Synthesis of 1-functionalized-6-hydroxy-4-methyl and 6,11-dihydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinones

Using 2-methoxy- and 2,5-dimethoxyacetophenones 8a and 8b as starting materials, 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ) and its 6-bromo derivative 7 were obtained via multistep sequences. Whereas Diels-Alder condensation of the former compound with homophthalic anhydride ( 22 ) led to a mixture of the two possible isomers: 1-chloro-11-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 23 ) and 1-chloro-6-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 24 ), this last tetracyclic chloroquinone was specifically obtained from 6-bromo-1-chloro-4-methylisoquinoline-5,8-quinone ( 7 ) and homophthalic anhydride. The 6,11-dihydroxy derivative was then prepared by ammonium nitrate oxidation or photochemically by cycloaddition of benzocyclobutenedione ( 28 ) and 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ). Chloro compounds were easily substituted by diamines to provide corresponding 1-amino substituted hydroxy tetracyclic quinones.     

1,4-Cycloaddition reactions. II. Preparation of p-dioxino[2,3-g]furo[3,2-c] quinolines,p-dioxino[2,3-f] furo[3,2-c] quinolines,and [1,3] dioxolo[4,5-g] furo[3,2-c] quinolines from 2,3-dihydro-5-methylfuran and schiff bases

The boron trifluoride catalyzed 1,4-addition of 2,3-dihydro-5-methylfuran to N-(p-methoxy-benzylidene)-1,4-benzodioxan-6-amine (II) gave 2 pairs of epimers, 2,3,3a,4,5,8,9,11b-octahydro-4-(p-methoxyphenyl)-11b-methyl-p-dioxino[2,3-g]furo[3,2-c]quinoline (IIIa and b) and 2,3,7,8,8a,9.10,1la-octahydro-8-(p-methoxyphenyl)-11a-methyl-p-dioxino[2,3-f]furo[3,2-c]quinoline (IVa and b). When N-(p-methoxybenzylidene)-3,4-methylenedioxyaniline (V) was condensed with 2,3-dihydro-5-methylfuran in an analogous manner, a mixture of 2 epimers of 2,3,3a,4,5,10b-hexahydro-4-(p-methoxyphenyl)-10b-methyl[1,3]dioxolo[4,5-g]furo[3,2-c]quinoline (VIa and b) was isolated. Treatment of this mixture with sulfur afforded 6-(p-methoxyphenyl)-8-methyl-1,3-dioxolo[4,5-g]quinoline-7-ethanol (VIII). Structural assignments for all of the products were made from NMR spectra. None of the compounds possessed appreciable biological activity.     

The synthesis of ω-dialkylaminoalkylaminopyrazino[2,3-d]-, pyrido[2,3-d]-, imidazo[4,5-c]- and imidazo[4,5-d]pyridazines

The synthesis of 5-chloro-8-(ω-dialkylaminoalkylamino)pyrazino[2,3-d]pyridazine (II) proceeded smoothly when 5,8-dichloropyrazino[2,3-d]pyridazine (I) was allowed to react with ω-dialkylaminoalkylamines. Similarly, the reaction of 5,8-dichloropyrido[2,3-d]pyridazine (IV) with ω-dialkylaminoalkylamines gave the two expected products 8-chloro-5-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (V) and 5-chloro-8-(ω-dialkylaminoalkylamino)pyrido[2,3-d]pyridazine (VI) in a 2:3 ratio. 4,7-Dichloroimidazo[4,5-d]pyridazine (XII) was found to be much less reactive towards nucleophilic substitutions and more vigorous conditions resulted in disubstituted products (XIII). 7-Chloroimidazo[4,5-c]pyridazine (XVIII) was also found to be much less reactive towards nucleophilic substitution. In both of these cases one of the imidazole nitrogen atoms was blocked by a tetrahydropyranyl group which increased the reactivities and led to the desired monosubstituted products XVII from XII and in the latter case the expected products (XIX).     

The synthesis of pyridazino[4,5-d] pyridazines,pyrazino [2,3-d] pyridazines and a pyrimido [4,5-d] pyridazine

The synthetic chemistry of the relatively unknown pyridazino [4,5-d]pyridazine ring system has been extended. 1,4-Diaminopyridazino [4,5-d]pyridazine (VIII) has been prepared by two routes, the most interesting of these being the one-step conversion of 4,5-dicyanopyridazine into VIII with hydrazine. Upon nitration VIII gave only the mononitramine (X). Attempts to prepare 1,4-dichloropyridazino [4,5-d]pyridazine gave only 4-chloro-2H-pyridazino [4,5-d]pyridazin-1-one (XII). Pyrimido [4,5-d]pyridazine-1,3-dione (XIV) was prepared from pyridazine-4,5-dicarboxamide (IV). The hydrolysis of 5,8-dichloropyrazino [2,3-d]pyridazine (XV) gave 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) and likewise the ammonolysis of XV gave 5-amino-8-chloropyrazino [2,3-d]pyridazine (XX). As expected the hydrolysis of 5,8-dibromo-pyrazino [2,3-d]pyridazine (XXI) gave 5-bromopyrazino [2,3-d]pyridazin-8-one (XXII). Attempted catalytic dechlorination of 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) gave 1,2,3,4-tetrahydropyrazino [2,3-d]pyridazin-5-one (XIX).     

Synthesis of 2H-benzo[2,3-g]pyridazino-[4,5-d,e]quinolin-3-one derivatives

Summary Condensation-cyclization of hydrazine with 4-methoxycarbonylbenzo[g]quinolinequinone or its corresponding carboxylic acid afforded 7-hydrazino-2H-benzo[2,3-g]pyridazino[4,5-d,e]-quinolin-3-one. Starting with the 9-hydroxy derivative, a similar double condensation of the nucleophile was observed, whereas its 6-hydroxylated regioisomer gave 2H-benzo[2,3-g]pyridazino-[4,5-d,e]quinolin-3,7-dione.

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Synthese von 2H-Benzo[2,3-g]pyridazino[4,5-d,e]chinolin-3-on-Derivaten

Zusammenfassung Die Kondensation/Zyklisierung von Hydrazin mit 4-Methoxycarbonylbenzo-[g]chinolinchinon bzw. mit der entsprechenden Carbonsäure ergab 7-Hydrazino-2H-benzo[2,3-g]-pyridazino[4,5-d,e]chinolin-3-on. Ausgehend vom 9-Hydroxy-Derivat, wurde in analoger Weise doppelte Kondensation des Nucleophils beobachtet, wohingegen das 6-Hydroxy-Regioisomer zu 2H-Benzo[2,3-g]pyridazino[4,5-d,e]chinolin-3,7-dion reagierte.

     

1,4-Cycloaddition reactions. III. Synthesis of furo[3,2-c]pyrido[2,3-g]quinolines,Furo[2,3-a] [4,7]phenanthrolines,Furo[3,2-c]pyrrolo[2,3-g]quinolines,Furo[3,2-c]pyrrolo[3,2-g]quinolines,and Furo[3,2-c]furo[2′,3′:4,5]pyrido[2,3-g]quinolines from 2,3-dihydro-5-methylfuran and schiff bases

The 1,4-cycloaddition of 2,3-dihydro-5-methylfuran (II) to 1-acetyl-1,2,3,4-te trahydro-6-[(p-hydroxybenzylidene)amino]quinoline (VIII) in the presence of boron trifluoride gave two pairs of epimers, namely dl-10-acetyl-2,3,3a,4,5,7,8,9,10,11b-decahydro-4-(p-hydroxyphenyl)-11b-methylfuro[3,2-c]pyrido[2,3-g]quinoline (IXa and b) and dl-8-acetyl-2,3,3a,4,5,8,9,10,11,-11c-decahydro-4-(p-hydroxyphenyl)-11c-methylfuro[2,3-a][4,7]phenanthroline (Xa and b). dl-9-Acetyl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-hydroxyphenyl)-10b-methyl-2H-furo[3,2-c] pyrrolo-[2,3-g]quinoline (XIIIa) was the predominant product isolated from the reaction of II with 1-acetyl-5-[p-(hydroxybenzylidene)amino]indoline (XII). When 1-acetyl-6-[(p-hydroxybenzylidene)amino]indoline (XVI) was treated with 2,3-dihydro-5-methylfuran (II), two epimers of dl-7-acetyl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-hydroxyphenyl)-10b-methyl-2H-furo[3,2-c]pyrrolo[3,2-g]quinoline (XVIIa and b) were obtained. dl-2,3,3a,4,5,6b,8,9,9a,10,11,12b-Dodecahydro-4,10-bis(p-methoxyphenyl)-6b,12b-dimethylfuro[3,2-c]furo[2′,3′:4,5]pyrido[2,3-g]quinoline (XX) was formed when 2,3-dihydro-5-methylfuran was allowed to react with N,N'-bis(p-methoxybenzylidene)-p-phenylcnediamine (XIX). Structure assignments were made from NMR spectra. None of the compounds exhibited appreciable biological activity.     

Synthesis of 5,8-dihydroxynaphtho[2,3-c][1,2,5]thiadiazole-6,9-dione and 6,9-dihydroxybenzo[g]quinoxaline-5,10-dione

The synthesis of 5,8-dihydroxynaphtho[2,3-c][1,2,5]thiadiazole-4,9-dione 3 , 6,9-dihydroxybenzo[g]quinoxaline-5,10-dione 4 , and their lesser oxygenated analogs via Friedel-Crafts and Diels-Alder synthesis is reported.     

Studies of heterocyclic compounds. VIII. Synthesis,anti-inflammatory and antiallergic activities of n-alkyl-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-diones and related compounds

A series of new N-alkyl-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione and N-alkyl-4,9-dihydrofuro[2,3-b]-quinolin-4-one derivatives were prepared and evaluated for their anti-inflammatory activity by the carrageenin hind paw edema method and antiallergic activity by the rat passive cutaneous anaphylaxis method. Among those tested compounds, N-ethyl-2,3,4,9-tetrahydrofuro[2,3-b]quinoline-3,4-dione was the most promising agent which could provide a novel structural prototype for antiallergic agents.     

The synthesis of 5,8-difluoronaphtho[2,3-c]thiophene-4,9-dione and its facile conversion to 2-[2-(dimethylamino)ethyl]- 5-[2-(dimethylamino)ethylamino]-8-fluoro-naphtho[2,3-c] pyrrole-4,9-dione

The synthesis of 5,8-difluoronaphtho[2,3-c]thiophene-4,9-dione ( 2a ) has been accomplished. Treatment of 2a with 2,2-dimethylaminoethylamine leads to 2-[2-(dimethylamino)ethyl]-5-[2-(dimethylamino)ethylamino]-8-fluoronaphtho[2,3-c]pyrrole-4,9-dione ( 6 ).     

Reaction of dichloroketene and sulfene with N,N-disubstituted α-aminomethyleneketones. Synthesis of pyrano[2,3-e]indazole and 1,2-oxathiino[6,5-e]indazole derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-5-aminomethylene-1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones V, prepared from 1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones via the 5-hydroxymethylene derivatives, gave in good yield N,N-disubstituted 4-amino-3,3-dichloro-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-(3H)ones VI, which are derivatives of the new heterocyclic system pyrano[2,3-e]indazole. Dehydrochlorination of VI with DBN afforded N,N-disubstituted 4-amino-3-chloro-6,7-dihydro(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(5H]-ones VII generally in satisfactory yield. Full aromatization with DDQ of VII was tried only in the case of dimethylamino derivatives, giving a moderate yield of 3-chloro-4-dimethylamino(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(7H)-ones. Cycloaddition of sulfene to V occurred only in the case of aliphatic N-substitution to give in moderate yield 4-dialkylamino-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)-3H-1,2-oxathiino[6,5-e]indazole 2,2-dioxides, which are derivatives of the new heterocyclic system 1,2-oxathiino[6,5-e]indazole.     

Furopyridines. XXVIII. Reactions of 3-bromo derivatives of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine and their N-oxides

Bromination of 3-bromofuro[2,3-b]- 1a , -[3,2-b]- 1b and - [3,2-c]pyridine 1d afforded the 2,3-dibromo derivatives 2a, 2b and 2d , while the -[2,3-c]- compound 1c did not give the dibromo derivative. Nitration of 1a-d gave the 2-nitro-3-bromo compounds 3a-d . The N-oxides 4a-d of 1a-d were submitted to the cyanation with trimethylsilyl cyanide to yield the corresponding α-cyanopyridine compound 6a-d . Chlorination of 4a and 4d with phosphorus oxychloride gave mainly the chloropyridine derivatives 7a, 7′a and 7d , while 4b and 4c gave mainly the chlorofuran derivatives 7′b and 7′c accompanying formation of the chloropyridine derivatives 7b, 7′b and 7c . Acetoxylation of 4a and 4b with acetic anhydride yielded the acetoxypyridine compounds 8a, 8′a and 8b , while 4c and 4d gave the acetoxypyridine 8′c, 8′d and 8′d , pyridone 8c and 8d , acetoxyfuran 8′c and dibromo compound 9c and 9′c.     

11H-Pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinoléines (aza-7 ellipticines) substituées sur leur position 6

6-Dialkylaminoalkylamino substituted 11H-pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinolines (7-aza ellipti-cines) were obtained by a six step synthesis starting from 2-chloro-3-nitro pyridine and 6-amino-5-methyl (and 5,8-dimethyl) isoquinoline-1-2H-ones already described. A brief survey of biological results shows that derivatives of this new heterocyclic ring system are less interesting than their 5H-pyrido(3',4':4,5]pyrrolo[2,3-g]isoquinolines (9-aza ellipticines) and pyrido[4,3-b]carbazoles (ellipticines) analogues.     

Pyrimidines. 65. Synthesis of 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones

Several 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives were synthesized. 6-Ethoxycarbonyl derivatives 3 and 7 were prepared by treatment of 6-chloro-5-formyluracil 1 and 6-chloro-5-cyanouracil 6 with ethyl 2-mercaptoacetate in the presence of a base. Electrophilic substitution reactions (Vilsmeier-Haack reaction, bromination, and nitration) of 5,6-unsubstituted thieno[2,3-d]pyrimidine 9 , prepared by condensation of 6-mercaptouracil 8 with chloroacetaldehyde, afforded the corresponding 6-formyl-, 6-bromo-, and 6-nitrothieno[2,3-d]pyrimidines 10, 15 and 16 , respectively.     

Synthèse et étude physicochimique des 1,2,4-triazolo[4,3-a]-pyridines et des 1,2,4-triazolo[2,3-a]pyridines

The synthesis of 1,2,4-triazolo[4,3-a] and [2,3-a]pyridines 7, 8 was achieved by cyclization of 2-hydrazino-8-nitropyridine 3a with formic acid. The 4,5,6,7-tetrahydro-1,2,4-triazolo[2,3-a]pyridine 13 and 8-amino-1,2,4-triazolo[2,3-a]pyridine 9 were obtained by catalytic hydrogenation. The reduction of triazolo pyridine 8 using stannous chloride led to the intermediate compound 10 which with acetic anhydride afforded 8-acetylamino-5-chloro-1,2,4-triazolo[2,3-a]pyridine 10a . The structure of the derivatives was determined by ¹H-nmr (DMSO-d₆).     

Polyazasteroids II.. 1,2,4-Triazolol[3′,4′:2,3]pyrimido[4,5-c]quinolin- 11(12H)ones,imidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3] pyrimido[4,5-c]quinolin-11(12H)ones

Starting with 2-substituted quinoline-3,4-dicarboxylic acids, a series of substituted 1,2,3,4-tetrahydropyrimido[4,5-c]quinolinone-3-thiones were obtained. The latter compounds were converted to the three novel polyazasteroid series: 1,2,4-Triazolo[3′,4′:2,3]pyrimido[4,5-c]-quinolin-11(12H)ones, imidazo[2′,1′:2,3]pyrimido[4,5c]quinolin-11(12H)ones and 2,3-dihydroimidazo[2′,1′:2,3]pyrimido[4,5-c]quinolin-11(12H)ones. The intermediate 3-hydrazino-1,2-dihydropyrimido[4,5-c]quinolinones and nitrous acid gave the 3-azido derivatives rather than the tetrazolo compounds.     

Polycyclic pyridazines. II [3]. Synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azine derivatives from dimethyl pyrazolo[3,4-d]pyrid-azine-5,6-dicarboxylates as the key intermediates

The synthesis of the novel pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine ring system and some of its derivatives has been accomplished such as 4-amino-1-phenyl-5,8-dioxo-, 4-amino-5,8-dioxo-, 1-phenyl-5,8-dioxo-, 5,8-dioxo-, 5,8-dichloro-1-phenyl-, 5-ethoxy-1-phenyl- and 8-ethoxy-1-phenylpyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azines.     

A new synthetic route to 2-substituted naphtho[2,3-b]furan-4,9-dione2-Substituted Naphtho[2,3-b]furan-4,9-dione

4,9-Dimethoxynaphtho[2,3-b]furan 9 was obtained in 91% yield via the reductive methylation of naphtho[2,3-b]furan-4,9-dione 2 . After treatment of 9 with butyllithium, the mixture was allowed to react with N,N-dimethylacetamide, followed by oxidization with cerium(IV) diammonium nitrate to give 2-acetylnaphtho[2,3-b]furan-4,9-dione 1 . 2-Formylnaphtho[2,3-b]furan-4,9-dione 13 and 2-trimethylsilyl-naphtho[2,3-b]furan-4,9-dione 14 were also obtained from 9 by a similar method. The halodesilylations of 14 easily gave 2-iodonaphtho[2,3-b]furan-4,9-dione 16 , 2-bromonaphtho[2,3-b]furan-4,9-dione 17 , and 2-chloronaphtho[2,3-b]furan-4,9-dione 18 in 82%, and 93% and 83% yield, respectively. Furthermore, the nitrodesilylation of 14 gave 2-nitronaphtho[2,3-b]furan-4,9-dione 3 in 77% yield.     

A new base-induced ring transformation of pyrido[2,3-d]pyrimidines

8-Substituted 5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates ( 3 ) rearranged to 8-substituted 7,8-dihydro-5-hydroxy-7-oxopyrido[2,3-d]pyrimidine-6-carboxaldehydes ( 5 ) when treated with sodium ethoxide in an aprotic polar solvent at room temperature. The 6-cyano analogue ( 18 ) also underwent ring transformation under the same mild conditions giving 7-amino-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxaldehyde ( 21 ). However, the ring transformations of the pyrido[2,3-d]pyrimidine bearing no N₈-substituent ( 12 ), ethyl 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine- ( 14 ) and -quinoline-3-carboxylates ( 16 ) failed to occur. A mechanism is discussed.     

Nucleophilic substitutions of 2-chloronaphtho[2,3-b]furan-4,9-dione with amines

2-Chloronaphtho[2,3-b]furan-4,9-dione 4 was allowed to react with pyrrolidine to produce 2-(1-pyrrolidinyl)naphtho[2,3-b]furan-4,9-dione 8 in 64% yield. In a similar manner, the reaction of 4 with cyclic amines (piperidine, morpholine, 4-substituted piperazines, etc.) gave the desired compounds. 2-Dimethylaminonaphtho[2,3-b]furan-4,9-dione 20 and 2-propylaminonaphtho[2,3-b]furan-4,9-dione 23 were obtained from the reactions of 4 with amines in 67% and 48% yields, respectively. Furthermore, the reactions of 4 with acyclic amines (diethylamine, dipropylamine, isopropylamine, butylamine, etc.) gave the desired compound. Compound 4 was treated with sodium azide to give 2-azidonaphtho[2,3-b]furan-4,9-dione 28 in 42% yield. All these nucleophilic substitutions were carried out at room temperature. It was found that 4 showed high reactivity for amines. Unexpectedly, 2-morpholinonaphtho[2,3-b]furan-4,9-dione 13 was obtained from the reaction of 4 with 1-morpholino-1-cyclohexene.     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.