Superbases, butyllithium-potassium tert-butoxide

Alkenes lacking hydrogen atoms at allylic positions are much less acidic than ordinary unsaturated hydrocarbons. Superbases regioselectively exchange allylic protons in alkenes whenever there is a choice. However, a few examples of metallation of alkenic C-H bonds with superbases are known and a compilation of them is reported in Table 1. Ethylene itself has been deprotonated by the superbasic mixture constituted by butyllithium, potassium tert-butoxide, and TMEDA.41... 

The n-butyllithium/potassium tert-butoxide mixture is immensely more powerful than butyllithium alone, and offers the possibility of functionalizing whole families of otherwise inert hydrocarbons. What should not be overlooked, however, is the fact that the chemical potential of the so-called superbase is attenuated when compared to butylpotassium. Thus, a manifold of aromatic, benzylic, and allylic organometallic intermediates can be generated in an ethereal medium under particularly mild and hence optimally selective conditions. The symbiotic action of two different metals obviously suppresses erratic side reactions without diminishing too much the deprotonation power of the superbasic reagent. 

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. 

The nonsteroidal anti-inflammatory flurbiprofen 100 has been prepared via deprotonation of 3-fluorotoluene 98 with Schlosser-Lochmann superbase (Scheme 26.29) [182]. The selectivity improves significantly when a combination of ieri-butyllithium and potassium ferf-butoxide is used as the mixed-metal reagent. The deprotonation occurs at the least-hindered position adjacent to fluorine. Trapping of the organometallic intermediate with fluorodimethoxyborane-diethyletherate and hydrolysis affords the boronic acid, which is then employed in a Suzuki-Miyaura coupling reaction. Another superbase metalation of 99, now with a combination of LDA and potassium tert-butoxide, allows the deprotonation of the benzylic position, followed by carboxylation and a second metalation, and trapping with Mel to afford flurbiprofen 100. 

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