5- Bromopyrimidine halogen-metal exchange

Simple 5-pyrimidineboronic acid is not trivial to make because the requisite lithiopyrimidine would add to the azomethine bond. The tendency towards these side reactions is less severe in case of 2,4-di-fert-butoxy-5-bromopyrimidine (20) and the halogen-metal exchange can be conducted at -75 °C [29], The nucleophilic attack towards the azomethine bond is retarded due to the steric hindrance. Therefore, the halogen-metal exchange of 2,4-di- -butoxy-5-bromopyrimidine (20) followed by quenching with n-butylborate, basic hydrolysis and... 

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. 

Pyrimidines lithiated in the 5-position can be boronated (299) (Scheme 48). The halogen-metal exchange between 5-bromopyrimidine and butyllithium has to be carried out at low temperature (— 100°C) to avoid 1 1-adduct formation with the lithiated species. The 2,4-di-t-butoxy analogue, however, can be lithiated in the normal manner at — 78°C. Boronation results from addition of tributyl borate with subsequent hydrolysis <90JHC2165>. 

Reactions of n-BuLi with halopyridines can lead also to Li-halogen exchange (see 5.5.2.3.3). The reaction between n-BuLi and 3-Br-2-Cl-pyridine gives products of Br-Li exchange and metallation of the ring at the 4-position . 5-Methyl- and 5-bromopyrimidines " also are ring metallated ... 

Reactions of 2-aminopyrimidine with a variety of heteroaromatic caibaldehydes have been studied [94H(37)1033], 5-Bromopyrimidine (64) has been shown to provide access to 5-pyrimidinecarboxaldehyde (66) and ethyl 5-pyrimidinecarboxylate (67) via a metal halogen exchange reaction I94SC(24)253). 

---