The chemistry of 2-aminobenzoyl hydrazides. 1. Effects of orthoester substituents on the mode of cyclization

Treatment of substituted 2-aminobenzoyl hydrazides with orthoesters has been found to yield different products depending upon the type of orthoester employed. Equimolar quantities of orthoester and hydrazide yield 3-amino-4(3H)-quinazolinones, whereas utilization of a two-fold excess (or greater) of orthoester yields, in some cases, 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones as minor products in addition to N-[4(3H)-quinaz-olinon-3-yl]imidate esters as major products. Treatment of hydrazides with trimethyl orthobenzoate yields substituted 5-(2-aminophenyl)-1,3,4-oxadiazoles and 3,4-dihydro-5H-1,3,4-benzotriazepin-5-ones. The steric bulk of the phenyl group in trimethyl orthobenzoate effects the formation of adduct at the β-nitrogen of the hydrazide which cyclized to the oxadiazole and benzotriazepinone products. In the aliphatic orthoester series, the formation of adduct to the aromatic amino group appears to be favored which gives rise to quinazolinone and benzotriazepinone products.     

Direct introduction of heterocyclic residues into 1,2,4-triazin-5(2H)ones

3-Aryl-1,2,4-triazin-5(2H)-ones 1a-c react with indoles 2a-c in trifluoroacetic acid/chloroform or in boiling butanol or acetic acid to give 3-aryl-6-(indolyl-3)-1,6-dihydro-1,2,4-triazin-5(2H)-ones 3a-g . Oxidation of the dihydro-1,2,4-triazin-5(2H)-ones 3a-e afforded 6-(indolyl-3)-1,2,4-triazin-5(2H)-ones 4a-e , products of nucleophilic substitution of hydrogen in 1a-c . Refluxing 1b with N-methylpyrrote 5b in butanol for an extended time resulted in the formation of 3-(4-chlorophenyl)-6-(1-meuiylpyrrolyl-2)-1,2,4-triazin-5(2H)-one 4h. The reaction of 1a-c with indoles 2a-c , pyrroles 5a,b , 1,3-dimethyl-2-phenylpyrazol-4-one (8) and aminothiazoles 9a,b in acetic anhydride affords the 1-acetyl-3-aryl-6-hetaryl-1,6-dihydro-1,2,4-triazin-5(2H)-ones 6a-s . Reaction of 1a-c with N-methyl-pyrrole 5b in acetic anhydride gives beside the 1:1 addition products 6h-k also the 2:1 addition products 7a-c .     

Alkaline condensation of 9,10-phenanthrenedione with N,N-dialkylguanidines. A novel synthesis of 2′-(dialkylamino)spiro[9H-fluorene-9,4′-[4H]imidazol]-5′(3′H)ones

9,10-Phenanthrenedione was reacted with equimolar amounts of N,N-dimethylguanidine or creatine in 0.2 N potassium hydroxide in ethanol-water, 7:3 to obtain 2′-(dimethylamino)spiro-[9H-fluorene-9,4′-[4H]imidazol]-5′(3′H)one or N-(3′,5′-dihydro-5′-oxospiro[9H-fluorene-9,4′-[4H]imidazol]-2′-yl)-N-methylglycine, respectively. These products are the first derivatives of this ring system with 2′-amino substituents. Formation of these products accounts for the previously reported absence of fluorescence when 9,10-phenanthrenedione reacts with N,N-di-substituted guanidines.     

Tetrazole compounds. 9. A new approach to tetrazolyl-substituted quinoline derivatives

The acid-catalyzed reaction of 1-aryl-5-(2-dimethylaminovinyl)-1H-tetrazoles 2 with arylamines suitably functionalized in the ortho-position resulted in Z-configurated transamination products which were cyclized to novel 3-tetrazolylquinolines by the action of sodium ethoxide. Thus, on reacting 2 with 2-aminoacetophenone or 2-aminobenzophenone, respectively, the 2-[2-(1-aryl-1H-tetrazol-5-yl)vinyl-amino]aryl ketones 3a-g were obtained, the cyclization of which gave 4-substituted 3-(1-aryl-1H-tetrazol-5-yl)quinolines 4 . In the case of the transamination products 3h-1 , prepared from 2 and methyl anthranilate, the ring closure afforded 3-(1-aryl-1H-tetrazol-5-yl)-1H-quinolin-4-ones 5 . Starting from 2 and anthranilonitrile 4-amino-3-(1-aryl-1H-tetrazol-5-yl)quinolines 10 were obtained via the corresponding intermediates 9 .     

The reactions of 4-dicyanomethylene-2-phenyl-4H-1-benzopyran and some benzologs with nucleophiles

4-Dicyanomethylene-2-phenyl-4H-1-benzopyran (1) reacts with primary amines under mild conditions to give 4-imino-3-alkyl-5-alkylimino-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]-pyridine derivatives which, in turn, are hydrolyzed with acid to 4-imino-3-alkyl-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones. When more vigorous conditions are employed for the reactions of 1 with primary amines, Dimroth rearrangements take place and the products are derivatives of 4-alkyl- (or aryl)amino-5-alkyl- (or aryl)imino-2-phenyl-5H-[1]benzopyrano-[3,4-c]pyridine. The latter compounds are hydrolyzed by acid to the corresponding 5-pyridone derivatives. The reaction of 1 with piperidine gives 2-phenyl-4-piperidyl-5H-[1]benzopyrano-[3,4-c]pyridin-5-one. Sodium methoxide reacts with 1 to give 3-cyano-2-methoxy-4-(2-hydroxyphenyl)-6-phenylpyridine. Two benzologs of 1 have been allowed to react with primary and secondary amines and the products are analogous to those obtained from 1 .     

Synthesis via pummerer intermediates. II.. Disproportionation reactions of 3-(methylsulfinyl)chromones and 3-(methyl-sulfinyl)quinolinones with hydrochloric acid

Sulfoxides ( 1 and 10 ) gave oxidation-reduction products when treated with 5N hydrochloric acid. 8-Methoxy-3-(methylsulfinyl)-4H-benzopyran-4-one (1) gave 8-methoxy-3-(methylthio)-4H-1-benisopyran-4-one ( 4 ) and 8-methoxy-3-(methylsulfonyl)-4H-1-benzopyran-4-one ( 5 ), whereas 1-melhyl-3-(methylsulfinyl)-4(1H)quinolinone ( 10 ) gave 1-methyl-3-(methylthio)-4(1H)-quinolinone ( 12 ) and 1-methyl-4(1H)-quinolinone ( 13 ).     

1,3-Dipolar cycloadditions of diazoalkanes to pyridazine derivatives. Thermal 1,5-sigmatropic rearrangement of methyl groups in 3,3-dimethyl-3H-pyrazolo[3,4-d]pyridazine derivatives

Thermal 1,5-sigmatropic rearrangements of one of the methyl group attached at position 3 of 3,3-dimethyl-3H-pyrazolo[3,4-d]pyridazin-4(5H)-ones 1–3 taking place either in a clock-wise or anti-clockwise direction gave N₂-methylated products 4–6 and C_3a-methylated products 7– 9 . The -7(6)-one derivative 10 and -4,7(5H,6H)-dione derivative 12 gave only N₂-methylated products 11 and 13 respectively, and 1,2-dihydro derivative 14 produced after elimination of methane, 15 .     

Amino acids in the synthesis of heterocyclic systems. Synthesis of γ-(5-(1,2,4-Triazinylidene))-α,β-dehydro-α-amino acid derivatives and 6H-pyrido[1,2-d][1,2,4]triazin-6-ones

5-(1,2,4-Triazinyl) substituted enamines 3 react with 5(4H)-oxazolones 4 in acetic anhydride to give acetylated products 5 , while in toluene-acetic acid mixture nonacetylated products 9 are formed. Both types of products were isolated as (E,Z) mixtures. Compounds 5 and 9 rearrange into 6H-pyrido[1,2-d]-[1,2,4]triazin-6-ones 12 by heating in formic acid or in xylene, respectively. Compounds 5 are transformed in the presence of nucleophiles, such as sodium alkoxides or sodium amides via anionic form 10 into corresponding esters 13 and amides 14 of γ-(5-(1,2,4-triazinylidene)) substituted derivatives of α-amino-2-butenoic acid, which exist in 2-(Z),4-(Z) form.     

Five-membered 2,3-dioxo heterocycles: LXIX. Direct heterocyclization of [3,4-dihydroisoquinolin-1(2H)-ylidene]-acetamides with 5-arylfuran-2,3-diones. Crystalline and molecular structure of (3E,5Z)-3-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-5-(2-oxo-2-phenylethylidene)pyrrolidine-2,4-dione

5-Arylfuran-2,3-diones react with (Z)-2-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]acetamides to give (3E,5Z)-5-(2-aryl-2-oxoethylidene)-3-[3,3-dimethyl-3,4-dihydroisoquinolin-1(2H)-ylidene]-pyrrolidine-2,4-diones. The crystalline and molecular structures of one of the products were determined by X-ray analysis.     

1,3-Dipolar cycloaddition reactions of nitrilimines with 1-aroyl-4,5-dihydro-3,4,4-trimethyl-5-methylene-1H-pyrazoles. Synthesis of 6-aroyl-8,9,9-trimethyl-1,2,6,7-tetrazaspiro[4.4]nona-2,7-dienes

From the 1,3-dipolar cycloaddition reactions of 5-methylene-1H-pyrazoles 3 with N-arylnitrilimines the novel spiro-cycloadducts 4 were isolated, in addition to the corresponding 5-(2-aroylhydrazono-1,1-dimethylpropyl)-1H-pyrazoles 5. These pyrazoles 5 were the only products from the reactions of 3 with N-methylnitrilimine 2d. The chemical behaviour of the spiro-cycloadducts 4 was also examined.     

Synthesis of imidazolyl dithiocarbamates and their reactions with phenacyl bromides

The reactions of ethyl (5-carbamoyl-3H-imidazol-4-yl)dithiocarbamate with phenacyl bromides afford the S-alkylation products as a mixture of E/Z-isomers, which undergo cyclization to 5-(2-oxo-4-arylthiazol-3-yl)-1H-imidazole-4-carboxamides under the action of a base.     

Synthesis of 3-Alkyl-6-aryl(arylamino)-7H-[1,2,4]triazolo- [3,4-b][1,3,4]thiadiazines

Starting from 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols and substituted chloroacetanilides, the corresponding (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilides were synthesized. The products underwent intramolecular cyclization in boiling phosphoryl chloride to afford 3-alkyl-6-arylamino-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines. 3-Alkyl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hydrobromides were obtained by reaction of 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols with substituted phenacyl bromides.     

2-Amino-4-aryl-6-(ω-carboxyalkyl)-5H-pyrrolo[3,4-d]pyrimidin-7-(6H)ones. Preparation via a one-pot synthesis of 1-(ω-carboxyalkyl)-4-carbethoxy-2,3-dioxopyrrolidines

1-(ω-Carboxyalkyl)-4-carboethoxy-2,3-dioxopyrrolidines were prepared by a one-pot synthesis from β-alanine or γ-aminobutyric acid, ethyl acrylate and diethyl oxalate. In a second one-pot process these products were hydrolyzed, decarboxylated and condensed with aromatic aldehydes under the influence of hydrochloric acid to yield 1-(ω-carboxyalkyl)-4-arylidene-2,3-dioxo-pyrolidines, which yielded 2-amino-4-aryl-6-(ω-carboxyalkyl)-5H-pyrrolo[3,4-d]pyrimidin-7-(6H)-ones upon treatment with guanidine. It was shown that 3,4-dihydro derivatives of certain 2-amino-4-aryl-5H-pyrrolo[3,4-d]pyrimidin-7-(6H)ones, formed initially in the guanidine reaction, readily undergo conversion to 5H-pyrrolo[3,4-d]pyrimidin-7-(6H)ones.     

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 .     

Synthesis of pyrimidino[4,5-b][1,5]benzodiazepin-2-ones and pyrimidino[1,6-a]benzimidazol-1-ones from 4-ethoxycarbonylamino-1H-1,5-benzodiazpine-3-carbonitrile via 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles

Reactions of 4-ethoxycarbonylamino-1H-1,5-benzodiazepine-3-carbonitrile (2) with aliphatic primary amines gave 1-substituted 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles 3. Analogous reactions of 2 with aromatic primary amines afforded 2-(2′-anilino-1′-cyanovinyl)benzimidazoles 5 and 6. Upon treatment with triethylamine, 3 underwent intramolecular cyclization to give 3-substituted 5-aminopyrimidino[4,5-b]-[1,5]benzodiazepin-2(3H,11H)-ones 8 . Heating of 3 with p-toluenesulfonic acid in ethanol gave 2-substituted pyrimidino[1,6-a]benzimidazol-1(2H)one-4-carbonitriles 9 . Reactions of 2 with hydrazines were also described. Mechanistic pathways are proposed to account for the products.     

Self-condensation of 3-cyanothiochromone upon the action of benzyl- and phenethylamine

Reflux of 3-cyanothiochromone with benzylamine in toluene afforded 17-benzyl-6,7,14,15-tetrahydro-7,15-epiminobis(8H,16H-dithiochromeno)[2,3-b:2′,3′-f][1,5]diazocine-6,14-dione, the self-condensation product of 2-amino-3-(benzyliminomethyl)thiochromone. Similar reaction with phenethylamine leads to 2-(thiochromon-3-yl)-5H-thiochromeno[2,3-d]-pyrimidin-5-one. Mechanism of formation of the dimeric products was considered.     

Studies in spiroheterocycles,Part XV. Investigation of the reaction of 3-(2-oxocycloalkylidene)-indol-2-ones with thiourea and urea derivatives

The reaction of 3-(2-oxocycloalkylidene)indol-2-one 1 with thiourea and urea derivatives has been investigated. Reaction of 1 with thiourea and urea in ethanolic potassium hydroxide media leads to the formation of spiro-2-indolinones 2a-f in 40–50% yield and a novel tetracyclic ring system 4,5-cycloalkyl-1,3-diazepino-[4,5-b]indole-2-thione/one 3a-f in 30–35% yield. 3-(2-Oxocyclopentylidene)indol-2-one afforded 5′,6′-cyclopenta-2′-thioxo/ oxospiro[3H-indole-3,4′(3′H)pyrimidin]-2(1H)-ones 2a,b and 3-(2-oxocyclohexylidene)indol-2-one gave 2′,4′a,5′,6′,7′,8′- hexahydro-2′-thioxo/oxospiro[3H-indole-3,4′ (3′H)-quinazolin]-2(1H)-ones 2c-f . Under exactly similar conditions, reaction of 1 with fluorinated phenylthiourea/cyclohexylthiourea/phenylurea gave exclusively spiro products 2g-1 in 60–75% yield. The products have been characterized by elemental analyses, ir pmr. ¹⁹F nmr and mass spectral studies.     

Reactions of 2H-3,1-benzoxazine-2,4-(1H)dione (isatoic anhydride) with anions of 1,4-dihydro-5H-pyrazol-5-ones: Synthesis of pyrazolo[5,1-b]quinazolin-9-ones

Reactions of 2H-3,1-benzoxazine-2,4-(1H)dione (isatoic anhydride) (1) with anions of 1,4-dihydro-5H-pyrazol-5-ones (2) gave pyrazolo[5,1-6]quinazolin-9-ones (3) via the nucleophilic attack of the anion 2b rather than 2a. However, in the case of 5-methoxyisatoic anhydride ( 10c) , both products 3e and 11c were obtained. A new synthetic method of preparation of 5-(alkylthio)-2-aminobenzoic acids (18) was described. These acids (18) were used to synthesize a series of substituted pyrazolo[5,1-b]quinazolin-9-ones (3) .     

Synthesis of 2-Aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2<Emphasis Type="Italic">H</Emphasis>-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyridazin-7-ones

Bromination of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates gave ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazol-3-carboxylates which were used to alkylate benzenethiol and heterocyclic thiones at the sulfur atom. Reactions of the resulting S-alkylation products with hydrazine or methylhydrazine involved closure of pyridazine ring to afford 2-aryl-3-methyl-4-[phenyl(or hetaryl)sulfanylmethyl]-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.     

Condensed isoquinolines. 38*. Azolo[<Emphasis Type="Italic">b</Emphasis>]isoquinolines from 2-(halomethyl)benzoic acid derivatives

On interacting 2-(chloromethyl)-, 2-(bromomethyl)benzonitrile or methyl 2-(bromomethyl)benzoate with 1-R-1H-imidazoles and 1-R-1H-benzimidazoles quaternary diazolium salts are formed, the heating of which with bases (K₂CO₃, Et₃N) led to the intramolecular acylation products, 1-alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium halides, 5-alkyl-6-amino-5H-benzimidazo[1,2-b]isoquinolin-12-ium halides, or 1-alkyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate halides.