Stereoselective synthesis of dihydrothiadiazinoazines and dihydrothiadiazinoazoles and their pyrolytic desulfurization ring contraction

Intramolecular base catalyzed C-C bond formation led to exclusive stereoselective syntheses of trans-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, trans-7,8-dihydro-6H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, and trans-3,4-dihydro-2H-[1,3,4]thiadiazino[2,3-b]quinazolin-10-one. trans-6,7-Dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines isomerize slowly in CDCl₃ and more rapidly in DMSO-d₆ into the corresponding cis-stereoisomers. The other trans-6,7-dihydro-[1,3,4]thiadiazines isomerize also in DMSO-d₆ into the corresponding cis-stereoisomers. Pyrolytic conversion of these heterocyclic condensed dihydrothiadiazines into their corresponding pyrazolo[5,1-b][1,2,4]triazoles, pyrazolo[5,1-c][1,2,4]triazin-4-ones and pyrazolo[4,3-b]quinazolin-9-ones via desulfurization ring contraction is described.     

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.     

Azolyl-substituted 1,2,3-triazoles

Huisgen reaction of (E)-1,5-diarylpent-2-en-4-yn-1-ones and (E)-1,5-diarylpent-1-en-4-yn-3-ones afforded 1-aryl-3-(5-aryl-1H-1,2,3-triazol-4-yl)prop-2-en-1-ones and 3-aryl-1-(5-aryl-1H-1,2,3-triazol-4-yl)-prop-2-en-1-ones, respectively. (E)-1-Aryl-3-(5-phenyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-ones reacted with hydrazine hydrate and phenylhydrazine to give 72–93% of 4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-5-phenyl-1H-1,2,3-triazoles which underwent dehydrogenation on heating in boiling acetic acid with formation of the corresponding pyrazole derivatives. The molecular structures of (E)-3-phenyl-1-(5-phenyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-one and 4-[3-(4-methylphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-5-phenyl-1H-1,2,3-triazole were studied by X-ray analysis. 4-(3-Aryl-4,5-dihydro-1H-pyrazol-5-yl)-5-phenyl-1H-1,2,3-triazoles showed toxicity against Daphnia magna.     

Reactions of vinyl 2,3-epoxypropyl ethers with 4,5-dihydro-1H-pyrazoles

Reactions of vinyl 2,3-epoxypropyl ether and 2-(vinyloxy)ethyl 2,3-epoxypropyl ether with 4,5-dihydro-1H-pyrazoles give, respectively, 3-vinyloxy-1-(4,5-dihydro-1H-pyrazol-1-yl)propan-2-ols and 3-(2-vinyloxyethoxy)-1-(4,5-dihydro-1H-pyrazol-1-yl)propan-2-ols in 70–91% yield.     

Isolation of the saddle and crown conformers of cyclotriveratrylene (CTV) oxime

The oxime of cyclotriveratrylene (CTV) has been prepared and the individual crown and saddle conformers were isolated and characterized. The equilibrium constant was measured in CDCl₃ and in DMSO-d₆ and was shown to favor the crown conformer by an order of magnitude in DMSO-d₆, relative to an approximately equal mixture at equilibrium in CDCl₃. The time course for interconversion of the saddle to the crown was measured by ¹H NMR and the t_1/2 of the saddle was determined to be 2.45 h in CDCl₃ at 25 °C, and 3.71 h in DMSO-d₆.     

Efficient synthesis of functionalized spiro-2,5-dihydro-1,2-λ-oxaphospholes

The reaction of ethyl propiolate with triphenylphosphine (Ph₃P) in the presence of N-alkylisatins led to ethyl 2,2,2-triphenyl-2,5-dihydro-1,2-λ⁵-oxaphosphole-4-carboxylate-spiro-1-alkyl-1,3-dihydro-2H-indol-2-ones in good yield. The reaction of dialkyl acetylenedicarboxylates with Ph₃P in the presence of N-alkylisatins led to dialkyl 2,2,2-triphenyl-2,5-dihydro-1,2-λ⁵-oxaphosphole-3,4-dicarboxylate-spiro-1-alkyl-1,3-dihydro-2H-indol-2-ones and alkyl 4-(alkoxy)-5-oxo-2,5-dihydro-3-furancarboxylate-spiro-1-alkyl-1,3-dihydro-2H-indol-2-ones.     

Synthesis of new imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one derivatives by iodocyclization of 6-alkenyl(alkynyl)-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones

6-Allyl(diallyl, prop-2-yn-1-yl)amino-1-R-pyrazolo[3,4-d]pyrimidin-4(5H)-ones reacted with iodine to give angularly fused 8-iodomethyl-7,8-dihydro-1-R-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones which were treated with sodium acetate to obtain 8-methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(6H)-ones as a result of elimination of hydrogen iodide. 8-Methylidene-1-R-7,8-dihydroimidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-ones were converted into 8-methyl-1-R-imidazo[1,2-a]pyrazolo-[4,3-e]pyrimidin-4(5H)-ones on heating to the melting point. 8-Methylidene-1-phenyl-7,8-dihydroimidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(6H)-one underwent isomerization into linearly fused 6-methyl-1-phenyl-1,8-dihydro-4H-imidazo[1,2-a]pyrazolo[3,4-d]pyrimidin-4-one on heating in sulfuric acid.     

Steric structure of alkyl 2-aryl(hetaryl)hydrazono-3-fluoroalkyl-3-oxopropionates

Steric structure of fluorinated 2-arylhydrazono-3-oxo esters was studied by ¹H, ¹⁹F, and ¹³C NMR spectroscopy and X-ray analysis. It was found that these compounds in the crystalline state and in solutions in acetone-d ₆, DMSO-d ₆, and CDCl₃ exist as Z isomers with the ester fragment involved in intramolecular hydrogen bond with the hydrazone NH proton. Exceptions are alkyl 2-arylhydrazono-4,4-difluoro-3-oxobutanoates which exist in acetone-d ₆ as mixtures of Z and E isomers, the former prevailing. Unlike fluorinated analogs, ethyl 2-(4-methylphenyl)hydrazono-3-oxobutanoate in crystal has the structure of E isomer in which intramolecular hydrogen bond is formed between the NH proton and acetyl carbonyl group. The same compound in acetone-d ₆, DMSO-d ₆, and CDCl₃ gives rise to a mixture of Z and E isomers, the latter prevailing.     

Experimental and Theoretical DFT Investigations in the [2,3]-Wittig-Type Rearrangement of Propargyl/Allyl-Oxy-Pyrazolones

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1H-pyrazol-5(4H)-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1H-pyrazol-5(4H)-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism.     

From Levulinic Acid to Biheterocycles: Synthesis of 1-[(5-Hydroxy-5-trifluoromethyl-3-substituted-4,5-dihydro-1H-pyrazol-1-yl)-3-(5-trifluoromethyl-1H-pyrazol-3-yl)propan-1-ones

We develop an efficient method to synthesize novel propionyl-spaced bisheterocyclic compounds. It entails cyclocondensation of 3-(5-trifluoromethyl-1H-pyrazol-3-yl)propanoyl hydrazide obtained from levulinic acid, with 1,1,1-trifluoro-4-methoxy-3-alken-2-ones proceeding regiospecifically to 1-[(5-trifluoromethyl-5-hydroxy-3-substituted-4,5-dihydro-1H-pyrazol-1-yl)-3-(5-trifluoromethyl-1H-pyrazol-3-yl)propan-1-one derivatives.     

Three-component reaction of methyl 2,4-dioxo-4-phenylbutanoate and methyl 2,4-dioxopentanoate with aromatic aldehydes and propane-1,2-diamine and chemical properties of the products

The reactions of methyl 2,4-dioxo-4-phenylbutanoate and methyl 2,4-dioxopentanoate with a mixture of an aromatic aldehyde and propane-1,2-diamine, depending on the initial reactant ratio, gave 4-acyl-1-(2-aminopropyl)-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones and 1,1′-(propane-1,2-diyl)bis(4-acetyl-3-hydroxy-5-phenyl-2,5-dihydro-1H-pyrrol-2-one). Reactions of substituted 1-(2-aminopropyl)-2,5-dihydro-1H-pyrrol-2-ones with aromatic amines and hydrazines were studied, and the structure of one of the products, 5-(2-aminopropyl)-3,4-diphenylpyrrolo[3,4-c]pyrazol-6-one, was proved by X-ray analysis.     

The synthesis of 3H-pyrazol-3-one derivatives containing a 9H-xanthene ring

2,4-Dihydro-5-methyl-2-phenyl-4-(9H-xanthen-9-yl)-3H-pyrazol-3-one ( 3 ) was prepared by the condensation of phenylhydrazine and ethyl α-acetyl-9H-xanthene-9-acetate ( 2 ), or 9H-xanthen-9-ol ( 1 ) and 2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one ( 4 ). 5-Amino-2,4-dihydro-2-phenyl-4-(9H-xanthen-9-yl)-3H-pyrazol-3-one ( 6 ) was obtained by the condensation of 1 and 5-amino-2,4-dihydro-2-phenyl-3H-pyrazol-3-one ( 5 ).     

Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,4-dihydro-3H-pyrazol-3-ones. One-pot synthesis of highly functionalized 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles

The reactive 1:1 intermediate produced in the reaction between isocyanides and dialkyl acetylenedicarboxylates was trapped by 2,4-dihydro-3H-pyrazol-3-ones to yield highly functionalized 7-oxo-1H,7H-pyrazolo[1,2-a]pyrazoles in fairly good yields.     

Haloacetylated enol ethers. 2. Synthesis of 5-trifluoromethylpyrazoles

1-Methyl-5-(trifluoromethyl)-1H-pyrazoles 2, 3 and 4,5-dihydro-1-phenyl-5-(trifluoromethyl)-1H-pyrazol-5-ol 4 were prepared by reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones 1 and hydrazine, methylhydrazine, and phenylhydrazine, respectively, in good yields. Compound 1 proved to be a versatile building block for the regiospecific construction of pyrazole rings having an 5-trifluoromethyl substituent.     

Microwave synthesis,characterization and antimicrobial study of new pyrazolyl-oxopropyl-quinazolin-4(3H)-one derivatives

Heterocyclic compounds containing pyrazolyl-oxopropyl-quinazolin-4(3H)-one are reported to possess significant biological activity. Syntheses of 6-bromo-2-(3-chloro-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 2 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl)quinazolin-4(3H)-one 3 and 6-bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 5a–j using microwave irradiation have been described. These compounds have been characterized on the basis of the UV, IR, ¹H NMR, ¹³C NMR, Mass and elemental analysis. Compounds have been evaluated for their antimicrobial activity.     

Synthesis of 5H-pyridazino[4,5-b]indoles and their benzofurane analogues utilizing an intramolecular Heck-type reaction

The title ring systems were prepared from pyridazin-3(2H)-one precursors in novel, efficient pathways. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-3(2H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared via reaction of 2-methyl-5-iodopyridazin-3(2H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2H)-one, respectively, with 2-bromophenol or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2H)-ones which were obtained via Buchwald-Hartwig amination of 2-methyl-5-halopyridazin-3(2H)-ones with 2-bromoaniline.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XIII. Synthesis of 2H-pyrano[3,2-d]-1-benzoxepin derivatives

Cycloaddition of dichloroketone to N,N-disubstituted (E)-4-aminomethylene-3,4-dihydro-1-benzoxepin-5(2H)-ones gave N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-pyrano[3,2-d]-1-benzoxepin-2-ones II, which are derivatives of the new heterocyclic system 2H-pyrano[3,2-d]-1-benzoxepin. Dehydrochlorination with triethylamine of II afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-pyrano-[3,2-d]-1-benzoxepin-2-ones III in good to moderate yields. In the triethylamine treatment of IIh (NR₂ = diphenylamino), 3-chloro-5,6-dihydro-2H-pyrano[3,2-d]-1-benzoxepin-2-one was isolated in low yield near to IIIh, whereas IIc (NR² = diisopropylamino) gave in low yield 4-diisopropylamino-5,6-dihydro-2H-pyrano(3,2-d)-1-benzoxepin-2-one.     

Pyrazolonderivate VII Synthese und Struktur von Metallchelatkomplexen mit 4-aminomethylen-Δ2-pyrazolinon-(5)-ligaden

In the reaction of 4-aminomethylene-Δ²-pyrazolin-5-ones with metal acetates new chelate complexes with a ligand-metal ratio of 2:1 are formed. For structural investigations¹⁵N-labeled compounds and azomethines of the pyrazole type are also prepared. The¹⁵N-,¹³C-, and¹H-chemical shifts have been measured in CDCl₃. Chemical shifts as well as coupling constantsnJ (¹³C?¹⁵N)n=1, 2;² J (HC=¹⁵N);² J (=CH?¹⁵N) are discussed with regard to the structure of metal complexes and azomethines. It has been shown that complex formation causes a considerable change of the π-electron structure within the merocyanin part.     

Synthesis of 3-alkyl-5-arylamino-6,11-dihydro-3H-anthra[1,2-d]-[1,2,3]triazole-6,11-dione 2-oxides by nitrosation of 3-alkylamino-5-arylamino-6H-anthra[1,9-cd]isoxazol-6-ones

Nitrosation of 3-alkylamino-5-arylamino-6H-anthra[1,9-cd]isoxazol-6-ones with sodium nitrite in acetic acid leads to the formation of the corresponding unstable N-nitroso derivatives which are converted into 3-alkyl-5-arylamino-6,11-dihydro-3H-anthra[1,2-d][1,2,3]triazole-6,11-dione 2-oxides on heating.     

Synthesis and biotests of 2-aryl-5-arylmethylidene-substituted 1,3-oxazol-5(4<Emphasis Type="Italic">H</Emphasis>)-ones and <Emphasis Type="Italic">N</Emphasis>-methyl-3,5-dihydro-4<Emphasis Type="Italic">H</Emphasis>-imidazol-4-ones as combretastatin A-4 analogs

A series of 2-aryl-5-arylmethylidene-1,3-oxazol-5(4H)-ones and 2-aryl-5-arylmethylidene-N-methyl-3,5-dihydro-4H-imidazol-4-ones was synthesized as structural analogs of combret- astatin A-4 (a compound possessing antitumor activity). (5Z)-5-[(4-Methoxyphenyl)methyl-idene]-3-methyl-2-(4-methylphenyl)-3,5-dihydro-4H-imidazol-4-one was found to exhibit the highest cytotoxicity against cells of human A549 lung carcinoma line (EC₅₀ = 6±0.8 μmol L^?1).