New chemistry of diazafulvenium methides: one way to pyrazoles

Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides participate in [8π+2π] cycloadditions giving pyrazolo[1,5-a]pyridine derivatives. 1-Methyl-diazafulvenium, generated under flash vacuum pyrolysis reaction conditions, undergoes an intramolecular sigmatropic [1,8]H shift giving 1-vinyl-1H-pyrazoles.     

Chemistry of diazafulvenium methides in the synthesis of functionalized pyrazoles

The chemistry of diazafulvenium methides generated by the thermal extrusion of sulfur dioxide from 2,2-dioxo-1H,3H-pyrazolo[1,5-c] [1,3]thiazoles is described. The diazafulvenium methides unsubstituted at C-7 participate in [8 pi + 2 pi] cycloadditions giving pyrazolo-annulated heterocycles resulting from the addition across the 1,7-position. 1-Methyl-diazafulvenium methides and 7,7-dimethyl-diazafulvenium methides undergo intramolecular sigmatropic [1,8]H shifts giving vinyl-1H-pyrazoles.     

Cycloaddition of trifluoromethyl azafulvenium methides: synthesis of new trifluoromethylpyrrole-annulated derivatives

The chemistry of trifluoromethyl azafulvenium methides was explored leading to a new route to trifluoromethylpyrrole-annulated systems. The first evidence of azafulvenium methides acting as 1,3-dipoles is reported. These azafulvenium methides showed site selectivity in the reaction with strong electron-deficient dipolarophiles leading exclusively to 1,3-cycloadducts. In the cycloaddition with less-activated dipolarophiles 1,7-cycloadducts resulting from [8π+2π] cycloaddition are also formed. FMO analysis of the cycloaddition reactions allowed the rationalization of the observed selectivity.     

Nitrogen-bridged heterocycles via cycloaddition of non-classical heterocyclic-fused-[c]thiazoles

The [4π+2π] cycloaddition of non-classical heterocyclic-fused-[c]thiazoles was explored allowing the synthesis of a range of new nitrogen-bridged bi-, tri- and tetracyclic heterocyclic compounds namely, pyrazolo[1,5-a]pyridines, thiazolo[2,3,4-cd]pyrrolizines and indolizines. For the first time, one non-classical pyrrolo[1,2-c]thiazole was isolated and its structure determined by X-ray crystallography.     

Intermolecular cycloaddition of nonstabilized azomethine ylides generated from 1,3-thiazolidine-4-carboxylic acids: synthesis of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles

The 1,3-dipolar cycloaddition of dimethyl acetylenedicarboxylate with nonstabilized azomethine ylides, generated via the decarboxylative condensation of 1,3-thiazolidine-4-carboxylic acids with aldehydes, afforded 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazole derivatives. 2-Substituted-1,3-thiazolidine-4-carboxylic acids led to the stereoselective formation of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles. Quantum-chemistry calculations were carried out allowing the rationalization of the observed stereoselective formation of the anti-dipole.     

‘Higher-order’ azomethine ylides in the synthesis of functionalized pyrroles and 5-oxo-5H-pyrrolizines

Azafulvenium methides generated by the thermal extrusion of SO₂ from 1-methyl- and 1,1-dimethyl-1H,3H-pyrrolo[1,2-c]thiazole-2,2-dioxides undergo [1,8]H sigmatropic shifts to give vinylpyrroles. Flash vacuum pyrolysis of the C-vinylpyrroles affords 5-oxo-5H-pyrrolizines or C-allyl-1H-pyrroles.     

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 of novel 3′-spirocyclic-oxindole derivatives and assessment of their cytostatic activities

The synthesis of some novel 3′-spirocyclic-oxindole compounds, based on the spiro[indole-3,5′-isoxazolidin]-2(1H)-one, the 2′H-spiro[indole-3,6′-[1,3]oxazinane]-2,2′(1H)-dione and the 2′H-spiro[indoline-3,3′-pyrrolo[1,2-c][1,3′]oxazine]-1′,2(1H)-dione heterocyclic structures, is described. These compounds were prepared from methyl α-(2-nitrophenyl)acrylate via [1,3]-dipolar cycloaddition reactions with two acyclic nitrones and one cyclic nitrone followed by reduction of the cycloadducts and then treatment with triphosgene. Two of these compounds showed significant cytostatic activity on three cancer cell lines with GI₅₀ values of 2.6-4.1 μM on the human breast cancer cell line, MCF-7.     

Unprecedented base-promoted cascade transformation of a pyrimidinone derivative into a novel tricyclic bis-diazepinone

In the presence of strong bases (NaH, DBU, KOH), ethyl 4-chloromethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate, 4, is transformed into a novel tricyclic compound, diethyl 9-methyl-5-methylene-3,11-dioxo-2,3,4,5,6a,7,10,11-octahydro-1,6-methano[1,3]diazepino[1,7-e][1,3,5]triazocine-6,8(1H)-dicarboxylate, 5, as a result of a cascade reaction.     

Substituted chromones in [3+2] cycloadditions with nonstabilized azomethine ylides: synthesis of 1-benzopyrano[2,3-c]pyrrolidines and 1-benzopyrano[2,3-c:3,4-c′]dipyrrolidines

Chromones bearing electron-withdrawing substituents at the 2- or 3-position react with nonstabilized azomethine ylides to produce 1-benzopyrano[2,3-c]pyrrolidines in good yields. Reactions of 3-cyanochromones proceed diastereoselectively to give 1-benzopyrano[2,3-c]pyrrolidines and tetrahydro-1H-spiro[chromeno[2,3-c]pyrrol-9,5′-oxazolidine]-9a-carbonitriles, depending on the reactant ratio, as a result of a 1,3-dipolar cycloaddition of the azomethine ylide at the double bond and carbonyl group of the chromone system. The latter undergoes demethylenation and recyclization into a novel hexahydrochromeno[2,3-c:3,4-c′]dipyrrole tetracyclic system on heating with hydrochloric acid.     

Synthesis of novel spiro[indole-3,3′-pyrrolidin]-2(1H)-ones

Diastereoselective [3+2] cycloaddition of azomethine ylide to 1,3-dimethyl-6-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3a,9a-diphenyl-3,3a,9,9a-tetrahydroimidazo[4,5-e]thiazolo[3,2-b]-[1,2,4]triazine-2,7(1H,6H)-dione yields hitherto unknown 1,1′,3-trimethyl-3a,9a-diphenyl-3,3a,9,9a-tetrahydrodispiro(imidazo[4,5-e]thiazolo[3,2-b][1,2,4]triazine-6,3′-pyrrolidine-4′,3″-indole)-2,2″,7(1H,1″H)-triones.     

Reactivity of allenoates towards aziridines: synthesis of functionalized methylenepyrrolidines and pyrroles

The reactivity of buta-2,3-dienoates towards aziridines is reported. Typically, allenoates react as the 2π-component in the [3+2] cycloaddition with azomethine ylides generated from aziridines, affording 4-methylenepyrrolidines in a site-, regio- and stereoselective fashion. However, N-cyclohexyl- or N-tert-butyl-2-benzoyl-3-phenylaziridines showed a different reactivity in the reaction with buta-2,3-dienoates. Pyrrole derivatives were obtained as single or major products resulting from a formal [3+2] cycloaddition via C-N bond cleavage of the three-membered ring heterocycle leading to functionalized pyrroles. From the reaction with allenoates bearing bulkier C-4 substituents 4-methylenepyrrolidines were also formed as minor products.     

A facile and efficient one-pot synthesis of thiochromans from bis(2-formylphenyl) disulfide and alkenols via iodine-promoted generation and subsequent intramolecular cycloaddition of ortho-thiobenzoquinone methides

Stereoselective synthesis of tetrahydrofuro- and tetrahydropyrano[3,2-c]benzothiopyrans was achieved by intramolecular [4+2]cycloaddition of o-thiobenzoquinone methides that were generated in situ from bis(2-formylphenyl) disulfide and alkenols in the presence of iodine under mild reaction conditions.     

3-Cyanochromones in [3+2] cycloadditions with an azomethine ylide derived from sarcosine and formaldehyde. A short synthesis of 1-benzopyrano[2,3-c:3,4-c′]dipyrrolidines

Reactions of 3-cyanochromones with sarcosine and paraformaldehyde proceed diastereoselectively to give 1-benzopyrano[2,3-c]pyrrolidines and tetrahydro-1H-spiro[chromeno[2,3-c]pyrrol-9,5′-oxazolidine]-9a-carbonitriles, depending on the reactant ratio, as a result of a 1,3-dipolar cycloaddition of the intermediate nonstabilized azomethine ylide at the double bond and carbonyl group of the chromone system. The latter undergoes demethylenation and recyclization into a novel hexahydrochromeno[2,3-c:3,4-c′]dipyrrole tetracyclic system on heating with hydrochloric acid.     

Reactivity of azafulvenium methides derived from pyrrolo[1,2-c]thiazole-2,2-dioxides: synthesis of functionalised pyrroles

Extrusion of sulfur dioxide from pyrrolo[1,2-c]thiazole-2,2-dioxides led to the synthesis of functionalised pyrroles via the generation of 1-azafulvenium methides. Sealed tube reaction conditions allowed the synthesis of N- and C-vinylpyrroles whereas from FVP methyl 1,3-dimethyl-5-oxo-5H-pyrrolizine-2-carboxylate and 4-oxo-1,4-dihydro-1-aza-benzo[f]azulene-3-carboxylates were obtained. These last compounds could also be obtained from the FVP of the N- and C-vinylpyrroles.     

A strategy for the synthesis of 2-aryl-3-dimethylaminopyrazolo-[3,4-c]pyridines that utilizes [4+1] cycloaddition reactions of 5-arylazo-2,3,6-trisubstituted pyridines

In order to explore the viability and generality of a recently uncovered [4+1] cycloaddition based strategy for the preparation of pyrazolo[3,4-c]pyridine derivatives, members of a series of 5-arylazo-2,3,6-trisubstituted pyridines were prepared by reactions of 3-oxo-2-arylhydrazonopropanals with 3-oxo-3-phenylpropionitrile. The results show that 3-oxo-3-phenylpropionitrile reacts with hydrazone substrates, which do not contain electron-withdrawing substituents on the N-aryl ring of the arylhydrazone moieties, to efficiently produce 6-aryl-2-phenyl-5-arylazonicotinonitriles. In contrast, 2-amino-6-aryl-5-arylazo-3-benzoylpyridines are generated in reactions of 3-oxo-2-arylhydrazonopropanals, which contain electron-withdrawing substituents on the N-aryl moiety. In the forecasted manner, the 6-aryl-2-phenyl-5-arylazonicotinonitriles undergo smooth reactions with dimethylformamide dimethylacetal (DMF-DMA) that led to formation of a new class of 2-aryl-3-dimethylaminopyrazolo[3,4-c]pyridines. The mechanism for this process involves a [4+1] cycloaddition reaction that takes place through initial nucleophilic addition of dimethylamino)methoxycarbene, generated from DMF-DMA, to the azadiene moiety of the arylazopyridines followed by cyclization of the formed zwitterionic intermediate.     

Cycloalkano[1″,2″:4,5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines): synthesis, structure and mechanism of their formation

Reactions of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with cyclohexyl- and cycloheptylamines in the presence of AgPy₂MnO₄ produce novel cycloalkano[1″,2″:4,5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines). Detailed information concerning the scope and mechanism of these transformations is discussed.     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

An elegant approach for stereocontrolled synthesis of furopyran building blocks

An elegant approach for stereocontrolled synthesis of furopyran (hexahydro-2H-furo[3,2-b]pyran) building blocks was reported. The key steps in the sequence involved an efficient intramolecular 3-oxidopyrylium-alkene [5+2] cycloaddition for the synthesis of cycloadduct 6 and Beckmann fragmentation of ketoxime 13 to yield the furopyrans (5a-c).     

Four-component tandem protocol for the stereoselective synthesis of highly functionalized [1,4]-thiazines

The one-pot, four-component tandem reaction of ethyl 2-[(2-oxo-2-arylethyl)sulfonyl]acetate/ethyl 2-[(2-ethoxy-2-oxoethyl)sulfonyl]acetate, an aromatic aldehyde and pyrrolidine provides a rapid and facile access to new ethyl 3-aroyl-1-benzyl-2,2-dioxo-4-aryloctahydro-2-pyrrolo[2,1-c][1,4]thiazine-1-carboxylates/diethyl 1-benzyl-2,2-dioxo-4-aryloctahydro-2-pyrrolo[2,1-c][1,4]thiazine-1,3-dicarboxylates. This reaction shows high stereoselectivity and proceeds in good yields.