Tetracyclic phenothiazines. III. . Intermolecular hydride transfer in acid induced disproportionation of 1,2-dihydro-3-hydroxy-3H-pyrido[3,2,1-kl] phenothiazines

1,2-Dihydro-3-hydroxy-3H-pyrido[3,2,1-kl]phenothiazines and 1H-pyrido[3,2,1-kl]phenothiazines undergo acid catalyzed disproportionation with intermolecular hydride transfer to form pyrido[3,2,1-kl]phenothiazinium salts and 1,2-dihydro-3H-pyrido[3,2,1-kl]phenothiazines. Sodium borohydride reduction of 3-alkyl- or 3-arylpyrido[3,2,1-kl]phenothiazinium salts gives 3-alkyl- or 3-aryl-1H-pyrido[3,2,1-kl]phenothiazines. In the presence of a proton source, borohydride reduction of pyrido[3,2,1-kl]phenothiazinium fluoroborate or 3-chloropyrido-[3,2,1-kl]phenothiazinium perchlorate gives 1,2-dihydro-3H-pyrido[3,2,1-kl]phenothiazine, while 1H-pyrido[3,2,1-kl]phenothiazine is formed in aprotic solvents with pyridine present.     

Tetracyclic phenothiazines V. Construction of the azepino[3,2,1-kl] -phenothiazine ring system by regioselective ring expansion

Solvolysis of 1,2-dihydro-3-hydroxy-3-(p-toluenesolfonyloxymethyl) 3H-pyrido[3,2,1-kl]-phenothiazine gave 1,2,3,4-tetrahydroazepino[3,2,1-kl]phenothiazin-3-one.     

Unambiguously confirmed structure of 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one

To determine the structures of two isomeric products, 2-phenacylidene-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (2) and 3-phenacylidene-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3) obtained by condensation of 2,3-diaminopyridine (1) with ethyl benzoylpyruvate [1–3], these compounds were hydrolyzed to give 2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (4) and 3-methyl-1H-pyrido[2,3-b]pyrazin-2-one (5) , respectively [4,5]. Both hydrolysates 4 and 5 were hydrogenated to afford 2-methyl-1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one (6) and 3-methyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (7) . The latter compound was identical with an unequivocally synthesized compound providing proof for the structures of all these compounds.     

Synthesis of 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-one derivatives

This paper reports the synthesis of new pyrido[2,3-d]pyrimidin-4-one derivatives as diuretic agents. Starting with 1,2-dihydro-5-nitro-2-oxo-3-pyridinecarboxylic acid 1 , ethyl 2-ethoxy-5-nitro-3-pyridincarboxylate 4 was obtained. Compound 4 reacts with ammonia, methylamine or S-methylpseudothiourea to give the respective 2-amino-5-nitro-3-pyridinecarboxamide derivatives 5 and 6 or 2-methylthio-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-one 8. Treating carboxamide 5 with arylaldehydes and zinc dichloride, new 2-aryl-1,2-dihydro-6-nitro-3H-pyrido[2,3-d]pyrimidin-4-ones 9 were synthetised. These compounds reduced with iron(II) hydroxide gave 6-amino-2-aryl-1,2-dihydro-3H-pyrido[2,3-d]pyrimidin-4-ones 10 as expected.     

Tetracyclic phenothiazines. VII. Electron impact promoted mass spectral fragmentation of some pyrido[3,2,1-kl]phenothiazines

The mass spectral fragmentation pattern of a series of pyrido[3,2,1-kl]phenothiazines is reported. The major fragments are derived from the breakdown of the pyrido ring and substituents thereon. The 1,2-/2,3-unsaturated, unsubstituted and most of the 3-substituted compounds show the molecular ion as the base peak indicative of their relative stability toward electron impact. The genesis of the base peaks from the molecular ions of the 2,2-dithiophenyl substituted compounds probably involves a concerted expulsion of a neutral diphenyldisulfide molecule and hydrogen atom transfer from the 1-position to the 2-position in the pyrido ring. On the other hand, 2-thiophenyl substituted molecular ions lead to base peaks involving simultaneous ring opening of the pyrido ring, cleavage of phenylthiomethylene moiety as a radical and contractive ring closure to the pyrrole system. These two mechanisms appear to be diagnostic for distinguishing 2,3- versus 2,2-positional isomers. The McLafferty rearrangement takes place in the 2-thiophenyl and 2,2-dithiophenyl substituted compounds. The retro-Diels-Alder fragmentation of the pyrido ring occurs in varying degrees depending on the nature of the 2- and 3- substituents and also the presence or absence of unsaturation in the pyrido ring. In the 2-thiophenyl-3-keto compounds, thiophenyl group participation with 3-carbonyl carbon and oxygen atoms is observed in the genesis of some interesting ion fragments. The detection of metastable ions in the spectra of 1,2-dihydro-2-thiophenyl-, 1,2-dihydro-2,2-dithiophenyl-3-hydroxy-, and 1,2-dihydro-2,2-dithiophenyl-3-keto-3H-pyrido[3,2,1-kl]phenothiazines; and spectra of 1,2-dihydro-3-methyl-, 1,2-dihydro-2-carbethoxy-3-keto- and 1,2-dihydro-2-thiophenyl-3-keto-3H-pyrido[3,2,1-kl]pheno-thiazines at low voltage support major fragmentation pathways.     

Total assignment of the 1H NMR spectra of 5H-indolo[1,7-ab] [1]benzazepine,6,7-dihydro-5H-indolo[1,7-ab][1]benzazepine and pyrrolo[3,2,1-kl ] phenothiazine

The total assignment of the ¹H nmr spectrum of the three tetracyclic compounds: 5H -indolo[1,7-ab][1]benzazepine,6,7-dihydro-5H -indolo[1,7-ab ][1]benzazepine and pyrrolo[3,2,1-kl ]phenothiazine is described. Assignments were based on decoupling experiments and the spectrum of 1,10-dideuteriopyrrolo[3,2,1-kl]phenothiazine and the spectral parameters were verified by spin-simulation techniques. A temperature study of 6,7-dihydro-5H -indolo[1,7-ab][1]benzazepine was also performed.     

2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indoles. II. Reversible transformation of 1-alkyl-2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)cyclohexanol into 1-alkylidene-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles

Treatment of 2-(4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl)-1-methylcyclohexanol ( 2a ) with acetic anhydride or methyl isocyanate gave 2-acetyl-2,3,4,9-tetrahydro-1-(6-oxoheptylidene)-1H-pyrido[3,4-b]indole ( 3 ) or 1,3,4,9-tetrahydro-N-methyl-1-(6-oxoheptylidene)-2H-pyrido[3,4-b]indole-2-carboxamide ( 4 ), respectively. Simpler analogues, 1-alkyl-4,9-dihydro-3H-pyrido[3,4-b]indoles, 7 , subjected to identical reaction conditions, gave 2-acetyl-1-alkylidene-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles 8 and 1,3,4,9-tetrahydro-N-methyl-1-alkyli-dene-2H-pyrido[3,4-b]indole-2-carboxamides 9 , respectively. A limited lanthanide shift reagent study to determine stereochemical assignments was also performed.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Efficient synthesis of 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinoline 4,4-dioxide

A new efficient and versatile synthesis to obtain different substituted 5,6-dihydro-8H-[1,2,4]thiadiazino[6,5,4-de]phenanthridine 4,4-dioxide and 5,6-dihydro-8H-[1,2,4]-thiadiazino[6,5,4-ij]thieno[2,3-c]quinolone 4,4-dioxide was developed. The four cyclic systems are achieved by a three-step synthesis proceeding under mild conditions in high yields.     

Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

Unexpected formation of a 11H-pyrido[2,1-b]quinazolin-11-one derivative from 5,11-dihydro-6H-pyrido[2,3-b]-1,4-benzodiazepin-6-one

The unexpected formation of 11H-pyrido[2,1-b]quinazolin-11-one derivative 6 from 5,11-dihydro-6H-pyrido[2,3-b]-1,4-benzodiazepin-6-one (2) has been observed. Its structure 6 was determined by X-ray crystallography. Detailed nmr study provided a complete set of proton and carbon-13 nmr parameters of compound 6 in solution.     

Synthesen von Heterocyclen, 31. Mitt.: Über kondensierte N-Heterocyclen

Zusammenfassung Es wird über Synthesen des 4,6-Dioxo-5,6-dihydro-4 Hpyrido[3,2,1-de]-carbazols I und 1,3-Dioxo-2,3-dihydro-1 Hpyrido[3,2,1-kl]-phenothiazins berichtet.Schweizer Priorität vom 9. 6. 1959.     

Cyclization of 1-acylaminoacridones into 7H-pyrido[2,3,4-kl]acridin-2(3H)-ones

1-Acylamino-10-methylacridones in a polar aprotic solvent underwent base-catalyzed cyclization into the corresponding 7-methyl-7H-pyrido[2,3,4-kl]acridin-2(3H)-ones. Heating of 1-butylaminoacridone in acetic anhydride in the presence of p-toluenesulfonic acid and potassium acetate afforded 3-butyl-7H-pyrido[2,3,4-kl]acridin-2(3H)-one, while heating of 1-aminoacridone under the same conditions gave 9-acetoxy-1-acetylimino-1,10-dihydroxy-acridine. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1433–1437, August, 2006.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

A reinvestigation of the synthesis of 3H-[1,2]diazepino[5,6-b]indoles. The synthesis of pyrido[4,3-b]indoles

Recently reported [1] syntheses of 6-methyl-1,2,4,5-tetrahydro-1,4-dioxo-3H[1,2]diazepino[5,6-b]indole ( 5 ) and 4-hydroxy-6-methyl-3H[1,2]diazepino[5,6-b]indole ( 12 ) were reinvestigated and shown to be in error. The correct assignments for these respective structures are 3-amino-1,9-dihydro-9-methyl-2H-pyrido[4,3-b]indol-2,4(3H)-dione ( 6 ) and 3-amino-3,9-dihydro-9-methyl-2H-pyrido[4,3-b]indol-2-one ( 13 ). Condensation of 6 and 13 with p-nitrobenzaldehyde produced benzylidene derivatives, which confirmed the presence of the amino groups.     

Heterocycles structurally influenced by a side chain. X. Effect of temperature and side chain on the imine-enamine tautomerism in the quinoxalinone and pyridopyrazinone systems

3-(1-Benzoyl)ethyl-1H-pyrido[2,3-b]pyrazin-2-one ( 7 ), 3-(1-ethoxycarbonyl)ethyl-1H-pyrido[2,3-b]-pyrazin-2-one ( 8 ), and 3-(1-benzoyl)ethyl-1H-quinoxalin-2-one ( 9 ) exist only in the imine form due to the steric effect of the methyl substituent. As regards the imine-enamine tautomerism, 3-(β-carbonylmethylene) derivatives of 1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one such as 12 and 15–18 gradually change from the enamine form to the imine form with elevated temperatures; however, 3-(carbonylmethylene) derivatives of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one such as 10, 19 and 20 show little temperature effect. 2-Phenacylidene-1,2-dihydro-4H-pyrido[3,4-b]pyrazin-3-one ( 21 ) and 3-phenacylidene-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one ( 22 ), which exist in the enamine form, show no temperature effect.     

New organic nitrates. II. Synthesis of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazin-2,4(3H)-diones

The preparation and the physico-chemical characterization of 2H-pyrido[2,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazine-2,4(3H)-diones, 2H-pyrido[4,3-e]-1,3-oxazin-4(3H)-ones, 2H-thieno[2,3-e]-1,3-oxazin-4(3H)-ones and 2H-thieno[3,4-e]-1,3-oxazine-2,4(3H)-diones are reported.     

Annelated piperazinyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidines

Tricyclic analogs of piperazinylthiopyrano[3,2-d]pyrimidine hypoglycemic agents were prepared. The angular tricyclic systems, 8,9-dihydro-7H-thiopyrano[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine and 8,9-dihydro-7H-tetrazolo[1,5-a]thiopyrano[2,3-e]pyrimidine derivatives were synthesized from 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine in three step sequences. Derivatives of the linear tricyclic system, 5,6-dihydro-7H-thiopyrano[3,2-d][1,2,4]triazolo[2,3-a]pyrimidine, were prepared by condensation of 3-amino-1,2,4-triazole with ethyl 3-oxo-tetrahydropyran-2-carboxylate. The tricyclic heteroaryl-piperazines lacked significant hypoglycemic activity.     

Spiro[(2,3-dihydro-2-oxo-imidazo[1,2-a]pyridine)-3,3-(3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide)]-A novel product derived from piroxicam

A novel compound, spiro[(2,3-dihydro-2-oxo-imidazo[1,2-a]pyridine)-3,3-(3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine 1,1-dioxide)] (3) , was isolated during an attempt to convert 4-hydroxy-2-methyl-N-(2-pyridinyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide ( 1 ) (Piroxicam) to an O-trifluoromethanesulfonyl ester. A possible mechanism is offered to explain this unusual transformation.     

Nitrogen bridgehead compounds. Part 55 Synthesis of substituted 7,8-dihydro-5H,13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-ones

Fischer indolization of 6-arylhydrazono-6,7,8,9-tetahydro-11H-pyrido[2,1-b]quinazolin-11-ones 1 afforded substituted 7,8-dihydro-5H,13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-ones 3-12 in high yields.