Synthesis of Some Novel Heterocyclic Xylidinyl Amines and Carboxamides

The xylidines 1a , 1b undergo condensation with ethyl cyanoacetate 2 and ethyl benzoyl acetate 15 to afford the cyano acetanilides 3a , 3b and the β‐diketones 16a , 16b , respectively. Compounds 3a , 3b react with hydrazine and phenyl hydrazine to afford the azine‐bis derivatives 5a , 5b and 7a , 7b , whereas 16a , 16b react with the same reagents to afford the pyrazolyl amine derivatives 17a , 17b and 18a , 18b , respectively. Compounds 3a , 3b react also with dimethylformamide dimethylacetal to afford the enaminonitriles 8a , 8b , whereas 16a , 16b react with the same reagent to afford only the enaminone 19b . The enaminonitriles 8a , 8b react with hydrazine and phenyl hydrazine to afford also the azine‐bis derivatives 11a , 11b and 14a , 14b , respectively.     

Synthesis of Dibutadienyl Piperazines, 1,1-Dithio and 1,4-Dithio Substituted Dienes from Nitrodienes

Nitrodiene 1a , 1b reacted with 1,4-dithiolbutan and gave the heterocyclic compounds 3a , 3b . 1b gave with 1,3-acetonedithiol the compound 5b . The nitrodiene compound 1b reacted with o-dithiolbenzene ( 6 ) and yielded the ketene dithioacetal ( 7b ). Heterocyclic compounds 11a , 11b , 12a , and 12b were prepared from the reactions of 9a with 2,2'-oxydiethanethiol. The compounds 9a , 9b were prepared from 2-nitropentachloro-1,3-butadiene and alkylthiols ( 8a , 8b ). Mono(thio) substituted diene compound 9b gave dibutadienyl piperazine 14b with piperazine in diethylether.     

Synthesis, properties, and redox behavior of di(1-azulenyl)(2- and 3-thienyl)methyl cations and dications composed of two di(1-azulenyl)methylium units connected with 2,5-thiophenediyl and 2,5-thienothiophenediyl spacers

The titled stable monocations, di(1-azulenyl)(2- and 3-thienyl)methyl cations 7a,b and 8a,b and dications composed of two di(1-azulenyl)methylium units connected with 2,5-thiophenediyl and 2,5-thieno[3,2-b]thiophenediyl spacers 9a,b and 10a,b were prepared by hydride abstraction of the corresponding methane derivatives. These mono- and dications 7a,b, 8a,b, 9a,b, and 10a,b showed high stability with large pK(R)+ values. The values of monocations 7a,b and 8a,b were 11.2-11.8 +/- 0.1 and 11.4-12.4 +/- 0.1, respectively. Two cation units in dications 9a,b and 10a,b were neutralized via one step at the pH of 11.1-11.7 +/- 0.1, which corresponds to the average of the pK(R)+ values of the dications and half-neutralized monocations. Electrochemical behavior of 7a,b, 8a,b, 9a,b, and 10a,b was examined by cyclic voltammetry (CV). Formation of the thienoquinoid products 18a,b and 19a,b from 9a,b and 10a,b was characterized by UV-vis spectroscopy under electrochemical reduction conditions. Chemical reduction of 9a,b and 10a,b with Zn powder in acetonitrile afforded 18a,b and 19a,b as deep-colored crystals, which exhibited rather high electron-donating ability.     

An approach to biologically important S‐heterocycles,dithiocarbamyls, and their relevant phosphono derivatives

The feasibility of insertions of carbanions between two sulfur atoms has been reported when 5‐(4‐chlorophenyl)‐4‐cyano‐1,2‐dithiol‐3‐thione ( 1 ) and tetramethylthiuram disulfide ( 17 ) were allowed to react with unsaturated 2a,b and active phosphonium salts 11a,b . The reactions afforded, mainly, 1,3‐dithiols 4a,b and 14a,b together with substituted thiophenes 10a,b and 16a,b . Reactions of 1 and 17 with α‐alkylthiomethyl phosphonates 24a,b afforded the phosphonates 25a,b and 26a,b , respectively.     

The Utility of Carbon Disulphide and Lawesson's Reagent for Synthesis of Different Fused Heterocycles for Antimicrobial Evaluation

Hexahydroquinolines 1a , 1b reacted with carbon disulphide in different conditions to yield the corresponding adducts 2a , 2b and 3a , 3b . Carrying out the same reactions in acetone as solvent produced the modified new products 4a , 4b . The interaction of pyrazolopyridine derivatives 5a , 5b , 5c , 5d with carbon disulphide under the same previous conditions furnished the isolated products 6a , 6b , 6c , 6d , 7a , 7b , 7c , 7d , and 8a , 8b , 8c , 8d . Studying the behavior of 1a , 1b or 5a , 5b , 5c , 5d toward Lawesson's reagent (LR) formed the final adducts 11a , 11b or 12a , 12b , 12c , 12d . The structure of synthesized compounds was confirmed with the spectroscopic and microanalytical data. The biological activities of 2a , 4a , 4b , 7a , 7c , 8d , 11a , 11b , 12b , and 12c were tested for antimicrobial evaluation.     

Synthesis and Stereochemistry of Thiapyranothiazoles as Diels-Alder Adducts Obtained from Spirodimers of 1,3-Thiazolidines with Cinnamic Acid and its Ester

Thiation of 5-Arylmethylene-3-phenyl-2-thioxo-1,3-thiazolidin-4-ones ( 1a and b ) with either P 4 S 10 1 or Lawesson's reagent 2 , gave mainly the spirodimers 3'phenyl-2'-thoxo-1',3'-thiazolidino[2,3-d]-spiro[6',7' diaryl-5,5'-perhydrothiapyrano]-3-phenyl-1,3-thiazolidin-4-thiones ( 3a and b ) beside, 5-(3-bromo-4-methoxyphenylmethylene)-3-phenyl-1,3-thiazolidin-2,4-dithione ( 2b ) as a mixture with 3b . 2b was allowed to react with ethyl cinnamate as a dienophile producing 4b and 5b . Moreover, prolonged heating of either 3b or 3a with ethyl cinnamate gave a mixture contains 40% of 4b and a mixture of 4a and 5a respectively. Furthermore, the dimer 3b reacted with cinnamic acid in glacial acetic acid to give the Diels-Alder-adduct 6b and 7b . Structures and stereo-chemistry of obtained compounds have been studied.     

The reaction of organophosphorus reagents with substituted‐1,3‐diphenylpropanetrione: New synthesis of azaphospholene derivatives

The reaction of 1,3‐diphenyl‐2‐(phenylimino)‐3‐(ylidenemethyl‐acetate)‐1‐propanone (5) with trisdialkylaminophosphines (6a,b) in refluxing toluene afforded the new oxazaphospholene products (7a–b) . On the other hand, the cyclic azaphospholene adducts 8a–b were isolated from the reaction of 5 with 6a,b without solvent. Trialkyl phosphites 1b–c react with compound 5 to give the respective dialkyl phosphate products (9a,b) . Moreover, trisdialkylaminophosphines (6a,b) react with 2a and 2b to give the dipolar adducts 10a,b and the phosphonate products 11a,b, respectively. Possible reaction mechanisms are considered, and the structural assignments are based on compatible analytical and spectroscopic results. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:511–517, 2001     

2‐Bromo‐1‐(1H‐pyrazol‐4‐yl)ethanone: Versatile Precursor for Novel Mono‐ and Bis[pyrazolylthiazoles]

The synthesis of novel bis(thiazoles) 20a , 20b , 20c and 23a , 23b , 23c is reported. Thus, reaction of 2‐bromo‐1‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)ethanone ( 6 ) with the corresponding thioamide derivatives 7a , 7b , in refluxing EtOH in the presence of triethylamine, afforded 4‐pyrazolylthiazoles 8a , 8b in good yields. On the other hand, the novel bis(thiazoles) 20a , 20b , 20c and 23a , 23b , 23c were obtained from the reaction of 6 with the corresponding benzaldehyde thiosemicarbazones 19a , 19b , 19c , 22a , 22b , 22c in refluxing EtOH. Compounds 19a , 19b , 19c and 22a , 22b , 22c were obtained by condensation of the corresponding bis(aldehydes) 18a , 18b , 18c and 21a , 21b , 21c with thiosemicarbazide.     

Mesoionic dimethyl derivatives of some 1,2,4-triazinones. The course of the reaction of 3,5-dimethoxy, 3-methoxy-5-methylthio, 5-methoxy-3- methylthio and 3,5-bis(methylthio)-1,2,4-triazine with methyl iodide

Treatment of 3,5-dimethoxy-1,2,4-triazine ( 1a ) with methyl iodide was found to give depending on the reaction time triazinium iodide 2a , triaziniumolates 4a and 6a as well as methoxytriazinones 7a and 8a . Thermolysis of 2a gave triaziniumolates 4a and 6a . Reaction of 2a , 4a or methoxytriazinone 9a with methyl iodide in acetonitrile yielded as the sole product 6a . Reaction of 3-methoxy-5-methylthio-1,2,4-tri-azine (1b ) with methyl iodide gave triazinium iodide 2b and methylthio triazinone 7b . Hydrolysis of 2a,b afforded 4a . Reaction of 5-methoxy-3-methylthio-1,2,4-triazine ( 1c ) with methyl iodide gave triazinium iodide 2c , triaziniumolate 4b , triazinium iodide 5b and triazinone 8b . Hydrolysis of 2c yielded 4b and its thermolysis gave a mixture of 4b and 5b . Reaction of 2c , 4b and triazinone 9b with methyl iodide afforded 5b . Treatment of 3,5-bis(methylthio)-1,2,4-triazine ( 1d ) with methyl iodide was found to give a mixture of N1 and N2 methiodides 2d and 3d which gave on hydrolysis 4b and 8b , respectively. Methylation of 6-methyl derivatives 1c-g gave analogous results, however the proportions of N1 methylated products were lower and the reaction rates higher in comparison to their respective lower homologues 1a,c,d . The structures of the mesoionic dimethyl derivatives were assigned from uv, ir, ¹H nmr and electron impact mass spectra. The structural assignments were eventually confirmed by quantum chemical calculations of net charge distributions, bond lengths and ipso angles of the C5?O bonds.     

Chemistry of Phosphorus Ylides. Part 37. The Reaction of Phosphonium Ylides with Indoles and Naphthofurans. Synthesis of Phosphanylidenes,Pyrans, Cyclobutenes,and Pyridazine as Antitumor Agents

The reaction of the stabilized phosphonium ylides 2a , 2b with indolinones 1a , 1b and naphthofuranone 13 afforded the corresponding propylidene and ethylidene derivatives 4a , 4b , 4c , 4d and 14a , 14b . On the other hand, the active phosphacumulenes 5a , 5b react with compounds 4a , 4b , 4c , 4d by [4 + 2]‐cycloaddition to give the stable phosphanylidene indole pyranones 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h . Although compounds 14a , 14b afforded the naphthofuropyrans 16a , 16b , 16c , 16d and triphenylphosphane. Moreover, the phosphallene ylide 7 react with compounds 4a , 4b , 4c , 4d and 14a , 14b to give phosphanylidenecyclobuteneindoline 9a , 9b , 9c , 9d and naphthalenones 18a , 18b , respectively. In addition, the naphthofuropyridazine 21 was obtained from the reaction of the hydrazone 19 and the phosphacumulene 5a . The antitumor activity of some of the new compounds was evaluated, in vitro, against colon and hepatocellular carcinoma cell lines. They showed values closed to that recorded by the reference drug Doxorubicin.     

Synthesis and antimicrobial activity of some new pyrazole, fused pyrazolo[3,4-d]-pyrimidine and pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidine derivatives

Hydrazonyl bromides 2a,b reacted with active methylene compounds (dibenzoylmethane, acetylacetone, ethyl acetoacetate, phenacyl cyanide, acetoacetanilide, ethyl cyanoacetate, cyanoacetamide and malononitrile) to afford the corresponding 1,3,4,5- tetrasubstituted pyrazole derivatives 5-12a,b. Reaction of 12a,b with formamide, formic acid and triethyl orthoformate give the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4- d]pyrimidin-4(3H)one and 5-ethoxymethylene-aminopyrazole-4-carbo-nitrile derivatives 13-15a,b, respectively. Compounds 15 a,b reacted with benzhydrazide and hydrazine hydrate to afford pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine and [4-iminopyrazolo- [3,4-d]pyrimidin-5-yl]amine derivatives 16 a,b and 17 a,b. Reactions of compounds 17 a,b with triethyl orthoformate and carbon disulfide give the corresponding pyrazolo[4,3-e]- [1,2,4]triazolo[1,5-c]pyrimidine derivatives 18a,b and 19 a,b, respectively.     

Polycondensed nitrogen heterocycles. X. 5,6,7,8-Tetrahydropyrrolo[1,2-e][1,5]benzodiazocin-7-ones. A new ring system

The synthesis of a new heterocyclic ring system is described. Condensation of 1,4-diketones 1a,b with β-alanine gave the substituted propionic acids 2a,b which upon reduction with palladium on charcoal afforded compounds 3a,b . Title compounds 4a,b were obtained by refluxing 3a,b in toluene with p-toluenesulphonic acid as catalyst.     

Desymmetrization of dichloroazaheterocycles

3,6-Dichloropyridizine 1a was converted in good yield into its mono-iodo derivative 1b when treated with a mixture of hydriodic acid and sodium iodide. Pure samples of the mono-iodo derivatives 2b, 3b and 4b could not be obtained from their corresponding dichlorinated precursors with these reagents. Compounds 1b and 4b underwent palladium catalysed Suzuki, Sonogashira and other coupling reactions.     

细胞色素b5-蛋白质相互作用研究

蛋白质-蛋白质相互作用在生命过程中发挥至关重要的作用,特别是血红素类蛋白。细胞色素b5(Cyt b5)是血红素蛋白的一个典型代表,在生物体内通过多种蛋白质-蛋白质相互作用来执行其生物功能。目前所揭示的与Cyt b5相关的蛋白质相互作用包括:细胞色素b5-细胞色素b5还原酶,细胞色素b5-细胞色素P450,细胞色素b5-细胞色素c,细胞色素b5-肌红蛋白或血红蛋白,细胞色素b5-融合蛋白(谷胱甘肽S-转移酶GST和绿色荧光蛋白GFP)和细胞色素b5-转运蛋白(蔗糖转运蛋白SUT1和山梨醇转运蛋白SOT6)等。同一蛋白能与众多不同蛋白相互作用的事实,使我们认识到某些特定蛋白的生物学重要性。另一方面,研究同一蛋白与不同蛋白质间的相互作用将会进一步加深我们对蛋白质结构与功能关系的理解,以及指导新颖蛋白的理性设计与最终应用。     

Synthesis of Some Pyrazole,Thiazole, Pyridine,and 1,3,4‐Thiadiazole Derivatives Incorporating 2‐Thiazolyl Moiety

Reaction of N‐(5‐acetyl‐4‐methylthiazol‐2‐yl)‐2‐cyanoacetamide 2 with hydrazonoyl chlorides ( 3a,b ) yielded the corresponding aminopyrazole derivatives ( 5a,b ), respectively. Reaction of 2 with α,β‐benzylidenemalononitrile derivatives 8a,b and 13a,b afforded the corresponding pyridine derivatives 12a,b and 17a,b , respectively. Treatment of 2 with phenylisothiocyanate in dimethylformamide/KOH followed by the addition of ethyl chloroacetate and the appropriate hydrazonoyl chlorides 3a,b and 27 gave the corresponding 1,3‐thiazole 21 and 1,2,4‐thiadiazole derivatives 24a,b and 30 , respectively. The newly synthesized compounds were confirmed from their elemental analyses and spectral data.     

Synthesis and Antimicrobial Activity of New Pyridothienopyrimidines and Pyridothienotriazines

5‐Acetyl‐3‐amino‐4‐aryl‐6‐methylthieno[2,3‐b]pyridine‐2‐carboxamides ( 5a,b ) were reacted with triethyl orthoformate or nitrous acid to give the corresponding pyrimidinones 6a,b and triazinones 7a,b . The reaction of 5a,b with acetic anhydride was carried out and its products were identified as a mixture of 8‐acetyl‐9‐aryl‐2,7‐dimethylpyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidine‐4(3H)‐one ( 9a,b ) and related 5‐acetyl‐4‐aryl‐3‐biacetylamino‐6‐methylthieno[2,3‐b]pyridine‐2‐carbonitrile ( 10a,b ). Reaction of 7a with some halocompounds afforded the N‐alkylated triazinones 8a‐c . Chlorination of 6a,b and 9a,b with phosphorus oxychloride produced 4‐chloropyrimidines 11a‐d which were used as precursors for the rest of the target heterocycles. Some of the prepared compounds were tested in vitro for their antimicrobial activities.     

2H-1,2,4-benzothiadiazine 1,1-dioxides 2. A condensation of 2-aminobenzenesulfonamide with chloroalkyl isothiocyanates

A reaction of 2-aminobenzenesulfonamide ( 1 ) with 2-chloroethyl or 3-chloropropyl isothiocyanate in isopropanol afforded 2-(2′-chloroethylthioureido)- and 2-(3′-chloropropylthioureido)benzenesulfonamides ( 2a,b ) in 67% and 55% yield respectively. Treatment of 2a,b with triethylamine in methanol at room temperature furnished 3-(2′-aminoethylthio)- and 3-(3′-aminopropylthio)-2H-1,2,4-benzothiadiazine 1,1-dioxides ( 9a,b ) in quantitative yield. Heating 2b to reflux in methanol under neutral conditions gave 9b but in the form of the hydrochloride 8b which could be converted into the free base 9b by treating with ammonia water. When compounds 2a,b were treated with triethylamine in methanol at elevated temperature, 3-(2′-mercaptoethylamino)- and 3-(3′-mercaptopropylamino)-2H-1,2,4-benzothiadiazine 1,1-dioxides ( 10a,b ) were obtained in good yield. Alternatively, 10a,b could also be prepared from 9a,b in 95% and 77% yield respectively.     

MOP-phosphonites: a novel ligand class for asymmetric catalysis

Chiral phosphonite ligands (S,R(b))-5a, (S,S(b))-5b, (R,R(b))-6a and (R,S(b))-6b are introduced, comprising a MOP-type backbone with a binol-based binaphthyl group bound to the phosphorus. Their reaction with [Pd(η(3)-C(4)H(7))Cl](2) affords η(3)-methallylpalladium chloride complexes 7a/b and 8a/b which have been isolated and structurally characterised. Solid-state and solution studies indicate subtle differences in their coordination behaviour, which ultimately affects their efficacy in the asymmetric hydrosilylation of styrene.     

1,3‐Dipolar cycloadditions of (4R*,5R*)‐1‐alkylidene‐4‐(benzoylamino)‐5‐phenyl‐3‐pyrazolidinon‐1‐azomethine imines

1,3‐Dipolar cycloadditions of azomethine imines 3a and 3b , available by acid‐catalyzed treatment of 3‐pyrazolidinone 1 with acetone ( 2a ) and butyraldehyde ( 2b ), respectively, were studied. Reactions of 3a with DMAD ( 4 ) afforded a mixture of products 9 and 10a , whilst treatment of 3b with DMAD ( 4 ) gave a mixture of compound 9 and epimeric cycloadducts 10 / 10′b . On the other hand, cycloadducts 13a,b‐16a,b were isolated as single diastereomers in 9–37% yields upon reactions of 3a,b with olefinic dipolarophiles 5–8 . The structures of cycloadducts 9, 10a, 10/10′b , and 13a,b‐16a,b were determined by ¹H nmr and NOESY spectroscopy. The structure of compound 13a was confirmed by X‐ray diffraction.     

Studies with polyfunctionally substituted heteroaromatics: A facile route for the synthesis of polyfunctionally substituted N-aminopyridines, 1,2,4-triazolo[1,5-a]pyridines and isoquinolines

The reactions of formaldehyde and acetaldehyde with active methylene compounds, followed by reaction with cyanoacetic acid hydrazide 2, afforded N-aminopyridine-2-one derivatives 5a-f. In contrast, the reactions of cyanoacetic acid hydrazide 2 with aliphatic aldehydes and cyanothioacetamide afforded pyridinethione derivatives 11a-b. Also, the reactions of active methylene compounds with formaldehyde and cyanoacetamide afforded pyridin(1H)-2-one derivatives 12a-c. The reactions of 5b with aldehydes and ketones afforded compounds 13a, b, 14, and 15, respectively. The reactions of 5b with arylidinemalononitriles 16a,b afforded isoquinoline derivatives 19a,b. Compound 19b by hydrolysis gave the final product 20. Compound 20 could also be formed by hydrolysis of 5b to give 21, followed by the reaction with 16b. © 1997 John Wiley & Sons, Inc.