Aldol reactions in organic solvents

the application of ketene silyl acetals was tried in the above aqueous reactions of silyl enolates with aldehydes. Ketene silyl acetals are useful ester enolate equivalents that can be isolated [27, 28], and the aldol-type reaction of ketene silyl acetals with aldehydes is among the most important and mildest methods of carbon-carbon bond formation [29]. Disappointingly, no aldol adduct was obtained when the ketene silyl acetal derived from methyl 2-methylpropionate (3) was employed as a representative ketene silyl acetal (structure 3 is shown later in Table 8.10). In aqueous media, hydrolysis of the ketene silyl acetal preceded the desired aldol reaction. 

The reaction was then carried out in organic solvents. First, ketene silyl acetal 3 was treated with benzaldehyde in the presence of 10mol% of Yb(OTf)3 in dichloromethane. The reaction proceeded smoothly at -78°C to afford the corresponding aldol-type adduct in a 94% yield. The same reaction 

the lanthanide-triflate-catalyzed aldol reactions of silyl enolates with aldehydes or acetals were successfully carried out not only in aqueous but also in organic solvents. The extreme mildness of the reaction conditions, the simple procedures, the successful use of both aqueous and organic solvents, and the striking feature of the reusability of these catalysts are especially noteworthy. 

5 Aldol reactions in water-ethanol-toluene and continuous use of the Ln( OTf) 3 catalyst 

Quite recently, the aldol reactions of silyl enol ethers with aldehydes were found to proceed smoothly in a new solvent system, water-ethanol-toluene [31]. The reactions proceeded much faster in the above solvent than in THF-water. Furthermore, the new solvent system realized continuous use of the catalyst by a very simple procedure. 

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The first example bismuth-catalyzed aldol reaction was reported by Wada and Akiba and co-workers in 1988, in which 5 mol% of Bids mediated the Mukaiyama aldol reaction efficiently at room temperature (Scheme 48) (189). Subsequently, metallic iodide-activated bismuth(III) chloride, and Bi(OTf)3, were also examined for the Mukaiyama aldol reactions in organic solvents or ionic liquids (190-193). An extension of bismuth triflate catalyzed aldol or aldol-type reaction to the synthesis of substituted 3,4-dihydro-2if-l-benzopyrans has also been reported by Mohan and co-workers (Scheme 49) (194). 

Several examples of the present aldol reactions in organic solvent using Yb(OTf)3, Eu(OTf)3, Gd(OTf)3, or Ho(OTf)3 as a catalyst are examined (Scheme 8.1) [30]. Silyl enolates derived from not only esters but also thioesters and ketones reacted with aldehydes to give the corresponding adducts in high yields. Furthermore, acetals reacted smoothly with silyl enolates to afford the corresponding aldol-type adducts in high yields. It should be noted that the catalysts could be easily recovered from the aqueous layer after the reactions were quenched with water and could be reused, and that the yields of the second run were almost comparable to those of the first run in every case. 

While the Lewis acid-catalyzed aldol reactions in aqueous solvents described above are catalyzed smoothly by several metal salts, a certain amount of an organic solvent such as THF had still to be combined with water to promote the reactions efficiently. This requirement is probably because most substrates are not soluble in water. To avoid the use of the organic solvents, we have developed a new reaction system in which metal triflates catalyze aldol reactions in water with the aid of a small amount of a surfactant, such as sodium dodecyl sulfate (SDS). 

Lanthanide triflates were found to be excellent Lewis acid catalysts not only in aqueous media but also in organic solvents. The reaction of ketene silyl acetal 3 with benzaldehyde proceeded smoothly in the presence of 10mol% Yb(OTf)3 in dichloromethane at -78°C, to afford the corresponding aldol-type adduct in 94% yield. The same reaction at room temperature also went quite cleanly without side reactions and the desired adduct was obtained in 95% yield. No adduct was obtained in THF-water or toluene-ethanol-water, because hydrolysis of the ketene silyl acetal preceded the desired aldol reaction in such solvents. In other organic solvents such as toluene, THF, acetonitrile, and DMF, Yb(OTf)3 worked well, and it was found that other Ln(OTf)3 also catalyzed the above aldol reaction effectively (85-95% yields). 

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. 

Aldol Reactions in Water Without Using Organic Solvents... 

The catalytic asymmetric aldol reaction has been applied to the LASC system, which uses copper bis(-dodecyl sulfate) (4b) instead of CufOTf. 1261 An example is shown in Eq. 6. In this case, a Bronsted add, such as lauric add, is necessary to obtain a good yield and enantioseledivity. This example is the first one involving Lewis acid-catalyzed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivity are still not yet optimized, it should be noted that this appredable enantioselectivity has been attained at ambient temperature in water. 

Very recently, Belokon and North have extended the use of square planar metal-salen complexes as asymmetric phase-transfer catalysts to the Darzens condensation. These authors first studied the uncatalyzed addition of amides 43a-c to aldehydes under heterogeneous (solid base in organic solvent) reaction conditions, as shown in Scheme 8.19 [47]. It was found that the relative configuration of the epoxyamides 44a,b could be controlled by choice of the appropriate leaving group within substrate 43a-c, base and solvent. Thus, the use of chloro-amide 43a with sodium hydroxide in DCM gave predominantly or exclusively the trans-epoxide 44a this was consistent with the reaction proceeding via a thermodynamically controlled aldol condensation... 

While the Lewis acid-catalysed aldol reactions in water-containing solvents described above were catalysed by several metal salts, a certain amount of organic solvents such as THF and ethanol still had to be combined with water to dissolve organic substrates and promote the reactions efficiently. However, it is desirable to avoid the use of harmful organic solvents. Therefore, we initiated investigations to develop a new system for Lewis acid-catalysed reactions in water without using any organic solvents. 

Catalytic asymmetric aldol reactions in water have been attained by a combination of Cu(DS)2 and chiral bis(oxazoline) ligand 4. In this case, addition of a Br0sted acid, especially a carboxylic acid such as lauric acid, is essential for good yield and enantioselectivity (Equation (5)) [29]. This is the first example of Lewis acid-catalysed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivities have not yet been optimized, it is noted that this enantioselectivity has been achieved at ambient temperature in water. 

Yb(OTf)3 is an excellent catalyst for the aldol reactions of silylenol ethers with aldehydes in aqueous solution, working better than in organic solvents like THF and MeCN, though the reactions can also be performed in organic solvents, and, after the reaction has been quenched by the addition of water, the triflate catalyst may be recovered from the aqueous layer. 

The catalyzed aldol reaction in pure water offers a cautionary tale on overinterpretation of computationally derived mechanisms. The term catalysis may seem to be inappropriately applied to the role of water in the aldol reaction. The aldol reaction is in fact usually much slower in water than in organic solvents. Rather, as will be demonstrated, the catalytic role of water is to create an alternate pathway with a lower barrier than that for the noncatalytic, but aqueous, reaction. 

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. 

Aldol reaction in water without organic solvents... 

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