12. Anil-Synthese. 17. Mitteilung. Über die Herstellung von styryl-derivaten des 2-phenyl-4H-1,2,4-triazolo [1,5-a]pyridins

Preparation of styryl derivatives of 2-phenyl-4H-1,2,4-triazolo [1,5-a]pyridine 7-Methyl-2-phenyl- and 2-(3-chloro-4-methylphenyl)-4H-1,2,4-triazolo[1,5-a]-pyridines react with anils of aromatic aldehydes in the presence of dimethyl-formamide and potassium hydroxide at 20–45° to yield the 2-phenyl-7-styryl- and 2-(2-chloro-stilben-4-yl)-4H-1,2,4-triazolo [1,5-a]pyridines respectively (‘Anil Synthesis’). Further, the Schiff's bases derived from o-chloroaniline and 2-(p-formyl-phenyl)- and 7-formyl-2-phenyl-4H-1,2,4-triazolo [1,5-a]pyridine yield, with methyl- and with p-tolyl-substituted heterocycles, the corresponding heterocyclic substituted styryl and stilbenyl derivatives.     

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.     

Anil-Synthese. 23. Mitteilung. Über die Herstellung von Styryl- und Stilbenyl-Derivaten des Pyrimidins

Preparation of Styryl and Stilbenyl Derivatives of Pyrimidines 2- and 4-(p-Tolyl)-substituted pyrimidines react with anils of hetero-aromatic aldehydes in the presence of dimethylformamide and potassium hydroxide or potassium t-butoxide to yield the corresponding 2- and 4-[4″-(heteroaryl)stilben-4′-yl]pyrimidines or the 2- and 4-[a-(heteroaryl)-4′-styryl]pyrimidines respectively (‘Anil synthesis’). Furthermore, the Schiff′s bases derived from p-chloroaniline and 4-(pyrimidine-2-yl and 4-yl)benzaldehydes give, with methyl- and with p-tolyl-substituted heterocycles, the corresponding heterocyclic substituted styryl and stilbenyl derivatives. Alkyl-, alkoxy- or phenyl-substituted pyrimidines undergo also the ‘Anil synthesis’.     

Synthesis of 3-Acyl-1,2-benzisoxazoles

A convenient method for the synthesis of 3-acyl-1,2-benzisoxazoles, which are unstable toward bases, is described. Base-catalyzed cyclization of 2-alkyl- and aryl-1,3-dithian-2-yl o-chlorophenylketoximes 4a-1 gave 3-(2-alkyl- and aryl-1,3-dithian-2-yl)-1,2-benzisoxazoles 8a-1 , which were converted into the corresponding 3-acyl-1,2-benzisoxazoles 1a-1.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides and of N,N-disubstituted 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 4-amino-3-phenyl-3-buten-2-ones (III) occurred in good yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-6-methyl-5-phenyl-1,2-oxathiin 2,2-dioxides, whereas N,N-disubstituted 4-amino-1-phenyl-3-buten-2-ones (IV) did not react at all. Polar 1,4-cycloaddition of dichloroketene to III and IV occurred partly in the case of aromatic N-substitution, with the exception of the morpholino derivative IVd, giving in low yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-(6-methyl-5-phenyl)(6-benzyl)-2H-pyran-2-ones (VII) in good yield. In some cases of aliphatic N,N-disubstitution of III and IV, cycloaddition led directly to N,N-dialkyl derivatives VII in low yield.     

Pyrimidines. 24. Analogues and derivatives of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP)

Preparation of a number of derivatives of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) including the 2-dialkylaminoalkylamino-, 2-hydroxyalkylamino-, 2-ethoxycarbonylamino- and 2-alkylaminocarbonyl-amino- groups substituted on the pyrimidine ring as well as preparation of 1-(alkylaminoalkyl)-4,6-dioxo-8-phenyl-2,3,4,6-tetrahydro-1H-pyrimido[1,2-α]pyrimidines and 3,5-dioxo-7-phenyl-1,2,3,5-tetrahydroimidazo-[1,2-α]pyrimidines with or without the bromo-substitution are reported.     

Pyrimidine derivatives. VII. Nucleophilic reactions of 5-bromo-1-(bromoalkyl)-6-bromomethyl-2,4(1H,3H)-pyrimidinediones

The reactions of 1-(bromoalkyl)-5-bromo-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1) with several nucleophiles were examined as follows: by reaction with sodium methoxide, 6-(bismethoxy)methyl-5-debrominated derivatives 2, 3 , and 4 were prepared; the corresponding di-substituted compounds (side chains in 1-and 6-positions) 5, 6, 7 , and 9 were obtained by treatment with silver nitrate, silver acetate, potassium thiocyanate, and potassium thioacetate; the reaction with thioacetamide and iso-butylamine gave bicyclic compounds [1,4]thiazino[4,3-c]- 11 , pyrazino[1,2-c]- 12 , and [1,4]diazepino[1,2-c]pyrimidinedione 13 , respectively; pyrrolidine, morpholine, and sodium azide afforded the corresponding 6-substituted compounds 14, 15 , and 16 .     

Anil-Synthese. 20. Mitteilung. Über die Herstellung von Stilbenyl-Derivaten des 1,2,4,-Oxadiazols

Preparation of Stilbenyl Derivatives of 1,2,4-Oxadiazoles Schiffs bases derived from 3- and 5-(p-formylphenyl)-phenyl-1,2,4-oxadiazoles and chloroanilines are reacted with various p-tolyl substituted aromatic heterocycles in the presence of dimethylformamide and potassium hydroxide to yield the corresponding heterocyclic substituted stilbenes (‘Anil synthesis’). The reactivity of 5-[4-(chlorophenylimino-methyl)phenyl]-3-phenyl-1,2,4-oxadiazoles is very low and side reactions will predominate.     

The structure of the diazonium coupling products of phenacyl thiocyanate and phenacyl selenocyanate with diazotized 3-phenyl-5-aminopyrazole

The reaction of diazotized 3-phenyl-5-aminopyrazole with phenacyl thiocyanate 1a and phenacyl selenocyanate 1b afforded directly 2-imino-3-(3-phenyl-5-pyrazolyl)-5-benzoyl-2,3-dihydro-1,3,4-thiadiazole monohydrate 9a and 2-imino-3-(3-phenyl-5-pyrazolyl)-5-benzoyl-2,3-dihydro-1,3,4-selenadiazole monohydrate 9b , respectively. The products 9a and 9b were also obtained from the reaction of C-benzoyl-N-(3-phenyl-5-pyrazolyl)formohydrazidoyl bromide 10 with potassium thiocyanate and potassium selenocyanate, respectively. Acetylation, benzoylation, and nitrosation of 9 afforded the corresponding diacetyl, dibenzoyl, and nitroso derivatives 11-13 , respectively. Cyclization of C-benzoyl-N-(3-phenyl-5-pyrazolyl)-nitrilimine 6 was shown to give the pyrazolo [5,1-d]triazole 8 and not the pyrazolo[5,1-c]-as-triazine derivative 7 , as previously reported.     

Attempts to prepare some 3-substituted azolo[1,2-x]azines,intermediates in the synthesis of azaaplysinopsin derivatives

Some 3-substituted pyrrolo[1,2-a]azines 4a-d were prepared in low yields from the corresponding 2-methylpyridines 1a,b and pyrazine derivatives 1c,d by quaternization with methyl bromoacetate followed by treatment with N,N-dimethylformamide dimethyl acetal. Ethyl 2-pyridinylacetate ( 5 ) and 2-pyridinylaceto-nitrile ( 6 ) were converted with 4-(2-bromo-1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone ( 9 ) into pyrrolo[1,2-a]pyridine derivatives 10 and 12 , intermediates in the synthesis of azaaplysinopsins.     

Research on nitrogen heterocyclic compounds. XV. Synthesis of 1H,4H-pyrazolo[4,3f]pyrrolo[1,2-a][1,4]diazepine derivatives

The synthesis of derivatives of 1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine, a new tricyclic nitrogen-containing nucleus is reported. Condensation of arylaldehydes with 4-aminomethyl-1-phenyl-5-(1-pyrryl)pyrazole afforded the title compounds. Bischler-Napieralski intramolecular cyclization of 4-acetamidomethyl-1-phenyl-5-(1-pyrryl)pyrazole was also studied. The reaction led to 6-methyl-1-phenyl-1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine or alternatively to 4-chloromethyl-1-phenyl-5-(1-pyrryl)pyrazole depending on the solvent used.     

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°.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XI. Synthesis of 2H-pyrano[3,2-g]benzothiazole derivatives

Cycloaddition of dichloroketene to N,N-disubstituted 6-aminomethylene-5,6-dihydro-2-phenylbenzothiazol-7-(4H)ones gave in good yield N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-8-phenyl-2H-pyrano[3,2-g]benzothiazol-2-ones II, which are derivatives of the new heterocyclic system 2H-pyrano[3,2-g]benzothiazole. Dehydrochlorination with triethylamine of II afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-8-phenyl-2H-pyrano[3,2-g]benzothiazol-2-ones III in good to moderate yield. The dimethylamino adduct was dehydrochlorinated in high yield by refluxing in toluene, whereas the diisopropylamino adduct gave in low yield 6-(2,2-dichloroethylidene)-5,6-dihydro-2-phenylbenzothiazol-7-(4H)one with the triethylamine treatment. The dehydrochlorinated product IIId (NR₂ = pyrrolidino) was obtained directly in low yield by cycloaddition of dichloroketene to the corresponding enaminone. Full aromatisation of IIIa,g [NR₂ = N(CH₃)₂ and N(CH₃)C₆H₅, respectively] to the corresponding N,N-disubstituted 4-amino-3-chloro-8-phenyl-2H-pyrano-[3,2-g]benzothiazol-2-ones was accomplished with DDQ in refluxing benzene.     

Photoinduzierte 1, 3-dipolare Cycloaddition von 3-Phenyl-2H-azirinen an Azodicarbonsäure-diäthylester. 32. Mitteilung über Photoreaktionen

Irradiation of 2, 2-dimethyl-3-phenyl- ( 1a ), 2, 3-diphenyl-2H-azirine ( 1b ) or the azirine-precursors 1-azido-1-phenyl-propene ( 2a ) and 1-azido-1-phenyl-ethylene ( 2b ), respectively, in benzene in the presence of azodicarboxylic acid diethylester, yields the corresponding 1, 2-carbethoxy-3-phenyl-Δ³-1, 2, 4-triazolines 4a–d (Scheme 1). Refluxing 4 ( a, c or d ) in 0, 2–0, 4M aqueous ethanolic potassium hydroxide leads to the formation of the 1-carbethoxy-3-phenyl-Δ²-1, 2, 4-triazolines 6 ( a, c or d ). Under the same conditions 4b is converted to 3, 5-diphenyl-1, 2, 4-triazole ( 7b , Scheme 2). In 10M aqueous potassium hydroxide solution heating of either 4 ( c or d ) or 6 ( c or d ) yields the 3-phenyl-1, 2, 4-triazoles 7 ( c or d ). Photolysis of 1-carbethoxy-5, 5-dimethyl-3-phenyl-Δ²-1, 2, 4-triazoline ( 6a ) in benzene in the presence of oxygen and trifluoroacetic acid methylester gives the 5-methoxy-2, 2-dimethyl-4-phenyl-5-trifluoromethyl-3-oxazoline ( 13 , Scheme 5). 5, 5-Dimethyl-3-phenyl-1, 2, 4-triazole seems to be the intermediate, which on losing nitrogen gives the benzonitrile-isopropylide ( 3a ).     

Facile synthesis and characterization of novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one and pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine incorporating 1,3-diarylpyrazole moiety

4-(3-(4-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-6-phenyl-2-thioxo-1,2-di hydro-pyridine-3-carbonitrile (1) reacted with ethyl chloroacetate (2) in ethanolic sodium acetate solution to yield the corresponding ethyl (3-cyanopyridin-2-ylsulphanyl)acetate derivative 3. Intramolecular cyclization of compound 3 was achieved by its heating in DMF containing potassium carbonate to afford the corresponding ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate derivative 4 which reacted with hydrazine hydrate in refluxing pyridine to yield the starting material 3-aminothieno[2,3-b]pyridine-2-carbohydrazide derivative 7. Compound 7 reacted with different reagents such as triethylorthoformate, formic acid, acetic acid and acetic anhydride to afford the target molecules pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives 8–10, 12 and 13 in good to excellent yields. On the other hand, pyridine-2(1H)-thione derivative 1 reacted with hydrazine hydrate in refluxing pyridine to give the other starting material 3-amino-1H-pyrazolo[3,4-b]pyridine derivative 20 which reacted with acetylacetone under reflux to afford the target molecule pyrido[2′,3′:3,4]pyrazolo[1,5-a]-pyrimidine derivative 21 in a good yield. The structures of target molecules were elucidated using elemental analyses and spectral data.     

Reaction of sulfene with heterocyclic N,N-disubstituted α-aminomethyleneketones. VII. Synthesis of 1,2-oxathiino-[5,6-g]benzothiazole derivatives

The polar 1,4-cycloaddition of sulfene to N,N-disubstituted 6-aminomethylene-5,6-dihydro-2-phenylbenzothiazol-7-(4H)ones gave, generally in good yield, N,N-disubstituted 3,4,5,6-tetrahydro-8-phenyl-1,2-oxathiino-[5,6-g]benzothiazol-4-amine 2,2-dioxides, which are derivatives of the new heterocyclic system 1,2-oxathiino-[5,6-g]benzothiazole. This reaction did not occur only with the N,N-diphenylenaminone.     

Tetrazole compounds. 8. Synthesis of tetrazolylpyrimidines from tetrazolyl-substituted enamino ketones

Tetrazolyl-substituted enamino ketones 1 react with various amidines 2 to give 5-(1-phenyl-1H-tetrazol-5-yl)pyrimidines 3 . In the case of the chloroacetyl enamine 4 4-(N,N-dimethylaminomethyl)-substituted tetra-zolylpyrimidines 5 were obtained. Subsequent hydrolysis of the 4-trifluoromethyl derivatives 3b, 3d and 3g afforded the corresponding 5-(1-phenyl-1H-tetrazol-5-yl)pyrimidine-4-carboxylic acids 6 .     

Studies on 2,1-benzisoxazoles. Behaviour towards electrophilic substitution and cycloaddition reactions

The behaviour of 2,1-benzisoxazoles (anthranils) towards electrophilic substitutions has been studied. Nitration of 5-chloro-2,1-benzisoxazole (VII) exclusively gives 4-nitro-5-chloro-2,1-benzisoxazole (XII). However, 5-chloro-3-phenyl-2,1-benzisoxazole (VIII) gives dinitrated products XIII, one nitro group entering at position C₇ instead of C₄ of the carbocyclic ring and the other at the 4′ position of the 3-aryl ring. When 6-nitro-3-carbalkoxy-2,1-benzisoxazoles (X and XI) are nitrated, 4-nitroisomers XV and XVI are obtained exclusively. The substituents already present in the carbocyclic ring exert decisive directing influence. While the parent 2,1-benzisoxazole (Ia) fails to react with dimethyl acetylenedicarboxylate, 6-nitro-2,1-benzisoxazole (XVII) and 5-chloro-2,1-benzisoxazole (VII) react to give 1,4-cycloadducts XIX and XX, respectively. These results suggest that 2,1-benzisoxazoles possess benzenoid as well as ortho-quinonoid character.     

Synthesis of 3-alkoxycarbonylaminomethylcarbonylamino-4-benzoyl-1,2-dihydropyridines and their cyclization to 5-phenyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones

The regiospecific reaction of 3-benzyloxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6a) , or 3-t-butoxycarbonylaminomethylcarbonylamino-4-benzoylpyridine (6b) , with either acetyl chloride or ethyl chloroformate, and either n-butylmagnesium chloride or phenylmagnesium bromide afforded the respective 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-benzyloxy (or t-butoxy) carbonylaminomethylcarbonylami-no-4-benzoyl-1,2-dihydropyridines 7 in 60-75% yield. Reaction of 1-acetyl (or ethoxycarbonyl)-2-n-butyl (or phenyl)-3-t-butoxycarbonylaminomethylcarbonyl-4-benzoyl-1,2-dihydropyridines 7b, 7f, 7d, 7h with trifluoroacetic acid gave the corresponding 5-phenyl-8-acetyl (or ethoxycarbonyl)-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b, 8c, 8d respectively in 45–63% yield. N¹-Methylation of 5-phenyl-8-acetyl-9-n-butyl (or phenyl)-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-ones 8a, 8b using sodium hydride and iodomethane yielded the corresponding N¹-methyl derivatives 9a (48%) and 9b (54%). Oxidation of 5,9-diphenyl-8-ethoxycarbonyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8d) using p-chloranil afforded 1,3-dihydro-5,9-diphenyl-2H-pyrido[3,4-e]-1,4-diazepin-2-one (10) . 5-Phenyl-8-acetyl-9-n-butyl-1,3,8,9-tetrahydro-2H-pyrido[3,4-e]-1,4-diazepin-2-one (8a) and the corresponding 8-ethoxycarbonyl analog 8c exhibited weak anticonvulsant activity indicating that 8a and 8c may be acting at the same site as the 7-halo-1,4-benzodiazepin-2-one class of compounds.     

Photolyse des 3-Phenyl-2, 1-benzisoxazols und einiger seiner Derivate in Bromwasserstoffsäure

Photolysis of 3-phenyl-2, 1-benzisoxazole and some derivatives in hydrobromic acid The behaviour of 3-phenylanthranils (3-phenyl-2, 1-benzisoxazoles) towards photolysis in hydrobromic acid differs greatly from that in hydrochloric and sulfuric acid. Thus, reduction and substitution products are obtained. The formation of the reduction products involves hydrogen abstraction by a nitrenium ion species in the triplet state and that of the substitution products can be attributed to a subsequent S_E-bromination.