Enolates deprotonation regioselectivity

For example, 2-phenylcyclohexanone can be deprotonated regioselectively with LDA (Figure 13.11). This reaction is most successful at -78 °C in THF because the reaction is irreversible under these conditions as long as a small excess of LDA is employed. Hence, the reaction is kinetically controlled and proceeds via the most stable transition state. The standard transition state of all enolate formations from C,H acids with LDA is thought to be cyclic, six-membered, and preferentially in the chair conformation (A and B in Figure 13.11). To be as... 

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. 

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... 

Scheme 1.1 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A consistent relationship is found in these and related data. Conditions of kinetic control usually favor formation of the less-substituted enolate, especially for methyl ketones. The main reason for this result is that removal of a less hindered hydrogen is faster, for steric reasons, than removal of a more hindered hydrogen. Steric factors in ketone deprotonation are accentuated by using bulky bases. The most widely used bases are LDA, LiHMDS, and NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide9 and bis-(dimethylphenylsilyl)amide10 may be useful for specific cases. 

Two consecutive enolate alkylations were utilized to generate the quaternary carbon atom (Scheme 38). Alcohol 238 was transformed into the protected hydroxy enone 244. Regioselective deprotonation at the a-position of the ketone 244 led to a cross-conjugated enolate that was alkylated with the allylic iodide 245. The vinyl silyl moiety in 245 represents a masked keto group [127]. The choice of the TBS protecting group for the hydroxyl group at of 244 was crucial in order to prevent the deprotonation at the y-posi-... 

The regio- and stereoselectivity of enolate formation are essential for the control of alkylation reactions. The regioselectivity of ketone deprotonation has been extensively investigated and this important step in alkylation reactions has been discussed in many reviews (e.g., refs 1-4, 71) and textbooks (e.g., refs 5, 6). Therefore, this topic will be discussed here only in general terms. 

The stereo- and regioselectivity of deprotonation can be kinetically or thermodynamically (equilibrium) controlled. Equilibrium between enolates occurs when a proton donor is present. The proton donor can be the solvent or an excess of the ketone in relation to the strong base present for generation of the enolate. Ketone enolate equilibration can also proceed via an aldol-rever-... 

Kinetic control can be achieved by slow addition of the ketone to an excess of strong base in an aprotic solvent. Kinetic control requires a rapid, quantitative and irreversible deprotonation reaction 2-6. The use of a very strong, sterically hindered base, such as lithium diisopropylamide or triphenylmethyllithium (trityllithium), at low temperature (— 78 °C) in an aprotic solvent in the absence of excess ketone has become a general tool for kinetic control in selective enolate formation. It is important to note that the nature of the counterion is sometimes important for the regioselectivity. Thus, lithium is usually better than sodium and potassium for the selective generation of enolates by kinetic control. 

Reaction of Z-a./j-unsaturated iron-acyl complexes with bases under conditions similar to those above results in exclusive 1,4-addition, rather than deprotonation, to form the extended enolate species. However, it has been demonstrated that in the presence of the highly donating solvent hexamethylphosphoramide, y-deprotonation of the -complex 6 occurs. Subsequent reaction with electrophiles provides a-alkylated products such as 736 this procedure, demonstrated only in this case, in principle allows access to the a-alkylatcd products from both Z- and it-isomers of a,/j-unsaturated iron-acyl complexes. The hexamethylphosphoramide presumably coordinates to the base and thus prevents precoordination of the base to the acyl carbonyl oxygen, which has been suggested to direct the regioselective 1,4-addition of nucleophiles to -complexes as shown (see Section 1.1.1.3.4.1.2.). These results are also consistent with preference for the cisoid conformations depicted. 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at — 72°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioselectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2B0S02CF3, at low temperatures (D A. Evans, 1979). Both types of fraiu-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

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... 

With this end in view, phenyldimcthylsilyl tri-n-butylstannane was added under the influence of zero-valent palladium compound with high regioselectivity and in excellent yield to the acetylene 386 to give the metallated olefin 387 (Scheme 56). The vinyl lithium carbanion 388 generated therefrom, was then converted by reaction with cerium(lll) chloride into an equilibrium mixture (1 1) of the cerium salts 389 and 390 respectively. However, the 1,2-addition of 389 to the caibonyl of 391, which in principle would have eventually led to ( )-pretazettine, did not occur due to steric reasons — instead, only deprotonation of 391 was observed. On the other hand, 390 did function as a suitable nucleophile to provide the olefinic product 392. Exposure of 392 to copper(II) triflate induced its transformation via the nine membered enol (Scheme 55) to the requisite C-silyl hydroindole 393. On treatment with tetrafluoroboric acid diethyl ether complex in dichloromethane, compound 393 suffered... 

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.)...

Figures 13.13 and 13.14 demonstrate that deprotonation might afford certain enolates with only one regioselectivity. However, there might be other reaction paths that lead to the other regioisomer (Figures 13.19-13.21).

Accordingly, trimethylsilyl enol ethers are enolate precursors (Figure 10.16). Fortunately, they can be prepared in many ways. For instance, silyl enol ethers are produced in the silylation of ammonium enolates. Such ammonium enolates can be generated at higher temperature by partial deprotonation of ketones with triethylamine (Figure 10.18). The incompleteness of this reaction makes this deprotonation reversible. Therefore, the regioselectivity of such deprotonations is subject to thermodynamic control and assures the preferential formation of the more stable enolate. Consequently, upon... 

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