Interactions of aroyl-and heteroaroyltrifluoroacetones with thiobenzoylhydrazine

The interaction of aroyl(heteroaroyl)trifluoroacetones with thiobenzoylhydrazine may occur at both carbonyl groups. Reaction at the trifluoroacetyl group is facilitated by terminal substituents in the 1,3-dicarbonyl part, which leads can effectively conjugate with the adjacent carbonyl group. The products of condensation at the trifluoroacetyl group are 2-[2-aryl(heteroaroyl)-2-oxoethyl]-5-phenyl-2-trifluoromethyl-2,3-dihydro-1,3,4-thiadiazoles, while condensation at the aroyl(heteroaroyl)group gave 3-aryl(heteroaryl)-5-hydroxy-1-thiobenzoyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazoles, which are not prone to tautomeric transformations in solution. In Memory of Professor A. A. Potekhin __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 765–775, May, 2008.     

Heterocyclization of 2,4-disubstituted thiosemicarbazides with haloketones

2,4-Disubstituted thiosemicarbazides were allowed to react with α-bromoacetophenone to give the anticipated 2,3-dihydro-6H-1,3,4-thiadiazines, whereas with β-propiophenone and γ-butyrophenone to afford the unexpected 2,3-dihydro-1,3,4-thiadiazole. The reaction mechanism was also discussed.     

1,3,4-THIADIAZOLES. REGIOSELECTIVE O-DEMETHYLATION ON DEHYDRATIVE CYCLIZATION OF 1-(3,4,5-TRIMETHOXYBENZOYL)4-SUBSTITUTED THIOSEMICARBAZIDES WITH SULPHURIC ACID

Cyclization of 1-(3,4,5-trimethoxybenzoyl)-4-substituted thiosemicarbazides 2a–g with sulphuric acid at ambient temperature afforded the selectively demethylated products 2-(4-hydroxy-3,5-dimethoxyphenyl)-5-substituted amino-1,3,4-thiadiazoles 4a–g. Meanwhile, dehydrative cyclization of 1-(3,4,5-trimethoxybenzoyl)-4-(benzyl or t-butyl)thiosemi- carbazides 2h, i with sulphuric acid yielded 2-(4-hydroxy-3,5-dimetho xyphenyl)-5-amino-1,3,4-thiadiazole 5. On the other hand, dehydration of 2h, i by heating with phosphorus oxychloride yielded 2-(3,4,5-trimethoxyphenyl)-5-amino-1,3,4-thiadiazole 6.     

The structure of the diazonium coupling products of phenacyl thiocyanate and phenacyl selenocyanate with diazotized 3-phenyl-5-aminopyrazole

The reaction of diazotized 3-phenyl-5-aminopyrazole with phenacyl thiocyanate 1a and phenacyl selenocyanate 1b afforded directly 2-imino-3-(3-phenyl-5-pyrazolyl)-5-benzoyl-2,3-dihydro-1,3,4-thiadiazole monohydrate 9a and 2-imino-3-(3-phenyl-5-pyrazolyl)-5-benzoyl-2,3-dihydro-1,3,4-selenadiazole monohydrate 9b , respectively. The products 9a and 9b were also obtained from the reaction of C-benzoyl-N-(3-phenyl-5-pyrazolyl)formohydrazidoyl bromide 10 with potassium thiocyanate and potassium selenocyanate, respectively. Acetylation, benzoylation, and nitrosation of 9 afforded the corresponding diacetyl, dibenzoyl, and nitroso derivatives 11-13 , respectively. Cyclization of C-benzoyl-N-(3-phenyl-5-pyrazolyl)-nitrilimine 6 was shown to give the pyrazolo [5,1-d]triazole 8 and not the pyrazolo[5,1-c]-as-triazine derivative 7 , as previously reported.     

Syntheses of substituted-oxazolo-1,3,4-thiadiazoles, 1,3,4-oxadiazoles,and 1,2,4-triazoles

Starting from readily available methyl 5-methyloxazole-4-carboxylate ( 1 ) and 4-methyl-5-oxazolylcar-boxylic acid hydrazide ( 11 ) the title compounds were prepared. The reaction of compound 1 with hydrazine hydrate afforded the corresponding hydrazide 2 . The reaction of compound 2 with formic acid yielded 1-formyl-2-(5-methyloxazole-4-carboxyl)hydrazine ( 3 ). Refluxing of the latter with phosphorus pentasulfide in xylene gave compound 5 in 62% yield. The reaction of compound 3 with phosphorus pentoxide afforded compound 4 . Starting from hydrazide 11 , compounds 13 and 14 were prepared similarly. Reaction of compound 2 with substituted isothiocyanate yielded compound 9 which was cyclized in basic medium to 4-alkyl-5-(5-methyl-4-oxazolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione ( 10 ). The isomer 19 was prepared similarly. Methylation and subsequent oxidation of compound 19 gave compound 21 . Reaction of the acid 7 with thiosemicarbazide in the presence of phosphorus oxychloride gave 2-amino-5-(5-methyl-4-oxazolyl)1,3,4-thiadiazole ( 8 ). 2-Amino-5-(4-methyl-5-oxazolyl)-1,3,4-thiadiazole ( 17 ) was prepared from acyl chloride 15 by the usual method.     

Redox Transformation of Adducts from Cycloaddition of Diazoacetic Ester to β-Arylacryloyloxiranes

It was established that, in addition to ethyl 4-aryl-3-(2,3-epoxyalkanoyl)-4,5-dihydro-1H-pyrazole-5-carboxylates, the reaction of diazoacetic ester with β-arylacryloyloxiranes also gives ethyl 4-aryl-3(5)-(3-hydroxy-2-methylalkanoyl)-1H-pyrazole-5(3)-carboxylates. The latter are formed from the tautomeric ethyl 4-aryl-5-(2,3-epoxyalkanoyl)-4,5-dihydro-1H-pyrazole-3-carboxylates as a result of intramolecular oxidative-reductive disproportionation. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1150–1160, August, 2005.     

2H-1,4-benzothiazines from the reaction of 2-aminoethanethiol with nascent 4-methyl-o-benzoquinone

4-Methyl-o-benzoquinone, generated oxidatively, reacts readily with 2-aminoethanethiol giving 5-hydroxy-7-methyl-1,3,4-dihydro-2H-1,4-benzothiazine (I) or 5-oxo-7-methyl-8-(2-hydroxy-4-methylphenoxy)-3,5-dihydro-2H-1,4-benzothiazine (VIII), depending on the conditions under which the reaction is performed. Chemical and spectral (uv, ir, nmr and ms) evidence for the assigned structures, as well as the course of the above mentioned reaction is described. A study of the behaviour of compound VIII in the presence of acids and alkalies is also reported.     

Glyconothio-O-lactones. Part III. Thermolysis of a 4,5-Dihydro-1,2,3- and a 2,5-Dihydro-1,3,4-thiadiazole

Addition of CH₂N₂ to 2,3:5,6-di-O-isopropylidene-1-thio-mannono-1,4-lactone ( 1 ) gave the 2,5-dihydro-1,3,4-thiadiazole 2 and the 4,5-dihydro-1,2,3-thiadiazole 3 . First-order kinetics were observed for the thermolysis of 3 (Scheme 3) at 80–110° in C₆D₅Cl solution and of 2 (Scheme 3) at 20–35° in CDC1₃, respectively. The 1,2,3-thiadiazole 3 led to mixtures of the thiirane 9 , the starting thionolactone 1 , the thiono-1,5-lactone 8 , and the enol ether 7 , while the isomeric 1,3,4-thiadiazole 2 led to mixtures of the anomeric thiiranes 9 and 12 , the O-hydrogen S,O,O-ortholactone α-D - 14 , the S-methyl thioester 15 , the S,S,O-ortholactone 13 , and the 2,3:5,6-di-Oisopropylidene-mannono-1,4-iactone ( 16 ). Pure products of the thermolysis were isolated by semipreparative supercritical fluid chromatography (SFC), whereas preparative HPLC led to partial or complete decomposition. Thus, the β-D -mannofuranosyl β-D -mannofuranoside 10 , contaminated by an unknown S species, was isolated by preparative HPLC of the crude product of thermolysis of 3 at 115–120° and partially transformed in CD₃OD solution into the symmetric di(α-D -mannofuranosyl) tetrasulfide 11 . Its structure was evidenced by X-ray analysis. Similarly, HPLC of the thermolysis product of 2 gave the enethiol 17 , the sulfide 19 , and the mercapto alcohol 18 as secondary products. Thermolysis of the thiirane 9 at 110–120° (Scheme 4) led to the anomeric thiirane 12 which was transformed into mixtures of the enethiol 17 and the enol ether 7. Addition of H₂O to 17 and 7 gave the corresponding hemiacetals 18 and 20. The mechanism of the thermolysis of the dihydrothiadiazoles 2 and 3 , and the thiiranes 9 and 12 is discussed.     

Studies on reactive intermediates. Part I. An approach to the synthesis of 2-phenyl-7-carbethoxy-5H-1,3,4-thiadiazolo[2,3-a]pyrimidin-5-one

2-Phenyltetrazolo[4,5-a]-1,3,4-thiadiazole ( 4 ), in its azido form, reacted with diethyl fumarate and diethyl maleate to give 2-phenyl-7-carbethoxy-5H-1,3,4-thiadiazolo[2,3-a]pyrimidin-5-one ( 5 ). To assign the structure of compound 5 , 2-phenyl-5-carbethoxy-7H-1,3,4-thiadiazolo[2,3-a]pyrimidin-7-one ( 6 ) was prepared from the reaction of 2-amino-5-phenyl-1,3,4-thiadiazole ( 7 ) with diethylacetylene dicarboxylate. Physical properties and spectral data of compound 6 were different from compound 5 . Theoretical and experimental aspects are discussed.     

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.     

Synthesis of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione and its reactions with C-electrophiles

4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N₍₂₎ atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1088–1094, July, 2007.     

Heterocyclization of 2-(Propargylsulfanyl)-1,3-thiazole Derivatives by the Action of Halogens

Reactions of 2-(propargylsulfanyl)-5-methyl-1,3,4-thiadiazole, N-[5-(propargylsulfanyl)-1,3,4-thiadiazol- 2-yl]benzamide, 2-(propargylsulfanyl)-1,3-benzothiazole, and 2-(propargylsulfanyl)-4,5-dihydro-1,3- thiazole with iodine involved annulation of the unsaturated substituent with formation of fused thiazole ring. 2(5)-(Propargylsulfanyl)-1,3,4-thiadiazole derivatives reacted with bromine to give mixtures of heterocyclization products and bromine adducts to the triple bond. The bromination of 2-(propargylsulfanyl)-4,5-dihydro- 1,3-thiazole afforded only the bromine addition product to the triple bond.     

Synthesis,Reactions, and Anticancer Activity of Some 1,3,4-Thiadiazole/Thiadiazine Derivatives of Carbazole

A novel method for the synthesis of 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives bearing a carbazole moiety is described. Carbazole was transformed into carbazole-9-thiocarbohydrazide in two steps. This compound was allowed to react with various electrophiles to yield 1,3,4-thiadiazole derivatives. The reaction with bifunctional electrophiles led to 1,3,4-thiadiazines. 2-(Carbazol-9-yl)-5,6-dihydro-4H-1,3,4-thiadiazin-5-one reacted with piperidine and formaldehyde to yield the 4-(piperidin-1-ylmethyl) derivative. The reaction with aromatic aldehydes led to the corresponding 6-arylidene derivatives, which were transformed into pyrimidino[4,5-e]-1,3,4-thiadiazines and pyrazolo[3,4-e]-1,3,4-thiadiazines by a reaction with guanidine, acetamidine, or phenylhydrazine, respectively. Structures of the products were confirmed by ¹H NMR, ¹³C NMR, IR, and mass spectrometric measurements. Selected examples of products were screened for anticancer activity.     

Synthesis of Carbamoyl-Containing N,S-Heterocyclic Compounds

Monothioxamides unsubstituted at the thioamidic nitrogen atom were obtained by the reaction of NS-morpholino-NO-R-thioxamides with ammonia. Carbamoyl-containing 5-phenylcarbamoyl-1,2,4-dithiazoles, 6-phenylcarbamoyl-5,6-dihydro-[1,2,4,5]-dithiadiazin-3-one, and 5-phenylcarbamoyl-2-oxy-1,3,4-thiadiazole were synthesized by the reaction of monothioxamides or thiohydrazides of oxamic acids with chlorocarbonylsulfenyl chloride.     

Synthesis and Physicochemical Properties of Heterocyclic Compounds Based on 5,7-Diimino-2,5,6,7-tetrahydro-1H-cyclopenta[cd]phenalene

N,N'-Bis(7-amino-2,5-dihydro-1H-cyclopenta[cd]phenalen-5-ylidene)-substituted derivatives of 2,5-diamino-1,3,4-thiadiazole, 2,6-diaminopyridine, and 3,5-diamino-1-phenyl-1,2,4-triazole were synthesized. The products are soluble in water, and they attract interest as potential biologically active substances.     

Condensed isoquinolines. 21. Condensation of <Emphasis Type="Italic">o</Emphasis>-bromomethylphenylacetonitrile with substituted anthranilic acids

The reaction of substituted anthranilic acids and esters with o-bromomethylphenylacetonitrile give 2,3-R,R¹-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one hydrobromides. It was found that 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones can exist in the two tautomeric imine and enamine forms. The tautomeric equilibrium position depends on the nature and position of the substituent in the quinazoline fragment. The borohydride reduction, oxidation, and reaction of 2,3-R,R¹-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones with electrophilic reagents has been studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 562–573, April, 2007.     

Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products

Acylhydrazines react with 1,3-diketones of the general formula CF₃COCH₂COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl₃ as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.     

Benzoid-Quinoid Tautomerism of Schiff Bases and Their Structural Analogs: LI. Photoacylotropic Enaminoketones with a Fluorophoric Migrant

The acylation of ortho-substituted (R = OH, OMe, NHTs) 2-arylaminomethylene-2,3-dihydro- benzo[b]thiophen-3-ones with (4-methyl-2-oxobenzo[b]pyran-7-yloxy)acetyl chloride results in formation of the corresponding N-acyl enaminoketones. The same reaction with 2-(2-hydroxyphenylaminomethylene)-2,3- dihydrobenzo[b]thiophen-3-one gives rise to a tautomeric mixture of acyloxyphenyl and N-acyl enaminoketone isomers. Irradiation at a wavelength corresponding to the absorption region of the N-acyl enaminoketone isomer leads to NO acyl group transfer to afford O-acylated isomer. The complex formation ability of all tautomeric forms with respect to Zn²⁺ and Ni²⁺ cations and their fluorescence properties were studied.     

Synthesis and properties of diaminothiadiazoles

Refined synthetic procedure for preparation of 3,5-diamino-1,2,4-thiadiazole and 2,5-diamino-1,3,4-thiadiazole based on the reaction of dithiourea or amidinothiourea with hydrogen peroxide is developed. The optimal reagents ratio was found, and monitoring methods were developed. It resulted in the increase of the target product yield and in a shorter reaction time. On the basis of 2,5-diamino-1,3,4-thiadiazole the alkylsubstituted 1,3,4-diaminothiadiazolidines were synthesized. The compounds prepared were characterized by the elemental analysis data, the IR, ¹H NMR, and electronic spectra, and also by mass spectrometry.     

Synthesis of Some New Thieno[2,3-b]pyridines,Pyrimidino[4′,5′:4,5]thieno[2,3-b]-pyridines,and 2,3-Dihydro-1,3,4-thiadiazoles

Thieno[2,3-b]pyridines were synthesized from 6-benzofuran-2-yl-4-phenyl-2-sulfanylpyridine-3-carbonitrile and each of chloro acetone, ethyl chloroacetate, ω -bromoacetophenone, and chloroacetonitrile. These compounds were conveniently converted into novel pyrido[4′,5′:4,5]thieno[3,2-d]pyrimidines. Also, 2,3-dihydro-1,3,4-thiadiazole was synthesized from hydrazonoyl halides and 2-benzofuran-2-yl-3-(phenylamino)-3-thioxopropanenitrile. The structures of the products have been elucidated by elemental analyses, spectral data studies, and alternative syntheses whenever possible. The newly synthesized compounds were tested towards microorganisms.