Pyrimidines typical reactivity

Typical Reactivity of the Diazines Pyridazine, Pyrimidine and Pyrazine... 

Typical reactivity of the diazines pyridazine, pyrimidine and pyrazine... 

Acylation reactions can be done at the nucleophilic sites on pyrimidines using activated forms of carboxylic acids. Acylation of functional groups in nucleotides typically is used for protection during synthesis (Reese, 1973). However, for bioconjugate applications, the reactivity of native groups on pyrimidines is not as great as that obtained using an amine-terminal spacer derivative, such as those described in Chapter 27, Section 2.1. Yields and reaction rates are typically low for direct acylation or alkylation of pyrimidine bases, especially in aqueous environments. 

Methyl groups in the 2-, 4- or 6-position of pyrimidine are also more reactive. In addition to typical reactions such as condensation with benzaldehyde, selenium dioxide oxidation and halogenation, they can be converted into oximino groups by nitrous acid, and undergo Claisen condensation with (C02Et)2. In the reaction of 2,5-dimethylpyrimidine with benzaldehyde, only the electrophilic 2-methyl group reacts preferentially to yield the 2-styryl derivative (631). In quinazolines partial double bond fixation makes a methyl group in the 4-position more reactive than that in the 2-position. 

The pyrimidine system shows side-chain reactivity typical of azines. CH3 groups at the 2-, 4- or 6-position undergo aldol condensations (with aldehydes in the presence of Lewis acids) or Claisen condensations (with esters in the presence of strong bases) with marked preference at C-4, e.g. ... 

Tetrafluoropyrimidine Perfluorinated diazines (pyrimidine, pyrazine, and pyridazine) are typically 1000 times more reactive toward nucleophiles than pentafluoropyridine. Various reactions of tetrafluoropyrimidine with a small range of nucleophiles have been reported (Fig. 8.15) and, in all cases, nucleophilic substitution occurs selectively at the 4-position, consistent with the mechanistic principles discussed above. 

As a typical pi-deficient system, hydroxyl groups on the pyrimidine are involved in tautomeric equilibrium with the 0x0 form, and it is this form that greatly dominates in the equilibrium. Nevertheless, electrophilic substitution is easily effected on the oxopyrimidine stmcture. As an example, the diketo pyrimidine uracil (9.120) reacts readily with nitric acid to give the 5-nitro product 9.121. This suggests that the reactive species may be the hydroxyl form, albeit in a low concentration (Scheme 9.60). 

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