Schlosser superbases

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) °. 

Although there is a kinetic barrier to the direct deprotonation of tertiary amines, Ahlbrecht and Dollinger showed in 1984 that the Schlosser superbase, i c-BuLi/f-BuOK, can deprotonate A-methylpiperidine selectively on the methyl group (Scheme 3). This superbase probably yields an a-amino-organopotassium species (and f-BuOLi), but treatment with LiBr effects transmetalation to the more nucleophilic, and less basic, a-amino-organolithium species. Electrophilic quench with several aldehydes and ketones gives substitution products in good yields as typified by the example in Scheme 3. Similarly,... 

In the case of a /3-phenyl substituted a-methoxy vinyl anion, the acetal 541 has been treated with the Lochmann-Schlosser superbase to promote /3-elimination followed by a-deprotonation. The corresponding anion has been trapped with tri-n-butylchlorostannane to give stereoselectively the stannane 542 (Scheme 146)823. 

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. 

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... 

Baston, E. Maggi, R. Friedrich, K. Schlosser, M. Dimetalation the acidity of monometalated arenes towards superbasic reagents. Eur. J. 

In the wake of the successful use of Schlosser s base, a variety of superbasic reagents have been studied, showing sometimes a modulated behavior. It must be pointed out, however, that the simple substitution of one component with a similar reagent (e.g., potassium tert-butoxide with another potassium alcoholate) affects the overall behavior of the base only to a small extent. In contrast, the use of different organolithium components (butyl-, sec-butyl, tert-butyl, and methyllithium) is often responsible for marked differences in the reactivity profiles.40... 

The selective and efficient metallation of alkenes in the allylic position by the Schlosser s base is certainly one of the major achievements in the field of superbase chemistry. A complete list of successful alkene metallations by superbases would be too long for the purpose of this chapter but some representative examples are shown in Tables 2 and 3 as a general trend for the unsubstituted and heterosubstituted alkenes, respectively. 

A more versatile approach to 4,7-disubstituted dihydroacepentalenes 65 is via the stable acepentalene dianion 64 as an easily accessible intermediate. Dipotassium acepentalenediide 64 can be obtained in virtually quantitative yield by treatment of triquinacene 10 with the superbasic mixture of potassium f-pent-oxide and butyllithium [or even better potassium f-butoxide, butyllithium and tetramethylethylenediamine (TMEDA)] in hexane, the so-called Lochmann-Schlosser base (Scheme 15) [62, 63]. Mechanistically this transformation has... 

Schlosser M, Hartmann J (1973) Angew. Chemie 85 544 (1973) Int Ed (Engl) 12 508 and subsequent papers by Schlosser et al. see also the review on superbases Schlosser M (1988) Pure and Applied Chem 60 1627... 

Schlosser, M. (1992) Superbases as powerful tools in organic synthesis. Modern Synthetic Methods, 6, 227-271. 

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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