Reactions of some 4-dicyanomethylenepyran derivatives with malononitrile and hydrazines

4-Dicyanomethylene-2-phenyl-4H-benzo[b]pyran, the corresponding thiapyran, and 4-dicyanomethylene-2,6-diphenyl-4H-pyran react with malononilrile under basic conditions to give 5-amino-4-cyano-2-phenylbenzo[b]pyrano[4,3,2-de] [1,6]naphthyridine, the corresponding thia-pyranonaphthyridine derivative, and 5-amino-6-cyano-2,8-diphenylpyrano[4,3,2-de] [1,6]naphthyridine, respectively. Certain other related reactions were studied in the course of investigating the above reactions. Hydrazine hydrate and 4-dicyanomethylene-2-phenyl-4H-benzo[b]pyran gave 5-(2-hydroxyphenyl)-3-phenylpyrazole, and phenylhydrazine gave 5-(2-hydroxyphenyl)-1,3-diphenylpyrazole.     

The reaction of ethyl 4H-pyran-4-one-2-carboxylate with 1,2-diaminobenzene

Ethyl 4H-pyran-4-one-2-carboxylate was allowed to react with 1,2-diaminobenzene and related diamines. The resulting products were found to be 8H-5,6-dihydro-6,8-dioxopyrido[1,2-a]quinoxaline and derivatives. The synthesis 3H-5,6-dihydrobenzo[g]pyrido[1,2-a]quinoxaline-3,5-dione ( 2c ) constitutes the synthesis of a derivative of previously unknown benzo[g]pyrido[1,2-a]quinoxaline ring system.     

Chlorination of 1H-pyrrolo[3,2-c]pyridin-4,6(5H,7H)dione (3,7-dideazaxanthine) and its 5-methyl derivative

The chlorination of 1H-pyrrolo[3,2-c]pyridin-4,6(5H, 7H)dione (3,7-dideazaxanthine) ( 2 ) and 5-methyl-1H-pyrrolo[3,2-c] pyridin4,6(5H,7H)dione (1 -methyl-3,7-dideazaxanthine) ( 3 ) with phenylphosphonic dichloride has yielded 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (2,6-dichloro-3,7-dideazapurine) ( 1 ). A mechanism for the demethylation of the 5-methyl derivative under these conditions is proposed. Ammonolysis of 4,6-dichloro-1H-pyrrolo[3,2-c] pyridine was unsuccessful while catalytic reduction of this dichloro derivative produced 1H-pyrrolo[3,2-c]-pyridine ( 4 ).     

Cycloaddition reactions of some analogs of the acridizinium ion

The 1-aryl-2-imidazo[1,2-b]isoquinolin-4-ium system ( 3 and 4 ), prepared by the action of aniline, or a suitable aniline derivative upon 2-phenacyl-3-chloroisoquinolinium bromide undergoes cycloaddition reactions only with the more nucleophilic alkenes such as cyclopentadiene or 9-vinylcarbazole. The pyrazino[1,2-b]isoquinolin-5-ium-2-oxide ( 8–10 ) system reacts with nucleophilic alkenes more readily than does the acridizinium system 1. For both systems the cycloaddition appears to occur across the meso position of the central ring.     

The reaction between 3,3-bis(methoxyphenyl)-3H-naphtho[2,1-b]pyran and 1,3-bis(methoxyphenyl)-1H-naphtho[2,1-b]pyran, 2,2-diphenyl-2H-chromen and 2,4-diphenyl-4H-chromen,and related compounds

The reaction between 3,3-bis(methoxyphenyl)-3H-naphtho[2,1-b]pyran and 1,3-bis(methoxyphenyl)-1H-naphtho[2,1-b]pyran under acid conditions gives a 7a,15a-dihydro-7a,15-bis(methoxyphenyl)-16-[2,2-bis(methoxyphenyl)-l-vinyl]dinaphtho-[2,1-b:2,1-g]-4H,5H-pyrano[2,3-b]-pyran.     

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.     

2‐Triazolylpyrimido[1,2,3‐cd]purine‐8,10‐diones via 1,3‐dipolar cycloadditions to 2‐ethynylpyrimido[1,2,3‐cd]purine‐8,10‐dione

This paper presents the synthesis of a series of 5,6‐dihydro‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ring system derivatives with a [1,2,3]triazole ring bonded in position 2. The procedure is based on cycloaddition of substituted alkyl azides to the terminal triple bond of 5,6‐dihydro‐2‐ethynyl‐9‐methyl‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 4 ). This cycloaddition produced two regioisomers ?5,6‐dihydro‐9‐methyl‐2‐(1‐substituted‐1H‐[1,2,3]triazol‐5‐yl)‐4H,8H‐pyrimido[1,2,3‐cd]purine‐8,10(9H)‐dione ( 7 ) and 2‐(1‐substituted‐1H‐[1,2,3]triazol‐4‐yl) derivative 8 . The required 2‐ethynyl deriva tive 4 was obtained from the starting 2‐unsubstituted compound 1 by bromination to yield the 2‐bromo derivative 2 , which was converted by Sonogashira reaction to trimethylsilylethyne 3 and finally, the protective trimethylsilyl group was removed by hydrolysis.     

Nitrogen bridgehead compounds. Part 86. Synthesis and reactivity of 7,12-dihydropyrimido[1′,2′;1,2]pyrido[3,4-b]indol-4(6H)-ones. Debenzologues of rutaecarpine alkaloids

A series of 7,12-dihydropyrimido[1′2′:1,2]pyrido[3,4-b]mdole-4(6H)-ones was prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrirmdin-4-ones. Quantum chemical calculations (ab initio and AM1) indicate that position 3 of 7,12-dihydropyrimido[1′,2′:1,2]pyrido-[3,4-b]indole-4(6H)-one can be involved in electrophilic substitutions, while position 2 is sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12-tetrahydropyrimido[1′,2′:1,2]pyrido-[3,4-b]indol-4(6H)-one 16 with bromine afforded 3-bromo derivative 25 , which was reacted with cyclic amines to give 2-ammo-7,12-dihydropyrirmdo[1′2′:1,2]pyrido[3,4-b]indol-4(6H)-ones 26–30 in an addition-elimination reaction. Vielsmeier-Haack formylation of compound 16 gave 12-formyl 31 and 3,12-diformyl 32 derivatives (an N-formyl-1-deaza derivative of nauclefidine alkaloid 34 ) at 60° and 100°, respectively. 3,12-Diformyl compound 32 was oxidized to 3-carboxyl derivative 33 with potassium permanganate. The quaternary salt 35 , obtained from compound 16 with dimethyl sulfate, suffered a ring opening on the action of aqueous sodium hydroxide. The new compounds have been characterized by elemental analyses uv, ¹H nmr and in some cases by ¹³C ruler, CD spectra and X-ray investigations.     

Synthesis of some 3-alkenyl-4-oxo-6,7-dihydro-4H-pyrano[3,4-d]isoxazoles

A series of 3-alkenyl-4-oxo-6,7-dihydro-4H-pyrano[3,4-d]isoxazole derivatives was prepared by reaction of hydroxylamine with 4,5-dioxo-2,3,7,8-tetrahydro-4H,5H-pyrano[4,3-b]pyran derivatives.     

Carbenoid induced irreversible ring opening of naphthopyrans

Contrary to expectation rhodium carbenoids do not undergo cycloaddition to the 2H-pyran unit of the isomeric naphthopyrans 3 and 5. With 3, a naphtho[2,1-b]pyran-8-ylacetate, 4 is formed and a novel merocyanine dye 6 results from a cycloaddition across the C-5-C-6 double bond of the naphtho[1,2-b]pyran 5. Tethering the carbenoid to the naphtho[1,2-b]pyran system 5, as in 10, results in a similar mode of addition and affords the intensely coloured tetracycle 11.     

Intramolecular 1,3-Dipolar Cycloaddition of Azomethine Ylides Leading to Pyrido[2,3-b]quinolines

A convenient six-step route to the previously unknown 1H-pyrrolo[2,3-f]benzo[b][1,8]naphthyridine ring system using an intramolecular 1,3-dipolar cycloaddition of nonstabilized azomethine ylides has been described.     

Synthesis of perimidine and fused perimidine derivatives from reaction of 1,8-naphthalenediamine with an iminoisocoumarin

The isocoumarin derivative 1H-1-acetylimino-3-methylbenzo[c]pyran-4-carbonitrile reacts with 1,8-naphthalenediamine under basic conditions to give, primarily, 12-acetylisoquino[2,1-a]perimidin-13-amine. This undergoes a variety of reactions to give other isoquino[2,1-a]perimidine derivatives, ring opening to 2-(1H-perimidin-2-yl)phenylacetic acid derivatives and, in polyphosphoric acid, a new hexacyclic system, 6-methyl-7,13,13d-triazadibenzo[def,qr]chrysene.     

New heterocyclic syntheses from hydrazidoyl halides. Convenient syntheses of fused pyrimidines,pyridazines, and quinazolines

Aminocyanopyrazole derivatives and pyrazolo[2,3-a]quinazolones were obtained in good yields from hydrazidoyl halides and malononitrile. Pyrazolo[3,4-d]pyridazine and pyridazo[4′,5′: 1,2]pyrazolo[1,5-a]quinazoline derivatives were synthesized in quantitative yields by reaction of hydrazine hydrate with 2 and 16 , respectively. A novel ring system, a 3-substituted tetrahydro derivative of 7-oxo-6H,8H-pyridazo[3′,4′,5′-c'd']-pyrazolo[3,4-d]pyrimidine was prepared by reaction of 6 with dimethyl carbonate. Pyrazolo[3,4-d]pyrimidine-4,6-dithiones were obtained in good yields by reaction of 2 with carbon disulfide. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible. The structures of the parent fused heterocyclic systems discussed in this work are summarized in Scheme 1 .     

Synthesis and Reactions of 1,6-Dibenzoyl-5H,10H-diimidazo[1,5-a;1',5'-d;]pyrazine-5,10-dione

5,10-Dioxo-5H,10H-diimidazo[1,5-a;1',5'-d]pyrazine-5,10-dicarboxylic acid dichloride in Friedel-Crafts reaction conditions formed with benzene the corresponding 1,6-dibenzoyl derivative 2, which reacted with alcohols and amines to give the keto esters and keto amides of 4(5)-benzoylimidazol-5(4)-carboxylic acids. The reaction of compound 2 with hydrazine gave substituted imidazo[4,5-f]pyridazine, and with o-phenylenediamine gave a derivative of imidazo[4,5-f]-1,4-benzodiazocine - a new heterocyclic system.     

The reactions of some pyraiiylideneiminium salts with amines. II

The iminium salt, N,N-dimethyl-N-[2-(2-phenyl-4H-l-benzopyran-4-ylidene)ethylidene] imin-ium perchlorate ( 3 ), reacts with secondary amines by exchanging the dimethylimino group for the added amine. Primary amines also reacted with 3 in the same manner. The bis iminium salts, N,N,N',N'-tetramethyl-N,N'-[2-(2-phenyl-4H-l-benzopyran-4-ylidene)-1,3-propanediylidene]-bis(immium perclilorate) ( 4 ) and the corresponding thiapyran derivative ( 5 ), react with ammonia to give 5-dimethylamino-2-phenyl-5H-1-benzopyrano[3,4-c]pyridine ( 10 ) and the thia analog 11 . The reactions of 4 and 5 with primary amines give 3-alkyl-5-dimethylamino-2-phenyl-5H-l-beiizopyrano[3,4-c]pyridinium perclilorate salts or the corresponding thiapyrano compounds. Compounds 4 and 5 react with secondary amines by exchanging the dimethylimino groups with the secondary amine and addition of the amine at the 2-position of the pyran or thiapyran ring.     

Synthesis of 5,7-disubstituted-4-β-D-ribofuranosylpyrazolo[4,3-d]-pyrimidines and 2,4-disubstituted-1-β-D-ribofuranosylpyrrolo[3,2-d]-pyrimidines as congeners of uridine and cytidine

The synthesis of the congeners of uridine and cytidine in the pyrazolo[4,3-d]pyrimidine and pyrrolo[3,2-d]-pyrimidine ring system is described. Glycosylation of the trimethylsilyl (TMS) derivative of pyrazolo[4,3-d)pyrimidine-5,7(1H,4H,6H)-dione (4) with either 1-bromo- or 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose 5 and 6 , respectively in the presence of a Lewis acid catalyst gave the protected nucleoside 7 , which on debenzoylation afforded the uridine analogue 4-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidine-5,7(1H,6H)-dione (8). Thiation of 7 gave 13 , which on deprotection yielded 4-β-D-ribofuranosyl-5-oxopyrazolo[4,3-d]pyrimidine-7(1H,-6H)-thione (14). Ammonolysis of 13 gave a low yield of the cytidine analogue 15. A chlorination of 7 , followed by amination furnished an alternative route to 15. A similar glycosylation of TMS-4 with 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride (16) gave mainly the N4 glycosylated product 17 , which on debenzylation furnished 4-β-D-arabinofuranosylpyrazolo[4,3-d]pyrimidine-5,7(1H,6H)-dione (18). 7-Amino-4-β-D-arabinofuranosylpyrazolo[4,3-d]pyrimidin-5(1H)-one (23) was prepared from 17 via the pyridinium chloride intermediate 21. Condensation of the TMS derivative of pyrrolo[3,2-d]pyrimidine-2,4(1H,3H,5H)-dione (24) with 6 , followed by deprotection of the reaction product gave 1-β-D-ribofuranosylpyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (26). Similarly, TMS-24 was reacted with 16 to give a mixture of the blocked nucleosides 31 and 32 , which on debenzylation afforded a mixture of two isomeric compounds 34 and 35. 1-β-D-Arabinofuranosylpyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-dione (34) was converted to the ara-C analogue 38 via the 3-nitrotriazolyl intermediate 36. The structure of 38 was confirmed by single crystal X-ray diffraction studies.     

A new synthesis of pyrimido[5,4-e]-as-triazine 4-oxides and their ring transformation to pyrrolo[3,2-d]pyrimidines

A new synthesis of certain pyrimido[5,4-e]-as-triazine 4-oxides and their ring transformation to pyrrolo-[3,2-d]pyrimidines by the 1,3-dipolar cycloaddition reaction is described. Thus, reaction of 6-hydrazino-1,3-dimethyluracil ( 1 ) with triethyl orthoformate gave 6-ethoxymethylenehydrazino-1,3-dimethyluracil ( 2 ). Treatment of 2 with arylamines gave 6-arylaminomethylenehydrazino-1,3-dimethyluracils ( 3a-e ). Nitrosative cyclization of 3a-e with sodium nitrite afforded 3-arylaminofervenulin 4-oxides ( 6a-e ). Reaction of 6a-e with acetylenic esters yielded 7-alkoxycarbonyl-6-arylamino-1,3-dimethylpyrrolo[3,2-d]pyrimidine-2,4(1H,3H-diones ( 15a-e and 16 ).     

Synthesis of new heterocycles. 3,4-dihydropyrano[2,3,4-hi]indolizine and derivatives

Interaction of the lithium derivative of 2,3-dihydro-4H-pyrano[3,2-b]pyridine with the diethyl acetal of bromoacetaldehyde, followed by hydrolysis and subsequent ring closure afforded the novel heterocycle 3,4-dihydropyrano[2,3,4-hi]indolizine which was inacessible by the Tschitschibabin method. However, the 2-phenyl derivative was easily prepared by the Tschitschibabin method.     

Condensed Pyridazines. Part I. Synthesis of 2-Oxo-2H-pyrano[2,3-D]-pyridazine and 2-Oxo-2H-pyrano[2,3-c] pyridazine

The reaction of 4,7-diehlorofuro[2,3-d]pyridazine (1) with potassium cyanide in DMSO gave two products, (E)-3,6-diehloro-5-(2-cyanovinyl)-4-hydroxypyridazine (II) and 5,8-dichloro-2-oxo-2H-pyrano[2,3-d]pyridazine (III) as a result of ring opening or ring expansion. A new ring system, 2-oxo-2H-pyrano[2,3-c]pyridazines (IX, XII, XIII) was obtained from 5,8-dichloro-3-methyl-2-oxo-2H-pyrano[2,3-d]pyridazine (VI).     

New synthesis of 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine

This paper describes two new access routes to 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine from 2-(2-thienyl)ethylamine or its N-(2-chlorobenzyl) derivative. One of these two syntheses involves a new ring expansion from a 6,7-dihydro[3,2-c]pyridinium derivative, chloromethylated in position 4.