Ketones enolates, also

This deprotonation may reform the ketone enolate that was the intermediate en route to the Michael adduct. However, the regioisomeric ketone enolate also can be formed. Figures 13.71-13.74 show such enolate isomerizations B — D, which proceed via the intermediacy of a neutral Michael adduct C. This neutral adduct is a 1,5-diketone in Figure 13.71, a 5-ketoaldehyde in Figure 13.72, and a 5-ketoester in Figure 13.73. 

Compared with other synthetic intermediates, enolates show a decreased reactivity. The differences in reactivity are most striking in reactions with alkylating agents [1] and epoxides [6]. The reactivities of the various types of enolates towards alkyl halides decrease in the order C=C(0 )NR2 (amide-enolate) C=C(0 )0R (ester enolate) C=CO (ketone-enolate). Metallated nitriles, imines, and S,S-acetals are, in general, much better nucleophiles than enolates in alkylations and ft-hydroxyalkylations [1], Furthermore, the alkylation of aldehyde and ketone enolates usually does not stop after the mono-functionalization [12]. The decreased reactivity of (especially) aldehyde and ketone enolates also appears in thiolations with disulfides [2]. A solution of lithiated cyclohexanone in THF does not react at 20°C with CH3SSCH3 [1,2]. 

The Pd enolates also undergo intramolecular Michael addition when an enone of suitable size is present in the allyl d-keto ester 744[465]. The main product is the saturated ketone 745, hut the unsaturated ketone 746 and ally-lated product 747 are also obtained as byproducts. The Pd-catalyzed Michael... 

Structural effects on the rates of deprotonation of ketones have also been studied using veiy strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as lithium di-/-propylamide (LDA) and potassium hexamethyldisilylamide (KHMDS) give solutions of the enolates in relative proportions that reflect the relative rates of removal of the different protons in the carbonyl compound (kinetic control). The least hindered proton is removed most rapidly under these... 

Enol ethers, A -3-ketones and enol acetates have also been employed in the preparation of A -3-ketones (see also sections VI-B and VI-E) and permit the use of milder conditions than do A -3-ketones. ... 

Fluoroalkenolphosphates are not only stable but also sufficiently reactive to undergo olefinaaon reactions with yiides themselves. These enol phosphates are not only precursors to enolates or ketones but also can be used directly as electrophilic reagents [79] (equation 66) (Table 26). 

Fluoroalkyl ketone enolates and enol etliers have also been use in condensation reactions with ketones [22] Interestingly, these materials fail to undergo Dar/ens-type side reactions (equation 18)... 

The (3-elimination of epoxides to allylic alcohols on treatment with strong base is a well studied reaction [la]. Metalated epoxides can also rearrange to allylic alcohols via (3-C-H insertion, but this is not a synthetically useful process since it is usually accompanied by competing a-C-H insertion, resulting in ketone enolates. In contrast, aziridine 277 gave allylic amine 279 on treatment with s-BuLi/(-)-spar-teine (Scheme 5.71) [97]. By analogy with what is known about reactions of epoxides with organolithiums, this presumably proceeds via the a-metalated aziridine 278 [101]. 

Enolates also result from the deprotonation of ketones 4 by means of dieyclohcxylchloro-borane. As expected, the (A)-enolboranes 5 formed in this way lead to rw/Z-aldols. Remarkably simple induction of diastereoselectivity is achieved in aldol additions with isobutyraldehyde53d< ... 

THF but a dimer in DME. X-ray crystallography of ketone enolate anions have shown that they can exist as tetramers and hexamers. There is also evidence that... 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

Route (b) offers a short cut since the reaction between (5) and PhCHO under dehydrating conditions needs no control as (3) is the only possible enone from a ketone enolate attacking the more reactive aldehyde (p T 167). The Michael reaction is also better by this route as explained on p T 171, This is the published synthesis. 

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

Cyclopropyl ketones 95 also react with enol ether 100 in presence of 5 mol% of [Au(NTf2)(lPr)] in a [4+2] cycloaddition reaction to afford the bicycle[3.2.0] heptane skeleton 101 (Scheme 5.26) [26]. 

The equilibrium ratios of enolates for several ketone-enolate systems are also shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be established by the presence of an excess of ketone, which permits reversible proton transfer. Equilibration is also favored by the presence of dissociating additives such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for kinetically controlled conditions. In general, the more highly substituted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as to interfere with solvation, there can be exceptions. This factor, along with CH3/CH3 steric repulsion, presumably accounts for the stability of the less-substituted enolate from 3-methyl-2-butanone (Entry 3). 

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

Note also the stereochemistry. In some cases, two new stereogenic centers are formed. The hydroxyl group and any C(2) substituent on the enolate can be in a syn or anti relationship. For many aldol addition reactions, the stereochemical outcome of the reaction can be predicted and analyzed on the basis of the detailed mechanism of the reaction. Entry 1 is a mixed ketone-aldehyde aldol addition carried out by kinetic formation of the less-substituted ketone enolate. Entries 2 to 4 are similar reactions but with more highly substituted reactants. Entries 5 and 6 involve boron enolates, which are discussed in Section 2.1.2.2. Entry 7 shows the formation of a boron enolate of an amide reactions of this type are considered in Section 2.1.3. Entries 8 to 10 show titanium, tin, and zirconium enolates and are discussed in Section 2.1.2.3. 

Methyl 1-phenylthiovinyl ketones can also be used as enones in kinetically controlled Robinson annulation reactions, as illustrated by Entry 6. Entry 7 shows a annulation using silyl enol ether as the enolate equivalent. These reactions are called Mukaiyama-Michael reactions (see Section 2.6.3). 

II and 12 indicate, the selenenylation of ketones can also be effected by reactions of enol acetates or enol silyl ethers. 

Ketones can also be reduced to alkenes via enol triflates. The use of Pd(OAc)2 and triphenylphosphine as the catalyst and tertiary amines as the hydrogen donors is effective.226... 

The silyl enol ethers of ketones are also oxidized to a-hydroxy ketones by m-chloroperoxybenzoic acid. If the reaction workup includes acylation, a-acyloxy ketones are obtained.250 These reactions proceed by initial epoxidation of the silyl enol ether, which then undergoes ring opening. Subsequent transfer of either the O-acyl or O- l MS substituent occurs, depending on the reaction conditions. 

The method can be further improved using trimethylsilyl (TMS) enol ethers, which can be prepared in situ from aldehydes and ketones [49]. TMS enol ethers of cyclic ketones are also suitable, and diversity can be enhanced by making either the kinetic or thermodynamic enol ether, as shown for benzyl methyl ketone. Thus, reaction of the kinetic TMS enol ether 10-133 with the amino aldehyde 10-134 and dimethylbarbituric acid 10-135 yielded 10-136, whereas the thermodynamic TMS enol ether 10-137 led to 10-138, again in excellent purity, simply by adding diethyl ether to the reaction mixture (Scheme 10.33). 

Addition of ketene silyl acetals to aldehydes and ketones is also mediated by achiral palladium(ll) acetate-diphosphine complexes (Equation (109)).46S,46Sa Although the precise mechanism is still unclear, high catalytic activity may be ascribed to the intermediacy of palladium enolates. 

Diboration of a,/ -unsaturated ketones is promoted by platinum(O) complexes. Reaction of 4-phenyl-3-buten-2-one with bis(pinacolato)diboron in the presence of a platinum catalyst affords a boryl-substituted (Z)-boron enolate, that is, a 1,4-diboration product, in high yield with high stereoselectivity (Scheme 8). The isolated boron enolate is easily hydrolyzed by exposure to water, giving / -boryl ketones in high yields.66 Similar diboration of a,/ -unsaturated ketones has also been achieved with Pt(bian)(dmfu) (bian = bis(phenylimino)acenaphthene, dmfu = dimethyl fumarate).67 Although the... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Other related chiral erythro selective ketone enolates (iS -139 and (i )-139, readily prepared from (5)- and (i )-atrolactic acid, also exhibit good aldol diastereoface selection (3). From the data summarized in Table 34a, the influence of asymmetry in both condensation partners (entries C-F) has been amply demonstrated. The... 

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