Quino[1,2-c]quinazolines. I. Synthesis of quino[1,2-c]quinazolinium derivatives and the related indazolo[2,3-a]quinoline derivatives as analogs of the antitumor benzo[c]phenanthridine alkaloids

9,10-Dimethoxy-1,2,3,4,12,13-hexahydro-1-oxoquino[1,2-c]quinazolinium perchlorate, 1,2,3,4,13,24-hexahydro-1-oxo[1,3]dioxolo[4,5-g]quino[1,2-c]quinazolinium perchlorate, 6-methyl-2,3,9,10-tetramethoxyquino-[1,2-c]quinazolinium perchlorate and 2,3-dimethoxy-13-methyl[1,3]dioxolo[4′,5′:6,7]quino[1,2-c]quinazolinium perchlorate were synthesized as analogs of the potent antitumor benzo[c]phenanthridine alkaloids nitidine and fagaronine. The related 2,3,8,9-tetramethoxyindazolo[2,3-a]quinoline and 2,3-dimethoxy[1,3]dioxolo-[4,5-g]indazolo[2,3-a]quinoline were also synthesized. Further, the novel formation of 6,7-dimethoxy-2-(2-ethylamino-4,5-dimethoxyphenyl)quinoline via reductive alkylation with Raney nickel in refluxing ethanol is also reported.     

Reactions of Indole and Its Derivatives with Cotarnine. Rearrangement of 5-(1-Indolyl)-4-methoxy-6-methyl- 5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolines

A synthetic route to compounds of the indolyltetrahydroisoquinoline series was developed on the basis of the reaction of cotarnine with indole derivatives. Aminoalkylation of indole and its derivatives with cotarnine occurs regioselectively at the nitrogen atom of the indole fragment to give the corresponding 5-(1-indolyl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolines. The products were found to undergo rearrangement into isomeric 5-(3-indolyl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolines which constitute a new class of indolyltetrahydroisoquinoline systems.     

Quino[1,2-c]quinazolines. II. Synthesis of 12,13-dihydro-11bH-quino-[1,2-c]quinazolines via the versatile intermediates 2-(2-amino-4,5-dimethoxyphenyl)-6,7-disubstituted-1,2,3,4-tetrahydroquinolines

The versatile intermediates 2-(2-amino-4,5-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroquinoline ( 2a ) and 6-(2-amino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]quinoline ( 2b ) were used in the preparation of a wide variety of 12,13-dihydro-11bH-quino[1,2-c]quinazolines by reaction with triethyl orthoformate, cyanogen bromide, urea and carbon disulfide in pyridine. Reaction of the thio and keto products with methyl iodide and phosphorus oxychloride, respectively, gave the requisite methylthio and chloro derivatives. Novel Reissert type reactions occurred when the intermediates 2a,b were reacted with acetic anhydride or benzoyl chloride. The attempted dehydrogenation of 12,13-dihydro-2,3,9,10-tetramethoxy-11bH-quino[1,2-c]quinazoline ( 3a ) is also reported.     

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.     

Synthesis of some pyrimido[4′,5′:4,5]thieno[2,3-b]quinolines and related heterocycles

Several thieno[2,3-b]quinolines 6a-i have been synthesized. These compounds were used as key intermediates in the synthesis of oxazino[4′,5′:4,5]thieno[2,3-b]quinoline 8 , pyrimido[4′,5′:4,5]-thieno[2,3-b]quinolines 9–12 , triazino[4′,5′:4,5]thieno[2,3-b] quinolines 14 and imidazo[4′,5′:4,5]-thieno[2,3-b]quinolines 17 .     

Syntheses of substituted pyrazolo[3,4-b]quinolines, 3,4-dihydro-4-oxopyrimido[4′,5′:4,5]theino[2,3-b]quinoline and pyrido[1′,2′:1,2]pyrimido[4,5-b]quinoline

Syntheses of substituted pyrazolo[3,4-b]quinolines, 3,4-dihydro-4-oxopyriraido[4′,5′:4,5]theino[2,3-b]quinoline and 12-phenylpyrido[1′,2′:1,2[pyrimido[4,5-b]quinoline are described.     

Fused 1,2,4-triazole heterocycles. IV. Synthesis of four new heterocyclic ring systems of [1,2,4]triazolo[1,3]thiazinoquinolines

Syntheses of 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,4-c]quinolines 8, 5H-[1,2,4]triazolo[3′,4′:2)3][1,3]thiazino[5,4-c]quinolines 9, 5H-[1,2,4]triazolo[5′,1′:2,3][1,3]thiazino[5,6-c]quinolines 14 and 5H-[1,2,4]triazolo[3′,4′:2,3][1,3]thiazino[5,6-c]quinolines 15 are described starting from 4-chloro-3-chloromethylquinaldine (4) and 1,2,4-triazole-5-thiols 5 taking advantage of different reactivity of the chlorine atoms of 4 under different reaction conditions. The structures of products 8, 9, 14 and 15 and the intermediates leading to them were confirmed by desulfurization, unequivocal syntheses and nmr spectroscopy as well.     

The synthesis of monomethoxy[1]benzothieno[2,3-c]quinolines

A series of monomethoxy[1]benzothieno[2,3-c]quinolines 24-28 were prepared by photocylization of the appropriate 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamides 9–13 to [1]benzothieno[2,3-c]quinolin-6(5H)-ones 14-18 followed by chlorination to 6-chloro[1]benzothieno[2,3-c]quinolines 19-23 then dechlorination resulting in the title compounds except for 25 which was achieved by direct reduction of 15 . Reaction of 24-28 with methyl iodide provided the corresponding N-methyl quaternary salts 29-33 . Also, conversion of 4-meth-oxy[1]benzothieno[2,3-c]quinolin-6(5H)-one 16 to 4-methoxy-6-methylthio[1]benzothieno[2,3-c]quinoline 35 and 4,6-dimethoxy[1]benzothieno[2,3-c]quinoline 36 is described.     

The synthesis of monomethoxynaphtho[1′,2′:4,5]thieno[2,3-c]quinolines

A series of monomethoxynaphtho[1′,2′:4,5]thieno[2,3-c]quinolines has been prepared by photocyclization of the appropriate N-methoxyphenyl-1-chloronaphtho[2,1-b]thiophene-2-carboxamides. Some of the lactams obtained were converted into the thiolactams and their S-methyl derivatives. The lactams were also converted into the corresponding 6-chloro derivatives. Some of these were catalytically dechlorinated into the monomethoxynaphtho[1′,2′:4,5]thieno[2,3-c]quinolines which were then quaternized into the N-methyl quaternary salts.     

New synthetic approach to epoxyisoindolo[2,1-a]quinolines based on cycloaddition reactions of 2-furyl-substituted tetrahydroquinolines with maleic anhydride and acryloyl chloride

A procedure was developed for the synthesis of hydrogenated furyl-substituted furo[3,2-c]quinolines, pyrano[3,2-c]quinolines, and 4-ethoxy-and 4-(2-oxopyrrolidin-1-yl)quinolines. The reactions of these compounds with acryloyl chloride and maleic anhydride produce epoxyisoindolo[2,1-a]quinoline derivatives through successive acylation at the quinoline nitrogen atom and intramolecular exo-[4+2]-cycloaddition at the furan moiety. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1023–1038, May, 2007.     

1,3-Dipolar Cycloaddition of Ethyl Propiolate to 4,4-Dimethyl-4,5-dihydro-1,2-dithiolo-[5,4-c]quinoline-1-thiones

The interaction of ethyl propiolate with 4,4-dimethyl-4,5-dihydro-2,3-dithiolo[3,4-c]quinoline-1-thiones leads to 1,3-dithiol-2-ylidenes, 1,6,6a(l4)-trithiapentalene, or thiino[2,3-c]quinolines depending on the conditions.     

Synthesis of 3-methyl-3,4-dihydroisoquinolines based on myristicin

The reaction of a natural allylbenzene, myristicin, with nitriles afforded a series of 7,8-dihydro-[1,3]dioxolo[4,5-g]isoquinoline and 6,7-dihydro[1,3]dioxolo[4,5-h]isoquinoline derivatives.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 9. Phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline,benzo[f]phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline,and benzo[h]-phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline

The synthesis of three novel polycyclic heterocyclic ring systems are reported via photocyclization. The specific final products in these ring systems are: phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline ( 13 ), benzo[h]-phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline ( 14 ), and benzo[f]phenanthro[9′,10′:4,5]thieno[2,3-c]quinoline ( 15 ).     

Synthesis of 4,5-diaminopyrrolo[1,2-a]quinoline derivatives by annulation of N,N-dialkyl[2-(pyrrol-1-yl)benzylidene]ammonium salts in the presence of an isocyanide

A facile synthetic method for 4,5-diaminopyrrolo[1,2-a]quinoline derivatives has been developed. Treatment of 2-(pyrrol-1-yl)benzaldehydes with secondary amine hydrochloride/NaI/TMSCl/Et₃N in the presence of an isocyano compound leads to the formation of 4-alkyl(or aryl)amino-5-dialkylaminopyrrolo[1,2-a]quinolines.     

The synthesis of [1]benzothieno[2,3-c]quinolines, [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline,and [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline

Photocyclization of 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamide 10 afforded [1]benzothieno[2,3-c]-quinolin-6(5H)-one 11 which was chlorinated to 6-chloro[1]benzothieno[2,3-c]quinoline 12 followed by dechlorination to give [1]benzothieno[2,3-c]quinoline 5 . A series of 6-substituted alkoxy and thioalkoxy[1]benzothieno[2,3-c]quinoline derivatives were prepared along with the N-methyl quaternary salt 13 of 5 . 6-Chloro[1]-benzothieno[2,3-c]quinoline 12 was converted into 6-hydrazino[1]benzothieno[2,3-c]quinoline 23 which upon treatment with formic acid yielded [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline 6 . Treatment of 23 with nitrous acid resulted in [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline 7 . Compounds 6 and 7 are novel heterocyclic ring systems.     

One‐pot Sequential Reactions Featuring a Copper‐catalyzed Amination Leading to Pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines and Dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines

Tetracyclic skeletons combining an imidazo[1,2‐a]pyridine moiety with a quinoline framework such as pyrido[2′,1′:2,3]imidazo[4,5‐b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines through one‐pot sequential reactions of commercially available or readily obtainable 2‐aminopyridines, 2‐bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step‐by‐step operations.     

Pyrimido[5,4-b]quinolines. I. Synthesis of substituted tricyclic systems related to riboflavin

Two alternative synthetic routes were investigated for the synthesis of 2,4,10-substituted-7,8-dimethylpyrimido[5,4-b]quinolines: (1) cyclization of 5-(3,4-xylidino)-2,4-disubstituted-pyrimidine-6-carboxylic acids, and (2) cyclization of N-5-(2,4-disuhstituted-pyrimidinyl)-4,5-dimethylanthranilic acids. Route (1) invariably led to isomeric mixtures of the corresponding 7,8- and 8,9-dimethylpyrimido[5,4-b]quinolines which were difficult to separate, while route (2) yielded only the desired 7,8-dimelhyl derivatives. The required intermediates were synthesized by Ullman-type condensation of the appropriate pyrimidine and benzene derivatives. Cyclization with polyphosphoric acid, or phosphorus oxychloride (under various conditions) led to a number of new pyrimido[5,4-b]quinoline derivatives, with oxo, methoxy and/or chloro substituents in the 2,4 and 10 positions. A mild, but effective chlorination procedure was developed for the chlorination of the 10-(oxo) position without the cleavage of methoxyl groups at positions 2 and 4.     

An unusual arylation of 4-oxo-3,4-dihydropyrimido[4,5-b]quinoline

Treatment of 4-oxo-3,4-dihydropyrimido[4,5-6 ]quinoline (II) with phosphorus oxychloride and a dialkylaniline resulted in the introduction of a p-dialkylaminophenyl group at position-5, and reduction of the central (pyridine) ring, as well as substitution of oxygen by chlorine at po-sition-4, forming compounds considered to be 4-chloro-5-(p-dialkylaminophenyl)-5, 10-dihydro-pyrimido[4,5-6 ]quinolines (XV). Several 4-oxo-3,4-dihydropyrimido[4,5-b ]quinolines having phenyl substituents at position-5 were synthesized unequivocally, and could be readily reduced to the corresponding 4-oxo-5-phenyl-3,4,5,10-tetrahydropyrimido[4,5-6]quinolines, and the 4-oxo group replaced by chlorine, in the usual manner, leading to compounds related structurally to XV. Comparison of the chemical and physical properties of these compounds established the structure of XV, and a mechanism which rationalizes the formation of XV from II is presented.     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

Synthesis of 10-deazariboflavin and related 2,4-Dioxopyrimido[4,5-b]quinolines

Condensation of substituted anthranilaldehydes with barbituric acid results in the formation of 2,4-dioxopyrimido[4,5-b]quinolines. Using this general synthetic approach, 7,8-dimethyl-2,4-dioxo-10-ribityl-2,3,4,10-tetrahydropyrimido[4,5-b]quinoline (10-deazariboflavin) was prepared by the condensation of barbituric acid with 4,5-dimethyl-N-ribitylanthranilaldehyde. The latter was obtained in situ by the treatment of 1-[4,5-dimethyl-N-(ribityl)anthraniloyl]-2-(p-toluenesulfonyl)hydrazine, prepared from 4,5-dimethylanthranilic acid with anhydrous sodium carbonate.