Solvents enol formation

It does not matter whether it is the cis- or the trans-isomer of the allyl alcohol that is more easily accessible. According to Figure 14.51, by selecting the appropriate solvent, enolate formation can be directed to convert both the cis- and the tranr-allyl alcohols into rearranged products that contain either a syn- or an anti-arrangement of the vicinal alkyl groups. 

To obtain complete conversion of ketones to enolates, it is necessary to use aprotic solvents so that solvent deprotonation does not compete with enolate formation. Stronger bases, such as amide anion ( NH2), the conjugate base of DMSO (sometimes referred to as the dimsyl anion),2 and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide (LDA), which is generated by addition of w-butyllithium to diisopropylamine, is widely used as a strong... 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.5.2), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the /r-enolate is preferred under kinetic conditions using a strong base such as LDA in THF solution. Inclusion of a strong cation solvating co-solvent, such as HMPA or tetrahydro-1,3 -dimethyl-2(1 Z/)p y r i m i d o nc (DMPU) favors the Z-enolate.13... 

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. 

The enolate formation and subsequent alkylation of alkyl 3-dialkyl-2-silyloxycyclopropane-l-car-boxylates has been investigated in detail65-68. In a relatively polar solvent like teLrahydrofuran, especially in the presence of HMPA, the main product is the mms-isomer 12a, whereas in a nonpolar medium (e.g., pentane) the selectivity is reversed and the civ-product 12b is favored. 

The alkylations are performed in the usual way. Deprotonation is achieved with a strong base, usually lithium diisopropylamide or sometimes butyllithium, added to the amide 1 in tetrahydrofuran at low temperature, usually —78 C7. Sometimes a mixture of solvents is used. To ensure complete enolate formation, warming to 20 °C is usually employed. An excess of alkylating agent is added at —78 or — 20 °C and the products 2 and 3 are isolated in the conventional way (see Tables 7 and 8). 

Stoichiometric, irreversible formation of enolates from ketones or aldehydes is usually performed by addition of the carbonyl compound to a cold solution of LDA. Additives and the solvent can strongly influence the rate of enolate formation [23]. The use of organolithium compounds as bases for enolate formation is usually not a good idea, because these reagents will add to ketones quickly, even at low temperatures. Slightly less electrophilic carbonyl compounds, for example some methyl esters [75], can, however, be deprotonated by BuLi if the reactants are mixed at low temperatures (typically -78 °C), at which more metalation than addition is usually observed. A powerful lithiating reagent, which can sometimes be used to deproto-nate ketones at low temperatures, is tBuLi [76],... 

Silyl ketene acetals from esters.1 Ireland has examined various factors in the enolization and silylation of ethyl propionate (1) as a model system. As expected from previous work (6, 276-277), use of LDA (1 equiv.) in THF at —78 -+ 25° results mainly in (E)-2, formed from the (Z)-enolate. The stereoselectivity is markedly affected by the solvent. Addition of TMEDA results in a 60 40 ratio of (Z)- and (E)-2 and lowers the yield significantly. Use of THF/23% HMPA provides (Z)- and (E)-2 in the ratio of 85 15 with no decrease in yield. This system has been widely used for (E)-selective lithium enolate formation from esters and ketones. Highest stereoselectivity is observed by addition of DMPU, recently introduced as a noncar-... 

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). 

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... 

The acidity of carbonyl-containing compounds and their solvent effects have been well documented " ". Typically, enolate formation is less favoured in DMSO than H2O due to lower stabilization of its oxy-anion (i.e. the pATa of the corresponding carbonyl compound in DMSO is higher than in H20). However, under certain circumstances, the reverse can be true , as with certain ammonium salts , for ethyl 2-trifluoromethylsulfonylacetate (21) was found to be more acidic in DMSO [p fa(DMSO) = 6.40 ] than in H20. This unusual behaviour is presumably due to the corresponding enolate existing as a carbanion as opposed to its normal enolic form ". In comparison, for ethyl nitro-acetate (22) and ethyl cynanoacetate (23) the usual trend returns, even... 

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. ... 

Deprotonation of the ketone must be fast, complete, and irreversible for kinetic control of enolate formation. No equilibration of the enolates can be allowed to occur. Optimum conditions for kinetic control of deprotonation are Add the ketone slowly to an excess of very strong base (usually i-Pr2NLi, the anion of diisopropyl amine, p iabH = 36) in an aprotic solvent (such as dry tetrahydrofuran or dimethoxyethane). Since the A"eq for deprotonation of a ketone with this base is 10 = lO -, the reaction is... 

In an important experiment, Mukaiyama and coworkers enolized carbonyl compounds under much milder conditions (low temperatures) with dialkylboryl triflate and a sterically hindered tertiary amine base such as 2,6-lutidine (2,6-dimethylpyridine) or diisopropylethylamine (DPEA).95-97 Less-hindered bases led to formation of a stable borane-amide complex (Lewis acid-Lewis base) and prevented the reaction with the carbonyl compound. Masamune et al,98 and Evans et a/.99100 carried out a study to investigate the reasons for the selective enolate formation. They showed that it depends on the boron ligand, base, solvent and the group attached to the carbonyl moiety. Ketones give (Z)-enolates with often excellent selectivity, whereas r-butyl thiolates give selectively the ( )-enolates (equations 32 and 33).100 101 Evans suggests that reactions with 9-BBN triflate are often under thermodynamic control.15 In equation... 

PEP carboxylase avoids the thermodynamic problem of enolate formation by beginning with PEP instead of pyruvate. Provided that the enolate is shielded from solvent, this offers a thermodynamically favorable approach to the car-boxylation step. PEP carboxylase achieves a high concentration of CO2 at the active site of the enzyme by starting with HCOs" and using the phosphate bond energy to dehydrate it. Protection of the active site from solvent is also important in order to ensure that CO2 is available for reaction with the enolate, rather than dissociating. 

Furthermore, decomposition of the unlabeled cobaloxime in CH3OD provided mainly 1-deuterio-phenylacetaldehyde, indicating the involvement of solvent in formation of the aldehyde product. Thus the mechanism must involve a cis ehmination of hydridocobaloxime to form an enol (Eqn. 40)... 

Enolate formation is an acid-base equilibrium process. For reactions A and B, discuss the relative acidity of all hydrogens in 3-methyl-2-butanone. Discuss the role of solvent, base, temperature and reaction time for reactions A and B. 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

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