Aldol-conjugate reaction

Conjugation of the newly formed double bond with the carbonyl group stabilizes the a p unsaturated aldehyde provides the driving force for the dehydration and controls Its regioselectivity Dehydration can be effected by heating the aldol with acid or base Normally if the a p unsaturated aldehyde is the desired product all that is done is to carry out the base catalyzed aldol addition reaction at elevated temperature Under these conditions once the aldol addition product is formed it rapidly loses water to form the a p unsaturated aldehyde... 

Again, this produces a favourable tertiary carbocation. Loss of a proton gives the required alkene. Note that potentially three different carbons could lose a proton. The reaction shown generates the most stable product this has the maximum number of alkyl substituents and also benefits from extended conjugation. We then get another aldol-type reaction. The enolate anion is produced from the ethyl chloroacetate, and simple addition yields an anion that is subsequently protonated. 

Then follows an aldol-like reaction with subsequent dehydration, favoured by the conjugation in the product. 

Yamamoto and coworkers described a highly enantioselective asymmetric domino 0-nitroso aldol-conjugate addition seqnence using cyclic enones 221 and aromatic nitroso compounds 222 as depicted in Scheme 36 [346]. A related reaction with imines was also reported by Cdrdova and coworkers (Scheme 37) [228]. 

The same type of reaction has been applied to the preparation of 1,2-dihydroquinoline-3- and 277-l-benzothiopyran-3-carboxylic acid derivatives (equation 38) via a magnesium amide-induced sequential conjugate addition-aldol condensation reaction between 2-(alkylamino)phenylketones or 2-mercaptobenzophenones . 

For the synthesis of tris-annulated benzene rings, the aldol trimerization of cyclic ketones has been known as a powerful tool since the 19 century. Why the reaction works so well with some ketones (e.g., indanone) but fails so miserably with others (e.g., tetralone), however, has never been adequately explained. This chapter outlines the development and scrutiny of a hypothesis that says formation of an a,/ -unsaturated (conjugated) dimer from a cyclic ketone is vital to the success of an aldol trimerization reaction for the synthesis of a tris-annulated benzene the reaction will fail with ketones that form only / ,y-unsaturated (unconjugated) dimers. This hypothesis unifies much experimental chemistry and is supported by theoretical calculations. 

The mechanistic proposal for the formation of these p-laclonc products is related to that for the formation of y-lactones (Scheme 17). Initial formation of the conjugate enamine Ila is followed by a proton transfer from oxygen to carbon thereby forming the enolate V. In an aldol-type reaction this enolate attacks the electrophilic ketone providing zwitte-rions VI. The subsequent cyclization to the lac tone 18 then liberates the NHC catalyst. 

The aldol condensation reaction yields either a jS-hydroxy aldehyde/ketone or an a,jS-unsaturated aldehyde/ketone, depending on the reactant and on the experimental conditions. By learning how to think backward, it s possible to predict when the aldol reaction might be useful in synthesis. Any time the target molecule contains either a -hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction. 

Asymmetric aldol, conjugate addition, and Diels-Alder reactions compared The Asymmetric Diels-Alder Reaction... 

The tin(IV) enolate can be quenched with a variety of electrophiles to form new carbon-carbon bonds, including carbonyl addition (aldol-type) reactions, alkylations and conjugate additions of tin(IV) enolates. Tin(IV) enolates react readily with aldehydes in both intra- and intermolecular aldol-type reactions [5J]. The best conditions for the intermolecular aldol condensation reaction were to initially generate the tin enolate by reacting the desired enone with tributyltin hydride and then... 

You have seen that alcohols are dehydrated when they are heated with acid (Section 12.5). The )8-hydroxyaldehyde and j8-hydroxyketone products of aldol addition reactions are easier to dehydrate than many other alcohols because the double bond formed as the result of dehydration is conjugated with a carbonyl group. Conjugation increases the stability of the product (Section 8.3) and, therefore, makes it easier to form. If the product of an aldol addition is dehydrated, the overall reaction is called an aldol condensation. A condensation reaction is a reaction that combines two molecules while removing a small molecule (usually water or an alcohol). 

Intramolecular aldol condensations. Swiss chemists have reported two examples of preparation of cyclic aldols by reaction of f-oxo-a,j3-enones by conjugate addition of dimethylcopperlithium followed by a directed intramolecular aldol condensation. Both aldols are products of kinetic control they are not... 

Yamamoto and coworkers reported a tandem highly enantioselective 0-nitroso aldol-conjugate addition reaction catalysed by 5a. Cyclic enones and aromatic nitroso compounds afforded the corresponding bicyclic products with excellent enantioselectivity (Scheme 9.49). The results considerably extended the control of regio- and stereochemistry for the synthesis of nitroso Diels-Alder adducts. 

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