Pyrazolones as Building Blocks in Heterocyclic Synthesis: Synthesis of New Pyrazolopyran,Pyrazolopyridazine and Pyrazole Derivatives of Expected Antifungicidal Activity

A series of new pyrazolone and pyrazole derivatives with expected antifungicidal activity have been prepared through the reactions 3‐phenyl‐1‐H‐pyrazol‐5(4H)‐one ( 3 ) and 4‐(dimethylaminomethylene)‐3‐phenyl‐1H‐pyrazol‐5(4H)‐one ( 5 ) with a variety of electrophilic reagents and nucleophilic reagents. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral studies.     

Synthesis of chromenone,pyrimidinone, thiazoline,and quinolone derivatives as prospective antitumor agents

Hydrazide-hydrazone namely, 2-cyano-N′-((1-phenyl-3-[thiophen-2-yl]-1H-pyrazol-4-yl)methylene)acetohydrazide (3) underwent a series of reactions with some chemical reagents to construct new biologically active N-heterocycles, for example, chromenone, benzochromenone, thiazoline, and quinolone derivatives. Treating the nitrile derivative 3 with 2,4-dichlorobenzaldehyde and pyrazole aldehyde 1 afforded the corresponding condensed products. Some of the synthesized compounds were screened for their in vitro antitumor activities against two different human tumor cell lines including hepatocellular liver carcinoma (HepG2) and breast adenocarcinoma (MCF7) activities. Compound 3 was the most potent against the two tumors.     

Synthesis and Reactivity of the New Chiral Silylphosphite Esters {(+)-O,O-Dimethyl-L-tartrate}POSiR3 (R3 = Ph3, tBuMe2, Et3)

The new, chiral silylphosphite compounds (O,O-dimethyl-L-tartrato)POSiR₃, (R₃ = Ph₃, ^tBuMe₂, Et₃) have been synthesised and their activity as asymmetric phosphonylating reagents investigated.     

Synthesis,Characterization, and Antimicrobial Evaluation of Some Novel 4-Hydroxyquinolin-2(1H)-ones

Vilsmeier–Haack formylation of 3-acetyl-1-methyl-4-hydroxyquinolin-2(1H)-one (2) produced the novel 6-methyl-4,5-dioxo-5,6-dihydro-4H-pyrano[3,2-c]quinoline-3-carboxaldehyde (3). Reactions of carboxaldehyde 3 with a diversity of nucleophilic reagents were studied and a variety of products were obtained via ring-opening, ring-closing (RORC) sequence. Also, some novel heteroannulated pyrano[3,2-c]quinolines were prepared. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.     

Synthesis of new pyrazoles,oxadiazoles, triazoles,pyrrolotriazines, and pyrrolotriazepines as potential cytotoxic agents

4-Oxo-4-phenylbutanehydrazide (1) reacted with many active methylene reagents such as acetylacetone, diethylmalonate, ethylacetoacetate, ethylcyanoacetate, benzoyl-acetonitrile, and malononitrile under neat conditions to afford the corresponding pyrazoles (2–7) , also, treatment of butanehydrazide (1) with electrophilic reagents as triethylorthoformate, dimethylformamide-dimethylacetal, acetic anhydride, and carbon disulfide to give 1,3,4-oxadiazoles (8,10,11) and N′-acetyl-butanehydrazide (9) . Reacted of butanehydrazide (1) with potassium thiocyanate gave 1,2,4-triazoles (12) . Similarly, treatment of (1) with chloroacetamide gave 1,2,4-triazinones (13) . The pyrrolotriazinones (14) was obtained by cyclization of (13) . Also, butanehydrazide ( 1 ) was utilized as a starting material for the synthesized of new Schiff bases as N′-(4-sub-benzylidene)-phenylbutane-hydrazide (15a-c) , which are used as an initiative to prepare new compounds such as 1,2,4-triazepinones (16a-c) , pyrrolotriazepinones (17a-c) , 1,2,4-triazines (18a-c) , and pyrrolotriazines (19a-c) by reacted of (15a-c) with each chloroacetamide or formamide. The chemical structure of the newly prepared compounds was determined through the spectrum data, including IR, NMR, and MS. The prepared compounds were tested for their in vitro antitumor activities. The compounds 17a-c , 16a-c , and 19a-c displayed activity against several types of cancer cell lines.     

Synthesis of Some New Nitrogen Bridge‐head Triazolopyridines,Pyridotriazines, and Pyridotriazepines Incorporating 6‐Methylchromone Moiety

Some new triazolo[1,5‐a]pyridines, pyrido[1,2‐b][1,2,4]triazines, and pyrido[1,2‐b][1,2,4]triazepines incorporating 6‐methylchromone moiety were prepared from the reaction of 1,6‐diamino‐4‐(6‐methyl‐4‐oxo‐4H‐chromen‐3‐yl)‐2‐oxo‐1,2‐dihydropyridine‐3,5‐dicarbonitrile ( 4 ) with some electrophilic reagents.     

Preparation of Solid,Substituted Allylic Zinc Reagents and Their Reactions with Electrophiles

The treatment of various allylic chlorides or bromides with zinc dust in the presence of lithium chloride and magnesium pivalate (Mg(OCOtBu)₂) in THF affords allylic zinc reagents which, after evaporation of the solvent, produce solid zinc reagents that display excellent thermal stability. These allylic reagents undergo Pd‐catalyzed cross‐coupling reactions with PEPPSI‐IPent, as well as highly regioselective and diastereoselective additions to aryl ketones and aldehydes. Acylation with various acid chlorides regioselectively produces the corresponding homoallylic ketones, with the new C? C bond always being formed on the most hindered carbon of the allylic system.     

Sensitive enantioseparation and determination of isoprenaline in human plasma and pharmaceutical formulations

A simple, sensitive and fast RPHPLC method was developed and validated for the enantioselective determination of (RS)‐isoprenaline (Ipn) in human plasma. The enantiomers were converted to diastereomeric derivatives using s‐triazine (cyanuric chloride) based chiral derivatizing reagents. l ‐isoleucine and l ‐methionine were introduced as chiral auxiliary in s‐triazine and two new monochloro‐s‐triazine reagents were synthesized. These reagents were characterized and used for synthesis of diastereomeric derivatives of (RS)‐Ipn spiked in human plasma. (RS)‐Ipn was isolated (purified and characterized) from a commercial pharmaceutical formulation and was used as the standard racemic sample. Structures of the two diastereomeric derivatives were optimized for lowest energy using the Gaussian 09 Rev A. 02 program and hybrid density functional B3LYP with 6‐31G* basis set which showed the spatial orientation of hydrophobic groups on stereogenic centers in the diastereomeric derivatives. The results were correlated with the mechanism of separation and elution order. Limit of detection values were found to be 24.6 and 26.8 ng mL^?1 for the first and second eluting diastereomeric derivatives, respectively.     

Preparation and Application of Solid,Salt‐Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

The treatment of various N‐morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t _1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd‐ and Cu‐catalyzed cross‐couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N‐morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti‐breast‐cancer drug candidate in six steps and 23 % overall yield.     

An investigation of the abnormal products from the reaction of 2-thenyl and benzyl grignard reagents by gas chromatography.

The products of the reaction of 2-thenylmagnesium chloride (I) with a variety of reagents has been studied by gas chromatography. Carbon dioxide and ethylene oxide produced significant amounts of 5-substituted (“para”) products as well as 3-substituted (“ortho”) and normal addition products. Several other reagents, including acetyl chloride and formaldehyde, produced mainly “ortho” products along with small amounts of normal products. The dependence of product distribution on temperature, added salts and solvent character was found to correlate with the reported rates of inversion about the carbon-magnesium bond in primary Grignard reagents. Blocking the “ortho” position, in 3-methyl-2-thenylmagnesium chloride, increased the proportion of “para” product from 3 to 33%. In addition, the reactions of benzylmagnesium chloride with certain reagents were re-examined.     

Activated Anilide in Heterocyclic Synthesis: Synthesis of New Dihydropyridines,Dihydropyridazines and Thiourea Derivatives

A series of new dihydropyridines, butanamide, dihydropyridazines and thiourea derivatives have been prepared through the reactions of 3‐aminopyridine ( 1 ) and N‐(pyridin‐3‐yl)‐3‐(pyridin‐3‐ylimino)butanamide 3 with some electrophilic reagents, aryl diazonium salts and isothiocyanates. Elementary analysis, MS, IR, and ¹H NMR spectra confirmed the identity of the products.     

Chiral α-Amino Acid-Based NMR Solvating Agents

Four new chiral α-(nonafluoro-tert-butoxy)carboxylic acids were synthesized from naturally occurring α-amino acids (alanine, valine, leucine and isoleucine, respectively), and tested in ¹H- and ¹⁹F-NMR experiments as chiral NMR shift reagents. The NMR studies were carried out at room temperature, using CDCl₃ and C₆D₆ as solvents, and (RS)-α-phenylethylamine and (RS)-α-(1-naphthyl)ethylamine as racemic model compounds. To demonstrate the applicability of the reagents, the racemic drugs ketamine and prasugrel were also tested.     

Vinylation of Nitro‐Substituted Indoles,Quinolinones, and Anilides with Grignard Reagents

The reaction of vinyl Grignard reagents with o‐methoxynitroarenes containing an electron‐releasing substituent para to the nitro group proceeds through a pathway that is different from the initially expected Bartoli indole synthesis. Thus, instead of giving fused indole derivatives, these reactions provide a very mild and efficient new procedure for the synthesis of synthetically relevant aromatic systems containing an o‐nitrovinyl moiety, such as 5‐nitro‐4‐vinylindoles, 6‐nitro‐7‐vinylindoles, 6‐nitro‐5‐vinyl‐2(1H)quinolinones, and 4‐nitro‐3‐vinylanilines.     

Synthesis of Pyrano[3,2‐c]quinoline‐3‐carboxaldehyde and 3‐(Ethoxymethylene)‐pyrano[3,2‐c]quinolinone and Their Chemical Behavior toward Some Nitrogen and Carbon Nucleophiles

Synthesis of novel 3‐(ethoxymethylene)‐pyrano[3,2‐c]quinolinone and pyrano[3,2‐c]quinoline‐3‐carboxaldehyde was accomplished efficiently via a simple method. These two scaffolds were used as precursors to afford new biologically interesting products in good yield and short reaction times. The chemical reactivity of ethoxy methylene 2 and carboxaldehyde 3 toward different nucleophilic reagents was studied. Structures of the new synthesized compounds were elucidated by their analytical and spectral data.     

Pyridine‐2(1H)‐thiones: Versatile Precursors for Novel Pyrazolo[3,4‐b]pyridine,Thieno[2,3‐b]pyridines,and Their Fused Azines

Pyridine‐2(1H)‐thiones were prepared and reacted with several active halogenated reagents to afford novel thieno[2,3‐b]pyridines in excellent yields. Thieno[2,3‐b]pyridine‐2‐carbohydrazide derivative was prepared by the reaction of either ethyl 2‐((3‐cyanopyridin‐2‐yl)thio)acetate derivative or thieno[2,3‐b]pyridine‐2‐carboxylate derivative with hydrazine hydrate. On the other hand, the reaction of either pyridine‐2(1H)‐thione or ethyl 2‐((pyridin‐2‐yl)thio)acetate derivative with hydrazine hydrate afforded the corresponding 1H‐pyrazolo[3,4‐b]pyridine derivative. Thieno[2,3‐b]pyridine derivatives reacted with several reagents to afford the corresponding pyrimidine‐4(3H)‐ones and [1,2,3]triazin‐4‐(3H)‐one. Moreover, 2‐carbohydrazide derivative reacted with β‐dicarbonyl reagents to give 2‐((3‐methyl‐1H‐pyrazol‐1‐yl)carbonyl)thienopyridines. The structure of the target molecules is elucidated using elemental analyses and spectral data.     

Synthesis of a Novel Tri‐enaminone as Building Block for Polyaza‐heterocycles

The new tri‐enaminone, namely, 3,4‐bis (3‐dimethylamino‐2‐propenoyl)‐1‐[4‐(3‐dimethylamino‐2‐propenoyl)phenyl]‐5‐methyl‐1H‐pyrazole was prepared and used as building block for synthesis of novel polyaza‐heterocycles. The latter compounds were obtained via an efficient one‐pot reaction of the tri‐enaminone with 1,3‐dipoles and various electrophilic and nucleophilic reagents. The structures of the new products were confirmed based on elemental and spectral analyses. Also, alternative synthetic methods were carried out wherever possible as further evidence for some of the newly synthesized products.     

Synthesis of novel 1-phenyl-1H-indole-2-carboxylic acids. II. Preparation of 3-dialkylamino, 3-alkylthio, 3-alkylsulfinyl,and 3-alkylsulfonyl derivatives

The synthesis of novel indole-2-carboxylic acids with amino- and sulfur-containing substituents in the indole 3-position is described. An Ullmann reaction with bromobenzene converted 1H-indoles with 3-(acetylamino)- and 3-(diethylamino)-substituents into 1-phenyl-1H-indoles. Reaction of 3-unsubstituted indoles with thionyl chloride provided indole 3-sulfinyl chlorides, which reacted with alkyl and aryl Grignard reagents to form the corresponding sulfoxides. The indole sulfoxides thus obtained were reduced to sulfides or oxidized to sulfones.     

An Eco‐friendly Synthesis and Biological Screening of Fused Heterocyclic Compounds Containing a Thiophene Moiety via Gewald Reaction

5‐Amino‐3‐phenyl‐1‐(2,4,6‐trichlorophenyl)‐1H‐thieno[3,2‐c]pyrazole‐6‐carbonitrile ( 2 ) was designed and synthesized by one‐pot multicomponent reaction. Compound 2 was reacted with different reagents to obtain new condensed moieties with our thienopyrazole skeleton. The compounds were prepared by using environmentally benign techniques as microwave irradiation, ultrasonic irradiation, and ball‐milling. The structure of the prepared compounds was elucidated through spectroscopic methods. The new compounds were evaluated for their in vitro antibacterial and antifungal potentialities.     

Synthese neuer Aryl-(3,-dichloro-4-pyridazinly)-ketone und ihre Reaktion mit N,N-Dinucleophilen

Synthesis of New Aryl (3,6-Dichloro-4-pyridazinyl) Ketones and their Reaction with N,N-Dinucleophiles The synthesis of the new aryl (3,6-dichloro-4-pyridazinyl) ketones 3a–e vïa Friedel-Crafts acylation of the aromatic compounds 2a–e with 3,6-dichloro-4-pyridazincarbonyl chloride (1) is described. The ketones 3a–e cyclized with N,N-dinucleophilic reagents to the 3-aryl-5-chloro-l H -pyrazolo[3,4-c]pyridazines 4a–d , and 3a–c are converted into the 3-aryl-5-chloro-l H -pyrazolo[3,4-c]pyridazin - l -ethanols 5a–c and to the hitherto unknown ring system of the 5-aryl-3-chloro-7,8-dihydro-9 H -pyridazino[3,4-e][1,4]diazepines ( 6a-c ).     

Application of optically pure amines as chiral auxiliaries to develop trichloro‐s‐triazine‐based new chiral derivatizing reagents for reversed‐phase high‐performance liquid chromatographic enantioseparation of dl‐selenomethionine

(R)‐(+)‐naphthylethyl amine and (S)‐(+)‐1‐benzyl‐3‐aminopyrrolidine were incorporated as chiral auxiliaries, by nucleophilic substitution of chlorine atoms, in cyanuric chloride (CC) or its 6‐butoxy derivative. There were obtained four new chiral derivatizing reagents (CDRs) as two dichloro and two monochloro triazine reagents. The CDRs so obtained were characterized and their optical purity was ascertained. Diastereomers of dl ‐selenomethionine were synthesized under microwave irradiation for 60 or 90 s (at 80% power of 800 W). Reversed‐phase high‐performance liquid chromatographic separation of diastereomers was carried out on a C₁₈ column using mixtures of acetonitrile with aqueous trifluoroacetic acid as mobile phase. The detection was made at 230 nm using a photodiode array detector. The separation behaviors in terms of retention times and resolutions were compared. The separation method was validated for limit of detection, linearity, accuracy, precision, and recovery. Copyright © 2013 John Wiley & Sons, Ltd.