Aldol reactions in aqueous media

In 1986, Lubineau et al. reported the water-promoted aldol reaction of silyl enol ethers with aldehydes [15]. While the report that the aldol reactions proceeded without catalyst in water was unique, the yields and the substrate range were not satisfactory. 

The effects of lanthanide triflates in the reaction of the silyl enol ether of propiophenone (1) with commercial formaldehyde solution were examined [19]. In most cases, the reactions proceeded smoothly to give the corresponding adducts in high yields (Table 8.1). The reactions were most effectively carried out in commercial formaldehyde solution-THF medium under the influence of a catalytic amount of Yb(OTf)3. 

the use of lanthanide triflates in the activation of aldehydes other than formaldehyde was investigated [21]. The model reaction of 1-trimethyl-siloxycyclohexene (2) with benzaldehyde under the influence of a catalytic amount of Yb(OTf)3 (10mol%) was examined (Table 8.2). The reaction proceeded smoothly in H2O-THF (1 4), but the yields were low when water or THF was used alone. Among several lanthanide triflates screened, neodymium triflate (Nd(OTf)3), gadolinium triflate (Gd(OTf)3), Yb(OTf)3 and lutetium triflate (Lu(OTf)3) were quite effective, while the yield of the desired aldol adduct was lower in the presence of lanthanum triflate (La(OTf)3), praseodymium triflate (Pr(OTf)3) or thulium triflate (Tm(OTf)3) (Table 8.2). 

The mixture of the hydroxythioester and the lactone (2 1) was obtained. The other diastereo-mers were not observed. 

The effect of ytterbium salts was also investigated (Table 8.3) [22]. While the Yb salts with less-nucleophilic counter-anions such as OTT or CIO4 effectively catalyzed the reaction, only low yields of the product were obtained when the Yb salts with more-nucleophilic counter-anions such as CT, OAc , NOs and S04 were employed. The Yb salts with less-nucle-ophilic counter-anions are more cationic and the high Lewis acidity promotes the desired reaction. 

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Selective retro-aldol has also been reported by using aqueous HC1 in THF.243 Recently, catalytic aldol reactions in aqueous media have generated great interest due to the atom-economy related to the reaction. Reaction of 2-alkyl-1,3-diketones with the aqueous formaldehyde using aqueous 6-10 M potassium carbonate as base afforded aldol reaction products, which are cleaved by the base to give vinyl ketones (Eq. 8.96).244... 

Sc(OTf)3 is effective in aldol reactions in aqueous media (water-THF, Scheme 15).49 Direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enol ethers affords the corresponding aldol adducts in good yields. Water-sensitive silicon enolates can be used in aqueous solutions in the presence of a catalytic amount of Sc(OTf)3. 

A lead(II) triflate-crown ether complex functions as a chiral Lewis-acid catalyst for asymmetric aldol reactions in aqueous media (Scheme 86).352 This is the first example of a chiral crown-based Lewis acid that can be successfully used in catalytic asymmetric reactions. 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

In the present Ln(OTf)3-catalyzed aldol reactions in aqueous media, the amount of water strongly influences the yields of the aldol adducts. The effects of the amount of water on the yields in the model reaction of benzaldehyde with the silyl enol ether 2 in the presence of 10 mol% Yb(OTf)3 in THF were investigated (Eq. 2). The best yields are obtained when the amount of water present in THF is in the range 10-20 %. When the amount of water is increased, the yield begins to decrease The reaction system becomes a two phase one when the... 

Catalytic Asymmetric Aldol Reactions in Aqueous Media 7... 

Tiible 3. Catalytic asymmetric aldol reactions in aqueous media... 

Asymmetric Mukaiyama aldol reactions in aqueous media [EtOH-H20 (9 1)] were reported with FeCl2 and PYBOX ligands 27a [36] and 27b [37]. The latter provides product 28 with higher yield and diastereo- and enantioselectivity (Scheme 8.9). The ee values given are for the syn-diastereoisomer. Whereas ligand 27a is a derivative ofL-serine, compound 27b has four stereogenic centers, since it was prepared from... 

T. Hamada et al., Catalytic asymmetric aldol reactions in aqueous media using chiral bis-pyridino-18-crown-6-rare earth metal trillate complexes. J. Am. Chem. Soc. 125, 2989-2996 (2003)... 

Table 14-2. Sc(OTf)3-Catalyzed aldol reaction in aqueous media.

Catalytic asymmetric aldol reactions in aqueous media using praseodymium trif-late-chiral tetraoxa[4.4]-2,6-pyridinophane as catalyst 03YGK445. 

Kobayashi et al. recently developed the Pb(OTf)2-crown ether 56 complex as an efficient chiral catalyst of asymmetric aldol reactions in aqueous media (Scheme 10.51) [146]. This catalyst system achieves good to high yields and high levels of diastereo- (syn-selective) and enantioselectivity in the aldol reaction of a variety of aldehydes with propiophenone TMS enolate. The hole size of 56 is essential because 57 and 58 show no chiral induction. The unique structure of the Pb(OTf)2-56 complex as a chiral catalyst has been revealed by X-ray diffraction. 

Lewis acid-catalyzed asymmetric aldol reactions of silyl enol ethers with aldehydes are among the most powerful carbon-carbon bond-forming methods aprotic anhydrous solvents and low reaction temperatures are, however, usually needed for successful reaction. To perform the catalytic asymmetric aldol reaction in aqueous media a chiral crown ether-Pb(OTf)2 complex was employed as a chiral catalyst stable in water-ethanol [9]. Good to high yields and high levels of diastereo-and enantioselectivity were obtained at 0°C in aqueous media (Scheme 13.64). 

Poly(ethylene glycol) grafted on crosslinked polystyrene (PEG-PS) resin has often been used as a polymer support for chiral catalysts of reactions performed in aqueous media. Peptides immobilized to PEG-PS resin have been developed and used as a catalyst for direct asymmetric aldol reactions in aqueous media (Scheme 3.19) [42]. When tripeptide-supported PEG-PS 67 was used as chiral catalyst in the reaction between 70 and acetone, the corresponding aldol product 69 was obtained with 73% ee. Kudo further developed the one-pot sequential reaction of acidic deacetalization and enanhoselective aldol reaction by using an Amberhte and PEG-ST-supported peptide catalyst 67 [43]. The enantioenriched aldol product 72 was obtained in 74% isolated yield from acetal 70 in a one-pot reaction (Scheme 3.20). 

Lanthanide triflates are stable Lewis acids in water and are successfully used in several carbon-carbon bond-forming reactions in aqueous solutions. The reactions proceed smoothly in the presence of a catalytic amount of the triflate under mild conditions. Moreover, the catalysts can be recovered after the reactions are completed and can be re-used. Lewis acid catalysis in micellar systems will lead to clean and environmentally friendly processes, and it will become a more important topic in the future. Finally, catalytic asymmetric aldol reactions in aqueous media have been attained using Ln(OTf)3-chiral crown ether complex as a catalyst. 

Table 4. Lanthanide triflate-catalyzed aldol reactions in aqueous media Entry Aldehyde Silyl End Ether...

Aldol reaction. Triflyl and nonaflyl derivatives of (5)-(2-pyirolidinyl)methylamine mediate asymmetric aldol reactions in aqueous media/ The latter is a typically recyclable fluorous catalyst ... 

Lanthanide(ni) on ion exchange resins catalyse Mukaiyama aldol reactions in aqueous media, acetalisations, additions of silyl enol ethers to imines, saz-Diels-Alder reactions and the ringopening of epoxides with alcohols as depicted in Scheme 3.6.7. 

A chiral lanthanide complex catalyzes asymmetric Mukaiyama aldol reactions in aqueous media (Scheme 24). The changes in the water-coordination number is key to the mechanism of die catalytic reaction. The precatalysts yielded -hydroxy carbonyl compounds from aliphatic and aryl substrates widi high diastereomeric ratios and enantiomeric excesses of up to 49 1 and 97%, respectively. 

Scheme 13.27 Catalytic asymmetric Mulaiyama-aldol reactions in aqueous media promoted by Pr(OTf)3 complex.

Applying the results of this study, the catalyst prepared fi-om Ga(OTf)3 and chiral semicrown 5 was found to be effective for asymmetric aldol reactions in aqueous media. Interestingly, in the presence of the chiral ligand, hydrolysis of a silyl enol ether was suppressed, while rapid hydrolysis occurred in the absence of the ligand (Scheme 3.20). In addition, water was necessary to give satisfactory yield and enantioselectivity of the aldol adduct. A similar system using pybox-type ligand 6 and Zn(OTf)2 for aqueous asymmetric aldol reactions was also reported (Scheme 3.21). 

Darbre, T. and Machuqueiro, M., Zn-proline catalyzed direct aldol reaction in aqueous media, Chem. Commun., 2003, 1090-1091. 

Nagayama, S. and Kobayashi, S., Anovel chiral lead(II) catalyst for enantioselective aldol reactions in aqueous media, /. Am. Chem. Soc., 2000,122, 11531-11532. 

Munoz-Muniz, O., Quintanar-Audelo, M. and Juaristi, E., Reexamination of CeCla and InCla as activators in the diastereoselective Mukaiyama aldol reaction in aqueous media, J. Org. Chem., 2003, 68, 1622-1625. 

Direct asymmetric aldol reactions in aqueous media catalysed by phenolic proli-namides show enhanced de and ee when the catalysis is augmented by LiCl, ZnClj or 0... 

A Novel Chiral Lead(II) Catalyst for Enantioselective Aldol Reactions in Aqueous Media, J. Am. Chem. Soc. 122,11531, 2000 and 12S, 2989,2003. 

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