Novel polycyclic heterocycles. IX. Dibenz[b,f] [1,4]oxazocin-11 (12H)one, 6,11-dihydro-12H-dibenz[b,f] [1,4]oxazocine,and their derivatives

Dibenz[b,f][1,4]oxazocin-11 (12H)one, 14 , was synthesized by the dicyclohexylcarbodiimide induced cyclization of α-(o-aminophenoxy)-o-toluic acid ( 13 ). Reduction of 14 by lithium aluminum hydride gave 6,11-dihydro-12H-dibenz[b,f][1,4]oxazocine ( 16 ). Both 14 and 16 were converted to a series of 12-alkylated and -acylated derivatives. The pmr spectra of some of these compounds are discussed.     

Synthése de la benzopyranno[1][2,3-b]quinoxalinone-12

3-Benzyl-2-quinoxalinones were obtained by condensation of o-phenyl-enediamine with phenylpyruvic acids. These quinoxalinones were easily substituted in position 2 and which permitted the preparation of many derivatives, however, cyclisation of these compounds into 12H-[1]benzopyrano[2,3-b]quinoxalines failed. This new heterocycle might be synthesized from ethyl 2-phenoxy-3-quinoxalinecarboxylate.     

Condensed Isoquinolines. 14. Spirocyclic Systems Containing a Benzo[5,6][1,2,4]thiadiazino[4,3-b]isoquinoline Ring

We propose a convenient preparative method for synthesis of derivatives of novel heterospirane systems with a benzo[5,6][1,2,4]thiadiazino[4,3-b]isoquinoline ring, based on the reaction of 1-(2-bromomethylphenyl)-1-cyclopentanecarbonitrile and 4-(2-bromomethylphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carbonitrile with o-aminobenzenesulfamide.     

The synthesis of benzofuroquinolines. I. Some benzofuro[2,3-b]quinoline and benzofuro[3,2-c]quinoline derivatives

Benzofuro[2,3-b]quinoline ( Ia ) and its 11-methyl derivative ( Ib ) were synthesized by demethylcyclization of 3-(o-methoxyphenyl)-1,2-dihydroquinolin-2-ones (VIa,b). Benzofuro[2,3-b]quinoline-11-carboxylic acid (Id) was synthesized by chlorination followed by the action of potassium hydroxide of a lactone (IX) prepared by demethyl-cyclization of 3-(o-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (VIII). Isomeric benzofuro[3,2-c]quinoline (Ha) and its 6-methyl derivative (IIb) were synthesized by demethyl-cyclization of 3-(o-methoxyphenyl)-1,4-dihydroquinolin-4-ones (XIa,b). Both the methyl derivatives (Ib and IIb) were converted to the carboxylic acids (Id and IId) through condensation with benzaldehyde followed by oxidation. The benzofuroquinolines (Ia,b,d and IIa,b) thus obtained were oxidized to the corresponding N-oxides (IIIa,b,d and IVa,b).     

Heterocycles from Pyrazoloylhydroximoyl Chloride: Synthesis of Certain Quinoxaline,Benzothiadiazine, Benzoxadiazine,Quinazolinone, Imidazo[1,2-a]pyridine,Imidazo[1,2-a]pyrimidine,Isoxazole, Pyrazolo[3,4-d]pyridazine and Pyrrolidino[3,4-d]isoxazolin-4,6-dione Derivatives

3-Ethoxycarbonyl-5-methyl-1-(4-methylphenyl)-4-pyrazoloylhydroximoyl chloride (1) reacted with o-phenylenediamine, o-aminothiophenol, o-aminophenol and methyl anthranilate to afford 3-nitrosoquinoxaline, benzothiadiazine, benzoxadiazine, and 3-hydroxyquinazoline, respectively. Imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and isoxazole derivatives were obtained via the reaction of 1 with 2-aminopyridine, 2-aminopyrimidine and the appropriate active methylene compounds, respectively. Pyrazolo[3,4-d]pyridazines, and pyrrolidino[3,4-d]isoxazolines derivatives were also synthesized. The structures of the newly synthesized compounds were established on the basis of spectral data and alternate synthesis whenever possible.     

Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

1,3-cycloaddition reactions of 2-oxo-2H-[1]benzopyran-4-carbonitrile N-oxide. Synthesis of several new 4-substituted coumarins

1,3-Cycloaddition reactions of new 2-oxo-2H-[1]benzopyran-4-carbonitrile N-oxide 2 with dipolarophiles, o-aminophenols and o-phenylenediamine resulted in 4-heterocyclic substituted coumarin derivatives. These derivatives are screened for antiinflammatory activity in vitro through their antiproteolytic activity, the interaction with 1,1-diphenyl-2-picrylhydrazyl and the ability to affect superoxide anion and to inhibit β-glucuronidase and soybean lipoxygenase.     

1,2,3-benzotriazines. II. Reactions of benzimidazo[1,2-c][1,2,3]benzotriazines and naphth[1′,2′(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine

A number of methyl- and halogeno-substituted benzimidazo[1,2-c][1,2,3]benzotriazines were subjected to a series of hydrolytic cleavages in acid media. The reactions of these compounds with dilute sulfuric acid yielded 2-(o-hydroxyphenyl)benzimidazoles. Concentrated hydrochloric acid produced a mixture of 2-(o-chlorophenyl)- and 2-(o-hydroxyphenyl)benzimidazoles. Hydrogen chloride in ethanol caused the formation of 2- phenylbenzimidazoles contaminated with small amounts of 2 - (o-chlorophenyl)benzimidazoles. The benzimidazo[1,2-c][1,2,3]benzotriazines underwent the Sandmeyer reaction to form 2-(o-chlorophenyl)- and 2-(o-bromophenyl)benzimidazoles in excellent yields. These reactions illustrated the behavior of these 1,2,3-triazines as internal diazonium compounds. Naphth[1′,2′(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine behaved similarly. Bromination of some benzimidazo[1, 2 - c][1,2,3]benzotriazines in aqueous medium yielded bromine-substituted [1,2-c][1,2,3]benzotriazines.     

The synthesis of benzofuroquinolines. X. Some benzofuro[3,2-c]isoquinoline derivatives

Condensation of salicylonitrile with ethyl α-bromo-α-(o-ethoxycarbonylphenyl)acetate (4) effectively gave 5 (6H)-benzofuro[3,2-c]isoquinolinone (2) , which was converted to some 5-substituted benzofuro-[3,2-c]isoquinoline derivatives 1a-g.     

Synthesis of new spirobenzazolines including a furo[3,4-b]pyran ring system

A series of 4,5-dihydrofuro[3,4-b]pyran-6-spiro-2′-benzazolines 3 were prepared by reaction of 4,4-dimethyl-2,6-dioxo-4,5-dihydrofuro[3,4-b]pyran 1 with o-phenylenediamine, o-aminophenol, o-aminothiophenol or their derivatives. Most of these compounds exhibited a significant analgesic activity.     

Condensed 1,2,4-triazines. Synthesis and reactions of some condensed benzo[e]as-triazines

2-o-Chlorophenyl-2H-naphtho[1,2-d]v-triazole-4,5-quinone condenses with semicarbazide and some of its derivatives at the 4 position and the products cyclize into the corresponding 1,2,4-triazines. Reactions of these triazines with some reagents are described.     

Condensed Isoquinolines. 15. Synthesis of 5,10-Dihydro[1,2,4]triazolo[1,5-b]isoquinolines and Related Spiranes

Condensation of o-bromomethylphenylacetonitrile with arylcarbohydrazides gave, depending on the reaction conditions, 2-arylcarboxamido-1,4-dihydroisoquinoline-3(2H)-imine hydrobromides or 2-aryl-5,10-dihydro[1,2,4]triazolo[1,5-b]isoquinolines. Analogous condensation of 4-(2-bromomethylphenyl)tetrahydro-2H-pyran-4-carbonitrile and 1-(2-bromomethylphenyl)-1-cyclopentanecarbonitrile with arylcarbohydrazides gave respectively 2-aryl-2,3,5,6-tetrahydrospiro[4H-pyran-4,10'(5'H)-[1,2,4]triazolo[1,5-b]isoquinolines and 2-arylspiro[1,2,4]triazolo[1,5,b]isoquinoline-10(5'H)-1'-cyclopentanes, derivatives of new spirane heterocycles. The reaction with condensing agents of 3-imino-2,2',3,3'5',6'-hexahydrospiro[isoquinoline-4(1H),4'-4H-pyran]-2-amine and 3-imino-2,3-dihydrospiro[isoquinoline-4(1H),1'-cyclopentane]-2-amine hydrobromides, synthesized from the corresponding bromo nitriles and hydrazine, may serve as an alternative route for the synthesis of these compounds. The structure of obtained triazoloisoquinolines was established from IR, ¹H and ¹³C NMR spectra. An X-ray crystallographic study of 2-phenylspiro[1,2,4]triazolo[1,5-b]isoquinoline-10(5H),1'-cyclopentane was carried out.     

Some fatty acids having an O-heterocycle in their terminal positions. II. ω-(3-Coumarinyl)alkanoic acids and ω-(2-chromonyl)alkanoic acids

Some ω-3-coumarinyl)alkanoic acids 1a , n = 3-6 were synthesized by cyclization of corresponding ethyl o-formylphenyl alkanedioate 3 with DBU followed by hydrolysis. By a similar cyclization, some ω-(2-chromonyl)alkanoic acids 2a , n = 3-6 were also obtained from the cyclization of corresponding o-acetylphenyl ethyl alkanedioate 4 .     

Antifilarial and antimalarial agents. Basically substituted 10-aminobenzo[b] [1,5] naphthyridines, 10-Aminobenzo[b] [1,5] naphthyridine N-Oxides,and 8-Amino-1,5-naphthyridines

Various 2-alkoxy 7-chloro-10-[[[(dialkylamino)alkyl]amino]]benzo[b][1,5]naphthyridines (XI) and N-oxides (XV, XVII, XVIII, XXII), 4-[(2-alkoxy-7-chlorobenzo[b][1,5]naphthyridin-10-yl)-amino]-α-(diethylamino)-o-cresol derivatives (XII-XIV, XXI) and N-oxides (XIX, XX, XXV), 2-butoxy-8-[[[(dialkylamino)alkyl]amino]]-1,5-naphthyridines (XXVIa and b), and 2-butoxy-8–[[3-[(diethylamino)methyl]-p-anisidino]]-1,5-naphthyridine (XXVII) were synthesized for antifilarial and antimalarial evaluation. The compounds were obtained in 13–91% yield by the condensation of 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridines, 2-alkoxy-7,10-dichlorobenzo[b][1,5]naphthyridine 5-oxides, and 2-butoxy-8-chloro-1,5-naphthyridine with the appropriate diamine in phenol, or by perbenzoic acid oxidation of the parent 10-amino-7-chlorobenzo-[b][1,5] naphthyridines in chloroform. Among them, eight compounds killed adult Litomosoides carinii in gerbils when administered in daily gavage doses of 25–400 mg./kg. for 5 days. Azacrine 5-oxide (XVII), the most active compound, was equipotent with amodiaquine (1a), azacrine (IX), and quinacrine 10-oxide (VI). Twelve substances were active orally against Plasmodium berghei in mice at doses ranging from 3.8–155 mg./kg./day for 6 days. 7-Chloro-10-[[-3-[(diethylamino)-methyl]-p-anisidino]]-2-methoxybenzo[b][1,5]naphthyridine 5-oxide dihydrochloride (XX) was approximately 12 times as potent as quinine against P. berghei, but was highly cross-resistant with chloroquine (IV). Structure-activity relationships are discussed.     

1,2,3-benzotriazines. I. The synthesis of some benzimidazo [1,2-c][1,2,3]-benzotriazines and naphth[1′,2,(2′,1′):4,5]imidazo[1,2-c][1,2,3]benzotriazine

A number of substituted benzimidazo[1, 2-c][1,2,3]benzotriazines were prepared by the diazotization of the appropriate 2-(o-aminophenyl)benzimidazoles. Diazotization of 2-(o-aminophenyl)naphth[1,2-d]imidazole yielded a new heterocyclic ring system. Various methods of preparation of 2 - (o-aminophenyl)benzimidazoles were investigated. The condensation of o-phenylenediamines with anthranilic acids, in the presence of polyphosphoric acid, provided a convenient route to 2-(o-aminophenyl)benzimidazoles but in several cases the products were contaminated with considerable amounts of 6-(o-aminophenyl)benzimidazo[1,2 -c]quinazolines. 2 - (o-Aminophenyl)benzimidazoles were also obtained by the catalytic hydrogenation of 2-(o-nitrophenyl)benzimidazoles which resulted from the condensation of an o-phenylenediamine with an o-nitrobenzaldehyde in ethanol, nitrobenzene or acetic acid. When the condensation was carried out in nitrobenzene, small amounts of 2-(o-aminophenyl)benzimidazoles were also formed. The Weidenhagen synthesis, which involves the reaction of an aromatic diamine with an aldehyde in the presence of copper acetate and subsequent decomposition of the cuprous salt of the benzimidazole, yielded 2-(o-aminophenyl)benzimidazoles instead of the expected 2-(o-nitrophenyl)benzimidazoles when the decomposition was carried out in ethanol. When the cuprous salt was treated with hydrogen sulfide in dilute hydrochloric acid, a mixture of amino- and nitrobenzimidazoles resulted. The ultraviolet and infrared spectra of all the compounds prepared were examined.     

Heterocyclic derivatives of naphthalene-1,8-dicarboxylic anhydride. Part I. Nitro-7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones

Condensation of o-phenylenediamine with 2-, 3- and 4-nitronaphthalene-1,8-dicarboxylic anhydrides gives, in each case, an isomer mixture. Separation of the mixtures into the six isomeric mononitro-7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-ones is described and the isomers characterised in respect of previously reported data on some isomers; ir and mass spectrum data are reported, the latter showing fragmentation ions which may be used in characterising dyes based on this chromophore. Other new derivatives of 7H-benzimidazo[2,1-a]benz[de]isoquinolin-7-one are also described.     

Formation of [5.5]cyclopentadienidophanes by macrocyclization of [3-(methylammonio)propyl]cyclopentadienides under Mannich conditions

2-Acyl-1,4-bis(methoxycarbonyl)-3-[3-(methylammonio)propyl]cyclopentadienides 1 and aqueous formaldehyde can undergo a double Mannich reaction leading to the bisbetainic 2,12-diazonia-[5,5](1,3)cyclopentadienidophanes 2. The success of this macrocyclization reaction seems to depend on the length of the ω-ammonioalkyl chain and the individual acyl substituent. In the cases of ω-(methylammonio)butyl and ω-(methylammonio)pentyl chains, as well as with ω-ammoniopropyl derivatives bearing particularly electron-rich 4-methoxybenzoyl or 2-furoyl substituents, a mixture of oligomers is formed. On the other hand, DCC-assisted cyclocondensation of 1b,d (acyl=4-methoxybenzoyl and thiophene-2-carbonyl, respectively) occurs only intramolecularly, leading to the bicyclic 6-aminopentafulvenes 4b,d in good yields.     

Ring closure reactions with nitriles. II. Formation of pyrrolo[1,2-a] quinazolines and thiazolo[3,2-a] quinazolines

2-Quinazolinepropionic acids have been obtained from the reactions of potassium cyanide with o-carboxy- or o-acyl-3-chloropropionanilides. Some of these compounds have been cyclized to pyrrolo [1,2-a] quinazolines. The reaction of an o-carbethoxy-2-chloroacetanilide with potassium thiocyanate formed a 2-quinazolinylthioacetic acid, which was cyclized to a thiazolo-[3,2-a]quinazoline. A mechanism is presented for the formation of these compounds.     

Synthesis of 1H-Cyclopropa[b]naphthalenes via Trapping of o-Benzoquinodimethanes

1H-Cyclopropa[b]naphthalene ( 10a ) and 3-methyl or dimethyl derivatives have been synthesized by interception of appropriately substituted o-quinodimethanes 3 with 1-bromo-2-chlorocyclopropene 5 , and subsequent dehydrohalogenation of the adducts. The o-quinodimethane derivatives 3 in turn were obtained from the diynes 7 via base-induced isomerization to bisallenes 8 and thermal electrocyclic ring closure.     

Reactions with Naphthoylhydroxlmoyl Chlorides: Synthesis of Derivatives of Isoxazole,Pyrrolidino[3,4-d]isoxazoiin-4,6-dione,lmidazo[1,2-a]pyridine,lmidazo[1,2-a]pyrimidine,Benzotriazine and Benzothiadiazine

Hydroximoyl chlorides 3 react with acrylonitrile, N-arylmaleimide and maleic anhydride to give isoxazolines 5 , pyrrolidino[3,4-d]isoxazolines 8 , and furolidino[3,4-d]isoxazolines 9 , respectively. 3 reacted with 2-aminopyridine, 2-aminopyrimidine, o-phenylenediamine and o-aminothiophenol to yield 3-ni-trosoimidazo[1,2-α]pyridines 20 , 3-nitrosopyrimidines 22 , 3-naphthoyl-1,4-dihydrobenzo-1,2,4-triazines 24 , and 3-naphthoyl-4H-1,3,4-benzothiadiazine 27 , respectively. Compound 3 reacted with benzoylacetonitrile, acetoacetanilide, thiophenol, benzencsulfinic acid in ethanolic sodium ethoxide solution to give the corresponding isoxazoles 12–13 and oximes 16–17 , respectively. The structures of these products were confirmed by elemental analyses, spectral data and, wherever possible, alternative synthesis.