Bases Butyllithium

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Metalation of unsymmetrical mines. Pioneering studies on the metalation and subsequent alkylation of unsymmetrical imines indicated that the reaction occurs predominantly at the less substituted a-position.5 This pattern has since been observed generally with lithium diethylamide, LDA, and ethylmagnesium bromide. Recent studies6 indicate that the site of alkylation is independent of the alkylating group but is dependent on the substituent on the imine and particularly on the basicity of the base. Butyllithium ( -, sec-, and /-) can abstract a proton from the more substituted a-carbon of the acyclic imine 1 to some extent. In the case of the cyclic imine 2, alkylation at the more substituted position is actually the main reaction. However, only substitution at the less substituted position of the dimethylhydrazone of 2-methylcyclohexanone is observed with either LDA or jcc-butyllithium (7,126-128). 

The very strong bases, butyllithium and tert. butyllithium add to (31) to give the corresponding alkenes in moderate yields 208-209>. The addition of butyllithium has also been observed with cyclooctyne19) and cyclooctenynes 108). 

Corey s synthesis of leukotrienes, human metabolites that control many important natural defence reactions like inflammation, involves the lithium derivative of an alkyne prepared by deprotonation with the very strong base butyllithium. The tosyl derivative of a primary alcohol reacts with this lithium derivative and a perfectly normal S>j-2 reaction follows. The alkyne provides the carban-ion (Chapter 8) for the displacement of the tosylate. 

Thus, as shown in Scheme 11.63, compound 215 was treated with propanedithiol in the presence of boron trifluoride etherate at 0°C to give dithiane 294 in 80% yield. Treatment of the latter with Schlosser s base (butyllithium/tBuOK) in pentane at — 78°C followed by addition of oxalate 295 gave a 60% yield of the coupling product 296. Subsequent removal of the dithiane ring afforded the hemiacetal 297 in good yield. This method is the umpolung version of the method used by Ireland to solve the same synthetic problem (see Section 11.4.2.2) [155]. Another example of... 

The simplest application of the Darzens reaction is outlined in Scheme 29. The production of the phosphoryl carbanion has been normally carried out with a metal alkoxide in this respect, r r -butoxide is better than ethoxide, some reactions proceeding only with the former base butyllithium or Ida has also been employed. The carbanion 357 is also available through the chlorination of dialkyl methylphosphonate carbanion with PhSO.CP ... 

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. 

These conditions are so harsh that they are applicable only to indoles with the most inert substituents. Cyclization can be achieved at much lower temperatures by using alkyllithium reagents as the base. For example, treatment of o-methylpivalanilide with 3 eq. of n-butyllithium at 25 C gives 2-terr-butylindole in 87% yield[2]. These conditions can be used to make... 

When butyllithium is used as a base it abstracts a proton in this case a proton attached to nitrogen The source of lithium diethylamide must be diethylamine... 

The conjugate base of 1,3-dithiane has proven valuable in synthetic applications as a nucleophile (Part B, Chapter 13). The anion is generated by deprotonation using n-butyllithium ... 

Most other studies have indicated considerably more complex behavior. The rate data for reaction of 3-methyl-l-phenylbutanone with 5-butyllithium or n-butyllithium in cyclohexane can be fit to a mechanism involving product formation both through a complex of the ketone with alkyllithium aggregate and by reaction with dissociated alkyllithium. Evidence for the initial formation of a complex can be observed in the form of a shift in the carbonyl absorption band in the IR spectrum. Complex formation presumably involves a Lewis acid-Lewis base interaction between the carbonyl oxygen and lithium ions in the alkyllithium cluster. 

Tlie interest in the preparation and use of dithiolium salts in connection with the synthesis of TTF derivatives led to the development of a new uses of heteroaromatic cations in organic synthesis. Based on that, a new carbonyl olefination for the synthesis of numerous heterofulvalenes was developed (77S861). For example, 2-dimethoxyphosphinyl-l,3-benzodithiole was deprotonated with butyllithium in THF at -78°C and the resulting phosphonate carbanion reacted with 9-alkyl-acridones to give the dithia-azafulvalenes of type 45 (78BCJ2674) (Scheme 15). 

A broad scope is documented for the preparation of suspensions of 2-alkenylpotassium lithium toV-butoxide complexes from unsaturated hydrocarbons by means of butyllithium/ potassium /erf-butoxidc (Schlosser Lochmann base LICKOR reagents )38-45,432 456. Examples are given in Section D.1.3.3.3.3.2.1. 

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. 

For the deprotonation of less acidic precursors, which do not lead to mesomerically stabilized anions, butyllithium/TMEDA in THF or diethyl ether, or the more reactive, but more expensive,. seobutyllithium under these conditions usually are the most promising bases. Het-eroatomic substitution on the allylic substrate, which docs not contribute to the mesomeric or inductive stabilization often facilitates lithiation dramatically 58. In lithiations, in contrast to most other metalations, the kinetic acidity, caused by complexing heteroatom substituents, may override the thermodynamic acidity, which is estimated from the stabilization of the competing anions. These directed lithiations59 should be performed in the least polar solvent possible, e.g.. diethyl ether, toluene, or even hexane. 

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