Enolate of unsymmetrical carbonyl compounds

Sometimes, specific lithium enolates of unsymmetrical carbonyl compounds are formed because of chelation of the Uthium atom with a suitably placed substituent. For example, lithiation and alkylation of the mixed ester 1 took place a- to the MEM ester group, presumably as a result of intramolecular chelation of the lithium atom with the ethereal oxygen atom (1.14). ... 

What happens when an unsymmetrical carbonyl compound like 2-methylcyclohexanone is treated with base Two enolates are possible, one formed by removal of a 2° hydrogen, and one formed by removal of a 3° hydrogen. 

Reactions in which the enol or enolate (or equivalent) of one carbonyl compound reacts with an electrophilic carbonyl compound (usually both are aldehydes or ketones) are often loosely called aldol reactions. In the last chapter we saw how the use of lithium enolates and other specific enolate equivalents conquers the problem of chemoselectivity in enolisation of aldehydes and acid derivatives. In this chapter, we are going to use the same intermediates to solve the problem of regioselectivity in crossed aldol reactions in which the enolising component is an unsymmetrical ketone. 

Deprotonation of the corresponding carbonyl compound is a fundamental method for the generation of enolates, and we discuss it here for ketones and esters. An unsymmetrical dialkyl ketone can form two regioisomeric enolates on deprotonation. 

A new method of kinetically controlled generation of the more substituted enolate from an unsymmetrical ketone involves precomplexation of the ketone with aluminium tris(2,6-diphenylphenoxide) (ATPH) at —78°C in toluene, followed by deprotonation with diisopropylamide (LDA) highly regioselective alkylations can then be performed.22 ATPH has also been used, through complexation, as a carbonyl protector of y./)-unsaturated carbonyl substrates during regioselective Michael addition of lithium enolates (including dianions of /i-di carbonyl compounds).23... 

A broad spectrum of a,/J-unsaturated carbonyl compounds becomes accessible in this way because a great variety of aldehydes is suited for aldol condensation. Table 13.7 exemplifies the broad scope by way of the reactions of an aldehyde enolate (center) and of the enolate of an unsymmetrical ketone (right). The right column of Table 13.7 also shows that the regio-selectivity of the aldol condensation of the ketone is not easy to predict. Subtle substituent... 

Reactions of unsymmetrical methylene 1,3-dicarbonyl compounds with enol ethers have been investigated by Yamauchi et al. [137]. As we have mentioned earlier, the a,/ -unsaturated ketone moiety in alkylidene-/ -ketoesters reacts exclusively as the oxabutadiene. However, high regioselectivity is also observed with mixed alkyl-phenyl-1,3-diketones with exclusive reaction of the aliphatic carbonyl group, whereas in alkylidene-1,3-dicarbonyl compounds bearing an aldehyde and a keto-moiety, the a,/J-unsaturated aldehyde reacts preferentially as oxabutadiene, but not exclusively [130a]. 

The first step must be the formation of an enolate anion using NaOH as a base. Though both carbonyl compounds are unsymmetrical, there is only one site for enolization as there is only one set of a protons, on the methyl group of the ketone. The aldehyde has no ot protons at all. 

A greater degree of regiocontrol over the above methods can be achieved by quenching the enolate of carbonyl compounds with either brominei or iodine.Thus, in the case of unsymmetrical ketones (Scheme 3), low temperature formation of the enolate allows exclusive bromination of the kinetic enolate to afford foe haloketone (1), which on elimination gives foe enone (2). A similar procedure allows... 

Equilibrium favors the keto form for most carbonyl compounds largely because a C=0 is much stronger than a C=C. For simple carbonyl compounds, < 1 % of the enol is present at equilibrium. With unsymmetrical ketones, moreover, two different enols are possible, yet they still total <1%. 

Structural effects on the rates of deprotonation of ketones have also been studied using very strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as LDA and KHMDS give solutions of the enolates that reflect the relative rates of removal of the different protons in the carbonyl compound kinetic control). The least hindered proton is removed most rapidly under these conditions, so for unsymmetrical ketones the major enolate is the less-substimted one. Scheme 6.1 shows some representative data. Note that for many ketones, both E- and Z-enolates can be formed. 

Time to recap and summarize the various kinds of enol and enolate that can form from carbonyl compounds. You have already seen that ketones and aldehydes enolize. With an unsymmetrical ketone, more than one enol or enolate ion is possible. 

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. 

Silylation Reactions. In the presence of a catalytic amount of tetra-n-butylammonium fluoride (TBAF), ester (1) is a very efficient silylating agent for a wide variety of substrates including carbonyl compounds, alcohols, phenols, carboxylic acids, and alkynes. With unsymmetrical ketones the kinetic enol ether is the preferred product. Indeed, the use of (1) can provide superior selectivity to the use of hindered bases forenolate formation. This is illustrated with a 8,y-epoxy ester which provides an entry to /-keto-a, 8-unsaturated esters (eq 2). These silylation reactions of (1) can also be catalyzed by TBAF supported on silica. ... 

Addition of tributylstannyl-lithium to crotonaldehyde and protection of the resulting alcohol with chloromethyl methyl ether gives the stannane (192), which reacts with both alkyl and aryl aldehydes RCHO to form specifically the t/rr o-hydroxy-enol ethers (193). These latter compounds have been used to prepare tra/i5-4,5-disubstituted butyrolactones by hydrolysis and subsequent oxidation. Palladium-catalysed carbonylation of RX in the presence of organotin species constitutes a useful synthesis of unsymmetrical ketones, and in the example reported this year RX is an arenediazonium salt. The reaction, which is basically an aromatic acylation, proceeds in good to excellent yield. Another Pd-catalysed reaction of aromatics, this time aryl bromides, is their reaction with acetonyltributyltin (194), prepared from methoxytributyltin and isopropenyl acetate, to give the arylacetones (195). ... 

The bromination of ketones is believed to occur via acid-catalyzed enolization, followed by electrophilic attack on the enol form. Unsymmetrical ketones can give rise to mixtures of bromo ketones due to mixtures of enols, and several approaches to overcome this shortcoming have been reported. Radical bromination in the presence of epoxides (as acid scavengers) allows for substitution at the more highly substituted position (eq 17). Silyl enol ethers of aldehydes and ketones react with bromine (or NBS) to give the a-brominated carbonyl compounds (eq 18). This, combined with the ability to regiospecifically prepare silyl enol ethers (kinetic vs. thermodynamic), makes for an extremely useful technique for the preparation of a-bromo carbonyl compounds. 

Metalation of dimethylhydrazone derivatives of aldehydes and ketones occurs cleanly. Unsymmetrical ketones suffer proton abstraction from the lesser-alkylated a-carbon atom specifically, and the a-lithiated dimethylhydrazones react more vigorously than the corresponding enolates with halides (Scheme 23), oxirans, and carbonyl compounds (Scheme 23). Cuprate derivatives can be obtained from the lithiated species in the usual manner and the cuprates undergo Michael addition to ajS-unsaturated ketones. 

The reaction of monodeprotonated [ C2]acetylene with carbonyl compounds has been exploited as a means of extension of the carbon chain of various terpenes and steroids by two [ " C]carbon atoms. In the simplest case, reaction of potassium [ C2]acetylide with steroid ketone 1 and subsequent acid catalyzed cleavage of the enol ether protecting group gave 17a-[ C2]ethynyltestosterone (2). The sequential addition of deprotonated [ C2]acetylene to carbonyl compounds opens access to symmetrical or unsymmetrical [2,3- C2]alkyn-l,4-diols is exemplified in the synthesis of all-tran -/3-[15,15 - C2]-carotene ([ C2]provitamin A). Thus, treatment of lithium [ C2]acetylide with terpene aldehyde 2 followed by double deprotonation of the resultant alkynol 4 and reaction with a second equivalent of 3 provided alkyne-l,4-diol 5 the requisite key intermediate. Subsequent acid-catalyzed dehydration of 5 followed by Lindlar s catalyst-mediated partial hydrogenation and photoisomerization afforded the final product". ... 

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