Sterically hindered ketones, enolization

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.

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 ... 

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). 

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). 

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. ... 

The use of hydrazines as chiral auxiliaries was initiated by Enders and coworkers [315]. They have developed the chemistry of hydrazones derived from epimeric 1 -amino-2-methoxymethylpyrrolidines 1.76, Samp and Ramp [161, 169, 253, 261, 315, 316], These compounds are commercially available, or they can easily be prepared from (S)-prolinol 1.64 (R = CH2OH) or (R)-glutamic add [261]. Hydrazones have some advantages over their related imine derivatives. First, they are formed in quantitative yield even from sterically hindered ketones. Second, their derived anions are often more reactive than the related aldehyde or ketone enolates. 

Interestingly, CO has a positive effect on the yield of the reaction, although it is not incorporated [112]. It is observed, that the combination TMEDA/CO (tetramethylethylenediamine) is superior to HMPA/NEtj under the same reaction conditions. Under these modified conditions, not only sterically hindered ester enolates, but also deprotonated amides, lactams, ketones, sulfones, and the Evans enolates can be transformed [113]. Tertiary anions give the best results. 

Formation of Enol Silyl Ethers. Various sterically hindered ketones have been converted into enol silyl ethers by treatment with 1-2 equiv of TBDMS triflate and 1.5 equiv of tri-ethylamine in CH2CI2 or 1,2-dichloroethane at rt. A representative example is depicted in eq 2. ... 

Alkyl and acylsilanes Tetraalkylsilanes are inert to the carbonyl coupling reaction conditions, as shown by the syntheses of 43 and 44 [61, 62]. Despite their dose similarity to sterically hindered ketones, McMurry reactions of acylsilanes are limited to the preparation of the 1,2-disilylated stilbenes 45 (R = H, Br or OMe) silyl enol ethers are also obtained as by-products, resulting from silatropic migration [63], No such coupling of aliphatic acylsilanes has yet been reported. 

In the research groups of Seebach [67, 153] and Tidwell [154], alkyl and aryl lithium compounds were found to add readily to ketenes 153 that are accessible by various methods, as, for example, treatment of acid chlorides with triethy-lamine or acid bromides with zinc. As a result, ketone enolates 154 are formed. Due to the high reactivity of the ketenes, the protocol permits to access even sterically hindered trisubstituted enolates, the configuration of which depends on the steric demand of the substituents and R. Thus, alkyllithium reagents add from the sterically less hindered side, so that enolates 154 form with high diastereoselectivity. Of course, the ketone enolates thus generated are pure regioisomers. 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

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. 

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 . ... 

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. 

Stereoselectivity is observed when one face of the enolate is more hindered than the other. This situation is clearly demonstrated by a comparison of the stereospecificity of the alkylation of 4-tert-butylcyclohexanone (6)34 with that of a more rigid and sterically hindered bicyclic ketone 835. 

Hydroboration-oxidation of alkynes preparation of aldehydes and ketones Hydroboration-oxidation of terminal alkynes gives syn addition of water across the triple bond. The reaction is regioselective and follows anti-Markovnikov addition. Terminal alkynes are converted to aldehydes, and all other alkynes are converted to ketones. A sterically hindered dialkylborane must be used to prevent the addition of two borane molecules. A vinyl borane is produced with anU-Markovnikov orientation, which is oxidized by basic hydrogen peroxide to an enol. This enol tautomerizes readily to the more stable keto form. 

Deoxygenation ofketones. Enol triflates, readily available by reaction of ketones and triflic anhydride catalyzed by this sterically hindered base, undergo rapid hydrogenolysis to the saturated hydrocarbon. Overall yields are 65-90%. ... 

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