Lithium di isopropyl amide

Apparently a substantial spacer is also allowable between I he aromatic ring and the carboxy group. Gemfibrozi 1 (52), a iiypotriglyceridemic agent which decreases the influx of steroid into the liver, is a cl ofibrate homologue. It is made readily liy lithium di isopropyl amide-promoted alkylation of sodium iso-propionate with alkyl bromide 51. 

These reactions likely proceed vi a the formation of an intermediate carban-ion. Indeed, the carbanion 496 generated by treatment of 491 and 492 with lithium di isopropyl amide gave 81% of 491 (H=D) and 19% of 492 (H=0). The preferential formation of 491 can be explained on the basis of stereoelectronic effects which influence the reactivity of the intermediate carbanion... 

Even with fairly strong bases such as hydroxides or alkoxides, most carbonyl compounds are converted to their enolates only to a very small extent. A typical p Ta for the protons next to a carbonyl group is 20-25, while the pKa of methoxide is around 16, so we can only hope for about 1 part enolate in 104 parts carbonyl compound. With a much stronger base, this all changes, and the enolate is formed quantitatively from the carbonyl compound. This is a very important result which we shall capitalize on in Chapters 26 and 27. The base usually used is LDA (Lithium Di-isopropyl Amide), and it works like this. 

Phosphine oxide anions are often superior to ylids in olefmation reactions, and the anion of 68, made with lithium di-isopropyl-amide (LDA), has none of the disadvantages of the ylid 67. We have made 41 a range of vinyl ethers 70 this wayc, and as part of a synthesis of stiychnos alkaloids43, we were able41 to convert the acyl indole 71 into the aldehyde 72... 

An ylide generated from the phosphonium salt (76) with lithium di-isopropyl-amide has been used in the synthesis of the 9,11-aza-analogue of prostaglandin endoperoxide PGHg. ... 

What is needed for the alkylation is rapid conversion of the ester into a reasonably stable enolate, so rapid in fact that there is no unenolised ester left. In other words the rate of proton removal must be faster than the rate of combination of enolate and ester. These conditions are met when lithium enolates are made from esters with lithium amide bases at low temperature, often 78 °C. Hindered bases must be used as otherwise nucleophilic displacement will occur at the ester carbonyl group to give an amide. Popular bases are LDA (Lithium Di-isopropyl Amide, 66), lithium hexamethyldisilazide 67, and lithium tetramethylpiperidide 68, the most hindered of all. These bases are conveniently prepared from the amine, e.g. 65 for LDA, and BuLi in dry THF solution. 

The direct monoalkylation of a steroidal 4-en 3-one at C-4 calls for delicate control of reaction conditions and at best gives products containing some 4,4-dialkylated material. Indirect procedures for monomethylation (e.g. 4-thio-methylation-desulphurization ) are now supplemented by a novel method using the 3-imino-derivatives (315). Metallation (e.g. with lithium di-isopropyl-amide) gives the salt (316). which is selectively mono-alkylated at C-4, giving the 4-alkyl-4-en-3-one (317) after hydrolysis. 

As can be seen in the Table, lithium di isopropyl amide (LOA) is a satisfactory base in cases where the carbon group (R) of a methyl ketone (RCOCH3) either is bulky or does not contain an a-niethylene or a-methine group. In the other cases, LDA Is relatively ineffective. In such cases, however, the use of lithium 2,2,6,6-tetramethylpiperidide (LTMP) in place of LDA gives satisfactory results. The LTMP procedure appears to be the only documented method that is satisfactory for the conversion of the above-mentioned type. 

Methyl 2-trifluoromethyl-2-siloxycyclopropanecarboxylate was found to undergo successive smooth deprotonation with lithium di-isopropyl amide and reaction with carbon disulfide and methyl iodide to afford a dihydrothiophene derivative most likely via ring-expansion of the anionic intermediate by a [1,3] sigmatropic rearrangement (14JOC4492).The dide-hydrothiophene derivative was then converted to the corresponding 5-trifluoromethylthiophene by treatment with phosphoryl chloride in refluxing pyridine. An example of this reaction is shown below. 

A number of other types of chiral auxiliaries have been employed in enolate alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation occurs anti to the a-oxybenzyl group.93 The reactions involve the Z-enolate and there is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine.94... 

Lithium-diisopropylamid (LDA) in THF/Hexan ist das Reagenz der Wahl zur Erzeugung der Carbonsaure-enolate. In vielen Fallen wird HMPTA als Cosolvens zugesetzt515,516. Eine Kombination von Natriumhydrid und LDA ist ebenfalls wirksam516. Weiterhin wur-den andere Lithium-amide fur diesen Zweck eingesetzt, so z. B. Lithium-dimethyl-, -diethyl- und -dicyclohexyl-517, -bis-[trimethylsilyl]-5lS, -cyclohexyl-isopropyl-519 oder -di-tert.-butyl-amid520. 

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