Synthesis of 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one. Derivatives and their ring transformation into 5-benzamido-1,2,4-triazolidine-3,5-dione derivatives

Some 5-aryl-3-carbazoyl-1,3,4-oxadiazol-2(3H)-one derivatives 6 and 9 have been synthesized in two ways. The expected thermal ring transformation into 2,5-disubstituted 1,3,4-oxadiazoles did not occur but, by acid hydrolysis of 5-aryl-3-[3-benzylidene-2-methyl(or phenyl)carbazoyl]-1,3,4-oxadiazol-2(3H)-ones 6 , a new ring transformation took place and the corresponding 4-benzamido-1-methyl(or phenyl)-1,2,4-triazolidine-3,5-dione derivatives 11 were formed. The 4-amino-1-phenyl-1,2,4-triazolidine-3,5-dione ( 19 ) has been prepared and its structure was confirmed by some reactions.     

Tetrahydropyran-2,4-diones in the Synthesis of Fused N,O-Heterocycles

Condensation of 6-methyl(or phenyl)-tetrahydropyran-2,4-diones with 2-aminonaphthalene or 6-aminoquinoline and aromatic aldehydes in an aliphatic alcohol gave 5-aryl-2,2-dimethyl(or 2-phenyl)-1,2,5,6-tetrahydro-4H-benzo[f]pyrano[3,4-c]quinolin-4-ones and 5-aryl-2-methyl-1,2,5,6-tetrahydro-4H-pyrano[4,3-a][4,7]phenanthrolin-4-ones which are new N,O-heterocyclic systems containing fused aza- and diazaphenanthrene moieties and a 2-pyranone ring.     

Reactions of 4-acyl-1-alkoxyaryl-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones with nucleophilic reagents

4-Acetyl-1-alkoxyaryl-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones reacted with amines to give 1-alkoxyaryl-5-aryl-4-(1-R-aminoethylidene)pyrrolidine-2,3-diones. Reactions of amines with 4-benzoyl-substituted analogs involve nucleophilic attack on the C³ atom in the heteroring to produce the corresponding 3-R-amino-1-alkoxyaryl-5-aryl-4-benzoyl-2,5-dihydro-1H-pyrrol-2-ones. Reactions of the title compounds with hydrazine hydrate, regardless on the substituent on C₄, afforded 4-aryl-3-methyl(phenyl)-5-[2(4)-methoxyphenyl]-4,6-dihydropyrrolo[3,4-c]pyrazol-6-ones.     

Reactions of <Emphasis Type="Italic">N</Emphasis>-(2,2-dichloro-1-cyanoethenyl)-<Emphasis Type="Italic">N</Emphasis>′-methyl(phenyl)ureas with aliphatic amines

Novel derivatives of 3,3-dichloroprop-2-enenitrile containing methylurea or phenylurea fragments have been synthesized. The obtained N-(2,2-dichloro-1-cyanoethenyl)-N′-methyl(phenyl)ureas undergo intramolecular cyclization in the presence of triethylamine to form 4-(dichloromethylidene)-5-imino-1-methyl (phenyl)imidazolidin-2-ones. Reactions of N-(2,2-dichloro-1-cyanoethenyl)-N′-methylurea with aliphatic amines have afforded 4-(alkylamino)-4-(dichloromethyl)-5-imino-1-methylimidazolidin-2-ones.     

Conformational and configurational studies on 3-azabicyclo[3.3.1]nonane (3-abn) derivatives and related systems employing carbon-13 NMR spectroscopy

The ¹³C nmr spectra of 4 cis-2,4-diphenyl-3-azabicyclo[3.3.1]nonanes, 11 cis-2,4-diaryl-3-azabicyclo[3.3.1]-nonan-9-ones, 26 cis-2,4-diaryl-3-azabicyclo[3.3.1]-nonan-9-ols or acetates thereof, 5 cis-2,4-diaryl-3-azabi-cyclo[4.3.1]decan-10-ones or -10-ols and 5 cis-2,4-diphenyl-3-aza-7-thiabicyclo[3.3.1]nonan-9-ones, -9-ols or 9-yl acetates have been recorded. Except for the 7-thia compounds, which appear to exist mainly in the configuration and conformation with the nitrogen-containing ring in the boat form, these compounds seem to exist overwhelmingly in chair-chair conformations. The configuration of the 9-ols and their acetates (syn or anti to the nitrogen-containing ring) has been deduced from the spectra. In a number of cases, the structures assigned differ from those earlier postulated. Broadening of one set of aryl signals (probably those due to the ortho carbons) in the case of N-methyl (but not N-H) compounds without ortho substituents is ascribed to restricted phenyl rotation.     

Synthesis of 3-alkoxycarbonylaminomethylcarbonylamino-4-benzoyl-1,2-dihydropyridines and their cyclization to 5-phenyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones

The regiospecific reaction of 3-benzyloxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6a) , or 3-t-butoxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6b) , with either acetyl chloride or ethyl chloroformate, and either n-butylmagnesium chloride or phenylmagnesium bromide afforded the respective 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-benzyloxy (or t-butoxy) carbonylaminomethylcarbonylami-no-4-benzoyl-1,2-dihydropyridines 7 in 60-75% yield. Reaction of 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-t-butoxycarbonylaminomethylcarbonyl-4-benzoyl-1,2-dihydropyridines 7b, 7f, 7d, 7h with trifluoroacetic acid gave the corresponding 5-phenyl-8-acetyl (or ethoxycarbonyl)-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b, 8c, 8d respectively in 45–63% yield. N¹-Methylation of 5-phenyl-8-acetyl-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b using sodium hydride and iodomethane yielded the corresponding N¹-methyl derivatives 9a (48%) and 9b (54%). Oxidation of 5,9-diphenyl-8-ethoxycarbonyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8d) using p-chloranil afforded 1,3-dihydro-5,9-diphenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one (10) . 5-Phenyl-8-acetyl-9-n-butyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8a) and the corresponding 8-ethoxycarbonyl analog 8c exhibited weak anticonvulsant activity indicating that 8a and 8c may be acting at the same site as the 7-halo-1,4-benzodiazepin-2-one class of compounds.     

Reaction of dichloroketene and sulfene with N,N-disubstituted α-aminomethyleneketones. Synthesis of pyrano[2,3-e]indazole and 1,2-oxathiino[6,5-e]indazole derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-5-aminomethylene-1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones V, prepared from 1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones via the 5-hydroxymethylene derivatives, gave in good yield N,N-disubstituted 4-amino-3,3-dichloro-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-(3H)ones VI, which are derivatives of the new heterocyclic system pyrano[2,3-e]indazole. Dehydrochlorination of VI with DBN afforded N,N-disubstituted 4-amino-3-chloro-6,7-dihydro(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(5H]-ones VII generally in satisfactory yield. Full aromatization with DDQ of VII was tried only in the case of dimethylamino derivatives, giving a moderate yield of 3-chloro-4-dimethylamino(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(7H)-ones. Cycloaddition of sulfene to V occurred only in the case of aliphatic N-substitution to give in moderate yield 4-dialkylamino-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)-3H-1,2-oxathiino[6,5-e]indazole 2,2-dioxides, which are derivatives of the new heterocyclic system 1,2-oxathiino[6,5-e]indazole.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XX. Synthesis of 2H-pyrano[2,3-f]quinazoline derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-6-aminomethylene-7,8-dihydro-(2-methyl)(2-phenyl)quinazolin-5(6H)-ones III , prepared in good yields from 7,8-dihydro-(2-methyl)-(2-phenyl)quinazolin-5(6H)-ones via their 6-hydroxymethylene derivatives I and II , gave in satisfactory to excellent yields N-N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-(8-methyl)(8-phenyl)-2H-pyrano- [2,3,-f]quinazolin-2-ones IV , which are derivatives of the new heterocyclic system pyrano[2,3-f]quinazoline. This cycloaddition occurred both in the case of aliphatic and aromatic N-substitution only with 2-phenyl-enaminones III , whereas with 2-methyl derivatives III the reaction took place only in the case of aromatic N-monosubstitution. Dehydrochlorination of IV with DBN afforded, generally in excellent yields, N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-y]quinazolin-2-ones, which were dehydrogenated with DDQ to give N,N-disubstituted 4-amino-3-chloro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-f]quinazolin-2-ones in excellent yields.     

Synthesis of some new 5-chloro-7-mercapto-1-methyl/phenyl-1,2,4-triazolo[4,5-b]pyrazin-2(1H)-ones and 5-chloro-3-thiopyrazin-2(1H)-one derivatives as possible antibacterial and antifungal agents

Several new 5-chloro-7-mercapto-1-methyl/phenyl-1,2,4-triazolo[4,5-6]pyrazin-2(1/H)-ones V and their disul-phides VI, 5-chloro-3-mercapto-2(1H)-pyrazinonones III, 5-chloro-3-(N-aryl-N-acetylthioureido)-1-methyl/-phenyl-2(1H)-pyrazinones VII, 5-chloro-1-methyl/phenyl-3-sulphonamido-2(1H)-pyrazinones X and chloro-2-methyl/phenyl-(3-methyl)-3-thio-2(1H)-pyrazinones XI were synthesized starting from 3,5-dichloro-1-methyl/phenylpyrazin-2(1H)-ones I. Fifteen of these compounds were screened for their antibacterial and antifungal activity against two bacteria B. subtilis and S. aureus, and two fungi A. niger and H. oryzae. A possible structure activity relationship is given.     

Reactions of 4-Hydroxy-5-methyl(phenyl)-2-styryl-6H-1,3-oxazin-6-ones with Nucleophiles

4-Hydroxy-5-methyl(phenyl)-2-styryl-6H-1,3-oxazin-6-ones react with hydrazine and phenylhydrazine to give the corresponding 3,5-substituted triazoles. Treatment of the title compounds with ethanol and methanol leads to formation of N-cinnamoylmalonamates. The structure of the products was confirmed by the IR and ¹H and ¹³C NMR spectra.     

On the synthesis of geometric isomers of 2-methyl (or phenyl)-4-[α-arylethylidene]-5(4H)-oxazolones

Several Z-2-methyl(or phenyl)-4-[α-arylethylidene]-5(4H)-oxazolones 3Z, 4Z were prepared. The results obtained were compared by diazomethane insertion and condensation procedure. In order to synthesize E-2-phenyl-4-[α-arylethylidene]-5(4H)-oxazolones 4E hydrogen bromide isomerization in dry benzene was used.     

Synthesis of 2-Aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2<Emphasis Type="Italic">H</Emphasis>-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyridazin-7-ones

Bromination of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates gave ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazol-3-carboxylates which were used to alkylate benzenethiol and heterocyclic thiones at the sulfur atom. Reactions of the resulting S-alkylation products with hydrazine or methylhydrazine involved closure of pyridazine ring to afford 2-aryl-3-methyl-4-[phenyl(or hetaryl)sulfanylmethyl]-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.     

A facile retro-ene reaction of 5-(methoxyamino)-3-aryl-1,3,4-oxadiazol-2(3H)-ones

5-(N-Methoxy-N-methyl)amino-3-aryl-1,3,4-oxadiazol-2(3H)-ones 3 undergo a heteroretro-ene reaction in refluxing methanol in which the leaving enophile is formaldehyde. The resulting 5-(methylimino)-3-aryl-1,3,4-oxadiazolidin-2-one 4 may be viewed as a kinetic product which tautomerizes to the more stable 5-(methylamino)-3-aryl-1,3,4-oxadiazol-2(3H)-one 5 as the thermodynamic product. Comparison of calculated reaction energies reveals that the presence of the heterocyclic ring facilitates the retro-ene reaction, but the expulsion of formaldehyde is predicted to be highly exothermic even in its absence.     

Reactions of 6-Alkoxy(alkylthio)carbonylamino-4-hydroxy-2H-pyran-2-ones with Some Electrophilic Reagents

Alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones readily react with electrophiles to give substitution products at C³. Hard electrophilic reagents replace hydrogen both in position 3 and in position 5 of the pyran ring. Methylation of 6-alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones with diazomethane leads to formation of O- and N-methyl derivatives.     

Electron ionization mass spectra of some 4β-phenyl-substituted cycloalkane-cis-fused 1,3-oxazin-2(3H)-ones, -2(3H)-thiones and 1,4-oxazepin-3(4H)-ones

The 70 eV mass spectra of 4β-phenyl-substituted cyclopentane- and cyclohexane cis-fused 1,3-oxazin-2(3H)-ones, the two related 2-thiones, 6,7-cis-trimethylene-5β-phenyl-1,4-oxazepin-3(4H)-one and its 2β-methyl derivative were recorded and their fragmentations examined by means of metastable ion analysis, collision induced dissociation technique and exact mass measurement. The fragmentation patterns of the 1,3-oxazin-2(3H)-ones were relatively simple: the favored formation of cycloalkene ions implied that a considerable proportion of the molecular ions might possess an enol structure. Changes in the size of the fused cycloalkane ring had little or no effect on the fragmentations. Instead, small changes in the heterocyclic part of the molecule caused remarkable effects on the fragmentation behavior. Compared to 1,3-oxazin-2(3H)-ones studied, both 1,3-oxazine-2(3H)-thiones and 1,4-oxazepin-3(4H)-ones showed much more complicated fragmentation patterns.     

Effect of the Structure of 1- and 3-Methylpyrimidin-4-ones on the Rate of Nucleophilic Substitution of the 2-Methylsylfanyl Group

Rate constants for substitution of the 2-methylsulfanyl group in 1- and 3-methyl-2-methylsulfanyl-pyrimidin-4-ones and their 5-fluoro analogs were measured in the reaction with butylamine, alkaline hydrolysis, and methanolysis. The rate of substitution in 1-methyl isomers having a zwitterionic structure is greater by a factor of ~2 than the rate of substitution in 3-methyl isomers with conjugated double bonds in the ring. The presence of a fluorine atom in position 5 accelerates nucleophilic substitution in 1-methyl isomers, while 5-fluoro-3-methyl-2-methylsulfanylpyrimidin-4-ones react at a lower rate than their 5-unsubstituted analogs. According to the NMR data, the reactions involve formation of a tetrahedral intermediate. Anchimeric effect of the methyl group on N¹ hampersattack by basic reagent on the C⁶atom.     

Benzimidazole condensed ring systems. 5. Studies on the Synthesis of Pyrimido[1,6-α]benzimidazole-1,3(2H,5H)-diones

The reaction of ethyl 1H-benzimidazole-2-acetate (1) with methyl or ethyl isocyantes 2a,b resulted in excellent yields of the respective 2-methyl- or 2-ethylpyrimido[1,6-a]benzimidazole-1,3(2H,5H)-diones 3a,b , while the reaction of 1 with phenyl isocyanate (2c) gave, unexpectedly, ethyl 2-(1-phenylcarbamoyl-1H,3H-benzimidazol-2-ylidene)-2-phenylcarbamoylacetate (4). Alkylation of 3 with trimethyl or triethyl phosphates 5a,b led to the 5-methyl or 5-ethyl derivatives 6a-d . Chlorination of 6 with sulfuryl chloride afforded the 4-chloro derivatives 7a-d.     

Imidazolyl derivatives of the chroman ring 3

The synthesis of 2-methyl-3-(1-methyl-1H-imidazol-2-yl)-4H-1-benzopyran-4-ones 4 is described starting from 2-acetoxybenzoyl chlorides and 1,2-dimethylimidazole. Chromones 4 undergo alkaline ring opening to the corresponding 1-(2-hydroxyphenyl)-2-(1-methyl-1H-imidazol-2-yl)ethenols 5 which give ring closure to 2-substituted 3-(1-methyl-1H-imidazol-2-yl)-4H-1-benzopyran-4-ones or 2,3-dihydro-3-(1-methyl-1H-imidazol-2-yl)-4H-1-benzopyran-4-ones. The corresponding chromanols and chromenes can be easily obtained from chromones 4 .     

Arbeiten über Phosphorsäure- und Thiophosphorsäure ester mit einem heterocyclischen Substituenten. 2. Mitteilung. Eine verbesserte Methode zur Herstellung von 1, 3, 4-Oxadiazol-2(3H) onen und von Thio- und Dithiophosphorsäure-O,O-dialkyl-S-[(1, 3, 4-oxadiazol-2(3H)-on-3-yl)-methyl]-estern

Some 1,3,4-oxadiazol-2(2H)-ones with aliphatic substituents in 5-position are prepared in good yields and converted via the 3-hydroxymethyl derivatives to the corresponding 3-chloromethyl derivatives which are suitable starting materials for the preparation of insecticidal O,O-dialkyl-S-[(5-subst.-1,3,4-oxidiazol-2(3H)-one-3-yl)-methyl]-thiophosphates and dithiophosphates.     

Synthesis of 3-substituted 4H-1-benzothiopyran-4-ones

3-Substituted 2-phenyl-4H-1-benzothiopyran-4-ones (thioflavones) were prepared to test antimicrobial activity. It was found that 3-(phenyl)thiochromone derivatives (isothioflavones) were prepared by the Meerwein reaction of thiochromone with p-nitrobenzenediazonium ion. 3-(Formyl)thioflavone exhibits weak antimicrobial activity against Trichophytons and Candida.