Aldehyde enols

Flydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

Aldehyde Enolate Alkoxide ion from nucleophilic addition... 

Although the methodology described so far produces <5-oxo esters via diastereoselective enolate additions to enones, the same product may be obtained via an alternate sequence, i.e., addition of ketone or aldehyde enolates to a,j3-unsaturated esters or amides. Enolates of ketones are known to react with a,/ -unsaturated esters to give the Michael adducts50, however, the study of simple diastcrcoselectivity has, so far, been limited to special cases (MIMIRC reactions, Section 1.5.2.4.4.). 

Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and applied synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One reason is that aldehydes are rapidly converted to aldol addition products by base. (See Chapter 2 for a discussion of this reaction.) Only when the enolate can be rapidly and quantitatively formed is aldol formation avoided. Success has been reported using potassium amide in liquid ammonia67 and potassium hydride in tetrahydrofuran.68 Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions are discussed in Section 1.3. 

Titanium ate species have also been used to add aldehyde enolates to ketones. This reaction is inherently difficult because of the greater reactivity of aldehyde... 

The coupling of enals and glyoxals was realized by hydrogen-mediated reaction with the cationic Rh complex and PI13P [35]. The intermediate aldehyde enolates derived via Rh-catalyzed hydrogenation were trapped with glyoxals to form (l-hydroxy-y-kclo-aldchydes, which were treated sequentially with hydrazine to give pyridazines in a one-pot transformation to provide, for example, a 62% yield of 72 (Scheme 21). 

Scheme 22.7 Catalytic addition of metallo-aldehyde enolates to ketones.

Perhaps the most elusive variant of the aldol reaction involves the addition of metallo-aldehyde enolates to ketones. A single stoichiometric variant of this transformation is known [29]. As aldolization is driven by chelation, intramolecular addition to afford a robust transition metal aldolate should bias the enolate-aldolate equilibria toward the latter [30, 31]. Indeed, upon exposure to basic hydrogenation conditions, keto-enal substrates provide the corresponding cycloal-dol products, though competitive 1,4-reduction is observed (Scheme 22.7) [24 d]. 

Intermolecular cross aldolization of metallo-aldehyde enolates typically suffers from polyaldolization, product dehydration and competitive Tishchenko-type processes [32]. While such cross-aldolizations have been achieved through amine catalysis and the use of aldehyde-derived enol silanes [33], the use of aldehyde enolates in this capacity is otherwise undeveloped. Under hydrogenation conditions, acrolein and crotonaldehyde serve as metallo-aldehyde enolate precursors, participating in selective cross-aldolization with a-ketoaldehydes [24c]. The resulting/ -hydroxy-y-ketoaldehydes are highly unstable, but may be trapped in situ through the addition of methanolic hydrazine to afford 3,5-disubstituted pyridazines (Table 22.4). 

A method for the stoichiometric addition of metallo-aldehyde enolates to ketones has recently been reported K. Yachi, H. Shinokubo, K. Oshima, /. Am. Chem. 

Entry Aldehyde Enolate activation Aldehyde activation ... 

The ozonolyses of enol ethers has been reviewed <91MI 4l6-0l>. The relative dipolarophilicity of certain species to attack by carbonyl oxides has been investigated and, in general, the order of reactivity is aldehydes > enol ethers > esters ss ketones. It is apparent that enol ethers are very reactive towards carbonyl oxides, so much so that 1,2-dioxolane formation can be a major reaction pathway (especially for formaldehyde-O-oxide) <85JOC3365>. 

The formation of aldehyde enolates is complicated by the disposition of aldehydes to undergo aldol condensation. Therefore, there are very few examples of direct asymmetric alkylations of aldehydes. 

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)... 

The /S-bromodihydropyran (652) on halogen-metal exchange with f-butyllithium affords a useful organometallic (653) that can function as the equivalent of a 5-hydroxy aldehyde enolate (Scheme 151) (79TL67). The vinyllithium species adds to ketones and aldehydes at -110 °C in good yield and also reacts in a conjugate mode with a,/S-unsaturated carbonyl compounds in the presence of copper(I) ions. On hydrolysis and oxidation, the dihydropyran component (654) can be transformed into a substituted 5-lactone (655). 

The use of aldehyde enolates for conjugate additions is precluded by competing polymerization and al-dolization processes however, introduction of the OfeCHO moiety is accomplished with aldehyde enolate equivalents. For example, dianions of nitroethanes, e.g. 3-phenylnitroethane (165) or methyl 3-nitropropionate (166), add exclusively in the 1,4-mode to ot,3- nones.,36a-b Similarly, the dianion of 4-nitro-1-butene (167) adds in a 1,4-mode exclusively unlike typical dienolates (Section 1.2.2.2.2) which react at the ot-position, this dianion is formally equivalent to the crotonaldehyde >-enolate (Scheme 64).l36c... 

The arylation of acetaldehyde enolate by iodobenzene17-128 or p-iodoaniline73 failed, and the reduced products, benzene or aniline were obtained. In the reaction of aldehyde enolates with o-substituted derivatives, however, arylation does occur and in these cases subsequent cyclization reactions usually take place (see Section 2.2.4.2). The special effect of the o-substituents in facilitating reactions with aldehyde enolates is shown by the rare example of simple substitution (i.e. without concomitant cyclization) in equation (34).71... 

If die enolate nucleophile is derived from an aldehyde or ketone different than die carbonyl electrophile, a crossed-aldol condensation results. Normally best success is achieved if the carbonyl electrophile employed for the crossed-aldol condensation is more reactive than the carbonyl electrophile from which the enolate is derived. For example, ketone etiolates react with aldehydes effectively, but aldehyde enolates do not give the crossed aldol with most ketones but self-condense instead. 

The concentration of the ketone enolate is higher than that of the aldehyde enolate. This is true under thermodynamic control as the stability of an enolate increases with its degree of substitution. It is also true under kinetic control since enolization is an acid-base equilibrium, the increased enolate concentration reflects the higher acidity of the ketone protons. 

The involvement of an aldehyde-enolate as a ligand on IBX has also been postulated in a first oxidative C C bond cleavage reaction using IBX. N-Protected amino alcohols 14 have been oxidized with IBX in DMSO to the corresponding imides 15 [17]. 

Palladium catalysed allylation of ordinary ketone and aldehyde enolates... 

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