Reaction of 2-aryl(methyl)-4-cyano-5-hydrazino-1,3-oxazoles with aryl Isothiocyanates

Accessible 2-aryl(methyl)-4-cyano-5-hydrazino-1,3-oxazoles add to aryl isothiocyanates. The resulting products undergo recyclization to form new 1,3,4-thiadiazole derivatives bearing an acylamino group on C² and an (acylamino)(cyano)methyl group on C⁵. The structure of the new compounds was proved by their IR and ¹H NMR spectra, as well as by conversion in other 1,3,4-thiadiazole derivatives.     

2-Azido-1,3,4-thiadiazoles, 2-Azido-1,3-thiazoles,and Aryl Azides in the Synthesis of 1,2,3-Triazole-4-carboxylic Acids and Their Derivatives

Diazotization of 2-amino-1,3,4-thiadiazoles gave 1,3,4-thiadiazole-2-diazonium sulfates which were converted to 2-azido-1,3,4-thiadiazoles. The latter reacted with ethyl acetoacetate in the presence of sodium methoxide in methanol to produce 1-(5-R¹-1,3,4-thiadiazol-2-yl)-5-R²-1H-1,2,3-triazole-4-carboxylic acid derivatives. The reactions of 2-azido-5-methyl-1,3,4-thiadiazole and 2-azido-1,3-thiazole with ethyl 3-(1,3-benzodioxol-5-yl)-3-oxopropanoate led to the formation of 1,2,3-triazole ring under milder conditions (K₂CO₃, DMSO). Various 1,2,3-triazole-4-carboxylic acid derivatives were synthesized.     

Study of Nitrogen- and Sulfur-Containing Heterocycles. 57. Synthesis and Conversion of 4′-Substituted 5-(5-Amino-6-Pyrimidylthio)-2,2-Dimethyl-4,6-Dioxo-1,3-Dioxanes

By reaction of 4-substituted 5-amino-6-mercaptopyrimidines with 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, we have obtained 4′-substituted 5-(5-amino-6-pyrimidylthio)-2,2-dimethyl-4,6-dioxo-1,3-dioxanes. We have studied diazotization of these compounds by isoamyl nitrite. In the case of 4′-methoxy- and 4′-dimethylamino-substituted derivatives, we have obtained derivatives of novel heterocyclic systems: pyrimido[5,4-e][1,3,4]thiadiazine and pyrimido[5,4-e][1,3,4]thiadiazine-7-spiro-5′-1,3-dioxane, and in the case of the 4′-isopropylamino-substituted derivative we obtained 4-isopropyl-7-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1,2,3-triazolo[5,4-d]pyrimidin-7-ylidene.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 613–623, April, 2005.     

Synthetic routes towards tetrazolium and triazolium dinitromethylides

Tetrazolium-5-dinitromethylide sodium salt has been prepared (91%) by cyclization of 1-amino-1-hydrazino-2,2-dinitroethene with nitrous acid in water. 5-Imino-1-(hydroxyiminonitromethyl) derivatives were obtained by nitration of 2-(5-amino-1,3-dimethyl-1H-1,2,4-triazol-4-ium-4-yl)- and 2-(5-amino-4-methyl-1H-tetrazolium-1-yl)acetate complex salts. Treatment of 4-methyl-1-(2-oxopropyl)-1-tetrazolium methylsulfate with nitric and sulfuric acid gave methyl (3-nitro-1,2,4-oxadiazol-5-yl)amine (27%) probably via dinitromethylide followed by cyclization and loss of nitrogen.__________Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 127–134, January, 2005.     

Synthesis of 4-hetaryl-substituted 5-amino- and 5-sulfanyl-1,3-oxazole derivatives

Previously unknown 5-amino- and 5-sulfanyl-1,3-oxazole derivatives containing a 1,3,4-oxadiazole, 1,3,4-thiadiazole, or 1,2,4-triazole fragment at C⁴ were synthesized from accessible 1,3-oxazole-4-carboxylic acid hydrazides.     

2-aryl-5-arylsulfanyl-1,3-oxazole-4-carboxylic acids and their derivatives

A convenient preparative procedure has been developed for the synthesis of previously unknown 2-aryl-5-arylsulfanyl-1,3-oxazole-4-carboxylic acids and their functional derivatives from accessible multicenter substrates of the general formula Cl₂C=C(NHCOR)C(O)OMe. The products turned out to be suitable for various subsequent transformations. Some oxazole-4-carboxylic acid hydrazide derivatives containing a substituted oxazol-5-yl fragment at the N² atom in the hydrazine moiety underwent recyclization on heating in acetic acid; as a result, one oxazole ring was converted into 1,3,4-oxadiazole.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Derivatives of 5-(Dimethylamino)-4-tosyl-1,3-oxazole-2-carbaldehyde and Its Analogs

Treatment of N-(2,2,2-trichloro-1-tosylethyl)dichloroacetamide with excess dimethylamine, piperidine, or morpholine gave substituted aminals of the oxazole series, whose facile acid hydrolysis provided 5-(dimethylamino)-4-tosyl-1,3-oxazol-2-carbaldehyde and its analogs having the piperidino and morpholino group in the 5 position of the oxazole ring. The resulting aldehydes and their aminals were condensed with phenylhydrazine, thiosemicarbazide, N-alkylrhodanines, and 1,3-dimethylbarbituric acid to obtain 2,5-disubstituted derivatives of 4-tosyl-1,3-oxazole.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 6, 2005, pp. 1002–1006.Original Russian Text Copyright © 2005 by Vyzhdak, Danielova, Kiselev, Drach.     

Synthesis,Structures, and Fungitoxicity of Novel Organophosphorus Compounds

Abstract

A series of biologically active organophosphorus compounds have been synthesized by the reactions of O,O-diethylchlorophosphate with Schiff bases derived from 5-(phenyl/substituted phenyl)-2-hydrazino-1,3,4-oxadiazole and salicylaldehyde/2-hydroxyacetophenone. The compounds have been characterized on the basis of analyses and spectral (IR, ¹H, ¹³C NMR) data. Fungicidal activities of these derivatives against Colletotrichum falcatum, Fusarium oxysporum, and Curvularia pallescence have been evaluated. All compounds showed moderate to significant antifungal activity.     

Reaction of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acyl isothiocyanates

The reactions of diethyl 5-hydrazino-2-(4-methylphenyl)-1,3-oxazol-4-ylphosphonate with acetyl, benzoyl, and ethoxycarbonyl isothiocyanates result in the previously unknown (1,3,4-thiadiazol-2-yl)-substituted aminomethylphosphonic acids.     

Synthesis of Some New Fused and Polyfused [1,2,4]Triazolo-[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazepines

7-[1,3-Dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-dione and 7-[5-oxo-1,3-dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]-thiadiazepine-6,8-diones were obtained by treating 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo-[3,4-b][1,3,4]thiadiazepine-6,8-diones with CS₂ and chloroacetyl chloride, respectively. Treatment of the above compounds with mercaptoacetic acid gave 1,2-dibromoethane or the corresponding spiro polyfused heterocycles. Some other triazolothiadiazepine derivatives including spiro polyfused compounds were also synthesized. __________ Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1256–1264, August, 2005.     

Recyclization of 5-Amino- oxazoles as a Route to new Functionalized Heterocycles (Developments of V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine)

The recyclizations of 5-amino- and 5-hydrazine-1,3-oxazoles mainly with electron-withdrawing group in 4^th position are considered. The chemical behavior of these heterocycles is due to the presence of two hidden amide fragments; therefore, the recyclization processes include a stage of nucleophile attack on 2^nd or 5^th position of the oxazole cycle. When the nitrile group is present in 4^th position, it is often involved in the recyclization forming α-aminoazoles. 5-Amino/hydrazine-1,3-oxazoles undergo recyclization both in nucleophilic (amines, hydrazine, thionating agents) and electrophilic medium ((trifluoro)acetic acid, other acylating agents). The numerous types of functionalized heterocycles can be easily obtained with the usage of these recyclizations, such as the derivatives of 3-amino-6,7-dihydro-5H-pyrrolo[1,2–a]imidazole, imidazolidine-2,4-dione, 1H-pyrazole-3,4,5-triamine, 5,6-diamino-2,3-diphenylpyrimidin-4(3H)-one, 2-(2-R-7-oxo-5-(trifluoromethyl)oxazolo[5,4–d]pyrimidin-6(7H)-yl)acetic acid, 2-R-4-(5-R′-1,3,4-oxadiazol-2-yl)oxazol-5-amine, (amino(5-amino-1,3,4-thiadiazol-2-yl)methyl)phosphonate.     

Mass spectra of derivatives of N-alkyl- and N-alkoxyalkylideneimine-2-carboxylic acids

The fragmentation of compounds of the RN(CH₂)_nCHCOX (n=1–5) and RNCH₂C(COX)₂ type, where X=OAlk and NH₂ and R=H, D, OAlk, and Cl, under electron impact was studied. When n=2–5, the chief fragmentation process is amine fragmentation, and the (M–COX)⁺ ion peak is the principal peak in the spectra at 30 and 12 eV. The fragmentation of three-membered heterocycles differs radically. The dominant fragmentation for 1-alkylaziridine-2-carboxylic and -2,2-dicarboxylic esters is splitting out of a radical from the ester group. This process is absent when R=H, D, C, and OAlk. Fragmentation with splitting out of the elements of alcohol for the esters and of ammonia for the amines is characteristic in the case of derivatives of 1-alkoxyaziridine-2-carboxylic and-2,2-dicarboxylic acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 624–633, May, 1977.     

Synthesis and Structure of 4-Trifluoromethylsulfonamidotrichloroethyl-5-chloropyrazoles

Reactions of trifluoromethanesulfonic acid N-(2,2,2-trichloroethylidene)amide with 1,3-dialkyl-5-chloropyrazoles and 1-phenyl-3-methylpyrazole afforded 4-(amidotrichloroethyl)-substituted pyrazole derivatives. 4-Chloropyrazoles were not involved into this process. The structure of compounds synthesized was studied by means of IR and NMR spectroscopy. The presence of intra- and intermolecular hydrogen bonds was revealed by a decrease in the absorption frequencies and a complicated form of ν(NH) and ν_as(SO₂) absorption bands in the IR spectra, and also in splitting of signals in ¹H and ¹³C NMR spectra.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005, pp. 749–752.Original Russian Text Copyright © 2005 by Kondrashov, Rozentsveig, Sarapulova, Larina, Levkovskaya, Savosik, Bozhenkov, Mirskova.     

Reactions of <Emphasis Type="Italic">N</Emphasis>-(1-chloro-2-oxo-2-phenylethyl) carboxamides with thiosemicarbazide and its derivatives

N-(1-Chloro-2-oxo-2-phenylethyl)acet-, -benz-, and -4-methylbenzamides reacted with thiosemicarbazides and aromatic aldehyde thiosemicarbazones to give derivatives of 5-amino-2-hydrazino-1,3-thiazole. The latter underwent recyclization and acid hydrolysis on heating with hydrochloric acid to produce substituted 3-amino-2-thiohydantoins.     

Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27–2.58 Å) and longer N..C-distances (3.02–3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.     

Efficient,One-Pot Synthesis of Triazolothiadiazinyl-pyrazolone and Pyrazolyl-triazolothiadiazine Derivatives via Multicomponent Reaction

A one-pot, multicomponent reaction of 3-(2-bromo acetyl)coumarins, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and different derivatives of ethyl 2-(2-(aryl)hydrazono)-3-oxobutanoates provide an efficient and direct method for the synthesis of 4-(arylydrazono)-3-methyl-1-(6-(coumarin-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5(4H)-ones (4a–h). A similar methodology was also developed for the synthesis of pyrazolyl-triazolothiadiazines (9a–f) using acetyl acetone, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and different derivatives of phenacylbromide. The resulting products were characterized by analytical and spectral data.     

5-Phenyl-2-(pyrazol-4-yl)-1,3,4-thiadiazoles

By recyclization of 2-R-6-ethyl-7-hydroxy(methoxy)-3-(5-phenyl-1,3,4-thiadiazol-2-yl)chromones when treated with hydrazine hydrate and phenylhydrazine, we synthesized 5-phenyl-2-(3-R-5-R1-1H-pyrazol-4-yl)-1H-1,3,4-thiadiazoles and 2-(3-R-5-R1-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1H-1,3,4-thiadiazoles. We confirmed the structure of the latter from ¹H NMR spectra.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 781–787, May, 2005.     

Bridgehead nitrogen heterocycles from 2,4,6-triphenyl- pyrylium cation and thiosemicarbazide or thiocarbohydrazide

2,4,6-Triphenylpyrylium with thiosemicarbazide and thiocarbohydrazide, gives 2-pyrazolines $\text{3a}$ and $\text{3b}$ which undergo cyclization yielding pyrazolo(1,5-c]pyrimidine 5 and pyrazolo [2,3-d]-1,2,4-triazepine $\text{7}$ derivatives, respectively. Reaction of $\text{7}$ with phenacyl bromides gave 1,3-thiazolo[3,2-b]pyrazolo [2,3-d]-1,2,4-triazepin-4-iums $\text{10}$. Compound $\text{3a}$ on treatment with phenacyl bromides gave 1-(4'-aryl-thiazol-2'-yl)-2-pyrazoline derivatives $\text{6}$. Compound $\text{3b}$ reacts with acyl chlorides to give pyrazolo[1,5-c]pyrimidine derivatives $\text{14}$, and with aromatic aldehydes giving the 2-(Δ^2'1 pyrazolin-1-yl)-5-aryl-1,3,4-Δ²-thiadiazolines $\text{12}$ which were easily converted to the corresponding 2-(Δ²-pyrazolin-1-yl)-5-aryl-1,3,4-thiadiazoles $\text{13}$.     

Synthesis,anticancer, and computational studies of 1, 3, 4-oxadiazole-purine derivatives

Theophylline-7-acetic acid (acefylline) ( 3 ) and its derivatives are pharmacologically active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of 2-((5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-yl)thio)-N-arylacetamides ( 10a-j ) has been reported. All the synthesized derivatives ( 10a-j) were structurally verified by FT-IR, ¹H NMR, ¹³C NMR and evaluated for their anti-cancer (using MTT assay), hemolytic and thrombolytic potential. N-(4-Chlorophenyl)-2-(5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)acetamide ( 10g ) was found to be the most active against human liver cancer cell lines (Huh7) having cell viability 53.58 ± 1.28 using 100 μg/mL concentration of compound which was further in-silico modelled to describe the possible mechanistic insights for its anti-proliferative activity. The results of hemolytic and thrombolytic activities indicated that these derivatives were less toxic and hold considerable potential as a drug candidate. 2-(5-((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(2-fluorophenyl)acetamide ( 10c ) of the series was found to be least toxic with 0.1% hemolysis relative to ABTS (95.5%) as positive control. 2-(5-((1,3-Dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-1,3,4-oxadiazol-2-ylthio)-N-(tetrahydro-2H-pyran-4-yl)acetamide ( 10j ) exhibited potent clot lysis activity (90%) as compared to negative control DMSO (0.57%).