Polyfluorinated heterocyclic compounds

The treatment of 2-phenyl-4-carbomethoxy-6,7,8,9-tetrafluorobenz[f]oxazepin-1,3 (I), 3-benzamido-5,6,7,8-tetrafluorocoumarin (V), and -benzamido--(2-hydroxy-3,4,5,6-tetrafluorophenyl)-acrylic acid (III) with a mixture of glacial acetic acid and a mineral acid gave (IV), the -complex of 3-hydroxy-5,6,7,8-tetrafluorocoumarin (VII) and benzoic acid. Treatment of (IV) with acetic anhydride gave 3-acetoxy-5,6,7,8-tetrafluorocoumarin (VI) and benzoic acid. Treatment with diazomethane gave 3-methoxy-5,6,7,8-tetrafluorocoumarin (VIII) and methyl benzoate. IV was also obtained from an equimolar mixture of its components. A mechanism for the formation of IV from I is proposed.For part II, see [1].     

Synthesis of 3-amino-3,4-dihydroquinazolin-4-one derivatives from anthranilic acid hydrazide and dicarboxylic acids

Treatment of anthranilic acid hydrazide with 2 equiv of ethoxalyl chloride gave the corresponding diester which underwent cyclization in acetic anhydride to produce ethyl 3-(ethoxalylamino)-4-oxo-3,4-dihydroquinazoline-2-carboxylate. Acylation of anthranilic acid hydrazide first with succinic anhydride and then with ethoxalyl chloride led to the formation of 4-[2-(2-{[ethoxy(oxo)acetyl]amino}benzoyl)hydrazino]-4-oxobutanoic acid whose cyclization in acetic acid afforded N-(2-ethoxycarbonyl-4-oxo-3,4-dihydroquinazolin-3-yl)succinamic acid, while in acetic anhydride ethyl 3-(2,5-dioxopyrrolidin-1-yl)-4-oxo-3,4-dihydroquinazoline-2-carboxylate was obtained. The latter was brought into reactions with amines and hydrazine hydrate and alkaline hydrolysis. Acylation of 2-[2-(2-aminobenzoyl)hydrazinocarbonyl]benzoic acid with ethoxalyl chloride gave ethyl N-[2-(phthalimidocarbamoyl)phenyl]oxamate, and with succinic anhydride, 3-[4-oxo-3-phthalimido-3,4-dihydroquinazolin-2-yl]propionic acid. 4-[2-(2-Aminobenzoyl)hydrazino]-4-oxobutanoic acid reacted with phthalic anhydride in boiling acetic acid to give phthalazino[1,2-b]quinazoline-5,8-dione via elimination of succinic acid residue.     

Anionic condensations of 3,5-di-<Emphasis Type="Italic">tert</Emphasis>-butyl-4(2)-hydroxybenzaldehydes in the presence of weak bases

Products of the reactions of 4- and 2-hydroxy-3,5-di-tert-butyl-benzaldehydes with malonic acid, diethyl malonate, and acetic anhydride in the presence of weak bases were isolated and identified. The reactions of 3,5-di-tert-butyl-4-hydroxybenzaldehyde with malonic acid and acetic anhydride in the presence of sodium acetate and piperidine gave 3,5-di-tert-butyl-4-hydroxycinnamic acid. The reaction of its 2-hydroxy isomer with acetic anhydride stopped at the stage of formation of the corresponding O-acetyl derivative, while in the reaction with malonic acid the corresponding substituted cinnamic acid and its lactone (coumarin derivative) were formed as intermediate products in a transformation sequence finally leading to 3-(3,5-di-tertbutyl-2-hydroxyphenyl)-3-piperidinopropionic acid and 6,8-di-tert-butyl-2-oxo-3,4-dihydro-2H-chromen-4-ylacetic acid. Analogous differences were typical of reactions of isomeric 4- and 2-hydroxy-3,5-di-tert-butylbenzaldehydes with diethyl malonate. The transformations of the 2-hydroxy isomer were accompanied by hydrolysis and formation of an adduct of intermediate coumarin derivative with diethyl malonate and piperidine.     

New derivatives of 4-quinaldinol

The reactions of 1, 1, 3-trichloro-1-propene and also 1, 1, 1-trichloro-2-propene with acetoacetic ester gave α-(γ, γ-dichlorallyl)acetoacetic ester (I). In the reactions with aniline and o- and p-toluidines, the corresponding α-(γ, γ-dichloroallyl)-β-arylamino-crotonic esters were produced, thermal cyclization of which gave 2-methyl-3-(γ, γ-dichloroallyl)-4-hydroxyquinoline (II) and its 6CH₃- (III) and 8CH₃- (IV) homologs. With phosphorus oxychloride, II–IV gave the corresponding 4-chloro-substituted quinolines (V–VII); with concentrated sulfuric acid, II–VII were converted into the corresponding β-quinolinylpropionic acids VIII–XIII.     

Transformations of 2-alkylamino-1,4-naphthoquinones under the action of nitrating mixture in acetic acid

Reactions of 2-alkylamino-1,4-naphthoquinones with a nitrating mixture in acetic acid afforded 2-alkyl-1-hydroxy-1H-naphtho[2,3-d]imidazole-4,9-diones.     

2-Nitroguanidine derivatives: XI. Reactions of <Emphasis Type="Italic">N</Emphasis>′-nitrohydrazinecarboximidamide and 2-methylidene-<Emphasis Type="Italic">N</Emphasis>′-nitrohydrazinecarboximidamide with glyoxal

The reaction of glyoxal with N′-nitrohydrazinecarboximidamide (1-amino-2-nitroguanidine) in the presence of sodium hydroxide at a molar ratio of 1 : 1 : 1 gave N′-nitro-2-(2-oxoethylidene)hydrazinecarboximidamide as a mixture of syn and anti isomers, whereas at a reactant ratio of 1:2:2 N′-nitro-2-[(5-nitroamino-2H-1,2,4-triazol-3-yl)methyl]hydrazinecarboximidamide and 3-nitroamino-4,5-dihydro-1,2,4-triazin-5-ol were formed. N′-Nitro-2-(2-oxoethylidene)hydrazinecarboximidamide reacted with N′-nitrohydrazinecarboximidamide in boiling ethanol to give N′-nitro-2-[(5-nitroamino-2H-1,2,4-triazol-3-yl)methyl]hydrazinecarboximidamide, while in glacial acetic acid 2,2′-(ethane-1,2-diylidene)bis(N′-nitrohydrazinecarboximidamide) was obtained. The latter was also formed in the reaction of glyoxal with N′-nitrohydrazinecarboximidamide in acetic acid at room temperature. The reaction of 2-methylidene-N′-nitrohydrazinecarboximidamide with glyoxal led to the formation of 3-nitroimino-2,3,4-5-tetrahydro-1,2,4-triazine-5-carbaldehyde or 1-(methylideneamino)-2-(nitroimino)imidazolidine-4,5-diol, depending on the conditions.     

Reactions of 3,5-di-<Emphasis Type="Italic">tert</Emphasis>-butyl-1,2-benzoquinone with mercapto carboxylic acids

Heating of an equimolar mixture of 3,5-di-tert-butyl-1,2-benzoquinone with thiosalicylic acid led to 2-[(4,6-di-tert-butyl-2,3-dihydroxyphenyl)thio]benzoic acid. In the case of β-mercaptopropionic acid, 2-[(4,6-di-tert-butyl-2,3-dihydroxyphenyl)thio]propionic acid was formed, which upon reflux in Ac2O was converted to 6,8-di-tert-butyl-9-hydroxy-3,4-dihydro-2H-1,5benzoxathiepin-2-one.     

Kinetics and mechanism of benzyl <Emphasis Type="Italic">para</Emphasis>-chlorophenyl ketone oxidation

The oxidation of benzyl para-chlorophenyl ketone in chlorobenzene at 100°C occurs through the formation of short chains. Non-peroxide reaction products (1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone, para-chlorobenzyl, benzaldehyde, and para-chlorobenzoic acid) are formed not only by the transformation of hydroperoxide (1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone) but also (or solely) through the recombination of α-ketoperoxyl radicals with or without chain termination. α-Hydroperoxide decomposes predominantly through a heterolytic route to form para-chlorobenzoic acid and benzaldehyde. Benzaldehyde and 1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone undergo radical chain oxidation in the reaction medium to form benzoic acid (benzaldehyde), para-chlorobenzyl, and benzoic and para-chlorobenzoic acids (1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone). The homolytic decomposition of α-hydroperoxy ketone and α-hydroxy-α-hydroperoxy ketone causes the self-acceleration of the process and affords 1-(4-chlorophenyl)-2-hydroxy-2-phenyl-1-ethanone or, to a lesser extent, benzaldehyde and para-chlorobenzoic acid (α-hydroperoxy ketone). para-Chlorobenzoic acid substantially accelerates the heterolytic decomposition of α-hydroxy-α-hydroperoxy ketone and the oxidation of benzyl para-chlorophenyl ketone with peroxy acids to ester according to the Baeyer-Villiger mechanism. The rate constants of the main steps of the process and kinetic parameters are calculated by solving the inverse kinetic problem.     

Synthesis of 6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidine-5-carboxylic acids and their methyl esters

6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylic acids and methyl 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylates were synthesized by fusion of 4-aryl-2,4-dioxobutanoic acids and their methyl esters, respectively, with 1H-tetrazol-5-amine and aromatic aldehydes. The reaction of methyl 2,4-dioxopentanoate with 1H-tetrazol-5-amine and 2-fluorobenzaldehyde in boiling acetic acid gave methyl 6-acetyl-5-hydroxy-7-(2-fluorophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine-5-carboxylate.     

Use of dodecanoyl isothiocyanate as building block in synthesis of target benzothiazine,quinazoline, benzothiazole and thiourea derivatives

Dodecanoyl isothiocyanate (I) reacts additively with anthranilic acid to afford derivatives of thiourea II and benzothiazine IIIin a one-pot reaction. The cyclisation of thiourea II was achieved using acetic anhydride to form quinazoline derivative IV. The heating of quinazoline IV in acetic anhydride or butan-1-ol gave quinazoline derivatives V or VI, respectively. Benzothiazine III underwent trans-acylation to benzothiazine VII in boiling acetic anhydride. The treatment of IV with hydrazine hydrate, anthranilic acid or ethyl carbazate afforded derivatives of triazoloquinazoline VIII, quinazolinoquinazoline XI or thiosemicarbazide X, respectively. The reaction of I with 2-aminophenol or 2-aminothiophenol afforded thiourea derivative XIII or benzothiazole derivative XIV, respectively. Most of the synthesised compounds bear a lauroyl (dodecanoyl) group (a hydrocarbon moiety). The structures of the synthesised compounds were confirmed by microanalytical and spectral data.     

Reactions of 2-(2-propynylsulfanyl)-5,6,7,8-tetrahydrobenzo[<Emphasis Type="Italic">b</Emphasis>]thieno[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidin-4(<Emphasis Type="Italic">3H</Emphasis>)-one with arylsulfenyl chlorides

2-(2-propynylsulfanyl)-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one with arylsulfenyl chlorides in chloroform gave products of anti-Markownikoff Ad _E-addition. The use of nitromethane as solvent in the presence of lithium perchlorate additives favored intramolecular electrophilic cyclization into 1-arylsulfanyl-1,2,6,7,8,9-hexahydro-4H-benzo[4,5]thieno[3,2-e][1,3]thiazolo[3,2-a]-pyrimidin-5-one.     

Condensation of diethyl 2,4,6-Trioxoheptanedioate with 2-(Aryliminomethyl)phenols. A new synthesis of chromeno[4,3-<Emphasis Type="Italic">b</Emphasis>]pyridines

Condensation of diethyl 2,4,6-trioxoheptanedioate with 4-methoxy-2-(4-methylphenyliminomethyl)-phenol in acetone gave diethyl 5-hydroxy-9-methoxy-1-(4-methylphenyl)-4-oxo-1,4a,5,10b-tetrahydro-4Hchromeno[ 4,3-b]pyridine-2,5-dicarboxylate as a mixture of diastereoisomers. The major (4aR,5R,10aR)-isomer was isolated as individual substance, and its structure was proved by X-ray analysis.     

Synthesis of New Functionally Substituted Aryl- and Hetarylcarbamates Based on Ninhydrin

The condensation of methyl (ethyl) phenylcarbamates with ninhydrin in concentrated sulfuric acid gave dialkyl [1,3-dioxoindan-2,2-diyldi(4,1-phenylene)]biscarbamates. Treatment of the latter with hydrazine hydrate resulted in the transformation of the indandione fragment into phthalazinone. Ninhydrin reacted with methyl (hydroxyphenyl)carbamates in glacial acetic acid to produce dihydroxy derivative of oxotrihydroindeno[ 1,2-b][1]benzofuran possessing a carbamate group. Tandem reaction of ninhydrin with methyl (acetylphenyl) carbamates on heating in boiling glacial acetic acid, followed by addition of hydrazine hydrate in acetonitrile, afforded methyl (5-oxo-5H-indeno[1,2-c]pyridazin-3-yl)phenylcarbamates.     

Synthesis and Biological Activity of Compounds Obtained by Reacting Methyl Aroylpyruvates with Sulfadimidine

The reaction of methyl aroylpyruvates and 2-(4-aminobenzenesulfamido)-4,6-dimethylpyrimidine in glacial acetic acid in the presence of anhydrous sodium acetate afforded (2Z)-4-aryl-2-hydroxy-N-{4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-4-oxobut-2-enamides. Reaction of the above reagents in a mixture of acetic acid and ethanol (1: 1) in the absence of anhydrous sodium acetate gave methyl (2Z)-4-aryl-2-{4-[(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenylamino}-4-oxobut-2-enoates. Analgesic and anti-inflammatory activities of the synthesized compounds was studied.     

Features of the reaction of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acid esters with acetone and <Emphasis Type="Italic">p</Emphasis>-toluidine

Three-component reactions of 3,4-dihydroxy-6-oxo-2,4-alkadienoic acids with acetone and p-toluidine were studied; their specific feature was the formation of the regioisomeric esters of 4-hydroxy-2,2-dimethyl-1-(4-methylphenyl)-5-(2-oxoalkyliden)-2,5-dihydro-1H-pyrrole-3-carboxylic acids and [4-alkanoyl-3-hydroxy-5,5-dimethyl-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-ylidene]acetic acid. Structure of the synthesized compounds was discussed based on the data of IR and ¹H NMR spectroscopy and X-ray diffraction analysis.     

Synthesis of 4-alkyl(aryl,hetaryl)-2-thioxo-5,6,7,8-tetrahydroquinoline-3-carbonitriles and their derivatives by cross-recyclization of 4-alkyl(aryl,hetaryl)-2,6-diamino-4<Emphasis Type="Italic">H</Emphasis>-thiopyran-3,5-dicarbonitriles with 4-(cyclohex-1-en-1-yl)-morpholine,alkyl halides,and cyclohexanone

Cross recyclization of 4-substituted 2,6-diamino-4H-thiopyran-3,5-dicarbonitriles with 4-(cyclohex-1-en-1-yl)morpholine, alkyl halides, and cyclohexanone gave the corresponding substituted 2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles, 2-alkylsulfanyl-5,6,7,8-tetrahydroquinoline-3-carbonitriles, 3-amino-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamides, and 4-oxo-2,2-pentamethylene-1,2,3,4,7,8,9,10-octahydropyrimido[4′,5′:4,5]thieno[2,3-b]quinolines. The structure of 3-(4-bromophenyl)-2,2-pentamethylene-11-(2-thienyl)-1,2,3,4,7,8,9,10-octahydropyrimido[4′,5′:4,5]thieno[2,3-b]quinoline was proved by X-ray analysis.     

Baeyer–Villiger oxidation of <Emphasis Type="Italic">N</Emphasis> <Superscript>1</Superscript>,<Emphasis Type="Italic">N</Emphasis> <Superscript>3</Superscript>,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides

Baeyer–Villiger oxidation of N¹,N³,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides with 30% hydrogen peroxide in acetic acid afforded 2-(4-aryl-3-carbamoyl-2-methyl-5-oxooxolan-2-yl)acetic acids.     

Reaction of 1,3,4,6-tetraketones with <Emphasis Type="Italic">p</Emphasis>-toluidine and benzaldehyde

Reactions of 1,6-diphenylhexane-1,3,4,6-tetraone, octane-2,4,5,7-tetra-one, and decane-3,5,6,8-tetraone with a mixture of p-toluidine and benzaldehyde afforded, respectively, 2-[4-benzoyl-3-hydroxy-1-(4-methylphenyl)-5-phenyl-1H-pyrrol-2-yl]-1-phenylethanone, (1E)-1-[4-acetyl-3-hydroxy-1-(4-methylphenyl)-5-phenyl-1,5-dihydro-2H-pyrrol-2-ylidene]propan-2-one, and 2-hydroxy-1-(4-methylphenyl)-2-(2-oxobutyl)-4-propanoyl-5-phenyl-1,2-dihydro-3H-pyrrol-3-one.     

Synthesis of new heterocycles by oxidation of functionalized cyclic derivatives of bis(2-chlorovinyl) sulfide and selenide

Oxidation of 4-substituted 2,6-bis[(E)-chloromethylidene]thiomorpholine with hydrogen peroxide in a mixture of chloroform with acetic acid afforded the corresponding 4-R-2,6-bis[(E)-chloromethylidene]-thiomorpholine 1-oxide. The results of oxidation of bis[(E)-chloromethylidene]-1,4-dichalcogenanes under analogous conditions depended on the chalcogen nature and its position in the ring. The reaction of 2,6-bis[(E)-chloromethylidene]-1,4-dithiane gave 2,6-bis[(E)-chloromethylidene]-1,4-dithiane-1,1,4,4-tetraone, whereas 3,5-bis[(E)-chloromethylidene]-1,4-thiaselenane-1,1-dione was unexpectedly obtained from 3,5-bis[(E)-chloromethylidene]-1,4-thiaselenane. 2,6-Bis[(E)-chloromethylidene]-1,4-thiaselenane and 2,6-bis[(E)-chloromethylidene]-1,4-diselenane decomposed under the oxidation conditions.     

Synthesis and Biological Activity of 3,4-Diaryl-5-[4-(acetylsulfamoyl)phenyl]-4,5-dihydropyrrolo[3,4-<Emphasis Type="Italic">c</Emphasis>]pyrazol-6(2<Emphasis Type="Italic">H</Emphasis>)-ones and Their Sodium Salts

3,4-Diaryl-5-[4-(acetylsulfamoyl)phenyl]-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-ones were synthesized be reaction of 5-aryl-4-aroyl-1-[4-(acetylsulfamoyl)phenyl]-3-hydroxy-1H-pyrrole-2(5H)-ones with hydrazine hydrate in glacial acetic acid, and their sodium salts were obtained by treatment with sodium methoxide in methanol–DMF (1: 1). Analgesic and anti-inflammatory activity and acute toxicity of the synthesized compounds were studied.