Lithium hexamethyldisilazane aldol reaction

The intramolecular aldol condensation route to fused tricyclic /3-lactams has been explored. The methylene group of an yV-tu-methoxycarbonyl alkyl chain is sufficiently acidic to react with a carbonyl group when treated with lithium hexamethyldisilazane (LHMDS) in THF at — 78 °C. Reaction times are short and yields high (Equation 59) <1996JOC7125>. 

One of these important bases, diisopropylaminomagnesium bromide, was first introduced by Frostick and Hauser in 1949 as a catalyst for the Claisen condensation. However, the most generally useful base has turned out to be lithium diisopropylamide (LDA), which was first used by Hamell and Levine for the same purpose in 1950 (equation 3). After the introduction of LDA, it was more than 10 years before it was used by Wittig for the stoichiometric deprotonation of aldimines in what has come to be known as the Wittig directed aldol condensation.In a seminal paper in 1970, Rathke reported that the lithium enolate of ethyl acetate is formed by reaction of the ester with lithium hexamethyldisilazane in THF. - Rathke found that THF solutions of the lithium enolate are stable indefinitely at -78 °C, and that the enolate reacts smoothly with aldehydes and ketones to give p-hydroxy esters (equation 4). 

Kuwajima and coworkers used very hindered bases such as (2) to deprotonate methyl alkyl ketones regioselectively in the presence of enolizahle aldehydes,21 One example of this amazing process is shown in equation (11) the reaction is reported to work equally well with other methyl ketones, including 2-pentanone. The process was also demonstrated with other bases in the reaction of 3-methyl-2-buta-none with dihydrocinnamaldehyde (equation 12). Among the bases that are effective are LDA, lithium hexamethyldisilazane, lithium f-butoxide and even lithium ethoxide. However, base (2) is superior, giving the aldol in 83% yield. 

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