The synthesis of dimethoxy- and trimethoxy[1]benzothieno[2,3-c]quinolines

Three dimethoxy[1]benzothieno[2,3-c]quinolines 24–26 were prepared by photocyclization of the appropriate 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamides 15–17 to [1]benzothieno[2,3-c]quinolin-6(5H)-ones 18–20 followed by chlorination to 6-chloro[1]benzothieno[2,3-c]quinolines 21–23 and then dechlorination resulting in the title compounds. Reaction of 24–26 with methyl iodide furnished the corresponding N-methyl quaternary salts 27–29 . Sodium methoxide readily converted 21–23 to trimethoxy[1]benzothieno[2,3-c]quinolines 30–32 .     

The synthesis of substituted [1]benzothieno[2,3-c]quinolines and their N-methyl quaternary salts

Four substituted [1]benzothieno[2,3-c]quinolines 14a-14d were prepared by photocyclization of the appropriate carboxamides 8a-8d to the corresponding [1]benzothieno[2,3-c]quinolin-6(5H)-ones 12a-12d followed by chlorination to 6-chloro[1]benzothieno[2,3-c]quinolines 13a-13d and dechlorination resulting in the title compounds. Treatment of 14a-14d with iodomethane furnished the corresponding N-methyl quaternary salts 5a-5d .     

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.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 5. [1]Benzothieno[2,3-c]naphtho[2,1-f]-quinoline and [1]benzothieno[2,3-c]naphtho[1,2-g]quinoline

Two previously unknown heterocyclic ring systems, namely, [1]benzothieno[2,3-c]naphtho[2,1-f]quinoline ( 4 ) and [1]benzothieno[2,3-c]naphtho[1,2-g]quinoline ( 5 ) were synthesized via photocyclization of 3-chloro-N-(2-phenanthryl)benzo[b]thiophene-2-carboxamide ( 8 ) followed by chlorination and dechlorination. The total assignment of their ¹H- and ¹³C-nmr spectra was determined by utilizing inverse-detected HMQC and HMBC two-dimensional nmr spectroscopic methods.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 8 . [1]Benzothieno[2,3-c]naphtho[1,2-h]quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline

The previously unknown polycyclic heterocyclic ring systems, namely, [1]benzothieno[2,3-c]naphtho[1,2-h]-quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline were synthesized via photocyclization of 3-chloro-N-(1′-phenanthryl)benzo[b]thiophene-2-carboxamide.     

The synthesis of difluoro[1]benzothieno[2,3-c]quinolines and their N-methyl quaternary salts

A series of difluoro[1]benzothieno[2,3-c]quinolines has been prepared by photocyclization of the appropriate carboxamides. The lactams obtained were converted into the corresponding chloro derivatives which were catalytically dechlorinated into the difluoro[1] benzothieno[2,3-c]quinolines. The latter compounds were transformed into the N-methyl quaternary salts.     

Synthesis of [1]benzothienonaphthyridines

3-Chlorobenzo[b]thiophene-2-carbonyl chloride reacted readily with 2-amino-, 3-amino-, or 4-aminopyridine to give the corresponding amides. Photocyclization of the amides afforded the following lactams: [1]ben-zothieno[2,3-c][1,5]naphthyridin-6(5H)-one ( 14 ), [1]benzothieno[2,3-c][1,6]naphthyridin-6(5H)-one ( 7 ), [1]benzo-thieno[2,3-c][1,7]naphthyridin-6(5H)-one ( 11 ), and [1]benzothieno[2,3-c][1,8]naphthyridin-6(5H)-one ( 3 ). These lactams have been converted to other derivatives including in two instances the unsubstituted ring system.     

[1,3]Dioxolo[5,6][1]benzothieno[2,3-c]-quinolin-6(5H)-ones

Summary The reaction of 3,4-methylenedioxycinnamic acid (1) with thionyl chloride resulted in the formation of 7-chlorothieno[2,3-f]-1,3-benzodioxole-6-carbonyl chloride (2) and cinnamoyl chloride (3). Subsequent reaction of the former withp-substituted anilines led to the formation of 7-chloro-N-(p-substituted phenyl)-thieno[2,3-f]-1,3-benzodioxole-6-carboxamides (4a–c) which on photocyclization afforded 2-substituted [1,3]dioxolo[5,6][1]benzothieno[2,3-c]quinolin-6(5H)-ones (5a–c) in fairly good yields and high purity. The structures have been confirmed by IR,¹H NMR, and analytical methods.Accepted for presentation at the Hong Kong International Symposium on Heterocyclic Chemistry (August 13–16, 1995)     

1,4-Cyeloaddition reactions. IV. preparation of Cyclopenta[g]furo[3,2-c]quinolines,Cyclopenta- [f]furo[3,2-c]quinolines,Benzo[H]furo[3,2-c]quinolines,and Furo- [3,2-c]indeno[1,7-gh] 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-methoxybenzylidene)-5-indanamine (VI) gave 2 pairs of epimers, dl-3,3a,4,5,7,8,9,10b-octahydro-4-(p-methoxyphenyl)-10b-methyl-2H-cyclopenta[g]furo[3,2-c]quinoline (VIIa and b) and dl-3,3a, 4,-5,8,9,10,10c-octahydro-4-(p-methoxyphenyl)-10c-methyl-2H-cyclopenta[f]furo[3,2-c]quinoline (VIIIa and b). When 4-(benzylideneamino)-1-naphthol (IXa) was condensed with 2,3-dihydro-5-methylfuran in an analogous manner, a mixture of two isomers of dl-1,2,2a,3,4,5a-hexahydro-5a-methyl-2-phenylbenzo[h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? H)] was obtained. Likewise, 4-[(p-hydroxybenzylidene)amino]-1-naphthol (IXb) and 4-(p-methoxybenzylidene)amino]-1-naphthol (IXc) gave a mixture of two isomers of dl-1,2,2a,3,4,5a-hexahydro-2-(p-hydroxyphenyl)-5a-methylbenzo[h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? OH)] and dl-1,2,2a,3,4,5a-hexahydro-2-(p-methoxyphenyl)-5a-methylbenzo [h]furo[3,2-c]quinolin-7-ol [Xa and b (R ? OCH₃)], respectively. The condensation of N-(p-methoxybenzylidene)-5-acenaphthenamine (XI) with 2,3-dihydro-5-methylfuran afforded a mixture of two isomers of dl-2,3,3a,4,5,9,10,-11b-octahydro-4-(p-methoxyphenyl)-11b-methylfuro[3,2-c]indeno[1,7-gh]quinoline (XIIa and b). Structural assignments for all of the products were made from NMR spectra. None of these compounds possessed appreciable biological activity.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 2 . Benzo[h][1]benzothieno[2,3-c]quinoline and benzo[h][1]benzothieno[2,3-c]quinoline

The synthesis of two previously unknown unsubstituted heterocyclic ring systems namely, benzo[h][1]benzothieno[2,3-c]quinoline ( 6 ) and benzo[f][1]benzothieno[2,3-c]quinoline ( 12 ) is reported. These two novel ring systems have been assembled by photocyclization of the appropriate amides.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 3 . 12-Methylbenzo[h][1]benzothieno[2,3-c][1,6]naphthyridine

The synthesis of the 12-methyl derivative of a novel heterocyclic ring system, namely benzo[h][1]benzothieno[2,3-c][1,6]naphthyridine ( 8 ) was prepared by photocyclization of 3-chloro-N-(2′-methyl-4′-quinolyl)benzo-[6]thiophene-2-carboxamide ( 5 ) to 12-methylbenzo[h][1]benzothieno[2,3-c][1,6]naphthyridin-6(5H)-one ( 6 ). Chlorination of 6 afforded 6-chloro-12-methylbenzo[h][1]benzothieno[2,3-c][1,6]naphthyridine ( 7 ) which upon dechlorination provided the novel title compound 8 .     

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.     

Inhibitors of platelet aggregation. 4. [1,2,5]Thiadiazolo[3,4-c]acridines, 7,8,9,10-Tetrahydro[1,2,5] thiadiazolo[3,4-c]acridities,and 8,9-Dihydro-7H-cyclopenta[b][1,2,5] thiadiazolo[3,4-H]quinolines

The condensation of 4-amino-2,1,3-benzothiadiazole (IV) with diphenyliodonium-2-earboxylate gave N-(2,1,3-benzothiadiazoI-4-yl)anthranilic acid (V) (28%), which was cyclized with phosphorus oxychloride to 6-chloro[1,2,5]thiadiazolo[3,4-c]acridine (VI) (84%). Treatment of VI with 3-(dimethylamino)-1-propanethiol hydrochloride in phenol afforded 6-[ [3-(dimethylamino)-propyl]thio] [1,2,5]thiadiazolo[3,4-c]acridine (VII) (65%). The reaction of IV with a mixture of methyl and ethyl 2-oxocyclohexanecarboxylate gave the adduct, which was ring closed in Dowtherm to 7,9,10,1 1-tetrahydro[1,2,5] thiadiazolo[3,4-c]acridin-6(8H)one (VIII) (70%). Chlorination of VIII with phosphorus oxychloride gave 6-chloro-7,8,9,10-tetrahydro[1,2,5]thiadiazolo[3,4-c]acridine (IX) (84%), which was condensed with 3-(dimethylamino)-1-propanethiol hydrochloride in phenol yielding 6-[ [3-(dimethylamino)propyl]thio]-7,8,9,10-tetrahydrof 1,2,5]-thiadiazolo[3,4-c]acridine (X) (27%). 6-[ [3(1)imethylamino)propyl]thio]-8,9-dihydro-7H-cyclopenta[b] [1,2,5]thiadiazolo[3,4-h]quinoline (XIII) (25%) was prepared similarly from IV and a mixture of methyl and ethyl 2-oxocyclopentanecarboxylate via 7,8,9,10-tetrahydro-6H-cyclopenta[b][1,2,5]thiadiazolo[3,4-h]quinolin-6-one (XI) (85%) and 6-chloro-8,9-dihydro-7H-cyclopenta[b][1,2,5]thiadiazolof3,4-h]quinoline (XII) (56%). The effects of compounds VII-XIII as inhibitors of platelet aggregation are discussed.     

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.     

Complete assignment of the 1h- and 13c-nmr spectra of [1]benzothieno[2,3-c]naphtho[1,2-h]quinoline and [1]benzothieno[2,3-c]naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline. Concerted use of two-dimensional nmr techniques

The ¹H- and ¹³C-nmr spectra of [1]benzothieno[2,3-c]naphtho[1,2-h]quinoline and [1]benzothieno[2,3-c]-naphtho[1,2-h][1,2,4]triazolo[4,3-a]quinoline were totally assigned using a combination of two-dimensional nmr techniques. After correlation of the proton signals by a COSY spectrum and one-bond heteronuclear correlation, complete assignment of the ¹H- and ¹³C-nmr spectra of the novel heterocyclic compounds required the application of long-range CH coupling information particularly for quarternary resonance assignments and the orientations of individual spin systems relative to one another.     

Synthetic studies on pyrroloquinolines. II. Studies on the syntheses and chemical properties of 1H-pyrrolo[2,3-b] quinolmes

This paper describes the syntheses and the properties of 1H-pyrrolo[2,3-6]quinolines derived from 2,3-dihydrofuro[3,2-c]quinolines or 3-(β-chloroethyl)-2,4-dichloroquinolines. The discrepancy on the physical data of 1H-pyrrolo[2,3-b]quinoline between our product and Perkin's previously reported product is also discussed.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 7. [1]Benzothieno[2,3-c]naphtho[2,1-h]quinoline and [1]benzothieno[2,3-c]naphtho[2,1-h][1,2,4]triazolo[4,3-a]quinoline

The synthesis of two novel polycyclic heterocyclic ring systems via photocyclization is described. These are [1]benzothieno[2,3-c]naphtho[2,1-h]quinoline and [1]benzothieno[2,3-c]naphtho[2,1-h][1,2,4]triazolo[4,3-α]-quinoline. In the ¹H nmr spectrum the proton at position 6 is strongly deshielded in the first ring system while the proton at position 6 in the second ring system is shifted considerably upfield while the proton at position 8 in the second ring system is the most deshielded proton in that ring system. The bay regions in both ring systems are severely congested.     

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.     

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.     

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.