Hindered ketones, enolization

Interestingly enough, both protons at C-11 are exchanged quite readily in 12-keto steroids. In these compounds C-11 is the only possible enolization site where the axial (/3) proton is probably expelled first. During ketonization, the deuteron attack is more likely to occur from the less hindered a-side. By this sequence the proton which was originally at the lla-equato-rial position becomes axial and readily available for expulsion in the next enolization step. Thus, isomerization of the C-11 hydrogens may be an important reason for the facile exchange at this position. (For a more detailed discussion of the mechanism of enolization and ketonization reactions, see ref 114.)... 

Another side-reaction can be observed with sterically hindered ketones that contain an a-hydrogen—e.g. 18. By transfer of that hydrogen onto the group R of RMgX 2, the ketone 18 is converted into the corresponding magnesium enolate 19, and the hydrocarbon RH 14 is liberated ... 

Twofold Michael additions have been utilized by the groups of Spitzner [2] and Hagiwara [3] to construct substituted bicyclo[2.2.2]octane frameworks. In Hagiwara s approach towards valeriananoid A (2-6) [4], treatment of trimethylsily-enol ether 2-2, prepared from the corresponding oxophorone 2-1, and methyl acrylate (2-3) with diethylaluminum chloride at room temperature (r.t.) afforded the bicyclic compound 2-4 (Scheme 2.2). Its subsequent acetalization allowed the selective protection of the less-hindered ketone moiety to provide 2-5, which could be further transformed into valeriananoid A (2-6). 

The success of this transformation depends upon the oxidation potential of the ESE group (Eox 1.5 V), which is lower than that of the alkyl silyl ether group (Eax 2.5 V). Recently, Schmittel et al.35 showed (by product studies) that the enol derivatives of sterically hindered ketones (e.g., 2,2-dimesityl-1-phenyletha-none) can indeed be readily oxidized to the corresponding cation radicals, radicals and a-carbonyl cations either chemically with standard one-electron oxidants (such as tris(/>-bromophenyl)aminium hexachloroantimonate or ceric ammonium nitrate) or electrochemically (equation 10). 

Enolization of ketonic substrates can be carried out under far milder conditions if the dialkylboryl trifluoromethanesulfonate esters 59 (eq. [24]) are employed in the presence of hindered tertiary amines (eq. [43]) (6,63). At low temperatures (-78 0°C),... 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

Ketones may direct lateral Uthiation even if the ketone itself is enoUzed enolates appear to have moderate lateral-directing ability. Mesityl ketone 522, for example, yields 523 after silylation—BuLi is successlnl here because of the extreme steric hindrance around the carbonyl group (Scheme 204). The lithium enolate can equally well be made from less hindered ketones by starting with a silyl enol ether . ... 

The second is that sterically hindered ketones bearing hydrogen atoms on their a-carbons, R2CH(CO)R (cf. 3b), tend to be converted to their enolates (6), where the Grignard reagent, R MgX, is lost as R —H in the process via 4b (Scheme 4). 

Magnesium enolates derived from hindered ketones are also possible Michael donors. For example, enolization of f-butyl alkylketones with (i-Pr)2Mg allows the 1,4-addition on the chalcone. A long reaction time (>3 h) limits the competing 1,2-addition and increases the proportion of the threo isomer (equation 77). 

Magnesium enolates derived from hindered ketones are able to initiate polymerization. For example, addition of 2, 4, 6 4-trimethylacetophenone in toluene to a suspension of (DA)2Mg results in the isolation of (DA)Mg(OC(=CH2)-2,4,6-Me3C6H2), which is found to be an excellent initiator for the living syndioselective (a > 0.95) polymerization of methyl methacrylate (equation 86). 

Enolization is an acid-base reaction (2-24) in which a proton is transferred from the a carbon to the Grignard reagent. The carbonyl compound is converted to its enolate ion form, which, on hydrolysis, gives the original ketone or aldehyde. Enolization is important not only for hindered ketones but also for those that have a relatively high percentage of enol form, e.g., p-keto esters, etc. In reduction, the carbonyl compound is reduced to an alcohol (6-25)... 

Aldehyde synthesis.1 Hindered ketones, which do not react with methoxy-iiietliylenetriphenylphosphoranc (I, 671), do react with 1 to form an enol ether, which is readily hydrolyzed by acid to the homologous aldehyde. Representative aldehydes (and the yield) available by this method are formulated. 

Dicarbonyl compounds.1 The reaction of enol silyl ethers with methyl vinyl ketone catalyzed by BF3 etherate results in 1,5-dicarbonyl compounds. Almost quantitative yields can be obtained, even from hindered ketones, by addition of an alcohol or even, to a less extent, of water. 

In Methods 3a to 3d. enolization of carbonyl compound and reduction of RMgX are side reactions that become important for hindered ketones and bulky Grignard reagents (Section 14-12A). Ammonium chloride is used to hydrolyze the reaction mixtures in preparation of tertiary alcohols to avoid dehydration. Organolithium compounds are superior to RMgX for preparation of bulky tertiary alcohols. 

Step 3 The reaction of a tertiary Grignard reagent with a hindered ketone may result in reduction and/or enolization of the ketone. However, in the present example, the use of formaldehyde (an excellent electrophile) circumvents these side reactions. 

Figure 13.30 shows that even sterically hindered ketone enolates can he alkylated. The carbon atom in the /3-position relative to the carhonyl carhon of an ,/i-dialkylated a,/3-unsatu-rated ketone can be converted into a quaternary C atom via 1,4-addition of an Gilman cuprate (for conceivable mechanisms, see Figure 10.46). As can he seen, a subsequent alkylation allows for the construction of another quaternary C atom in the a-position even though it is immediately adjacent to the quaternary center generated initially in the /1-position.

Beyond the scope discussed so far, Michael additions also include additions of stoichio-metrically generated enolates of ketones, SAMP or RAMP hydrazones, or esters to the C=C double bond of ,/Tun saturated ketones and a,/Tunsaturated esters. These Michael additions convert one kind of enolate into another. The driving force stems from the C—C bond formation, not from differential stabilities of the enolates. It is important that the addition of the preformed enolate to the Michael acceptor is faster than the addition of the resulting enolate to another molecule of the Michael acceptor. If that reactivity order were not true, an anionic polymerization of the Michael acceptor would occur. In many Michael additions, however, the enolate created is more hindered sterically than the enolate employed as the starting material, and in these cases Michael additions are possible without polymerization. 

Simple saturated ketones, however, were recovered unchanged even when a twofold excess of the lithiocyclopropyl phenyl sulfide 116 a was employed apparently due to problems of enolization, but hindered ketones or a-enones underwent complete carbonyl condensation 61 ... 

The free monomeric hydroxy aldehydes are difficult to obtain by hydrolysis of the oximes. Bromomagnesium enolates prepared from Grignard reagents and sterically hindered ketones act as true Grignard reagents. /3-keto alcohols are formed by their reaction with aldehydes or ketones. ... 

Parham and Roosevelt noted differences in the two methods for preparation of silyl enol ethers. Stork s method appears to be more suitable for hindered ketones, whereas House s method is better for less hindered, easily condensable ketones. 

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