Synthesis of new 2H,4H-benzopyrano[3,4-b]yridine-1,3,5-trione derivatives via carbon suboxide

The new 2H,4H-[1]benzopyrano[3,4-b]pyridine-1,3,5-trione derivatives 10a-f were prepared in the following three steps: first the preparation of new N-(tert-butoxycarbonyl)-3-amino-2H-1-benzopyran-2-one derivatives 5a-f by reaction of coumarin-3-carboxylic acids and diphenylphosphorylazide, then hydrolysis of 5a-f with gaseous hydrogen chloride to give the corresponding amines 7a-f , and finally the preparation of 10a-f by reaction of 7a-f and carbon suboxide in the presence of a Lewis acid.     

Reaction of N-(4-pyridylmethyl)benzamide N-oxides with ethyl cyanoacetate in the presence of acetic anhydride

Reaction of N-(4-pyridylmethyl)benzamide N-oxides 2a-f with ethyl cyanoacetate in the presence of acetic anhydride yield dimerization compounds 3a-f and (E)-ethyl 2-cyano-3-(4-pyridyl)-3(benzoylamino)acrylates 4a-f , which react with hydrazine to give 4-cyano-3-(4-pyridyl)-3-pyrazolin-5-one 9 and the corresponding benzamides 10a-f .     

Synthesis of new 1,2,4-triazolo[4,3-b]pyridazines and related compounds

The synthesis of novel 6-[4-(1H-imidazol-1-yl)phenyl]-1,2,4-triazolo[4,3-b]pyridazines 8a-f and related compounds is described. Although the intermediate hydrazine derivatives 7 and 9 possess good positive inotropic activity, the fused bicyclic pyridazines 8a-f are significantly less potent than the 3(2H)-pyridazinone 5. Compounds 8a-f are potent but nonselective inhibitors of cardiac phosphodiesterase.     

Synthesis and regiospecificity in methylation of pyrido[1,2-a]pyrazinium-1- and 3-olates and pyrido[1,2-b]pyridazinium-2- and 4-olates

New methods have been developed for the synthesis of pyrido[1,2-a]pyrazinium-1- and 3-olates 5a-f, 9 and 1-thiolate 24 as well as of pyrido[1,2-b]pyridazinium-4- and 2-olates 14, 20 . The methylation of these new compounds was studied by soft and hard methylating agents. Depending on the nature of the reagent used, the pyrido[1,2-a]pyrazinium-1-olates 5a-f gave NMe 22a-f and/or OMe 23a-f products, whereas the 3-olate 9 and both the 4- and 2-pyridazinium-olates 14, 20 afforded solely OMe compounds 10, 15, 21 . A selectivity rule for methylation is proposed.     

ω-Dialkylaminoalkyl ethers of phenyl-(5-substituted 1-phenyl-1H-pyrazol-4-yl)methanols with analgesic and anti-inflammatory activity

A series of carbinols 3a-f was prepared starting from methanols 1a-f via oxidation with pyridinium chlorochromate to aldehydes 2a-f , followed by a Grignard reaction of the latter. Reaction of 3a-f with ω-chloroalkyldialkylamine hydrochlorides afforded a series of aminoether derivatives 4g-t . Compounds 4i,m-p,s showed a good analgesic activity in the acetic acid writhing test in mice. Moreover, compounds 4h,1,s exhibited a moderate anti-inflammatory activity in the carrageenan-induced edema assay in rats.     

Thallation-iodination studies of heterocyclic systems

The thallation-iodination of 3-carbonylindoles ( 4a-f ) results in orientation control with substitution occurring at the 4-position ( 6a-f ). Also described is the dithallation of N-methylpyrrole-2-carboxaldehyde ( 2 ).     

Thermolysis of hexasubstituted-4,5-dihydro-3H-pyrazoles: Synthesis of 1-alkoxy- and 1-acetoxy-1,2,2,3,3-pentasubstituted-cyclopropanes

A series of 5-alkoxy- and 5-acetoxy-4,4-dimethyl-3,3,5-trisubstituted-4,5-dihydro-3H-pyrazoles 2a-f (hexasubstituted pyrazolines) was synthesized by oxidation of the corresponding 3,4-dihydro-2H-pyrazoles with lead tetraacetate in the appropriate solvents. The 5-acetoxy compounds were produced when the oxidations were carried out in methylene chloride. Oxidation with lead tetraacetate in dry alcoholic solvents resulted in the formation of the 5-alkoxy derivatives as the major products. Thermolysis of the hexasubstituted-4,5-dihydro-3H-pyrazoles 2a-f in cyclohexane or as the melt at high temperature yielded the 1-alkoxy- and 1-acetoxy-1,2,2,3,3-pentasubstituted cyclopropanes 3a-f in good yields. Trace amounts of alkene products were formed in several reactions. No products attributable to cycloreversion pathways were detected. The product distributions were consistent with extrusion of nitrogen gas from 2a-f to yield the singlet 1,3-diradical, closure of which resulted in cyclopropane formation with partial retention of stereochemistry.     

A Convenient One-Pot Synthesis of Indane-1,2,3-triones by Oxidation of Indan-1-ones with N-Bromosuccinimide-dimethyl Sulfoxide Reagent

Indane-1,2,3-triones (2a-f) have been synthesized via bromination of indan-1-ones (1a-f), followed by oxidation of the resulting brominated indan-1-ones with dimethyl sulfoxide in one pot in good yields.     

The synthesis of pyrazolo[1,2-a]pyrazoles. Regio- and stereo-selective 1,3-dipolar cycloadditions of (1Z)-rel-(4R,5R)-1-arylmethylene-4-benzoylamino-5-phenyl-3-pyrazolidinon-1 -azomethinimines

Reaction of rel-(4R,5R)-4-benzoylamino-5-phenyl-3-pyrazolidinone (4) with aromatic aldehydes 5a-f gave the corresponding (1Z)-rel-(4R,5R)-1-arylmethylene-4-benzoylamino-5-phenyl-3-pyrazolidinon-1-azomethinimines 6a-f . 1,3-Dipolar cycloadditions of azomethinimines 6a-f to various dipolarophiles, which were found to proceed regio- and stereo-selectively, afforded the corresponding pyrazolo[1,2-a]-pyrazoles 8a-f, 10 , and 13–16 . Reaction of azomethinimine 6a with hydrogen cyanide gave rel-(5R,6R)-6-benzoylamino-5,6-dihydro-3,5-diphenyl-1-oxo-1H,7H-pyrazolo[1,2-a][1,2,3]triazole (18) as a representative of a new ring system.     

Synthesis of 1-alkoxy-5-alkyluracils

1-Alkoxy-5-alkyluracils 2a-f have been prepared by the reaction of 2-alkyl-3-methoxyacryloyl isocyanates 8a-b with alkoxyamines 9a-c followed by cyclization of the resulting N-alkoxy-N'-(2-alkyl-3-methoxyacryloyl)ureas 10a-f. The isocyanates 8a-b were prepared from ethyl 2-alkylacrylates 3a-b in 5 steps.     

Reaction of E-2-arylidene-1-indanones,Z-aurones,Z-1-thioaurones and Z-2-arylidene-2,3-dihydro-1H-indol-3-ones with diazomethane

1,3-Dipolar cycloaddition of E-2-arylidene-1-indanones 1a-h and Z-aurones 3a-c with diazomethane provided trans-spiro-1-pyrazolines 2a-h and 4a-c , respectively, as sole products. However, the same cycloaddition of Z-1-thioaurones 5a-f afforded a mixture of Z-α-methyl-1-thioaurones 6a-f and trans-cyclopropane derivatives 7a-f as a result of the spontaneous denitrogenation of the initially formed 1-pyrazolines. Similar reaction of Z-2-arylidene-2,3-dihydro-1H-indol-3-ones 8a,b and diazomethane yielded trans-cyclopropanes 9a,b . Structure and stereochemistry of the compounds synthesized have been elucidated by nmr spectroscopic measurements.     

Rearrangement of 3-arylhydantoins into 3-aminoglycocyamidines

The action of hydrazine hydrate on 5-arylidene-3-aryl-2-methylmercaptohydantoins led to ring opening and rearrangement into 5-arylidene-3-amino-N²-aryl-glycocyamidines ( 9a-f ). The structure of the products 9a-f was established and the mechanism of their formation was discussed.     

Zur Synthese von Imidazo(2,1-b)-1,3,4-thiadiazolo(3,2-a)-pyrimidonen-(6)

2-Amino-6-aryl-imidazo(2,1-b)-1,3,4-thiadiazoles (1 a-f) were condensed with 1,3-ketocarboxylates e. g. ethyl-butyroacetate, ethyl-benzoylacetate, 4-nitrobenzoylacetate or ethyl-cyclopentanone(2)-carboxylate and ethyl-cyclohexanone(2)-carboxylate directly to imidazo(2,1-b)-1,3,4-thiadiazolo(3,2-a) pyrimidones-(6) (4 a-f, 5 a-f, 6 d, e, 7 a-f, 8 a, d).

11. Mitt. über Heterocyclen; 10. Mitt.Paul, H., Sitte, A., Wessel, R., Arch. Pharm. (Weinheim), im Druck.     

Synthesis of 2-substituted naphtho[1′,2′:4,5]thiazolo[3,2-b]-1,2,4-triazoles

N-Amination of 2-aminonaphtho[1,2-d]thiazole ( 1 ) with O-mesitylenesulfonylhydroxylamine ( 2 ) afforded the corresponding 2,3-diaminonaphthothiazolium salt 3a . Cyclocondensation of 3a or its free base 3b with appropriate carboxylic acid derivatives 4a-f gave the title compounds 5a-f in satisfactory yields (54–95%). Structures of the products were assigned on the bases of spectral and elemental analyses.     

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids

The synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-benzo-1,4-thiazine-2-carboxylic acids 4a, b, 6a -e is presented. After the condensation of o-aminothiophenols with diethyl 2-bromo-2-methylmalonate in the presence of KF as a catalyst the nitrogen in the fused derivatives 3a, b , was alkylated to provide 5a-f , the corresponding esters 3a, b, 5a-f were hydrolysed.     

Synthesis,structural, conformational and pharmacological study of new fentanyl derivatives of the camphidine system

A series of N-phenethyl-8-β-amidocamphidines 4a-f (3-phenethyl-8-β-(N-arylamido)-3-azabicyclo-[3.2.1]octane) has been designed, synthesized and stereochemically characterized as semirigid analogous of the 4-anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. In deuteriochloroform and deuteriobenzene solution, compounds 4a-f display the same preferred conformation. The cyclopentane and piperidine rings adopt an envelope and distorted chair conformation respectively flattened at N-3, with the N and C-8 substituents in equatorial and axial positions with respect to the piperidine ring. In vivo pharmacological testing demonstrated that compounds 4a-f were inactive in the analgesic test, with the exception of compound 4f which showed an ED₅₀ of 250 mg/kg p.o.     

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.     

(8,9-Dihydro-7H-imidazo[1,2-c][1,3]diazepin-5-yl)-cyanamide und homologe imidazo-bizyklen

The reaction of the 2-(ω-aminoalkyl)imidazoles 4a-f with N-cyanodi-phenylimidocarbonate ( 7 ) leads to appropriately hydrogenated imidazo-[1,5-a]imidazoles, imidazo[1,2-c][1,3]diazepines and imidazo[1,2-c][1,3]diazocines ( 9a-f ), which are similar to (7,8-dihydroimidazo)[1,2-c]pyrimidin-5-yl)cyanamides ( 3 )[1] in respect to their chemical and spectroscopic properties.     

Structure of 5-Amino-4-Arylazopyrazoles in Ethanolic Aqueous Media

The structure and tautomerism of 5-amino-4-arylazopyrazoles (2a-f) are investigated in aqueous media. In solutions of pH>5 these compounds exist as ring N—1 protonated species. At pH>10 they afford anions which are stabilized by delocalization of the negative charge in the ring as well as on the arylazo moiety. Controlled potential electrolysis and polarographic analysis indicate that 2a-f are reduced via a four electron reduction process to triaminopyrazole and the corresponding substituted aniline derivative. A mechanism is suggested and discussed.     

Photocyclization reactions. Part 6. Solvent and substituent effects in the synthesis of dihydrobenzofuranols using photocyclization of 2-alkoxybenzophenones and ethyl 2-benzoylphenoxyacetates

Photocyclization reactions were carried out on 2-alkoxybenzophenones 1a-h and ethyl 2-benzoyl-phenoxyacetates 5a-e in three solvents of different polarity (benzene, acetonitrile and methanol) to examine solvent and substituent effects on the cyclization of 1,5-biradical intermediates to dihydrobenzofuranols. Irradiation of 1a-f in benzene gave dihydrobenzofuranols 4a-f in 80–94% yields. The ratios of cis-and trans-isomers of 4b-f were 12:1 to 1:0, showing stereoselective formation of cis-isomers. On the other hand, irradiation of 1a-f in acetonitrile and methanol gave 4a-f in 68–81% and 7–75% yields, respectively. However, the ratios of cis- and trans-isomers of 4b-f were 3.5:1 to 1.3:1 in acetonitrile and 2.0:1 to 1:1.7 in methanol, showing decreased stereoselectivity. The decrease in stereoselectivity was attributed to intermolecular hydrogen bonding between the hydroxyl group of 1,5-biradicals and solvents (acetonitrile and methanol). Similarly, irradiation of 5a-e in benzene afforded cis-dihydrobenzofuranols cis- 11a-e stereo-selectively. In contrast, irradiation of 5a-e in acetonitrile and methanol gave a mixture of cis- and trans-isomers of 11a-e because of intermolecular hydrogen bonding between the hydroxyl group of 1,5-biradicals and solvents. The cis and trans ratios of 11a-e varied from 1.5:1 to 17.8:1 in acetonitrile and from 2.6:1 to 1:4.5 in methanol. Solvent and substituent effects on the cyclization of 1,5-biradicals and reaction pathways are discussed.