Quinazolines and 1,4-benzodiazepines. LXI. Syntheses of 7-Acetyl-1,4-benzodiazepines

Methods for the synthesis of the biologically active 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 6 ) are described. This includes two new methods for the preparation of 5-acetyl-2-aminobenzophenone ( 4 ). The crucial steps in these syntheses involve, respectively, the oxidation of an ethyl group to an acetyl group with permanganate or ceric ions ( 2 → 3; 5 → 6 ), the selective reaction of methyl lithium with the cyano group of 7-cyano-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 8 ) and the efficient condensation of benzyl cyanide with the ethylene ketal of p-nitroacetophenone to form the anthranil 11 .     

Quinazolines and 1,4-benzodiazepines LXVIII. 5-Heterocyclic-substituted benzodiazepinones

The synthesis of a number of new 1,4-benzodiazepin-2-ones containg the 2-thiazolyl, 5-isothiazolyl, 1-rnethyl-2-imidazolyl. 1-methyl-5-pyrazolyl, and 3,5-dimethyl-4-isoxazolyl groups in the 5-position of the benzodiazepine ring are described.     

Quinazolines and 1,4-benzodiazepines. XCV. Synthesis of 1,4-benzodiazepines by ring expansion of 2-chloromethylquinazolines with carbanions

1,4-Benzodiazepines bearing a carbon substituent at the 2-position were obtained by reaction of 2-chloromethylquinazoline 3-oxides with stabilized carbanions. The carbanions of alkyl acetates, N,N-disubstituted acetamides, acetonitrile, dimethylsulfone, N,N-dimethyl methanesulfonamide and 2-methylpyridine were successfully applied. The conversion of some of the 2-carbon substituted 1,4-benzodiazepines to imidazo[1,5-a][1,4]benzodiazepines and [1,2,5]oxadiazino[5,4-a][1,4]benzodiazepines is described.     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

Quinazolines and 1,4-benzodiazepines. XCIV. Pyrazino[1,2-a][1,4]benzodiazepines

A series of pyrazino[1,2-a][1,4]benzodiazepines were prepared by acylating the primary amino group of an α-amino-1,4-benzodiazepine-2-ylideneacetic acid ester ( 1 ) with α-chloroacyl chlorides followed by cyclo-dehydrohalogenation with triethylamine in dimethylformamide. Some pharmacological data for CNS-activity are discussed.     

Quinazolines and 1,4-benzodiazepines. XCVI. Compounds derived from benzodiazepine-2-acetic acid

1,4-Benzodiazepine-2-acetic acid derivatives were prepared and converted to compounds with a heterocyclic ring fused to the a-face of the benzodiazepine system. Representatives of pyrido[1,2-a][1,4]benzodiaze-pines, pyrimido[1,6-a][1,4]benzodiazepines and [1,3]oxazino[3,4-a][1,4]benzodiazepines are described. Some of the compounds showed marked CNS-activity as measured by the antimetrazole test which is a well established primary screening method for assessment of benzodiazepine type activity.     

Quinazolines and 1,4-benzodiazepines. LXXVIII Pyrazolo[1,5-a] [1,4]-benzodiazepines and Imidazo[1,5-a] [1,4]benzodiazepinones

The syntheses of novel 8-chloropyrazolo[1,5-a][1,4]benzodiazepines and of an imidazo-benzodiazepinone utilizing products from the nucleophilic substitution of fluorine in 2-fluoro-5-nitrobenzophenone ( 1 ) by pyrazole-3,5-dicarboxylic acid, dimethyl ester ( 2 ) and by 2-methyl-imidazole-4,5-dicarboxylic acid, diethyl ester ( 30 ) are described.     

Quinazolines and 1,4-benzodiazepines LXXXII. Reaction of 2-hydrazino-benzodiazepines with 1,3-diearbonyl compounds

The 2-hydrazinobenzodiazepines 1 were reacted with acelylacelone to form the hydroxy-pyrazolines 2 which were converted to the triazolobenzodiazcpines 6 and the 2-pyrazolyl-benzodiazepine 4 . Ring cleavage of the hydrazone 8 obtained from cyclohexane-1,3-dione and 1a led similarly to the 1-(4-oxopentyl)triazolol)enzodiazepine 12 .     

Divergent regioselective synthesis of 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones and 5H-1,4-benzodiazepines

A novel and simple one-pot synthesis of 3-substituted 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones from 1,2-diaza-1,3-dienes (DDs) and N-unsubstituted aliphatic 1,3-diamines is described. Here we also report a procedure to selectively obtain alkyl 5H-1,4-benzodiazepine-3-carboxylates from the DDs and 2-aminobenzylamine. Both processes occur by means of sequential 1,4-conjugated addition followed by regioselective 7-exo cyclization. The behavior of N-methyl- and N,N'-dimethyl-1,3-diaminopropanes toward the DDs furnished pyrazol-3-ones and bis-α-aminohydrazones, respectively.     

Synthesis of 5-amino-2,3-dihydro-1H-1,4-benzodiazepines

A number of 5-amino-2,3-dihydro-lH-1,4-benzodiazepines (II) have been prepared from the reaction of 5-methylmercapto-2,3-dihydro-1H-1,4-benzodiazepine (I) with amines. Another alternate approach based on the cyclodehydration of the ureic compounds (IV) was unsuccessful. The synthesis of I was accomplished by methylation of the 1,2,3,4-tetrahydro-5H-5-thioxo-1,4-benzodiazepine (VI) with dimethyl sulfate in methanol-dioxane. Another attempted method for the synthesis of I is also presented. J. Heterocyclic Chem., 14, 985 (1977)     

Quinazolines and 1,4-benzodiazepines. LXXXVII. Synthesis of 1- and 3-phenylimidazo[1,5-a] [1,4]benzodiazepines

The synthesis of the 1-phenylimidazobenzodiazepine 5 from 1 and the anion of the nitrone 2 is described. The 3-phenyl-derivative 14 was prepared via the ammo alcohol 11 which was obtained by condensation of the nitrosamine 9 with benzaldehyde followed by catalytic hydro-genolysis of the nitroso group.     

Quinazolines and 1,4-benzodiazepines LXXIX. 8-nitro-pyrazolo[1,5-a]-[1,4] benzodiazepines

The preparation of 8-nitro substituted pyrazolobenzodiazepines from 2-fluoro-5-nitrobenzo-phenone ( 1 ) and 3,5-diacetoxymethylpyrazole ( 2 ) is reported.     

Quinazolines and 1,4-benzodiazepines. XCIII. Synthesis of imidazo[1,5-a][1,4]benzodiazepines from nitrooximes

The displacement of the nitro group in nitrooximes by other nucleophiles was used to prepare various 2-(hydroxyimino)methyl- and 2-(methoxyimino)methyl-1,4-benzodiazepines. These compounds were converted to imidazo[1,5-a][1,4]benzodiazepines bearing a tertiary amine, methoxy or thiomethyl group in the 3-position.     

Quinazolines and 1,4-benzodiazepines. LXXXV syntheses of 3-substituted lmidazo[1,5-a] [1,4]benzodiazepines

1,4-Benzodiazepines having a leaving group in the 2-position were condensed with carbanions of 1,3-dicarbonyl compounds. The products obtained were converted to the title compounds by a sequence of steps involving hydrolytic decarboxylation, nitrosation, catalytic hydrogenation and condensation with an orthoester or an amide acetal. Oxidative condensation of the enediamine 12 with a variety of aldehydes also led to imidazo-benzodiazepines with various substituents in the 1-position.     

Quinazolines and 1,4-benzodiazepines. LXXIII. The ring expansion of 2-chloromethylquinazoline 3-oxides with nitromethane

The reaction of 2-chloromethylquinazoline 3-oxides (3) with the anion of nitromethane gave the 2-nitromethylene benzodiazepine oxides (4) as a result of ring expansion. Other nucleophiles led only to products derived from substitution of the halogen. The ring expansion of 2,2-dichloro-1,2-dihydroquinazolines with nitromethane anion is also described.     

Quinazolines and 1,4-benzodiazepines XXXVI . The formation of 1,3-dihydro and 1,5-dihydro-1,4-benzodiazepines from tosyl and Mesyl - substituted 1,3,4,5-tetrahydro-5-phenyl- 1,4-benzodiazepine derivatives

The treatment of 4-sulfonyl derivatives of 5-phenyl-1,3,4,5-tetrahydro-1,4-benzodiazepin-2-ones (I) with base was shown to result in the formation of 1,3-dihydro or 1,5-dihydro-1,4-benzodiazepin-2-ones (III and II respectively) depending upon the conditions used. The base treatment of 1-sulfonyl substituted 2,3-dihydro-1,4-benzodiazepines (V) was shown to give the vinylimines VI.     

Quinazolines and 1,4-benzodiazepines. LXXI. Reactions of 2-(triazol-4-yl)benzophenones

Some new triazolylbenzophenones 3 were prepared by reaction of the corresponding quinazolines 2 with formic acid. Conversions of compounds 3 to known triazolobenzodiazepines are described. One of the processes proceeds via the double bond isomer 13 . The reaction of the aldehyde 9 with hydrazine interestingly yielded the triazoloquinolines 11 and 12 . The cyclization of the benzophenones 3 to the triazoloindoles 15 and the alkylation of the latter to derivatives with basic and acidic side chains are also reported. Quaternization of compound 16 with ethyl bromoacetate followed by treatment with hydroxide resulted in the formation of the triazinoindole 12 .