Synthesis of 3-amino-8-hydroxy-1,6-dioxo-4-cyano-2,7-diazaspiro[4.4]non-3-en-2-ides ammonium salts

Reaction of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-en-4-carbonitriles with amines in 2-propanol at room temperature provided the corresponding ammonium salts of 3-amino-8-hydroxy-1,6-dioxo-4-cyano-2,7-diazaspiro[4.4]non-3-en-2-ides.     

Directed synthesis of alkyl-substitued pyrrolo[3,4-c]pyrrole-1,3,4,6-tetraones

Reactions of 3-amino-8-hydroxy-1,6-dioxo-2,7-diazaspiro[4.4]non-3-ene-4-carbonitriles with aqueous hydrohalic acid led to the formation of alkyl-substituted pyrrolo[3,4-c]-pyrrole-1,3,4,6-tetraones.     

Five-membered 2,3-dioxo heterocycles: CIII. Spiro heterocyclization of 4,5-diaroyl-1H-pyrrole-2,3-diones with 3-aminobut-2-enenitrile

1-Aryl-4,5-diaroyl-1H-pyrrole-2,3-diones reacted with 3-aminobut-2-enenitrile to produce 1,6-diaryl-4-aroyl-3-hydroxy-8-methyl-2-oxo-1,7-diazaspiro[4.4]nona-3,6,8-triene-9-carbonitriles.     

Reduction of 7-aryl-6,8-dioxo-2-oxa-3,7-diazabicyclo[3.3.0]oct-3-ene-4-carboxylic and 7-aryl-6,8-dioxo-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid esters

Ethyl 7-aryl-6,8-dioxo-2-oxa-3,7-diazabicyclo[3.3.0]oct-3-ene-4-carboxylates and ethyl 7-aryl-6,8-dioxo-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylates were selectively reduced with sodium tetrahydridoborate at the carbonyl group in the β-position with respect to the oxygen atom in the isoxazole ring.     

Five-membered 2,3-dioxo heterocycles: LXXXIX. Reaction of methyl 1-aryl-3-cinnamoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with (E)-4-arylaminopent-3-en-2-ones. Crystalline and molecular structure of 9-acetyl-4-cinnamoyl-3-hydroxy-1-(4-methoxyphenyl)-8-methyl-7-phenyl-1,7-diazaspiro[4.4]nona-3,8-diene-2,6-dione

Methyl 1-aryl-3-cinnamoyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with 4-benzylamino- and 4-arylaminopent-3-en-2-ones to give 1-aryl-7-benzyl- and 1,7-diaryl-9-acetyl-4-cinnamoyl-3-hydroxy-8-methyl-1,7-diazaspiro[4.4]nona-3,8-diene-2,6-diones. The crystalline and molecular structures of 9-acetyl-4-cinnamoyl-3-hydroxy-1-(4-methoxyphenyl)-8-methyl-7-phenyl-1,7-diazaspiro[4.4]nona-3,8-diene-2,6-dione were studied by X-ray analysis.     

Hydrolysis and acylation of imino group in E/Z-isomers of 3,4-dialkyl-8-amino-1-imino-6-morpholin-4-yl-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles

Acid-catalyzed hydrolysis of 3,4-dialkyl-substituted 8-amino-1-imino-6-morpholin-4-yl-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles under mild conditions led to the formation of 8-amino-6-morpholin-4-yl-1-oxo-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles, and their acylation afforded N-(8-amino-9-cyano-6-morpholin-4-yl-2-oxa-7-azaspiro-[4.4]nona-3,6,8-trien-1-ylidene)acetamides. The NMR spectra of compounds synthesized in contrast to the spectra of initial N-unsubstituted imins contained no doubled proton and carbon signals.     

Five-membered 2,3-dioxo heterocycles: XCIII. Spiro heterocyclization of 4,5-diaroyl-1H-pyrrole-2,3-diones with acyclic enamine. Crystalline and molecular structure of substituted 1,7-diazaspiro[4.4]nonane

4,5-Diaroyl-1-aryl-1H-pyrrole-2,3-diones reacted with ethyl 3-amino-3-phenylprop-2-enoate to give ethyl 4-aroyl-1,6-diaryl-3-hydroxy-2-oxo-8-phenyl-1,7-diazaspiro[4.4]nona-3,6,8-triene-9-carboxylates. The crystalline and molecular structures of ethyl 4-benzoyl-3-hydroxy-1-(4-methylphenyl)-2-oxo-6,8-diphenyl-1,7-diazaspiro[4.4]nona-3,6,8-triene-9-carboxylate were determined by X-ray analysis.     

2-Methylthio-imidazolins: a rare case of different tautomeric forms in solid state and in solution

Structural Chemistry - The synthesis and structure elucidation of two new compounds, 2-(methylthio)-1,3-diazaspiro[4.4]non-2-ene-4-one (1) and 2-(methylthio)-1,3-diazaspiro[4.4]non-2-ene-4-thione...     

Synthesis of pyrrolo[2,3-c]2,7-naphthyridine derivatives by cascade heterocyclization reaction of 2-amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles

Alkylation of the title pyridinedicarbonitriles with N-substituted chloroacetamides was found to give 5,6-diamino-8-dialkylamino-2,3-dihydro-2-oxo-1H-pyrrolo[2,3-c]2,7-naphthyridine-9-carbonitriles. The structure of obtained compounds was unambiguously confirmed by X-ray crystallographic study. The heterocyclization reaction proceeded regioselectively involving 3-CN group of the starting pyridines without participation of 5-CN. The reasons of the selectivity were discussed. An interaction of prepared naphthyridine derivatives with acetic acid anhydride and cyclohexanone yielded 2-dialkylamino-6,8,9,10-tetrahydro-5-methyl-9-oxopyrimido[4,5,6-ij]pyrrolo[2,3-c]2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-4,5,6,8,9,10-hexahydro-9-oxospiro{pyrimido[4,5,6-ij]pyrrolo[2,3-c]2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles, respectively. All fused 2,7-naphthyridines obtained were derivatives of novel heterocyclic systems.     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to 3,3-methylene-5,5-dimethyl-2-pyrrolidinone

Summary Nitrile oxides add regioselectively to the carbon-carbon double bond of 3,3-methylene-5,5-dimethyl-2-pyrrolidinone (1), giving exclusively spiro-isoxazolines: 3-aryl-6-oxo-8,8-dimethyl-1-oxa-2,7-diazaspiro[4.4]non-2-enes3 a–l. The regiochemistry of the 1,3-dipolar cycloaddition to 1 seems to be controlled by the steric effect of the methyl groups at the ring junction and by frontier orbital interactions.Part XXV in the series 1,3-Dipolar Cycloaddition on Heterocycles. Part XXIV Ref. [10]     

Five-membered 2,3-dioxoheterocycles: XC. Reaction of 4,5-bis(methoxycarbonyl)-1H-pyrrole-2,3-diones with enaminoesters. crystal and molecular structure of 4-methyl 9-ethyl 7-benzyl-3-hydroxy-8-methyl-1-(4-methoxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-4,9-dicarboxylate

1-Aryl-4,5-bis(methoxycarbonyl)-1H-pyrrole-2,3-diones react with ethyl 3-(benzylamino)but-2-enoate and ethyl 3-(benzylamino)-3-phenylacrylate giving 4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-methyl- and 4-methyl 9-ethyl 1-aryl-7-benzyl-3-hydroxy-8-phenyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-4,9-dicarboxylates.     

Spiro heterocyclization of 4-aryl-4-oxobutane-1,1,2,2-tetracarbonitriles to 3H-pyrrole derivatives, 2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes

4-Aryl-3-methyl-4-oxobutane-1,1,2,2-tetracarbonitriles reacted with morpholine to give 8-amino-3-aryl-1-imino-4-methyl-6-(morpholin-4-yl)-2-oxa-7-azaspiro[4.4]nona-3,6,8-triene-9-carbonitriles.     

Five-membered 2,3-dioxo heterocycles: LV. Reaction of methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrrole-2-carboxylates with ethyl 3-arylaminobut-2-enoates

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with ethyl 3-aryl-aminobut-2-enoates to give the corresponding ethyl 1,7-diaryl-4-aroyl-3-hydroxy-8-methyl-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-9-carboxylates.     

Synthesis of furo[2,3-c]-2,7-naphthyridine derivatives via domino heterocyclization reaction

2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles were found to react with substituted oxiranes yielding 5,6-diamino-8-dialkylamino-1,2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitriles. The oxirane ring was shown to be opened selectively from the unsubstituted side and further cyclization occurred with participation of 3-CN, but not 5-CN of the starting pyridines. The furonaphthyridines obtained were converted into 2-dialkylamino-5-methyl-9,10-dihydro-4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-1-carbonitriles and 2-dialkylamino-5,6,9,10-tetrahydro-4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-5,1′-cyclohexane}-1-carbonitriles by treatment with acetic anhydride and cyclohexanone, respectively. The structure of prepared compounds was confirmed unambiguously by X-ray crystallographic study.     

Spirobisheterocyclization of 5-(Methoxycarbonyl)-1<Emphasis Type="Italic">H</Emphasis>-pyrrol-2,3-diones by the action of enaminoesters. Crystal and molecular structure of 1,7-diazaspiro[4.4]nonane

1-Aryl-4-aroyl-5-(methoxycarbonyl)-1Н-pyrrole-2,3-diones react with methyl 4-aryl-2-(arylamino)-4-oxobut-2-enoates with the formation of methyl 1,7-diaryl-4,9-diaroyl-3-hydroxy-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-8-carboxylates.     

Five-membered 2,3-dioxo heterocycles: CV. Reaction of methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with methyl 2-arylamino-4-(2-naphthyl)-4-oxobut-2-enoates. Crystal and molecular structure of substituted 1,7-diazaspiro[4.4]nonane

Methyl 1-aryl-3-aroyl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with methyl 2-arylamino-4-(2-naphthyl)-4-oxobut-2-enoates to give methyl 1,7-diaryl-4-aroyl-3-hydroxy-9-(2-naphthalen-2-ylcarbonyl)-2,6-dioxo-1,7-diazaspiro[4.4]nona-3,8-diene-8-carboxylates.     

Synthesis of a new series of N-substituted-3-[l-alkyl(aryl)- 4-piperidyl]azetidin-2-ones as possible muscarinic agents

A new series of N-substituted-3-[1-alkyl(aryl)-4-piperidyl]azetidin-2-ones 2a-j structurally related to the previously reported 2,7-diazaspiro[3.5]nonan-1-ones 1 have been synthesized and tested for their activity as muscarinic agents, both in vitro and in vivo. Preliminary pharmacological results showed that compounds 2 are devoid of significant cholinergic properties.     

Stereoselective 1,3-Dipolar Cycloadditions to (S)-1-Benzoyl-3-(cyanomethylidene)-5-(methoxycarbonyl)pyrrolidin-2-one

(5S)-1-Benzoyl-3-[(E)-cyanomethylidene]-5-(methoxycarbonyl)pyrrolidin-2-one ( 5 ) was prepared in four steps from L -pyroglutamic acid ( 1 ). 1,3-Dipolar cycloadditions of diazomethane ( 6 ) and 2,4,6-trimethoxybenzonitrile oxide ( 7 ) gave substituted 1,2,7-triazaspiro[4.4]non-1-en-6-one 12 and 1-oxa-2,7-diazaspiro[4,4]non-1-en-6-one 13 in 38 and 20% de, respectively. On the other hand, reaction of 5 with N-phenylbenzonitrile imines 8 and 9 , generated in situ from the corresponding hydrazonoyl chlorides 10 and 11 , respectively, and Et₃N, furnished racemic pyrrolo[3,4-c]pyrazoles 14 and 15 in 61 and 56% de, respectively. Cycloaddition of nitrile oxide 7 , when performed in the presence of Et₃N, led to pyrrolo[3,4-d]isoxazole 16 in 85% de.     

Syntheses based on 8-substituted 3-bromoacetyl-3,8-dimethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones

By reaction of 8-substituted 3-bromoacetyl-3,8-dimethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones with thiourea and substituted thioureas under Hansch reaction conditions, we have obtained the novel heterocycles 3-[2′-amino(arylamino)thiazol-4-yl]-3,8-dimethyl-2,7-dioxaspiro[4,4]nonane-1,6-diones. By reacting the above-indicated bromoacetyl spirodilactones with 5-aryl-3-mercapto-1,2,4-triazoles, we obtained 8-substituted 3-(aryl-3,8-dimethyl-1′,2′,4′-triazol-3′-yl)thioacetyl-2,7-dioxaspiro[4,4]nonane-1,6-diones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 123–129, January, 2006.     

Five-membered 2,3-dioxo heterocycles: LVI. Reaction of 3-aroyl-1<Emphasis Type="Italic">H</Emphasis>-pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4-triones with acyclic enamino ketones

3-Aroyl-1H-pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones react with 4-arylaminopent-3-en-2-ones and 3-amino-1,3-diphenylprop-2-en-1-ones to give substituted 4-aroyl-3-hydroxy-1-(o-hydroxyphenyl)-1,7-diazaspiro[4.4]nona-3,8-diene-2,6-diones.