Enolate regioisomers

The enolate that is die most stable usually has die most highly substituted double bond and is called the thermodynamic enolate. If a slight excess of the ketone is used or a trace of protic impurities is present, equilibrium between die enolates is established and isomerization to die more highly substituted enolate occurs. 

The thermodynamic enolate is lower in energy so it is the one favored if equilibrium is achieved. For this reason, great care must be taken in die preparation and 

The most common group G is an ester function (aldiougli many odier groups have been employed as well). The starting /f-ketoester, which can be prepared easily by a Claisen-type reaction of an ester enolate and an acid chloride, has a 

A diird strategy for controlling enolate formation is to convert the carbonyl group to a jV,jV-dimediylhydrazone. The hydrazone is less reactive than die carbonyl group, and removal of an a proton by a strong base takes place at the least hindered a position. Alkylation followed by hydrolysis gives back carbonyl product that is die same as die result of kinetic control of enolate 

The use of hydrazones is particularly important to form die enolate equivalents of aldehydes. Aldehydes are quite reactive as electrophiles, so as soon as some enolate has been formed, it reacts witii die unreacted aldehyde present in solution. Conversion of die aldehyde to its /V, /V-dimetliy 1 hydrazone (=NNMe2) lowers the electrophilicity so that a-proton removal can take place and then the electrophile of choice can be added. Hydrolysis gives back the aldehyde. In this case the geometry of die hydrazone is unimportant since aldehydes have only one a position from which protons can be removed by base. 

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The transfer of electrons is not susceptible to steric hindrance so substituted alkenes pose no problem. In the next example, the enolate reacts with allyl bromide to give a single stereoisomer of the product (the allyl bromide attacks from the face opposite the methyl group). Naturally, only one regioisomer is formed as well, and it would be a tall order to expect formation of this single enolate regioisomer by any form of deprotonation method. 

The decarboxylation-allylation of allyl enol carbonates proceeds smoothly[450]. The isomeric enol carbonates 699 and 701 of the enone 698 undergo regiospecific allylation, giving the regioisomers 700 and 702 selectively. 

Full exploitation of the synthetic potential of enolates requires control over the regioselectivity of their formation. Although it may not be possible to direct deprotonation so as to form one enolate to the exclusion of the other, experimental conditions can often be chosen to favor one of the regioisomers. The composition of an enolate mixture can be governed by kinetic or thermodynamic factors. The enolate ratio is governed... 

These reactions were proposed to proceed via electrophilic attack on the enol by the SN reagents at N followed by cyclization either via a second enol as in compound 151 or by cyclization onto the more reactive carbonyl <1997J(P1)2831>. Unsymmetrical 1,3-diketones can give a mixture of regioisomers if both carbonyls have similar reactivities however, aroylacetones react regiospecifically to afford only the 3-aroyl-4-alkyl-l,2,5-thiadiazoles 154 (R = Me). 

Reactions involving ketones are generally controlled by the thermodynamic stability of the enolate anion. However, 2-phenylcyclohexanone reacts with bulky Michael acceptors to form the 2,6-regioisomer preferentially [17], indicating that the reaction is mainly kinetically controlled with the approach of the Michael acceptor to the substituted 2-position being sterically hindered. 

Alternative furan ring fusion involves the reactions of phenyliodonium ylides of cyclic seven-membered jS-diketones with alkynes. These processes lead under mild conditions to cyclization products 152. The high regioselectivity can be explained by the formation of dipolar intermediate 151 favored by the predominant enolization of the carbonyl adjacent to phenyl ring. Terminal alkynes react in the similar fashion, although, in this case, mixtures of regioisomers have been reported due to steric hindrance in the intermediate enol (Scheme 30 (1993JOC4885)). 

Trimethylsilyl enol ethers can be prepared directly from ketones. One procedure involves reaction with trimethylsilyl chloride and a tertiary amine.20 This procedure gives the regioisomers in a ratio favoring the thermodynamically more stable enol ether. Use of... 

Regioisomer 49a was obtained in the form of its ring tautomer 3-hydroxy-3,5,5-trimethyl-l,2-dioxolan, produced by ketonization of the initial enol and cyclization. 

The carbonyl ylide precursor can be generated by lead tetraacetate oxidation of the hydrazone 58. Thermolysis of 59 in the presence of perdeuterated acetone led to a variety of products, some of which are shown above. An internal quench of the ylide via a 1,4-proton migration led to enol ether 61, while cycloaddition with perdeuterated acetone formed the dioxolane 62 and its regioisomer. Interestingly, the presence of products such as acetone and propene-t/s are proposed to indicate a reversible fragmentation of the ylide to a carbonyl derivative and a carbene. 

Under conditions for thermodynamic control, the major regioisomer formed is usually the enolate Carrying most substituents at the double bond. This can be attributed to the fact that the stability of C-C double bonds increases with increasing substitution6. Conditions for kinetic control in enolate formation usually favor formation of the enolate with the least substituents at the double bond. The rational for this is based on steric reasons, i.e., the less hindered proton is abstracted more rapidly than the hindered proton, giving the less substituted enolate. 

Regioisomer 49a was obtained in the form of its ring tautomer 3-hydroxy-3,5,5-trimethyl-l,2-dioxolan, produced by ketonization of the initial enol and cyclization. b No products from 49a and 49b could be detected. r 8% of i S.S), (S,/ )-54J was formed as side products in a 23 77 ratio. d Only ( )-configured hydroperoxides 44g were detected. 

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