Solvent effects directed aldol reaction

The importance of aqueous reactions is now generally recognized, and development of carbon-carbon bond-forming reactions that can be performed in aqueous media is now one of the most challenging topics in organic synthesis [59]. It has been found that Sc(OTf)3 was effective in aldol reactions of silyl enolates with aldehydes in aqueous media (water-THF Eq. 16) [4]. Reaction between aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde and silyl enolates have been performed successfully in aqueous solvents. In addition, direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enolates affords the corresponding aldol adducts in good yields. Water-sensitive silyl enolates could be used in aqueous solutions with Sc(OTf)3 as catalyst. 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

To better evaluate both methods the results of the direct aldol reaction of acetone with selected aromatic aldehydes catalyzed by prohne are presented in Figure 21.2. Although in general the Kotsuki approach offers much better yields, in the Hayashi method higher enantioselectivities (temperature effect) can be obtained. This methodology was also tested in a solvent-free aldol reaction with cyclopentanone but no improvement was noticed [23]. 

The Kotsuki group investigated the effect of high-pressure conditions on the direct proline-catalyzed aldol reaction [79a], a process which, interestingly, does not require use of DMSO as co-solvent. Use of high-pressure conditions led to suppression of the formation of undesired dehydrated by-product and enhancement of the yield. Study of the substrate range with a range of aldehydes and ketones revealed that enantioselectivity was usually comparable with that obtained from experiments at atmospheric pressure. Additionally, proline catalyzed aldol reactions in ionic liquids, preferably l-butyl-3-methylimidazolium hexafluorophosphate, have been successfully carried out [79b,c]. 

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaCls 7H2O with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 °C for 50 h. Another efficient procedure for the preparation of LLB starts from La(0-/-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium (3 mol equiv.) at 0 C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2CI2 and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

Sc(OTf)3 can behave as a Lewis acid catalyst even in aqueous media. Sc(OTf)3 was stable in water and was effective in the aldol reactions of silyl enolates with aldehydes in aqueous media. The reactions of usual aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde with silyl enolates were carried out in both aqueous and organic solvents, and water-soluble formaldehyde and chloroacetaldehyde were directly treated as water solutions with silyl enolates to afford the aldol adducts in good yields. Moreover, the catalyst could be recovered almost quantitatively from the aqueous layer after the reaction was completed. The recovered catalyst was also effective in the second reaction, and the yield of the second run was comparable to that of the first run (Eq. 2). 

Moyano, Rios, and co-workers [38] have shown that the beneficial effect of hydrogen-bond donors in proline-catalyzed aldol reactions in nonpolar solvents [39] is due both to the facilitation of proline solubilization by formation of an oxazolidinone with the ketone and to the stabilization of the iminium carboxylate zwitterionic form that is the direct precursor of the reactive enamine intermediate,... 

Direct asymmetric cross-aldol reactions of ketones with aromatic aldehydes proceed in the presence of an l-proline-derived tertiary diamine and additives using water as a solvent (Scheme 26). L-Proline-derived diamines give racemic product in the absence of an acid cocatalyst. While trifluoroacetic acid (TFA) is the most effective additive for the aldol addition of cyclohexanone to 4-nitrobenzaldehyde in the presence of L-proline-derived diamine, addition of scandium triflate is also effective for the reaction with similar enantioselectivity. 

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