Enolate anions, kinetic diketones

The intermediate AD is a 1,5-diketone and as such accessible by means of a Michael addition of D (as an enolate anion) to A (in a yield of 52%). It is a characteristic of the photochemical synthesis of 123b that the kinetical-ly favored cw-orientation of the ethyl and vinyl groups on the five-membered ring of the Michael adduct AD ensures the thermodynamically disfavored fran -fusion of rings C and D in the Diels-Alder adduct of type ABCD. The overall yield of 123b, based on D, amounts to 11% ). The achiral building block A is accessible by conventional means [118d]. 

The synthesis begins with an Sn2 reaction (Chapter 10, Section 10.2) of bromide 141 with potassium cyanide to give 144. Note the use of the aprotic solvent DMF to facilitate the 8 2 reaction. A Grignard reaction of the nitrile with methylmagnesium bromide followed by hydrolysis leads to the requisite ketone (see Chapter 20, Section 20.9.3). The final step simply reacts the methyl ketone with LDA under kinetic control conditions to give the enolate anion (143), which is condensed with the ester (142) to give the diketone target, 140 (Section 22.7.2). 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

An ester enolate is formed by reaction with a strong base, and the resulting enolate anion can condense with an aldehyde, a ketone, or another ester. Ester enolates react with aldehydes or ketones to form p-hydroxy esters. Aldehyde or ketone enolate anions react with esters to form p-hydroxy esters, 1,3-diketones, or p-keto aldehydes 56,57,84,99,100,102,108,110,114,115. Enolate anions react as nucleophiles. They give nucleophilic acyl substitution reactions with acid derivatives. The condensation reaction of one ester with another is called a Claisen condensation and it generates a P-keto ester. A mixed Claisen condensation under thermodynamic conditions leads to a mixture of products, but kinetic control conditions can give a single product 52, 53, 54, 55, 59, 68, 69,98,99,101,125. 

One possible reaction for 60 is an intramolecular condensation with the other carbonyl (see Chapter 22, Section 22.6, for reactions of this type), but that would lead to a four-membered ring product, 61. The activation barrier to form this strained ring is high, so this reaction is slow (see Chapter 8, Section 8.5.3). The reaction conditions favor thermodynamic control (protic solvent, hydroxide, heat see Chapter 22, Section 22.4.2), which means that enolate anion 60 is in equilibrium with the neutral diketone. Further reaction with hydroxide generates the kinetic enolate anion 62 as part of the equilibrium mixture. If 62 attacks the carbonyl in an intramolecular aldol reaction (Chapter 22, Section 22.6), a six-membered ring is formed (63) in a rapid and highly favorable process. 

Simple ketones have pK values of about 20, so they are significantly more difficult to deproton-ate than diketones, and a stronger base will be needed to produce an enolate anion. Although 0-alkylation is rare, poly alkylation does occur, and for nonsymmetric ketones, regioselectiv-ity is often poor. If we consider the deprotonation of 2-methylcyclohexanone (Figure 17.42) under a variety of conditions (Table 17.2), either enolate can be obtained with fair selectivity. Under conditions of kinetic control, the most accessible proton is removed, particularly when the base used is very bulky. 

It is noteworthy that - in principle - other cyclization products can also result from the diketone 129. Evidently, conjugation to the aromatic ring stabilized the enolate formed by deprotonation of the acetyl side chain at C-1 of 129 in such a way that this anion reacted as the nucleophile in kinetically controlled aldol reactions. 

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See also in sourсe #XX -- [ ]

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