Acetophenone aldol reaction

Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

Riant et al. in 2006 reported an enantioselective reductive aldol reaction of acetophenone and methyl acrylate mediated by PhSiH3 (140 mol %) and catalyzed by a complex generated in situ from [CuF(Ph3P)3]2MeOH (1-3 mol %) and a chiral bisphosphine (1-3 mol %) [57]. According to Mori s... 

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. 

Catechol and related phenolics 13,16,19, 31, and 32 were also isolated after alkaline treatment of D-glucose and sucrose. Several other substituted acetophenones were isolated. The mechanism of formation of phenolic compounds from monosaccharides under alkaline conditions has yet to be thoroughly investigated. The similarity in the types of aromatic products from D-glucose and D-xylose indicates the formation of the same C2, C3, or C4 fragments, with subsequent recombination and cycliza-tion. Base-catalyzed aldol reactions are, no doubt, predominant pathways in the initial formation of these aromatic products. 

The salt 18 was explored in the Mukaiyama aldol reaction with acetophenone, and a yield of 96% was obtained after 1 h at -78 °C (Scheme 11). When MejSiOTf was used as a catalyst, a yield of 0% was observed. Me3SiNTf3 and Et3SiNTf3 resulted in 12% and 8% yield, respectively. 

An attempt to prepare 2-(2-nitrophenyl)-4,6-diphenylpyrylium from l,3-diphenylprop-2-en-1 -one and 2-nitroacetophenone gave only 2,4,6-triphenylpyrylium (58BSF1458). Similarly, substantial formation of this symmetrical pyrylium salt was observed during syntheses of unsymmetrically substituted salts. Thus, pinacolone and chalcone afforded both 2-f-butyl-4,6-diphenylpyrylium and the 2,4,6-triphenyl derivative. The latter product is considered to arise from a retro-aldol reaction of the enone into a mixture of benzaldehyde and acetophenone the latter reacts with unchanged chalcone to give the unrequired salt (80T679). 

On the other hand, a remarkable difference between catalysis by Y and 13 zeolites has been found for the Claisen-Sohmidt condensation of acetophenone and benzaldehyde (Table 5). When the cross aldolic reaction is carried out in the presence of HY, together with the expected trans and ois chalcones 5, the 3,3-diphenylpropiophenone 6 is also formed, this product being not detected on 13 zeolites. A likely explanation for the absence of 6 using zeolite beta is that the crystalline structure of this zeolite exerte a spatial constraint making difficult the formation of a big size molecule like 6, especially in the smaller channel. Similar effects due steno limitations on 6 catalysis have been found for the formation of multi-branched products during the cracking of alkanes (ref 8). 

Shibasaki et al. also developed a barium complex (BaB-M, 14, Scheme 5) for the aldol reaction of acetophenone (la), making use of the strongly basic characteristic of barium alkoxide. The catalyst was prepared from Ba(0-z-Pr)2 and BINOL monomethyl ether, and the products were obtained in excellent yield with up to 70% ee (Scheme 6) [8], Shibasaki et al. attempted to incorporate a strong Bronsted base into the catalyst and developed a lanthanide heterobime-tallic catalyst (15) possessing lithium alkoxide moieties, which promoted the aldol reaction with up to 74% ee (Scheme 6) [9]. Noyori and Shibasaki et al. reported a calcium alkoxide catalyst (16) that was prepared from Ca[N(SiMe3)2]2,... 

An iron-catalyzed multicomponent reaction of aldehyde 4a, acetophenone, acetyl chloride and acetonitrile, which was used as the solvent, gave P-amino ketones such as 32 (Scheme 8.11) [41]. It was assumed that the sequence starts with an aldol reaction of aldehyde and ketone and then proceeds further with a displacement of a P-acetoxy group by the nucleophilic nitrile-nitrogen. 

Further examination of the fluoride ion-catalyzed asymmetric aldol reaction of the enol silyl ethers prepared from acetophenones and pinacolone with benzaldehyde using 4b and its pseudoenantiomer 4c revealed the dependence of the stereochemistry of the reactions on the hydroxymethyl-quinudidine fragment of the catalyst (Table 9.3) [10,15]. 

Reductive aldol reaction of an allenic ester (52) to a ketone such as acetophenone can give y- (53-y) or a-product (53-cy).159 Using as catalysts a copper salt and a range of chiral phosphines, together with phosphine additives such as the triphenyl or tricy- clohexyl compounds, a highly selective set of outcomes can be achieved, e.g. (53-y) almost exclusively cis- with 99% ee, or - without additive - significant amounts of (53-a) can be formed (as a syn-anti mixture). A diastereoselective implementation of the latter has also been developed. 

Chalcones such as 80 are very easily made by an aldol reaction between acetophenone and benzaldehyde conjugate addition of the enolate of 81 and cyclisation occur all in the same reaction.15 The ester 82 is formed as a mixture of diastereomers in high yield hydrolysis and decarboxylation give 78. 

An example that illustrates the potential of this catalytic C-C bond-forming process to build up key structural subunits of natural products is shown in Scheme 2. The reaction of acetophenone with aldehyde 18 in the presence of 8 mol% catalyst 1 affords the aldol adduct 19 in 70% yield and 93% ee, which is subsequently transformed into 20, a key intermediate of the anticancer agent epothilone A [8b]. Similarly, Scheme 3, the aldol reaction of hydroxyacetylfuran 21 with valeralde-hyde in the presence of 5 mol% catalyst 3 produces syn diol 23 with high efficiency [10d]. Further chemical elaboration of 23 leads to 24, a key intermediate in the synthesis of (+)-boronolide, a folk medicine with emetic and anti-malaria activity. 

Although typical equilibrium constants for formation of a tertiary aldol prohibit direct forward aldol synthesis (0.002 M 1 for the aldol reaction of acetone with acetophenone) (Guthrie and Wang, 1992), the retro-aldol reaction is greatly favored (a 1 mM solution of the resulting tertiary aldol is converted almost completely to acetone and acetophenone at equilibrium) (List et al., 1999). 

Bis(pentafluorophenyl) tin dibromide effects the Mukaiyama aldol reaction of ketene silyl acetal with ketones, but promotes no reaction with acetals under the same conditions. On the other hand, reaction of silyl enol ether derived from acetophenone leads to the opposite outcome, giving acetal aldolate exclusively. This protocol can be applied to a bifunctional substrate (Equation (105)). Keto acetal is exposed to a mixture of different types of enol silyl ethers, in which each nucleophile reacts chemoselectively to give a sole product.271... 

To determine the aetivated faee of a carbonyl group in an acetylenic aldehyde-CAB 2 complex, an aldol reaction of acetylenic aldehydes with the trimethylsilyl enol ether derived from acetophenone was performed in the presence of 20 mol % 2 under conditions similar to those in the Diels-Alder reaction (Eq. 32). Good enantioselec-tivity was, with the predominant enantiomer corresponding to attack on the re face, as expected. Although it is essential to stress that the results of an aldol reaction cannot be directly used to explain the transition state in cycloaddition, the effective steric shielding of the si face of the coordinated aldehyde is consistent with cycloaddition via the proposed transition-state model 16. 

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. 

A pair-selective aldol reaction proved to be possible and is illustrated in Eq. (25) from the four starting materials, only two products were obtained [100], This clearly indicates that the coupling of the ketene silyl acetal and acetophenone and that of the enol silyl ether and benzaldehyde dimethylacetal are very favorable paths, whereas the reactions of other combinations are not. A similar phenomenon is illustrated by Eq. (26) [100]. 

When a slurry of /7-methylbenzaldehyde (1.5 g, 12.5 mmol), acetophenone (1.5 g, 12.5 mmol) and NaOH (0.5 g, 12.5 mmol) was ground using a mortar and pestle at room temperature for 5 min, the mixture turned into a pale yellow solid. This solid was combined with water and filtered to give p-methylchalcone (2.7 g) in 97% yield (Table 15-11) [18], When the condensation was carried out in 50% aqueous EtOH according to the reported procedure [19] for the same reaction time as above (5 min), the product was obtained only in 11% yield (Table 15-10). Other aldol reactions of benzaldehyde (41) and acetophenone derivatives (48) also proceed efficiently in the solid state (Table 15-11). 

Although we might not have been able to make predictions concerning the relative rates of the Cannizzaro and the aldol reactions, we could have predicted that the crossed aldol reaction would proceed faster than the reaction between two molecules of acetophenone. Both aldol reactions would involve the same intermediate carbanion (VII), but benzaldehyde would be expected to be a better acceptor molecule than acetophenone (see p. 155). 

Trost and coworkers developed a chiral zinc phenoxide for the asymmetric aldol reaction of acetophenone or hydroxyacetophenone with aldehydes (equations 62 and 63) . This method does not involve the prior activation of the carbonyls to silyl enol ethers as in the Mukaiyama aldol reactions. Shibasaki and coworkers employed titanium phenoxide derived from a phenoxy sugar for the asymmetric cyanosilylation of ketones (equation 64). 2-Hydroxy-2 -amino-l,l -binaphthyl was employed in the asymmetric carbonyl addition of diethylzinc , and a 2 -mercapto derivative in the asymmetric reduction of ketones and carbonyl allylation using allyltin ° . ... 

Sodeoka et al. have developed novel chiral diaqua Pd(II)-BINAP and -Tol-BINAP complexes 67 as efficient asymmetric catalysts of the aldol reaction of SEE (Scheme 10.57) [157]. These complexes are readily prepared from PdCl2(BINAP) and PdCl2(Tol-BINAP) by treatment of 2 equiv. AgBE4 in wet acetone, and are quite stable to air and moisture. The results of H NMR experiments indicate that reaction of 67b with acetophenone TMS enolate forms an O-bound Pd enolate. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

The highly substituted 6-aryl-2-pyrones 28 react with acetophenones 29 in a stepwise base-induced formal cycloaddition reaction. The reaction proceeds via a sequential Michael and aldol reaction in the presence of an alkali metal hydroxide. In this case, the formal cycloadduct 31 extrudes CO2, providing the diene 32, which subsequently undergoes dehydration to afford aromatic products 33 (Scheme 9) <03TL3363>. 

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