Uracils halogenation

Having a 5-methyl group, thymine is not nitrated or halogenated normally, but with aqueous bromine it does give the dihydropyrimidine (948) (25JBC(64)233) its other reactions parallel those of uracil although its behavior on irradiation is somewhat different (Section 2.13.2.1.4). 

In the uracil dihydrate the harmonic NiH and N3H stretching modes are shifted by more than 200 cm [97JST323, 98JST307]. The influence of halogen substituents on selected vibrations has been investigated for 5-halogenouracils [98JST115]. 

In a study of the catabolic pathway of pyrimidines, it was found that the reduction of uracil was blocked almost completely by 5-cyanouracil (XXXV) in an in vitro test with the rat enzyme dihydropyrimidine dehydrogenase [303]. 5-Halogenated uracils and thymine are weakly active in this regard, and 5-acetyluracil and 5-trifluoromethyluracil are completely inert. 

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]. 

Two traditional methods have been used to Introduce a carboxyl substituent at C-5 of uracil. 0ns iasolves bromlnatlon at C-5, metalatlon via a lithium-halogen exchange, and finally quenching with carbon dioxide (32) to give the C-5 carboxylic acid. The... 

Uracils and related pyrimidines undergo oxidative addition to the 5,6-double bond, and the reaction with a number of oxidants to form 5,6-epoxides and 5,6-diols was discussed in CHEC-II(1996) <1996CHEC-II(6)93>. Oxidative halogenation can also occur <1996SC3583, 1998NN1125>, as shown by the formation of 5-bromo-5,6-dihydro-6-methoxyuracil 100 from uracil 99 by treatment with a mixture of potassium bromate and potassium bromide in the presence of Dowex ion-exchange resin in methanol <1996SC3583>. 

It is interesting to look at the effect of substituents on the dipole moment of uracil (or thymine). An examination of the data collected in Table XX shows that among the four positions (N-l, N-3, C-5, C-6) available for substitution, the one at C-6 is the most sensitive. An alkyl substituent at C-6 of uracil (or thymine) increases the dipole moment by about 0.4 0.5 D, while the same substituent at N-l, N-3, or C-5 has only a small effect. Similarly, a halogen does not greatly alter the dipole moment of the molecule when at C-5 whereas 6-halogen decreases the value of the dipole moment considerably (cf. the data for 1,3- dimethyl-uracil and for its 5- and 6-chloro derivatives, Table XX). An attempt has been made by Kufakowska and Wierzchowski402 to interpret these... 

A variety of N-, 0- and 5-heterocyclic halides have been found to undergo the palladium-catalyzed al-kene substitution reaction. Halogen derivatives of furan, thiophene, pyridine, pyrazine, uracil, indole, quinoline and isoquinoline, for example, undergo the reaction. Iodoferrocene also reacts normally. 

Halogen atoms in nucleosides can be replaced photochemically by sulphur as has been demonstrated in the photoinduced alkylthiolation of halogenated purine nucleosides433,749, in the synthesis of 2-(methylthio)adenosine from 2-iodoadenosine750 and in the photochemical formation of a cysteine-uracil adduct from 5-bromouracil and A-acetylcysteine methyl ester435. Photochemical synthesis of phosphonopyrimidine and phosphonopurine nucleosides by reaction of bromonucleosides with triethyl phosphite has also been reported751. 

Halogens are displaced by sulfur nucleophiles as in the phthalazine analogue (24) (67T681). In the thiation of the fused uracil (25) the higher reactivity at C-4, for the reasons discussed above, can be used to effect selective thiation in this position (78CPB2497). 

Table IV. Polarographic data for the reduction of halogenated uracils and their glycosides...

The facility with which the bromo, chloro and iodo analogues undergo reduction, with maintenance of the 5,6-double bond and replacement of the halogen by hydrogen, has been exploited for the electrochemical synthesis of 5-(3H)-uracil by conducting the reaction in tritiated water121). This procedure should be equally effective for the synthesis of labelled uracil nucleosides and nucleotides. 

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