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.     

Condensed Isoquinolines. 17. Enamine Properties of Benzimidazo[1,2-b]isoquinolin-11(5H)-one in Alkylation Reactions

The alkylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one has been studied. This occurs at N₍₅₎ or C₍₆₎ depending on the type of alkylating agent and the reaction conditions. It was shown that C₍₆₎ alkylation is effected in reactions with reactive alkyl halides. A repeat alkylation occurs preferentially at the same position. Interaction with o-xylylidene dibromide leads to spiro[benzimidazo[1,2-b]-isoquinolin-6,2'-indan]-11-one and 1,6-dihydro-11H-6a,11b-diazobenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one, which are derivatives of new heterocyclic systems.     

Synthesis of spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones,spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones and spiro[benzofuran-2,1′-isobenzofuran]-3,3′-diones via transannular reactions of eight membered ring intermediates

An auto oxidation-rearrangement product 4 was isolated from a high dilution reaction of ninhydrin with 3,4,5-trimethoxyaniline in water. A general synthesis of this compound and its derivatives 4–6 was devised by oxidation of tetrahydroindeno[1,2-b]indol-10-ones 1–3 with sodium periodate to give isoindolo[2,1-a]-indole-6,11-diones 4–6 in good yield. Compounds 4–6 can be easily transformed into spiro[1H-isobenzofuran-1,2′-2H-indole]-3,3′-diones 8–10 , spiro[2H-indole-2,1′-1H-isoindole]-3,3′-diones 11–13 and isoindole[1,2-a:2′,1′-b]pyrimidine-5,15-diones 15, 16 in high yields. Analogous reactions were performed on 3-amino-5a, 10a-dihydroxybenzo[b]indeno[2,1-d]furan-10-one ( 17 ) to give a dibenzoxocintrione 18 , spiro-[benzofuran-2,1′-isobenzofuran]-3,3′-dione 19 and an isoindol-1-one 20 .     

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.     

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.     

Thermal and photochemical reaction of isoxazolone with indole-2,3-dione derivatives

The reaction of indole-2,3-dione derivatives with five membered heterocycle, viz isoxazolone under ther mal as well as photochemical conditions is described. While under refluxing ethanol these conditions afforded 2,3-dihydro-3-(5′-oxo-3′-phenylisoxazolidyl)indol-2-one 3 and a spiro product 2′,3′-dihydro-3,7-diphenylspiro[diisoxazolo[4,5-e:4,5-b]pyran-8,3′-indol]-2′-one 4 , the uv light induced irradiation mainly produced 4,5-dioxo-3-phenylisoxazolo[5,4-b][1]benzazepine 5 and 3-phenylisoxazolo[5,4-b]quinoline-4-carboxylic acid 6 . The products have been characterised on the basis of spectral data and elemental analyses.     

Condensed Pyridopyrimidines. 7. Synthesis of Condensed Triazolo[4,3-c]- and Tetrazolo[1,5-c]pyrimidines

Novel dihydro-5H-pyrano[3',4':5',6']pyrido[2,3-d]-1,2,4-triazolo[4,3-c]pyrimidines and 1,2,3,4-tetrazolo[1,5-c]pyrimidines have been synthesized from 2-amino-3-cyano-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine.     

Studies in spiroheterocycles. Part XVII. synthesis of novel fluorine containing spiro[indole-pyranobenzopyran] and spiro[indenopyran-indole] derivatives

An elegant one-step synthesis of two novel spiro ring systems viz: spiro[3H-indole-3,4′-(2′-amino-3′-carbonitrile-[4′H]-pyrano[3,2-c]benzopyran)]-2,5′(1H)-dione8 and spiro[(2-amino-3-carbonitrile-indeno[1,2-b]pyran)-4(5H)>3′-[3H]indole]-2′,5(1′H)-diones in 80–85% yields is described. The spiro heterocycles were prepared by the reactions of fluorine containing 3-dicyanomethylene-2H-indol-2-ones with 4-hydroxy-2H-1-benzopyran-2-one and 1H-indene-1,3(2H)-dione respectively. The synthesized compounds have been characterized on the basis of elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral data.     

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.     

Condensed Thienopyrimidines. 19. Study of the Heterocyclization of 2-Hydrazino-6,6-dimethyl-5,6-dihydro-8H-pyranothieno[2,3-d]pyrimidin-4-one

Novel condensed pyrano[4',3':4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidine derivatives have been synthesized from 2-amino-3-carbethoxy-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]pyran.     

Synthèse et propriétés photochromiques de 1, 3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4-f][1,4]benzoxazines] et de 1,3-dihydrospiro[2H-indole-2,7′-[7H]thiazolo[5,4-f][1,4]benzoxazines]

Synthesis and Photochrmic Characteristics of 1,3-Dihydrospiro[2H-indole-2,3′-[3H-]pyrimido[5,4-f][1,4]benzoxazines] and 1,3-Dihydrospiro[2H-indole-2,7′[7H]thiazolo[5,4-f][1,4]benzoxazines] Two new series of 1,3-dihydrospiro[2H-indole-ozazine] derivatives were synthesized, the 1,3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4]pyrimido[5,4-f][1,4]benzoxaines] 4-10 and the 1,3-dihydrospiro[2H-indole2,7′-[7H]thiazolo-[5,4-f][1,4]benzoxaines] 11–17 . These series extend the available range of photochromic properties (rate constant of thermal bleaching, UV/VIS spectrum of the opened coloured form, and photocoloration yield), an interesting feature of variable-transmission materials. The synthesis of these compounds (Scheme 1) required the preliminary synthesis of intermediate β-hydroxy-α-nitrosotherocycles 18 and 19 (Scheme 2). Important amounts of a coloured, non-photochromic, stable secondary product (See 20 ) were found in the condensation in the spiro[indole-thiazolobenzoxazine] series. The photochromic characteristics of the new derivatives were determined using a flash-photolysis apparatus coupled to a fast-scanning spectrometer. The role of the heteroatoms in the oxazine moiety and the role of substitutents in the indole moiety were investigated quantitatively through the study of the photochromic properties and the solvent effects. The presence of an S-atom gives rise to interesting properties which open up new prospects for synthesis and application.     

Condensed Thienopyrimidines. 14. Synthesis of 10H-Thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines

Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular cyclization of the obtained N'-methyl(phenyl) thioureido derivatives, and work up of the cyclization products with hydrazine hydrate gave 2-hydrazinodihydrothiopyranothienopyrimidines. Treatment of the latter with pyruvic acid gave the novel 10H-thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines.     

Saturated heterocycles. 57. Synthesis of 4-substituted-9,10-dialkoxy-1,6,7,11b-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-2-ones

A large number of 4-substituted-9,10-dialkoxy-1,6,7,11b-tetrahydropyrimido[6,1-a]isoquinolin-2-ones were prepared by the reaction of 1-(ethoxycarbonylmethyl)-6,7-dialkoxy-1,2,3,4-tetrahydroisoquinolines with iminoethers. Reaction of the corresponding isoquinoline-1-acetic acid derivatives with iminoethers led to the formation of N-acyl-1,2,3,4-tetrahydroisoquinolin-1-acetamides. In the hydrolysis of the prepared 4-substituted-pyrimido[6,1-a]isoquinolin-2-ones, the corresponding N-acyl-1,2,3,4-tetrahydroisoquinolin-1-acetamides were obtained. While reduction of the 4-phenyl derivative resulted in the corresponding 1,3,4,6,7,11b-hexahydropyrimidinone. The steric structures of the tetrahydro- and hexahydropyrimido[6,1-a]isoquinolines were determined by nmr spectroscopy.     

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.     

Non-steroidal antiinflammatory agents. VI. Synthesis of 10-oxo-5H-pyrrolo[1,2-b]isoquinoline-3-acetic Acid,a conformationally restricted analogue of tolmetin

The synthesis of 10-oxo-5H-pyrrolo[1,2-b]isoquinoline-3-acetic acid 4 , a tricyclic analogue of tolmetin which might show significant analgesic-antiinflammatory activity, has been accomplished in four steps. Alkylation of ethyl 2-pyrrolylglyoxylate ( 15 ) with 2-cyanobenzyl bromide afforded derivative 16 , which was transformed by the Huang-Minion reaction into the dicarboxylic acid 6 . Cyclization of this key intermediate to 17 , followed by alkaline hydrolysis, afforded 10-oxo-5H-pyrrolo[1,2–6]isoquinoline-3-acetic acid ( 4 ). Various attempted syntheses of 6 are also discussed.     

3-Hydrazino-1,2,4-triazin-5(2H)-ones in Reactions with Compounds Containing Carbonyl and Active Methylene Groups

Boiling of ethyl cyanoacetate with 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one in alkalinemedium yielded 6-tert-butyl-3-(5-hydroxy-3-oxo-2'3-dihydro-1H-pyrazol-1-yl)-1'2'4-triazin-5(2H)-one.Acylation of 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one with benzoyl chloride furnished 3-benzoyl-hydrazido-1'2'4-triazine that cyclized when treated with POCl₃ providing a derivative of[1'2'4]triazolo[4'3-b][1'2'4]triazine. Boiling of 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one in glacialacetic acid gave rise to diacetylated derivative whereas the boiling with acetic anhydride in an inert solventafforded monoacetylated product.     

Derivatives of Condensed Thienopyrimidimines. 13. Synthesis and Structure of Pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines

Methods for the synthesis of 5-substituted 10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines have been developed. An X-ray crystallographic study of 5-(2-ethoxymethylhydrazino)-10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidine has been carried out.     

Regioselectivity of cyclization of 3-allyl(propargyl)sulfanyl-5<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indoles

The interaction of 3-allylsulfanyl-5H-[1,2,4]triazino[5,6-b]indole with iodine led to 1-iodomethyl-1,2-dihydro[1,3]thiazolo[2',3':3,4][1,2,4]triazino[5,6-b]indol-11-ium pentaiodide with an angular structure, on the basis of which 1-iodomethyl-1,2-dihydro[1,3]thiazolo-, 1-methylidene-1,2-di-hydro[1,3]thiazolo, and 1-methyl[1,3]thiazolo derivatives were obtained. The intramolecular cyclization of 3-propargyl(allyl)sulfanyl-5H-[1,2,4]triazino[5,6-b]indoles under the influence of concentrated sulfuric acid led to linear annelated products:3-methyl[1,3]thiazolo[3',2':2,3][1,2,4]tri-azino[5,6-b]indole or its 2,3-dihydro derivative.     

Condensed Isoquinolines. 10. Borohydride Reduction in the 5H-Isoquino[2,3-a]quinazolin-5-one Series

Borohydride reduction in a series of 7-benzyl- and newly synthesized 7-arylmethylene-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones leads stereoselectively to erythro-7-benzyl-6,6a,7,12-tetrahydro-5H-isoquino[2,3-a]quinazolin-5-ones. 7,7-Disubstituted 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones are inert to the action of sodium borohydride, but spiro[5H-isoquino[2,3-a]quinazolin-7(12H),2'-indane]-5-one is reduced under rigid conditions to 6,6a-dihydrospiro[5H-isoquino[2,3-a]quinazolin-7(12H),2'-indan]-5-one. 7-Acetyl- and 7-benzoyl-6,11-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones are converted in an aqueous alcoholic solution of sodium borohydride to the previously described 6,6a,7,12-tetrahydro-5H-isoquino[2,3-a]quinazolin-5-one. The structure and special features of the conformational behavior of the reduction products obtained were demonstrated by ¹H NMR spectroscopy.!     

Spirocyclization of 1-(o-aminophenyl)cycloalkanols and 1-(2′-amino-3′-pyridinyl)cycloalkanols

A one-step synthesis of spiro[cycloalkane-1,4′-2H-3′,1-benzoxazin]-2′-ones and spiro[cycloalkane-1,4′-1H-pyrido[2′,3′-d][1,3′]oxazin]-2′-ones, obtained in good yield from the corresponding 1-(o-aminophenyl) and 1-(2′-amino-3′-pyridinyl)cycloalkanols is described using ethyl carbonate in presence of n-butyllithium.