Lithium dialkylamides, metalation

Dialkylamino derivatives of elements located in the periodic table to the left or below those listed above cannot be prepared by the above method due to either the ionic character of some of the inorganic halides or the formation of stable metal halide-amine addition products. Therefore, other methods must be applied. Dialkylamino derivatives of tin7 and antimony8 are conveniently obtained by reaction of the corresponding halides with lithium dialkylamides. Others, such as the dialkylamino derivatives of aluminum,9 are made by the interaction of the hydride with dialkylamines. Dialkylamino derivatives of beryllium10 or lithium11 result from the reaction of the respective alkyl derivative with a dialkylamine. 

This reaction type, known as directed ortho metalation reaction, requires strong bases, normally an alkyllithium reagent (most lithium dialkylamides are of insufficient kinetic basicity). Alkyllithium bases show high solubility in organic solvents due to association into aggregates of defined structure, typically as hexamers in hydrocarbon solvents e. g. hexane or tetramers-dimers in polar solvents e. g. THF (see Chapter 5). 

LDA and related, sterically hindered, lithium dialkylamides, first investigated by Levine [1], have completely replaced the more nucleophilic sodium amide, which had been the base of choice for many years [2], Because the reactivity of an organo-metallic compound depends to a large extent on its state of aggregation (i.e. on the solvent and on additives) and on the metal, transmetalation of the lithiated intermediates and the choice of different solvents and additives emerged as powerful strategies for fine-tuning the reactivity of these valuable nucleophiles. 

Gohier, F. Mortier, J. ortho-Metalation of unprotected 3-bromo and 3-chlorobenzoic adds with hindered lithium dialkylamides. 

Diaslereoselective Mannich reaction. Mannich bases can be prepared by addition of a lithium dialkylamide to a nonenolizable aldehyde to form a lithium alkoxide. Trans-metallation provides a trichlorotitanium alkoxide, which reacts with a lithium enolate to form a Mannich base. 

The nucleophilicity of silyl enol ethers has been examined. Base-induced formation of the enolate anion generally leads to a mixture of (E)- and (Z)-isomers, and dialkyl amide bases are used in most cases. The (EjZ ) stereoselectivity depends on the structure of the lithium dialkylamide base, with the highest EjZ) ratios obtained with LiTMP-butyllithium mixed aggregates in THF. ° The use of LiHMDS resulted in a reversal of the (E/Z) selectivity. In general, metallic (Z) enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. 

Metallated imines can be formed from imines derived from enolizable carbonyl compounds by deprotonation with Grignard reagents or organolithium reagents, but more recent studies have generally involved the use of lithium dialkylamides, e.g. LDA, as the base. Alternative methods of producing metallated imines, e.g. addition of r-butyllithium to the imine double bond of 2-azadienes, are known. 

The metallation of aldimines (2 = H) may be readily achieved using lithium dialkylamides and... 

A solution of 0.055 mol (Note 1) of butyllithium in hexane (38 ml) is added (using a syringe) to a flask containing 40 ml of Et20 or THF and cooled to below 0 °C. Subsequently a mixture of 0.055 mol (5.5 g) of diisopropylamine and 20 ml of THF or Et20 is added dropwise over a few minutes. Temperature control during this addition is not essential however,in the metallation reaction, which is usually carried out with the lithium dialkylamide at low temperatures, the solution may be cooled to 0 °C or lower. The formation of LDA is very fast, even in the temperature... 

Vinylic hydrogen atoms in strained ring systems have an increased acidity [65]. Cyclopropenes can be smoothly metallated with alkyllithium [66] (in the case of the unsubstituted hydrocarbon, addition across the double bond occurs), lithium dialkylamides in THF [9], or with alkali amides in liquid ammonia [16]. Whereas reaction of propene with strong bases results in the exclusive formation of the allylic derivative, the kinetically preferred process with 1-methylcyclopropene is vinylic deprotonation ... 

The most generally applicable reagents for the a-metallation of nitriles in organic solvents are lithium dialkylamides, in particular LDA (e.g., Refs. [6] and [7]). 

The indole formation from o-tolylisocyanide 23, which is brought about by metallation with lithium dialkylamides, is related to the Madelung synthesis. The lithium compound 24 can undergo cyclization to form indole (via iV-lithioindole) or, after alkylation and renewed metallation, to produce 2-substituted indoles ... 

E)-Selective etiolate formation Corey and Gross (12,285) have noted that (E)-lithium enolates are formed with high selectivity by treatment of ketones with a lithium dialkylamide followed by trapping with ClSi(CH3)3. The (E)-selectivity may be the effect of LiCI formed on trapping, since the addition of LiCI or LiBr to LiTMP also results in (E)-selective lithium enolates. The best experimental conditions involve metalation with crystalline 2,2,6,6-tetramethylpiperidinium bromide, which generates both LiTMP and LiBr under anhydrous conditions. 

To effect P-eliminative oxirane ring openings, lithium dialkylamides are a safer bet than alkyllithiums as the latter may metalate an oxygen-adjacent position instead. The medium-sized six- to ten-membered epoxycycloalkanes are particularly prone to a-metalation and subsequent enolate (after neutralization, cycloalkanone) formation and, on the other hand, insertion into transannular C-H bonds. ... 

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