Regioselective Metallation Of Bromopyridines
Directed ortho-metallation is an important laboratory technique which has been scaled up on many occasions for the preparation of specifically functionalised aromatic and heterocyclic compounds. Lithiation of 2-bromopyridine with LDA in THF at -78oC followed by quenching with TMS chloride gives the major product with the TMS in the 3 position with minor amounts of the 4-TMS-2-bromopyridine. With LiTMP in ether at -78oC, however, the 6-TMS-2-bromo isomer is formed exclusively (Imahora T et al, Chem Commun, 2001, 2450). To avoid byproducts formed by pyridyne intermediates, and via lithium halogen exchange, the Japanese scientists examined zincation using the zinc reagents TMP zincate and DA zincate (see Scheme), followed by iodine quench, with the regioselectivities shown below, with no indication of pyridyne formation.
