-4H-furo[3,2-c]pyran-4-one fragments promising for biomedical applications.     

Synthesis of derivatives of pyrido[3′,2′:4,5]furo[3,2-c]isoquinoline heterocyclic system

An approach to the synthesis of derivatives of new heterocyclic system, pyrido[3′,2′:4,5]-furo[3,2-c]isoquinoline, was suggested. A condensation reaction of substituted 3-cyanopyridin-2(1H)-ones with methyl 2-(chloromethyl)benzoate and subsequent treatment of the condensation product with potassium tert-butoxide leads to substituted pyrido[3′,2′:4,5]furo[3,2-c]-isoquinolin-5(6H)-ones. Similarly, a condensation reaction of substituted 3-cyanopyridin-2(1H)-ones with 2-(chloromethyl)benzonitrile and subsequent treatment of the condensation product with potassium tert-butoxide gives substituted 5-aminopyrido[3′,2′:4,5]furo[3,2-c]-isoquinolines.     

Transformations of 2-trifluoroacetyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines by the action of ethyl propynoate. A novel synthesis of 2-trifluoroacetyl-4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocines

2-Trifluoroacetyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines reacted with ethyl propynoate in acetonitrile and methanol to give ethyl 2-trifluoroaceyl-4,7,8,9-tetrahydro-1H-pyrrolo[2,3-d]azocine-5-carboxylates. The reactions of 2-trifluoroacetyl-1-vinyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines with ethyl propynoate in alcohols were accompanied by cleavage of the tetrahydropyridine fragment with formation of alkyl 3-{benzyl[2-(3-alkoxy-5-trifluoroacetyl-1-vinyl-1H-pyrrol-2-yl)ethyl]amino}acrylates.     

Catalyst-free one-pot synthesis of a new class of 2H-furo[3,2-c]chromene-2,4(3H)-dione and arylamino-bis(coumarin)methane derivatives on water

A catalyst-free, environmentally benign, and simple procedure has been developed for the efficient synthesis of novel 2H-furo[3,2-c]chromene-2,4(3H)-dione and 3,3′-((arylamino)methylene)bis(4-hydroxycoumarin) derivatives from one-pot three-component condensation of 4-hydroxycoumarin, glyoxalic acid monohydrate and various amines in water under reflux condition. In this green synthetic protocol, the solvent water itself catalyzed the reaction via hydrogen bonding. One-pot, high yields, short reaction times, simple operation, environmental friendly and easy workup procedure are highlights. This is the first report for the synthesis of 2H-furo[3,2-c]chromene-2,4(3H)-dione and arylamino-bis(coumarin)methane derivatives.     

Synthesis of 3-(trifluoromethyl)indeno[2,1-c]pyran-1,9-diones from 4-aryl-3-carbethoxy-6-(trifluoromethyl)-2-pyrones and their reaction with sodium azide leading to new carbostyril derivatives

Treatment of ethyl 4-aryl-6-(trifluoromethyl)-2-oxo-2H-pyran-3-carboxylates, prepared from 4,4,4-trifluorobutane-1,3-diones, PCl₅ and sodium diethyl malonate, with sulfuric acid afforded the intramolecular Friedel–Crafts acylation products, 3-(trifluoromethyl)indeno[2,1-c]pyran-1,9-diones, from which 2-(trifluoromethyl)-6H-pyrano[3,4-c]quinoline-4,5-diones were obtained via the Schmidt reaction in moderate yields. The latter reacted with sodium azide to give 2-oxo-4-(5-trifluoromethyl-1,2,3-triazol-4-yl)-1,2-dihydroquinoline-3-carboxylic acids in good yields.     

Synthesis, reactions and antineoplastic activity of 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromene derivatives

The key 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromen-5-yl acetates 3 were synthesized in high yields by cyclocondensation of 4-oxo-4H-chromen-3-carbaldehydes 1 with coumarin-3-acetic acids 2 under mild conditions. The reaction pathway involves aldol condensation and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton 3. Further treatment of acetates 3 with alcohols, water or nitrogen containing compounds led to 5-alkoxy-, 5-hydroxy- or 5-acylamino-2H,5H-pyrano[3,2-c]chromen-2-ones 4-6 via nucleophilic substitution of acetyloxy group at C-5. Acetates and hydroxyl derivatives 3 and 5 undergo facile rearrangement in an acid medium yielding 5-hydroxypyrano[2,3-b]chromen-2(10aH)-ones 7. Twelve prepared compounds were evaluated on their antineoplastic activities on 60 human tumour cell line panels in NCI USA. The obtained biological results confirmed that 3-(2-oxo-2H-chromen-3-yl)-2H,5H-pyrano[3,2-c]chromen-2-one represents a new leading skeleton suitable for further antitumour activity study.     

Heteroyohimbane a noyau furannique. Nouvelle voie d'acces aux derives de la furo[3,2-c]pyrone et de la furo[3,2-c]pyridine

3,4-Dicarbomethoxyfuran bearing an acetonyl or a phenacy group in the 2 position w3as prepared by pyrolysis of the dihydrocyclo adduct from methyl acetylendicarboxylate and 2-acetonyl- or 2-phenacylfuran. Condensation of 2-acetonyl-3,4-dicarbomethoxyfuran with tryptamine gave a new heteroyohimbane with a furan ring, indolo[2,3-a]furo[3,2-c]quinolizine, a potential precursor of yohimbane. Ketodiacids from saponification allow one to obtain derivatives of the following heterocyclic ring systems, namely 4H-furo[3,2-c]pyran-4-one and furo[3,2-c]pyridine.     

Diethyl ethoxymethylenemalonate in triheterocycles: A new synthesis of pyrido[3,2-e]pyrimido[1,2-c]pyrimidines

Diethyl ethoxymethylenemalonate was used for the novel synthesis of the triheterocyclic 3-carbethoxy-9,ll-disubstituted-4-oxo-4H-pyrido[3,2-e]pyrimido[1,2-c]pyrimidines from 4-aminopyrido[2,3-d]pyrim-idines via thermal cyclization of the intermediate ethyl 2-carbethoxy-3-[5,7-disubstituted-4-amino-pyrido[2,3-d]pyrimidin-4-yl]acrylates. The alkaline hydrolysis of 3-carbethoxy-4-oxo-4H-pyrido[3,2-e]-pyrimido[1,2-c]pyrimidines was performed to give corresponding acid derivatives.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Synthesis and antimicrobial evaluation of the novel heteroannulated furo[3′,2′:6,7]chromeno[2,3-b]pyridines: Part 1

The chemical behavior of 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile ( 1 ) was investigated toward some acyclic and cyclic active methylene ketones namely acetylacetone, ethyl acetoacetate, ethyl benzoylacetate, acetoacetanilide, dimedone, indanedione, pyrazolidine-3,5-dione and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, barbituric acid and 1-allylthiobarbituric acid, and hippuric acid. A variety of novel heteroannulated furochromenopyridines were efficiently synthesized through a cascade reactions between 4,9-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbonitrile ( 1 ) and the carbon nucleophilic reagents. Structures of the new products were inferred based on their analytical and spectral data.     

Microwave assisted synthesis of some new thiazolopyrimidine, thiazolodipyrimidine and thiazolopyrimidothiazolopyrimidine derivatives with potential antioxidant and antimicrobial activity

Biginelli reaction of ethyl acetoacetate, thiourea and the appropriate aromatic aldehyde was used to produce ethyl 4-aryl-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylates, that reacted with bromomalononitrile to give ethyl 3-amino-5-aryl-2-cyano-7-methyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylates rather than the isomeric 7H-thiazolo[3,2-a]pyrimidines. Thiazolopyrimidine derivatives reacted with carbon disulphide to yield ethyl 9-aryl-7-methyl-2,4-dithioxo-2,3,4,9-tetrahydro-1H-thiazolo[3,2-a:4,5-d']dipyrimidine-8-carboxylates, that reacted with phenacyl bromide to produce ethyl 8-methyl-10-(4-methoxyphenyl)-3-substituted-5-thioxo-2(un)subatituted-10H-thiazolo[3',2':1',2']pyrimido[4',5':4,5]thiazolo[3,2-a]pyrimidine-9-carboxylates. The aforementioned reactions were carried out using both conventional chemical methods and with the assistance of microwave irradaition. Comparison between both methods showed that the microwave assisted method is preferable because of the time reduction and yield improvements achieved. The new compounds were tested for their biological activity as antioxidants, antibacterial or antifungal agents. Some of the new compounds were found to have moderate to good antioxidant and antimicrobial activities.     

N-quaternary compounds. Part LIX. Facile synthesis of 3-vinyl-4(3H)-pyrimidinethiones

3-Vinyl derivatives of 4(3H)-pyrimidinethiones have been prepared from 2,3-dihydrothiazolo[3,2-c]pyrimidinium derivatives through ring-opening by a strong base such as potassium t-butoxide in DMF. The pyrimidinium derivative is initially prepared from 4(3H)-pyrimidinethiones. 3-Vinyl-4(3H)-pyrimidinethiones are also formed by the ready decarboxylation of 2,3-dihydrothiazolo[3,2-c]pyrimidinium-3-carboxylates. In the mass spectrometer the nature of the volatile species was elucidated by means of appearance potentials and fragmentation patterns.