An efficient synthesis of new fluorinated uracil derivatives

A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields.     

New acetenyl acyclic nucleosides synthesis of 1-(propargyloxymethyl) derivatives of uracil

Alkylation of trimethylsilyl derivatives of uracil, thymine, 5-fluorouracil, and 6-methyluracil with propargyloxymethyl chloride afforded the corresponding 1-(propargyloxymethyl) derivatives, new unsaturated acyclic nucleosides having an end carbon-carbon triple bond.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 797–799, June, 1993.     

A convenient, high-yield synthesis of 1-substituted uracil and thymine derivatives

Novel reagents for the synthesis of 1-substituted uracil and thymine derivatives have been developed. The aminolysis of 2- or 4-nitrophenyl 3-ethoxyacryloylcarbamate and 3-ethoxy-2-methylacryloylcarbamate with a variety of primary amino derivatives proceeded smoothly under very mild reaction conditions yielding almost quantitatively the 1,3-disubstituted urea derivatives. Their subsequent cyclization provided the 1-substituted uracil and thymine compounds, in almost quantitative yield.     

Regioselective synthesis of 1-allyl- and 1-arylmethyl uracil and thymine derivatives

2,4-Bis(trimethylsiloxy) pyrimidines 1 with allyl halides and arylmethyl halides in 1,2-dichloroethane in the presence of I₂ regioselectively provide 1-allyl-/1-arylmethyl-uracil and thymine derivatives. The secondary aryl alkyl and diaryl methyl halides with 1 provide chiral 1-arylalkyl/1-(diarylmethyl) uracil/thymine derivatives. The procedure has been extended to the synthesis of fluorescent uracil/thymine derivatives.     

Macrocyclic 5-bromouracil derivatives: synthesis and transformation of a uracil ring

Cyclization of 1,3-bis(ω-bromoalkyl)-5-bromouracil with p-methoxybenzylamine or sodium sulfide led to a series of pyrimidinophanes containing heteroatoms in bridges. An unusual behaviour of the 5-bromouracil ring, namely its contraction into hydantoin units during the cyclization reactions with p-methoxybenzylamine was observed. Sodium sulfide does not affect the 5-bromouracil ring, and no transformation products were observed in the synthesis of pyrimidinophanes with sulfur bridges. A possible reaction mechanism is given.     

Antioxidant activity of uracil derivatives

The antiradical properties of a number of uracil derivatives are studied in initiated 1,4-dioxane oxidation as a model reaction. The antioxidant activity of the uracil derivatives as inhibitors is estimated. The antiradical activity of the compounds is quantitatively characterized in terms of the effective rate constant of inhibition, fk _In.     

Polarographic study of uracil derivatives

Eighteen uracil derivatives were studied by d.c. polarography, differential-pulse (d.p.)polarography and d.p. cathodic stripping voltammetry. In a borax buffer at ca. pH 7.6, uracil, thymine and derivatives such as 5-halouracils, 5-trifluoromethyl-,5-aza-,5-acetyl-, 5-formyl- and 5-vinyl-uracil produced well-defined peaks at potentials between 0 V and ca. 160 mV vs. silver/ silver chloride (satd. KCl). The peaks are ascribed to the formation of sparingly soluble mercury salts. For the other derivatives tested (e.g., 5-nitro- and 5-ethynyl-uracil and 6-substituted uracils), the peaks were less well-defined and in some cases the polarographic curves were very complex. 2-Thiouracil produced a single peak at ca. ?400 mV, but only at pH 12.2. The shapes, heights and potentials of the peaks depended on the kind and position of the substituent on the pyrimidine ring. Rectilinear relationships of peak current vs. concentrations were found for most compounds (10^?5-10^?4 M) by d.p. polarography; d.c.polarography was not tested quantitatively. For 5-fluorouracil and 5-vinyluracil, linear calibrations were found for concentrations of 0.5–5 × 10^?7 M by d.p. cathodic stripping voltametry. Interference studies showed that small amounts of chloride and phosphate did not interfere but 5-fluorodeoxyuridine, which did not itself produce a peak, and proteins interfered seriously.     

Reactivity of nucleophilic uracil derivatives

The reactivity of uracil derivatives bearing acidic methylene groups at N1 was investigated. On treatment with strong base, compounds with nitrile as the activating group underwent extensive dimerisation to give new tricyclic systems. Ester-activated compounds also produced dimers in the absence of an external electrophile, but their monomeric carbanions could be trapped by prompt addition of benzyl bromide to give normally alkylated products.     

Desulfurizative stannylation of uracil derivatives

Phenylthio group in the C-6 or C-5 position of uracil moiety can be removed by radical mediated stannylation with tributyltin hydride followed by protonolysis, providing a new route to 5-substituted uridines.     

Electrophilic ipso-substitution in uracil derivatives

Treatment of 5-iodo-1,3,6-trimethyluracil with 50% H₂SO₄ gives 1,3,6-trimethyluracil; with 5-bromo-1,3,6-trimethyluracil, a mixture of 1,3,6-trimethyluracil and 6-bromomethyl-1,3-dimethyluracil is obtained. 5-Chloro-1,3,6-trimethyluracil remains inert under these conditions. According to the DFT modeling of the reactions of 5-halo-1,3,6-trimethyluracils, a nucleophilic agent can abstract either Hal⁺ or the methyl proton from the carbocation formed by protonation of the starting halouracil at position 5, which accounts for the formation of two products from the 5-bromo derivative. Under similar conditions, 6-methyluracil dibromohydrin yields N-bromo-5-bromo-6-hydroxymethyluracil. Bromination or chlorination of 5-hydroxymethyl- or 5-formyl-6-methyluracils follows the ipso-substitution scheme leading to 6-methyluracil 5-halo- and 5,5-dihalohydrins.     

Synthesis of uracil derivatives by oxidation of Fischer tungsten-carbene uracil complexes

A study on the oxidation of Fischer tungsten-carbene uracil complexes has been carried out. Several commonly used oxidants gave results strongly influenced by the presence of substituent on nitrogen atoms. In particular, usual oxidants failed in the oxidation of 3-alkyl uracil carbene complexes. Finally, we showed that t-butyl hydroperoxide is able to oxidize successfully also 3-alkyl uracil carbene complexes and can be used as a good alternative to the other methods.     

Hydrothermal deamidation of 4-N-acylcytosine nucleoside derivatives: efficient synthesis of uracil nucleoside esters

[reaction: see text] N,O-Peracylated cytidine and 2'-deoxycytidine derivatives in superheated water/DME solutions (oil bath at 125 degrees C) undergo hydrolytic deamidation (and/or N-deacylation). Acylated starting materials derived from arylcarboxylic acids give the corresponding uridine esters cleanly, and such derivatives crystallize selectively from the cooled reaction mixtures in high yields.     

Resonance electron capture by uracil derivatives

The enol forms of uracil and its derivatives were detected in the gas phase by mass spectrometry. The [M - H]⁻ ion is produced by resonance electron capture to the lowest unoccupied molecular orbitals, the process being accompanied by the detachment of the hydrogen atom from the nitrogen atom of the diketo form (low-energy peak at 0.8 eV) and from the oxygen atom of the enol form (in the energy region of 1.4 eV). The gas phase contains ∼10⁻³% of the enol form. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1360–1362, June, 2005.     

New synthesis of 3-fluoropyridine derivatives

The reaction of 2,2-bis(dimethylamino)-3,3-difluoro-1-methylcyclobutane-carbonitrile with alkyl lithiums leads to the formation of 6-alkyl-2-(dimethylamino)-3-fluoro-5-methylpyridines in moderate to good yields.