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.     

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.     

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.     

A new one-step synthesis of 2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2h,6h[1,3]thiazino[2,3-b] quinazolin-6-one

2,3-Dihydro-5H-thiazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2H,6H[1,3] thiazino[2,3-b]-quinazolin-6-one have been synthesized in one step by the reaction of methyl anthranilate with ehloroalkyl isothiocyanates.     

A facile synthesis of 1-alkylthio and acylthio-2,3-dihydro-1H-naphtho[2,1-b]thiopyrans and 4-alkylthio and acylthio-3,4-dihydro-2H-naphtho[1,2-b]thiopyrans

The reaction of 3-(2-naphthylthio)propionaldehyde ( 3 )and its (1-naphthylthio)isomer (7)with a variety of thiols and thio acids in the presence of sulfuric acid at room temperature afforded 1-alkylthio and acylthio-2,3-dihydro-1H-naphtho[2,1-b]thiopyrans 5 and 4-alkylthio and acylthio-3,4-dihydro-2H-naphtho[1,2-b]thiopyrans 9 in excellent yield.     

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.     

Synthesis of 2,3-dihydro-1H-imidazo[1,2-b]pyrazoles

Two novel 2,3-dihydro-1H-imidazo[1,2-b]pyrazole derivatives 7 and 8 have been prepared by hydrazinolysis with 2,4-dinitrophenylhydrazine of 1-(benzylideneamino)-2-(2-ethoxycarbonyl-2-nitromethylidene)-imidazolidine 4 . The precursor 4 was conveniently prepared from ethyl nitroacetate and 1-(benzylidene-amino)-2-(methylthio)imidazoline 3 . Two examples are presented in which ethyl aceto(and trifluoroaceto)acetate 2-nitrophenyl-hyrazone, 9 and 10 , both of which also feature the β-hydrazinoacrylate arrangement, are refluxed in ethanol containing hydrochloric acid and thereby converted into pyrazolones 11 and 12 , pyrazoles 13 and 14 , and ketone 2-nitrophenylhydrazones 15 and 16 , respectively.     

Reactions of anthranilamide with isocyanates: A new facile synthesis of 2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one and 3,4-dihydro-2H,6H-[1,3]oxazino[2,3-b]quinazolin-6-one [1]

2,3-Dihydro-5H-oxazolo[2,3-b]quinazolin-5-one 5a was synthesized from anthranilamide 1 and 2-chloro-ethyl isocyanate either by a direct reflux in methanol, or by stirring at room temperature in acetonitrile leading to the intermediate, 2-(2-chloroethyl ureido)benzamide 6a which was subsequently cyclized on heating with an organic base. However, when compound 6a was refluxed with concentrated hydrochloric acid, it furnished 3-(2-chloroethyl)-2,4-dioxo-1H,3H-quinazoline 2a in good yields. 3,4-Dihydro-2H,6.H-[1,3]-oxazino[2,3-b]quinazolin-6-one 5b , 3-(3-chloropropyl)-2,4-dioxo-1H,3.H-quinazoline 2b and 2-(3-chloropropyl ureido)benzamide 6b were obtained similarly from 1 and 3-chloropropyl isocyanate.     

Synthesis and in vitro cytotoxic evaluation of 2-hydrazinylpyrido[2,3-b]pyrazin-3(4H)-one derivatives

A series of novel 2-hydrazinylpyrido[2,3-b]pyrazin-3（4H）-one derivatives were synthesized and evaluated for their cytotoxic activities against A549,MDA-MB-231 and HT-29 cell lines in vitro.Pharmacological data indicated that compounds 5b,5c,10a and 10g possessed marked cytotoxicity,especially 10a(with IC₅₀ values of 0.81,2.56 and 1.63μmol/L against A549,MDA-MB- 23 1 and HT29 cell lines,respectively),which had emerged as a lead compound.     

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.     

Synthesis of 2H-pyrano[2,3-b]quinolines. Part II. Preparation and 1H-nmr investigations of 4-hydroxy-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines

Diastereoisomers of 4-hydroxy-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines 8 and 9 were synthesized starting from the appropriate 2-chloroquinoline-3-carboxaldehydes 1. The relative configuration of the 1,3-diol intermediates 4 and 5 was determined on the basis of the ¹³C-nmr spectra of their acetonides. The relative stereochemistry of title compounds was confirmed by using homonuclear NOE and selective decoupling experiments, as well as by analysis of the coupling patterns observed in their ¹H-nmr spectra.     

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.     

Synthesis and lactim-lactam tautomerism of 1,2-dihydrofuro[2,3-b]quinol-4-one derivatives

The reaction of O-ethylbutyrolactonium tetrafluoroborate with derivatives of ethyl anthranilate was used to synthesize tetrafluoroborates of cyclic imido esters, which were cyclized to furo[2,3-b]quinol-4-one derivatives by heating in a solution of sodium ethoxide. A number of N- and O-alkyl derivatives were obtained by alkylation of these compounds. The tautomerism of 6-chloro- and 7-chloro-2,3-dihydrofuro [2,3-b]quinol-4-ones that are unsubstituted in the benzene ring was studied, and a dependence of the position of the tautomeric equilibrium on the solvent and the substituent in the benzene ring was established.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 376–381, March, 1984.     

9-Hydroxy-2-methyl-4H-pyrido[1,2-α] pyrimidin-4-one and its derivatives

2-Amino-3-(o-bromobenzyloxy)pyridine ( 1 ) and ethyl acetoacetate gave 9-(o-bromobenzyl-oxy)-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one ( 2 ) in 2% yield. When 1 and methyl β-amino-crotonate ( 3 ) were reacted, benzyl ether cleavage occurred and the products were 9-hydroxy-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one ( 4 ) and its ammonium salt ( 5 ). These observations led to an alternative synthesis in which 2-amino-3-pyridinol ( 6 ) and either 3 or methyl acetoacetate, ( 8 ) in diethylbenzene at 185° gave 4 in 86 and 87% yields, respectively, and the anion of 4 and o-bromobenzyl bromide gave 2 in 61% yield. Even in diethylbenzene at 185°, 1 and 8 gave only trace amounts of 2 . Thus, o-bromobenzylation of the 3-hydroxyl group in 6 markedly decreased the reactivity of the amino group in 6 toward reactions with acetoacetic esters.     

A convenient synthesis of 3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-2-carboxylic acids and 3,4-dihydro-2-methyl-3-oxo-2H-pyrido[3,2-b]-1, 4-oxazine-2-carboxylic acid

A convenient one pot synthesis of ethyl 3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-2-carboxylates and 3,4-dihydro-2-methyl-3-oxo-2H-pyrido[3,2-b]-1,4-oxazine-2-carboxylates and their conversion into the respective carboxylic acids are described.