Crossed Enolate Reactions Using LDA

Conjugate Addition to a,j8-Unsaturated Carbonyl Compounds Crossed Enolate Reactions Using LDA... 

Preformed enolate anions using LDA can be used to carry out a wide variety of crossed enolate reactions, including aldol reactions, Claisen condensations, Michael additions, alkylations, and acylations. 

Reaction between Two Different Aldehydes. In the most general case, this will produce a mixture of four products (eight, if the alkenes are counted). However, if one aldehyde does not have an a hydrogen, only two aldols are possible, and in many cases the crossed product is the main one. The crossed-aldol reaction is often called the Claisen-Schmidt reaction. The crossed aldol is readily accomplished using amide bases in aprotic solvent. The first aldehyde is treated with LDA in THF at —78°C, for example, to form the enolate anion. Subsequent treatment with a second aldehyde leads to the mixed aldol product. The crossed aldol of two aldehydes has been done using potassium ferf-butoxide and Ti(OBu)4. ... 

Directed aldol reaction (Section 19.5B) A crossed aldol reaction in which the desired enolate anion is generated first and rapidly using a strong base (e.g., LDA) after which the carbonyl reactant to be attacked by the enolate is added. If both a kinetic enolate anion and a thermodynamic enolate anion are possible, this process favors generation of the kinetic enolate anion. 

No aldol reaction is possible until the LDA is consumed and a second carbonyl compound is added. This procedure is a convenient way to do crossed aldol reactions in a controlled fashion. When there is a choice, LDA forms the more accessible, less substituted enolate. Lithium diisopropylamide is a large, sterically encumbered base and removes a proton from the sterically less hindered position to give what is called the kinetic enolate. Notice that this reaction can be used to generate two new stereocenters adjacent to each other. This procedure is very useful and has received considerable attention in the past 30 years. 

In both these last two examples, a very strong base is used in the form of LDA such that the enolate ion is formed quantitatively (from ethyl acetate and acetone respectively). This avoids the possibility of self-Claisen condensation and limits the reaction to the crossed Claisen condensation. 

We shall therefore consider crossed aldol condensations by two general approaches that allow control over the distribution of products. The first approach hinges on structural factors of the carbonyl reactants and the role that favorable or unfavorable aldol addition equilibria play in determining the product distribution. In this approach relatively weak bases such as hydroxide or an alkoxide are used in a protic solvent such as water or an alcohol. The second approach, called a directed aldol reaction, involves use of a strong base such as LDA in an aptotic solvent. With a strong base, one reactant can be converted essentially completely to its enolate, which can then be allowed to react with the other carbonyl reactant. 

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