Reactions of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with Electrophiles

Summary.  Treatment of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with haloalkanes yielded oxadiazole S-alkyl derivatives, whereas its reaction with formaldehyde and amines resulted in formation of oxadiazole N(3)-aminomethyl derivatives. The alkylation of 2-alkylsulfanyl-5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazoles with methyl bromoacetate proceeded at the N(1)-position of pyrimidine to give 2-alkylsulfanyl-5-(1-methoxycarbonylmethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazoles, whereas aminomethylation, bromination, or nitration took place at position 5 of pyrimidine ring and afforded the corresponding 5-pyrimidine substituted derivatives. Received May 9, 2001. Accepted (revised) August 17, 2001     

Synthesis of 5-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione and its Reactions with Polyfunctional Electrophiles

Summary.  In the reaction of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-1,3,4-oxadiazole-2-thione with hydrazine hydrate, 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-amino-1,2,4-triazole-3-thione was formed. The reactions of the latter with ethyl bromoacetate and chloroacetonitrile in the presence of triethylamine proceeded under formation of the corresponding S-alkylated derivatives, whereas from its reaction with ω-bromoacetophenone and ethyl 4-chloroacetoacetate triazolothiadiazines were obtained. Treatment of the title compound with ethyl 2-chloroacetoacetate led to the formation of 5-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)-methyl-4-N-acetylamino-(3-ethoxy-carbonylmethylthio)-1,2,4-triazole. Performing of the latter reaction without basic catalyst gave a triazolothiadiazine. Treatment of the S-alkylated derivatives with sodium methoxide resulted in triazolothiadiazines via a cyclocondensation reaction. Received November 20, 2000. Accepted January 15, 2001     

Synthesis of 11-bromo-9-methyl-6-methylene-3-methylthio-5,6,9,10-tetrahydro-8H-[1,2,4]triazolo[3′,4′;3,4]pyrazino[1,2-c]pyrimidine-8,10-dione from 4-allyl-1-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinylcarbonyl)thiosemicarbazide

4-Allyl-1-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinylcarbonyl)thiosemicarbazide is cyclized in alkaline medium into 4-allyl-3-(3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinyl)-1,2,4-triazoline-3-thione, which is converted on alkylation with iodomethane into the methylthio derivative. Reaction of the latter with bromine occurs with formation of 3-(5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-6-pyrimidinyl)-4-(2,3-dibromopropyl)-5-methylthio-1,2,4-triazole, dehydrobromination of which with potassium carbonate leads to formation of the first representative of a new heterocyclic system, viz. 11-bromo-9-methyl-6-methylene-3-methylthio-5,6,9,10-tetrahydro-8H-[1,2,4]triazolo[3,4:3,4]pyrazino[1,2-c]pyrimidine-8,10-dione.Vilnius University, Vilnius 2734, Lithuania. e-mail: sigitas.tumkevicius@chf.vu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 67–70, January, 1999.     

Alkylation of Pyrimidine Derivatives with Chloroacetic Acid Esters

Alkylation of 6-methyluracil, 5-hydroxy-6-methyluracil, and 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylammonium sulfate with isopropyl and ethyl chloroacetates afforded previously unknown alkyl 2-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetates, alkyl 2-(1-alkoxycarbonylmethyl-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-3-yl)acetates, 1,3-bis(alkoxycarbonylmethyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylammonium sulfates, and alkyl 2-[1,3-bis(alkoxycarbonylmethyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yloxy]acetates.     

Synthesis of new pyrido[2,3-d]pyrimidine derivatives

The mutual condensation of 4-aminouracil or 2,4-diamino-6-hydroxypyrimidine with bisacetonitrile and aldehydes was used to synthesize 2,4-dioxo-5-R-7-methyl-6-cyano-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine and 2-amino-4-oxo-5-R-7-methyl-6-cyano-3,4,5,8-tetrahydropyrido[2,3-d]pyrimidine derivatives, which were oxidized with chromic anhydride to the corresponding 2,4-dioxo-5-R-7-inethyl-6-eyano-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 2-amino-4-oxo-5-R-7-methyl-6-cyano-3,4-dihydro[2,3-d]pyrimidines. The IR and UV spectra of the synthesized compounds were recorded.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 422–425, March, 1972.     

Synthesis and properties of (6-methyl-2-oxo-4-thioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)acetic acid methyl ester

On interacting of the methyl ester of (6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-3-pyrimidinyl)acetic acid with the Lawesson’s reagent the corresponding 4-thioxo derivative is synthesized. Its alkylation with methyl bromoacetate has been studied as has its interaction with N-nucleophiles, amines, and hydrazines. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 590–594, April, 2007.     

Interaction of Cyclic Schiff's Bases with 2-Methylthiopyrimidine-4,6-dione Enol Acetate. Synthesis of 5-(2-Acetyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl)-6-hydroxy-2-methylthio-1,4-dihydro-4-pyrimidinones

5-(2-Acetyl-1,2,3,4-tetrahydro-1-isoquinolyl)-6-hydroxy-2-methylthio-1,4-dihydro-4-pyrimidinones have been obtained by the interaction of 3,4-dihydroisoquinolines with 2-methylthio-4-oxo-1,4-dihydro-6-pyrimidinyl acetate. It was shown that N,O-methyl derivatives are formed in interaction of the obtained products with diazomethane.     

Synthesis and Biological Evaluation of Some Novel N,N ′-Bis-(1,2,4-Triazin-4-Yl)Dicarboxylic Acid Amides and Some Fused Rings with 1,2,4-Triazine Ring

Some of novel N , N '-bis-(1,2,4-triazin-4-yl)dicarboxylic acid amides ( 2-5 ) and thiadiazolo[2,3- b ][1,2,4]triazin-7-yl carboxylic acid derivatives ( 6 , 7 ) were prepared by heating 4-amino-6-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine ( 1 ) with different dicarboxylic acids (oxalic, malonic, fumaric, maleic, succinic, and phthalic acids respectively) in POCl 3 . Refluxing 1 with 1-chloro-2,4-dinitrobenzene in DMF yielded 3-methyl-6-nitro-10 H -benzo[1,2,4]thiadiazino[2,3- c ][1,2,4]triazin-4-one ( 8 ). Condensation of 1 with 2,4-pentandione in refluxing acetic acid furnished 6-methyl-4-(1-methyl-3-oxobut-1-enylamino)-3-thioxo-3,4-dihydro-2 H -[1,2,4]triazin-5-one ( 9 ). 3,8-D imethyl[1,2,4] triazino[3,4- b ][1,3,4]thiadiazine-4,7-dione ( 11 ) was prepared by refluxing 1 with 2-bromopropionyl bromide in anhydrous benzene to afford the corresponding N -acetylated derivative 10 , which was cyclized by using triethylamine. Also, some triazinylquinazolinones 13a , b were obtained by fusion of 1 with 6-bromo(and/or 6,8-dibromo)-2-methyl-3,1-benzoxazin-4 H -ones.     

Reactions with 2-mercaptopyrimidines. Synthesis of some new thiazolo[3,2-a]- and triazolo[4,3-a]pyrimidines

Alkylation of 5-cyano-4-oxo-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine I with methyl iodide, chloroacetic acid or 3-chloro-2,4-pentanedione, afforded the S-alkyl derivatives IIa-c. 2-Carboxymethylthio and 2-(2′,4′-dioxopentan-3-ylthio) derivatives IIb and IIc could be cyclised by acetic anhydride or polyphosphoric acid to give 6-cyano-3,5-dioxo-5H-7-phenylthiazolo[3,2-a]pyrimidine III and 2-acetyl-6-carboxamido-5H-3-methyl-7-phenylthiazolo[3,2-a]pyrimidine-5-one IX , respectively. Benzoylation of 2-hydrazinopyrimidine derivative XII , in anhydrous dioxan, afforded the N-benzoyl derivative XIII , which could be cyclised by heating in dimethylformamide to give 5-amino-6-cyano-3,7-diphenyl-s-triazolo[4,3-a]pyrimidine ( XIV ). The 2-hydrazinopyrimidine derivatives XII and XV reacted with benzoyl isothiocyanate in dioxane to yield 4-benzoylthiosemicarbazide derivatives XVI and XVII , which were converted into the 2-s-trizolopyrimidine derivatives XVIII and XIX , respectively. Also, XVI and XVII reacted with 2,4-pentanedione and 3-chloro-2,4-pentanedione to yield 2-pyrazolopyrimidine derivatives XX and XXI , respectively.     

Synthesis and structure of hydrazones obtained by the reaction of 2-[6-methyl-2,4-dioxo-1-(thietan-3-yl)-1,2,3,4-tetrahydropyrimidin-3-yl]acetic acide hydrazide with β-dicarbonyl compounds

Reaction of 2-[6-methyl-2,4-dioxo-1-(thietan-3-yl)-1,2,3,4-tetrahydropyrimidin-3-yl]acetic acid hydrazide with β-dicarbonyl compounds proceeds regioselectively; the structure of the formed hydrazones is governed by the structure of the β-dicarbonyl reaction component. The reaction with acetyl- and propionylacetone afforded 3-[2-(5-alkyl-3-methyl-1H-pyrazol-1-yl)-2-oxoethyl]-6-methyl-1-(thietan-3-yl)pyrimidin-2,4(1H,3H)-diones, with aroylacetones, 5-hydroxypyrazoline derivatives which are present in DMSO solutions in E′ conformation with respect to the amide bond. The condensation products with acetoacetic acid derivatives have a linear structure and consist of mixtures of E,Z- and E′,Z′-isomers owing to the geometric and conformational isomerism.     

Synthesis of bisarylmethyl-substituted pyrimidines and quinolines

The condensation of 2-chloro-8-methylquinoline-3-carbaldehyde, 2-chloroand 2-chloro-7,8,9,10-tetrahydrobenzo[h]quinoline-3-carbaldehydes, 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde, and 2-chloropyrido[1,2-a]pirimidine-3-carbaldehyde with N-substituted anilines gave the corresponding diaryl(hetaryl)methanes.     

Synthesis of α,ω-Bis(3-methyl- or 3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1-pyrimidinyl)alkanes

The reactions of stoichiometric amounts of sodium salts of 2-hydroxy-3-methyl-4-oxo-3,4-dihydropyrimidine or 2-hydroxy-3,6-dimethyl-4-oxo-3,4-dihydropyrimidine and dibromoalkanes in dimethylformamide were used to synthesize ,-bis(3-methyl- or 3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1-pyirimidinyl)alkanes with 1 and 3-5 methylene units in the hydrocarbon brigde.     

Synthesis of 3,3′-(1,6-hexanediyl)bis-pyrimidine derivatives and 3,4-dithia[6.6](1.3)pyrimidinophane

Several 3,3′-(1,6-hexanediyl)bis[6-methyl-2,4(1H,3H)-pyrimidinedione] derivatives ( 4a, 4b , and 4c ) were synthesized from 1,6-(hexanediyl)bis[6-methyl-2H-1,3-oxazine-2,4(3H)-dione] (3) . Compound 4c was converted to 6, which reacted with thiourea giving thiuronium salt 7 . 3,3′-(1,6-Hexanediyl)bis [1-(2-mercaptoethyl)-6-methyl-2,4(1H,3H)-pyrimidinedione] (9) was obtained by the hydrolysis of 7 , and then 9 was oxidized to 12,22-dimethyl-3,4-dithia[6.6] (1.3)-1,2,3,4-tetrahydro-2,4-dioxopyrimidinophane (10) .     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Transformations of unsymmetrical N-hetarylformazans in acidic media

1-Aryl-3-phenyl-5-hetarylformazans undergo acid cleavage to give benzaldehyde hetarylhydrazones, whereas 1-hetaryl-3-phenyl-5-(4-nitrophenyl)formazans undergo acid cleavage to give benzaldehyde 4-nitrophenylhydrazones. 1-Aryl-3-phenyl-5-(6-oxo-4-methyl-2-pyrimidinyl)-formazans undergo cyclization to 1,2,4-triazolo[4,3-a]pyrimidine derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1268–1270, September, 1977.     

Thermal ring transformation of 5-aryl-2-carbazoyl-1,2,3,4-tetrazole derivatives

Unstable 5-aryl-2-(3-benzylidene-2-phenylcarbazoyl)-1,2,3,4-tetrazoles 8 have been prepared. By thermal ring transformation, they gave 5-aryl-2-(2-benzylidene-1-phenylhydrazino)-1,3,4-oxadiazoles 9. , Hydrazinolysis of 9 afforded 5-aryl-2-(1-phenylhydrazino)-1,3,4-oxadiazoles 10. Elimination of a molecule of benzonitrile from 9 on heating converted them into 2-anilino-5-aryl-1,3,4-oxadiazoles 11.     

SPECIFIC PHOTOCOUPLING OF 5-BROMOURIDINE TO TRYPTOPHAN IN AQUEOUS FROZEN SOLUTION§

Abstract —5-Bromouridine (BrUd) photochemically reacted with l -tryptophan (trp) only in aqueous frozen solution giving rise to 2-[1,2,3,4-tetrahydro-1-(β-d -ribofuranosyl)-2,4-dioxo-5-pyrimidinyl]-l -tryptophan ( 1a ). Under similar conditions irradiation of 5-bromouracil (BrU) and trp gave the corresponding coupled product 2. Addition of acetone, potassium carbonate or sodium chloride to the frozen system completely inhibited the photocoupling reaction. These photocoupling reactions are suggested to proceed via mixed aggregate formation between trp and BrUd (or BrU) in frozen aqueous solution. Stacking interactions in these aggregates are characterized by an efficient quenching of trp fluorescence by BrUd. Under the same conditions other amino acids such as phenylalanine, tyrosine, histidine and lysine did not react with BrUd, indicating that the photocoupling of BrUd (or BrU) is specific for trp.     

Synthesis of 6-[4-(allyl/phenyl)-5-thioxo-1,2,4-triazol-3-yl]pyrimidine-2,4-diones and their reaction with electrophiles

Cyclization of 1-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)carbonyl-4-R-thiosemicarbazides in basic medium gave 6-(4-R-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-diones (R = Allyl, Ph). Alkylation of the latter with iodomethane occurred at the sulphur atom to give the corresponding methylsulfanyl derivatives. Acetylation using acetyl chloride occurred at the N₍₁₎ atom of the triazole ring to the corresponding acetyl derivative when R = Ph but for R = Allyl the acetylation did not occur under the same conditions. In the presence of bromine in refluxing methanol the indicated allyl-substituted compound cyclizes to 6-bromomethyl-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-6-yl)-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole. Under Mannich and bromination conditions the methylsulfanyl derivatives prepared form derivatives at the 5 position of the uracil ring: 5-methylmorpholino-(piperidino)-and 5-bromo-(4-R-5-thioxo-1,2,4-triazol-3-yl)pyrimidine-2,4-diones respectively. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 906–912, June, 2006.     

Synthesis of 1,3-Bis[3-X-2-(X-acetoxy)propyl]-6-methyl- 1,2,3,4-tetrahydropyrimidine-2,4-diones

A procedure was developed for synthesizing nitrogen-and-sulfur-containing pyrimidine derivatives by reactions of 1,3-bis(3-chloro-2-hydroxypropyl)-6-methyluracil with 1-butanethiol and chloroacetyl chloride, followed by treatment of the resulting 1,3-bis[3-chloro-2-(chloroacetoxy)propyl]-6-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione with 1-butanethiol, morpholine, and piperidine. Oxidation of the sulfur-containing products with NaIO₄ gave the corresponding sulfoxides.     

Pyrimidines. 24. Analogues and derivatives of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP)

Preparation of a number of derivatives of 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP) including the 2-dialkylaminoalkylamino-, 2-hydroxyalkylamino-, 2-ethoxycarbonylamino- and 2-alkylaminocarbonyl-amino- groups substituted on the pyrimidine ring as well as preparation of 1-(alkylaminoalkyl)-4,6-dioxo-8-phenyl-2,3,4,6-tetrahydro-1H-pyrimido[1,2-α]pyrimidines and 3,5-dioxo-7-phenyl-1,2,3,5-tetrahydroimidazo-[1,2-α]pyrimidines with or without the bromo-substitution are reported.