Design and synthesis of new series of 3-cyanopyridine and pyrazolopyridine derivatives

Reaction of 3-cyano-4,6-dimethyl-2-pyridone with ethyl chloroacetate afforded ethyl 2-([3-cyano-4,6-dimethylpyridin-2-yl]oxy)acetate 2 and ethyl 2-(3-cyano-4,6-dimethyl-2-oxopyridin-1[2H]-yl)acetate 3 , the reaction product yield depend on the reaction condition (potassium carbonate concentration and reaction time). These compounds used as precursors to synthesize pyridine derivatives 4 , 6-10 , 15, 17-20 , furopyridines 5, 16 , pyrazolopyridine 12 , pyridopyrazolopyrimidines 14a,b . The structure of the newly synthesized compounds was confirmed by spectral data (IR, NMR, and mass spectra) and elemental analysis.     

Novel Triazole-, Oxadiazole-, and Pyrazole-Nicotinonitrile Hybrids: Synthesis,DFT Study,Molecular Docking,and Antimicrobial Activity

Russian Journal of General Chemistry - The present study is devoted to functionalization of ethyl 2-{[3-cyano-6-(4-cyanophenyl)-4-(2,4-dichlorophenyl)pyridin-2-yl]oxy}acetate (1) by triazole-,...     

A new Oxyma derivative for nonracemizable amide-forming reactions in water

An Oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-cyano-2-(hydroxyimino)acetate (2), displayed remarkable physicochemical properties as a peptide-coupling additive for peptide-forming reactions in water. Short peptides to oligopeptides could be synthesized by using 2, EDCI, and NaHCO(3) in water without measurable racemization. Significantly, a simple basic and acidic aqueous workup procedure can remove all reagents utilized in the reactions to afford only coupling products in consistently excellent yields.     

Highly diastereoselective multicomponent synthesis of polysubstituted 2-hydroxy-2-trifluoromethylpiperidineswith four and five stereogenic centers

The Michael–Mannich cascade cyclization of cyano olefins, ethyl 4,4,4-trifluoro-3-oxobutanoate, aromatic aldehydes and ammonium acetate provides convenient stereoselective formation of ethyl 5,5-dicyano-4,6-diaryl-2-hydroxy-2-(trifluoromethyl)piperidine-3-carboxylates with fourstereogenic centers and dialkyl 4,6-diaryl-5-cyano-2-hydroxy-2-(trifluoromethyl)piperidine-3,5-dicarboxylates with five stereogenic centers. Ammonium acetate plays dual role, acting as a base and as a nitrogen source.     

Efficient syntheses of ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate

Ethyl 2-chloroacetoacetate and its 4-chloro isomer react with cyanoacetamide in the presence of the mild, nonnucleophilic base, triethylamine under stoichiometric conditions to give high yields of ethyl 4-cyano-2-hydroxy-2-methyl-5-oxopyrrolidine-3-carboxylate and ethyl (4-cyano-2-hydroxy-5-oxopyrrolidin-2-yl)acetate, respectively. These, under acid-catalyzed dehydration conditions, afforded ethyl 4-cyano-5-hydroxy-2-methyl-1H-pyrrole-3-carboxylate and ethyl (2Z)-(4-cyano-5-oxopyrrolidin-2-ylidene)ethanoate, respectively. Similarly, the 4-chloro isomer reacted with ethyl cyanoacetate to give the novel product, diethyl 2-cyano-4-oxohexanedioate. The use of triethylamine enables access to a whole new library of pyrrole derivatives from easily accessible, commercially available starting materials. The reactions described in this Letter enable access to libraries of important pyrrole systems in any of the isotopically enriched forms.     

Kinetic resolution of ketone cyanohydrin acetates with a microbial enzyme

Incubation of d1-1-cyano-1-methylalkyl (or alkenyl) acetates (methyl ketone cyanohydrin acetates) with cells of IAM 4682 afforded optically active acetates and the corresponding ketones via asymmetric hydrolysis. Resulting (S)-2-cyano-2-undecyl acetate was converted to the aminofuranone derivative without losing its optical purity.     

Synthesis of 2H-Thiopyrans by Rhodium(II) Acetate-Catalyzed Reaction of 4-Amino-2,5-dihydro-3-thiophenecarbonitriles with a-Diazocarbonyl Compounds II [1]

Summary.  The reaction of 4-amino-2,5-dihydro-2- and -5-methyl-3-thiophenecarbonitriles with α-diazocarbonyl compounds in the presence of rhodium(II) acetate gave regioselectively 4-cyano-2H-thiopyrans (C₂-S insertion) in moderate to good yields; 5-cyano-2H-thiopyrans (C₅-S insertion) were not isolated. The starting compounds were synthesized by reaction of tetrahydro-2- and -5-methyl-4-oxo-3-thiophenecarbonitriles with morpholine, piperidine, and pyrrolidine in the presence of formic acid in ethanol. Received November 13, 2000. Accepted December 12, 2000     

Abnormal Beckmann rearrangement in 23-hydroxyiminodiosgenin acetate

A new transformation of the spiroketal side chain of diosgenin is reported: treatment of 23-hydroxyiminodiosgenin acetate with phosphorous oxychloride in pyridine produced an abnormal Beckmann rearrangement directing to the cleavage of the spiroketal side chain and generating 23,24-bisnorchol-5-enic skeletons: (2′R)-3′-cyano-2′-methylpropyl 3β-acetoxy-16α-chloro-23,24-bisnorchol-5-en-22-oate as the main product, and small amounts of (2′R)-3′-cyano-2′-methylpropyl 3β-acetoxy-16β-hydroxy-23,24-bisnorchol-5-en-22-oate and vespertilin acetate.     

Synthesis and Optical Properties of Ethyl 2-Cyano-2-[3,4-dicyanopyridin-2(1H)-ylidene]acetate Derivatives

Russian Journal of Organic Chemistry - Derivatives of ethyl 2-cyano-2-[3,4-dicyanopyridin-2(1H)-ylidene]acetate have been synthesized by reaction of 2-chloropyridine-3,4-dicarbonitriles with ethyl...     

Oxidative cyclization of 3-oxopropanenitriles with α,β-unsaturated amides by manganese(III) acetate. Regio- and stereoselective synthesis of 4-cyano-2,3-dihydrofuran-3-carboxamides

4-Cyano-2,3-dihydrofuran-3-carboxamides were obtained from the oxidative cyclization of 3-oxopropanenitriles with unsaturated amides using manganese(III) acetate. Treatment of 3-oxopropanenitriles with (2E)-3-(5-methyl-2-furyl)acrylamide and (2E)-3-(2-thienyl)acrylamide gave 2-(5-methyl-2-furyl) and 2-(2-thienyl) substituted 4-cyano-2,3-dihydrofuran-3-carboxamides in moderate yields, respectively. However, (2E)-3-(2-furyl)acrylamide and (2E)-3-phenylacrylamide did not produce any product under the same conditions. On the other hand, reaction of a dienamide such as (2E,4E)-5-phenylpenta-2,4-dienamide with 3-oxopropanenitriles gave diastereomeric mixtures of 2-(2-vinylphenyl)-4-cyano-2,3-dihydrofuran-3-carboxamides. Mechanisms are proposed for the formation of all of these compounds.     

Reaction of 3-acetonyl-5-cyano-1,2,4-thiadiazole with phenylhydrazine hydrochlorides: indolization and phenylpyrazolation

Treatment of 3-acetonyl-5-cyano-1,2,4-thiadiazole (1) with 4-methyl or 4-methoxyphenylhydrazine hydrochloride provided 5-cyano-3-(2,5-dimethylindol-3-yl)-1,2,4-thiadiazole (2) or 5-cyano-3-(5-methoxy-2-methylindol-3-yl)-1,2,4-thiadiazole (3) as the sole product, respectively. In contrast, treatment of 1 with phenylhydrazine hydrochloride resulted in the formation of 5-cyano-3-(2-methylindol-3-yl)-1,2,4-thiadiazole (4) and the unexpected 5-cyano-3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-1,2,4-thiadiazole (5). In a similar manner, when 1 was treated with 4-chlorophenylhydrazine hydrochloride, indolization was suppressed by phenylpyrazolation giving rise to 5-cyano-3-(5-chloro-2-methylindol-3-yl)-1,2,4-thiadiazole (6) and 5-cyano-3-[1-(4-chlorophenyl)-3,5-dimethylpyrazol-4-yl]-1,2,4-thia diazole (7). The reaction mechanism is discussed. Compounds 4, 5 and 6 exhibited weak antimicrobial activity against Helicobacter pylori.     

2-氨基-3-氰基-4-芳基-6-二茂铁基吡啶的合成

以乙酰二茂铁、芳香醛、丙二腈为原料, 在乙酸铵存在下以乙醇为溶剂, 采用一锅煮的方法合成了8个2-氨基-3-氰基-4-芳基-6-二茂铁基吡啶化合物, 产率中等. 并通过X射线衍射分析确证产物4e的结构.     

Synthesis and molecular structure of ethyl [N-tosyl-(R)-prolyloxy]-2(S)-[4-cyano-8,8-ethylenedioxy-5-oxo-5,6,7,8-tetrahydroindolizin-3-yl] acetate, a key intermediate in the total synthesis of (20S)-camptothecins

The synthesis of optically active [N-tosyl-(R)-prolyloxy]-2(S)-[4-cyano-8,8-ethylenedioxy-5-oxo-5,6,7,8-tetrahydroindolizin-3-yl] acetate (4a), a key intermediate for the total asymmetric synthesis of 20(S)-camptothecin anticancer drugs, is described. Its structure was characterized by 2D-NMR techniques and the absolute configuration was further confirmed for the first time by X-ray crystal structure analysis.     

Ring transformations of 4H-pyrans. Pyridines from 2-amino-4H-pyrans

Ring transformations of 4H-pyrans into pyridines are reported. Treatment of 2-amino-4,6-diaryl-3,5-dicyano-4H-pyrans (I) with nitrosylsulfuric acid brings about their transformation into 3,5-dicyano-4,6-diaryl-2-pyridones (VI) which can also be obtained from α-benzoylcinnamonitriles (IX) and cyanoacetamide. Similarly, 2-amino-4,6-diaryl-5-carbethoxy-3-cyano-4H-pyrans (II) lead to 4,6-diaryl-5-carbethoxy-3-cyano-2-pyridones (VII). Treatment of both series of pyrans with sulfuric acid results in the formation of the corresponding 3,4-dihydro-2-pyridones (IV and V). Reaction of pyrans II with ammonium acetate in acetic acid yields 2-amino-4,6-diaryl-5-carbethoxy-3-cyanopyridines (XII). Pyrans I undergo an entirely different type of reaction upon treatment with this reagent leading to 2,4,6-triaryl-3,5-dicyano-1,4-dihydropyridines (XV).     

Studies on the metabolism of 4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3- diphenylpropyl ester hydrochloride in rat bile by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry

4-Methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride (TM208) is a newly synthesized compound which has shown excellent in vivo and in vitro anticancer activity and low toxicity. In the present study, the major metabolites of TM208 in rat bile were studied by high-performance liquid chromatography/tandem mass spectrometry with an electrospray ionization (ESI) interface. It was demonstrated that TM208 was extensively metabolized in rat bile and nine metabolites (M1-M9) were definitely or tentatively identified: (2-aminoethyl)dithiocarbamic acid 3-cyano-3,3-diphenylpropyl ester (M1), (2-methylaminoethyl)dithiocarbamic acid 3-cyano-3,3-diphenylpropyl ester (M2), 4-[(4-methylpiperazin-1-yl)thioxomethanesulfinyl]-2,2-diphenylbutyronitrile (M3), 4-methylpiperazine-1-carbodithioic acid 3-cyano-3-(4-hydroxyphenyl)-3-phenylpropyl ester(M4), the sulfine of (4-methylpiperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester) (M5), 4-methylpiperazine-1-carbothioic acid S-(3-cyano-3,3-diphenylpropyl) ester (M6), piperazine-1-carbodithioic acid 3-cyano-3,3-diphenylpropyl ester (M7), 4-hydroxymethylpiperazine-1-carbothioic acid S-(3-cyano-3,3-diphenylpropyl) ester (M8) and the sulfine of [4-methylpiperazine-1-carbodithioic acid 3-cyano-3-(4-hydroxyphenyl)-3-phenylpropyl ester] (M9).     

Novel oxidations of 1,3-disubstituted indoles

A study of oxidation versus nitration of 1,3-disubstituted indole derivatives with nitric acid in acetic acid was carried out. Oxidation of methyl and ethyl 2-cyano-2-(1-alkoxycarbonyl-1H-indol-3-yl)acetates 1 and 2 under the above conditions gave rise to novel functionalized 2-hydroxyindolenines as single products possessing the Z-configuration, 8 and 10 , respectively. The structure of 10 was determined by an X-ray analysis. In contrast, 1-methoxycarbonyl-1H-indol-3-acetonitrile ( 3 ) was nitrated to the corresponding 6-nitroindole derivative 11 , whereas the reaction of ethyl 2-cyano-2-(1-methyl-1H-indol-3-yl)acetate ( 4 ) with nitric acid effected an oxidative nitration to provide the corresponding ethyl Z-5-nitroisatyliene cyanoacetate ( 12 ), which in solution isomerized to the E isomer.     

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.     

Total, asymmetric synthesis of (1r-1-c-(6′-amino-7′h-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy-d-erythro-pentitol.

The “naked sugar” (+)-(1R,2R,4R)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((+)-3) was converted in ten synthetic steps into the new C-nucleoside (1R)-1-C-(6′-amino-7′H-purin-8′-yl)-1,4-anhydro-3-azido-2,3-dideoxy- D-erythro-pentitol ((+)-2) in 19% overall yield.     

Synthesis of 3- and 5-amino-5-(3)-(pyrrol-2-yl)isoxazoles

5-Amino-3-(pyrrol-2-yl)isoxazoles were selectively prepared by the reaction of 2-(2,2-dicyano-1-ethylthioethenyl)pyrroles with hydroxylamine in methanol. Under analogous conditions, 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl) pyrroles with hydroxylamine gave 5-aminoisoxazoles and their structural isomers, 3-aminoisoxazoles (3-5% yield). The latter were selectively prepared by reacting 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles with hydroxylamine in the presence of aqueous NaOH and from the products of intramolecular cyclization of 2-(2-carbamoyl-2-cyano-1-ethylthioethenyl)pyrroles, 1-ethylthio-3-iminopyrrolizines and hydroxylamine.     

2-氰基-3-N-烷氨基-3-(N-2-氟苯乙氨基)丙烯酸乙酯类化合物的合成及生物活性研究

把由氰基乙酸乙酯、二硫化碳、硫酸二甲酯在乙醇钠作用下反应得到的2-氰基.3,3-二甲硫基丙烯酸乙酯中间体用邻氟苯乙胺胺化,再和甲胺等烷胺进行胺化反应,合成了含氟2-氰基丙烯酸乙酯类化合物.结构经元素分析、IR、1H NMR、13C NMR等证实,抗烟草花叶病毒(TMV)生物活性的初步测定表明,所合成的化合物有一定抗TMV活性.