One-pot,three-component synthesis of polyfunctionalized benzo[h]pyrazolo[3,4-b][1,6]naphthyridine and benzo[g]pyrazolo[3,4-b]quinoline derivatives in the presence of silver nanoparticles (AgNPs)

An efficient and straightforward protocol for one-pot, three-component reaction of aryl glyoxal monohydrates 1a-h , 5-amino-1-aryl-3-methylpyrazoles 2a , b and 4-hydroxyquinoline-2(1H)-one ( 3 ) or 2-hydroxy-1,4-naphthoquinone ( 4 ) using silver nanoparticles (AgNPs) as a high performance nanocatalyst in H₂O/EtOH at 60°C afforded the corresponding polyfunctionalized benzo[h]pyrazolo[3,4-b][1,6]naphthyridines 5a-h and benzo[g]pyrazolo[3,4-b]quinolines 6a-i , respectively. Excellent catalytic activity, high yields, employing green media and green nanocatalyst, cost-effective and simple procedure are some notable advantages of using AgNPs as a noble metal nanocatalyst in this synthetic strategy. The structures of fused heterocycles were confirmed by their Fourier transform infrared, proton nuclear magnetic resonance (¹H-NMR), and ¹³C-NMR spectral data and microanalysis.     

Synthesis of pyrazolo[3,4-d]pyrimidine derivatives using ketene dithioacetals

The cyclization of 5-amino-3-methylthiopyrazole-4-carbonitriles or 4-carboxamides 3a-j , which were prepared by the reaction of ketene dithioacetals 1a,b [1a : bis(methylthiomethylenemalononitrile; 1b : bis(methylthio)methylenecyanoacetamide] with hydrazines (hydrazine hydrate, phenylhydrazine, p-chlorophenylhydrazine, p-nitrophenylhydrazine), with formamide or carbon disulfide proceeded to give the corresponding 4-amino- or 4-hydroxy-3-methylthiopyrazolo[3,4-d]pyrimidines 6a-h in good yields. 3-Aminopyrazolo[3,4-d]pyrimidine derivatives 6i-1 were also obtained by the application of the cyclization reaction of 3,5-diaminopyrazoles with formamide.     

Substituted 3-and 5-formylpyridin-2-ones in the synthesis of 1-aryl-1, 6-naphthyridinone derivatives

New 1-aryl-6-[2-(dimethylamino)vinyl]4-oxo-1,4-dihydropyrimidine-5-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbonitriles containing electron-withdrawing substituents in the benzene ring were synthesized from enamino amides and dimethylformamide dialkylacetals. The influence of various dimethylformamide acetals on the yield of 3-(4-chloro-anilino)-2-cyano-5-(dimethylamino)penta-2,4-dienoic acid N-(dimethylamino)methyl-ideneamide was investigated in the reaction of these acetals with 3-(4-chloroanilino)-2-cyanocrotonamide. New 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbaldehydes containing electron-withdrawing substituents in the benzene ring were synthesized. The latter compounds were converted into new substituted l,6-naphthyridinones by the action of various CH acids. A new approach to the synthesis of 4-(4-fluoroanilino)-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitrile using dimethylformamide diisopropylacetal under mild conditions was developed. The comparative reactivity of the formyl group in the reactions of 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles and in 4-arylamino-2-oxo-1,2-dihydropyridine-3-carb-aldehydes with malononitrile was determined using HPLC.     

Reactions of α,β-unsaturated ketones with cyanoacetamide

3-Aryl-1-phenyl-2-propen-1-ones Ia-f and aroylphenylacetylenes Va-d reacted under reflux for 3 hours with cyanoacetamide in the presence of sodium ethoxide to give the corresponding 4-aryl-3-cyano-6-phenyl-2-(1H)pyridones VI. However, when ketones Ia-e were refluxed with cyanoacetamide for one hour in the presence of sodium ethoxide or piperidine, they gave the corresponding 4-aryl-3-cyano-3,4-dihydro-6-phenyl-2-(1H)pyridones IIIa-e, which upon heating with selenium gave the corresponding 2-pyridones VI. The structures of the products are based on chemical and spectroscopic evidence.     

Facile one-pot,three-component synthesis of novel bis(heterocycles) incorporating thieno[2,3-b]thiophenes via Michael addition reaction

A synthesis of novel series of bis(2-amino-3-cyano-4H-chromene), bis(2-amino-3-cyanopyrano[3,2-c]chromene), bis(6-amino-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole), and bis(2,7-diamino-3,4,6-tricyanopyrazolo[1,5-a]pyridine) derivatives linked to thieno[2,3-b]thiophene core via ether or ester linkages was reported. The formation of the target compounds presumably proceeds through a three component reaction of the appropriate bis(aldehyde) with 2 M of each of malononitrile and the corresponding active methylene compounds namely; dimedone, 4-hydroxycoumarine, 5-methyl-2,4-dihydro-3H-pyrazol-3-one, or cyanomethylpyrazole in dioxane at reflux in the presence of piperdine as a basic catalyst. The chemical structures of the new compounds were elucidated by several spectral tools.     

Synthesis of new unsaturated derivatives of functionally substituted 2-imino-2,5-dihydrofurans

5,5-Substituted 2-imino-4-methyl-2,5-dihydrofuran-3-carbonitriles reacted with aromatic aldehydes to give the corresponding 5,5-substituted 2-imino-4-(2-R-vinyl)-2,5-dihydrofuran-3-carbonitriles. The latter were converted into hydrochlorides which were hydrolyzed to 3-cyano-4-(2-R-vinyl)-2,5-dihydrofuran-2-ones whose condensation with malononitrile afforded dicyanomethylidene derivatives.     

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.     

Synthesis and structure of some substituted 2-amino-4-aryl-7-propargyloxy-4H-chromene-3-carbonitriles

A series of 2-amino-7-hydroxy-4H-chromene-3-carbonitriles 4a–l were synthesized through three-component reaction using sodium carbonate as a catalyst. The reaction was carried out in 96% ethanol-water medium (1:20 ratio in volume). Propargyl ether compounds 5a–l of these chromene-3-carbonitriles were successfully synthesized from corresponding hydroxyl chromene derivatives by reaction with propargyl bromide. Two different procedures were applied in this process: the procedure that used potassium carbonate in dried acetone and the procedure that used sodium hydride in dried DMF. The latter gave the ethers 5a–l in higher yields. The single-crystal X-ray structure of propargyl ether 5g has been recorded.     

Reaction of N1,N2-diarylacetamidines with (2,4,7-trinitro-9H-fluoren-9-ylidene)propanedinitriles

Novel spiro[fluorene-9,4′-(1′,2′,3′,4′-tetrahydropyridine)]-5′-carbonitriles 6a-c have been obtained from the reaction of N¹,N²-diarylacetamidines 1a-c with (2,4,7-trinitro-9H-fluoren-9-ylidene)propanedinitrile ( 2 ) in ethyl acetate solutions at ambient temperature for 6a,b or under reflux for 6c , respectively.     

3-对甲氧基苯基-和3-对羟基苯基-1-氨基-3a,4,5,9b-四氢化-9b-羟基-3H-环戊烯并[a]萘-2-甲腈的合成和晶体结构

用低价钛试剂(TiCl₄-Zn)与2-氰基-3-对甲氧基苯基-3-(1-四氢萘酮-2-基)丙腈反应合成了3-对甲氧基苯基-1-氨 基-3a,4,5,9b-四氢化-9b-羟基-3H-环戊烯并[a]萘-2-甲腈和3-对羟基苯基-1-氨基-3a,4,5,9b-四氢化-9b-羟基-3H-环戊烯并[a]萘-2-甲腈, 并用X射线衍射分析确定了这两个产物的结构.     

Synthesis of thiazolo[3,2-a]pyridines via an unusual Mannich-type cyclization

The Mannich-type reaction of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with 3-(1,3-benzodioxol-5-yl)-2-methylpropanal (ocean propanal) and p-toluidine afforded 7-aryl-2-(1,3-benzodioxol-5-ylmethyl)-2-methyl-3-[(4-methylphenyl)amino]-5-oxo-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyridine-8-carbonitriles in modest (25–46%) yields. The structure of the key compound was confirmed by X-ray crystal structure analysis.     

Ringerweiterung unter Lactonisierung von methylierten 1-(3′-Hydroxypropyl)-2-oxocyclododecan-1-carbonitrilen

Ring Enlargement by Lactonization of Methylated 1-(3′-Hydroxypropy1)-2-oxocyclododecane-1-carbonitriles The title compounds were prepared by Michael reaction of 2-oxocyclododecane-1-carbonitrile ( 1 ) and acrylaldehyde and its derivatives followed by NaBH₄ reduction or methylation of the aldehyde group with [(CH₃)₂Ti(i-PrO)₂] (Scheme 1). In all cases, the ring enlargement was performed with Bu₄NF/THF to give different methylated derivatives of 12-cyano-15-pentadecanolide ( 13 ) in 95–99% yield. The Yields of the rearrangement products are not dependent on the positions and numbers of the CH₃ groups in the side chain of 3 . The lactonization reaction is of unremarkable stereoselectivity.     

Gas-phase reactions of brominated diphenyl ethers with OH radicals

A small volume reaction chamber coupled to a mass spectrometer was used to study the gas-phase kinetics and mechanism of the reaction of OH radicals with diphenyl ether and seven polybrominated diphenyl ethers (PBDEs) with 1-2 bromines. Relative rate constants for these reactions were determined using isopropyl nitrite photolysis in He-air mixtures at approximately 740 Torr between the temperatures of 326-388 K. The Arrhenius expression for each compound was used to extrapolate the following OH rate constants at 298 K (in units of 10(-12) cm3 molecule(-1) s(-1), with 95% confidence intervals): diphenyl ether, 7.45 +/- 0.13; 2-bromodiphenyl ether, 4.7; 3-bromodiphenyl ether, 4.6; 4-bromodiphenyl ether, 5.7; 2,2'-dibromodiphenyl ether, 1.3; 2,4-dibromodiphenyl ether, 3.8; 3,3-dibromodiphenyl ether, 3.2; and 4,4'-bromodiphenyl ether, 5.1. The measured OH rate constants are in reasonable agreement with those predicted by structure activity relationships. Positive temperature dependences of these OH rate constants are observed for all compounds measured except for diphenyl ether and 4,4'-dibromodiphenyl ether. Bromophenols (in yields up to 20% relative to the amount of PBDE consumed) and Br2 were characterized as products of these reactions, suggesting that OH addition to ipso positions of these brominated aryls may be an important reaction pathway.     

Mannich reaction in the synthesis of N,S-containing heterocycles. 14*. Unexpected formation of thiazolo[3,2-a]pyridines in the aminoalkylation of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates by isobutyraldehyde and primary amines

Treatment of N-methylmorpholinium 4-aryl-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates with an excess of isobutyraldehyde and primary aromatic amines in refluxing ethanol gives the corresponding 7-aryl-3-arylamino-2,2-dimethyl-5-oxo-2,3,6,7-tetrahydro-5 H-thiazolo[3,2-a]pyridine-8-carbonitriles in 18-38 % yields.     

Reactions 1-acetyl-3-oxo-2,3-dihydroindole with alkyl 2-cyano-3-alkoxypropenoate and alkyl 2-alkoxycarbonyl-3-alkoxy-propenoate. Synthesis of 9-acetoxypyrrolo[1,2-a]indol-3-one derivatives

1-Acetyl-3-oxo-2,3-dihydroindole reacted with methyl 2-cyano-3-methoxypropenoate and ethyl 2-cyano-3-ethoxypropenoate in the presence of sodium hydride, affording compounds 3 (2-(2-cyano-2-alkoxycarbonyl-vinyl)-3-hydroxyindole). Methyl 2-methoxycarbonyl-3-methoxypropenoate gave compounds 4 or compounds 5 (in the presence of Triton B). Heating compounds 3 or their acetylated derivatives in acetic anhydride at reflux afforded 9-acetoxy-(3H)-pyrrolo[1,2-a]indol-3-one 8 .     

Synthesis of pyrimidine derivatives by the reaction of ketene dithioacetals with amides

Reactions of methyl 2-cyano-3,3-bis(methylthio)acrylate ( 1a ) with carboxamides 2a-g in the presence of sodium hydride in a mixture of benzene and N,N-dimethylacetamide took place displacement with the methylthio group to give the corresponding methyl 3-N-acylamino-2-cyano-3-(methylthio)acrylates 3a-g which were readily converted to the corresponding pyrimidine derivatives at reflux in methanol in good yields. Reactions of 2-cyano-3,3-bis(methylthio)acrylonitrile ( 1b ) with the carboxamides 2a-f gave directly pyrimidine-5-carbonitrile derivatives 7a-f . Ketene dithioacetals 1a,b smoothly reacted with thioamide 2g or urea 2h,i to give the expected pyrimidine derivatives 9,10a,b . Polyfunctionalized pyrimidines, thus obtained, were also used for the synthesis of fused pyrimidine derivatives.     

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.     

Sulfur derivatives of 1-methylpyrrole

Metalation of 1-methylpyrrole using n-butyllithium and tetramethylethylenediamine (TMEDA) in ether furnished 1-methyl-2-pyrrolyllithium, which in turn was converted to 1-methyl-2-methylthiopyrrole upon treatment with dimethyldisulfide. Further formylation with dimethylformamide, phosphorus oxychloride in dichloroethane led to the corresponding pyrrole-2-carboxaldehyde, which was then condensed with malononitrile and methylcyanoacetate under Knoevenagel reaction conditions to give 2-cyano-3-(1-methyl-5-methylthio-2-pyrrolyl)acrylonitrile and 2-cyano-3-(1-methyl-5-methylthio-2-pyrrolyl)acrylic acid methyl ester, respectively. Their oxidation by hydrogen peroxide furnished the corresponding sulfones. Analogously, 5-phenylthio derivatives were prepared.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Synthesis of 4,6-diaryl-1-benzyl-6-hydroxy-5,5-dimethyl-2-oxopiperidine-3-carbonitriles and their analogs via a modified Reformatsky reaction

Organozinc compounds obtained from 1-aryl-2-bromo-2-methylpropanone and zinc react with N-benzyl-3-aryl-2-cyanoacrylamides or N-[6-(2-cyano-1-oxo-3-phenylprop-2-enylamino)hexyl]-2-cyano-3-phenylacrylamide to give 4,6-diaryl-1-benzyl-6-hydroxy-5,5-dimethyl-2-oxopiperidine-3-carbonitriles or 1,6-bis(6-aryl-3-cyano-6-hydroxy-5,5-dimethyl-2-oxo-4-phenylpiperidyl)hexanes as a single isomer with trans-located piperidine hydrogen atoms.