Studies of pyridazine compounds. XXVI. The synthesis of Pyridazino[4,5-b]pyrrolo[1,2-d][1,4]oxazines and a pyridazino[4,5-b]pyrrolo[1,2-d][1,4]thiazine

The tricyclic oxazines 3 and 5 were obtained by ring closure of (2-hydroxymethyl-1-pyrrolidinyl)-3(2H)-pyridazinones 2d,e,g , respectively, prepared from 4,5-dichloro-3(2H)-pyridazinones with L-prolinol. The synthesis of the thiazine analogue 4a was achieved by treatment of 2d with thionyl chloride and the subsequent reaction with sodium sulfide. The structures of the compounds were supported by spectroscopic evidence.     

Unexpected behaviour of the oxidizing agent sodium m-nitrobenzenesulfonate: Synthesis of a new class of 5-hydroxy benzopyrano-[4,3-c]pyridazin-3(2H)-ones

Sodium m-nitrobenzene sulfonate, widely used in dehydrogenation of 4,5-dihydro-3(2H)-pyridazinones to their corresponding aromatic derivatives, behaves in an unexpected way when 4,4a-dihydro-5H[1]benzopyrano[4,3-c]pyridazin-3(2H)-ones are employed as substrate. The synthesis of a new class of 5-hydroxy[1]benzopyrano[4,3-c]pyridazin-3(2H)-ones is described.     

A New and Convenient Synthesis of 3(2H)-Pyridazinones by Reacting Carbanion of Ethyl Trimethylsilylacetate with Phenylhydrazones

A one-pot synthesis of 5,6-disubstituted-2-phenyl-3(2H)-pyridazinones 4 is achieved on treatment of carbanion of ethyl trimethlsiylacetate with phenylhydrazones of 1,2-dicarbonyl compounds 1.     

Reaction of Triethyl Phosphonoacetate Anion with Phenylhydrazones: A New Method for the Preparation of 3(2H)-Pyridazinones

Various 5,6-disubstituted-2-phenyl-3(2H)-pyridazinones 4 have been synthesised by reacting triethyl phosphonoacetate anion with monophenylhydrazone of 1,2-dicarbonyl compounds 2.     

An Efficient and Practical Method for the Synthesis of 1-(2,6-Difluorobenzoyl)-3-(2-alkyl-3-oxopyridazin-4-yl)ureas as Potential Chitin Synthesis Inhibitors

Summary. A mild and efficient method for the synthesis of 4-amino-3(2H)-pyridazinones from their corresponding 4,5-dichloropyridazinones under microwave-assisted conditions is described. A series of novel chitin synthesis inhibitors, benzoylphenylureas containing the 3(2H)-pyridazinone, were synthesized. The biological activity of these target compounds was evaluated.     

An Efficient and Practical Method for the Synthesis of 1-(2,6-Difluorobenzoyl)-3-(2-alkyl-3-oxopyridazin-4-yl)ureas as Potential Chitin Synthesis Inhibitors

A mild and efficient method for the synthesis of 4-amino-3(2H)-pyridazinones from their corresponding 4,5-dichloropyridazinones under microwave-assisted conditions is described. A series of novel chitin synthesis inhibitors, benzoylphenylureas containing the 3(2H)-pyridazinone, were synthesized. The biological activity of these target compounds was evaluated.     

Pyridazines with hetero-atom substituents in position 3 and 5, part VII. Halogenation of 2-aryl-5-hydroxy-pyridazin-3(2H)-ones in position 4

Summary The reaction of 2-ary-5-hydroxy-3(2H)-pyridazinones (1a, b) with bromine yields the 4-bromo derivatives2a, b and with sulfuryl chloride the chloro compounds3a, b are obtained. However, with an excess of chlorine or sulfuryl chloride the 4,4-dichloro-pyridazine-dione4 is produced. Hydrolysis of4 leads to5, and in a similar manner the open chain hydrazone8 is obtained from the carboxylic acid6.

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Pyridazine mit Heteroatom-Substituenten in Stellung 3 und 5, 7. Mitt. Halogenierung von 2-Aryl-5-hydroxy-pyridazin-3(2H)-onen in 4-Stellung

Zusammenfassung Die Reaktion von 2-Aryl-5-hydroxy-pyridazin-3(2H)-onen (1a, b) mit Brom liefert die 4-Bromderivate2a, b, während mit Sulfurylchlorid3a, b erhalten werden. Ein Überschuß von Sulfurychlorid oder Chlorgas gibt jedoch das 4,4-Dichlor-pyridazin-dion4. Die Hydrolyse von4 führt unter Ringöffnung und Decarboxylierung zu5. In analoger Weise gibt die freie Carbonsäure6 das Hydrazon8.

     

Pyridazine derivatives. XIX: Functionalization studies at the 5 position in the 6-phenyl-3(2H)-pyridazinone system

A series of 6-phenyl-3(2H)-pyridazinones bearing different substitution at the 5 position of the pyridazinone ring were prepared in the search for new platelet aggregation inhibitors. The structure of the final compounds was determined on the basis of spectroscopics methods.     

The reaction of 2-substituted-4,5-dichloro-3(2H)-pyridazinones with alkoxides and alkylthiolates

The reaction of 2-substituted-4,5-dichloro-3(2H)-pyridazinones 1a-b with alkoxides and alkylthiolates was investigated. Regiospecific displacement of either the 4 or 5 chlorine atom could be achieved in most cases by appropriate selection of the reaction solvent.     

Efficient Aromatization of 4,5-Dihydro-3(2H)-Pyridazinones Substituted at 5 Position by Using Anhydrous Copper (II) Chloride

An efficient conversion of 5-substituted-4,5-dihydro-3(2H)-pyridazinones into their corresponding dehydrogenated derivatives was achieved by treatment with anhydrous copper(II) chloride in acetonitrile.     

Pyridazine derivatives. Part 33: Sonogashira approaches in the synthesis of 5-substituted-6-phenyl-3(2H)-pyridazinones

Several 6-phenyl-3(2H)-pyridazinones bearing different alkynyl groups at position 5 have been prepared by a palladium-catalysed Sonogashira cross-coupling reaction. An interesting base-promoted electronically permitted isomerization has been observed during the coupling of 1-phenyl-2-propyn-1-ol. This rearrangement afforded the E-chalcone 6 in excellent yield.     

Synthesis of 4-amino-6-phenyl-3(2H)-pyridazinones: A general procedure

A method for the synthesis of 3,4-dichloro-6-phenylpyridazine 5 was described. The compound 5 was used as an intermediate for the synthesis of a series of 4-amino-6-phenyl-3(2H)-pyridazinones.     

1,2,4-Triazines. 8. Reduction of 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride. Regioselective preparation of dihydro-1,2,4-triazin-5(4H)-ones

Reduction of 3-methylthio-1,2,4-triazin-5(4H)-one ( 1a ) with sodium borohydride afforded 3-methylthio-1,6-dihydrotriazin-5(4H)-one ( 2b ) selectively. 3-Methylthio-6-t-butyl-1,2,4-triazin-5(4H)-one ( 1d ) reacted with sodium borohydride to give mainly 6-t-butyl-2,3-dihydro-1,2,4-triazin-5(4H)-one ( 3d ). The reaction of various 4-methyl-1,2,4-triazin-5(4H)-ones with sodium borohydride and the influence of bulkiness and electronic effect of the substituents at the 3- and 6-positions upon the product ratio, are also discussed.     

Pyrimidine derivatives. IX . Synthesis of bromosubstituted 5-nitro-2,4(1H,3H)-pyrimidinedione derivatives

The following 5-nitro-2,4(1H,3H)-pyrimidinediones possessing bromo substituted side chains at the 1- and 6-positions were prepared by bromination of 3,6-dimethyl-1-(ω-hydroxyalkyl)-5-nitro-2,4(1H,3H)-pyrimidinediones 4a and 4b and its nitrates 2a and 2b . The three of mono-bromo derivatives are: 1-(ω-acetoxyalkyl and ω-hydroxyalkyl)-6-bromomethyl-3-methyl. 6a, 6b, 7a and 7b and 1-(ω-bromoalkyl)-3,6-dimethyl-2,4(1H,3H)- pyrimidinediones 8a and 8b . The one type dibromo derivatives are: 1-(ω-bromoalkyl)-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinediones 5a and 5b .     

Studies in spiroheterocycles. Part XVII. synthesis of novel fluorine containing spiro[indole-pyranobenzopyran] and spiro[indenopyran-indole] derivatives

An elegant one-step synthesis of two novel spiro ring systems viz: spiro[3H-indole-3,4′-(2′-amino-3′-carbonitrile-[4′H]-pyrano[3,2-c]benzopyran)]-2,5′(1H)-dione8 and spiro[(2-amino-3-carbonitrile-indeno[1,2-b]pyran)-4(5H)>3′-[3H]indole]-2′,5(1′H)-diones in 80–85% yields is described. The spiro heterocycles were prepared by the reactions of fluorine containing 3-dicyanomethylene-2H-indol-2-ones with 4-hydroxy-2H-1-benzopyran-2-one and 1H-indene-1,3(2H)-dione respectively. The synthesized compounds have been characterized on the basis of elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral data.     

Synthetic studies directed toward the pseurotins. Part II. Synthesis of related highly functionalized furan-3(2H)-ones

The synthesis of 2,2-bis(hydroxymethyl)-4-methyl-5-phenylfuran-3(2H)-one ( 9 ), 5-[(1S,2S,Z)-1,2-(ethylidenedioxy)hex-3-enyl]-2,2-bis(hydroxymethyl)-4-methylfuran-3(2H)-one ( 24 ), and 5-[(1S,2S,Z)-1,2-(ethylidenedioxy)hex-3-enyl]-2-(hydroxymethyl)-4-methylfuran-3(2H)-one ( 28 ), which represent more advanced, suitably functionalized intermediates for the synthesis of pseurotin A ( 1 ), a secondary metabolite of Pseudeurotium ovalis STOLK , is described.     

Synthesis of 3-alkyl-6-phenyl-4(3H)-pteridinones and their 8-oxides. Potential substrates of xanthine oxidase

Synthetic routes for the preparation of 3-alkyl-6-phenyl-4(3H)-pteridinones 6 and their corresponding 8-oxides 5 (R = CH₃, C₂H₅, (CH₂)₂CH₃, (CH₂)₃CH₃, CH(CH₃)C₂H₅, CH(CH₃)₂ and CH(C₂H₅)CH₂OCH(OC₂H₅)₂ are described and their reactivities towards xanthine oxidase from Arthrobacter M-4 are determined. Only the 3-methyl derivative of 6-phenyl-4(3H)-pteridinone and its 8-oxide i. e. 6a and 5a are found to be substrates although their reactivities are still very low. Oxidation takes place at C-2 of the pteridinone nucleus. All the 3-alkyl derivatives are less tightly bound to the enzyme than 6-phenyl-4(3H)-pteridinone. Introduction of the N-oxide at N-8 considerably lowers the binding of the substrates. Inhibition studies have revealed that 3-methyl-6-phenyl-4(3H)-pteridinone ( 6a ) is a non-competitive inhibitor with a Ki-value of 47 μM and the 3-ethyl derivative ( 6b ) an uncompetitive one with a Ki-value of 19.6 μM.     

Chemistry of 5(2H)-isoxazolones: Novel conversion of positional isomers

Reactions of 4-arylidene-3-methyl-5(4H)-isoxazolones with nucleophiles lead to 4-substituted-benzyl-3-methyl-5(2H)-isoxazolones. Formation of 5(4H)- and 5(2H)-isoxazolone derivatives have been observed when 4-substituted-arylidene-3-rriethyl-5(4H)-isoxazolones are reacted with methyl magnesium iodide. Oxidation of 4-substituted-benzyl-3-methyl-5(2H)-isoxazolones with manganic acetate and pyridinium chlorochromate, gives 4,4′-bis[4-substituted-benzyl-3-methyl-5(4H)-isoxazolone]. Oxidation of 4-substituted-benzyl-3-methyl-5(2H)-isoxazolones with metachloroperbenzoic acid gives 4-hydroxy-4-substituted-benzyl-3-methyl-5(4H)-isoxazolones and reactions of the same substrates with N-bromosuccinimide furnish 4-bromo-4-substitutedbenzyl-3-methyl-5(4H)isoxazolones.     

Substituted γ-Lactones. 35 . Reduction of 4-aroyl-3-hydroxy-2(5H)-furanones

The reduction of 4-aroyl-3-hydroxy-2(5H)-furanons 1a-c was investigated using different reducing agents. Sodium borohydride reacts with type 1 compounds by loss of water to yield 4-(arylmethylene)-2,3(4H,5H)-furandiones 2a-c . Platinum or charcoal supported by pallodium chloride transforms 1a to 4-benzyl-3-hydroxy-2(5H)-furanone ( 3). Compounds 2a and 2b react with o-phenylenediamine to give 3-(E-(1′-hydroxymethyl-2′-aryl)ethenyl]-2-quinoxalinones 4a and 4b . The lactone 3 under the same conditions splits out formaldehyde and forms 3-(2′-phenylethyl)-2-quinoxalinone ( 6 ). The structure assignments of the novel compounds are based on elemental analysis and nmr as well as ir spectroscopic data.     

1,2,4-Triazines, 9. The synthesis of novel 4-amino-1,6-dihydro-1,2,4-triazinones

3-Alkylthio-4-amino-1,6-dihydro-1,2,4-triazin-5(4H)-ones were synthesized by the reduction of 3-thio-4-amino-1,2,4-triazine-3,5(2.H,4H)-diones and successive S-alkylation. The regiospecific alkylation on the N-1 position or the exo amino group leads to a variety of 1,6-dihydro-1,2,4-triazin-5(4H)-one derivatives. An alternative synthesis of 3-thio-4-amino-1,6-dihydro-1,2,4-triazine-3,5(2H,4H)-diones was accomplished through the cyclization of 1-thiocarbohydrazidoacetamide derivatives.