Lithium diisopropylamide, formation reaction with ketones

A number of methods for the generation of acyl anion equivalents from aldehydes have been developed. Related to the benzoin condensation, aldehyde cyanohydrins, protected as their ether derivatives, are readily transformed into anions by treatment with lithium diisopropylamide (LDA). Reaction with an alkyl halide gives the protected cyanohydrin of a ketone from which the ketone is liberated easily. Reaction with an aldehyde or ketone leads to the formation of an a-hydroxy ketone (1.109). ... 

Enolate alkylation can be difficult to carry out with simple aldehydes and ketones. It is not always possible to limit the reaction to monoalkylation, and aldol condensation competes with alkylation, especially with aldehydes. The formation of regioisomeric alkylation products is an issue with unsymmetrical ketones but can be minimized by selecting reaction conditions that favor either kinetic or thermodynamic control of enolate formation. The kinetic enolate of 2-methylcyclohexanone, for example, was prepared by deprotonation with lithium diisopropylamide then treated with benzyl bromide to give predominantly 2-benzyl-6-methylcyclohexanone,... 

The stereochemical information is introduced by (J )-methyl p-toluenesulfoxide 110. This compound is deprotonated with lithium diisopropylamide and reacted with a-chloro methylacetate 109 to give a-chloroketone 111. This ketone when reacted with diisobutylaluminum hydride at —78°C gives (J )-chlorohydrine 112, whereas reaction of ketone 111 with diisobutylaluminum hydride and zinc chloride gives the corresponding (S)-chlorohydrine 113. Treatment of both chlorohydrines with potassium carbonate resulted in the formation of epoxides 114 and 116. These can now be reacted with either (Z)- or (T)-vinyl cuprates to give the desired homoallylic alcohols 115 and 117 in diastereomeric excesses around 90%. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Metallation of TTF (5) has been accomplished at — 78°C by either lithium diisopropylamide or by -butyllithium (Scheme 82) <77CC161,79JOC1476>. It has been found that strict temperature control is essential for the success of these reactions, since at — 20°C a redistribution of product formation is observed <79J0C1476>. 1-Lithio-TTF (426) reacts at —70°C with a series of electrophiles to afford the corresponding alcohols, aldehydes, ketones, carboxylic acids, and esters as well as monoalkylated TTF <77CCi6i, 79JOCi476>. Improvement of this procedure allowed the synthesis of carboxy-TTF (427), formyl-TTF (428), and hydroxymethyl-TTF in 80-92% yield (Scheme 83) <94S489>. 

Many examples of the formation of new six-membered rings containing a nitrogen atom in the reaction of isatoic anhydrides with ketones, diketones, various ether derivatives, lactones, and organometallic compounds are known. Thus, the anhydrides 2 and 34 condense with acetophenones and co-methoxyacetophenones in the presence of lithium diisopropylamide at low temperatures with the formation of derivatives of quinolone 35 [17, 18],... 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

Cleavage of enol trimethylsilyl ethers or enol acetates by methyllithium (entries 1 and 2, Scheme 1.3) as a route to specific enolate formation is limited by the availability of these materials. Preparation of the enol trimethylsilyl ethers and enol acetates from the corresponding ketones usually affords a mixture of the two possible derivatives, which must be then separated. It is sometimes possible to find conditions that favor the formation of one isomer for example, reaction of 2-methyl-cyclohexanone with lithium diisopropylamide and trimethylchlorosilane affords the less highly substituted enol ether preferentially by 99 1 over the more highly substituted one (kinetically controlled conditions). ... 

Irradiation of 231 gives, after the re ra-Mannich fragmentation of the photoadduct 232, a 91% yield of 233. The single stereogenic center in the photosubstrate leads to complete stereochemical control in the formation of the cyclobutane intermediate 232, which contains two new strereogenic centers. Treatment of 233 with lithium diisopropylamide, followed by an excess of ier butyldimethylsilyl triflate and reaction of the crude product with tetrabutylammonium fluoride, results in the formation of the desired tetracyclic product 234 in 51% yield. This compound is converted to tetracyclic ketone 235, which is an advanced intermediate in Buchi s synthesis of vindorosine. 

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