Lp...π Interactions involving π-systems with different degrees of electron density delocalization: uracil and isocyanurate

A comparative analysis of non-covalent interactions in the crystals of uracil and isocyanurate derivatives was performed. Most of interactions involving the uracil moiety are formed via π...π-type overlap, but Lp...π-type interactions also occur in some crystals. A comparison of the lone pair—π-system interactions showed that the energy of these interactions in uracil derivatives is lower than that in isocyanurate derivatives, which is attributed to a lower positive charge on the uracil moiety.     

PHOTOCHEMICAL COUPLING OF 5-BROMOURACIL TO TRYPTOPHAN, TYROSINE AND HISTIDINE, PEPTIDE-LIKE DERIVATIVES IN AQUEOUS FLUID SOLUTION

Direct irradiation of 5-bromouracil (BU) in aqueous fluid solution in the presence of tryptophan (trp), tyrosine (tyr) or histidine (his) derivatives using a XeCl excimer laser at 308 nm yielded photocoupling of BU to the aromatic ring of each amino acid. Irradiation of BU at 308 nm most likely results in excitation of the n-φ* transition, intersystem crossing to the triplet manifold, and coupling via electron transfer from the aromatic amino acid. The coupling observed was regiospecific between the 5-position of uracil (U) and the 2-position of the indole and phenol rings and the 5-position of the imidazole ring of the respective amino acids. Quantum yields of photocoupling to BU ranged from 1 × 10^-3 to 7 × 10^-3 and paralleled known rates of electron transfer and ionization potentials of the aromatic rings. The photocoupling between BU and some of the aromatic amino acid peptide-like derivatives possibly mimics photocrosslinking of BU-DNA to associated proteins, a potentially useful photoreaction for studying nucleic acid-protein interactions. Formation of crosslinks of the type proposed here might be detected by the characteristic fluorescence emission of the uracil amino acid adducts.     

Synthesis and Antiviral Activity of 1-{[2-(Phenoxy)ethoxy]methyl}uracil Derivatives

The synthesis of novel 1-{[2-(phenoxy)ethoxy]methyl}uracil derivatives with different substituents in positions and 6 of the pyrimidine ring has been carried out. It has been shown that the alkylation of trimethylsilyl derivatives of uracil with 2-(4-chlorophenoxy)- and 2-(4-methylphenoxy)ethoxymethyl chloride under Hilbert-Johnson reaction conditions gives N₍₁₎-substitution products. It was found that the 1-{ [2-(phenoxy)ethoxy]methyl}uracil derivatives show viral inhibition properties relative to human immunodeficiency type 1 virus in vitro. The most active compounds are 5-bromo-6-methyluracil derivatives which suppress viral reproduction by 50% at 7.2 and 7.8 micromolar concentrations.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 726–731, May, 2005.     

A convenient method for N-1 arylation of uracil derivatives

1-(4-Nitrophenyl)- and 1-(2,4-dinitrophenyl)uracil derivatives have been obtained by direct arylation of uracil and its 5-substituted derivatives using 1-fluoro-4-nitrobenzene or 1-fluoro-2,4-dinitrobenzene in the presence of a base. The application of the newly obtained uracil derivatives in further synthesis is also presented.     

Polymerization of cyclic derivatives of uracil and thymine

Cyclic derivatives of uracil and thymine were synthesized from their corresponding 1-(2′-chloroethyl) derivatives by dehydrochlorination. These compounds were found to undergo a variety of reactions, giving many valuable derivatives of uracil and thymine. The cyclic derivatives, as monomers, were polymerized with a cationic initiator by a unique ring-opening process. The polymerization proceeded by ring opening with isomerization of the pyrimidine ring to give a polymer in which pyrimidine rings were connected with ethylene between N-1 and N-3 or O-4 in the pyrimidine ring. The structure of these polymers was determined by nuclear magnetic resonance (NMR), ultraviolet (UV), infrared (IR), and mass spectra. The structure was affected by polymerization temperature.     

Synthesis of acyclic and macrocyclic analogs of Di-, Tri-, and tetranucleotides

Compounds consisting of two or three uracil fragments were synthesized by reaction of methyl-substituted uracil sodium salts with 1-(6-bromohexyl)-3,6-dimethyluracil or 1,6-dibromohexane. Treatment of these compounds with paraformaldehyde gave the corresponding pyrimidinophanes and acyclic compounds in which the uracil fragments are linked through methylene bridges. Uracil derivatives having no substituent on N³ were synthesized by reactions of silylated uracils with 1,3-bis(6-bromohexyl)uracil or 4,4′-(6-bromohexyloxy)diphenylmethane. The acyclic compound was converted into pyrimidinophane containing uracil fragments with N³H groups. A trinucleotide analog including uracil and two adenine fragments was synthesized from 1,3-bis(6-bromohexyl)uracil.     

Synthesis of novel uracil based 2,5-diaminofurans using multi-component reactions

A simple synthesis of highly functionalized 2,5-diaminofurans based pyrimidine derivatives from l-(carboxymefhyl)uracil via a multi-component reaction is described.The reactive 1:1 intermediate produced from the reaction of tert-butyl isocyanide and dialkyl acetylenedicarboxylates was trapped at room temperature by l-(carboxymethyl)uracil derivatives to yield polyfunctionalized furan rings in fairly good yields.     

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.     

Intra- and intermolecular interactions in the series of acyclic and macrocyclic compounds containing nucleotide bases and their derivatives

Intra-and intermolecular interactions in acyclic compounds containing nucleotide base (uracil and thymine) derivatives and their macrocyclic analogs (pyrimidinophanes) were studied by IR, UV, luminescence, and NMR spectroscopy. Molecules of these compounds include one or two N³-methylsubstituted or N³-unsubstituted uracil fragment or two adenine fragments linked through a hexamethylene spacer to an uracil, 5,5′-methylenediuracil or diphenylmethane fragment. The examined compounds almost all are characterized by π-π interactions and intramolecular hydrogen bonding between the terminal uracil or adenine fragments. Intramolecular association constants were determined and factors affecting them were discussed. Complex formation of acyclic and macrocyclic ligands with adenine and thymine derivatives was studied. The low values of the association constants were interpreted in terms of a competition between intra-and intermolecular bonding and very labile ligand structure.     

Synthesis of [2-(vinyloxy)ethyl]uracil and [2-(allyloxy)ethyl]uracil

A synthesis is reported for N¹-mono- and N¹,N³-disubstituted uracil derivatives containing a terminal carbon-carbon double bond in the side-chain. Alkylation of vinyl 2-chloroethyl ether by uracil potassium salts leads to a mixture of 1-[2-(vinyloxy)ethyl] and 1,3-di[2-(vinyloxy)ethyl] derivatives while treatment of 2,4-bis(trimethylsilyloxy)pyrimidines by vinyl 2-chloroethyl ether leads exclusively to N¹-monosubstituted products. Alkylation of cytosine by this chloroether gave 1-[2-(vinyloxy)ethyl]cytosine. The synthesis of 1-[2-(allyloxy)ethyl]uracil derivatives was carried out by treatment of uracil potassium salts by 1-(allyloxy)-2-(p-toluenesulfonyloxy)ethane.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 393–397, March, 1993.     

An Efficient Method for the Synthesis of N‐uracil‐4‐oxo‐thiazolidines without Catalyst

We have developed highly efficient, one‐pot three component reaction of 5‐amino‐uracil and aromatic aldehydes with thioglycolic acid for the synthesis of N‐uracil‐thiazolidinones in excellent yields. The same products were also prepared by the reaction of Schiff bases of 5‐amino‐uracil with thioglycolic acid. In addition, benzylation of thiazolidinone derivatives and Schiff bases by using benzyl chloride was investigated. The results obtained from elemental microanalysis and different spectral data are in agreement with the assigned structures.     

Macrocyclic and acyclic 1,3-bis[5-(trialkylammonio)pentyl]-5(6)-substituted uracil dibromides: synthesis,antimicrobial properties,and the structure—activity relationship

Russian Chemical Bulletin - A series of acyclic onium uracil derivatives was synthesized, including 1,3-bis[5-(alkyldiethylammonio)pentyl]-5(6)-substituted uracil dibromides and isostructural...     

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.     

Carbocyclic analogs of cytosine nucleosides

The carbocyclic analogs of cytidine, 2′-deoxycytidine, and 3′-deoxycytidine were synthesized from the analogous uracil derivatives. The route consists of complete benzoylation of the uracil derivative, selective removal of a benzoyl group attached to the pyrimidine ring, conversion of the 4-oxo to a 4-chloro group with the dimethylformamide-thionyl chloride reagent, and replacement of the chloro group with an amino group in methanolic ammonia. When the total products of the deoxychlorination reaction were employed, the desired cytosine derivatives were frequently accompanied by small amounts of the corresponding N,N-dimethylcytosine derivatives, which could be removed by ion-exchange chromatography. Carbodine (VIa), the carbocyclic analog of cytidine, was obtained in 84% yield from the pure 4-chloropyrimidinone intermediate, after the latter was prepared by deoxychlorination in carbon tetrachloride. Carbodine has antileukemic, antiviral, and antibacterial activity.     

Removal of n-benzyl-and n-benzyloxymethyl substituents from substituted uracils with boron tribromide

N₁,N₃-Dibenzyl uracil derivatives have been successfully deblocked by using boron tribromide in refluxing xylene. Also N₁, N₃-dibenzyloxy methyl uracil derivatives can be easily converted to uracils by treatment with boron tribromide in benzene in the cold and subsequent boiling of the intermediate with water.     

Effect of Sr2+ association on the tautomerization processes of uracil and its dithio- and diseleno-derivatives

The structures and relative stabilities of the complexes formed by uracil and its thio- and seleno-derivatives with the Sr(2+) cation, in the gas phase, have been analyzed by means of G96LYP density functional theory (DFT) calculations. The attachment of the Sr(2+) cation to the heteroatom at position 4 is preferred systematically. Although the enolic forms of uracil and its derivatives should not be observed in the gas phase, the corresponding Sr(2+) complexes are the most stable. The enhanced stability of these tautomers is two-fold, on the one hand Sr(2+) interacts with two basic sites simultaneously, and on the other hand an aromatization of the six-membered ring takes place upon Sr(2+) association. Sr(2+) attachment also has a clear catalytic effect in the tautomerization processes involving uracil and its derivatives. This catalytic effect increases when oxygen is replaced by sulfur or selenium. The Sr(2+) binding energy with uracil and its derivatives is bigger than the tautomerization barriers connecting the dioxo forms with the corresponding enolic tautomers. Consequently, when associated with Sr(2+), all tautomers are energetically accessible and should all be observed in the gas phase.     

Electrofluorination of uracil

In view of the importance of the medical applications of fluorinated uracil and derivatives, synthetic methods directed to obtain such compounds are of particular interest. Several aspects of the electrochemical fluorination of uracil in different experimental conditions will be discussed.     

Etude de la fragmentation de derives de L'uracile et de la thymine par Spectrometrie de masse

Original mass spectra of uracil and thymine derivatives are presented with the corresponding fragmentation schemes. In the first series of spectra, the fragmentations of thymine derivatives, including ¹⁴C-2-thymine, dimers, and bromo thymines, confirm the basic retro Diels-Alder mechanism. The second series includes dihydro 5,6-derivatives of uracil (hydroxy and bromo substituents). The behaviour of these molecules is quite different; they are more sensitive to the substituents and a part of the fragmentation is often explained by protonated molecular ions.     

A new synthesis of n-blocked dihydrouracil and dihydroorotic acid derivatives using lithium tri-sec-butyl borohydride as reducing agent

1,3-Di-N-substituted uracil and its derivatives have been reduced with lithium-tri-$\text{sec}$-butyl borohydride to the corresponding 5,6-dihydro compounds in excellent yields. Alkylation of 5-position of uracil is also very conveniently accomplished.     

Specific Intermolecular Interactions in the Supramolecular Structure of 5‐Hydroxy‐6‐Methyluracil: A DFT Study of the Hydrogen‐bonded Dimers

Studying the self‐assembly of uracil derivatives has great importance for biochemistry and nanotechnology. For example, modification of the sorbent surfaces by 5‐hydroxy‐6‐methyluracil (HMU ) enhances their adsorption activity. It is assumed that these changes are caused by the self‐assembly of the network‐like supramolecular associates of the uracil derivative on the sorbent surface. In the present work, the relative stabilities of 15 hydrogen‐bonded dimers HMU have been studied by the TPSSh /TZVP density functional theory method and the strengths of the noncovalent interactions analyzed in terms of the reduced density gradient and natural bond orbital approaches. It was found that the symmetric dimer stabilized by two intermolecular hydrogen bonds N1 –H∙∙∙O–C2 (dimer 1‐1) is the most stable. This suggests that the self‐assembly of HMU should occur through the intermediate formation of the dimer 1‐1. The results may be useful for understanding the processes of self‐assembly of the uracil derivatives and the rationalized design of the uracil‐based supramolecular structures with specific properties.