Synthesis and reactions of 1-(4-bromo-, 4-fluoro-, and 4-trifluoromethylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles

From 2-formyldimedone and 4-bromo-, 4-fluoro-, and 4-trifluoromethylphenylhydrazines we have obtained the corresponding 2-arylhydrazinomethylenedimedones, which in acid medium undergo ring closure to form 1-substituted 6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles. Oxidation of the latter by selenous acid leads to the corresponding 4,5-dioxo-4,5,6,7-tetrahydroindazoles, which then were converted to derivatives of 4,5-dihydro-3H-pyrazolo[4,3-a]phenazine and 4,5-dihydro-1H(3H)-indazolo[4,5-d]imidazole.Riga Technical University, Riga LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1669–1675, December, 1997.     

Syntheses Based on 4-Chloro-1-[3,5-di(trifluoromethyl)phenyl]-, 4-Chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles,and 4-Chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles

Vilsmeier formylation of 1-[3,5-di(trifluoromethyl)phenyl]- and 1-(2,4-difluorophenyl)-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles gave the corresponding 1-aryl-4-chloro-5-formyl-3-methyl-6,7-dihydroindazoles. Reaction of the latter with amidines, o-phenylenediamine, hydrazine, or hydroxylamine gave a series of 1-aryl-3-methyl-6,6-dihydroindazoles annelated at positions 4 and 5. The reaction of 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazole with substituted anilines gave 5-arylaminomethylene-4-oxo- or 5-arylaminomethylene-4-arylimino-3-methyl-1-(2-pyridyl)-4,5,6,7-tetrahydroindazoles depending on the molar ratio of reagents and the nucleophilicity of the amines.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 740–750, May, 2005.     

4,5-Dioxo-and 4-oxo-2,3-diaryl-5-diazo-6,6-dimethyl-4,5,6,7-tetrahydroindazoles

The oxidation of 2,3-diphenyl-, 3-(4-chlorophenyl)-2-phenyl-, 3-(4-dimethylaminophenyl)-2-phenyl-, 3-(4-methoxyphenyl)-2-phenyl-, 2-phenyl-3-(3-pyridyl)-, 3-phenyl-2-(2-pyridyl)-, and 3-(4-dimethylaminophenyl)-6,6-dimethyl-4-oxo-2-(2-pyridyl)-4,5,6,7-tetrahydroindazoles using H₂SeO₃ in acetic acid in the presence of sulfuric acid gave the corresponding 4,5-dioxo derivatives. Reaction of these with tosylhydrazine gave 4-oxo-5-tosylhydrazino derivatives which were decomposed by alkali to give the corresponding 2,3-diaryl-5-diazo-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1829–1833, December, 2005     

1- and 2-(4-Hydroxycarbonylphenyl)-4-oxo-4,5,6,7-tetrahydroindazoles

Reactions of 4-hydrazinobenzoic acid with 2-formyl- and 2-acetyldimedones were utilized to synthesize 6,6-dimethyl- and 3,6,6-trimethyl-1-(4-hydroxycarbonylphenyl)-4-oxo-4,5,6,7-tetrahydroindazoles corre-spondingly, and the reaction with 2-cyano-3-ethoxy-5,5-dimethylcyclohex-2-en-1-one gave 2-(4-hydroxy-carbonylphenyl)-3-amino-4-oxo-6,6-dimethyl-4,5,6,7-tetrahydroindazole. Riga Technical University, Riga LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 516–519, April, 1997.     

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.     

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.     

Di-6R,7R1-4(3H)-Oxo-2-quinazolinyl-substituted Cyclobutanes from Pinic and sym-Homopinic Acids

The corresponding diamides were obtained from reaction of cis-3-carboxy-2,2-dimethylcyclobutylacetic acid (pinic acid) and of cis/trans-3-(carboxymethyl)-2,2-dimethylcyclobutylacetic acid (homopinic acid) dichlorides with two equivalents of 5-bromo-, 4-chloro-, and 4,5-dimethoxyanthranilic acids. Treatment of them with formamide leads to the formation of the corresponding 2,2-dimethyl-3-[4(3H)-oxo-2-quinazolinyl]methyl-1-[4(3H)-oxo-2-quinazolinyl]cyclobutanes and 2,2-dimethyl-1,3-di[4(3H)-oxo-2-quinazolinylmethyl]cyclobutanes.     

Reactions of 3-methyl-1-(2-pyridyl)-4-chloro-5-formyl-6,7-dihydroindazole

The reactions of 3-methyl-1-(2-pyridyl)-, 3-methyl-1-phenyl-, and 3-methyl-1,6-diphenyl-4-chloro-5-formyl-6,7-dihydroindazoles with guanidine and benzo- and 3- and 4-pyridinecarbamidines gave the corresponding 8-substituted 1-methyl-3-(2-pyridyl)-and 1-methyl-3-phenyl-4,5-dihydropyrazolo[5,4-h]quinazolines. With acetic anhydride the same indazole derivatives gave the 4-acetoxy-5-formyl derivatives, and with hydroxylamine they gave4-chloro-5-hydroxyiminomethyl-6,7-dihydroindazoles. Thereactionof4-acetoxyl-1-(2-pyridyl)-5-formyl-6,7-dihydroindazole with hydroxylamine gave 8-methyl-6-(2-pyridyl)-4,5-dihydroisoxazolo[5,4-e]indazole, while dehydration of 5-hydroxyiminomethyl-3-methyl-4-chloro-6,7-dihydroindazole gave the 4-chloro-5-cyano derivative. The reaction of the latter with nucleophilic reagents was investigated.Riga Technical University, Riga, Latvia LV-1658. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1209–1213, September, 1998.     

Reactions of 2-Amino-4-methyl-6-(2-pyridyl)- and 2-Amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazoles with Aldehydes

The reaction of 2-amino-4-methyl-6-(2-pyridyl)-7,8-dihydroindazolo[4,5-d]thiazole, obtained by treating 3-methyl-4-oxo-1-(2-pyridyl)-4,5,6,7-tetrahydroindazole with pyridinium bromide perbromide and then with thiourea, and 2-amino-4-methyl-6-phenyl-7,8-dihydroindazolo[4,5-d]thiazole with 4-bromo-, 4-fluoro-, 4-dimethylamino-, 4-methoxy-, 3,4-dimethoxy-, and 3,4-methylenedioxybenzaldehydes, furfural, pyridinecarbaldehyde, and thiophenecarbaldehyde gave the corresponding Schiff bases. The products of the condensation of these aminothiazoles with cinnamaldehyde, 1-(2-pyridyl)- and 4-chloro-1-(2,4-difluorophenyl)-5-formyl-3-methyl-6,7-dihydroindazoles, 2-formyl-dimedone, and 2-formyl-1,3-indanedione were also obtained.     

1-(2-Quinoxalyl)-, 1-[3,5-Di(trifluoromethyl)phenyl]-, 1-(2-Carboxyphenyl)-, and 1-Ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydroindazoles

The corresponding 1-(2-quinoxalyl)-, 1-[3,5-di(trifluoromethyl)phenyl]-, and 1-ethoxycarbonyl-3-methyl-4-oxo-4,5,6,7-tetrahydroindazoles have been obtained from reactions of 2-acetyl-1,3-cyclohexanedione, its 5,5-dimethyl and 5-(2-furyl) derivatives, with 2-hydrazinoquinoxaline, 3,5-di(trifluoromethyl)phenylhydrazine, and ethoxycarbonylhydrazine. On interaction with ethoxycarbonylhydrazine the intermediate 2-[1-(-ethoxycarbonyl)hydrazino]ethylidene-1,3-cyclohexanediones were also isolated. From the potassium salt of 2-formyldimedone and 2-carboxyphenylhydrazine hydrochloride, 2-(2-carboxyphenyl)hydrazinomethylene-5,5-dimethyl-1,3-cyclohexanedione was obtained, the cyclization of which in ethanol in the presence of HCl led to 1-(2-carboxyphenyl)- and 1-(2-ethoxycarbonylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole.     

Pyrazolo[5,4-h]quinazolines

The reaction of 1-phenyl- and 4-chloro-5-formyl-3-methyl-1-(2-pyridyl)-6,7-dihydroindazoles with carbamidinopyrrolidine, 4-carbamidinomorpholine, creatine, 2-carbamidinopyrazine, and 2-carbamidino-5-trifluoromethylpyridine gives the corresponding 3,8-substituted 1-methyl-4,5-dihydropyrazolo-[5,4-h]quinazolines and with 2-aminobenzimidazole gives 3-phenyl- and 3-(2-pyridyl)-1-methyl-4,5-dihydrobenzo[b]indazolo[4,5-e]imidazolo[1,2-a]pyrimidines.Riga Technical University, Riga LV-1658, Latvia; e-mail; marina@osi.lv . Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 962–965, July, 2000.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Derivatives of condensed thieno[2,3-d]-pyrimidines. 20. Synthesis of 2-substituted 5,6-dihydro-8H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-ones and 5,6,7,8-tetrahydrobenzo-[b]thieno[2,3-d]pyrimidin-4-ones

We have developed a method for obtaining 2-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4′,3′:4,5]-and 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones, converted by deamination to the corresponding dihydropyranothieno-3H-pyrimidinones. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 441–444, March, 2006.     

Purines, Pyrimidines, and Condensed Systems Based on them. 18. Reaction of 6,8-Dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)dione N(2)-oxide with Alkylamines

Heating 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione N₍₂₎-oxide (2) with piperidine or morpholine gave a moderate yield of 3-piperidino- and 3-morpholino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones (3a,b). Reaction of N-oxide (2) with ammonia and alkylamines in the presence of an oxidant led to formation of the 3-amino derivatives of 2 and the corresponding desoxy products 3. The latter were also obtained by an independent method by heating 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with alkylamines in butanol.     

Reactions of 1-aryl- and 2,3-diaryl- 5-diazo-6,6-dimethyl-4-oxo-4,5,6,7-tetra- hydroindazoles with N-ethyl- and N-phenyl-substituted maleimides

[3+2] Cyclocondensation reactions of a series of 1,3- and 2,3-disubstituted 5-diazo-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazoles with N-ethyl- and N-phenyl-substituted maleimides have been used to obtain the corresponding 6,6-dimethyl-4,4',6'-trioxo-4,5,6,7-3',3'a,4',5',6',6'a-decahydrospiro-[indazole-5,3'-pyrrolo[3,4-c]pyrazoles]. On boiling these compounds in toluene nitrogen is split off and they are converted into 6',6'-dimethyl-2,4,4'-trioxo-4',5',6',7'-tetrahydro-1'H-spiro[3-azabicyclo-(3.1.0)hexane-6,5'-indazoles].     

Condensed pyridazines. Part III. Rearrangement and ring cyclization during the thermolysis of (z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate

The thermolysis of (Z)-methyl 3-(6-azido-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazin-5-yl)-2-methylacrylate ( II ) provides a new synthetic route to pyrrolo[2,3-c-]pyridazines, specifically, methyl 3-chloro-1,6-dimethyl-4-oxo-1,4-dihydro-7H-pyrrolo[2,3-c]pyridazine-5-carboxylate ( III ) in 91% yield. Treatment of III with ozone provides an entry into the novel pyridazino[3,4-d][1,3]oxazine ring system, specifically, 3-chloro-1,7-dimethylpyridazino[3,4-d][1,3]oxazine-4,5-dione ( IV ) in 73% yield. Compound IV is smoothly hydrolyzed into 6-acetylamino-3-chloro-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( V ) which is readily recyclized into IV by dehydration with acetic anhydride. Furthermore, IV undergoes a facile reductive ring opening reaction with sodium borohydride to give 3-chloro-6-ethylamino-1-methyl-4-oxo-1,4-dihydropyridazine-5-carboxylic acid ( VI ) in 95% yield.     

Synthesis of some 5,6,7,8-tetrahydro-4-cinnolone derivatives and 1-methyl-3-arylacetyl-4,5,6,7-tetrahydroindazoles

2-Arylidene-3-oxo-2,3,4,5,6,7-hexahydrobenzo[b]furans 2 react with hydrazine hydrate to afford 5,6,7,8-tetrahydro-4-cinnolones. By methylation, these compounds gave the corresponding N-1 and N-2 methyl derivatives. The mesoionic compounds are obtained, accompanied by 3-arylacetyl-4,5,6,7-tetrahydroindazoles upon reaction of 2 with methylhydrazine.     

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.     

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.     

Studies on organophosphorus compounds—XXVII: Synthesis of thiono-, thiolo- and dithiolactones

Unsubstituted and alkyl- or cyanosubstituted lactones such as dihydro-2(3 H)-furanone, dihydro-5-methyl-2(3 H)-furanone, dihydro-5,5-dimethyl-4-propyl-2(3 H)-furanone and tetrahydro-2,2-dimethyl-5-oxo-3furan-carbonitrile react with the dimer of p-methoxyphenylthionophosphine sulfide, 1, in anhydrous xylene or toluene to give the corresponding thionolactones, 3a-d, in good yields. Dihydro-2(3 H)-thiophenone and 1 produce dihydro-2(3 H)-thiophenthione. Aromatic lactones such as 2 H-1-benzopyran-2-one give the corresponding 2-thione. 1-Oxa-4-thiaspiro[4,5]decan-2-one, when treated with 1 at 120-125°, gave 1,4-dithiaspiro[4,5]decan-2-one and 1,4-dithias-piro[4,5]decan-2-thione. Tetrahydro-5,5-dimethyl-2-oxo-4-propyl-3-furancarboxylic acid ethyl ester reacted with 1 at 110° giving the corresponding 2-thione and 5,5-dimethyl-4-propyl-4,5-dihydrothieno[2,3-c]-1,2-dithiole-3-thione.