Regioselectivity with ketone enolates

Some unsymmetrical ketones show regioselectivity in favour of the less hindered side 29 is an impressive example as both sides of the ketone are primary with branching occurring on one side only at the P carbon atom.8 You are advised to consult the literature before planning a stereoselective synthesis with ketone enolates. 

The studies of this system were extended to other analogs in order to determine the ring-size preferences in the cyclizations, the effects of hydrogens 3 to the carbonyl group, and the regioselectivity with ketones that can give two enolate... 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

In the case of a,/ -unsaturated ketones, enolates of 3-Mi4 ketones were obtained regioselectively and characterized chemically (Scheme 29)173. The reaction with a,(S-unsaturated amides is shown in equation 166175. 

Figure 12.13 shows that the iso-A enols of the /3-diketones A react with an a,/3-unsaturated carboxonium ion C that acts as a C electrophile. This oxocarbenium ion is formed by reversible protonation of the oc,/3-unsaturated methyl vinyl ketone in acetic acid. However, the oxocarbenium ion C in this figure does not react with the iso-A enols at its carbonyl carbon atom—as the protonated acetone in Figure 12.12 does with the enol of acetone—but at the center C-/3 of the conjugated C=C double bond. Accordingly, an addition reaction takes place whose regioselectivity resembles that of a 1,4-addition of an organometallic compound to an 0C,/3-unsaturated carbonyl compound (see Section 10.6). 1,4-additions of enols (like in this case) or enolates (as in Section 13.6) to a,/3-unsaturated carbonyl and carboxyl compounds are referred to as Michael additions. 

Fig. 13.11. Regioselective generation of ketone enolates, I the effects of different substituents in the Aland appositions. Enolate D is formed in THF at -78 °C with LDA irrespective of whether a substoichiometric amount or an excess of LDA is used. However, if one employs slightly less than the stoichiometric amount of LDA (so that a trace of the neutral ketone is present), then, upon warming, the initially formed enolate D isomerizes quantitatively to enolate C with its more highly substituted C=C double bond. It should be noted that LDA removes an axially oriented a-H from the cyclohexanone this is because only then does the resulting lone pair of electrons receive optimum stabilization by the adjacent C=0 bond. With the kinetically preferred deprotonation leading to the enolate D the axial of-H is transferred to the base (via transition state B), but not the equatorial of-H (via transition state iso-B.)...

In constrast, kinetic regioselectivity does not usually correspond to the thermodynamic stability ratio between the two enolates. Indeed, when the ketone is ionised in protic solvents which make equilibration possible, the more substituted enolate is formed (e.g. [45] and [46] are in the ratios 10 90 and 40 60 for the lithium and sodium ion pairs, respectively, in dimethyl ether) (House, 1972). This means that the hyperconjugative effect, which is predominant in the enolate, is less important than inductive and steric effects in the transition state, a result which is in agreement with the carbanion character. The regioselectivity of preparative enolate formation in organic solvents has been reviewed by D Angelo (1976). 

OL-Methylenecyclohutanones. The reagent reacts regioselectively with activated alkenes (vinyl ethers, silyl enol ethers) to give cyclobutanones. These products undergo ring expansion with diazomethane to cyclopentanones. Both products undergo desilylative elimination in the presence of fluoride ion to form a-methylene ketones. 

Kinetic enolates.2 The kinetic enolate of a ketone or ester is generated with enhanced selectivity by a lithium dialkylamide in the presence of chlorotrimethylsilane. In addition, LOBA is superior to LDA for regioselective generation of enolates and for stereoselective formation of (E)-enolates. 

Enamino ketones, e.g. 1. react with various enol ethers in hetero-Diels Alder reactions, with inverse electron demand - yields are high. Reactions are regioselective, but not stereoselective. Although the endo approach is favored, stereoselectivity also depends on the EjZ configuration of the heterodiene. The use of high pressure (3.75 MTorr) improves the endo selectivity. ... 

The regio- and stereoselectivity of enolate formation has been discussed in many reviews . In general, the stereo- and regioselectivity of ketone deprotonation can be thermodynamically or kinetically controlled. Conditions for the kinetic control of enolate formation are achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent at low temperature. In this case the deprotonation occurs directly, irreversibly and with high regioselectivity (equation 1). By using a proton donor (solvent or excess of ketone) or a weaker base, an equilibration between the enolates formed may... 

An alternative method for the preparation of a kinetic zinc ketone enolate (123) from an arene thiol ester 121 and bis(iodozincio)methane (122) in the presence of a palladium(O) catalyst was developed by Matsubara and coworkers (equation 36) . The modest reactivity of the zinc reagent 122 makes this transformation highly chemo- and regioselective neither isomerization of the kinetic enolate 123 nor a palladium-catalyzed coupling with the thiol ester 121 could be observed. Thus, treatment of zinc enolate 123 with various aldehydes or ketones led regioselectively to one aldol product 124. The method provides access to reactive functionalized zinc enolates which are otherwise hard to obtain. 

Regioselectively generated silyl enol ethers react with methyllithium to afford regio-chemically pure lithium enolates. Treatment of these enolates with reactive electrophiles leads to regiospecifically alkylated ketones. 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

But before we go, a special example40 of double regioselectivity with a doubly nucleophilic enol equivalent attacking a double electrophile. When the pyrrolidine enamine 112 of cyclohexanone attacks the unsaturated ester 113, the bicyclic ketone 114 is formed in good yield. 

With ketones we come to the problem of regioselectivity, and the situation from chapter 3 is that methyl ketones 98 and ketones with one primary and one secondary alkyl group, particularly cyclic ketones such as 103 give the less substituted lithium enolate 97 or 102 by kinetically controlled deprotonation with LDA, and the more substituted silyl enol ether 99 or 104 on silylation under equilibrium conditions. Either derivative (lithium enolate or silyl enol ether) may be used to make the other, e.g. 96 and 100. 

With the replacement of one ester grouping by a ketone, the ketone enolate acts as the nucleophile. Thus (66) cyclizes regioselectively to (67) and (68) cyclizes to (69 Scheme 29). This reaction is described more fully in Section 3.6.4. 

A number of bases may be used for deprotonation, but the most important ones are lithium amide bases such as those illustrated in Figure 3.3. Although other alkali metals may be used with these amides, lithium is the most common. Amide bases efficiently deprotonate virtually all ctirbonyl compounds, and do so regioselectively with cyclic ketones such as 2-methylcyclohexanone i.e., C2 vs. C6 deprotonation) and stereoselectively with acyclic carbonyls (i.e., E(O)- vs. Z(O)- enolates. If the carbonyl is added to a solution of the lithium amide, deprotonations are irreversible and kinetically controlled [36-38]. Under such conditions, the con-... 

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