Synthesis and spectroscopic studies of some heterocyclic compounds. Reaction of 3-aryl-1-phenyl-2-propen-1-ones with ethyl phenylacetate

3-Aryl-1-phenyl-2-propen-1-one I reacted with ethyl phenylacetate (II) in the presence sodium ethoxide at room temperature to give the corresponding ethyl β-aryl-γ-benzoyl-α-phenyl-butyrate III. However,' when the same ketones were refluxed with ethyl phenylacetate, they gave the corresponding 4-aryI-3,6-diphenyl-3,4-dihydro-2H-pyran-2-ones IV. The reactions of III and IV with hydrazine hydrate afforded the corresponding hydrazones VI and 2-pyridones VIII, respectively. The structure and configuration of the products are based on chemical and spectroscopic evidence.     

Synthesis of heterocyclic compounds. XXIV. Synthesis of pyridines from β-substituted α-phenylacrylonitriles

The reaction of malononitrile with α-phenylcinnamonitriles in ethanolic sodium ethanethiolate is studied as a convenient route to 2-amino-4-aryl-5-cyano-6-ethylthio-3-phenyl-3,4-dihydropyridines ( 5 ) and the corresponding pyridines 6 . From the study of the structure of 5a (Ar = Ph) we can conclude that this cyclization reaction proceeds via a site-selective addition of the ethanethiolate to the cyano group i of the 1,3-tricarbonitrile ( 2 ).     

Synthesis of New 1H-indazole derivatives

Reactions of 3-aryl-1-phenyl-2-propen-1-ones IIa-d with ethyl phenylacetate (I) in the presence of sodium ethoxide under reflux for one hour gave only the corresponding 3,5-diaryl-2,4-dibenzoyl-6-phenyl-cyclo-hexanones IIIa-d. The reaction of these compounds with hydrazine hydrate afforded the corresponding 5-benzoyl-4,6-diaryl-3,7-diphenyl-1,4,5,6,7-pentahydro-1H-indazole IVa-d. The structures of the products were established by spectroscopic (ir, uv, nmr and mass spectra), single-crystal X-ray analysis and chemical evidence.     

Acetylinic ketones. Part II.. Reaction of acetylenic ketones with nucleophilic nitrogen compounds

Aroylphenylacetylenes (I) reacted with ethyl and phenyl hydrazinecarboxylates (II) to give ω-aroylacetophenone-N-ethoxycarbonyl-(Vla-f) and N-phenoxycarbonyl-(VIg-l) hydrazones, respectively. When these were healed with acetic anhydride they were converted to 5-aryl-1-ethoxycarbonyl-and 1-phenoxycarbonyl-3-phenylpyrazoles (VII), respectively, which on hydrolysis with rnethanolic potassium hydroxide gave the corresponding 5(3)aryl-3(5)phenylpyrazoles (VIII). Reaction of the above acetylenic ketones with guanidine hydrochloride in the presence of sodium carbonate gave the corresponding 2-amino-6-aryl-4-phenylpyrimidines (XII). Similarly, reaction of benzoylphenylacetylene with thiourea and with urea in the presence of sodium ethoxide gave rise to 2,4-diphenylpyrimidine-2-thione (XVIII) and 2,4-diphenyl-2(1H)pyrimidin-one (XV), respectively.     

Some reactions with ω-bromoacetophenone: Synthesis of Δαβ-butenolide and its transformation into pyrrole derivatives

ω-Bromoacetophenone reacts with the sodium salt of ethyl cyanoacetate to afford α-cyano-β-phenyl-Δ^αβ-butenolide. This butenolide undergoes azo coupling with diazotized aromatic amines (ArNH₂) to afford the hydrazo derivatives. These hydrazo derivatives (ArPh, 4-ClC₆H₄, 4-MeC₆H₄, 4-MeOC₆H₄) were transformed into the corresponding 3(2H)-pyridazinone derivatives on stirring in methanol in the presence of potassium hydroxide. These latter compounds were converted into the corresponding 3-cyano-2,5-dihydroxy-4-phenyl-N-arylpyrrole derivatives on reduction with zinc dust in refluxing acetic acid, presumably via reductive cleavage of the N N bond of the pyridazine followed by recyclization via loss of ammonia.     

Synthesis of dihydrofuro[2,3‐b]pyridines by the reaction of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles with α,β‐unsaturated carbonyl compounds

The reactions of 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles 1a‐d with α,β‐unsaturated carbonyl compounds in the presence of sodium ethoxide (0.1 equivalent) gave the corresponding Michael adducts 2a‐d , 3a‐d and 4a‐d. Compounds 2a‐d and 3a‐c reacted with sodium alkoxide (1 equivalent) to yield the corresponding 7a‐alkoxyhexahydrofuro[2,3‐b]pyridines 5a‐d, 6a‐d, 7a‐c and 8a‐c . Treatment of 5a‐d, 6a‐d, 7a‐c and 8a‐c with potassium tert‐butoxide produced the corresponding dihydrofuro[2,3‐b]pyridines 9a‐d and 10a‐c . The reaction of 4a‐c with sodium ethoxide (1 equivalent) afforded the corresponding dihydro‐furo[2,3‐b]pyridines 11a‐c .     

Synthesis of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles, 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles and pharmacologically active 1-aryl-1H-pyrazole-4-acetic acids

Lithium aluminum hydride reduction of 5-substituted or unsubstituted ethyl or methyl 1-aryl-1H-pyrazole-4-carboxylates gave, generally in excellent yields, 5-substituted or unsubstituted 1-aryl-1H-pyrazole-4-methanols which afforded the corresponding 1-aryl-4-(bromomethyl)-1H-pyrazoles with hydrobromic acid in acetic acid solution. These crude intermediates gave by reaction with potassium cyanide in dimethylsulfoxide solution 1-aryl-1H-pyrazole-4-acetonitriles only in the case of 5-unsubstituted compounds, otherwise mixtures of 5-substituted 1-aryl-1H-pyrazole-4-acetonitriles and 4-methyl-1-phenyl-1H-pyrazole-3-carbonitriles were generally obtained. Acetonitriles IIIa,b,i,l gave in excellent yields the corresponding 1-aryl-1H-pyrazole-4-acetic acids Va,b,i,l by alkaline hydrolysis. Compounds Vb,i,l showed in the writhing test appreciable analgesic properties, associated with low acute toxicity; moreover, compound VI exhibited a statistically significant antiinflammatory activity in the carrageenan-induced edema assay.     

Reactions of acetylenic ketones with methyl α-naphthylacetate. A synthesis of l-amino-2-pyridone derivatives

Reactions of acetylenic ketones (Ia-f) with methyl α-naphthylacetate in the presence of sodium methoxide gave the corresponding 6-aryl-3-α-naphthyl-4-phenyl-2-pyrones (IIa-f) which upon refluxing with hydrazine hydrate in ethanol gave the corresponding 1-amino-2-pyridone derivatives (VIa-f). The structure of the products was established by chemical and spectroscopic evidence.     

Tetrazole compounds. 9. A new approach to tetrazolyl-substituted quinoline derivatives

The acid-catalyzed reaction of 1-aryl-5-(2-dimethylaminovinyl)-1H-tetrazoles 2 with arylamines suitably functionalized in the ortho-position resulted in Z-configurated transamination products which were cyclized to novel 3-tetrazolylquinolines by the action of sodium ethoxide. Thus, on reacting 2 with 2-aminoacetophenone or 2-aminobenzophenone, respectively, the 2-[2-(1-aryl-1H-tetrazol-5-yl)vinyl-amino]aryl ketones 3a-g were obtained, the cyclization of which gave 4-substituted 3-(1-aryl-1H-tetrazol-5-yl)quinolines 4 . In the case of the transamination products 3h-1 , prepared from 2 and methyl anthranilate, the ring closure afforded 3-(1-aryl-1H-tetrazol-5-yl)-1H-quinolin-4-ones 5 . Starting from 2 and anthranilonitrile 4-amino-3-(1-aryl-1H-tetrazol-5-yl)quinolines 10 were obtained via the corresponding intermediates 9 .     

Synthesis of 2-alkoxy-6-aryl-5-cyano-4(3H)-pyrimidinones

The reaction of methyl 3-aryl-2-cyano-3-methoxypropenoates 1 with cyanamide and sodium methoxide in methanol afforded after acid hydrolysis the methyl 3-[(aminocarbonyl)amino]-3-aryl-2-cyanopropenoates 4 . By performing the reaction in higher boiling alcohols the 2-alkoxy-6-aryl-5-cyano-4(3H)-pyrimidinones 2 were obtained in good yields.     

Synthesis of 2-(β-D-ribofuranosyl)pyrimidines,A new class of C-nucleosides

A new C-glycosyl precursor for C-nucleoside synthesis, 2,5-anhydroallonamidine hydrochloride ( 4 ) was prepared and utilized in a Traube type synthesis to prepare 2-(β-D-ribofuranosyl)pyrimidines, a new class of C-nucleosides. The anomeric configuration of 4 was confirmed by single-crystal X-ray analysis. Reaction of 4 with ethyl acetoacetate gave 6-methyl-2-(β-D-ribofuranosyl)pyrimidin-4-(1H)-one ( 5 ). Reaction of 4 with diethyl sodio oxaloacetate gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxylic acid ( 6 ). Esterification of 6 with ethanolic hydrogen-chloride gave the corresponding ester 7 which when treated with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxamide ( 8 ). Condensation of 2,5-anhydroallonamidine hydrochloride ( 4 ) with ethyl 4-(dimethylamino)-2-oxo-3-butenoate ( 9 ), gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboxylate ( 10 ). Treatment of 10 with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ). Single-crystal X-ray analysis confirmed the β-anomeric configuration of 11. Acetylation of 11 followed by treatment with phosphorus pentasulfide and subsequent deprotection with sodium methoxide gave 2-(β-D-ribofuranosyl)pyrimidine-4-thiocarboxamide ( 14 ). Dehydration of the acetylated amide 12 with phosphorous oxychloride provided 2-(β-D-ribofuranosyl)pyrimidine-4-carbonitrile ( 15 ). Treatment of 15 with sodium ethoxide gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboximidate ( 16 ), which was converted to 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamidine hydrochloride ( 17 ) by treatment with ethanolic ammonia and ammonium chloride. Treatment of 16 with hydroxylamine yielded 2-(β-D-ribofuranosyl)pyrimidine-4-N-hydroxycarboxamidine ( 18 ). Treatment of 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ) with phosphorus oxychloride gave the corresponding 5′-phosphate, 19 , Coupling of 19 with AMP using the carbonyldiimidazole activation procedure gave the corresponding NAD analog, 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide-(5′ ? 5′)-adenosine pyrophosphate ( 20 ).     

Synthesis and reaction of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one derivatives

Reaction of aryl and styryl methyl ketones 1a-m with dimethyl bis(methylthio)methylenemalonate ( 2 ) in the presence of potassium hydroxide in dimethyl sulfoxide gave the corresponding methyl 6-aryl- and 6-styryl-4-methylthio-2-oxo-2H-pyran-3-carboxylates 3a-m . 6-Aryl derivatives 3a-d,g were treated with sodium methoxide in methanol to give the corresponding 6-aryl-4-methoxy-2H-pyran-2-ones 8a-d and 9. Phenylcoumalin ( 7a ) and paracotoin ( 7b ) were synthesized by the desulfurization of 6-aryl-4-methylthio-2H-pyran-2-ones 4a,b. Similarly, anibine ( 8e ) was also synthesized from 3g . Treatment of 3 with hydrogen peroxide or 3-chloroperoxybenzoic acid gave the corresponding 4-methylsulfiny-2H-pyran-2-ones 10a-f in good yields. Displacement reactions of 10a-f with nucleophilic reagents are also described.     

Heterocycles. Part V. Reaction of α,β-unsaturated carbonyl compounds with arylacetamides. A synthesis of 2-pyridone derivatives

The reaction of 1,3-diaryl-2-propene-1-ones I with arylacetamides II, in the presence of sodium ethoxide under reflux, for two hours, gave the corresponding 3,4,6-triaryl-3,4-dihydro-2(1H)-pyridones IV. However, when the reaction of these ketones was carried out in the presence of sodium hydride, they gave the corresponding 3,4,6-triaryl-2(1H)-pyridones VI or a mixture of IV and VI. When 1,3-diaryl-2-propyne-1-ones V were reacted with arylacetamides, in the presence of sodium hydride, they yielded the corresponding 2-pyridones VI. Treatment of compounds IV with selenium produced the corresponding 2-pyridones VI. Acetylation of the latter compounds gave the corresponding 2-acetyl derivatives VIII. The structure of all products was confirmed by chemical and spectroscopic evidence, and the mechanism of the reactions was discussed.     

Synthesis and characterization of some new pyridines,thieno[2,3-b] pyridines and pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4(3H)-ones bearing styryl moiety

3-Cyano-5-ethoxycarbonyl-6-methyl-4-styrylpyridine-2(1H)-thione ( 3 ) was prepared by reaction of 2-cyano-5-phenylpenta-2,4-dienethioamide ( 2 ) with ethyl acetoacetate or by multicomponent reaction of cinnamaldehyde ( 1 ), cyanothioacetamide and ethyl acetoacetate in a moderate yield. Reaction of compound 3 with some N-aryl-2-chloroacetamides, in the presence of sodium acetate, gave the corresponding 2-(N-arylcarbamoylmethylsulfanyl)-3-cyano-5-ethoxycarbonyl-6-methyl-4-styrylpyridines 4a-f . When compounds 4a-f were subjected to Thorpe-Ziegler reaction conditions, they converted into the corresponding 3-amino-5-ethoxycarbonyl-2-(N-arylcarbamoyl)-6-methyl-4-styrylthieno[2,3-b]pyridines 5a-f . Compounds 5a,e,f were reacted, in turn, with 2,5-dimethoxytetrahydrofuran to furnish the corresponding 3-(pyrrol-1-yl)thieno-pyridines 6a,e,f . Reactions of 5a-f with triethyl orthoformate or nitrous acid were also carried out and their products were identified. Structural formulas of all synthesized compounds was characterized and confirmed on the basis of their elemental and spectral analyses.     

Cycloacylation of <Emphasis Type="Italic">N</Emphasis>-Phenyl-3-oxobutanethioamide with 3-Aryl-2-propenoyl Chlorides

Reactions of N-phenyl-3-oxobutanethioamide with 3-aryl-2-propenoyl chlorides in acetone in the presence of potassium carbonate give rise to 4-aryl-5-acetyl-1-phenyl-6-thioxopiperidin-2-ones, 2-aryl-5-acetyl-6-phenylamino-2,3-dihydro-4H-thiopyran-4-ones, and 6-aryl-2-acetonylidene-3-phenyl-5,6-dihydro-4H-1,3-thiazin-4-ones whose structure was proved both by spectral methods and chemical transformations.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 2, 2005, pp. 292–296.Original Russian Text Copyright © 2005 by Britsun, Borisevich, Samoilenko, Lozinskii.     

5-Cyano-6-aryluracil and 2-thiouracil derivatives as potential chemotherapeutic agents. IV

A series of 5-cyano-6-aryluracils and 2-thiouracils 1a-h has been prepared and alkylated to 1,3-dialkyluracils 2a-d and 2-alkylthiouracils, 3, 4 and 6 , by electrophilic substitution with alkyl halides. Reaction of 1b with dibromoethane and 1,3-dibromopropane gave the corresponding bicyclic products, 7-aryl-6-cyano-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones 5a,b and 8-aryl-7-cyano-3,4-dihydro-2H-pyrimido[2,3-b][1,3]thiazin-6-ones 5c-g . Nucleophilic substitution on 6 with hydrazine led to 7 which on refluxing with formic acid gave 5-aryl-6-cyano-8-methyl-s-triazolo[3,4-b]pyrimidin-7-ones ( 9 ), while with acetic and propionic acids only 2-acylhydrazino-3-methyl-4-oxo-5-cyano-6-arylpyrimidines 8a,b were isolated. The hydrazine 7 undergoes cyclization with acetylacetone and methyl dimethylmercaptoacrylate providing 2-(pyrazol-1-yl)-3-methyl-4-oxo-5-cyano-6-substituted pyrimidines 10 , and 11 . Some of the compounds were screened for antibacterial-, antifungal- and antiviral activities and a few of them showed significant chemotherapeutical activities.     

Reactions of 2-benzylidenemalononitrile and 2-nitro-3-phenylacrylonitrile with aryl azides

Reactions of 2-benzylidenemalononitrile and 2-nitro-3-phenylacrylonitrile with aryl azides in diethyl ether at room temperature gave mixtures of regioisomeric 1(3)-aryl-5-phenyl-4,5-dihydro-1(3)H-1,2,3-triazole-4,4-dicarbonitriles and 1-aryl-5(4)-phenyl-1H-1,2,3-triazole-5(4)-carbonitriles, respectively. 2-Benzylidenemalononitrile reacted with the same arylazides on heating in boiling chloroform to produce 1-aryl-2-phenylaziridine-2,2-dicarbonitriles.     

Reactions of some 4-dicyanomethylenepyran derivatives with malononitrile and hydrazines

4-Dicyanomethylene-2-phenyl-4H-benzo[b]pyran, the corresponding thiapyran, and 4-dicyanomethylene-2,6-diphenyl-4H-pyran react with malononilrile under basic conditions to give 5-amino-4-cyano-2-phenylbenzo[b]pyrano[4,3,2-de] [1,6]naphthyridine, the corresponding thia-pyranonaphthyridine derivative, and 5-amino-6-cyano-2,8-diphenylpyrano[4,3,2-de] [1,6]naphthyridine, respectively. Certain other related reactions were studied in the course of investigating the above reactions. Hydrazine hydrate and 4-dicyanomethylene-2-phenyl-4H-benzo[b]pyran gave 5-(2-hydroxyphenyl)-3-phenylpyrazole, and phenylhydrazine gave 5-(2-hydroxyphenyl)-1,3-diphenylpyrazole.     

Synthesis of 6-aryl-1,3-dimethyl-6,7-dihydro-6-azalumazin-7-(6H)ones and their conversion into 2-aryl-1,2,4-triazine-3,5-(2H,4H)odiones. A new synthesis of 1-aryl-6-azauracils

Treatment of 6-amino-5-arylazo-1,3-dimethyluracils with urea or N,N′-carbonyldiimidazole gave the respective 6-aryl-1,3-dimethyl-6,7-dihydro-6-azalumazin-7-(6H)ones, which were hydrolyzed with alkali to afford 2-aryl-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acids (1-aryl-6-azauracil-5-carboxylic acids). Thermal decomposition of these carboxylic acids gave the corresponding 2-aryl-1,2,4-triazine-3,5-(2H,4H)diones (1-aryl-6-azauracils). Methylation of the latter with methyl iodide gave the corresponding 2-aryl-4-methyl-1,2,4-triazine-3,5-(2H,4H)diones (1-aryl-3-methyl-6-azauracils).     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.