Acetone aldol addition

Butene isomerization, 1,3-butadiene hydrogenation, and acetone aldol addition are catalyzed by rare earth oxides. The activity sequences of a series of rare earth oxides for the reactions are shown in Fig. 3.15. The activity sequence is the same for... 

Fig. 3.15 Catalytic activities of rare earth oxides for 1-butene isomerization (0)i 1, 3-butadiene hydrogenation (9), and acetone aldol addition (A).

As with other reversible nucleophilic addition reactions the equilibria for aldol additions are less favorable for ketones than for aldehydes For example only 2% of the aldol addition product of acetone is present at equilibrium... 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

Aldol addition, 2 63-64 acetone, 1 164 Aldolases, 3 675 4 711 Aldol process, for higher alcohol manufacture, 2 27t, 41-43 Aldonic acid, 14 132 Aldoses, 4 696... 

Rate and equilibrium constants have been determined for the aldol condensation of a, a ,a -trifluoroacetophenone (34) and acetone, and the subsequent dehydration of the ketol (35) to the cis- and fraw -isomeric enones (36a) and (36b)." Hydration of the acetophenone, and the hydrate acting as an acid, were allowed for. Both steps of the aldol reaction had previously been subjected to Marcus analyses," and a prediction that the rate constant for the aldol addition step would be 10" times faster than that for acetophenone itself is borne out. The isomeric enones are found to equilibrate in base more rapidly than they hydrate back to the ketol, consistent with interconversion via the enolate of the ketol (37), which loses hydroxide faster than it can protonate at carbon. 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

The equilibrium constant is favorable for the aldol addition of ethanal, as in fact it is for most aldehydes. For ketones, however, the reaction is much less favorable. With 2-propanone (acetone) only a few percent of the addition product diacetone alcohol, 11, is present at equilibrium ... 

Acid Catalyzed. Although ketonic carbonyl groups are less reactive than aldehydic carbonyls in the presence of basic catalysts, this is not the case with acid catalysts. Thus acetone undergoes aldol addition in the presence of sulfuric acid to give mesityl oxide, which then condenses with a third molecule of acetone to give a mixture ofphorone (2,6-dimethyl-2,6-heptadien-4-one) and mesitylene (1,3,5-trimethylbenzene). Ketones also condense with activated aromatic products in the presence of sulfuric acid to give coupled aromatic products. For example, acetone and phenol condense to bisphenol A (4,4 -isopropylidenediphenol), which is used in the manufacture of epoxy resins (qv) and polycarbonates (qv). 

Cu(II) and Sn(II) Bisoxazolinc Complexes. Evans has prepared and studied a family of Cu(II) complexes prepared from bisoxazoline ligands [8]. Utilizing these complexes a number of different addition reactions can be successfully conducted on pyruvate, benzyloxyacetalde-hyde, and glyoxylates. Whereas the focus of the work in the context of aldol addition reactions has been on the use of silyl ketene acetals (vide infra), the addition of ketone-derived enoxy silanes 8a-b with methyl pyruvate has been examined (Eq. 8B2.1). The additions of 8a-b proceed in the presence of 10 mol % Cu(II) catalyst at -78°C in CH2Cl2, affording adducts of acetophenone 9a and acetone 9b with 99% and 93% ee, respectively. 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

A wide range of donor ketones, including acetone, butanone, 2-pentanone, cyclopentanone, cyclohexanone, hydroxyacetone, and fluoroacetone with an equally wide range of acceptor aromatic and aliphatic aldehydes were shown to serve as substrates for the antibody-catalyzed aldol addition reactions (Chart 2, Table 8B2.6). It is interesting to note that the aldol addition reactions of functionalized ketones such as hydroxyacetone occurs regioselectively at the site of functionaliztion to give a-substitutcd-fi-hydroxy ketones. The nature of the electrophilic and nucleophilic substrates utilized in this process as well as the reaction conditions complement those that are used in transition-metal and enzymatic catalysis. 

Scheme 4. Synthesis of (S)-ipsenol using the proline-catalyzed direct aldol addition reaction as key transformation, (a) L-Proline (10-20mol%), acetone (solvent), 3-7days, 34% (73% ee). (b) TBSCI, imidazole ...

Scheme 7. Proposed enamine mechanism of the proline-catalyzed direct aldol addition reaction of acetone [25].

Zhang, G., Hattori, H. and Tanabe, K. Aldol addition of acetone, catalyzed by solid base catalysts magnesium oxide, calcium oxide, strontium oxide, barium oxide, lanthanum-(III) oxide and zirconium oxide, Appl. Catal., 1988, 36, 189-97. 

Cationic Pd complexes can be applied to the asymmetric aldol reaction. Shibasaki and coworkers reported that (/ )-BINAP PdCP, generated from a 1 1 mixture of (i )-BINAP PdCl2 and AgOTf in wet DMF, is an effective chiral catalyst for asymmetric aldol addition of silyl enol ethers to aldehydes [63]. For instance, treatment of trimethylsi-lyl enol ether of acetophenone 49 with benzaldehyde under the influence of 5 mol % of this catalyst affords the trimethylsilyl ether of aldol adduct 113 (87 % yield, 71 % ee) and desilylated product 114 (9 % yield, 73 % ee) as shown in Sch. 31. They later prepared chiral palladium diaquo complexes 115 and 116 from (7 )-BINAP PdCl2 and (i )-p-Tol-BINAP PdCl2, respectively, by reaction with 2 equiv. AgBF4 in wet acetone [64]. These complexes are tolerant of air and moisture, and afford similar reactivity and enantioselec-tivity in the aldol condensation of 49 and benzaldehyde. Sodeoka and coworkers have recently developed enantioselective Mannich-type reactions of silyl enol ethers with imi-nes catalyzed by binuclear -hydroxo palladium(II) complexes 117 and 118 derived from the diaquo complexes 115 and 116 [65]. These reactions are believed to proceed via a chiral palladium(fl) enolate. 

The catalytic aldol addition process has been extended to include the addition reactions of dienolsilane 49 to a broad range of aldehydes (Eq. (8.12)) [26]. The addition reactions of 49 are conducted at 23 "C utilizing 5 mol% of catalyst, giving adducts in up to 94% ee. This dienolsilane is easily prepared by enolization of the commercially available acetone-ketene adduct followed by quenching with chlorotrimethyl silane. The resulting dienolsilane is isolated typically in 78% yield as a clear colorless liquid that can be conveniently purified by distillation. 

Baeyer-Drewson indigo synthesis. Formation of indigos by an aldol addition of o-nitrobenzal-dehydes to acetone, pymvic acid, or acetaldehyde. Of interest mainly as a method of protecting o-nitro-benzaldehydes. 

The aldol addition of aldehyde 38 and acetone to give aldols 39 is an excellent test reaction for a catalytic aldolization. We found that anti-33 antibodies combine with primary amine 37 to form an aldolase antibody which catalyzes the reaction with good enantioselectivities (Scheme 13) [58]. Analysis of the reverse aldolization process shows that (S)-aldols undergo retroaldolization with the... 

The Robinson annelation The proline-catalysed aldol reaction Reactions with hydroxy-acetone Conjugate addition... 

In addition to the efficiency exhibited by catalyst 165 with a broad spectrum of aldehydes in acetate aldol addition reactions, this catalyst has been shown to function competently in enantioselective additions of dienol silane 87. The requisite dienolate is readily synthesized from 2,2,6-trimethyl-4H-l,3-dioxin-4-one 84 (diketene-i-acetone adduct) by deprotonation with LDA and quenching with MejSiCl (Eq. 24). Dioxinone 84 is commercially available at a nominal price in addition, the silyl dienolate 87 is easily purified by distillation and stable to prolonged storage. The addition reactions of 87 with aldehydes were conducted with 1-3 mol % of 165 at 0 °C (Eq. 25). A variety of aldehydes serve as substrates and give aldol adducts in 79-97% yields and up to 99% ee after a single recrystallization. 

Fig. 9. NARC sequences initiated by aldol additions of ester enolates to acetone...

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