Efficient access to some new pyrimidine derivatives and their antimicrobial evaluation

1-[4-(3-Hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]ethanone ( 1 ) was used as a precursor for heterocyclic synthesis. Condensation of compound 1 with monochloroacetic acid and benzaldehyde gave thiazolopyrimidine 2 which in turn underwent cyclization with malononitrile dimmer to afford malononitrile derivative 3 . Also, the reaction of compound 1 with benzaldehyde under a basic condition produced chalcone 4 . Chalcone 4 can be used as a key intermediate for further preparation of heterocyclic compounds. In addition, compound 1 was allowed to react with malononitrile dimmer and/or ethyl chloroacetate to give pyrimidines 8 and 9 , respectively. Alkylation of compound 8 with ethyl chloroacetate afforded S-alkylated product 10 which was treated with hydrazine hydrate to yield the hydrazino derivative 11 . Alternative synthesis of compound 10 was taken place through reaction of compound 9 with malononitrile dimmer. The biological activity of the synthesized compounds was investigated. Compounds 1 , 4 , 5 , and 8 recorded high activities against Gram positive bacteria (S. aureus). Structures of the new synthesized compounds were elucidated by elemental analysis and spectral data.     

Multicomponent reaction of conjugated enynones with malononitrile and sodium alkoxides: Complex reaction mechanism of the formation of pyridine derivatives

Reaction of conjugated enynones,1,5-diarylpent-2-en-4-yn-1-ones, with malononitrile and sodium alkoxides in the corresponding alcohols at room temperature for 3–23 h results in the formation of two types of compounds (E)-/(Z)-6-aryl-4-(2-arylethenyl)-2-alkoxypyridine-3-carbonitriles (substituted nicotinonitriles), as the major reaction products in yields up to ca. 40–80%, and 6-aryl-4-arylethynyl-2-alkoxypyridines, as the minor reaction products in yields of 5–17%. Plausible mechanism of this complex and multistep reaction is discussed. The obtained pyridines possess fluorescent properties.     

Efficient one-pot three-component method for the synthesis of highly fluorescent coumarin-containing 3,5-disubstituted-2,6-dicyanoaniline derivatives under microwave irradiation

A simple and concise approach to the synthesis of coumarin-containing highly fluorescent asymmetric/symmetric 3,5-diaryl/heteroaryl-2,6-dicyanoaniline derivatives are reported. The compounds were synthesized through base catalyzed three-component one-pot synthesis reaction of 2-(1-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)ethylidene)malononitrile, aliphatic, aromatic/heteroaromatic aldehydes, and malononitrile in solvent-free reaction medium, catalyzed by piperidine under microwave irradiation method. The reaction gave the novel, highly fluorescent coumarin-containing 3,5-disubstituted-2,6-dicyanoaniline derivatives in good yields at 300?W, 80?°C in 2?min. This method provides several advantages; such as shorter reaction time, environmental friendliness, simple workup procedure, lower energy consumption and, generally, good yields with high purity. In addition, the synthesized compounds are fluorescently active dyes even in day light, except for compounds including nitro substituent, and show maximum absorption wavelengths (λ_abs.max) in the visible region in DMSO at room temperature. Thermal properties of all the synthesized compounds were also evaluated with thermal gravimetric analysis for usability as optic dye. Optical and thermal screening studies of the compounds showed that the dyes have excellent photophysical and thermal stability properties.     

Visible-light-induced novel cyclization of 2-(2-(arylethynyl)benzylidene)-malononitrile derivatives with 2,6-di(tert-butyl)-4-methylphenol to bridged spirocyclic compounds

A green and highly efficient strategy for the preparation of bridged spirocyclic compounds via visible-light-induced cyclization of 2-(2-(arylethynyl)benzylidene)malononitrile derivatives with 2,6-di(tert-butyl)-4-methylphenol (BHT) at room temperature was developed. The photoinduced radical reactions generated the corresponding products in good yields under simple and mild reaction conditions.     

4-(4-β-D-吡喃阿洛糖苷-苯基)-2-芳基-5-氰基-6-甲氧基吡啶的合成及镇静活性研究

以豆腐果苷为原料,与4-取代苯乙酮发生Schmidt-Claisen反应,得到一系列查儿酮结构的E-4-β-D-吡喃阿洛糖苷-苯乙烯基-4-取代苯乙酮衍生物3a-3h,其中3c、3e、3f为新化合物。 3a-3h在甲醇钠存在下,与1,3－丙二氰发生1,4-Michael加成,经关环、重排、氧化,得到4-(4-β-D-吡喃阿洛糖苷-苯基)-2-芳基-5-氰基-6-甲氧基吡啶系列豆腐果苷衍生物10a-10h,联氨催化还原10e而得到10i。共获得十二个未见文献报道的新化合物,其结构经1H NMR、IR和HRMS确证,并进行了药理活性筛选,结果表明,部分化合物具有比母体化合物更好的镇静催眠活性。同时,本文对Schmidt-Claisen反应存在的主要副反应进行了分析;对查儿酮与1,3－丙二氰在甲醇钠存在下反应生成吡啶衍生物反应机理进行了推导,提出了氧化脱氢形成吡啶的新机理。     

Synthesis and study of the fluorescent behavior of 3-pyridinecarbonitriles

Abstract  

A series of (2E)-3-(1-chloro-6-methoxy-3,4-dihydronaphthalen-2-yl)-1-(4-aryl)prop-2-en-1-ones (chalcones) have been synthesized by a new synthetic route. The 3-pyridinecarbonitrile derivatives were synthesized by the Michael reaction of malononitrile (in base) and aroylacetonitriles (in acid) with chalcones in one pot. The fluorescent properties and quantum yields of these compounds were studied.     

New chromophores based on 2-(4-vinylchromen-2-ylidene)malononitrile and 2-(2-vinylchromen-4-ylidene)malononitrile

New derivatives of 2-(4-vinylchromen-2-ylidene)malononitrile and 2-(2-vinylchromen-4-ylidene)malononitrile were synthesized using the Knoevenagel reaction of 2-(4-methyl-chromen-2-ylidene)malononitrile and 2-(2-methylchromen-4-ylidene)malononitrile, respectively, with the participation of [1-(2-n-butoxyethyl)-2,2,4,7-tetramethyl-1,2,3,4-tetrahydroquinolin-6-yl)]-carbaldehyde. First hyperpolarizability (β) was calculated for the obtained compounds using the M05-2X functional and 6-31+G (d) basis. Optical properties and solvatochromism in solvents of different polarity (toluene, 1,4-dioxane, chlorobenzene, dichloromethane, DMF, and ethanol) were also investigated.

     

Pseudo four-component reaction of salicylaldehydes and cyclic ketones with two molecules of malononitrile: A facile and efficient way to synthesize 4-[2-(dicyanomethylene)cyclic or heterocyclic]-2-amino-4H-chromenes

A new type of catalytic cascade pseudo four-component reaction has been found. The simple and facile pseudo four-component reaction of salicylaldehydes and cyclic or heterocyclic ketones with two molecules of malononitrile catalyzed by sodium acetate at ambient temperature results in the formation of 4-substituted 2-amino-4H-chromenes in 70–90% yields. Thus, a new simple and efficient ‘one-pot’ method to synthesize substituted 2-amino-4H-chromenes was found directly from such reasonable starting compounds as salicylaldehydes, cyclic or heterocyclic ketones and malononitrile.     

Solvent-free cascade reaction: direct multicomponent assembling of 2-amino-4H-chromene scaffold from salicylaldehyde, malononitrile or cyanoacetate and nitroalkanes

The new type of solvent-free cascade reaction was found: the direct heating of the mixture of salicylaldehyde, malononitrile or cyanoacetate and nitroalkanes at 60 °C in the presence of catalytic amounts of KF or NaOAc results in the formation of 2-amino-4-(1-nitroalkyl)-4H-chromene-3-carbonitriles or methyl 2-amino-4-(1-nitroalkyl)-4H-chromene-3-carboxylates in 80-90% yields. Thus, the new simple and efficient solvent-free ‘one-pot’ way to substituted medicinally privileged 2-amino-4H-chromene scaffold was found directly from such simple and reasonable starting compounds as salicylaldehyde, malononitrile or cyanoacetate and nitroalkanes.     

Efficient and Green Method for the Synthesis of Highly Substituted Cyclohexadiene Derivatives in Aqueous Media

Three-component reaction of aromatic aldehyde, malononitrile, and 2-(1-(3-chlorophenyl)propylidene)malononitrile in aqueous media catalyzed by tetraethylbenzylammonium chloride (TEBAC) at 90 °C gave 2-amino-6-(3-chlorophenyl)-5-methyl-4-arylcyclohexa-1,5-diene-1,3,3-tricarbonitrile derivatives. The structure of 4e was further confirmed by x-ray diffraction. This three-component reaction had the advantages of green solvent, good yield, and operational simplicity.     

A highly diastereoselective five-component synthesis of 1-(alkylimino)-5,5-dicyano-3a-aryloctahydro-3-oxacyclobuta[cd]pentalene-1a,2,5a,5b(2H,3aH)-tetracarboxylates

A novel one-pot, five-component synthesis of 1-(alkylimino)-5,5-dicyano-3a-aryloctahydro-3-oxacyclobuta[cd]pentalene-1a,2,5a,5b(2H,3aH)-tetracarboxylates is described. A mixture of phenacyl bromide, malononitrile, isocyanide, and two equivalents of a dialkyl acetylenedicarboxylate undergoes a novel 1:1:1:2 addition reaction at ambient temperature in absolute ethanol to produce diastereoselectively the title compounds in good yields.     

A three component one-pot synthesis of N-amino-2-pyridone derivatives catalyzed by KF-Al2O3

Synthesis of 1,6-diamino-4-phenyl-3,5-dicyano-2-pyridone derivatives via a one-pot, three-component reaction of aryl aldehydes, malononitrile, and cyanoacetic hydrazide at room temperature using KF-Al₂O₃ as a recyclable catalyst have been developed. The reaction proceeds through the initial Knoevenagel condensation between aldehyde and malononitrile in the presence of KF-Al₂O₃ to form the benzylidene derivative which then undergoes Michael addition with cyanoacetic hydrazide followed by intramolecular cyclization of the resulting intermediate to produce the N-amino-2-pyridones in good to excellent yields. The structure of the synthesized compounds were characterized and established on the basis of their spectral data analysis and single-crystal XRD analysis.     

The reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with dimethylsulfonium dicyanomethylide: an improved synthesis of (4-chloro-1,2,3-dithiazolylidene)malononitrile

4,5-Dichloro-1,2,3-dithiazolium chloride 6 (Appel salt) reacts with dimethylsulfonium dicyanomethylide 11 to give 5-(4-chloro-1,2,3-dithiazolylidene)malononitrile 1 and a mixture of E/Z isomers of 3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-3-chloro-2-(methylthio)acrylonitrile 13. The reaction of 4-chloro-5H-1,2,3-dithiazole-5-thione 10 with dimethylsulfonium dicyanomethylide 11 gives (dithiazolylidene)malononitrile 1 in 92% yield. All new compounds are fully characterised and rational mechanisms are proposed for the formation of all key compounds.     

Efficient synthesis of 3H-imidazo[4,5-b]pyridines from malononitrile and 5-amino-4-(cyanoformimidoyl)imidazoles

1-Aryl-5-amino-4-(cyanoformimidoyl)imidazoles 2 were reacted with malononitrile under mild experimental conditions and led to 3-aryl-5,7-diamino-6-cyano-3H-imidazo[4,5-b]pyridines 5, when the reaction was carried out in the presence of DBU, or to 3-aryl-5-amino-6,7-dicyano-3H-imidazo[4,5-b]pyridines 3, in its absence. Both reactions evolved from the adduct formed by nucleophilic attack of the malononitrile anion to the carbon of the cyanoformimidoyl substituent. A 5-amino-1-aryl-4-(1-amino-2,2-dicyanovinyl)imidazole 4 was isolated when this reaction was carried out in the presence of DBU. The structure of compound 4 was confirmed by spectroscopic methods and by reaction with triethyl orthoformate and with acetic anhydride, leading respectively to 9-aryl-6-(cyanomethylidene)purines 11 and 12. Imidazole 2b was also reacted with ethyl acetoacetate, a carbon acid with a pK(a) comparable to that of malononitrile. Similar reaction conditions were used and the product isolated was a 6-carbamoyl-1,2-dihydropurine 10, showing that a different mechanism was operating in this case.     

One‐Pot Synthesis of Pyrido[2,3‐d]Pyrimidine‐2‐Thiones and a Study of Their Reactivity Towards Some Reagents

A series of pyrido[2,3‐d]pyrimidine‐2‐thione derivatives ( 5a‐c ) were synthesized by the one‐pot reaction of the appropriate aldehyde, malononitrile and 6‐aminothiouracil ( 1 ) in dimethyl‐formamide. The same compounds were also synthesized by the reaction of arylidine malononitrile ( 4 ) with 6‐aminothiouracil ( 1 ). Moreover, the chemical behaviour of the produced pyrimidines towards different reagents was studied.     

Sodium acetate catalyzed tandem Knoevenagel–Michael multicomponent reaction of aldehydes, 2-pyrazolin-5-ones,and cyano-functionalized C–H acids: Facile and efficient way to 3-(5-hydroxypyrazol-4-yl)-3-aryl-propionitriles

Sodium acetate catalyzed multicomponent reaction of aryl aldehydes, 2-pyrazolin-5-ones, and malononitrile or alkyl cyanoacetates in alcohols results in the formation of substituted 3-(5-hydroxy-3-methylpyrazol-4-yl)-3-arylpropionitriles in 80–99% yields. The developed efficient catalytic approach to the substituted 3-(5-hydroxy-3-methylpyrazol-4-yl)-3-arylpropionitriles – the promising compounds for human cardiovascular diseases therapy and different biomedical applications – is beneficial from the viewpoint of diversity-oriented large-scale processes and represents facile, efficient and environmentally benign synthetic concept for multicomponent reactions strategy.     

Novel Schiff bases–based thiophenes: Design,synthesis and biological evaluation

2-amino-5-(3-fluoro-4-methoxyphenyl)thiophene-3-carbonitrile derivatives have been synthesized from 1-(3-fluoro-4-methoxyphenyl)ethanone, malononitrile, mild base, and sulfur powder using the Gewald method through a multistep reaction sequence. The structures of newly synthesized compounds were established on the basis of their elemental analyses, IR, ¹H NMR, ¹³C NMR, and mass spectral data, and then synthesized compounds were screened for their in vitro antimicrobial activity. Among them, derivatives 3b (thiphene), 3f (pyrazole), and 3d (halogen) showed good activity and remaining derivatives exhibited moderate activity.     

Synthesis of Functionalized (2-Thienylcarbonyl)thiazoles and 4-(2-Thienyl)pyridines by Reaction of (2-Thienylcarbonyl)thioacetanilides and their Enamine Derivatives

Summary. The condensation of two molecules of 2-(2-thienylcarbonyl)thioacetanilides catalyzed by piperidine yielded thiazole derivatives as confirmed by X-ray crystal structure analysis. The reaction of malononitrile with 3-morpholino-3-(2-thienyl)acrylic acid thioanilides furnished 6-amino-1-aryl-4-(2-thienyl)-1,2-dihydro-2-thioxopyridine-5-carbonitriles. A similar reaction of malononitrile with 3-morpholino-3-(2-thienyl)acrylic acid anilides provided 2-oxopyridine-5-carbonitriles.     

New approaches to the synthesis of functionally substituted pyrido[3′,2′:4,5]thieno[3,2-b]pyridines and the structure of the products obtained

Substituted pyrido,[3',2':4,5]thieno[3,2-b]pyndines were obtained by the reaction of 3-amino-2-benzoylthieno [2,3-b]pyridines with malononitrile and the reaction of 3-cyanopyridine-2(IH)-thiones with 2-aryl-3-bromo-I,I-dicyanopropene. 2-Amino-4-(4-bromophenyl)-7, 9-dimethyl-3-cyanopyrido [3',2':4,5]thieno[3, 2-b]-pyridine was used for the synthesis of a derivative of pyrido[3",2":4', 5']thieno[2',3':5,6]pyrido[2,3-d]-pyrimidine. The structure of these compounds was confirmed by spectral data and x-ray diffraction structural analysis.Deceased.     

6-溴-N-芳基噻吩[2,3-d]并嘧啶-4-胺类化合物的合成新方法

研究了6-溴-N-[3-氯-4-(3-氟苄氧基)苯基]噻吩[2,3-d]并嘧啶-4-胺的合成新方法.以相对廉价的2,5-二羟基-1,4-二噻烷和丙二腈为原料,依次通过Gewald反应、芳环溴代、缩合、环合以及Dimroth重排四步反应得到目标产物6-溴-N-[3-氯-4-(3-氟苄氧基)苯基]噻吩[2,3-d]并嘧啶-4-胺,总产率为56.9%.用1H NMR,IR,MS和HRMS对产物进行了结构表征.并应用该方法,合成了一系列的6-溴-N-芳基噻吩[2,3-d]并嘧啶-4-胺类化合物.研究表明该方法具有原料易得、操作简便、收率较高,且产物容易分离纯化等优点.