Metalations 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... 

Sabinene was obtained from (-)-a-thujene using /f-butyllithium-potassium tert-butoxide for the metalation. The unreacted (-)-a-thujene can be easily separated from (+)-sabinene. 

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. 

Table 1 Metalation of alkenes with n-butyllithium/potassium tert-butoxide...

Table 2 Metalation of conjugated n-butyllithium/potassium tert-butoxide and homoconjugated dienes with...

Metalation of aUylsilanes with n-BuLi/t-BuOK shows good levels of y-selectivity (attack on the unsubstituted terminus of the aUyhnetaUic moiety). Increasing steric hindrance on silicon leads to a higher y-selectivity with perfect -stereocontrol. Good levels of a-selectivity are obtained only when the y-position is substituted and the electrophile is not sterically hindered. Examples of n-butyllithium/potassium tert-butoxide metalations of aUylsilanes are shown in Table 3. 

A few n-butyllithium/potassium tert-butoxide metalations of vinylic C-H bonds are known. For example, the metalation of ethene itself, or of l,7,7-trimethylbicyclo[2.2.1]hept-2-ene. 

Heteroelements in general facilitate metalation reactions. A-Methylpiperidine and, by extension, trimethylamine react smoothly with the 5ec-butyllithium/potassium tert-butoxide (LIS-KOR) mixture at their methyl groups. The same happens when... 

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. 

This procedure consists of the synthesis of a precursor, methoxymethyl vinyl ether, an a-hydroxy enol ether, and the intramolecular hydrosilylatlon of the latter followed by oxidative cleavage of the silicon-carbon bonds. The first step, methoxymethylation of 2-bromoethanol, is based on Fujita s method.7 The second and third steps are modifications of results reported by McDougal and his co-workers. Dehydrobromination of 2-bromoethyl methoxymethyl ether to methoxymethyl vinyl ether was achieved most efficiently with potassium hydroxide pellets -9 rather than with potassium tert-butoxide as originally reported for dehydrobromination of the tetrahydropyranyl analog.10 Potassium tert-butoxide was effective for the dehydrobromination, but formed an adduct of tert-butyl alcohol with the vinyl ether as a by-product in substantial amounts. Methoxymethyl vinyl ether is lithiated efficiently with sec-butyllithium in THF and, somewhat less efficiently, with n-butyllithium in tetrahydrofuran. Since lithiation of simple vinyl ethers such as ethyl vinyl ether requires tert-butyllithium,11 metalation may be assisted by the methoxymethoxy group in the present case. 

Later work elaborating on the chemistry of glycals demonstrated the ease of formation of 1-stannyl glycals. These compounds, introduced in Scheme 3.1.1, are useful substrates for the direct formation of C-glycosides as well as for metal-metal exchanges with lithium to be discussed later in this chapter. As shown in Scheme 3.1.3, Hanessian, eta/.,4 utilized potassium tert-butoxide and butyllithium to effect the formation of 1-stannyl glycals. 

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. 

Several examples of -butyllithium/potassium terf-butoxide promoted metalations of benzenes, naphthalenes, tert-alkyl-substituted benzenes, phenyl acetylenes, and silylated arenes can be found in Table 4. 

P-Elimination-coupled to in situ metalation opens an entry also to halogen-free organometallic intermediates. For example, the I-ethoxy-1,3-butadiene emerging from a 1,4-elimination of ethanol from the 2-butenal diethyl acetal reacts rapidly in an ensuing step with 5ec-butyllithium and potassium tert-butoxide to give 1-ethoxy-1,3-butadienyl-potassium/lithium (242), a synthetic equivalent of the 2-butenoyl ("crotonoyl") anion (Scheme 1-187). Numerous applications of such sequences to organic preparations have been reported by Paolo Venturello et... 

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