Studies on the synthesis of heterocyclic compounds. Part IV. Further investigation of the pschorr reaction with some pyrazole derivatives

Thermal decomposition of the diazonium sulfate derived from N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-aminobenzamide afforded products formulated as 1-phenyl-3-methyl[2]benzopyrano[4,3-c]pyrazol-5-one (yield 10%), 1,4-dimethyl-3-phenylpyrazolo[3,4-c]isoquinolin-5-one (yield 10%), N-methyl-(1-phenyl-3-methylpyrazol-5-yl)-2-hydroxybenzamide (yield 8%) and 4′-hydroxy-2,3′-dimethyl-1′-phenylspiro[isoindoline-1,5′-[2]-pyrazolin]-3-one (yield 20%). Decomposition of the diazonium sulfate derived from N-methyl-(1,3-diphenylpyrazol-5-yl)-2-aminobenzamide gave products formulated as 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]-diazocin-10-(9H)one (yield 8%), 4-methyl-1,3-diphenylpyrazolo[3,4-c]isoquinolin-5-one (yield 7%) and 4′-hydroxy-2-methyl-1′,3′-diphenylspiro[isoindoline-1,5′-[2]pyrazolin]3-one (yield 10%). The spiro compounds 6a,b underwent thermal and acid-catalysed conversion into the hitherto unknown 2-benzopyrano[4,3-c]pyrazole ring system 7a,b in good yield. Analytical and spectral data are presented which supported the structures proposed.     

Zur addition von nucleophilen an C(2) heterocyclischer 2-methylsubstituierter quartärsalze

1-(4-Chlorophenyl)-2-methyl-3-phenylquinoxalinium perchlorate ( 5 ) obtained by two different routes, on treating with nucleophiles HX or X⁻ yielded 1,3-diaryl-2-methyl-2X-1,2-dihydroquinoxalines 10 . Alkylation of 10e yielded 4-(4-chlorophenyl)-1,3-dimethyl-3-nitromethyl-2-phenyl-3,4-dihydroquinoxalinium perchlorate ( 11e ). The ¹H-nmr and mass spectra are presented. Diastereoisomerism of the products is discussed.     

Studies on the synthesis of heterocyclic compounds. Part VI. The action of methyl salicylate on some 5-aminopyrazoles

Some 1-phenyl-3-R-5-aminopyrazoles reacted with methyl salicylate to give N-(1-phenyl-3-R-pyrazol-5-yl)-2-methoxybenzamides ( 3a,b,c ), 1-phenyl-2-methyl-3-R-salicyloilimino-3-pyrazolines ( 4a,b,c ) together with 1-phenyl-3-R-5-methylamino pyrazoles ( 5a,b,c ). The structures of the new compounds 3 and 4 were determined on the basis of analytical and spectroscopic data as well as on the acid hydrolysis products.     

The reaction of indole and the indole grignard reagent with phosgene. A facile synthesis of indole-3-carboxylic acid derivatives

Indole-3-carboxylic acid (as well as indole-3-glyoxylic acid) derivatives are readily prepared from indoles (including oxindoles) and phosgene (oxalyl chloride), respectively. The interaction of these reagents with the indole Grignard reagent afforded several products including the cyclo-tetramers, 21 and 30 . Indolo-fused heterocycles can be readily prepared from the reaction of phosgene (or oxalyl chloride) with suitable reactants. Thus e.g., phosgene and 2-(2-hydroxy-phenyl)-N-methylindole readily gave 5,6-dihydro-11-methyl-6-oxobenzo[a]pyrano[4,3-b] indole ( 33 ).     

Novel heterocycles. Synthesis of 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide and related compounds

The reaction of 2-chloro-4-(methylsulfonyl)benzoyl chloride ( 5 ) with 1-methyl-1H-2,1-benzothiazin-4-(3H)-one 2,2-dioxide ( 4 ) gave the O-benzoyl compound, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 2-chloro-4-(methylsulfonyl)benzoate ( 6 ), which rearranged to give the C-benzoyl isomer, [2-chloro-4-(methylsulfonyl)phenyl] (4-hydroxy-1-mefhyl-2,2-dioxido-1H-2,1-benzothiazin-3-yl)methanone ( 7 ). The O-cinnamoyl compound 13 that resulted from the addition of 2,4-dichlorocinnamoyl chloride ( 11 ) to compound 4 rearranged to give the C-cinnamoyl compound, 3-(2,4-dichlorophenyl)-1-(4-hydroxy-1-methyl-2,2-dioxido-1H-2,1-benzothiazin-3yl)-2-propen-1-one ( 15 ). On the other hand, 1-methyl-2,2-dioxido-1H-2,1-benzothiazin-4-yl 3-phenyl-2-propenoate ( 19 ) (from cinnamoyl chloride ( 17 ) and compound 4 ) rearranged to give 2,3-dihydro-6-methyl-2-phenyl-4H,6H-pyrano[3,2-c][2,1]benzothiazin-4-one 5,5-dioxide ( 21 ), an example of a hitherto unknown ring system. Additional examples of this novel heterocycle were prepared from 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 23 ) and 1-methyl-1H-thieno[3,2-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 8 ).     

Lead tetraacetate oxidation of phenylhydrazones of 3-benzoylazoles. Synthesis of azoacetates and their conversion into indazoles

Lead tetraacetate (LTA) oxidation of (E)- and (Z)-phenylhydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole, 3-benzoyl-5-phenylisoxazole, and 3-benzoyl-4-methyl-1,2,5-oxadiazole has been studied. Conversion of azoacetate products into 3-(azol-3-yl)-substituted indazoles has been achieved by reacting them with aluminium chloride in benzene at room temperature.     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.     

A study of the friedel-crafts acylation of 1-benzenesulfonyl-1H-pyrrole in the preparation of 3-aroylpyrroles

In this work, we studied the aluminum chloride catalyzed reaction of 1-benzenesulfonyl-1H-pyrrole with a series of eleven aroyl chlorides. The products formed were not isolated, but hydrolyzed to the target 3-aroylpyrroles in overall yields, usually, higher than 50%. However, in the cases with the π electron rich 1-phenyl-1H-pyrrole-3-carbonyl chloride and 1-methyl-1H-indole-3-carbonyl chloride significant C-2 substitution occured, resulting in the isolation of the corresponding 1-benzenesulfonyl-2-aroylpyrroles as the predominant or the sole products. The desired C-3 isomers were synthesized starting with 1-triisopropylsilanyl-1H-pyrrole.     

Studies on quinones. XII. Cycloketalization of michael adducts from hydroxyquinones

The reaction of 2-hydroxy-3-(1-phenyl-3-oxobutyl)-1,4-naphthoquinone ( 1 ) with either acidic methanol or a mixture of trimethyl orthoformate, methanol and ammonium chloride resulted in the formation of the p-quinonic cycloketals: trans- and cis-4-phenyl-2-methyl-2-methoxy-3,4-dihydro-2H-naphtho[2,3-b]pyran-5,10-dione ( 2a,2b ). Cyclization of the Michael adducts 6, 10 and 11 , which are structurally related to 1 , with trimethyl orthoformate-methanol-ammonium chloride gave the corresponding p-quinonic cycloketals 7, 12 and 13 . The structures of the regioisomers 2a and 2b are proposed based on the spectral properties of compound 7 and by analysis of its proton nmr spectra.     

Synthesis of benzazepines and their rearrangement to quinolines and pyrrolo(2,3-b) quinolines

BECKMANN or SCHMIDT rearrangement of ethyl trans-4-oxo-1-phenyl-2-tetralincarboxylate ( 2 ) affords ethyl trans-2,3,4,5-tetrahydro-2-oxo-5-phenyl-1H-benzo [b] azepine-4-carboxylate ( 4 ). Mild treatment of trans-2,3,4,5-tetrahydro-1-methyl-2-oxo-5-phenyl-1 H-benzo-[b] azepine-4-carboxylic acid ( 7 ) with thionyl chloride and pyridine in dimethylformamide and subsequent reaction with an amine yields the corresponding benzazepine-4-carboxamide. If he it is applied during the preparation of the acid chloride, rearrangement occurs yielding cis and trans derivatives of hydrocarbostyril. 2,3,4,5-Tetrahydro-1,4-methano-1-methyl-5-phenyl-1 H-benzo-[b] azepinium chloride ( 25 ) reacts with primary or secondary amines to cis-tetrahydroquinoline derivatives. When heated above its melting point, trans-4,5-dihydro-2-methylamino-5-phenyl-3H-benzo-[b] azepine-4-carboxylic acid ( 29 ) rearranges with elimination of water to a mixture of cis-and trans-2,3,3a,4-tetrahydro-1-methyl-2-oxo-4-phenyl-1H-pyrrolo [2,3-b] quinoline ( 32 and 31 ). The reduction of 31 was investigated. The mechanisms of the rearrangements are discussed.     

Copolymerization of new pyrazolone-containing monomers with certain vinyl comonomers

The polymerization ability of two new pyrazolone-containing monomers—3-methyl-1-phenyl-4-crotonoyl-pyrazolone-5 ( Cr ) and 3-methyl-1-phenyl-4-(3′-phenyl-acryloyl) pyrazolone-5 ( Cy )—was investigated. The monomers were obtained by acylation of 3-methyl-1-phenyl-pyrazolone-5 with crotonyl chloride or cinnamoyl chloride, respectively. It was established that the two monomers do not homopolymerize either under the action of ionic and radical initiators nor with γ-rays (doses between 2 and 10 MRad). In contrast to this, the two monomers copolymerize with other vinyl comonomers. Copolymers of Cr and Cy with methacrylic acid (MAA), methyl methacrylate (MMA), and Styrene (St) were synthesized by radical copolymerization. The molecular weights of the polymer products obtained were in the 10,000–65,000 range. It was established that the molecular weight characteristics of the copolymers were affected by the concentration of the pyrazolone-containing monomer and by the chemical nature of the solvent used. The copolymerization of Cr and Cy with MAA was investigated in detail in order to evaluate the relative activity of the new monomers during copolymerization. The reactivity ratios (r) were calculated by three different methods with good agreement. The values obtained for the monomer pairs are: r_MAA = 0.61 ± 0.01, r_Cr = 0.04 ± 0.01; r_MAA = 0.64 ± 0.05, r_Cy = 0.02 ± 0.02. The Q/e values for Cr and Cy were determined using the reactivity ratios of both monomers.     

Substituted pyridines

5-Methyl-4-phenyl-2-styryipyridine has been oxidized to 5-methyl-4-phenylpyridinie-2-carboxylic acid. The decarboxylation of this acid has given 3-methyl-4-phenylpyrldine. To prove the structure of -(5-methyl-4-phenyl-2-pyridyl)acetophenone, it has been converted into 2, 5-dimethyl-4-phenylpyridine. The reaction of benzyl chloride with the lithium derivative of 2, 5-dimethyl-4-phenylpyridine has been studied. 3,7-Dimethyl-2-azafluorene has been obtained from 2,5-dimethyl-4-p-tolylpyridine.     

Ringschlussreaktionen von 1-(2-Aminophenyl)-1-phenyl-äthylenen durch Kondensation mit Phosgen

Cyclization of 1-(2-aminophenyl)-1-phenyl-ethylenes or 1-(2-aminophenyl)-1-phenyl-propenes (II) by condensation with phosgene led to 4-phenyl-carbostyrils (III) or 2-chloro-4-phenyl-quinolines (IV). Similarly, thiophosgene afforded 4-phenyl-thiocarbostyril. Treatment of 1-(2-aminophenyl)-2-methyl-1-p-tolyl-propene (VII) with phosgene led to the corresponding isocyanate IX, which cyclized in the presence of aluminum chloride with loss of a methyl group to 3-methyl-4-p-tolyl-carbostyril (III-6). However, 1-(2-aminophenyl)-2-methyl-1-phenyl-propene (VIII) treated with phosgene gave the isocyanate XI and 3-phenyl-3-isopropenyloxindole (X). Cyclization of the isocyanate XI with aluminium chloride led simultaneously to 3-methyl-4-phenyl-carbostyril (XIV), and with migration of a methyl group to 3-methylene-4-methyl-4-phenyl-3. 4-dihydro-carbostyril (XV).     

Synthesis of hydrogenated indazole derivatives starting with α,β-unsaturated ketones and hydrazine derivatives

The reaction of hydrazine derivatives with α,β-unsaturated ketones, such as cyclohexenyl(phenyl)methanone and (E)-2-benzylidenecyclohexanone, were investigated.The reaction between methylhydrazine and e.g., cyclohexenyl(phenyl)methanone was particularly interesting as 3a,4,5,6,7,7a-hexahydro-1-methyl-3-phenyl-1H-indazole was obtained as the major product together with 4,5,6,7-tetrahydro-2-methyl-3-phenyl-2H-indazole as a minor product.     

3-Hydroxythiazole and 1-Hydroxyimidazole as Products of a Mutual Ring Closure Reaction: Extension to Selenium Derivatives

A thiazole derivative can be easily prepared, e.g., from an α -thiocyanatoketone and a nitrogen nucleophile. In this work, α -bromopropiophenone was chosen as a starting compound. Since the carbonyl group facilitates nucleophilic substitution, bromine can be simply replaced with the thiocyanato group. The following reaction with hydroxylamine hydrochloride provides an intermediate, which undergoes a ring closure reaction. Finally, 3-hydroxy-5-methyl-4-phenylthiazol-2(3H)-iminium chloride 4a or 1-hydroxy-4-methyl-5-phenyl-1,3-dihydro-2H-imidazole-2-thione 5a arises depending on the presence of a base. In the next part, this interesting phenomenon was successfully investigated on selenium derivatives as well. All prepared substances have not been described in the literature yet.     

Photochemische Cycloadditionen von 3-Phenyl-2H-azirinen an Carbonsäurechloride. 35. Mitteilung über Photoreaktionen

Irradiation of 2, 3-diphenyl-2H-azirine ( 1a ) and 1-azido-1-phenyl-propene, the precursor of 2-methyl-3-phenyl-2H-azirine ( 1b ), in benzene, with a high pressure mercury lamp (pyrex filter) in the presence of acid chlorides yields the oxazoles 5a–d (Scheme 2). Photolysis of 2, 2-dimethyl-3-phenyl-2H-azirine ( 1c ) under the same conditions gives after methanolysis the 5-methoxy-2, 2-dimethyl-4-phenyl-3-oxazolines 7a, b, d , while hydrolysis of the reaction mixture leads to the formation of the 1, 2-diketones 8a, c, d (Scheme 4). The suggested reaction path for all these reactions is a 1, 3-dipolar cycloaddition of the photochemically generated benzonitrilemethylides 2 to the carbonyl double bond of the acid chlorides to give the intermediates 4 , followed by either elimination of hydrogen chloride or solvolysis (Schemes 2 and 4). Irradiation of 1c in the presence of acetic acid anhydride leads via the intermediate 9 to the 5-hydroxy-3-oxazoline 10 and the 5-methylidene-3-oxazoline 11 (Scheme 5).     

Photochemische Cycloadditionen von 3-Phenyl-2H-azirinen mit kumulierten Doppelbindungen. Vorläufige Mitteilung

Irradiation of 2-methyl- ( 1c ) and 2,2-dimethyl-3-phenyl-2H-azirine ( 1d ) in benzene solution in the presence of carbon dioxide yields 2-methyl-4-phenyl- ( 3c ) and 2,2-dimethyl-4-phenyl-3-oxazolin-5-one ( 3d ), respectively. Similar cycloadducts are observed (see table) when 2,3-diphenyl-2H-azirine ( 1b ) and 1d are irradiated in the presence of phenylisocyanate, o-tolylisocyanate, phenylisothiocyanate or di-o-tolyl-carbodiimide.     

Formation of 3-phenylhydrazono-3-aroylpropionamides from the reaction of 5-aroyl-3(2H)-isothiazolones with phenylhydrazine

Reaction of 2-substituted-5-aroyl-3(2H)-isothiazolones 1 with phenylhydrazine in refluxing ethanol was found to give sulfur-free products, which were characterized as 3-phenylhydrazono-3-aroyl-N-substituted-pro-pionamides 4. Acid hydrolysis of the 3-benzoyl compounds 4 was shown to yield 1-phenyl-3-benzoyl-2-pyrazolin-5-one ( 7 ), whose structure was confirmed by an independent synthesis starting with the chloride of 1-phenyl-5-methoxypyrazole-3-carboxylic acid ( 10 ).     

Unequivocal syntheses of 6-methyl- and 6-phenylisoxanthopterin

Although 6-methyl- ( 1 ) and 6-phenylisoxanthopterin ( 2 ) have previously been synthesized, the requirement of high purity necessary for immunological testing has necessitated our development of the first reported synthesis of these compounds by unequivocal methods. In the process of so doing four new pyrazines, ethyl 3-amino-5-chloro-6-methyl-2-pyrazinecarboxylate ( 11 ), N,N-dimethyl-N'-(6-chloro-3-cyano-5-phenylpyrazin-2-yl)methanimidamide ( 16 ), 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide ( 19 ), and ethyl 3-amino-5-chloro-6-phenyl-2-pyrazinecarboxylate ( 20 ) were synthesized. Four new pteridines, 7-methoxy-6-methyl-2,4-pteridinediamine ( 7 ), 7-methoxy-6-phenyl-2,4-pteridinediamine ( 17 ), 2-amino-7-ethoxy-6-methyl-4(3H)-pteridinone ( 12 ), and 2-amino-7-ethoxy-6-phenyl-4(3H)-pteridinone ( 21 ) have also been synthesized enroute to these isoxanthopterins.     

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone derivatives and the properties of the obtained products

N′-(4-Oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides and N′-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides were synthesized by reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone or 2-methyl-1,4-naphthoquinone. The alkylated analogues of the above products were obtained using ethyl iodide. The interaction of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 2,3-dichloro-1,4-naphthoquinone was followed by formation of N′-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides. All these compounds were characterized using ¹H, ¹³C NMR, IR and mass spectra. Some of the new compounds were tested for the antimicrobial and antifungal activity.