Substituted uracil

Use pattern Terbacil is a substituted uracil herbicide used primarily to control annual and perennial grass and broadleaved weeds in apple orchards, alfalfa, asparagus, mint and sugar cane. Other minor uses include blueberries, strawberries and seed grasses... 

He Y, Wu C, Kong W (2003) Decay pathways of thymine and methyl-substituted uracil and thymine in the gas phase. J Phys Chem A 107 5145... 

Pyrimidinyl palladium reagents, prepared in situ from mercuric or iodo derivatives, react with 3,4-dihydro-2H-pyran to form isomeric products containing a dihydropyranyl group attached to C-5 of the substituted uracil... 

Photo-induced conversions are also important synthetically. The photocycloaddition of 5-substituted uracils 69 with ethylene has been used for the synthesis of 2-aminocyclobutanecarboxylic acids. The addition reaction worked well with carbon and fluorine substituents and also with a Cbz-protected amino. However, uracils with other 5-nitrogen substituents (NH2, NHBn and NO2) failed, only starting material being recovered. The sequence also worked for the 6-isomers but somewhat less consistently <06SL1394>. 

A study of the interaction of 6-pyridinium substituted uracil mesomeric betaines 80 with nucleic acid has been reported <060BC3056>. 

Platination of the N3 position in 1-substituted uracil and thymine derivatives requires proton abstraction and usually occurs only at high pH, but the Pt-N3 bond, once formed, is thermodynamically stable (log K 9.6) [7]. Platinum binding to N3 increases the basicity of 04, which becomes an additional binding site leading to di- and trinuclear complexes. A list of X-ray structurally characterized species is given by Lippert [7]. Pt complexes of uracil and thymine can form intensely colored adducts (e.g. platinum pyrimidine blues), which show anticar-cinogenic activity analogously to the monomeric species [7]. 

Unlike simple aryl halides, a regioselective Suzuki coupling of 2,4-dibromofuran may be achieved at C(2) [46]. The coupling between 2,4-dibromofuran and pyrimidylboronic acid 40 provided furylpyrimidine 41, which was then hydrolyzed to 5-substituted uracil 42. 

The Suzuki coupling of 44 was utilized to prepare 5-substituted uracils as potential antiviral agents [21, 22]. Adduct 45, derived from 44 and 2-bromo-3-methylthiophene, was transformed to the corresponding uracil 46 via acidic hydrolysis. Conveniently, reversal of the coupling partners also resulted in formation of adduct 45, assembled from the Suzuki coupling of 5-bromo-2,4-di-f-butoxypyrimidine (43) and 3-methyl-2-thiopheneboronic acid. 

Thymine (5-methyluracil) and related 5-substituted uracils do not yield isolable dihydropyrimidines under similar irradiation conditions [507,515,520]. Uptake of a water molecule was at first discounted [521]. Subsequent study... 

Herbicidal and chemotherapeutic activity have also been noted in other dihydropyrimidines. Certain 5,5-dihalo-6-methoxydihydropyrimidines, especially the 3-substituted derivatives such as (LXXXIll), are reported to have herbicide activity against many grasses and broad-leaf weeds [645] (herbicidal activity of some corresponding A -substituted uracils has been discussed in the preceding section). The compounds can generally be prepared by halogenation of uracil derivatives in alcohol [646, 647]. 

Phthaloylation of 2-aminoethanol followed by chloromethylation gave 872, which coupled with the silylated 5-substituted uracils, 6-dimethylami-... 

The synthesis of 3-nitro-l-substituted uracil derivatives 30 can readily be performed with trifluoroacetic nitric anhydride, and this procedure is used in nucleoside chemistry to convert the uracil 3-nitrogen to a good leaving group <1995JA3665, 1997JOC1547, 20020L1827>. 

Alkyl halides can also be used to generate the radical center, and N -substituted uracil and thymine derivatives have been used to prepare octahydropyrrolo[l,2-f]pyrimidinedione derivatives <2001TL6637, 2006CC844> as demonstrated by diasteroeoselective synthesis of the azabicycle 447 <2006CG844>. 

Pyrimidines can be formed in reactions involving multiple bond formations, and the reactions of this subgroup have a long history <1994HC(52)1>. A recent example is the synthesis of a 6-substituted uracil derivative 740 (Scheme 9), where an a,/3-unsaturated ester 737, A,0-bis(trimethylsilyl)hydroxylamine, phenyl chloroformate, and ammonia supplied the four components of C(4)-C(5)-C(6), N-1, C-2, and N-3, respectively <2000TL4307> ... 

It has recently been shown by Spikes150 that uracil and a number of substituted uracils are subject to dye-sensitized photooxidation under certain conditions. Methylene blue and Eosin Y were active photosensitizers in the pH range 8-11.5, but were inactive below pH 8. FMN was very active over the pH range of 2.4-11.5. Photooxidation was measured with a rotating platinum oxygen electrode. 

Several pyrrolo[3,2- / pyrimidines 208 were synthesized in excellent yields from the corresponding 5-substituted uracils 207 (Equation 71) <1998JOC3550>. 

The benzylidenehydrazino-substituted uracils 148 can act as starting materials for the synthesis of either the 3-phenyltoxoflavins 14 or the 8-demethyl 3-phenylfervenulin derivatives 29, depending upon whether the hydrazino uracil starting material 148 has an R substituent or not, as shown in Equations (22) and (23) <1997H(45)643, 2001J(P1)130>. 

Botta and coworkers recently developed an Oxone cleavage methodology for the solid-phase synthesis of substituted uracils (equation 57)165. Whereas some common methods of thioether cleavage, such as reduction with Na/NH3, acid catalyzed hydrolysis, heavy metal ions followed by treatment with hydrogen sulfide and iodotrimethylsilane proved to be unsuccessful for this reduction, Oxone was shown to be an efficient and selective reagent for cleavage of polymer bound thiouracils. 

Dimethyl- and l,3-dimethyl-5-halo-substituted uracil derivatives react with cesium fluor-oxysulfate under mild reaction conditions. The reaction carried out in an acetonitrile/water mixture or in an alcohol (methanol, ethanol, propan-2-ol or /a7-butyl alcohol) results in the regioselective formation of 5-fluoro-6-hydroxy- or 6-alkoxy-5-lluoro-l, 3-dimethyl-5,6-dihydro-uracil derivatives 27, respectively, while the stereochemistry of the reaction is strongly syn predominant.29... 

As in the case of cytosine, several NMR and NQR studies were performed in search of the predominating tautomeric structures of uracil and thymine and their nucleotides and nucleosides. Investigation of PMR spectra of these compounds in nonaqueous solvents, such as dimethyl sulfoxide, localized the mobile protons in a number of 5- and 6-substituted uracils.59,61,328 These and similar studies63,85,329,330 indicated that dilactam structure 32 predominates in uracil compounds in aqueous and nonaqueous solutions as well as in the solid state. Proton and N-15 magnetic resonance spectra of several pyrimidines85 confirmed the diketo structure usually ascribed to uracil. 

Substituted uracils 1 are of much interest due to their possible use as anti-cancer and anti-AIDS drugs, and both 2,4-dimethoxy-6-iodopyrimidine and l,3-dimethyl-6-iodouracil (1, R = Me, X = I) were required as starting materials for the synthesis of a variety of uracils 1 by palladium-catalysed C-C bond formation. It was reported in 1961 that treatment of 6-chloro-2,4-dimethoxypyrimidine with sodium iodide in refluxing DMF gave a 42% yield of the corresponding 2,4-dimethoxy-6-iodopyrimidine, but repetition of the reaction recently clearly established that the product was in fact the isomeric l,3-dimethyl-6-iodouracil (1, R = Me, X = I). 

Fujita S, Steenken S (1981) Pattern ofOFI radical addition to uracil and methyl-and carboxyl-substituted uracils. Electron transfer ofOFI adducts with N,N, Ar, Ar -tetramethyl-p-phenylenediamine and tetranitromethane. J Am Chem Soc 103 2540-2545 Fujita S, Nagata Y, Dohmaru T (1988) Radicals produced by the reactions of SO4 with uridine and its derivatives. Studies by pulse radiolysis and y-radiolysis. Int J Radiat Biol 54 417-427 Fujita S, Horii FI,Taniguchi R, Lakshmi S, Renganathan R (1996) Pulse radiolytic investigations on the reaction of the 6-yl radicals of the uracils with Cu(ll)-amino acid complexes. Radiat Phys Chem 48 643-649... 

Moorthy PN, Hayon E (1975) Free-radical intermediates produced from the one-electron reduction of purine, adenine and guanine derivatives in water. J Am Chem Soc 97 3345-3350 Mori M, Teshima S-l, Yoshimoto H, Fujita S-l, Taniguchi R, Hatta H, Nishimoto S-l (2001) OH Radical reaction of 5-substituted uracils pulse radiolysis and product studies of a common redox-ambivalent radical produced by elimination of the 5-substituents. J Phys Chem B 105 2070-2078 Morin B, Cadet J (1995) Chemical aspects of the benzophenone-photosensitized formation of two lysine - 2 -deoxyguanosine cross-links. J Am Chem Soc 117 12408-12415 Morita H, Kwiatkowski JS,TempczykA(1981) Electronic structures of uracil and its anions. Bull Chem Soc Jpn 54 1797-1801... 

In the 1-substituted uracils, the substituent exerted a profound effect on the stabilities of the reaction intermediates, but the intermediate adducts in the cytosines rapidly deaminated in water to yield uracil analogues 88JCS(P1) 1203]. 

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