Enolate of unsymmetrical ketones

Wittig reagents can represent enolates of unsymmetrical ketones. From Corey s work on arachidonic acid metabolites18 comes the coupling between the aldehyde 92 and the phosphonium salt 93. This is very impressive as both components have multiple functionality and there is no loss of stereochemical integrity even though the Wittig reaction is done in aqueous NaOH. 

There are numerous base-solvent combinations that are capable of quantitatively converting even weakly acidic simple ketones into their enolate anions. However, in order to avoid aldol condensation and unwanted equilibration of enolates of unsymmetrical ketones during enolate formation, it is best to choose conditions under which the ketone, the base and the metal enolate are soluble. Likewise, solutions should be produced when indirect methods of enolate formation are employed. While certain metal cations such as Hg form a-metallated ketones, most of the metal cations in Groups 1, II and III exist as 0-metallated tautomers. - For organotin derivatives both the 0-metallated and C-metallated forms probably exist in equilibrium. ... 

Ketone enolates.1 The kinetic enolate of unsymmetrical ketones can be generated with 1. The advantage over LDA is that the resulting enolate solution is free of amine. 

Lithium etiolates of imsymmetriealketones. House et a .2 find that the less highly substituted lithium enolates of unsymmetrical ketones are best obtained by kinetically controlled deprotonation of the ketone with the hindered base lithium diisopropyl-amide. Thus treatment of 1-decalone (1) with 1.03 eq. of the base in 1,2-dimethoxyethane for 10 min. gives predominantly the lithium enolate (2) alkylation of the mixture with a... 

Similarly, specific enolates of unsymmetrical ketones can be obtained by reduction of a,p-unsaturated ketones with lithium in liquid ammonia. Alkylation of the intermediate enolate gives an a-alkyl derivative of the corresponding saturated ketone which may not be the same as that obtained by base-mediated alkylation of the saturated ketone itself. For example, base-mediated alkylation of 2-decalone generally leads to 3-alkyl derivatives whereas, by proceeding from the enone 11, the 1-alkyl derivative is obtained (1.26). The success of this procedure depends on... 

The treatment of a,p-unsaturated ketones with organocopper reagents provides another method to access specific enolates of unsymmetrical ketones. Lithium dialkylcuprates (see Section 1.2.1) are used most commonly and the resulting enolate species can be trapped with different electrophiles to give a,p-dialkylated ketones (1.27). Some problems with this approach include the potential for the intermediate enolate to isomerize and the formation of mixtures of stereoisomers of the dialkylated product. The intermediate enolate can be trapped as the silyl enol ether and then regenerated under conditions suitable for the subsequent alkylation. Reaction of the enolate with phenylselenyl bromide gives the a-phenylseleno-ketone 12, from which the p-alkyl-a,p-unsaturated ketone can be obtained by oxidation and selenoxide elimination (1.28). 

Reaction of unsymmetrical ketones with strong bases may lead to two different enolates. Whether the eventual product derives from the more stable ( thermodynamie ) enolate, or from the more rapidly formed ( kinetie ) enolate, depends on reaetion conditions. 

No efforts to improve the diastcreoselectivity of the reaction of iron acetyl enolates with unsymmetrical ketones have been reported. 

Regioselectivity in the halogenation of unsymmetrical ketones can be attained by treatment of the appropriate enol borinate of the ketone with NBS or NCS. The desired halo ketone is formed in high yield. Another method for achieving the... 

The role of the trimethylsilyl group is to stabilize the enolate formed in the conjugate addition. The silyl group is then removed during the dehydration step. Methyl 1-trimethylsilylvinyl ketone can be used under aprotic conditions that are compatible with regiospecific methods for enolate generation. The direction of annulation of unsymmetrical ketones can therefore be controlled by the method of enolate formation. 

The method outlined here competes well with the method developed earlier by Danheiser, et al.618 Its superiority is based on the fact that phenyl ester enolates give almost the same results as the S-phenyl thiolester enolates. However, handling the malodorous benzenethiol for the preparation of the active acid derivative and during workup of the p-lactone can be avoided. In addition, phenol is much cheaper than benzenethiol. The method is well suited for the preparation of p-lactones from symmetrical and unsymmetrical ketones. In addition to 3,3-dimethyM-oxaspiro[3.5]nonan-2-one, ( )-3-ethyl-1-oxaspiro[3.5]nonan-2-one and (3R, 4R )- and (3R, 4S )-4-isopropyl-4-methyl-3-octyl-2-oxetanone were prepared by this procedure in high yields (Notes 11 and 12). In the case of unsymmetrical ketones the less sterically crowded diasteroisomer is formed preferentially. With aldehydes as the carbonyl component the yields are unsatisfactory, because of the competitive formation of 1,3-dioxan-4-ones.6... 

Silyl enol ethers Trimethylsilyl enol ethers can be obtained from a-silyl ketones by thermal rearrangement or by catalysis with HRh(CO)[P(C6H5)3]3, (CH3)3SiOTf, or ISi(CH3)3. The first two methods are (E)-selective in the case of unsymmetrical ketones, whereas the latter two are (Z)-selective. 

In the alkylation of unsymmetrical ketones, formation of more than one enolate anion is possible, and when this occurs, mixtures of products are obtained. Thus,... 

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... 

Selenenylation of lithium enolates is particularly inqxntant in the case of unsymmetrical ketones, when the product of kinetic control is preferentially formed. The more-substituted isomeric derivative is prepared by the selenenylation of the corresponding enol acetate. An interesting base-catalyzed transse-lenenylation reaction of a-alkyl-a-phenylseleneno ketones to the less-substituted a -position has recently been reported for which steric crowding at the a-position appears to be an essential requirement. 

Regioselective formation of thermodynamic enolates (or their corresponding silyl enol ethers) can be accomplished by treatment of unsymmetrical ketones with KH, or with KH, t-BuMe2SiCl in the presence of HMPAA ... 

The above results led to an explosion of interest in the use of lithium enolates in a-alkylation reactions. It was quickly demonstrated that specific lithium enolates of a variety of unsymmetrical ketones could be trapped with the more reactive alkylating agents in liquid ammonia or aprotic solvents such as... 

In contrast to the results of base-catalyzed alkylations of sodium or potassium enolates under thermodynamic control, alkylations of enamines of unsymmetrical ketones occur largely or exclusively at the less-substituted a-position. More-substituted ketone enamines are destabilized relative to the less-substituted isomers by A - -strain involving the substituents on the nitrogen atom and at the 3-carbon atom. Although in most systems some of the more-substituted enamine is present in equilibrium with the less-substituted isomer, the former is less reactive toward C-alkylation because steric effects prevent effective overlap of the lone pair of electrons on nitrogen with the carbon-carbon ir-bond. 

Astonishing behavior of ATPH in a carbonyl recognition event was highlighted in the kinetic generation of more substituted enolates of unsymmetrical dialkyl ketones [28]. Most likely, ATPH prefers coordination with one of the lone pairs of carbonyl oxygen anti to the more sterically hindered a-carbon of unsymmetrical... 

We shall discuss further aspects of the aldol reaction in the next two chapters where we shall see how to control the enolisation of unsymmetrical ketones, and how to control the stereochemistry of aldol products such as 121. We shall return to a more comprehensive survey of specific enol equivalents in chapter 10. In this chapter we are concerned to establish that chemoselective enolisation of esters, acids, aldehydes, and symmetrical ketones can be accomplished with lithium enolates, enamines, or silyl enol ethers, and we shall be using all these intermediates extensively in the rest of the book. 

After our discovery of Michael additions of lithium cuprates to enones in chapter 9, we are also now able to make specific enolates 106 and 108 of unsymmetrical ketones whose branchpoint is the P rather than the a atom, such as 3-alkyl cyclohexanones 107. That is, providing we don t try and make them from the ketone itself. 

Modem synthetic practice frequently requires the use of methods mote specific than those outlined above. Much attention has been focused on the mixed Claisen or Dieckmann reaction, i.e. the acylation of one ester by another, or its intramolecular equivalent, the regioselective cyclization of an unsymmetri-cal diester. A similar problem arises with the acylation of unsymmetrical ketones. This chapter thus describes the inter- and intra-molecular carbon-carbon bond-forming reactions in which a delocalized enolate anion (or close equivalent) reacts at an sp carbon atom in an addition-elimination sequence, as well as the acid-catalyzed equivalent employing an enol. In Table 1 we list the potential nucleophiles and the electrophiles that have been employed in these reactions, although not every possible combination has been reduced to synthetic practice. Table 2 gives details of acid-catalyzed acylations (see Section 3.6.4.3). 

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