Lithium dialkylamides, lithiation

Lithiation shifts obtained by comparison of 13C chemical shifts in lithium dialkylamides and the corresponding amines have been found to be quite substantial and decrease in the order a > p > 7 > 8 (439). 

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... 

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. 

D. B. Collum, Solution Structures of Lithium Dialkylamides and Related JV-lithiated Species Results from 6Li-15N Double Labeling Experiments , Acc. Chetn. Res. 1993, 26, 227-234. 

Among the methods for their preparations, two reactions described by House have been employed widely 7 a thermodynamically controlled sil-ylation with chlorotrimethylsilane/triethylamine in hot dimethylformam-ide or a kinetically controlled reaction which involves lithiation with a lithium dialkylamide followed by quenching with the chlorosilane. Each method has its own merits and drawbacks with respect to three important factors regio-, stereo-, and chemoselectivities. 

The cyclic oxime ether (69) can be selectively lithiated at either the 3-methyl or the 4-methylene position by choosing an appropriate lithium dialkylamide. Scheme 35 illustrates how this provides the basis for a new synthesis of a-methylene ketones. ... 

The O-lithiated derivatives of hemiaminals derived from dimethylformamide and homologous carboxamides by organolithium addition are relatively stable entities. They nevertheless begin to dissociate slowly into a carbonyl compound and lithium dialkylamide at temperatures at or above -25 °C. This explains why 2,6-dichloropyrid-3-yllithium and dimethylformamide produce a 10 1 mixture of 2-chloro-6-dimethylamino-... 

Lithium dialkylamides eject lithiumalkyl if the latter is sufficiently resonance-stabilized. When A -l-phenyl-A -2,2,2-(triphenylethyl)amine is treated with an alkyl- or aryllithium, the resulting lithium amide undergoes cleavage to triphenylmethyllithium and 7V-methylene-l-phenylethylamine, which immediately combines with the initially used alkyl- or aryllithium. Analogously, cyanide departs as soon as (benzylamino)acetonitrile is A-lithiated and again the organolithium, as far as not yet consumed in amide-generation, adds onto the transient A-methylenebenzylamine. ... 

Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The Af-metalated enamines 11 and 15 are enolate analogs and their contribution to the respective tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide—the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ( hyperbasic media ), the imine compound of methyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). 

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