Pyridine nucleosides related to 5-fluorouracil

5-Fluoro-2-methoxypyridine ( 3 ) synthesized from 5-amino-2-methoxypyridine was converted to 4-benzyloxy-5-fluoro-2-methoxypyridine ( 12 ) and 2,4-dimethoxy-5-fluoropyridine ( 13 ) by a four step procedure employing the intermediate 5-fluoro-2-methoxy-4-nitropyridine N-oxide (7). Condensation of 3 , 12 , and 13 with 2,3,5-tri-O-benzoyl-D -ribofuranosyl bromide gave, after removal of the protecting groups, 4-deoxy-5-fluoro-3-deazauridine (20), 5-fluoro-3-deazauridine (23) and 5-fluoro-4-methoxy-3-deazauridine (25). Several alkylated and dealkylated derivatives of 3 and 12 were also prepared. Structure proof and anomeric configuration were determined from the uv, nmr, and CD data.     

Pyridine nucleosides related to 5-fluorocytosine

4-Amino-5-fluoro-2-pyridone ( 4 ) [5-fluoro-3-deazacytosine] was isolated as the hydrochloride salt from the dealkylation of 4-amino-5-fluoro-2-methoxypyridine ( 2 ), which was obtained from the reduction of 5-fluoro-2-methoxy-4-nitropyridine-N-oxide ( 1 ). Acetylation of 2 gave 4-acetamido-5-fluoro-2-methoxypyridine ( 3 ), which was condensed with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide to give the blocked nucleoside ( 8 ). Removal of the protecting groups gave 5-fluoro-3-deazacytidine. Fusion of the trimethylsilyl derivative of 4 (10), with 2-deoxy-3,5-di-O-p-toluoyl-D-erythro pentofuranosyl chloride gave a mixture of the β and α-anomers 12 and 13 , which were separated and deblocked to yield 5-fluoro-2′-deoxy-3-deazacytidine ( 14 ) and its α-anomer ( 15 ). Several alkylated and acetylated derivatives of 2 were prepared as model compounds for use in the proof of structure.     

The Reaction of N-Oxide with Ethyl Bromoacetate

The reaction of 4-methoxypyridine 1-oxide with ethyl bromoacetate was found to produce a high yield of ethyl glyoxylate, trimethylamine N-oxide and pyridine 1-oxide also afforded the glyoxylate but in lower yield in the reaction, and 4-nitropyridine 1-oxide was found to be inactive with bromoacetate. Pyridine 1-oxide and trimethylamine N-oxide exhibit the same stoichiometry, while 4-methoxypyridine 1-oxide follows a different course.     

Nitration of some 3,5-disubstituted pyridine N-oxides

The preparation of 3-chloro-5-methoxypyridine N-oxide and its nitration are reported. Mononitration yields 5-chloro-3-methoxy-2-nitro-pyridine N-oxide while more drastic conditions give 3-chloro-5-methoxy-2,6-dinitropyridine. Removal of various substituents by base hydrolysis is also discussed.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

A novel hydrogen-bonding N-oxide–sulfonamide–nitro N—H…O synthon determining the architecture of benzenesulfonamide cocrystals

The structures of novel cocrystals of 4-nitropyridine N-oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C₅H₄N₂O₃·C₆H₆N₂O₄S, and 4-chlorobenzenesulfonamide–4-nitropyridine N-oxide (1/1), C₆H₆ClNO₂S·C₅H₄N₂O₃, are stabilized by N—H…O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N-oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N-oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N—H…O(N-oxide) and N—H…O(nitro) bridges. We present here a more detailed analysis of the N-oxide–sulfonamide–nitro N—H…O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N-oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.     

Thermochemical study of the trans- and cis-isomeric forms of 4-(4-methoxystyryl)pyridine N-oxide

The trans and cis form of 4-(4-methoxystyryl)pyridine N-oxide were studied. The spectral characteristics of cis-4-(4-methoxystyryl)pyridine N-oxide were determined in acetonitrile. The melting and thermal decomposition processes of the trans and cisforms of 4-(4-methoxystyryl)pyridine N-oxide were studied by thermochemical methods. It was establish that the thermal decomposition of 4-(4-methoxystyryl)pyridine N-oxide begins with the cleavage of the bond between the pyridine and benzene rings.

     

Nitration of 5,6,7,8-tetrahydro-5,8-methanoisoquinoline N-oxide with other aromatic substitutions. Isolation and mutagenicity of an α-nitropyridine N-oxide

Treatment of 5,6,7,8-tetrahydro-5,8-methanoisoquinoline N-oxide ( 2 ) with fuming nitric acid afforded 3-nitro-5,6,7,8-tetrahydro-5,8-methanoisoquinoline N-oxide ( 3 ), an example of formation of an α-nitropyridine N-oxide derivative by nitration of N-oxides. Further reaction of 3 resulted in deoxygenation giving 3-nitro-5,6,7,8-tetrahydro-5,8-methanoisoquinoline ( 4 ). No aromatic nitration was observed by similar treatment of 5,6,7,8-tetrahydro-5,8-methanoisoquinoline ( 1 ) or 5,6,7,8-tetrahydroisoquinoline N-oxide ( 11 ). Some other aromatic substitutions with 1 and 2 were caried out to obtain mainly the 3-substituted derivatives. Significant mutagenicity of 3 is briefly reported.     

Synthesis of mesoionic triazolo[4,3-a]quinoxalines

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 1 or 6-chloro-2-(1-methylhydrazino)-quinoxaline 5 with phenyl isothiocyanate under reflux in N,N-dimethylformamide gave 7-chloro-3-methyl-1,2,4-triazolo[4,3-a]quinoxalin-3-ium-1-thioate 4 , which was also obtained by refluxing of 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 2b or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 6 in N,N-dimethylformamide.     

Heterocyclic synthesis with N-oxides. Preparation of pyridine n-oxide substituted chromones,chromanones, coumarins,quinolones, dihydroquinolones and cinnolones

The synthesis of pyridine N-oxide substituted chromones, chromanones, coumarins, quinolines, dihydroquinolines and cinnolines from l-(2-hydroxyphenyl)-2-(2-pyridinyl)ethanone N-oxide, 1-(2-aminophenyl)-2-(2-pyridinyl)ethanone N-oxide and 1-[2-(methylamino)phenyl]-2-(2-pyri-dinyl)ethanone N-oxide is described.     

Polycyclic N-hetero compounds. XXII Reaction of pyridine N-oxides and Pyrazine di-N-oxides with formamide

Reactions of pyridine N-oxides, pyrazine di-N-oxides, and their benzologues with formamide are described. Carbamoylation mainly occurred at aromatic ring with loss of the N-oxide oxygen atom, however, 2,4,6-trimethylpyridine 1-oxide gave 2- and 4-pyrimidinyl derivatives.     

Reactions of phenylenedioxytrihalophosphoranes with arylacetylenes: VII. Reaction of 2,2,2-trichloro-4-fluoro-1,3,2λ<Superscript>5</Superscript>-benzodioxaphosphole with phenylacetylene

2,2,2-Trichloro-4-fluoro-1,3,2⁵-benzodioxaphosphole reacts with phenylacetylene to give 2,7-dichloro-5-fluoro-4-phenyl-2H-1,2⁵-benzoxaphosphinine 2-oxide. Hydrolysis of the latter leads to opening of the oxaphosphinine ring with formation of (E)-2-(4-chloro-2-fluoro-6-hydroxyphenyl)-2-phenylethenylphosphonic acid.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 12, 2004, pp. 1846–1851.Original Russian Text Copyright © 2004 by Mironov, Shtyrlina, Varaksina, Efremov, Konovalov.     

Reactions of N,N'-Dimethyl-N,N'-bis(trimethylsilyl)methylphosphonic Diamide with Chloral and Chloromethyldimethylchlorosilane

N,N'-Dimethyl-N,N'-bis(trimethylsilyl)methylphosphonic diamide reacts with chloral to form 1,2,3-trimethyl-4,4-dichloro-5-trimethylsiloxy-1,3,2-diazaphospholidine 2-oxide and with chloromethyldi- methylchlorosilane to form 1,2,3,4,4-pentamethyl-1,3-diaza-2-phospha-4-silacyclopentane 2-oxide.     

Reactions of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with nucleophiles

Reactions of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with aliphatic amines and sodium hydroxide resulted in removal of one N-oxide oxygen atom and formation of 4-alkylamino- or 4-hydroxy-substituted 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1-oxides, respectively. The title compound reacted with ammonia and methylamine in the presence of MnO₂ with conservation of both N-oxide moieties, and the products were 4-amino- and 4-methylamino-5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxides. The reactions with aromatic amines were accompanied by removal of both N-oxide oxygen atoms with formation of N-aryl-5-nitrospiro[benzimidazole-2,1′-cyclohexane]-4-amines. In the reactions of 5-nitrospiro-[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with sodium azide and aromatic amine hydrochlorides nucleophilic replacement of the 5-nitro group by azido or arylamino occurred, in the first case both N-oxide fragments being conserved. The reactions with aromatic amine hydrochlorides afforded N-aryl-5-nitrospiro[benzimidazole-2,1′-cyclohexan]-4-amine 1-oxides. Treatment of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with sodium cyanide led to the formation of 5-oxo-3,5-dihydrospiro[benzimidazole-2,1′-cyclohexane]-4-carbonitrile 1-oxide.     

Cobalt(II) complexes of the 2-aminopicolineN-oxides and 2-amino-4, 6-lutidineN-oxide

Summary Cobalt(II) complexes of the four 2-aminopicolineN-oxides and 2-amino-4, 6-lutidineN-oxide were prepared from Co(BF₄)₂ and CoCl₂, and characterized by partial elemental analyses, magnetic moments, molar conductivities, thermal analyses, and by plasma desorption mass, i.r., electronic, and e.s.r. spectroscopy. The compounds derived from CoCl₂ are 4-coordinate, tetrahedral, molecular solids with CoO₂Cl₂ chromophores. Dq values range from 332 to 382 cm^–1 and those of B from 758 to 813 cm^–1 for the five solids. Three of the compounds prepared from Co(BF₄)₂ are octahedral with the following stoichiometry: [CoL₆](BF₄)₂ where L=2-amino-4-picolineN-oxide and [CoL₅(H₂O)] (BF₄)₂ where L is either 2-amino-3-or 2-amino-5-picolineN-oxide. Both 2-amino-6-picolineN-oxide and 2-amino-4, 6-lutidineN-oxide gave square planar [CoL ₄ ²⁺ ] complex ions. While numerous square planar cobalt(II) centers are known, those described here are probably the first examples with monodentate ligands and a CoO₄ center. They have weak e.s.r. spectra, magnetic moments between 2 and 3 BM and characteristic d-d spectra.     

The synthesis of a potential anti-cancer agent containing the caffeine and 1,2,4-benzotriazine moieties

The potential anti-cancer agent 6 has been synthesised from 4-(4-chlorobutoxy)-2-nitroaniline, 15b by the conversion of the nitroaniline to the benzotriazine N-oxide 16 . Theophylline has been reacted with 16 to give the N-oxide 9 and this has been oxidised to the required N,N'-dioxide, 6 . The compound 6 has been found to be ineffective as a radiosensitizer.     

Thermooxidative decomposition of heterocyclic <Emphasis Type="Italic">N</Emphasis>-oxides

Thermooxidative decomposition of pyridine N-oxide, 4-(4-dimethylaminostyryl)pyridine N-oxide, 4-(4-methoxystyryl)pyridine N-oxide, quinoline N-oxide, 2-methylquinoline N-oxide, 4-chloroquinoline N-oxide, 2-styrylquinoline N-oxide, and 2-(4-dimethylaminostyryl)quinoline N-oxide was studied. The kinetic parameters of the thermooxidative processes were calculated according to three independent procedures. The relation between the nature of heterocyclic N-oxide and its stability to thermal oxidation was analyzed.     

Interaction of cellulose with amine oxide solvents

Cellulose I, mainly as ramie or as Avicel microcrystalline cellulose, has been monitored by optical microscopy and by ¹³C CPMAS NMR, over the course of its dissolution in hot N-methylmorpholine N-oxide solvent. Its interaction with the near-solvent N-ethylmorpholine N-oxide and related non-solvents has also been investigated. NMR shows that N-methylmorpholine N-oxide partly converts crystalline cellulose I into amorphous solid cellulose. The changes in chemical shift imply increased flexibility at the glycosidic bonds. In contrast, N-ethylmorpholine N-oxide converts cellulose I to cellulose III_I, without dissolution. Microscopy shows that the ramie fibres swell laterally, and at least some also shorten longitudinally, during dissolution. Model studies using methyl--d-glucopyranose show no evidence from ¹³C chemical shifts for different modes of binding with different solvents. However, N-methylmorpholine N-oxide binds more strongly to methyl--d-glucopyranose in DMSO than does N-ethylmorpholine N-oxide, whereas N-ethylmorpholine N-oxide binds better to H₂O. Also, ¹³C T ₁ values for aqueous cellobioside show increasing rotational freedom of the –CH₂OH sidechains as N-methylmorpholine N-oxide is added. Together, these observations imply the initial penetration of solvents and near-solvents between the molecular cellulose sheets. Subsequently, N-methylmorpholine N-oxide breaks H-bonds, particularly to O-6, just sufficiently to loosen individual chains and then dissolve the sheets.     

S<Stack><Subscript>N</Subscript><Superscript>H</Superscript></Stack> Reaction of lithiated nitronyl nitroxide with quinoline <Emphasis Type="Italic">N</Emphasis>-oxide

The S_N^H reaction of lithiated 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-1-oxyl 3-oxide with quinoline N-oxide affords 4,4,5,5-tetramethyl-2-(1-oxidoquinolin-2-yl)-4,5-dihydro-1H-imidazole-1-oxyl 3-oxide.     

Pyrrolizidine alkaloids from Solenanthus lanatus DC. with acetylcholinesterase inhibitory activity

The whole plant ethanolic extract of Solenanthus lanatus was used for the isolation of acetylcholinesterase inhibitors. A new pyrrolizidine alkaloid, 7-O-angeloylechinatine N-oxide, 1, was isolated together with three known compounds of the same class (3′-O-acetylheliosupine N-oxide, 2, heliosupine N-oxide, 3, and heliosupine, 4), by bioassay-guided approach. Their structures were elucidated by spectroscopic methods. All the isolated compounds showed inhibition activity against the AChE, with IC₅₀ 0.53–0.60 mM.