A Useful Methodology for the Regioselective Deprotection of 1,3-Dibenzyluracils

A practical, regioselective N-1 deprotection of 1,3-dibenzyl uracils 2 a-e is described. The same experimental procedure and longer reaction time afforded the complete deprotection of the uracils.     

Mass spectra of substituted uracils

The mechanisms for the major fragmentations obtained with selected substituted uracils are discussed. Interpretation of data was facilitated by use of metastable peaks, high-resolution data, and low-voltage spectra. The major fragmentation obtained with N-alkyl substituted uracils, when the alkyl group contains 2 or more carbons, is due to cleavage of the alkyl substituent. This cleavage is accompanied by a rearrangement of 1 or 2 hydrogens from the alkyl group to the uracil ring. Possible mechanisms for the rearrangements are discussed. It was found that the molecular ion of 1- and 3-alkyl substituted uracils (where the alkyl group has 2 or more carbons) does not undergo the expected ‘retro Diels-Alder Reaction’. Instead, the odd-electron ion formed by loss of the alkyl substituent with a single hydrogen rearrangement undergoes this reaction (loses HNCO). Since it is formed as a secondary reaction product, the relative abundance of the ‘retro Diels-Alder’ fragment is low compared to what is obtained in the spectra of the simple uracils. The ‘retro Diels-Alder Reaction’ can be used to differentiate between 2- and 4-thiouracils, and between 1- and 3-methyl and phenyl substituted uracils. It was found that 1- and 3-alkyl substituted uracils (alkyl group of 2 or more carbons) can be differentiated by the mass of the M-alkyl fragment since the 3-substituted compounds give predominantly a double hydrogen rearrangement and the 1-substituted compound gives mainly a single hydrogen rearrangement. In addition the intensity of the molecular ion, relative to the M-alkyl ion, is considerably stronger in the 1-substituted uracils.     

Spectrophotometric study of influences on the direct ferric perchlorate method for the determination of serum cholesterol

A spectrophotometric study of several influences on a direct colorimetric determination of serum cholesterol has been described. Interferences of in vitro and in vivo types were considered, and it was found that certain compounds such as bromide, uracils, and bilirubin could exert both positive and negative interfering influences on the reaction of ferric perchlorate with cholesterol in an ethyl acetate-ethanol-sulfuric acid medium. Some interferences such as bilirubin are noncompeting side reactions which are absolute in their interference capabilities, while others such as the uracils and bromide have an entirely different influence. In the latter circumstance, the fine structures of spectra are altered by a nonadditive phenomenon of the reactant and hyperchromic (bromide), and hypochromic (uracils) effects take place which appear to result in relative rather than absolute errors.     

Photochemical behaviour of 5-formyl and 5-acetyl uracils in the presence of ethene

Atypically for uracils, 5-formyl and 5-acetyl uracils react photochemically with excess ethene to produce non-acylated cyclobutane adducts whose formation can be explained by a novel, tandem [2+2] cycloaddition/Norrish-I α-cleavage process.     

Novel 6-(trifiuoromethyl)cytosines and 6-(trifluoromethyl)uracils

Ethyl 3-amino-4,4,4-trifluorocrotonate ( 3 ) has been converted by a one step reaction with alkyl and aryl isocyanates to novel 3-substituted-6-(trifluoromethyI)uracils. Also several 3-amino-4,4,4-trifluorocrotonitriles ( 11a-c ) have been cyclized to novel 6-(trifluoromethyI)cytosines ( 13a-c ) and then hydrolyzed to the corresponding uracils ( 4, 14b-c ). Alkylation studies with isopropyl bromide of three 6-(trifluoromethyl)uracils ( 1, 4, 5 ) are described.     

Synthesis of functionalized 5-(3-R-1-adamantyl)uracils and related compounds

Efficient synthetic approaches to functionalized 5-(3-R-1-adamantyl)uracils and related compounds (R=OH, COOH, NH₂, etc.) are described. The selective hydroxylation of the adamantane tertiary C-H bonds in 5-(1-adamantyl)uracils with H₂SO₄ in trifluoroacetic anhydride is used as the key step. Subsequent electrophilic reactions of 5-(3-hydroxy-1-adamantyl)uracils with N- and C-nucleophiles in CF₃COOH, H₂SO₄ or H₂SO₄/AcOH media yielded derivatives with amide, amino, aryl, carboxy and thiourea groups in the adamantane core. The preliminary evaluation of the antiviral activity revealed that some of the synthesized species display moderate antiviral activity against HSV-1 (SI∼20) in Vero cells.     

Practical and sustainable approach for clean preparation of 5-organylselanyl uracils

An eco-friendly,sustainable and practical method for the efficient preparation of 5-organylselanyl uracils through the electrochemical selenylation of uracils and dio rganyl diselenides at room temperature under oxidant-and external electrolvte-free conditions was developed.     

Synthesis and reactivity of acyclic and macrocyclic uracils bridged with five-membered heterocycles

Replacement of terminal atoms of Br in 1,3-bis(bromopentyl)-5(6)-substituted uracils with 2-mercapto-5-methyl-1,3,4-thiadiazole, 2,5-dimercapto-1,3,4-thiadiazole, 2-mercaptoimidazole, and 2-mercaptobenzimidazoles resulted in a series of acyclic compounds and isomeric heterocyclophanes. Structures of macrocyclic regioisomers were unambiguously determined by NMR data. One of the regioisomers exhibits a hypochromic effect with respect to model compounds. The acyclic uracils obtained bridged with five-membered heterocycles are alkylated with methyliodide and methyl tosylate, and oxidated with m-CPBA, H₂O₂, and I₂.     

A convenient synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-diones

The synthesis of 5-heteroaryl-substituted uracil derivatives is presented. The 1,3-dipolar cycloaddition reaction was applied for the construction of a heterocyclic ring. The nitrile oxides were obtained from the appropriate 4-substituted benzaldoximes using N-chlorosuccinimide (NCS) under basic conditions. [2+3] Cycloaddition of nitrile oxides with 5-cyanouracil as a dipolarophile gave the corresponding 5-(3-substituited-1,2,4-oxadiazol-5-yl)uracils in satisfactory yields under mild conditions. 5-Substituted uracils having an additional heterocyclic ring were obtained as a result of the [2+3] cycloaddition of 5-cyanouracil to nitrile oxides generated from thiophene-2-carbaldehyde and 5-formyluracil derivatives.     

A silicon-mediated synthesis of novel 5-substituted 2,4-dimethoxypyrimidines and 5-substituted uracils

A highly efficient and general method for the synthesis of 5-(2-acylethynyl)-2,4-dimethoxypyrimidines starting from 2,4-dimethoxy-5-/2-(trimethylsilyl)ethynyl/pyrimidine is described. The 5-(2-acylethynyl)-2,4-dimechoxypyrimidines have been converted to 5-(2-acyl-1-iodovinyl) uracils and 5-(2-acylethynyl) uracils.     

A versatile synthesis of fluorinated uracils in solution and on solid-phase

[reaction: see text] An efficient and convenient two-step synthesis of new fluorinated uracils is described. The first step involves the condensation of an ester enolate with a fluorinated nitrile to furnish fluorinated beta-enamino esters. In turn, these compounds react with organic isocyanates or isothiocyanates to give C-6 fluorinated uracils or thiouracils, respectively, in excellent yields. This synthesis has been successfully adapted to solid-phase conditions with high diversity, thereby facilitating the creation of small (thio)uracil libraries.     

Solid-phase synthesis (SPS) of substituted uracils via Oxone® cleavage methodology

An original and highly efficient Oxone® cleavage methodology for the solid-phase synthesis of substituted uracils has been developed. An example of application of this methodology to the solid-phase synthesis of uridine derivatives is also reported.     

Analogs of pyrimidine nucleosides

A new method was developed for the synthesis of 1-(2-tetrahydrofuryl) derivatives of uracil, 5-substituted uracils, 6-azauracil, and cytosine by alkylation of 2,4-bis(trimethylsilyl) derivatives of pyrimidine bases with 2-acetoxytetrahydrofuran in the presence of Lewis acids. In contrast to 2-chlorotetrahydrofuran, which is used in a previously described method, 2-acetoxytetrahydrofuran is stable at room temperature and reacts under these conditions with silyl derivatives of uracils in the presence of SnCl₄ to give 1-(2-tetrahydrofuryl) derivatives of pyrimidine bases in 80–85% yields.See [1] for communication X.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedineaii, No. 9, pp. 1258–1259. September, 1977.     

A Convenient Route for the Synthesis of 4-Aryl- and 4-Aminopyrimidines

Summary. A series of ureidopropenenitriles were synthesised by Knoevenagel condensation of ArCOCH₂CN and HC(OEt)₃ in presence of ureas in a one pot reaction. These ureidopropenenitriles were cyclised to 4-aryl-5-cyano-3-substituted pyrimidines (in acid) or to 4-amino-5-benzoylpyrimidines (in base) in 60–70% yields. The amine pyrimidine derivatives were further converted to substituted uracils by hydrolysis with isopentyl nitrite in DMF. Alkylation of uracils furnished 1,3-dimethyluracil derivatives with DMS in alkali. All new compounds were characterised by spectral and analytical methods.     

Intramolecular hetero-Diels-Alder reaction of 1-oxa-1,3-butadienes with terminal acetylenes in aqueous media using CuI

A new method for the preparation of tetracyclic uracils (oxa-helicene) 4 was developed. The intramolecular hetero-Diels-Alder reaction of 1-oxa-1,3-butadiene 3 and an unactivated alkyne in the presence of CuI led to tetracyclic uracils 4 in aqueous media with good yields. The 1-oxa-1,3-butadiene 3 was prepared through Knoevenagel reaction of O-propargylated salicylaldehyde derivatives and barbituric acid or 1,3-dimethylbarbituric acid.     

Investigation of azoles and azines. 76. Mass spectra of 5- and 6-substituted uracils

Peaks of molecular ions that generally have the maximum intensity are observed in the mass spectra of most of the investigated 5- and 6-substituted uracils and 5-substituted orotic acids and their deutero analogs and methylated derivatives. The principal pathway of the fragmentation of the molecular ions is retrodiene fragmentation with the formation of [O=C₍₄₎C₍₅₎R⁵C₍₆₎R₍₆₎N₍₁₎R¹]⁺ (F₁) ions. The stabilities of the latter depend on the nature and position of the substituents attached to the C₍₅₎ and C₍₆₎ atoms. The fragmentation of the F₁ ions can be realized via four principal pathways (B-E) with the detachment of N-CR⁶ (B), O=C=CR⁵ (C), CO (D), and R⁶ (E) fragments. The most general pathway for the fragmentation of 5-substituted uracils is pathway C, whereas the most general pathway for 6-substituted uracils is pathway E. In the spectra of 5-substituted orotic acids the intensities of the molecular-ion peaks are high (100%) only in the case of electron-donor R⁵ and decrease sharply with an increase in the electron-acceptor strength of the substituent. The principal pathways of fragmentation of the molecular ions are decarboxylation (F) and retrodiene fragmentation (A), the contribution of which is appreciably smaller. The M-CO₂ ions formed after decarboxylation undergo fragmentation via a scheme similar to that observed for 5-substituted uracils.See [1] for Communication 75.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 520–531, April, 1990.     

Analogs of pyrimidine nucleosides. 17. Synthesis of 1-[5(2)-fluoromethyltetrahydro-2-furyl]uracils

The synthesis of 2-fluoromethyltetrahydrofuran is described, and it is shown that chlorination of the latter gives 2-chloro-5- and 2-chloro-2-fluoromethyltetrahydrofurans in a ratio of 5:1. 2,4-Bis(trimethylsilyl) derivatives of uracil were alkylated by means of the mixture of -chloro ethers without separation, and a mixture of the cis and trans isomers of 1-(5-fluoromethyltetrahydro-2-furyl)uracils and 1-(2-fluoromethyltetrahydro-2-furyl)uracils were obtained. The reaction products were identified on the basis of the PMR spectra.See [1] for communication 16.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 256–259, February, 1982.     

A Convenient Route for the Synthesis of 4-Aryl- and 4-Aminopyrimidines

A series of ureidopropenenitriles were synthesised by Knoevenagel condensation of ArCOCH₂CN and HC(OEt)₃ in presence of ureas in a one pot reaction. These ureidopropenenitriles were cyclised to 4-aryl-5-cyano-3-substituted pyrimidines (in acid) or to 4-amino-5-benzoylpyrimidines (in base) in 60–70% yields. The amine pyrimidine derivatives were further converted to substituted uracils by hydrolysis with isopentyl nitrite in DMF. Alkylation of uracils furnished 1,3-dimethyluracil derivatives with DMS in alkali. All new compounds were characterised by spectral and analytical methods.     

Synthesis and anti-HIV-1 activity of 1,5-dialkyl-6-(arylselenenyl)uracils and -2-thiouracils

The 1,5-dialkyl-6-(arylselenenyl)uracils 10a-h and -2-thiouracils 10i-p have been synthesized as potential anti-HIV-1 agents. Cyclization of N-alkyl-N'-[3,3-di(methylthio)-2-alkylacryloyl]ureas 6a-d and -thioureas 6e-h in acetic acid either containing a catalytic amount of methanesulfonic acid at 80°or containing 1 equivalent of methanesulfonic acid at room temperature afforded 1,5-dialkyl-6-(methylthio)uracils 7a-d in 84–96% yields and 1,5-dialkyl-5,6-dihydro-6,6-di(methylthio)-2-thiouracils 11a-d in 88–99% yields, respectively. Oxidation of 7a-d and 11a-d with either 3-chloroperoxybenzoic acid in benzene or aqueous sodium periodate solution in methanol gave 1,5-dialkyl-6-(methylsulfonyl)uracils 8a-d in 88–98% yields and 1,5-dialkyl-6-(methylsulfinyl)-2-thiouracils 12a-d in 57–73% yields, respectively, which were subsequently treated with arylselenol 9a-b in ethanolic sodium hydroxide solution to afford 10a-p in 6099% yields. Of these compounds, 6-[(3,5-dimethylphenyl)selenenyl]-5-isopropyl-1-(3-phenylpropyl)uracil ( 10h ) inhibited HIV-1 replication in MT-4 cells at a 50% effective concentration (EC₅₀) of 0.0006 μM with a selective index of 44833, which is 7.7-fold more potent than AZT.