Bases Lithium diisopropylamide-Potassium

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 reaction of diiodomethane with a variety of bases (sodium hexamethyldisilazanide, lithium diisopropylamide, potassium triphenylmethanide, potassium iert-butoxide, potassium hydroxide under phase-transfer conditions, methyllithium) and alkenes does not afford iodocyclo-propanes. The thermal decomposition of diiodomethyl(phenyl)mercury in an alkene also does not result in the formation of iodocyclopropanes." ... 

Introduction. Potassium f-butoxide is intermediate in power among the bases which are commonly employed in modem organic synthesis. It is a stronger base than the alkali metal hydroxides and primary and secondary alkali metal alkoxides, but it is a weaker base than the alkali metal amides and their alkyl derivatives, e.g. the versatile strong base Lithium Diisopropylamide. ... 

Several reviews cover hetero-substituted allyllic anion reagents48-56. For the preparation of allylic anions, stabilized by M-substituents, potassium tm-butoxide57 in THF is recommended, since the liberated alcohol does not interfere with many metal exchange reagents. For the preparation of allylic anions from functionalized olefins of medium acidity (pKa 20-35) lithium diisopropylamide, dicyclohexylamide or bis(trimethylsilyl)amide applied in THF or diethyl ether are the standard bases with which to begin. Butyllithium may be applied advantageously after addition of one mole equivalent of TMEDA or 1,2-dimethoxyethane for activation when the functional groups permit it, and when the presence of secondary amines should be avoided. 

Kinetic control can be achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent. Kinetic control requires a rapid, quantitative and irreversible deprotonation reaction 2-6. The use of a very strong, sterically hindered base, such as lithium diisopropylamide or triphenylmethyllithium (trityllithium), at low temperature (— 78 °C) in an aprotic solvent in the absence of excess ketone has become a general tool for kinetic control in selective enolate formation. It is important to note that the nature of the counterion is sometimes important for the regioselectivity. Thus, lithium is usually better than sodium and potassium for the selective generation of enolates by kinetic control. 

A study investigated the use of various bases, such as potassium hydroxide, potassium tert-butoxide, sodium methoxide, methyllithium, rrrf-butyllithium, sec-butyllithium, phenyllithium, lithium diisopropylamide, and lithium hcxamethyldisila/anidc over a temperature range of — 78 to 80°C in the dehydrofluorination of 2-(fluoromethoxy)-l,l,l,3,3,3-hexafluoropropane to give 2-(fluoromethoxy)pentafluoropropene.28... 

To circumvent problems of nucleophilicity, lithium diisopropylamide (LDA), potassium hexamethyldisilylamide (KHMDS), and KH are often employed for proton removal since they are very strong bases (pKa > 35) but relatively poor nucleophiles. Hence they remove protons from acidic C-H bonds but normally do not attack carbonyl groups or other electrophilic centers. 

At this point, consideration was next accorded to proper introduction of the pair of substituents as in 34. As expected, the regiocontrolled introduction of a methyl group proved not to be problematic, and lithium diisopropylamide came to be favored as the base. The p isomer 29 predominted by a factor of 5 1 over the a isomer for the usual steric reasons (Scheme 5). To reach silyl enol ether 31, it was most efficient and practical to react the 29/30 mixture with chlorotrimethylsilane under thermodynamic conditions. This step proved to be critical, as it allowed for implementation of the Lewis acid-catalyzed acetylation of 31 under conditions where the benzyloxy substituent was inert. Equally convenient was the option to transform the modest levels of enol acetate produced competitively back to starting ketone by saponification with methanolic potassium hydroxide. 

Table 4.4 lists some common bases used in organic chemistry. Although butyl-lithium behaves as a very strong base in many reactions, it also exhibits other chemistry, so it is usually used to prepare other strong bases listed in the table. Lithium diisopropylamide, sodium amide, dimsyl anion, and sodium hydride are often used to prepare the conjugate bases of aldehydes, ketones, and esters for use in reactions. Potassium fert-butoxide is employed when a base somewhat stronger than the conjugate bases of most alcohols is needed. 

Bases Alumina, see p-Toluenesulfonylhydrazine. Dehydroabietylamine. 1,5-Diazabicyclo [4.3.0]nonene-5. 1,4-Diazabicyclo[2.2.2]octane. l,S-Diazabicyclot5.4.0]undecene-5. 2,6-Di-/-butylpyridine. N,N,-Diethylglycine ethyl ester, see /-Amyl chloroformate. 2,6-Dimethyl-piperidine. Ethanolamine. Lithium diisopropylamide, see Diphenylsulfonium isopropylide. Lithium nitride. Magnesium methoxide. N-Methylmorpholine. Piperidine. Potassium amide. Potassium hydroxide. Potassium triethylmethoxide. Pyridine. Pyrrolidine. Sodium methoxide. Sodium 2-methyl-2-butoxide. Sodium thiophenoxide. Thallous ethoxide. Triethyla-mine. Triphenylphosphine, see l-Methyl-2-pyrrolidone. 

NaNH2 is a powerful basic reagent which was widely used in chemical laboratories until lithium diisopropylamide was discovered and became more commonly used as it is much more soluble in classical solvents such as ether and tetrahydrofuran. NaNH2 is also a powerful reagent when associated with potassium t-butoxide to become a "complex base" (not described here) as shown by the research work of Caubere and co-workers (ref. 62). 

Deprotonation of carbonyl compounds by lithium dialkylamide bases is the single most common method of forming alkali enolates. Four excellent reviews have already been published. " Sterically hindered amide bases are employed to retard nucleophilic attack on the carbonyl group. The most common and generally useful bases are (i) lithium diisopropylamide (LDA 5) (ii) lithium isopropylcyclo-hexylamide (LICA 6) (iii) lithium 2,2,6,6-tetramethylpiperidide (LITMP 7) (iv) lithium hexamethyldisilylamide (LHMDS 8) and (v) lithium tetramethyldiphenyldisilylamide (LTDDS 9). Bases that are not amides include sodium hydride, potassium hydride and triphenylmethyllithium. 

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