Synthesis and Chemistry of 4-Aroyl-3-oxo- and 3-Chloropyridazine Derivatives

4H,5H-6-Phenyl (1a) and 6-p-phenoxyphenyl (1b) pyridazin-3(2H)-ones were reacted with aromatic aldehydes to give 4-arylmethylpyridazm-3(2H)-ones (2a-g), Oxidation of (2a-g) with various oxidising agents (selenium dioxide in ethanol or chromium trioxide in acetic acid) gave 4-aroyl-6-arylpyridazin-3(2H)-ones (3a-g). Chlorination of (3a-g) with phosphorous oxychloride afforded 4-aroyl-6-aryl-3-chloropyridazine (4a-g). 1H-3-Aryl-5-phenylpyrazolo[3,4-c]pyridazines (5a-d) were obtained by heating (4a-d) with excess hydrazine hydrate. Hydroxyamination of (3e-g) with iydroxylamine gave aryl-4(6-p-phenoxyphenyl-2,3-dihydro-3-oxo)pyridazinyl oxime (6a-c). Silylation of oximes (6b & 6c) gave (7a & 7b) as acyclic compound instead of the expected seven - membered - ring compound (8).     

Synthesis and anticancer activity of some novel tetralin-6-yl-pyrazoline, 2-thioxopyrimidine, 2-oxopyridine, 2-thioxo-pyridine and 2-iminopyridine derivatives

The title compounds were prepared by reaction of 6-acetyltetralin (1) with different aromatic aldehydes 2a-c, namely 2,6-dichlorobenzaldehyde, 2,6-diflouro-benzaldehyde, and 3-ethoxy-4-hydroxybenzaldehyde, to yield the corresponding a,b-unsaturated ketones 3a-c. Compound 3b was reacted with hydrazine hydrate to yield the corresponding 2-pyrazoline 4, while compounds 3a,b reacted with thiourea to afford the 2-thioxopyrimidine derivatives 5a,b, respectively. The reaction of 1, and the aromatic aldehydes 2a-c with ethyl cyanoacetate, 2-cyano-thioacetamide or malononitrile in the presence of ammonium acetate yielded the corresponding 2-oxopyridines 6a,b, 2-thioxopyridines 7a-c or 2-iminopyridines 8a,b, respectively. The newly prepared compounds were evaluated for anticancer activity against two human tumor cell lines. Compound 3a showed the highest potency with IC(50) = 3.5 and 4.5 μg/mL against a cervix carcinoma cell line (Hela) and breast carcinoma cell line (MCF7), respectively.     

Cyanothioacetamide in Heterocyclic Chemistry: Synthesis of Piperidine-3-carbonitrile,Pyrazolopyridine, Thiinopyridine-3-carbonitrile Derivatives,and Their Theoretical Calculations

Cyanothioacetamide ( 1 ) reacted with acrylonitrile ( 2 ) to afford the corresponding 6-oxo-2-sulfanylpiperidine-3-carbonitrile ( 6 ), which oxidized to give compounds 7 and 8 under different conditions. Moreover, compound 6 was used as a starting material to synthesize 12a-c , 16a-d , 26a-c , 27a-c , and 30a-c via reactions with aromatic aldehydes 9a-c , diazonium chlorides 13a-d , and 3-arylpropennitrile derivatives 18a-i respectively. Considering the data of IR, 1 H NMR, mass spectra, elemental analyses, and theoretical calculations, all the structures of the newly synthesized heterocyclic compounds were elucidated.     

Synthesis of Pyrimidines,Thienopyrimidines, and Pyrazolopyrimidines

5-Ethoxycarbonyl-4-methyl-2-phenylpyrimidin-6(1H)-thione ( 3 ), which was prepared from the reaction of ethyl g -aminocrotonate 1 with benzoyl isothiocyanate ( 2 ) in refluxing acetone, was reacted with a series of halopgenated reagents to give S-alkyl derivatives 4a-g . Upon treatment of compounds 4a-c with sodium ethoxide were cyclized into thienopyrimidine 10a-c . Pyrimidinethione 3 was reacted with hydrazine hydrate to give hydroxypyrazolopyrimidine derivative 6 . The later compound was obtained by heating compound 4a with hydrazine hydrate under neat conditions, but when the reaction was carried using hydrazine hydrate in ethanol, the corresponding carbohydrazide 5 was produced.     

SYNTHESIS OF PYRIDAZOTHIENOTHIAZINE AND PYRIMIDOTHIENOPYRIDAZINES

Abstract

3-amino-4,5-diphenylthieno[2,3-c]pyridazine-2-arylcarboxamide 2 underwent cyclization with triethyl orthoformate and with nitrous acid to give the pyrimidothienopyridazines 3a-c, 4b respectively. 3-amino-4,5-diphenylthieno[2,3-c] pyridazine-2-carbohydrazide 6 reacted with aromatic aldehydes to give the corresponding carbohydrazones 7a-c. Compound 7 reacts with triethyl orthoformate, acetic anhydride or with CS₂/pyridine to produce pyrimidothienopyridazines 8,9 and pyridazothienothiazine 11.     

An efficient synthesis and reactions of novel indolylpyridazinone derivatives with expected biological activity

Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl(3) for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl(3) was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene- or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, (1)H-NMR, (13)C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity.     

The reaction of isothiocyanates with 2-cyanoethanoic acid hydrazide. A novel synthesis of 1,3,4-thiadiazoles

Benzoyl and ethoxycarbonyl isothiocyanates reacted with 2-cyanoethanoic acid hydrazide 2 to afford 1-cyanoacetyl-4-substituted thiosemicarbazide ( 5a,b ). Compound 5a afforded the pyrazolo[1,5-a]-s-triazine derivative 6 on treatment with 5% potassium hydroxide, and cyclised to 2-benzoylamino-5-cyanomethyl-1,3,4-thiadiazole ( 8 ) when boiled under reflux in glacial acetic acid. Compound 8 condensed with aromatic aldehydes to yield the corresponding arylidene derivatives 9a-c . It undergoes coupling with aromatic diazonium salts to afford the hydrazones 11a-c . Similarly, it coupled with diazotised aminopyrazole to afford the cyclic product 12 .     

2,4,6-三芳基吡啶的微波辐射促进合成

微波辐射;查尔酮;缩合反应;吡啶;叶立德     

Lithiation of 1-chloromethylbenzotriazole: generation and elaboration of benzotriazolyloxiranes

1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a-g in good yields. The oxiranyllithiums 4a-d generated from 2a-d and n-BuLi at -78 degrees C were trapped by a variety of electrophiles to give oxiranyl derivatives 5a-j in good to excellent yields. Lewis-acid-promoted nucleophilic ring opening of benzotriazolyloxiranes 2a,f,g with allyltrimethylsilane gave the corresponding 1,7-octadien-4-ols 6a-c in 68-75% yield. Hydrolysis of alpha-acylbenzotriazolyloxiranes 5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.     

Facile Synthesis of Triarylpyrimidines with Microwave‐Irradiated Reactions of N‐Phenacylpyridinium Chloride

In a system of ammonium acetate and acetic acid under microwave irradiation, N‐phenacylpyridinium chloride 1 reacted with 2 mol of aromatic aldehydes 2a–h to give 2,4,6‐triarylpyrimidine 3a–h, reacted with pyridinecarboxaldehyde 4a–c and acetophenone 5 to yield bipyridine derivatives 6a–c. The structure of the products was characterized with ¹H NMR, ¹³C NMR, IR, and mass spectroscopy.     

Lewis acid-promoted deoxygenative di[beta,beta-bis(ethylthio)]vinylation of aldehydes with trimethylsilylketene bis(ethylthio)acetal

Silylketene dithioacetal 1 reacted with aldehydes 2a-o, 14, or cinnamaldehyde (11) in the presence of Lewis acid to give deoxygenative divinylation products, 3-substituted 1,4-pentadienes 3a-o, 15, or 5-phenyl-1,3,6-heptatriene 13b, in good to moderate yields. Similar reaction with 2-aminobenzaldehyde (16) or salicylaldehyde (17) produced quinoline 19 or chroman 20 in 40-58% yield. Treatment of 1 with alpha-diketones 22a-c or alpha-ketoester 24 led to tetrasubstituted furans 23a-c or allylic alcohol 25, respectively, in rather low yields. The formation mechanisms of these products are discussed.     

Synthesis of isocoumarins and alpha-pyrones via tandem Stille reaction/heterocyclization

A general route to alpha-pyrones and 3-substituted isocoumarins from (Z)-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c is described, including compounds bearing a substituent on the aromatic ring. Treatment of (Z)-beta-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c with various allenyltributyltin reagents in the presence of palladium acetate, triphenylphosphine, and tetrabutylammonium bromide in dimethylformamide provided good yields of the corresponding alpha-pyrones 3a-k or 3-substituted isocoumarins 5a-g via tandem Stille reaction and 6-endo-dig oxacyclization.     

Synthesis and antidiabetic activity of novel triazole derivatives containing amino acids

New series of triazole derivatives coupled with amino acids 1a-h were obtained via multicomponent reaction of 2-hydroxy benzaldehyde or 2-hydroxy acetophenone with thiosemicarbazide and different amino acids. The obtained compounds were reacted with p-toluinesulfonyl chloride 2 to give the corresponding sulfonamides 3a-h . Compound 1b was allowed to react with different aromatic aldehydes or cyclic ketone under alkaline conditions to afford the expected imino compounds 4a-d and 6a-c , respectively. These compounds were allowed to react with ethyl glycolate to yield the expected thiazolidinone derivatives 5a-d or 7a-c , respectively. Structures of the newly synthesized compounds were found to be in accordance with their elemental analyses and spectral data. The obtained compounds exhibited very prominent in vitro and in vivo antihyperglycemic effect at a dose of 40 mg/kg body weight compared to the standard drug gliclazide and control. The antidiabetic effect was investigated using oral glucose tolerance test in normal and non-insulin-dependent diabetes mellitus (NIDDM) in STZ-rat model. Compounds 3a - h , 5b , 5c , 5d , 7a , 7b , and 7c showed significant activity in lowering blood glucose (more than 80%) compared to the NIDDM control.     

KF-Al2O3 Induced the Condensation of 2-Nitrofluorene and Para-Substituted Acetophenones with Aromatic Aldehydes

In the presence of KF-Al₂O₃ as a solid base, 2-nitrofluorene 1 condensed with aromatic aldehydes 2a-f in methanol to give 2-nitrodibenzo-fulvenes 3a-f in high yield. The para-substituted acetophenones 4a-f reacted with cinnamic aldehyde to give 1, 5-diaryl-2, 4-pentadien-1-ones 6a-f in moderate yield.     

General synthetic entry to linearly-fused dihydrobenzocyclobutene-1,2-diones and benzocyclobutene-1,2-diones via annulation of 1,2-bis(methylene)carbocycles with 3-chloro-3-cyclobutene-1,2-dione

The tandem Diels-Alder/dehydrochlorination reaction of semisquaric chloride (1) with the 1,2-bis(methylene)cycloalkanes 2a-c and 1,2-bis(methylene)-4-cyclohexene (9) affords the linearly-fused cycloalkanodihydrobenzocyclobutene-1,2-diones 3a-c and 3,4,7,8-tetrahydrocyclobuta[b]-naphthalene-1,2-dione (10), respectively. On treatment with MnO2, 3a-c are dehydrogenated to the respective carbocycle-fused benzocyclobutene-1,2-diones 4a-c in good yields. 3a and 3b react with bromine to give the addition products 5a,b, which, on treatment with silver trifluoroacetate, afford the benzocyclobutene-1,2-diones 4a,b. For preparative purposes, the sequence 3-->5-->4 can be performed advantageously as a "one-pot procedure". Double-condensation reactions of 4a,b with alpha,alpha'-biscyano-o-xylene and o-phenylenediamine afford the pentacyclic biphenylenes 7a,b and the cyclobutahetarenes 8a,b, respectively. These cyclobutenediones suggest themselves as building blocks for the construction of extended linearly-fused polycyclic compounds with novel ring sequences. o-Quinodimethanes 12a-g generated in situ by the thermal decomposition of the respective 1,4-dihydro-2,3-benzoxathiin-3-oxides (sultines) 11a-g react with semisquaric chloride (1) to afford the 3,8-dihydronaphtho[b]cyclobutene-1,2-diones 13a-g. These, on dehydrogenation with bromine and/or MnO2, furnish the naphtho[b]cyclobutene-1,2-diones 14a-g in fair to good yields. As described for 4a,b the naphtho[b]cyclobutene-1,2-diones 14a-c are condensed with alpha,alpha'-biscyano-o-xylene and o-phenylenediamine to furnish the pentacyclic biphenylenes 15a-c and the pentacyclic cyclobutahetarenes 16a-c.     

Saturated heterocycles, 162 [1]. synthesis and steric structures of 3,4-disubstituted 1,6,7,11b-tetrahydropyrimido[6,1-a]isoquinolin-2-ones

The reaction of 1-(hydrazidomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 3 with aromatic aldehydes yield hydrazones 4a,b or pyrimido[6,1-a]isoquinolines 5a-c depending upon the proportions of the reagents. With ketones, 3 gives only hydrazones 4a-d and 7 , which can be transformed to pyrimidoisoquinolines 10a-e and 11 with aldehydes. The ring closures are stereospecific; the relative configurations were determined by DNOE measurements.     

A synthetic strategy leading to monodisperse PPV oligomers by coupling reactions of vinyltrimethylsilanes

A novel strategy for the synthesis of well-defined oligo(phenylenevinylene)s was developed. The procedure is entirely based upon two coupling processes, both involving vinyltrimethylsilanes. Bis(styryl)benzenes 2a-g bearing two octyloxy groups in the central aromatic ring and various substituents on the external aromatic rings were prepared in good yield by a regio- and stereoselective coupling reaction of 1 with different arenediazonium tetrafluoroborates. Oligomers with a more extended conjugated system, 4a-c, and with m-phenylene subunits 13a,b, were also readily obtained by conversion of the unsaturated trimethylsilyl derivatives 3a,c,d to the corresponding boron derivatives and a subsequent coupling reaction with compounds 2a and 2c.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Reaction of 2,4,6-substituted pyrylium salts with compounds containing a C = N bond

2,4,6-Substituted pyrylium salts add azomethines to give pyridinium salts and aromatic aldehydes. The latter can be condensed with the methyl groups of the pyridinium salts. Benzaldoxime, benzalazine, benzalphenylhydrazine, urea, thiourea, and phenyl isothiocyanate react with 2,4,6-triphenylpyrylium perchlorate similarly to give, respectively, 2,4,6-triphenylpyridine N-oxide, 2,4,6-triphenylpyridine, or N-substituted 2,4,6-triphenylpyridinium perchlorates.     

2-vinylpyrroles and pyrrolo[3,2-d]pyrimidines from direct addition of aldehydes to 4-amino-pyrrole-2-carboxylate derivatives

A new methodology for the direct preparation of 2-vinylpyrroles is presented. Treatment of 4-amino-pyrrole-2-carboxylates 5a-c and 6a-d with aliphatic aldehydes and TFA furnished 2-vinylpyrroles 2a-k in 9-87% yields. Under similar conditions ureidopyrroles 5a-c reacted with aryl aldehydes to provide pyrrolo[3,2-d]pyrimidines 1a-d in 28-63% yields.