Metallation of Heterosubstituted Arenes

The optional site selective metallation of fluorotoluenes158 with the superbasic mixture of butyllithium and potassium fert-butoxide has been applied to the synthesis of the anti-inflammatory and analgesic drug Flurbiprofen.171 3-Fluorotoluene is selectively metallated in the 4-position with LIC-KOR in THF at — 75 °C to afford, after reaction with fluorodimethoxyborane and hydrolysis, the corresponding boronic acid in 78% yield. A palladium-catalyzed coupling with bromobenzene gives the 2-fluoro-4-methylbiphenyl in 84% yield. This four-step sequence can also be contracted to a one-pot procedure with an overall yield of 79%. A double metallation with the superbasic mixture lithium diisopropylamide/potassium tert-butoxide (LIDA-KOR)172 173 is then required to produce flurbiprofen. 

---

Table 6 Metallation of heterosubstituted arenes with superbases Compound References...

Heterosubstituted Arenes. As a rule of thumb, the super-basic n-BuLi/f-BuOK reagent having coordinatively saturated lithium preferentially deprotonates such positions where charge excess is most efficiently stabilized. This may result in a different regiochemical behavior with respect to simple organolithium reagents exploiting the so-called optional site-selective metalation. Some representative examples of n-butyllithium/potassium ferf-butoxide metalations of heterosubstituted arenes are shown in Table 5. 

Table 5 -ButylUthium4>otassium tert-butoxide metalation of heterosubstituted arenes...

---