Reactions of 2-cyano-3-ethoxy-5,5-dimethyl-2-cyclohexen-1-one with 2-amino- and 2-hydrazionobenzimidazoles

The reactions of 2-cyano-3-ethoxy-5,5-dimethyl-2-cyclohexen-1-one with 2-amino- and 2-hydrazinobenzimidazoles gave 1-oxo-3,3-dimethyl-11-amino-1,2,3,4-tetrahydroquinazolino[3,2-a]benzimidazole and 2-(2-benzimidazolyl)-3-amino-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydroindazole, respectively.Riga Technical University, Riga LV-1658. Latvian Institute of Organic Synthesis, Riga LV-1006. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 235–240, Feburary, 1997.     

Reaction of 2-hydrazinoperimidine with acetylacetone

Heating 2-hydrazinoperimidine ( 2 ) with acetylacetone in absolute ethanol gave exclusively 2-(3,5-dimethyl-1-pyrazolyl)perimidine ( 4 ) via a [2 + 3] cyclization. The possible [4 + 3] condensate, 3,5-dimethyl-1H-1,2,4-triazepino[4,3-a]perimidine ( 5 ) was not produced. Spectral analyses were applied to the structure elucidation of the products.     

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

Isomerization in the Oxidative Cyclocondensation of 2-Aroylmethyl-1H-benzimidazoles with o-Aminothiophenol

Oxidative cyclocondensation of 2-aroylmethyl-1H-benzimidazoles with o-aminothiophenol gave the previously unknown 3-aryl-2-(2-benzimidazolyl)-4H-1,4-benzothiazines and (or) the isomeric 2H-1,4-benzothiazines. 2-(4-Nitrophenacyl)-1H-benzimidazole and 2-phenacylbenzothiazole gave 4H-1,4-benzothiazines which are not liable to isomerize but the reaction of the first compound is complicated by a hydrolytic fission which yields 2-[2-(4-nitrobenzoylamino)phenylthiomethyl]benzimidazole. A mixture of dimethylsulfoxide, acetic acid, and water was used as oxidant and solvent. The effect of the substituent and of the solvent on the tendency of the products to undergo prototropic isomerization in the benzothiazine ring have been studied.     

Synthesis and antimalarial effects of 5,6-dichloro-2-[(4-||4-(diethylamino)-i-methylbutyl] amino||-6-methyl-2-pyrirnidinyl)amino] benzimidazole and related benzimidazoles and lH-imidazo[4,5-b] pyridines

A group of fifty-five 2-[(4-11[(dialkylamino)alkyI]amino11-6-methyl-2-pyrimidinyl)amino]-benzimidazoles (VII) was synthesized in 3-88% yield by the condensation of the requisite 2-[(2-benzimidazolyl)amino]-4-chloro-6-methylpyrimidine (VI) with the appropriate polyamine in ethanol-hydrochloric acid or neat with excess amine containing potassium iodide. The 2-[(2-benzimidazolyl)amino]-6-methyl-4-pyrirnidinol precursors (V), obtained in 11-51% yield by cyclization of 2-(cyanoamino)-4-hydroxy-6-methylpyrimidine with a suitably substituted o-phenylenediamine, were chlorinated with phosphorus oxychloride to give the intermediate 2-[(2-benzimidazolyl)amino]-4-chloro-6-rnethylpyrimidines (VI) (27-99%). Oxidation of 5,6-dichloro-2-[(4-11[4-(diethylamino)-l-methylbutyl] amino 11-6-methyl-2-pyrimidinyl) amino ]benzimidazole ( 29 ) with m-chloroperbenzoic acid gave the distal N⁴'-oxide ( 31 ) (19%). Fusion of 2,3-uiaminopyridine with 2-(cyanoamino)-4-hydroxy-6-methylpyrimidine provided 2-[(4-hydroxy-6-tnethyl-2-pyrimidinyl)amino]-lH-imitlazo[4,5-b]pyrimidine (VIII) (30%), which upon chlori-nation with phosphorus oxychloride (63%) followed by amination with i N, N-diethylethylene-diamine afforded 2-(4-11[2-(diethylamino)ethyl] amino 11-6-methyl-2-pyrimidinyl)-lH-imidazo [4,5-b]pyridine (X) (8%). Thirty-eight of the novel 2-[(4-amino-6-methyl-2-pyrimidinyl)amino]-benzimidazoles possessed “curative” activity against Plasmodium berghei at single subcutaneous doses ranging from 20.640 mg./kg. Orally, thirty-one compounds exhibited suppressive activity against P. berghei comparable with or superior to the reference drugs 1-(p-chlorophenyl)-3-(4-11[2-(diethylarnino)ethyl]amino 11-6-methyl-2-pyrimidinyl)guanidine (I) and quinine hydrochloride, while twelve of them were 5 to 28 times as potent as I and quinine hydrochloride. Eight compounds also displayed strong suppressive activity against P. gallinaceum in chicks. 5,6-Dichloro-2-[(4-112-(diethylamino)ethyl]amino11-6-methyl-2-pyrimidinyl] benzimidazole (18) showed marked activity against a cycloguanil-resistant line of P. berghei, and the most promising member of the series, namely 5,6-dichloro-2-[(4-11[4-(diethylamino)-l-methylbutyl]amino11-6-methyl-2-pyrimidinyl)amino]benzimidazole ( 29 ) (Q = 28), was designated for preclinical toxico-logical studies and clinical trial. Structure-activity relationships are discussed.     

Unusual reactions of 5,5-dimethyl-2-(indenyl-2)-3-pyrazolidinone with acetylenedicarboxylates

[reaction: see text] Reaction of 5,5-dimethyl-3-pyrazolidinone (1) with 2-indanone (2) gave 5,5-dimethyl-2-(1H-indenyl-2)-3-pyrazolidinone (3) instead of the expected azomethine imine 4. Although reaction of 2-substituted 3-pyrazolidinones with acetylenedicarboxylates usually gives ring expansion products, such as 1,2-diazepines, treatment of 3 with dialkyl acetylenedicarboxylates (5, R = Me; 6 R = Et) resulted in the formation of rel-(7aR,12aS)-6,7-bis(alkoxycarbonyl)-3,4-dihydro-4,4-dimethyl-7aH-indano[1,2-b]pyrrolo[1,2-a]pyrimidin-2-ones (7, R = Me; 9, R = Et) as major products and 3,4-bis(alkoxycarbonyl)-7,7-dimethyl-2-(indenyl-2)-6,7-dihydro-2H,6H-1,2-diazepin-5-ones (8, R = Me: 10, R = Et) as minor products.     

Synthesis of 4H-1,3,4-oxadiazino[5,6-b]quinoxalines from 2-substituted quinoxaline 4-oxides

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with acetic anhydride resulted in the intramolecular cyclization to give 8-chloro-2,4-dimethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7a , while the reaction of compound 8 with acetic anhydride/pyridine or acetic anhydride/acetic acid afforded 3-(2,2-diacetyl-1-memymydrazmo)-7-chloro-2-oxo-1,2-dihydroquinoxaline 9 , effecting no intramolecular cyclization. The reaction of 2-(2-acetyl-1-methylhydrazino)-6-chloroquinoxaline 4-oxide 10a or 6-chloro-2-(1-methyl-2-trifluoroacetylhydrazino)quinoxaline 4-oxide 10b with phosphoryl chloride provided compound 7a or 8-chloro-4-memyl-2-trifluoromethyl-4H-1,3,4-oxadiazino[5,6-b]quinoxaline 7b , respectively. The reaction of compound 7b with phosphorus pentasulfide gave 7-chloro-3-(1-methyl-2-trifluoroacetylhydrazino)-2-thioxo-1,2-dihydroquinoxaline 11 , whose dehydration with sulfuric acid in acetic acid afforded 8-chloro-4-methyl-2-trifluoromemyl-4H-1,3,4-thiadiazino[5,6-b]quinoxaline 12 .     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

Reaction of 2,6-dibutylaminohepta-2,5-dien-4-one with malononitrile

Malononitrile reacted with the title compound to give 6-amino-5-cyano-2-(3,3-dicyano-2-methylallylidene-4-methyl-2H-pyran (3). Treatment of 3 with hot 80% sulfuric acid yielded 4,7-dimethyl-56-hydroxy-2(1H)quinolone. With concentrated aqueous sodium hydroxide, 3 gave 5-amino-3,6-dicyano-4,7-dimethyl-2(1H)quinolone and 5-amino-6-carbamoyl-3-cyano-4,7-dimethyl-2(1H)quinolone. The reaction of 3 with hydrochloric in acetic acid gave a mixture of 6-amino-3,7-dicyano-2,8-dimethyl-4-quinolizone and 3-cyano-4-methyl-6-(3,3-dicyano-2-methylallyl)-2-pyrone. Compound 3 also reacted with methylamine, butylamine and piperidine to give 8-amino-5-cyano-4-methyl-2-pyridone, 6-bulylamino-5-cyano-4-methyl-2-pyridone and 5-eyano-4-methyl-6-piperidino-2-pyridone respectively.     

Reaction of lumichrome or 2-thiolumichrome with alkylamines

The reaction of lumichrome ( 2 ) with alkyl (or allyl)amines such as n-butylamine, n-hexylamine and allylamine gave 2,3-disubstituted 6,7-dimethylquinoxalines 4a-d, 5a-d, 6a-d, 7a-d and 8a-d . Similar reaction of 2-thiolumichrome ( 3 ) with alkyl (or allyl)amines gave 2,3-disubstituted 6,7-dimethylquinoxalines 6a-c, 9a-c and 10a-c , 2-alkyl (or allyl)amino-6,7-dimethyl-3,4-dihydrobenzo[g]pteridine-4-ones 11a-c and 2,4-dialkyl (or allyl)amino-6,7-dimethylbenzo[g]pteridines 12a-c .     

Synthesis and some transformations of 6(8)-substituted 4-hydrazino-2-methylquinolines

6(8)-Substituted 4-hydrazino-2-methylquinolines were synthesized by reaction of the corresponding 4-chloro-2-methylquinolines with hydrazine hydrate. Reactions of the title compounds with ethyl acetoacetate and acetone gave 2,4-dimethyl-1H-pyrrolo[3,2-c]quinolines and 4-(5-ethoxy-3-methyl-1H-pyrazol-1-yl)-2-methylquinolines.     

Synthesis of novel acyclonucleosides. Reactions of 1-(1-bromo or 3-bromo-2-oxopropyl)pyridazin-6-ones

Reaction of 1-(3-bromo-2-oxopropyl)pyridazin-6-ones 1 and 2 with sodium azide at room temperature gave the corresponding 1-(3-azido-2-oxopropyl)pyridazin-6-ones 3 and 4 , whereas reaction of 1-(1-bromo-2-oxo-propyl)pyridazin-6-ones 5 and 6 with excess sodium azide afforded 4-azido-5-chloropyridazin-6-one 7 and 4,5-diazido-3-nitropyridazin-6-one 8 by dealkylation. Some 1-(2-hydroxypropyl)pyridazin-6-ones 9, 10, 11 were synthesized from the corresponding 1-(2-oxopropyl) derivatives 1, 2, 3 . 4,5-Dichloro-1-(2,3-dihydroxypropyl)-pyridazin-6-one 13 was also prepared from compound 9 via the corresponding 2,3-epoxypropyl derivative 12 . Treatment of compound 5 with thiourea gave 4,5-dichloro-1-(2-amino-4-methylthiazol-5-yl)pyridazin-6-one 14 . Reaction of compounds 1 and 2 with thiourea at 20° afforded the corresponding 3-formamidinylthio-2-oxo-propyl derivatives 15 and 16 , whereas treatment of compound 1 with thiourea at 45° gave 4,5-dichloro-1-[(2-aminothiazol-5-yl)methyl]pyridazin-6-one 17 . Compound 17 was also prepared from compound 15 by refluxing in ethanol.     

Di-4(3H)-quinazolinon-2-yl Derivatives from the Diacid Chlorides of Pinic and sym-Homopinic Acids

The corresponding diamides have been synthesized by the interaction of the diacid chlorides of cis-2,2-dimethyl-3-carboxycyclobutaneacetic acid (pinic acid) and cis-2,2-dimethylcyclobutane-1,3-diacetic acid (sym-homopinic acid) with two equivalents of anthranilic acid. Treatment of the diamides with formamide gave 2,2-dimethyl-1-[4(3H)-quinazolinon-2-yl]methyl-3-[4(3H)-quinazolinon-2-yl]cyclobutane and 2,2-dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane respectively.     

Three component condensation of 6-quinolylamine with aromatic aldehydes and cyclohexyl 1,3-diketones

A three component condensation of 6-quinolylamine with 4-bromo-or 4-methoxybenzaldehyde, and 1,3-cyclohexanedione or dimedone gave 12-(4-bromophenyl)-and 12-(4-methoxyphenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-7H-benzo[b][4,7]phenanthrolin-11-ones. The reaction intermediates obtained were N-arylmethylene-6-quinolylamines, 2-arylmethylenebis(1,3-cyclohexanediones), 3-(6-quinolylamino)-2-cyclohexenone, and 5,5-dimethyl-3-(6-quinolylamino)-2-cyclohexenone. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 6, pp. 877–885, June, 2007.     

1, 5, 6, 7-Tetrahydro-2H-[1,4]diazepin-5,7-dione aus Malonimiden und 3-Dimethylamino-2,2-dimethyl-2H-azirin

1, 5, 6, 7-Tetrahydro-2H-[1, 4]diazepin-5, 7-diones from Malonimides and 3-Dimethylamino-2, 2-dimethyl-2H-azirine Reaction of the aminoazirine 1 with malonimides of type 7 in 2-propanol at room temperature leads to the 1,4-diazepine derivatives of type 9 (Scheme 3). The structure of 6, 6-diethyl-3-dimethylamino-2,2-dimethyl-1,5,6, 7-tetrahydro-2H- [1,4] diazepin-5, 7-dione ( 9a ) has been proved by single crystal X-ray analysis (Chapter 4). Reduction of the 7-membered heterocycle 9a with sodium borohydride yields the perhydro-[1,4]diazepin-5, 7-dione 10 , while 9a in ethanol at 60° undergoes a ring contraction to the 4 H-imidazole derivative 11a (Scheme 4): Mechanisms of these two reactions are discussed in comparison with previously reported reactions (Chapter 5).     

Synthesis of 4-aryl-4,7,8,9-tetrahydro-6H-pyrazolo[3,4-b]quinolin-5-ones

Reaction of 5-amino-3-methyl-1-phenylpyrazole ( 1a ) and 5-amino-3-(4-chlorophenyl)-1H-pyrazole ( 1b ) with dimedone ( 2 ) and p-susbstituted benzaldehydes 3 in ethanol, afforded in all cases tricyclic linear 4-aryl-7,7-dimethyl-4,7,8,9-tetrahydro-6H-pyrazolo[3,4-b]quinolin-5-ones ( 4a-j ) in good yields. The linear structures and hence the regiospecificity of the reaction were established by nmr measurements.     

Selenium dioxide oxidations of dialkyl-3H-azepines: the first synthesis of 2-azatropone from oxidation of 2, 5-Di-tert-butyl-3H-azepine

Oxidation reactions of 2,5- and 3,6-di-tert-butyl-3H-azepines (1 and 2) with selenium dioxide (SeO(2)) were performed. The oxidation of 1 with SeO(2) gave 3-tert-butyl-7,7-dimethyl-4-oxo-octa-2,5-dienal 3 in 36% yield, 4-tert-butyl-5-(3,3-dimethyl-2-oxo-butylidene)-1, 5-dihydro-pyrrol-2-one 4 in 13% yield, 2, 6-di-tert-butyl-2-pyridinecarbaldehyde 5 in 12% yield, and 4, 7-di-tert-butyl-2H-azepin-2-one (2-azatropone) 6 in 6% yield, respectively. Oxidation of 2 with SeO(2) gave 2, 2-dimethyl-1-[2-(5-tert-butyl)-pyridyl]propanol 7 in 55% yield, and 3,6-di-tert-butyl-2H-azepine 8 in 5% yield, respectively. We found that selenium dioxide oxidation of 1 affords 4-oxo-octa-2,5-dienal 3 by a new ring cleavage reaction of 1, and we described the first synthesis of 2-azatropone 6 from this oxidation of 1. In the case of 2, pyridylpropanol 7 was obtained as the major product. We now report in detail result of these oxidation reactions, which have led to the synthesis of a novel azatropone derivative.     

3,6,6-trimethyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole in Schmidt reaction and Beckmann rearrangement conditions for the 4-hydroxyimino derivative

Treatment of 3,6,6-trimethyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with sodium azide in acids gives 3,7,7-trimethyl-5-oxo-1-(2-pyridyl)-5,6,7,8-tetrahydro(4H)pyrazolo[4,3-b]azepine. Heating 1-(2-pyridyl)-3,6,6-trimethyl- and 1-phenyl-6,6-dimethyl-4-hydroxyimino-4,5,6,7-tetrahydroindazoles in polyphosphoric acid gives 1-phenyl-5,6-dimethyl- and 1-(2-pyridyl)-3,5,6-trimethyl-4-aminoindazole respectively: The reactions of the latter with 4-dimethylaminobenzaldehyde gave the 4-(4-dimethylaminobenzalamino) derivative and with 2-formyldimedone the 4-(4,4-dimethyl-2,6-dioxocyclohexylidenemethylamino) derivative.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 830–834, June, 2000.     

Reactions of 1-[Benzoyl(2-hetaroyl)]-2,2-dimethyhydrazines with 1,3-Dibromopropyne, 2-Propynyl Bromide,and Allyl Bromide

Reactions of 1-[benzoyl(2-hetaroyl)]-2,2-dimethyhydrazines with 1,3-dibromopropyne in MeOH at 50°C afforded 2-phenyl(heteryl)-6-bromomethylidene-4,4-dimethyl-5H-1,3,4-oxadiazinium bromides. Reactions of 1-[benzoyl(2-hetaroyl)]-2,2-dimethyhydrazines with propargyl bromide and allyl bromide gave rise to 1,1-dimethyl-1-(2-propyn-1-yl)- and 1,1-dimethyl-1-(2-propen-1-yl)-2-benzoyl(hetaroyl)hydrazinium bromides. On treating these compounds with NaOH solution the corresponding imides were obtained.     

5-Diazo-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles in [3+2] cycloaddition reactions

The [3+2] cycloaddition reactions of a series of 1,3-substituted 5-diazo-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles with maleic anhydride and dimethyl acetylenedicarboxylate gave 1′,3′-substituted 3-spiro[4,6-dioxo-4,6,3a,6a-tetrahydro-3H-furo[3,4-c]pyrazole]-5′-[6′,6′-dimethyl-4′-oxo-4′,5′,6′,7′-tetrahydroindazoles] and 1′,3′-substituted 3-spiro[4,5-di(methoxycarbonyl)-3H-pyrazole]-5′-[6′,6′-dimethyl-4′-oxo-4′,5′,6′,7′-tetrahydroindazoles] respectively. When heated the former eliminate nitrogen and are transformed into 1′,3′-substituted 6-spiro[2,4-dioxo-3-oxabicyclo[3.1.0]hexane]-5′-[6′,6′-dimethyl-4′-oxo-4′,5′,6′,7′-tetrahydroindazoles]. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1784–1791, December, 2007.