Ketones aliphatic enolates

As noted in Chapter 1, this is one of the best methods for generating a specific enolate of a ketone. The enolate generated by conjugate reduction can undergo the characteristic alkylation and addition reactions that are discussed in Chapters 1 and 2. When this is the objective of the reduction, it is important to use only one equivalent of the proton donor. Ammonia, being a weaker acid than an aliphatic ketone, does... 

Analogous with the previous results of enol silyl ethers of ketones, nonsubstituted ketene silyl acetals are found to exhibit lower levels of stereoregulation, while the propionate-derived ketene silyl acetals display a high level of asymmetric induction. The reactions with aliphatic aldehydes, however, resulted in a slight reduction in optical and chemical yields. With phenyl ester-derived ketene silyl acetals, syn adducts predominate, but the selectivities are moderate in most cases in comparison with the reactions of ketone-derived silyl enol ethers. Exceptions are a,p-unsaturated aldehydes, which revealed excellent diastereo- and enantioselectivities. The observed syn selectivity and re-face attack of nucleophiles on the carbonyl carbon of aldehydes are consistent with the aforementioned aldol reactions of ketone-derived enol silyl ethers. 

Another side reaction, caused by changes in the solvent composition, was studied in 1980 (in the former USSR) and, unfortunately, was also published in rather inaccessible journals [37]. The reactions of phenylmagnesium bromide with the aliphatic ketones, 2-butanone and 3,3-dimethyl-2-butanone (methyl-fcrt-butyl ketone), were studied. Besides the carbonyl addition reaction, leading to a tertiary alcohol, enolization also takes place with this type of ketones. The enolate, on hydrolysis, yields the starting ketone however, before hydrolysis, in the reaction mixture of the Grignard reagent and the ketone, the enolate can react further with the ketone to form a condensation product (Scheme 16). 

The addition of ketone-derived enol silanes and aldehydes in the presence of 184 at -78 °C in propionitrile afforded the aldol adducts in excellent yields as well as diastereo- and enantioselectivity (Eq.29) [106]. The versatility of this catalyst is evidenced by the fact that enol silanes derived from aliphatic methyl and ethyl ketones as well as acetophenone are substrates for the aldol addition reaction. 

Six-membered chiral acetals, derived from aliphatic aldehydes, undergo aldol-type coupling reactions with a-silyl ketones, silyl enol ethers," and with silyl ketene acetals " in the presence of titanium tetrachloride with high diastereoselectivities (equation 41) significant results are reported in Table 20. This procedure, in combination with oxidative destructive elimination of the chiral auxiliary, has been applied... 

P,7-Unsaturated ethers of cyanohydrins, on formation of lithio derivatives, undergo a 2,3-sigmatropic rearrangement to form. y-unsaturated ketones (equation 21), whereas benzylic ethers of aliphatic cyanohydrins gave o-methylaryl ketones. The method has been used to prepare 3-methyi-l-(3-methyl-2-furyl)-l-butanones, a naturally occurring Cio terpene, a-allenic ketones and enolic monoethers of 7-keto aldehydes via 2,3-sigmatropic rearrangement of tiieir respective carbanions. ... 

This condensation finds considerable generality, enol silyl ethers of a variety of ketones and both aromatic and aliphatic aldehydes are usable For enol silyl ethers of substituted cyclohexanones the reaction is regio- and stereospecific [id]. 

The acylation of enamino ketones can take place on oxygen or on carbon. While reaction at nitrogen is a possibility, the N-acylated products are themselves acylating agents, and further reaction normally takes place. The first reported acylation of enamino ketones (72) was that of 129, prepared by acylation of the enamine (113), which was shown to have undergone O acylation because on mild hydrolysis the enol ester (130) could be isolated. A similar reaction took place with other aliphatic acid chlorides (80) and with dibasic acid chlorides [e.g., with succinyl chloride to give 118 above]. 

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (f )-l-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee. Molecular hydrogen (1 atm) was almost equally effective for the transformation. A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (7 )-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates. 

In the presence of strong alkali, the rhodium analog of 62, or RhCl(C8H,2)PPh3, hydrogenates aliphatic ketones at 1 atm and 20°C, and after treatment with borohydride the systems similarly reduce aromatic ketones to the alcohols (526). Deuterium exchange data for acetone reduction were interpreted in terms of hydrogen transfer within a mononuclear hydroxy complex containing substrate bound in the enol form (63). 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

Zirconium tetrachloride promotes a tandem nucleophilic addition and aldol-type condensation reaction of methyl propynoate, or /V,/V-dimethylpropynamidc, with aldehydes, or ketones, in the presence of tetra-n-butylammonium iodide (Scheme 6.13) [8] with a high selectivity towards the formation of Z-isomers. A similar reaction occurs between aliphatic and aromatic aldehydes and penta-3,4-dien-2-one to yield 1-substituted 2-acetyl-3-iodobut-3-enols (50-75%) [9]. 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

The gas-phase heats of formation of several enol positive ions of aliphatic aldehydes, ketones, acids, and esters were measured and compared with those of the corresponding keto ions. The enolic ions were found to be thermodynamically more stable by 58-129 kJ moLh This is in marked contrast to the neutral tau-... 

Unstabilized enolates react with allylic carbonates in the presence of metalacyclic iridium-phosphoramidite catalysts. Although ketones and aldehydes have not yet been used directly as pronucleophiles with this catalyst system, silyl enol ethers [80] and enamines [81] react with linear allylic carbonates to form, after workup, p-branched, y-8 unsaturated ketones (Scheme 13). Both methods form products in high yield, branched selectivity, and enantioselectivity for a range of cinnamyl and alkyl-substituted allylic carbonates. However, the silyl enol ethers derived from aliphatic ketones reacted in lower yields than enamines derived from the same ketones. 

In addition, unstabilized enolate nucleophiles have been generated by decarboxylation of (3-ketocarboxylates. In this case, no additives are required to activate the nucleophile, but the highest yields and selectivities were obtained in the presence of two equivalents of DBU [82]. Although reactions of allylic carbonates containing aromatic, heteroaromatic, and aliphatic substituents occurred, only reactions to form aryl ketone products were published. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

The strict differentiation of two a-positions in unsymmetric aliphatic ketones was a dif ficult problem in enolate formation until the mid 1980s (Scheme 6.2). For example, ketone 1 gives a mixture of 2 and 3 according to a conventional procedure. It is well known that while a-silylketones 4 and 5 are the immediate precursors of the corresponding enoxysilanes 2 and 3, there have been few reports on reliable routes for the selective synthesis of 4 or 5 [3]. 

Several examples of Bi(OTf)3-catalyzed Mannich-type reactions with various silyl enol ethers are summarized in Table 12. Silyl enol ethers derived from aromatic and aliphatic ketones were reacted with an equimolar mixture of aldehyde and aniline (Scheme 10). The corresponding (3-amino ketones 27 were obtained in good yields (Table 12, entries 1M-) from aromatic-derived silyl enol ethers, except for the more hindered isobutyrophenone derivative. Silyl enol ethers derived from cyclopentanone or cyclohexanone afforded the (3-amino ketones in good yields (Table 12, entries 5 and 6). 

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