Pyrimidine derivatives. IX . Synthesis of bromosubstituted 5-nitro-2,4(1H,3H)-pyrimidinedione derivatives

The following 5-nitro-2,4(1H,3H)-pyrimidinediones possessing bromo substituted side chains at the 1- and 6-positions were prepared by bromination of 3,6-dimethyl-1-(ω-hydroxyalkyl)-5-nitro-2,4(1H,3H)-pyrimidinediones 4a and 4b and its nitrates 2a and 2b . The three of mono-bromo derivatives are: 1-(ω-acetoxyalkyl and ω-hydroxyalkyl)-6-bromomethyl-3-methyl. 6a, 6b, 7a and 7b and 1-(ω-bromoalkyl)-3,6-dimethyl-2,4(1H,3H)- pyrimidinediones 8a and 8b . The one type dibromo derivatives are: 1-(ω-bromoalkyl)-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinediones 5a and 5b .     

Pyrimidine derivatives XII. A convenient preparation of 6-formylpyrimidinedione and 2- and 3-formylpyridine derivatives from corresponding nitrooxymethyl derivatives

The convenient preparation of 6-fomylpyrimidinedione derivatives and 2- and 3-formylpyridine are described. Thus, 5-bromo-1,3-dimethyl- ( 1a ), 5-bromo-3-methyl-1-(2-nitrooxyethyl)- ( 1b ), and 5-bromo-3-methyl-1-(3-nitrooxypropyl)-2,4(1H,3H)-pyrimidine-dione ( 1c ) were converted to the corresponding 6-formyl compounds 2a, 2b , and 2c , respectively, in excellent yields by the reaction with triethylamine and 1,4-diazabicyclo[2.2.2]octane. These 6-formylpyrimidinedione derivatives are key intermediates for the preparation of 6-carbon-carbon substituted compounds, which are expected to be potential antitumor and antiviral agents. Similarly, 2-(and 3-)formylpyridine ( 9a (and 9b )) were obtained by the reaction of 2-(and 3)nitrooxymethylpyridine ( 8a (and 8b )) with 1,4-diazabicyclo[2.2.2]octane.     

Pyrimidine derivatives. VII. Nucleophilic reactions of 5-bromo-1-(bromoalkyl)-6-bromomethyl-2,4(1H,3H)-pyrimidinediones

The reactions of 1-(bromoalkyl)-5-bromo-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1) with several nucleophiles were examined as follows: by reaction with sodium methoxide, 6-(bismethoxy)methyl-5-debrominated derivatives 2, 3 , and 4 were prepared; the corresponding di-substituted compounds (side chains in 1-and 6-positions) 5, 6, 7 , and 9 were obtained by treatment with silver nitrate, silver acetate, potassium thiocyanate, and potassium thioacetate; the reaction with thioacetamide and iso-butylamine gave bicyclic compounds [1,4]thiazino[4,3-c]- 11 , pyrazino[1,2-c]- 12 , and [1,4]diazepino[1,2-c]pyrimidinedione 13 , respectively; pyrrolidine, morpholine, and sodium azide afforded the corresponding 6-substituted compounds 14, 15 , and 16 .     

A reinvestigation of the structures for 5-diazouracil, 5-diazouridine, 5-diazo-2′-deoxyuridine and certain related derivatives by proton magnetic resonance spectroscopy

The structure of 5-diazouracil and several closely related derivatives have been revised on the basis of pmr spectroscopy. 5-Diazouracil, 5-diazouracil hydrate, 5-diazouracil methanol adduct, 5-diazouridine and 5-diazo-2′-deoxyuridine have been reassigned the structures 5-diazopyrimidin-2,4(3H)dione (XI), 5-diazo-6-hydroxy-1,6-dihydropyrimidin-2,4(1H,3H,6H)dione (XIII), 5-diazo-6-methoxy-1,6-dihydropyrimidin-2,4(1H,3H,6H)dione (XII), 1 -(β-D-ribofuranosyl)-O^5′ -6(S)cyclo-5-diazo-1,6-dihydropyrimidin-2,4(3H,6H)dione (XVII) and 1-(2-deoxy-β-D-ribofuranosyl)-O^5′ -6(S)cyclo-5-diazo-1,6-dihydropyrimidin-2,4(3H,6H)dione (XIX), respectively. Treatment of XII with dimethylamine resulted in a coupling of the 5-diazo group with dimethylamine and a concomitant rearomatization of the heterocyclic ring by expulsion of the 6-methoxy group to furnish 5-(3,3-dimethyl-1-triazeno)uracil (XIV). A similar reaction of XIX and XVII with dimethylamine furnished the corresponding 5-(3,3-dimethyl-1-triazeno)derivatives. The effect which certain resonance hybrids of the diazo moiety may exert in reactions of the above hetero-cycles and the assignment of S configuration at C-6 for the nucleoside derivatives is also discussed.     

Synthesis of new thietanylpyrimidine and thietanylimidazole derivatives

New thietanyl-substituted derivatives of pyrimidine-2,4(1H,3H)-dione and imidazole were synthesized. The alkylation of 6-methylpyrimidine-2,4(1H,3H)-diones with 2-chloromethylthiirane in water involved the N¹ atom of the pyrimidine ring and afforded 6-methyl-1-(thietan-3-yl)-pyrimidine-2,4(1H,3H)-diones. Under analogous conditions 6-aminopyrimidine-2,4(1H,3H)-dione gave rise to 6-(thietan-3-ylamino)pyrimidine-2,4(1H,3H)-dione. Unsymmetrically substituted 2-methyl-4(5)-nitro- and 5(4)-bromo-2-methyl-4(5)-nitro-1H-imidazoles reacted with 2-chloromethylthiirane to produce mixtures of isomeric 2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles and 5(4)-bromo-2-methyl-4(5)-nitro-1-(thietan-3-yl)-1H-imidazoles.     

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 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides

The method for the synthesis of 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones is described. It is shown that the reaction of phosphorus trichloride, 2-pyrrolidones and 6-aminopyrimidines brings to condensation producing 6-imino-5-tetrahydro-1H-2-pyrrolylidenhexahydro-2,4-pyrimidinediones as intermediates for the synthesis of C-azanucleosides. The reaction of 6-imino-1,3-dimethyl-5-tetrahydro-2-pyrrolylidenhexahydro-2,4-pyrimidinedione with benzoyl chloride produces 10-benzoyl-2,4-dimethyl-6-phenyl-1,2,3,4,8,9-hexahydropyrimido[5,4-e]pyrrolo[1,2-c]pyrimidine-1,3-dione. A method for the selective reduction of the carbomethoxy group of methyl 5-(4-imino-1,3-dimethyl-2,6-dioxohexahydro-5-pyrimidinyliden)-2-pyrrolidine carboxylate by system NaBH₄/1,4dioxane/CoCl₂/PEG-400 is described.     

Benzimidazole condensed ring systems. 5. Studies on the Synthesis of Pyrimido[1,6-α]benzimidazole-1,3(2H,5H)-diones

The reaction of ethyl 1H-benzimidazole-2-acetate (1) with methyl or ethyl isocyantes 2a,b resulted in excellent yields of the respective 2-methyl- or 2-ethylpyrimido[1,6-a]benzimidazole-1,3(2H,5H)-diones 3a,b , while the reaction of 1 with phenyl isocyanate (2c) gave, unexpectedly, ethyl 2-(1-phenylcarbamoyl-1H,3H-benzimidazol-2-ylidene)-2-phenylcarbamoylacetate (4). Alkylation of 3 with trimethyl or triethyl phosphates 5a,b led to the 5-methyl or 5-ethyl derivatives 6a-d . Chlorination of 6 with sulfuryl chloride afforded the 4-chloro derivatives 7a-d.     

Synthesis of 4H-pyrazolo- and 4H-pyrrolophenothiazin-4-one derivatives

5-Methyl- and 6-methyl-2-phenyl-2H-indazole-4,7-diones were condensed with 2-aminobenzenethiol or 6-substituted-3-aminopyridine-2(1H)thiones 4 to produce a new type of 5-methyl-2-phenyl-4H-pyrazolophenothiazin-4-ones or 8-substituted-7-aza-5-methyl-2-phenyl-4H-pyrazolophenothiazin-4-one derivatives. From 6-bromo-2,5-dimethyl-1,3-diphenyl-2H-isoindole-4,7-dione and 4 8-substituted-7-aza-2,5-dimethyl-1,3-diphenyl-4H-pyrrolophenothiazin-4-one derivatives were also prepared.     

Synthesis and reactions of halo-, nitro-, and arylazo-substituted 3-aminotropolones. Formation of 8H-cyclohept[d]oxazol-8-one derivatives

3-Acetamidotropolone ( 1a ) reacted with bromine and fuming nitric acid to afford respectively 3-acetamido-7-bromo- ( 1b ) and -5,7-dibromotropolone ( 1c ) and 3-acetamido-5-nitrotropolone ( 1d ). Azo-coupling reaction of 1a gave 3-acetamido-5-(4-methylphenylazo)tropolone ( 1f ). Bromination of 1d and 1f gave 7-bromo-substituted compounds 1e and 1g , respectively. The compounds 1b-g were hydrolyzed to afford 3-aminotropolones 4b-g , which reacted with triethyl orthoformate to give the corresponding 8H-cyclohept[d]oxazol-8-ones 5b-g . Heating of 3-acetamidotropolones 1a-d with polyphosphoric acid gave 2-methyl-8H-cyclohept[d]oxazol-8-ones 6a-d .     

Pteridine. Teil LXXXI. Mechanismus der Photooxidation von 5,6-Dihydro-1,3-dimethyl-6-thioxopteridin-2,4(1H,3H)-dion

Mechanism of the Photooxidation of 5,6-Dihydro-1,3-dimethyl-6-thioxopteridine-2,4(1H,3H)-dione The mechanism of the photooxidation of 5,6-dihydro-1,3-dimethyl-6-thioxopteridine-2,4(1H,3H)-dione ( 9 ) has been investigated in dependence of the pH. Photooxidation of the anion species in weak alkaline solution takes place by singlet oxygen as well as the superoxide radical anion forming 1,2,3,4-tetrahydro-1,3-dimethyl-2,4-dioxopteridine-6-sulfinate ( 5 ) as the first detectable reaction product. In acidic medium, a more complex photooxidation process is observed leading, in a radical-chain mechanism, to 6,6′-dithiobis[1,3-dimethylpteridine-2,4(1H,3H)-dione] ( 6 ).     

Attempts to prepare some 3-substituted azolo[1,2-x]azines,intermediates in the synthesis of azaaplysinopsin derivatives

Some 3-substituted pyrrolo[1,2-a]azines 4a-d were prepared in low yields from the corresponding 2-methylpyridines 1a,b and pyrazine derivatives 1c,d by quaternization with methyl bromoacetate followed by treatment with N,N-dimethylformamide dimethyl acetal. Ethyl 2-pyridinylacetate ( 5 ) and 2-pyridinylaceto-nitrile ( 6 ) were converted with 4-(2-bromo-1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone ( 9 ) into pyrrolo[1,2-a]pyridine derivatives 10 and 12 , intermediates in the synthesis of azaaplysinopsins.     

Reactions of 1,2,4-triazole derivatives with a “model” thiirane

Reactions of 3-mono- and 3,5-disubstituted 1,2,4-triazoles with a “model” thiirane, 8-bromo-1,3-dimethyl-7-(thiiran-2-ylmethyl)-3,7-dihydro-1H-purine-2,6-diones proceed at the positions N¹ and N² of the triazole ring and yield 7-(5-R-3-R′-1,2,4-triazol-1-yl)methyl- and/or 7-(5-R′-3-R-1,2,4-triazol-1-yl)methyl-1,3-dimethyl-6,7-dihydro[1,3]thiazolo[2,3-f]-purine-2,4-(1H,3H)-diones. 3-Methylsulfonyl-1,2,4-triazole reacted regiospecifically at the position N¹ forming 1,3-dimethyl-7-[(3-methyl-sulfonyl-1,2,4-triazole-1-yl)-methyl]-6,7-dihydro[1,3]thiazolo-[2,3-f]purine-2,4(1H,3H)-dione.     

An improved synthesis of 3,6-diamino-1,2,4,5-tetrazine. I

Treatment of 1,3-diaminoguanidine monohydrochloride ( 1 ) with 2,4-pentanedione ( 2 ) in alcohols under carefully controlled conditions gave 3,6-diamino-1,2-dihydro-1,2,4,5-tetrazine monohydrochloride ( 3 ) in 45-50% yields along with 3,5-dimethyl-1H-pyrazole ( 4 ) and its hydrochloride 5 . Oxidation of 3 with sodium perborate produced 3,6-diamino-1,2,4,5-tetrazine ( 6 ) in quantitative yield.     

Acetals and Vinyl Ethers of Unsaturated Aldehydes and Ketones in the New Syntheses of Heterocyclic Compounds: XII. New Alternatives of Acid Condensation of Cyclohexane-1,4-diones with Hydroxyarylaldehydes under Dehydration Conditions. Fluorecence Spectra of the Products

1,3-Diethoxy-2-R-5,5-R',R'-1-cyclohexenylium perchlorates in condensation with 2-hydroxyarylaldehydes under dehydration conditions give rise to 3-ethoxy-1,2-dihydroxanthylium perchlorates that with the second molecule of 2-hydroxyarylaldehyde afford 13H-chromeno[3,2-b]xanth-5-ylium perchlorates, and with primary and secondary amines yield 3-(R²,R³-amino)-1,2-dihydroxanthylium perchlorates. The condensation of 2-bromodimedone with salicylaldehydes in triethyl orthoformate and perchloric acid medium furnished 6-bromo-13,13-dimethyl-13H-chromeno[3,2-b]xanth-5-ylium perchlorates. The latter compounds show strong fluorescence in 530-630 nm region with 0.48-0.98 quantum efficiency. Under similar conditions the dimedone and 2-acetyldimedone afford with 2-hydroxyarylaldehydes tris-condensation products: 2,10-dimethoxy-6-(3-methoxy-6-oxo-2,4-cyclohexadienylidenemethyl)-7,7-dimethyl-7H-chromeno[2,3-a]-xanth-13-ylium perchlorate and 2,10-dimethoxy-6-(6-methoxychromylium-2-yl)-13,13-dimethyl-13H-chromeno[3,2-b]xanth-5-ylium diperchlorate respectively.     

Synthesis of tetronic acid enamine. Dienamine derivatives from 3-(2H)furanones

The synthesis of 5-aryl (or alkyl) aminomethylene-3-(1-amino or 1-alkylaminoethylidene)-2,4-dioxo-(3H,5H)furans and 5-arylaminomethylene-3-(1-hydroxyethylidene)-2,4-dioxo-(3H,5H)furans (new 3-acetyltetronic acid derivatives) are described. The stereochemistry of these compounds from the ¹H nmr data is discussed.     

Thiazolo[4,5-d]pyrimidines. Part I. synthesis and anti-human cytomegalovirus (HCMV) activity in vitro of certain alkyl derivatives

Alkyl derivatives of the thiazolo[4,5-d]pyrimidine congeners of guanine and uracil were prepared and assessed for in vitro activity against human cytomegalovirus (HCMV). The finding that the 3-pentyl 1b and 3-hexyl 1c derivatives of 5-aminothiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (1e) had potent in vitro anti-HCMV activity prompted a broader study of alkyl derivatives in this ring system. A series of 3-alkyl derivatives of 1e , viz. 1f-w , were prepared by direct alkylation of the sodium salt of 1e and by subsequent modifications, 2a-d. For comparison with 1c , 5-amino-2-hexylaminothiazolo[4,5-d]pyrimidin-7(6H)-one (4) was prepared and studied. The 3-(2-alkenyl) derivatives of 1e were found to be the more active antiviral agents with the Z isomer of 5-amino-3-(2-penten-1-yl)thiazolo[4,5-d]pyrimidine-2,7(3H,6H)-dione (1f) having the better therapeutic index. Analogous 4-(2-alkenyl) derivatives of 2-aminothiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione 6a and 6b were also prepared but were found to have poor therapeutic indices. Single crystal X-ray diffraction analysis was used to unequivocally establish the structure of 1f.     

α-Pyrones. II . Synthesis of tetrahydroquinoline derivatives of 4-aminobutanoic and 2-amino-2-pentenedioic acids

Ethyl 3-benzoylamino-2-oxo-6-triphenylphosphoranylidenemethyl-2H-pyran-5-carboxylate ( 1 ) reacts with 2- nitrobenzaldehydes ( 2 ) to give 6-(2-nitrostyryl)-2H-pyran-2-ones ( 3 ), as the E stereoisomers, in good yields. The reduction of compounds 3 , performed with hydrogen over Pd/C at room temperature and 1 atmosphere, leads to a mixture of 2-amino-4-tetrahydroquinolinylidene-2-pentenedioic acid derivatives 5a-d as the main products, the corresponding 3-butenoic acid derivatives 6 and a minor amount of pyrano[2,3-c]benzazocines 9a-c. At 40 atmospheres and 90°, the reduction gives 4-amino-2-tetrahydroquinolinylbutanoic acid derivatives 8a-d as the main products and their precursors 7a,b,d as the minor ones. Amines 4c,d are isolated by stopping the reduction after the uptake of 3 equivalents of hydrogen.     

Pyrimidines. 65. Synthesis of 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones

Several 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives were synthesized. 6-Ethoxycarbonyl derivatives 3 and 7 were prepared by treatment of 6-chloro-5-formyluracil 1 and 6-chloro-5-cyanouracil 6 with ethyl 2-mercaptoacetate in the presence of a base. Electrophilic substitution reactions (Vilsmeier-Haack reaction, bromination, and nitration) of 5,6-unsubstituted thieno[2,3-d]pyrimidine 9 , prepared by condensation of 6-mercaptouracil 8 with chloroacetaldehyde, afforded the corresponding 6-formyl-, 6-bromo-, and 6-nitrothieno[2,3-d]pyrimidines 10, 15 and 16 , respectively.     

Substituted pyrimidines. II. 1,3-Dimethylisocytosine and related compounds

1,3-Dimethyl-1,2-dihydro-2-imino-4(3H)pyrimidinone (1,3-dimethylisocytosine) was prepared by methylation of 2-amino-3-methyl-4(3H)pyrimidinone and was degraded in alkaline solution to a mixture of 3-methyl-2-methylamino-4(3H)pyrimidinone, 1,3-dimethyl-2,4-(1H,3H)pyrimid-indione, 2-methylamino-l-methyl-4(1H)pyrimidinone, 1-methyl-2,4-(1H,3H)pyrimidindione and 3-methyl-2,4-(1H,3H)pyrimidindione. Thiation of the title compound gave both 1,2-dihydro-1,3-dimethyl-2-thio-4(3H)pyrimidinone and 1,3-dimethyl-2,4-(1H,3H)pyrimidinedithione. The title compound is a tautomerically fixed pyrimidine and its uv spectra were compared with related compounds, notably 3-methyl-2-dimethylarnino-4(3H)pyrimidinone which is also tautomerically fixed.