Metalation and Nucleophilic Substitution

As mentioned above, the heterocycles can be easily metalated with a variety of bases. The oxazole ring and the benzoxazole ring can be metalated at C2 with a variety of strong bases. The major limitation of metalated oxazoles and benzoxazoles is their equilibrium with an open chain p-alkoxynitrile (see Section 6.3.1). In the ring-closed form, the oxazole is nucleophilic at C2. In the open chain form, the anion is nucleophilic at C4. This dual reactivity of the oxazole anion can lead to undesired regiochemistry unless carefiilly monitored. 

Vedejs and co-workers developed a regioselective iodination of lithiated oxazole. Iodination at the C4-position can be affected by dissolution of the oxazole substrate in THF with DMPU co-solvent prior to deprotonation and iodination by I2. Without DMPU as co-solvent, C2 iodination can be aeeomplished using less-reactive 1,2-diiodoethane as the electrophile. 

Of course, the issue of chemoselectivity in oxazole metalation can be alleviated if one or more positions are blocked in the starting oxazole. When the C2 position is blocked, the next most acidic site is C5. C5-metalated oxazoles do not suffer from ring opening equilibrium the way C2-metalated oxazoles do. If both C2 and C5 are blocked, metalation occurs at C4. 

C2 silylation as a protecting group strategy for oxazoles has historically been difficult due to the preferential oxophilicity of standard silyl chlorides protection of the ring opened oxygen atom typically predominates rather than protection of the C2 carbon atom. Miller has shown that treatment of imsubstituted oxazole with -BuLi followed by triisopropylsilyl triflate yields C2-silylated oxazole in near quantitative yield. Furthermore, this protected oxazole is stable to nonacidic aqueous workup and 

Williams and Fu have recently demonstrated a novel method for production of fully substituted oxazoles. Following the kinetic deprotonation of the 4-position of 5-bromo-2-phenylthio-l,3-oxazole to give the 4-lithio species, a thermal rearrangement occurs resulting in the 5-lithio-4-bromo species. This anion can be hydrolyzed to yield the 4-bromo-2-phenylthio-l,3- 

---

I ladlington, M., Rockett. B. W.. and Nelhans. A. Unsymmetrically disubstituted ferrocencs. 1. Synthesis of 1,2-disubstitutcd tcrrocencs by metallation and nucleophilic substitution reactions, J. Chem. S(K C. 1436, 1967. 

---