Synthesis of p-aminobenzamides of aminopiperidazines as potential antiarrhythmic agents

1,2-Dimethyl-4-aminopiperidazine ( 4 ), 1-(2-aminoethyl)2-methylpiperidazine ( 11 ), 2-(2-aminoethyl)-3-meth-yl-2,3-diazabicyclo[2.2.1]heptane ( 16 ), and 1,2-dimethyl-3-aminomethylpiperidazine ( 21 ) have been synthesized. Amines 4, 11 , and 16 were converted to the corresponding p-nitrobenzamides 7,12 , and 17. Catalytic reduction of the latter nitro derivatives gave the corresponding p-aminobenzamides 8,13 , and 18. For comparative studies, the acyclic analog, 4-amino-N[2-(1,1,2-trimethylhydrazino)ethyl]benzamide ( 25 ) was also synthesized. Compounds 8,13 and 25 which are analogs of procainamide were evaluated in the isolated cardiac Purkinje fiber preparation by measuring their effects on the action potential upstroke velocity.     

Naphth[1,2-d]oxazole intermediates in the preparation of 3-hydroxy-4-(1-alkyl-3-methyl-5-hydroxy-4-pyrazolyl)-azo-1-naphthalenesulfonamide dyes

Acylation of 4-amino-3-hydroxy-1-naphthalenesulfonic acid ( 3 ) with benzoyl chloride in pyridine gave pyridinium 3-hydroxy-4-(N-benzoylamino)-1-naphthalenesulfonate ( 12 ) which was converted by thionyl chloride followed by diethylamine into N,N-diethyl-2-phenylnaphth[1,2-d]oxazole-5-sulfonamide ( 14 ). The naphthoxazole moiety was hydrolyzed with potassium hydroxide and the resulting N,N-diethyl-4-amino-3-hydroxy-1-naphthalenesulfonamide ( 11 ) coupled with 1-alkyl-3-methyl-5-pyrazolones. The 2-phenylnaphth[1,2-d]oxazole intermediates and various by-products were investigated.     

Reaction of perfluorinated 1-ethyl-, 1,1-diethyl-, and 1,2-diethylcyclobutabenzenes with pentafluorobenzene in SbF<Subscript>5</Subscript>

Perfluoro(1-ethyl-1,2-dihydrocyclobutabenzene) reacts with pentafluorobenzene in SbF5 to give perfluoro(1-ethyl-2-phenyl-1,2-dihydrocyclobutabenzene). Analogous reaction of a mixture of perfluoro(1,1-diethyl-1,2-dihydrocyclobutabenzene) and perfluoro(1,2-diethyl-1,2-dihydrocyclobutabenzene) leads to the formation (after hydrolysis of the reaction mixture) of perfluorinated 7-phenyl-8,8-diethylbicyclo[4.2.0]octa-1,4,6-trien-3-one, 1,1-diethyl-2-(4-oxocyclohexa-2,5-dienylidene)-1,2-dihydrocyclobutabenzene, and 2-(pent-2-en-3-yl)benzophenone (from the 1,1-isomer) and perfluorinated (E)-1,2-diethyl-1-phenyl-1,2-dihydrocyclobutabenzene, 7,8-diethyl-8-phenylbicyclo[4.2.0]octa-1,4,6-trien-3-one, and 1-[2-(1-phenylprop-1-en-1-yl)-phenyl]propan-1-one (from the 1,2-isomer).     

Pyridyl-substituted porphyrins: I. Synthesis and basicity of monopyridylporphyrins

13,17-Diethyl-2,3,7,8,12,18-hexamethyl-5-(pyridin-2-yl)porphyrin, 13,17-diethyl-2,3,7,8,12,18-hexamethyl-5-(pyridin-2-yl)porphyrin, and 13, 17-diethyl-2,3,7,8,12,18-hexamethyl-5-(pyridin-4-yl)porphyrin were synthesized, and their basic properties were studied by spectrophotometric titration in the system ethanol-sulfuric acid. Concentration ranges for the existence of mono- and dicationic forms of meso-pyridyl-substituted porphyrins and the corresponding ionization constants were determined.     

Anil-Synthese 18. Mitteilung. Über die Herstellung von Styryl-Derivaten des 3-Phenyl-benzisoxazols

Preparation of styryl derivatives of 3-phenyl-benzisoxazole 3-(p-Tolyl)-1,2-or 2, 1-benzisoxazoles and 6-methyl-3-phenyl-1,2-benzisoxazoles react with anils of aromatic aldehydes in the presence of dimethylformamide and potassium hydroxide or potassium t-butoxide to yield the corresponding 3-(stilben-4-yl)-1,2- or 2,1-benzisoxazoles and the 3-phenyl-6-styryl-1,2-benzisoxazoles respectively (‘Anil Synthesis’). Further, the Schiff's bases derived form chloroanilines and 3-(p-formylphenyl)-1,2-benzisoxazoles yield, with methyl-and p-tolyl substituted heterocyles the corresponding heterocyclic substitued styryl and stilbenyl derivatives.     

The photochemical synthesis of novel heterocyclic compounds from s-triazolo[4,3-b]pyridazine (II)

s-Triazolo[4,3-b Jpyridazine (I) photochemically reacted with dihydropyran; 2,3-dihydro-p-dioxin; 2,5-dihydrofuran; 2,5-dimethoxy-2,5-dihydrofuran; and 1,3-dioxep-5-ene to give a new series of substituted pyrrolo[1,2-b]-.s-triazoles (II-IX). In most reactions, two or more products were formed. The following compounds have been prepared from I: 9-methylene-4a,5,6,7,8a,9-hexahydropyrano[2,3 :4,5]pyrrolo[1,2-b]-s-triazole (Ha), the corresponding 9-cyanomethyl product (III), and 9-methylene-4a,7,8,8a-tetrahydro-6H,9H-pyrano[3′,2′:4,5]pyrrolo[1,2-b]-s-triazole (IIb) from dihydropyran; 9-methylene-4a,6,7,8a-tetrahydro-9H-p-dioxino[2′,3′:4,5]-pyrrolo[1,2-6]-s-triazole (IV) from 2,3-dihydro-p-dioxin; 8-methylene-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]pyrrolo[1,2-b]-s-triazole (V) and the corresponding 8-cyanomethyl product (VI) from 2,5-dihydrofuran; 8-cyanomethyl-5,7-dimethoxy-4a,5,7a,8-tetrahydro-7H-furo[3′,4′:4,5]-pyrrolo[1,2-6]-s-lriazole (VII) from 2,5-dimethoxy-2,5-dihydrofuran; and 10-methylene-4a,5,9a,10-tetrahydro-9H-[1,3]dioxepino[5′,6′:4,5]pyrrolo[1,2-b]-s-triazole (VIII) and the corresponding 10-cyanomethyl product (IX) from 1,3-dioxep-5-ene. The addition of several other compounds (1,2,3,6-tetrahydropyridine, 1-acetylimidazole, 3-sulfolene, 2,3-dihydro-p-dithiin, and vinylene carbonate) was attempted, but no reactions were observed.     

Base- and acid-catalyzed condensation reactions of reissert compounds with vinylpyridines

The hydrochloric acid-catalyzed condensation of 2-p-anisoyl-1,2-dihydroisoquinaldonitrile ( 3 ) with 2-vinylpyridine gave 2-(1-isoquinolyl)-3-(2-pyridyl)-5-p-anisylpyrrole ( 4 ), and the corresponding reaction of 3 with 4-vinylpyridine afforded 2-(1-isoquinolyl)-3-(4-pyridyl)-5-p-anisylpyrrole (5). The condensation of the lithium salt of 3 with 4-vinylpyridine gave α-(4-pyridyl)-β-(1-iso-quinolyl)-p-methoxypropiophenone ( 10 ), which was cyclized to 2-(4-pyridyl)-3-p-anisylpyrrolo-[2,1-a]isoquinoline (7) by the action of concentrated hydrochloric acid. 2-(4-Pyridyl)-3-phenyl-pyrrolo[2,1-a]isoquinoline ( 6 ) and 2-(2-pyridyl)-3-p-anisylpyrrolo[2,1-a]isoquinoline ( 8 ) were prepared by analogous sequences of reactions.     

Spirans XX. Synthesis of 8,8-dialkylazaspiro[4.5] decanes and 9,9-dialkylazaspiro[5.5]undecanes

N-(2-Dimethylaminopropyl)-8,8-dimethyl-2-azaspiro[4.5]decane ( 1 ), N-(2-dimethylaminopropyl)-8,8-diethyl-2-azaspiro[4.5]decane ( 2 ), N-(3-dimethylaminopropyl)-9,9-dimethyl-3-azaspiro[5.5]undecane ( 3 ), and N-(3-dimethylaminopropyl)-9,9-diethyl-3-azaspiro[5.5]undecane ( 4 ) have been synthesized from 4,4-dimethylcyclohexanone ( 5 ) and 4,4-diethylcyclohexanone ( 6 ). Biological evaluation of these amines showed significant inhibition of cancer cell growth in human cancer cells grown in tissue culture.     

Effect of Substituents,Solvent, and Temperature on the Reactivity of the Zwitterionic Peroxides Arising from the Photo-Oxygenation of 2-(Methoxymethylidene)- and 2-(Phenoxymethylidene)adamantane

The photo-oxygenation of 2-(methoxymethylidene)adamantane ( 3 ) creates a zwitterionic peroxide which may be captured by acetaldehyde to give the corresponding pair of diastereoisomeric tricyclo[3.3.1.1^3,7]decane-2-spiro-6′ -(3′ -methyl-5′ -methoxyl′, 2′, 4′ -trioxanes) ( 4 ). Ease of capture depends strongly on solvent polarity and temperature. When these are low, yields of trioxine are high (～ 80%). Conversely, 1,2-dioxetane formation is favoured at high temperature and solvent polarity. 2-(Phenoxymethylidene)adamantane ( 5 ), on photo-oxygenation, only gives the corresponding 1,2-dioxetene, even in the presence of acetaldehyde. From a Hammett, study of the-oxygenation of the enol ether 5 and p-methoxy, p-methyl, p-chloro and m-chloro derivatives, 9, 11, 13 , and ( 15 ), a good linear relation was found between substituent constants and oxygenation rates which yielded reaction constants (ρ) of 2.59, ?2.40, ?1.09, and ?0.90 in benzene, AcOET, CH₂Cl₂, and MeOH respectively. This data to the formation of a zwitterionic peroxide which enjoys stabilization from its won substituents and by competing solvation and further explains the predominance of dioxetane to the detriment of trioxane formation.     

Synthesis of certain 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridines structurally related to nicotinamide ribonucleoside

Several substituted 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridines have been prepared as congeners of nicotinamide ribonucleoside. Direct glycosylation of the silylated 3-ethylcarboxylate 5 or 3-carbamoyl 6 derivative of 1,2-dihydro-2-oxopyridine with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose ( 7 ) in the presence of trimethylsilyl triflate gave the corresponding blocked nucleosides 8 and 9 , respectively in good yield. Ammonolysis of 8 and 9 with methanolic ammonia furnished 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridine-3-carboxa-mide ( 10 ), the structure of which was established by single-crystal X-ray diffraction analysis. Thiation of 9 with Lawesson's reagent and subsequent deacetylation of the thiated product 11 with methanolic ammonia furnished 1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridine-3-thiocarboxamide ( 12 ). Modification of the carbo-nitrile function of 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2-dihydro-2-oxopyridine-4-carbonitrile ( 13 ) gave a series of 4-substituted-1-β-D-ribofuranosyl-1,2-dihydro-2-oxopyridines, in which the 4-substituent is a thiocarboxamide 15 , carboxamide 16 , carboxamidoxime 17 , carboxamidine 18 and aminomethyl 19 group. None of these compounds exhibited any significant antitumor or antiviral effects in vitro.     

Carbon-nitrogen bond formation in cyclisation by deoxygenation,thermolysis or photolysis of phenylimidazo[1,2-a][1,8]naphthyridines

Triethyl phosphite deoxygenation of 2-(2-nitrophenyl)imidazo[1,2-a][1,8]naphthyridine (3) led to the C-insertion to give the indoloimidazonaphthyridine 5. Our attempt to promote the N-insertion by blocking the C-3 position failed. Triethyl phosphite deoxygenation of 1-nitroso-2-(4-fluorophenyl)imidazo[1,2-a][1,8]-naphthyridine (12) led to the corresponding amine structure (15). Thermolysis and photolysis of 6,8-dimethyl-2-(2-azidophenyl)imidazo[1,2-a][1,8]naphthyridine (17) are also reported.     

Cheritamine,A New N-Fatty Acyl Tryptamine and Other Constituents from the Stems of Annona cherimola

A new N-fatty acyl tryptamine, cheritamine ( 30 ), along with thirty-two compounds including nineteen benzenoids, p-hydroxybenzadehyde ( 1 ), p-hydroxybenzoic acid ( 2 ), methylparabene ( 3 ), 3-chlorobenzoic acid ( 4 ), vanillin ( 5 ), isovanillin ( 6 ), vanillic acid ( 7 ), isovanillic acid ( 8 ), methyl vanillate ( 9 ), methyl isovanillate ( 10 ), syringaldehyde ( 11 ), syringic acid ( 12 ), 3,4,5-trimethoxybenzoic acid ( 13 ), trans-methyl p-coumarate ( 14 ), ferulic acid ( 15 ), p-dihydrocoumaric acid ( 16 ), 3-(4-hydroxy-3,5-dimethoxyphenyl)-1,2-propanediol ( 17 ), 3,4,5 -trimethoxyphenyl-β-D-glucopyranoside ( 18 ) and thalictoside ( 19 ); one p-quinone, 2,6-dimethoxy-p-quinone ( 20 ); one purine, uridine ( 21 ); eight alkaloids, nicotinic acid ( 22 ), thalifoline ( 23 ), doryphornine ( 24 ), (–)-norstephalagine ( 25 ), (-)-romucosine ( 26 ), (+)-pronuciferine ( 27 ), (+)-norisocorydine ( 28 ) and oxoasimilobine (29) and three steroids, β-sitosterol-D-glucoside ( 31 ), stigmasterol-D-glucoside ( 32 ) and 6′-(β-sitosteryl-3-O-β-glucopyranosidyl)hexadecanoate ( 33 ), are isolated from the stems of Annona cherimola. These compounds were characterized and identified by physical and spectral evidence.     

Chemistry of sulfonyl isocyanates and sulfonyl isothiocyanates. XI. Cyclizations with epoxides

4-Toluenesulfonyl isocyanate cyclized with 1,2-epoxy-3-phenoxypropane and 2,3-epoxypropyl 4-methoxyphenyl ether, respectively, to give 3-(4-toluenesulfonyl)-5-phenoxymethylene-2-oxazolidone ( I ) and 3-(4-toluenesulfonyl)-5-(4-methoxyphenoxymethylene)-2-oxazolidone ( II ). Compounds I and II were hydrolyzed in 2 M sodium hydroxide solution to the corresponding uncyclized hydroxy amides, VII and VIII. Compound I was remarkably stable toward 6 M hydrochloric acid and amines. Styrene oxide, 1,2-epoxybutane, 3-chloro-1,2-epoxypropane, and 1-methoxy-2-methylpropylene oxide reacted with the isocyanate to afford 3-(4-toluene-sulfonyl)-4-phenyl-2-oxazolidone (III), 3-(4-toluenesulfonyl)-4-ethyl-2-oxazolidone ( IV ), 3-(4-toluenesulfonyl)-5-chloromethyl-2-oxazolidone ( V ), and 3-(4-toluenesulfonyl)-4,4-dimethyl-5-methoxy-2-oxazolidone ( VI ), respectively. The yield of VI was constant over a temperature range of 25–90°.     

Potential psychotropic agents. 7-Chloro-9-phenyl-3,3-diethyl-3H-pyrazolo-[5, 1-b]quinazolin-10-ium-2-olate and 9-Chloro-2,3,4,5-tetrahydro-1-methyl-3,3-diethyl-7-phenyl-1H-benzo-1,5,6-triazonine-2,4-dione

2-Amino-5-chloro-α-phenylbenzylidene hydrazone ( 1 ) or its methyl derivative 2 or acetyl derivative 10 react with diethylmalonic esters to give the corresponding malonyl derivatives 3, 4 and 8 . These esters were hydrolyzed to the acids 5 and 6 . Treating 5 with dehydrating agents the mesoionic compound 7-chloro-9-phenyl-3,3-diethyl-3H-pyrazolo[5,1-b]quinazolin-10-ium-2-olate (14) was obtained, while the methyl derivative 6 afforded the desired 9-chloro-2,3,4,5-tetrahydro-1-methyl-3,3-diethyl-7-phenyl-1H-benzo-1,5,6-triazonine-2,4-dione ( 17 ). Some derivatives of these compounds were also described. The structures of the new compounds were confirmed by an alternative synthesis and by mass and prnr spectral data.     

Synthesis and characterization of model compounds for carbazole-substituted N-acylated linear polyethylenimine (PEI). Synthesis and 1H-NMR spectra of N-acylated diethylamine and N,N′-dimethyl-1,2-ethanediamine containing 9-carbazolylacetyl, (R,S)- or (R)-2-(9-carbazolyl)propanoyl groups

The synthesis of N,N-diethyl-9-carbazolylacetamide ( 6 ), (R,S)- and (R)-N,N-diethyl-2-(9-carbazolyl)propanamide ( 7 ), N,N′-dimethyl-N,N′-di-(9-carbazolylacetyl)-1,2-ethanediamine ( 11 ), and (R)-N,N′-dimethyl-N,N′-di[2-(9-carbazolyl)propanoyl]-1,2-ethanediamine ( 13 ) is reported. The racemic compound, (R,S)-2-(9-carbazolyl)propanoic acid ( 2 ), was resolved by partial crystallization of the diastereomeric salts formed between 2 and (+)-α-methylbenzylamine. The ¹H-NMR spectra of 6 and 7 showed magnetic nonequivalence of the chemically equivalent protons of the methyl and methylene groups in 6 and 7 due to partial double bond character of the amide bond. The upfield resonances corresponding to the two sets of methyl and methylene protons were assigned by the aromatic solvent-induced shift (ASIS) method to the protons anti to the carbonyl oxygen in the conformation of amide bond in 6 and 7 . The ¹H-NMR spectra of 11 and (R)- 13 were used to determine the population of anti-anti, anti-syn (syn-anti) and syn-syn conformers in the structures of these dimer model compounds; the relative conformer populations were 0.45:0.47:0.08 and 0.28±0.02:0.29±0.01:0.43±0.01 in 11 and (R)- 13 .     

Synthesis of analogs of amrinone: 4-(3,4-Disubstitutedphenyl)pyridines and derivatives thereof

4-(3,4-Dimethoxyphenyl)pyridine ( 5c ) prepared by the coupling of 3,4-dimethoxyphenyldiazonium chloride with pyridine was converted to 4-(4-pyridinyl)benzene-1,2-diol ( 6c ) by treating with hydrobromic acid. Diazotization of 4-(4-pyridinyl)benzeneamine ( 7 ) and 3-(4-pyridinyl)benzeneamine ( 12 ) gave the corresponding phenols 8 and 13 which were nitrated to give 2-nitro-4-(4-pyridinyl)phenol ( 9 ) and 2-nitro-5-(4-pyridinyl)-phenol ( 14 ), respectively. Reduction of these nitrophenols gave the corresponding aminophenols 10 and 16 which in turn were reacted with N,N'-carbonyldiimidazole to yield benzoxazolones 11 and 17 , respectively. Catalytic reduction of 2-nitro-4-(4-pyridinyl)benzeneamine ( 18 ) gave 4-(4-pyridinyl)benzene-1,2-diamine ( 19 ) which was reacted with orthoesters, urea, tetraethoxymethane, and N,N'-di(carbomethoxy)methylpseudothiourea to give the corresponding benzimidazole derivatives 20, 21, 22 , and 23 .     

Irreversible enzyme inhibitors. CXI. Candidate active-site-directed irreversible inhibitors of dihydrofolic reductase derived from 4,6-diamino-1,2-dihydro-l-phenyl-s-triazines. V.

Condensation of 5-(p-nitrophenyl)-2-pentanone with phenylbiguanide hydrochloride (V) gave a 2-methyl-2-(p-nitrophenylpropyl)-1,2-dihydro-s-triazine (IX); hydrogenation of the nitro group to amino followed by bromoacetylation afforded the candidate irreversible inhibitor of dihydrofolic reductase, namely, 2-(p-bromoacetamidophenylpropyl)-4,6-diamino-1,2-dihydro-2-methyl-s-triazine hydrochloride (VIII). Similarly, the o, m, and p-isomers of 5-nitrophenoxy-2-pentanone were converted to the corresponding 2-(bromoacetamidophenoxypropyl)-1,2-dihydro-s-triazines (XI). The four candidate irreversible inhibitors were evaluated on the dihydrofolic reductases from pigeon liver, Walker-256 rat tumor, and L-1210/FR8 mouse leukemia. Only VIII was an irreversible inhibitor; VIII slowly inactivated the L-121-/FR8 mouse leukemia enzyme with a half-life of 2–3 hours at 37°, but VIII showed no inactivation of the other two dihydrofolic reductases—a species specific inactivation.     

Convenient synthesis of fused heterocycles from α-ketohydroximoyl chlorides and heterocyclic amines

Nitroso derivatives of imidazo[1,2-a]pyridine ( 11, 13, 14 ), imidazo[1,2-a]pyrimidine ( 15 ), imidazo[1,2-a]pyrazine ( 16 ), imidazo[1,2-b]pyrazole ( 17 ), and imidazo[1,2-b]-1,2,4-triazole ( 19 ) were obtained in good yields from α-ketohydroximoyl chlorides 3 and 2-aminopyridines ( 4–6 ), 2-aminopyrimidine ( 7 ), 2-aminopyrazine ( 8 ), 5-amino-3-phenylpyrazole ( 9 ), and 3-amino-2H-1,2,4-triazole ( 10 ), respectively. Under different conditions, the reaction of 3 with 3-amino-2H-1,2,4-triazole ( 10 ) and 2-aminopyrazine ( 8 ) afforded the noncyclized substitution products 18 and 22 , respectively. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible.     

11. Anil-Synthese. 16. Mitteilung. Über die Herstellung von styryl-derivaten des 2-phenyl-imidazo [1,2-a]pyridins

Preparation of styryl derivatives of 2-phenyl-imidazo [1, 2-a]pyridine 2-(p-Tolyl)-imidazo [1, 2-a]pyridines and 7-methyl-2-phenyl-imidazo [1,2-a]-pyridines can be converted, in dimethylformamide, on reaction with anils of aromatic aldehydes in the presence of potassium hydroxide or potassium t-butoxide, into the corresponding 2-(stilben-4-yl)- and 2-phenyl-7-styry1-imidazo [1, 2-a]-pyridines (‘Anil-Synthesis’). The 2-(p-tolyl)-imidazo [1,2-a]pyridines react far less readily than the 7-methyl-2-phenyl-imidazo[1,2-a]pyridines.     

Expansion of the pentafluorobenzene ring and other skeletal transformations in the reaction of perfluoro(1,2-diethyl-1-phenyl-1,2-dihydrocyclobutabenzene) with antimony pentafluoride

The reaction of perfluoro(1-phenyl-1,2-diethyl-1,2-dihydrocuclobutabenzene) with SbF5 at 20°C, followed by treatment of the reaction mixture with water gave perfluoro {4-[1-(2-propylphenyl)propylidene]-2,5-cyclohexadien-1-one} together with perfluoro[4b,10-diethylbenzo[a]azulen-7(4bH)-one] resulting from unusual expansion of the pentafluorobenzene ring to seven-membered ring. Analogous reaction at 90°C, apart from the above compounds, afforded perfluorinated 10-ethyl- and 3,10-diethylbenzo[a]azulen-6(10H)-ones via elimination of C₂F₅ group from the seven-membered ring or its migration to the benzene ring.