Enolate with bases

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

Only relatively few examples of interesting target molecules containing rings are known. These include caryophyllene (E.J. Corey, 1963 A, 1964) and cubane (J.C. Barborak, 1966). The photochemical [2 + 2]-cycloaddition applied by Corey yielded mainly the /ranr-fused isomer, but isomerization with base leads via enolate to formation of the more stable civ-fused ring system. 

Intramolecular reactions between donor and acceptor centres in fused ring systems provide a general route to bridged polycyclic systems. The cts-decalone mesylate given below contains two d -centres adjacent to the carbonyl function and one a -centre. Treatment of this compound with base leads to reversible enolate formation, and the C-3 carbanion substitutes the mesylate on C-7 (J. Gauthier, 1967 A. Belanger, 1968). 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

The reaction can be performed with base catalysis as well as acid catalysis. The former is more common here the enolizable carbonyl compound 1 is depro-tonated at the a-carbon by base (e.g. alkali hydroxide) to give the enolate anion 5, which is stabilized by resonance ... 

The rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

The enolate anion 1 may in principle be generated from any enolizable carbonyl compound 4 by treatment with base the reaction works especially well with /3-dicarbonyl compounds. The enolate 1 adds to the a ,/3-unsaturated compound 2 to give an intermediate new enolate 5, which yields the 1,5-dicarbonyl compound 3 upon hydrolytic workup ... 

Carboxylic acids having a second carbonyl group two atoms away lose C02 (clecarboxylatc) through an intermediate enolate ion when treated with base. Write the mechanism of this decarboxylation reaction using curved arrows to show the electron flow in each step. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

Hydroxy-substituted iron-acyl complexes 1, which are derived from aldol reactions of iron-acyl enolates with carbonyl compounds, are readily converted to the corresponding /i-methoxy or /1-acetoxy complexes 2 on deprotonation and reaction of the resulting alkoxide with iodomethane or acetic anhydride (Tabic 1). Further exposure of these materials to base promotes elimination of methoxide or acetate to provide the a,/ -unsaturated complexes (E)-3 and (Z)-3 (Table 2). 

Amidoalkylation of silyl enol ethers with /V-acyliiiiiiiium ions containing camphanoyl-derived acyl functions (see Appendix) as the chiral auxiliary leads to optically active 2-substituted piperidine derivatives with moderate to high diastereoselectivity, depending on the chiral auxiliary and the cnol ether82 99. The auxiliary is removed by hydrolysis with base or acid. 

It is not the aldehyde or ketone itself that is halogenated, but the corresponding enol or enolate ion. The purpose of the catalyst is to provide a small amount of enol or enolate. The reaction is often done without addition of acid or base, but traces of acid or base are always present, and these are enough to catalyze formation of the enol or enolate. With acid catalysis the mechanism is... 

This time conventional ester (38) was treated with base to give enolate (37). No doubt an ortho ester would do the same Job. 

Whereas reaction of the cyano-substituted indolizine 251 with a base results in the tf-fused product (Equation 34), the diester 255 reacts to give only the Afused product 256 <1987CL2043> (Equation 37). Similarly, when the acylindolizines 257 are prepared (Equation 38), very small amounts of the thienoindolizines are found in the product mixture. When such indolizines are substituted with both cyano and keto groups, treatment with a base gives a mixture of products resulting from reaction of the ester enolate with either of these electrophiles <1989BCJ119> (Equation 39). 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

The third procedure illustrated by this preparation involves the reaotion of ketones with trifluoromethanesulfonic anhydride in a solvent such as pentane, methylene chloride, or carbon tetrachloride and in the presence of a base such as pyridine, lutidine, or anhydrous sodium carbonate.7-11,15 This procedure, which presumably involves either acid-catalyzed or base-catalyzed enolization of the ketone followed by acylation of the enol with the acid anhydride, has also been used to prepare other vinyl sulfonate esters such as tosylates12 or methanesulfonates.13... 

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