Synthesis and chemical reactivity of indenoisoxazoles

Treatment of 2-pivaloyl-1,3-indandione ( 1 ) with hydroxylamine under acidic conditions, results in formation of 8-t-butylindeno[1,2-c]isoxazol-7-one ( 2 ) while treatment of the triketone with hydroxylamine at neutral or basic pH gave 6 which upon cyclization gave the isomeric 3-t-butylindeno[1,2-c]isoxazol-4-one ( 7 ). Compound 7 was readily reduced to amine 12 by treatment with hydrazine or hydrogen over platinum. The amine, although quite unreactive, was converted to 3-t-butylindeno[1,2-c]pyrazol-4-one ( 13 ) with hydrazine or reduced to 15 and 16 with sodium in liquid ammonia and alcohol. Surprisingly, the amine 3 obtained from isoxazole 2 gave reduction product 15 from a sodium-liquid ammonia reduction and not the expected product 18. Spectral evidence for each of the structures is discussed.     

Flash vacuum pyrolysis of 3-t-butylindeno[1,2-c]isoxazol-4-one. Formation of 2-carbonyl-1,3-indandione 2-azine

Flash Vacuum Pyrolysis (FVP) of 3-t-Butylindeno[1,2-c]isoxazol-4-one ( 1 ) and 3-t-Butylspiro[2H-azirine-2,2′-(2H)indene]-1′,3′-dione ( 2 ) were carried out. Reaction of 1 from 300–400° afford 2 and 2-carbonyl-1,3-indandione 2-azine ( 3 ) as the major products, whereas 2-t-Butylindeno[1,3-c]oxazol-4-one ( 4 ) was the main products in FVP of 2 together with minor amounts of 3.     

A Synthesis of imidazo- and pyrimido[1,2-g][1,6]naphthyridinones

Arylmethylimidazolines and (3-chlorophenyl)methyl-1,4,5,6-tetrahydropyrimidine amidated 2-chloro-3-pyridinecarbonyl chloride, and potassium t-butoxide cyclized the products to linearly fused, tricyclic imidazo-and pyrimido[1,2-g][1,6]naphthyridinones. Condensation of ethyl 2-chloro-3-pyridinecarboxylate with 2-(phenylmethyl)imidazoline in the presence of sodium methoxide directly formed the isomeric, angularly fused 8,9-dihydro-6-phenylimidazo[1,2-a ] [1,8]naphthyridin-5(7H-one.     

Heterocyclization of Functionalized Heterocumulenes with C,N- and C,O-Binucleophiles. 1. Cyclocondensation of 1-Chloroalkylheterocumulenes and N-(1-Chloroalkylidene)urethanes with 2-Cyanomethylpyridine

The interaction of 1-chloroalkyl isocyanates, 1-chloroalkylcarbodiimides, 1,1-dichloroalkyl isocyanates, and N-(1-chloroethylidene)-O-methylurethanes with 2-cyanomethylpyridine has been investigated. An effect of organic base has been detected on the regioselectivity of the cyclocondensation of 1-chloroalkyl isocyanates, which leads to 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-1-one or the isomeric 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-3-one. Irrespective of the cyclization conditions 1-chloroalkylcarbodiimides react with the formation of 1-imino-2,3-dihydro-1H-pyrido[1,2-c]pyrimidines. One type of product, a 1H-pyrido[1,2-c]pyrimidin-1-one, was also isolated from 1,1-dichloroalkyl isocyanates and N-(1-chloroalkylidene)urethanes.     

On Triazoles. XXXII. The reaction of 5-amino-1 H-1,2,4-triazolylcarbothiohydrazides with β- and γ-oxo-esters

5-Amino-lH-1,2,4-triazolylcarbothiohydrazides gave β and γ-oxo-esters in boiling ethanol [1,2,4]triazolo- [1,5-d][1,2,4,6]tetrazepine-5-thiones 3 . Analogously ethyl 2-oxocyclohexanecarboxylate provided a mixture of two diastereomeric spiro derivatives 5 and 6 . At 130°, 2-acetonyl-5-methyl-4,5-dihydro-1,3,4-oxadiazole-5-thione ( 8 ) was formed. Ring closure of 3e (R¹ = CH₃, R² = CH₂CH₂COOEt, Q = morpholino) lead to the isomeric pyrrolo[2,1-g][1,2,4]triazolo[1,5-d][1,2,4,6]tetrazepin-8(11H)-one ( 12 ) and pyrrolo[1,2-f][1,2,4]triazolo-[1,5-d][1,2,4,6]tetrazepin-10(7H)-one ( 13 ) derivatives representing two new ring systems.     

6H-indeno[1,2-b]pyrido[3,2-e]pyrazines. A new heterocyclic ring system

Condensation of 1,2-indanedione and 1,2,3-indanetrione hydrate (ninhydrin) with 2,3-diamino-pyridines gave a number of compounds belonging to the hitherto unknown 6H-indeno[1,2-b]-pyrido[3,2-e]pyrazine ring system. The unsymmetrical nature of the reactants can theoretically result in isomeric ring closure products. Assignment of the 6H- ring system was based upon the identity of 6H-indeno[1,2-b]pyrido[3,2-e]pyrazin-6-one obtained from 2,3-diaminopyridine and ninhydrin with material prepared by unequivocal synthesis. The direction of cyclization of ninhydrin and 1,2-indanedione with the diamines was shown to be the same by reduction of the indenopyridopyrazinones to the corresponding indenopyridopyrazines. Some physical, chemical, and tumor growth-inhibitory properties of the products are reported.     

Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

Reactions of 3-acetyltropolone and its methyl ethers with hydroxylamine. Formation of 8H-cyclohept[d]isoxazol-8-one and 8H-cyclohept[c]isoxazol-8-one

The reaction of 3-acetyltropolone ( 1 ) with hydroxylamine under the acidic condition gave 3-methyl-8H-cyclohept[d]isoxazol-8-one ( 4 ) and its oxime ( 5 ), and under the neutral condition gave 4 and 3-acetyltropolone oxime ( 6 ). The reaction of 3-acetyl-2-methoxytropone ( 2a ) with hydroxylamine under the acidic condition gave 4, 5 , and 4-methyl-1H-2,3-benzoxazin-1-one ( 7 ), and under the neutral condition gave 4, 7 , 3-methyl-8H-cyclohept[c]isoxazol-8-one ( 8 ), and its oxime ( 9 ). The reaction of 7-acetyl-2-methoxytropone ( 2b ) with hydroxylamine under the acidic condition gave 4 and 5 , and under the neutral condition gave 5, 7 , and 9 .     

A novel synthesis of the isoxazolo[5,4,3-kl]acridine ring system

The Schmidt reaction of 6,7-dihydro-3-phenyl-1,2-benzisoxazol-4(5H)-one ( 1 ) is described. In addition to the expected isomeric lactams, 3-phenyl-5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-4-one ( 3 ) and 7,8-dihydro-3-phenyl-4H-isoxazolo[4,5-b]azepin-5(6H)-one ( 4 ), 4-amino-3-phenyl 1,2-benzisoxazole (5) was isolated, along with 4,5-dihydro-3H-isoxazolo[5,4,3-kl]acridine ( 6 ). Possible mechanisms for the formation of these products are discussed and some chemistry of the little-known ring system represented by 6 is also described.     

Condensed heterocycles containing the pyrimidine nucleus

Continuing earlier studies designed to obtain derivatives of 1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and of the isomeric 7-one of pharmacological interest, some novel compounds 2 and derivatives of 6,7,8,9-tetrahydro-5H-1,3,4-thiadiazolo[2,3-b]quinazolin-5-one ( 3 ) were prepared. Derivatives of pyrimido[2,1-b]benzothiazol-2-one ( 6 ) and of the isomeric 4-one derivatives 8 were also synthesized. Structural identification was obtained by ¹H-nmr, ir and mass spectra.     

5,5,6-Trimethylbicyclo[2.2.1]heptan-2-one in the Synthesis of Carbocyclic Analogs of Prostaglandin Endoperoxides

1,3-Dipolar cycloaddition of nitrile oxides to 5,5,6-trimethyl-exo-2-ethynylbicyclo[2.2.1]heptan-endo-2-ol yields the corresponding 2-(isoxazol-5-yl) derivatives. Opening of the isoxazole ring in the latter gives rise to prostanoid precursors with partially built up or completed side chain. 5,5,6-Trimethyl-3-methylenebicyclo[2.2.1]heptan-2-one reacts with nitromethane in the presence of tetramethylguanidine to afford 5,5,6-trimethyl-exo-3-(2-nitroethyl)bicyclo[2.2.1]heptan-2-one which can be converted into the corresponding nitrile oxide by the action of phenyl isocyanate in benzene in the presence of triethylamine as catalyst. 1,3-Dipolar cycloaddition of the nitrile oxide to ethyl 4-pentynoate yields 3-exo-[5-(2-ethoxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one. Treatment of the latter with hydroxyl amine leads to formation of the corresponding Z-oxime whose reaction with n-hexyl bromide results in transalkylation of the ester group to afford 3-exo-[5-(2-hexyloxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one oxime.     

Core-Modified Coelenterazine Luciferin Analogues: Synthesis and Chemiluminescence Properties

In this work on the design and studies of luciferins related to the blue-hued coelenterazine, the synthesis of heterocyclic analogues susceptible to produce a photon, possibly at a different wavelength, is undertaken. Here, the synthesis of O-acetylated derivatives of imidazo[1,2-b]pyridazin-3(5 H)-one, imidazo[2,1-f][1,2,4]triazin-7(1 H)-one, imidazo[1,2-a]pyridin-3-ol, imidazo[1,2-a]quinoxalin-1(5 H)-one, benzo[f]imidazo[1,2-a]quinoxalin-3(11 H)-one, imidazo[1′,2′:1,6]pyrazino[2,3-c]quinolin-3(11 H)-one, and 5,11-dihydro-3 H-chromeno[4,3-e]imidazo[1,2-a]pyrazin-3-one is described thanks to extensive use of the Buchwald–Hartwig N-arylation reaction. The acidic hydrolysis of these derivatives then gave solutions of the corresponding luciferin analogues, which were studied. Not too unexpectedly, even if these were “dressed” with substituents found in actual substrates of the nanoKAZ/NanoLuc luciferase, no bioluminescence was observed with these compounds. However, in a phosphate buffer, all produced a light signal, by chemiluminescence, with extensive variations in their respective intensity and this could be increased by adding a quaternary ammonium salt in the buffer. This aspect was actually instrumental to determine the emission spectra of many of these luciferin analogues.     

Investigations in the field of benzoxa- zines. 15*. Tandem heterocyclizations with the participion of 2-formylbenzoic acid. The synthesis of isoindolo[1,2-<Emphasis Type="Italic">b</Emphasis>][1, 3]- and -[2,1-<Emphasis Type="Italic">a</Emphasis>][1, 3]benzoxazinones

Single stage reactions of 2-formylbenzoic acids with substituted 2-(1-aminoalkyl)phenols and 2-amino-phenylcarbinols give a novel series of isomeric isoindolobenzoxazinones. X-ray analysis was used to study the molecular structure of 9-bromo-5,5-diphenyl-5H-isoindolo[2,1-a][1, 3]benzoxazin-11(6aH)-one and 2-bromo-8,10-dimethyl-10H-isoindolo[1,2-b][1, 3]-benzoxazin-12(4bH)-one.     

Condensed imidazo-1,2,4-azines. 15. Reaction of 1,2-diaminobenzimidazole with 5-phenyl-2,3-dihydrofuran-2,3-dione

The reaction of 1,2-diaminobenzimidazole with 5-phenyl-2,3-dihydrofuran-2,3-dione in acetic acid gave a mixture of 2-benzoylmethyl-1,2,4-triazino [2,3-a]-benzimidazol-4H-3-one and 3-benzoylmethyl-1,2,4-triazino[2,3-a]benzimidazol-1H-2-one, the intramolecular cyclization of which gave isomeric 2-phenylfuro-[5,4-e]- and 2-phenylfuro[4,5-e]-1,2,4-triazino[2,3-a]benzimidazoles. Only the corresponding furo[4,5-e]-1,2,4-triazino[2,3-a]benzimidazole was isolated when the reaction was carried out in sulfuric acid.See [1] for Communication 14.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 533–535, April, 1987.     

Ring opening reactions of indeno[1,2-c]isoxazolones

Nucleophilic attack of 8-substituted indeno[1, 2-c]isoxazol-7-ones ( 1 ) and 3-phenylindeno[1, 2-c]isoxazol-4-one (4) by dimethylsulfoxide or triphenylphosphine results in cleavage of the nitrogen? oxygen bond of the isoxazole ring leading to the formation of sulfoximides ( 2 and 5 ) and phosphazenes ( 3 and 8 ).     

Bromination of Substituted 5H-Imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones

The reactions of substituted 5H-imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones with bromine and N-bromosuccinimide have been studied. Derivatives of 3- and 8-bromo-, 3,8-dibromoimidazo[1,2-b]-1,2,4-triazepine and 5H-2-bromomethyl-3-methyl-7,8-diphenylimidazo[1,2-b]-1,2,4-triazepin-4-one are formed, depending on the degree of substitution, the nature of the brominating agent, and the reaction conditions.     

Spatial Configuration of Derivatives of 5,5a,6,7-Tetrahydropyrido[1,2-a]benzimidazole and 6,7-Dihydro-5aH-pyrido[1,2-b]benzoxazole

The spatial configurations of 7,9-diphenyl-5a,6-tetramethylene-5,5a,6,7-tetrahydropyrido[1,2-a]benzimidazole and 7,9-diphenyl-5a,6-tetramethylene-2,5a,6,7-tetrahydropyrido[1,2-a]benzimidazol-2-one have been established by X-ray crystallography. Analogous configurations are proposed for a series of other derivatives of 5,5a,6,7-tetrahydropyrido[1,2-a]benzimidazoles and some derivatives of 6,7-dihydro-5aH-pyrido[1,2-b]benzoxazoles on the basis of ¹H NMR spectroscopic data and the results of quantum chemical calculations using the MNDO, AM1, and PM3 methods.     

Synthesis of nitrogen-containing heterocycles. 8. Preparation and ring-opening of spiro[cycloalkane-[1′,2′,4′]triazolo[1′,5′-c]pyrimidine] derivatives

Diaminomethylene- and aminomethylthiomethylenehydrazones [2] of cyclic ketones 1–8 readily reacted with ethoxymethylenemalononitrile to give spiro[cycloalkane-1,2′-[1,2′,4′]triazolo[1,5′-c]pyrimidine-8′-carbonitrile] derivatives 12–19 through the electrocyclic reaction of the initially formed condensation products 26 in moderate to high yields. The spiro[cyclopentanetriazolopyrimidine] derivatives underwent ring-opening at the cycloalkane moiety upon heating in solution to give 2-alkyl-5-substituted-[1,2,4]triazolo[1,5-c]pyrimidine-8′-carbonitriles 20–23 . When an alkyl substituent was introduced into the cyclopentane ring, cleavage of the spiro compounds occurred preferentially at the cyclopentane moiety between the spiro carbon and the more branched one. In contrast, the cyclohexane ring, especially of spiro-5-amino-triazolopyrimidines 17 and 18 strongly resisted to ring-opening under similar conditions, but those of 5-methylthiotriazolopyrimidines 14 gave up to 17 percent of cleavage after prolonged heating in hot ethanol. 2-t-Butyl-5-methylthio-2,3-dihydro[1,2,4]triazolo[1,5-c]pyrimidine-8-carbonitrile 25 [R³ = C(CH₃)₃] was highly susceptible to the cleavage even at room temperature and produced the corresponding 2-unsubstituted triazolopyrimidine 24 with loss of the t-butyl group.     

Reaction of 4,5-diaminopyrimidine and ethyl acetoacetate: Synthesis and chemistry of isomeric dihydropyrimido[4,5-b][1,4] diazepinones

Depending upon reaction conditions, 4,5-diaminopyrimidine and acetoacetic ester gave a variety of condensation products, including the two isomeric dihydropyrimido[4,5-b][1,4]-diazepinones. Under conditions leading to bicyclic products, the formation of 1,5-dihydro-4-methyl-2H-pyrimido[4,5-b][1,4]diazepin-2-one ( 2 ) was strongly favored. The isomeric 3,5-dihydro-2-methyl-4H-4-one compound ( 4 ) was best obtained by cyclization of ethyl 3-(4-amino-5-pyrimidylamino)crotonate ( 3 ) under base catalysis. Thermal rearrangement of 2 and 4 proceeded, in each instance, with loss of the isopropenyl moiety and gave 8-purinone. Compound 4 underwent ring contraction under the influence of alkoxide to yield a product which was shown to be the 7-isopropenyl-8-purinone ( 6 ).     

Behaviour of 5,6-dihydrothieno[2,3-h]cinnolin-3(2H)-one and 5,6-dihydrothieno[3,2-h]cinnolin-3(2H)-one towards hydrazine. Synthesis of thienocinnolinones and of 4-aminothienocinnolinones

The isomeric compounds 5,6-dihydrothieno[2,3-h]cinnolin-3(2H)-one ( 7a ) and 5,6-dihydrothieno-[3,2-h]cinnolin-3(2H)-one ( 7b ) rapidly tautomerise to the corresponding 1,4-dihydrothienocinnolinones 8a,b when kept in refluxing hydrazine hydrate. With longer reaction times the initially formed 8a,b dehydrogenate to the thienocinnolinones 9a,b which eventually are aminated to 4-aminothienocinnolinones 10a,b . This behaviour recalls that reported for the related 5,6-dihydrobenzocinnolin-3(2H)-one ( 1 ) which under the same conditions undergoes dehydrogenation to benzo[h]cinnolin-3(2H)-one ( 2 ) followed by 4-amination to 3 , but differs for the stability of the intermediates, for the mechanism of the final amination, and for the higher reaction rate. All these differences can be rationalised in terms of the heats of formation of the intermediates and products of the two series of transformations.