Lithium 2,2,6,6-tetramethylpiperidide regioselectivity

The presence of a sulfonyl group in 1-azulenyl p-tolylsulfone directs lithiation, by lithium tetramethylpiperidide, to ortho-positions. " Regioselective lithiation, at the 2- and 6-positions, has also been observed in the reaction of l-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide in tetrahydrofuran (THF). The metalation involves a rate-limiting deaggregation process with a dimer-based transition state. In the presence of lithium chloride, monomer-based pathways are favoured. ... 

The metallation, especially the lithiation, of pyridazines, mentioned briefly in CHEC-II(1996) <1996CHEC-11(6)1 >, has been developed extensively since 1995 by Queguiner and co-workers for the derivatization of pyridazines and benzopyridazines. The bases of choice are usually lithium 2,2,6,6-tetramethylpiperidide (LTMP) and lithium diisopropylamide (EDA). Special efforts have been made to achieve regioselective lithiations. 

Although the regioselectivity of the alkylation reaction is independent of the nature and the steric bulk of the electrophile, it is dependent on the steric bulk of the base used for deprotonation. Lithium diisopropylamide (LDA) is superior for endo deprotonation, whereas exo dcprotonation is best achieved with the sterically hindered lithium 2,2,6,6-tetramethylpiperidide (LTMP)11,16. 

Regioselective lithiation on the benzene moiety of 4-substituted quinazolines occurs at position peri to the N1 ring nitrogen. Thus, treatment of 4-methoxyquinazolines 8 with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at — 78 to 0 X followed by reaction with various electrophiles affords 8-substituted quinazoline derivatives 9. This regioselective lithiation provides easy access to a large range of substituted quinazolines which are not easily synthesized by other routes. ... 

Lithium 2,2,6,6-tetramethylpiperidide (LITMP) was introduced by Olofson and Dougherty in 1973. This base appears to be significantly more hindered than LDA, and is useful for regioselective enolate formation in cases where a very bulky base is desirable. " Another very hindered base is lithium t-butyl-t-octylamide, introduced by Corey and Gross."... 

Following conversion into its kinetic enol phosphate (terminal olefinic bond), treatment of a methyl ketone with LDA or lithium 2,2,6,6-tetramethylpiperidide effects highly regioselective /3-elimination to give a terminal acetylene e.g. Scheme 107).This is the first method for this transformation that works consistently, even for methyl ketones with a-methylene or a-methine hydrogen atoms, without significant quantities of allenes being formed concurrently. 

Control of Regioselectivity and Stereoselectivity. The recognition by Ireland and co-workers that Hexamethylphosphoric Triamide has a profound effect on the stereochemistry of lithium enolates has led to the examination of the effects of other additives, as the ability to control enolate stereochemistry is of utmost importance for the stereochemical outcome of aldol reactions. Kinetic deprotonation of 3-pentanone with Lithium 2,2,6,6-Tetramethylpiperidide at 0 C in THF containing varying amounts of HMPA or TMEDA was found to give predominantly the (Z)-enolate at a base ketone additive ratio of ca. 1 1 1, whereas with a base.ketone.additive ratio 1 0.25 1, formation of the ( )-enolate was favored (Table I). This remarkable result contrasts with those cases where HMPA base ratios were varied towards larger amounts of HMPA, which favored formation of the (Z)-enolate. ... 

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