Superbase metalation

SCHEME 26.29 Synthesis of nonsteroidal anti-inflammatory flurbiprofen. 

We have tried to summarize in this chapter the basic tendencies and mechanisms of directed metalation. DoM in presence of DMG(s) allows for the regioexhaustive functionalization of aromatics. DreM, frequently combined with migration of the DMG or rearrangement, gives a powerful tool for the synthesis of natural products. Peri and lateral lithiations have shown to further enable functionalization for aromatic scaffolds, and last but not least, when coordinated to and thus activated by a metal complex, aromatic ring systems can be subjected to enantiose-lective metalation reactions. Although such a chapter cannot cover the topic in an exhaustive manner, we hope to have found a compromise between scholarly presentation and citation of relevant literature. 

PMDTA Tiidentate A,A,A, A ,A -pentamethyldiethylenetriamine RINMR Rapid-injection nuclear magnetic resonance 

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The trilluoromethyl group behaves in a similar way , but it is now clear that deprotonation of sites ortho to such acidifying but non-coordinating and non-electrophilic substituents is best carried out with BuLi-KOBu-t superbases (see Section VI). A combination of BuLi metallation and superbase metallation of fluoroarenes has been used in the synthesis of components 163 and 164 for fluorinated liquid crystals (Scheme 82). ... 

The superbase metallation of alkenes in the allylic position followed by reaction with electrophiles is one of the best methods to access Z-alkenes with new functional groups. 

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. 

Above —60°C, ethereal solvents are rapidly attacked by n-BuLi in the presence of f-BuOK. Nevertheless, acetal functions are suitable protecting groups for superbase metalations of alkenols. 

Two important issues arise when functional groups are present on the alkene moiety their compatibility with the superbase metalation, and their effect on the regio- and stereochemical outcome of the reaction (eq 7). 

These conditions are also applicable to functionalized systems that are compatible with metallation by this superbase. 69... 

Standard organolithium reagents such as butyllithium, ec-butyllithium or tert-butyllithium deprotonate rapidly, if not instantaneously, the relatively acidic hydrocarbons of the 1,4-diene, diaryhnethane, triarylmethane, fluorene, indene and cyclopentadiene families and all terminal acetylenes (1-alkynes) as well. Butyllithium alone is ineffective toward toluene but its coordination complex with A/ ,A/ ,iV, iV-tetramethylethylenediamine does produce benzyllithium in high yield when heated to 80 To introduce metal into less reactive hydrocarbons one has either to rely on neighboring group-assistance or to employ so-called superbases. 

An olefinic double bond can be conceived as a two-membered ring . The specific geometry at the unsaturated centers makes the latter prone to deprotonation. Nevertheless, superbasic reagents are required for the metalation of heteroatom-free alkenes (see Section... 

Toluene itself can be lithiated by w-BuLi-TMEDA at or above room temperature, and deprotonation occurs almost exclusively at the methyl group—about 10% ring metallation (mainly in the meta position) is observed with w-BuLi-TMEDA (Scheme 188) . At lower temperatures deprotonation is very slow , and the best conditions for achieving the metallation of toluene are the Lochmann-Schlosser superbases (see Section VI) °. 

The combination of an alkyllithium with a metal aUcoxide provides a marked increase in the basicity of the organolithium . The most widely used of these superbases is the one obtained from BnLi and KOBu-t, known as LiCKOR (Li—C + KOR) °. The exact natnre of the prodncts obtained by snperbase deprotonations—whether they are organolithinms, organopotassiums, or a mixtnre of both—is debatable, as is the precise nature of the superbase itself. For example, while prolonged mixing of alkyllithium and... 

The violence of superbasic slurries towards functionalized organic molecules means that they are at their most effective with simple hydrocarbons they also tolerate ethers and fluoro substituents. LiCKOR will deprotonate allyUc, benzylic, vinylic, aromatic and cyclopropane C—H bonds with no additional assistance. From benzene, for example, it forms a mixture of mono and dimetallated compounds 617 and 618 (Scheme 241) . ( Li/K indicates metallation with a structurally ill-defined mixture of lithium and potassium.)... 

Deprotonation of 3-fluorotoluene 623 with n-BuLi—KOBu-f or, better, f-BuLi—KOBu-f follows the selectivity expected with these superbases and leads to metallation at the least hindered position ortho to the fluoro substituent. Trapping the metallated intermediate 624... 

Similar chemistry been used by Faigl and Schlosser in an elegant and simple synthesis of ibuprofen 632 using only superbase chemistry (Scheme 245). Starting with para-xylene 630, two successive metallations and alkylations give 631, which is once more metallated at the less hindered benzylic site and carbonated to give ibuprofen 632. 

It can be expected that solid bases could be successful for commercializing the alkylation of toluene with methanol as a route to styrene, or for selective alkene coupling. There is no doubt that achieving success in several important commercial processes will boost the field of solid base catalysis. Because it appears to be difficult to achieve superbasic organic resins, much more attention should be paid to enhancement of the base strengths of solid superbases. Further work should be done on supported alkali metals and mixed metal oxides. Development of new solid superbases will be improved by increasing our understanding of how alkali metal clusters (302-304) interact with supports and become stabilized. 

Alkali metal alkyls, particularly n-butyl lithium, are the most frequently used reagents to form metallated intermediates.246 247 In certain cases (di- and triphenyl-methane, acetylene and 1-alkynes, cyclopentadiene) alkali metals can be directly applied. Grignard reagents are used to form magnesium acetylides and cyclopenta-dienyl complexes.248 Organolithium compounds with a bulky alkoxide, most notably M-BuLi-ferf-BuOK in THF/hexane mixture, known as the Lochmann-Schlosser reagent or LICKOR superbase, are more active and versatile reagents.249-252... 

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