2-Halopyrimidines, nucleophilic displacement

The difference in reactivity between 2- and 4-halopyrimidines is relatively small and a discussion of the selectivity in nucleophilic displacement reactions of 2,4-dichloropyrimidine (an important synthetic intermediate) is instructive. 

In 9-substituted purines, the relative reactivity is 8 > 6 > 2, but in 9//-purines this is modified to 6 > 8 > 2, the demotion of the 8-position being associated with anion formation in the five-membered ring. Conversely, in acidic media the reactivity to nucleophilic displacement at C-8 is enhanced protonation of the five-membered ring facilitates the nucleophilic addition step." The relative reactivities of 2- and 6-positions is nicely illustrated by the conditions required for the reaction of the respective chlorides with hydrazine, a relatively good nucleophile." It is worth noting the parallelism between the relative positional reactivity here with that in halopyrimidines (4 > 2). 

For the halogen-metal exchange reaction of bulkier halopyrimidines, steric hindrance retards the nucleophilic attack at the azomethine bond. As a consequence, halogen-metal exchange of 5-bromo-2,4-di-r-butoxypyrimidine (43) with n-BuLi could be carried out at -75 °C [20]. The resulting lithiated pyrimidine was then treated with n-butylborate followed by basic hydrolysis and acidification to provide 2,4-di-f-butoxy-5-pyrimidineboronic acid (44). 5-Bromopyrimidine 43 was prepared from 5-bromouracil in two steps consisting of a dehydroxy-halogenation with phosphorus oxychloride and an SnAt displacement with sodium r-butoxide. 

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