Bases. lithium dialkylamides

Alkyllithium bases are generally less suitable for deprotofiation of compounds with strongly electron-withdrawing groups such as C=0, COOR and CsN. In these cases lithium dialkylamides, especially those with bulky groups (isopropyl, cyclohexyl), are the reagents of choice. They are very easily obtained from butyllithium and the dialkylamine in the desired solvent. 

Lithium dialkylamides are excellent bases for making ketone enolates as well Ketone enolates generated m this way can be alkylated with alkyl halides or as illus trated m the following equation treated with an aldehyde or a ketone... 

Ketone p-toluenesulfonylhydrazones are converted to alkenes on treatment with strong bases such as an alkyllithium or lithium dialkylamide.286 Known as the Shapiro reaction,2 7 this proceeds through the anion of a vinyldiimide, which decomposes to a vinyllithium reagent. Treatment of this intermediate with a proton source gives the alkene. 

Ketone p-toluenesulphonyl hydrazones can be converted to alkenes on treatment with strong bases such as alkyl lithium or lithium dialkylamides. This reaction is known as the Shapiro reaction68. When w./i-LinsaUi rated ketones are the substrates, the products are dienes. This reaction is generally applied to the generation of dienes in cyclic systems where stereochemistry of the double bond is fixed. A few examples where dienes have been generated by the Shapiro reaction have been gathered in Table 669. 

Although modest, the results obtained with nonracemic lithium dialkylamides demonstrated the feasibility of such enantioselective transformations and important work has been undertaken from this date to improve both the yield and the ee values as well as developing a catalytic process. With this objective, both the use of homochiral lithium amide (HCLA) bases and organolithium-homochiral ligand complexes have been explored. This field has been extensively reviewed " and the following section presents a selection of the most outstanding results and recent developments. 

In liquid ammonia with alkali amides, or in Et20 or THF with lithium dialkylamides, these complications do not occur, because these bases are considerably weaker than BuLi. 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

The deprotonation of 5,6-dihydro-3-tnethyl-4//-l,2-oxazine with lithium dialkylamides or butyl-lithium as base proceeds with high regioselectivity at the 4-methylene protons due to the greater kinetic and thermodynamic acidity of these protons relative to the exocyclic methyl protons3. 

In pyridine-A-oxide, 2-proton acidity is considerably enhanced by the inductive effect of the oxide and by the complexing capability of the lone pair on oxygen with lithium. Hence, 2-lithiation and sometimes 2,6-dilithiation with alkyllithium and lithium dialkylamide bases is feasible. In the case of ring substituted pyridine-A-oxides 498, fair to good yields of... 

Dehydrohalogenation.1 This lithium dialkylamide shows a greater preference for the Hoffmann product in the dehydrohalogenation of 2-bromobutane than less hindered bases of this type. The preference is increased by addition of 12-crown-4 (equation I). 

Formed from the imine using LDA in hexane, NMR studies reveal complex solvent-dependent distributions of monomers, dimers, and trimers in several ethereal solvents, although a mono-solvated dimer can be selected by appropriate choice of solvent. Study of C-alkylation rates suggests that both monomer- and dimer-based mechanisms operate. The lithioimines were compared with the isostructural lithium dialkylamides, but were shown to be not simply vinylogous analogues thereof. 

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. 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

R2N-Li (lithium dialkylamide) Lithium diisopropylamide Strong base, not nucleophilic when R is bulky. Deprotonation of weak organic acids with acidities as high as pKa 35... 

Again, it is more practical to use formal hydrogen chloride adducts of 6 together with an excess of lithium dialkylamide which acts both as base in the elimination step and reagent as in the substitution step (20)44). 

The direction of ring-opening of 5,10-epoxy-9(ll)-enes by bases depends upon the reaction conditions.235 Thus the a-epoxide (288) loses a proton from C-12 with potassium t-butoxide to give the 5a-hydroxy-9,11-diene (289), but lithium dial-kylamides favour formation of the 10a-hydroxy-4,9(1 l)-diene (290). These and related results suggest that the lithium dialkylamides are poorly dissociated, and favour a 1,2- rather than a 1,4-epoxide-opening reaction.235... 

Reacts with dialkylamines to yield lithium dialkylamide bases such as LDA [lithium diisopropyl-amide] (Section 22.5). 

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. 

In 1972, a further brilliant improvement on the Claisen rearrangement was realized by Ireland and co-woikers. Ester enolization wiA lithium dialkylamide bases, followed by silylation with TMS-Cl, generated reactive silyl ketene acetals at -78 °C or lower temperatures. Sigmatropic rearrangement to easily hydrolyzable 7,8-unsaturated silyl esters occurred at ambient tempontures (15 16 17 equa-... 

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