Reaction with LDA

The dianions of methylated thiophenecarboxylic acids e.g. 155) are also readily generated by reaction with LDA they undergo preparatively useful reactions with a range of carbon electrophiles (80JOC4528). 

Many types of carbonyl compounds, including aldehydes, ketones, esters, thioesters, acids, and amides, can be converted into enolate ions by reaction with LDA. Table 22.1 lists the approximate pKa values of different types of carbonyl compounds and shows how these values compare to other acidic substances we ve seen. Note that nitriles, too, are acidic and can be converted into enolate-like anions. 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones (entries 1 and 2, Scheme 1.12). Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,/J-unsaturated esters (entry 5, Scheme 1.12). 

OrPhenybelenenylation of a,f -unsaturated esters.3 (F)-3r,/MJnsaturated esters are converted to a-phenylseleno-a,0-unsaturated esters in 20-65% yield by reaction with LDA followed by C6H5SeBr. The reaction is related to the reaction of a,/ -enones with pyridine and C H5SeCl (9, 28-29), and is also believed to involve conjugate addition of the base followed by selenenylation of the enolate. 

Reaction with a hindered epoxide.l The trans-epoxide (1) of tetramethyllimonene is inert to KOH (130°), LiAlH4 (THF, 90°), and even lithium triethylborohydride. It is opened by aluminum isopropoxide (110°) to give 70 30 mixture of 2 and 3. Reaction with LDA is more selective and gives 2 in 95% yield. In contrast, reaction with N-lithioethylenediamine (1, 567 570) gives 3 in 90% yield. The 70 30 mixture of 2 and 3 is converted by N-lithioethylenediamine to the more stable isomer 3. 

How would the imine from Problem 8 react with LDA followed by tt-BuBr Draw mechanisms for each step reaction with LDA, reaction of the product with n-BuBr, and the work-up. 

In another work, Meyers and coworkers found that in asymmetric synthesis of macrocyclic ketones and a-alkyl ketones by using chiral imines, two intermediate lithioenamines were obtained. One of them was formed in the reaction with LDA at — 30 C and is the kinetically controlled is-isomer 36. The second product formed on reflux with LDA is the Z-isomer 37, which is the thermodynamically more stable isomer. Both formed anion 38 on heating (equation 10). 

Chiral -hydroxy carboxylic acids. The enolate of 1, prepared by reaction with LDA followed by transmetallation with MgBr, reacts with aldehydes to provide the diastereomers 2 and 3 in the ratio 92-97 8-3. The adducts are cleaved by KOH in aqueous methanol to chiral (3-hydroxy carboxylic acids (4) and the chiral diol 5. 

Lithiochloromethyl phenyl sulfoxide, CeHsSCHClLi. The anion is generated from chloromethyl phenyl sulfoxide by reaction with LDA in THF at —78°. 

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