Synthesis of 2H-pyrano[2,3-b]quinolines. Part I

3,4-Dihydro-2H-pyrano[2,3-b]quinolines 5a-e and 2H-pyrano[2,3- b ]quinolines 10a-c were synthesised starting from the appropriate ω-chloro-n-valeroylanilides 2a-e . Compounds 10a-c were transformed to analogs of the novel antihypertensive agent Cromakalim ( 1 ).     

Convenient Synthesis of 2,2-Dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines

A convenient general synthesis of 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines using the Wittig reaction is described. The o-nitrobenzaldehydes (1a–d) on reaction with phosphorane 2 provided ( E )-ethyl-α-(2,2-dimethylprop-2-ene)-2-nitrocinnamates (3a–d) in excellent yields, which on cyclization with polyphosphoric acid followed by reductive cyclization using Fe/HCl afforded dihydropyranoquinolines (5a–d). Alternatively, the pyranoquinolines 5a–d were also synthesised from esters 3a–d by employing domino reductive cyclization in a single step.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

3-Phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones and 2-Phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-ones

Condensation of 2,3-diaminopyridine ( 1 ) with ethyl o-, m- and p-substituted benzoylpyruvates 2–9 gave two isomeric products. The preferential formation of one or the other isomer has been achieved by different reaction conditions. All the products appear to exist in the enamine form as evidenced by their ¹H nmr and ir spectra.     

Intramolecularly hydrogen-bonded 3-phenacyl-lH-pyrido[3,4-b]-pyrazin-2-one and 2-Phenacyl-4H-pyrido[3,4-b]pyrazin-3-one

Twelve phenacyl derivatives of 1H-pyrido[3,4-b]pyrazin-2-ones and 4H-pyrido[3,4-b]pyrazin-3-ones have been synthesized. In these compounds, C = N double bonds at the 3 and 4 positions in the former compounds and those at the 1 and 2 positions in the latter compounds migrate onto the side chains to form phenacyli-dene structures. These migrations are facilitated by chelation between side chain carbonyl and the proton attached to the ring nitrogen atom which was generated by the migration. All the hydrogen-bonded structures appear to be stable as shown by their ir spectra in the crystalline state, and by their ¹H nmr spectra in solution.     

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).     

Pyridinethiones. VI. The synthesis of 2H-Thiopyrano[2,3-b]pyridin-2-ones

A general and versatile method for the preparation of 2H-thiopyrano[2,3-b]pyridin-2-ones is described. The starting materials, the β, β-disubstituted vinyl-1-t-butyl-2-(1H)pyridinethiones were prepared from the synthon 3-formyl-1-t-butyl-2-(1H)pyridinethione by condensation. ¹³H nmr spectra showed the vinyl double bond of the condensation products to have the trans configuration with the smallest group close to the sulfur atom. Some reactions of these new azaanalogues of thiocoumarins are reported.     

Synthesis of 2H-pyrano[2,3-d]pyrimidine derivatives

Two series of 2H-pyrano[2,3-d]pyrimidine-2,5(6H)-dione derivatives have been prepared. Thus, the reaction of 6-hydroxy-pyrimidin-4(3H)-ones (1 a–c) with bis-2,4,6-trichlorphenyl malonates (2 a–d) or diethyl malonates (3 a–d) afforded good yields of 4-hydroxy-2H-pyrano[2,3-d]pyrimidine-2,5(6H)-diones (4 a-l). Application of our modifiedPechmann reaction^9–11 using -aminocrotonate (5) or -keto esters (6, 7) in the presence of ammonium acetate yielded the 2H-pyrano[2,3-d]pyrimidinediones8 a–h.Dedicated to Prof. Dr.Karl Schlögl, University of Vienna, on the occasion of his 60th birthday.     

3,4-Dihydro-2-phenyl-2H-pyrano[2,3-b]pyridines. Novel aza analogs of flavans

Complementary approaches to the synthesis of the title compounds 1 are described. Metallation of 3,5-di-bromo-2-methoxypyridine ( 5b ) by bromine/lithium exchange gave selectively the 3-lithio intermediate 6 which was trapped with substituted cinnamaldehydes 7 , providing allylic alcohols 8 in good yields. Methyl ether cleavage and concomitant cyclization occurred on exposure to concentrated hydrobromic acid in hot acetic acid. The resulting 2-phenyl-2H-pyrano[2,3-b]pyridines were hydrogenated over Raney nickel to the title compounds which had antiviral activity. Alternatively, 1 were synthesized by Heck reaction of appropriately substituted 3-halo-2-methoxypyridines ( 5 or 24 ) with vinyl carbinol 15 to furnish ketones 16 or 26 which, upon reduction of the carbonyl group, were cyclized directly to 1 .     

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.     

Synthesis of 2,10-diphenyl-2H-pyridazino[4,5-b]quinolin-1-one and 2,3-dihydro-9-phenyl-2-phenylamino-1H-pyrrolo[3,4-b]quinolin-1-one derivatives as peripheral-type benzodiazepine receptor ligands

The reaction of 2-chloromethyl-3-ethoxycarbonyl-4-phenylquinoline with phenylhydrazine, afforded 2,3-dihydro-9-phenyl-2-phenylamino-1H-pyrrolo[3,4-b]quinolin-1-one derivatives 2 along with a major amount of 3-ethoxycarbonyl-4-phenylquinoline-2-carboxaldehyde phenylhydrazone 4a . The geometric isomers of phenylhydrazone 4a , displaying solvent-dependent E-Z isomerism, were isolated, characterized by ¹H-nmr and mass spectra, and the Z-form easily cyclized to pyridazino[4,5-b]quinoline derivative 5a . Analogously, compounds 2b, 2c, 4b , 4c, 5b and 5c were obtained. The title compounds were tested as potential ligands for central and peripheral-type of benzodiazepine receptors, and the results are reported.     

Pyrido[2,3-g]quinolines

The heretofore unknown sym-octahydro-4,9-dioxopyrido[2,3-g]quinoline was synthesized by carboxyethylation of dimethyl 2,5-diaminoterephthalate with -propiolactone with subsequent hydrolysis of the resulting 2,5-bis(-carboxyethylamino)terephthalic acid ester and cyclization of 2,5-bis(-carboxyethylamino)terephthalic acid. The structure of the product was confirmed by the UV and IR spectra and also by reduction to the known sym-octahydropyrido [2,3-g]quinoline.See [7] for preliminary communication.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1535–1537, November, 1970.     

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 substituted 1-benzyl-2,4,6-triphenyl-2,3-dihydro-pyrazolo [3,4-b] [1,4]diazepines

The acid catalyzed condensation of 4,5-diaminopyrazoles and chalcones gave the hitherto unknown 1-benzyl-2,4,6-triphenyl-2,3-dihydropyrazolo[3,4-b][1,4]diazepines derivatives. The structure of all products was supported by ir, ¹H and ¹³C-nmr and mass spectra.     

Furopyridines. II. Bromination and nitration of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine

In order to reveal the reactivities of furopyridines, we undertook bromination and nitration of four furopyridines ( 1, 2, 3 and 4 ) whose chemical properties had been almost unknown. Bromination of 1, 2, 3 and 4 gave the corresponding trans-2,3-dibromo-2,3-dihydro derivatives 6, 8, 10 and 12 , respectively, which were converted to 3-bromofuropyridines 7, 9, 11 and 13 by treatment with sodium hydroxide in aqueous methanol. Nitration of 1 with a mixture of fuming nitric acid and sulfuric acid afforded a mixture of addition products 14a, 14b and 14c and 2-nitro derivative 15 . Both 14a and 14b were easily converted to 15 by treatment with sodium bicarbonate. Compound 2 was nitrated to give a mixture of cis- and trans-2-nitro-3-hydroxy-2,3-dihydro derivative 16a and 16b and 2-nitro derivative 17 . The cis isomer 16a was transformed to the trans isomer 16b by refluxing on silica gel in ethyl acetate. Compound 16b was dehydrated with acetic anhydride to give 17 . Nitration of 3 gave a nitrolic acid derivative 20 . Nitration of 4 gave a mixture of 2-nitro derivative 22 and 3-(trinitromethyl)pyridin-4-ol ( 23 ). The structures of 20 and 23 were established by single crystal X-ray analysis. The differences of behavior observed in these reactions are discussed in connection with the results of the determination of pKa values and the relative reactivities of deuteriodeprotonation of these furopyridines.     

Acetylenchemie, 33. Mitt.: Synthese von 2-substituierten Dihydrofuro[2,3-b]chinolinen

Summary The reaction of 3-iodo-4-methoxy-2(1H)-quinolinone (1) and 3-iodo-4,6,8-trimethoxy-2(1H)-quinolinone (2) with 2-methyl-3-butyn-2-ol under modified Heck-conditions gave the 2-substituted derivatives 2-(1-hydroxy-1-methylethyl)-4-methoxyfuro[2,3-b]-quinoline (3) and 2-(1-hydroxy-1-methylethyl-4,6,8-trimethoxyfuro[2,3-b]-quinoline (4). By a subsequent hydrogenation-reaction with a homogeneous catalyst (PtO₂/Rh₂O₃), the furoquinoline-derivatives yielded the dihydrofuro-[2,3-b]quinolines, identified as 2-(1-hydroxy-1-methylethyl-4-methoxy-2,3-dihydrofuro[2,3-b]quinoline (5) (racemic platydesmine) and 2-(1-hydroxy-1-methylethyl)-4,6,8-trimethoxy-2,3-dihydrofuro-[2,3-b]quinoline (6) (racemic precursor of O⁴-methylptelefolonium salt).

     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 17. Thieno[3′,2′:4,5]thieno[2,3-c]naphtho-[2,1-f]quinoline and thieno[3′,2′:4,5]thieno[2,3-c]-naphtho[1,2-g]quinoline

The synthesis of two previously unknown novel polycyclic heterocyclic ring systems via photocyclization is described. The structural assignment of the isomeric ring systems, 4 and 5 , was achieved by the total assignment of their ¹H and ¹³C nmr spectra by the concerted usage of two-dimensional nmr methods.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

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 novel polycyclic heterocyclic ring system via photocyclization. 18. Benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c]quinoline and benzo[h]naphtho-[1′,2′:4,5]thieno[2,3-c] [1,2,4]triazolo[4,3-a]quinoline

The synthesis of two previously unknown polycyclic ring systems, benzo[h]naphtho[1′2′:4,5]-thieno[2,3-c]quinoline ( 1 ) and benzo[h]naphtho[1′,2′:4,5]thieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline ( 2 ), was achieved via oxidative photocyclization of 1-chloro-N-(1-naphthyl)naphtho[2,1-b]thiophene-2-carboxamide ( 5 ). The total assignment of their ¹H and ¹³C nmr spectra was determined by the concerted use of two-dimensional nmr methods.