Uracil selective methylation

The uracils with herbicidal activity do not necessarily contain 5-halo substituents. 3-Cyclohexyl-5-methyluracil [354] (XLIV), l,3-di-isopropyl-6-methyl-uracil [352] (XLV) and 3-s-butyl-5-thiocyanato-6-methyluracil [353] (XLVI), for example, are cited as having this type of activity. 3-Butyl-6-methyluracil (XLlllc) possesses interesting selective activities. For instance, this pyrimidine kills many annual weed species without damage to peas and peanuts, even when applied at twice the concentration needed to kill the weeds [346]. On the other hand, the related 5-bromo derivatives, such as (XLlIlb), are useful as industrial herbicides where it is desirable to kill all plants [346]. 

With unsubstituted 5-iodouracil 336, a trimagnesiated species 337 can be formed by sequential treatment with methylmagnesium chloride and isopropylmagnesium chloride, and reaction with various electrophiles then selectively gives 5-functionalized uracil derivatives 338 <20070L1639>. The same procedure was also successfully applied to the functionalization of 6-iodouracils, including the synthesis of Emivirine and l-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (ElEPT) precursors <20070L1639>. 

The covalent structures of RNA and DNA differ in one other way. Whereas RNA contains uracil, DNA contains a methylated uracil derivative termed thymine. This modification also serves to protect the integrity of the genetic sequence, although it does so in a less direct manner. As we will see in Chapter 27. the methyl group present in thymine facilitates the repair of damaged DNA, providing an additional selective advantage. 

Direct methylation with diazomethane [154] or alkylation of organotin derivatives of uridine 64 lead to non 2 -0-selective alkylations. The organotin approach using alkyl halides and temperatures up to 130 °C leads to the formation of equal amounts of 2 - and 3 -0-alky-luridines, which may be separated by chromatography after dimethoxytritylation. Alkylation of the uracil moiety does not occur with this method. Purification of the isomeric mixture may be achieved after further derivatization [155]. 

TBAF is very useful for alkylation of nucleic acid derivatives. Methylation or benzylation of uracil gives almost quantitative yields of alkylated product when using alkyl bromides, diaUcyl sulfates (eq 17), trialkyl phosphates, or alkyl chlorides with TBAF. Alkylation of the thiol anions generated from deprotection by 1,2-dibromoethane produces interesting tetrachalcogenofulvalenes. Under phase-transfer conditions, selective mono- and dialkylations of malononitrile have been achieved by using neat TBAF with Potassium Carbonate or Potassium tert-Butoxide and controlling the amount of alkyl bromides or iodides used (eqs 18 and 19). ... 

Fig. 5 shows the separation of a mixture of uracil, an unknown contaminant, methyl and ethyl benzoates, toluene, ethylbenzene, triphenylene, and o-terphenyl using firstly a modem very well covered hydrophobic phase (SynergiMAX RP) and secondly a non-endcapped, less covered, old phase with acidic silanol groups (Spherisorb ODSl). On SynergiMAX RP, the small mononuclear aromatic substances are separated very well, but the selectivity of the o-ter/tri separation is only just good enough (last two peaks). In the case of the strongly silanophilic, less covered, and non-endcapped Spherisorb ODSl, the observed selectivity is exactly the opposite. 

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