Mukaiyama aldol reaction without catalyst

Lewis acids are quite often used as catalysts in organic synthesis. Although most Lewis acids decompose in water, it was found that rare earth triflates such as Sc(OTf)3, Yb(OTf)3, etc. can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids) [6-9]. For example, the Mukaiyama aldol reactions of aldehydes with silyl enol ethers were catalyzed by Yb(OTf)3 in water-THF (1 4) to give the corresponding aldol adducts in high yields [10, 11]. Interestingly, when the reactions were carried out in dry THF (without water), the yield of the aldol adducts was very low (ca. 10%). Thus, this catalyst is not only compatible with water but also is activated by water, probably due to dissociation of the counteranions from the Lewis acidic metal. Furthermore, the catalyst can be easily recovered and reused. 

Recently, Kobayashi noticed that the presence of a small amount of a surfactant such as sodium dodecyl sulfate (SDS) showed a remarkable enhancement of the reactivity in the Mukaiyama-catalyzed aldol reaction in pure water using Yb(OTf)3 or better Sc(OTf )3 as the catalyst without addition of the surfactant, the reaction was very sluggish (Scheme 8.4). Other surfactants such as calix[6]arene derivatives bearing sulfonate and alkyl groups or aromatic and aliphatic anionic surfactants have also been found to be highly effective in the aqueous Mukaiyama aldol reactions in pure water, affording the aldol products in high yields. This was probably due to the formation of micelles which stabilized the labile silyl enol ethers and thus promoted the aldol reaction. 

A supported scandium catalyst prepared fi-om sulfonated polystyrene resin was found to be an effective catalyst for Mukaiyama aldol reactions in water, the use of this solvent being crucial for the reaction. The catalyst was easily recovered by a simple filtration and reused without any loss of catalytic activity (Scheme 8.7). Other similar work... 

The (OTfljSc-SOs-Ph-PMO also showed the highest catalytic reactivity and selectivity in water-medium Mukaiyama aldol reaction (Equation (8.62)) [106]. It exhibited significantly enhanced catalytic reactivity against that of Sc(OTf)3 homogeneous catalyst and higher catalytic efficiency than the (OTf)2Sc-S03-Ph-SBA-15 with Sc complex terminally bonded to the pore surface. Moreover, it could be easily reeycled and reused at least 10 times without significant loss of its catalytic activity. 

Carbonyl groups are also activated by Lewis acids to participate in various condensation reactions. One of the most important of these is the Mukaiyama aldol reaction. The first version of this in the 1970s (Figure 23.9) was not catalytic, but catalytic versions and enantioselective variants were quickly developed. The advantage of the process is that a crossed-aldol reaction is achieved without any risk of self-condensation of either component, and reaction conditions are exceptionally mild. However, the starting silyl enol ether does need to be prepared. Some examples are shown in Figure 23.10. The first reaction is one on which many common catalysts... 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

Other important aldol condensations are the Mukaiyama-type aldol reactions of silyl enol ethers with aldehydes that usually require catalyst activation. Yamamoto reported that such reactions under high pressure proceed (i) without catalyst even at room temperature, (ii) without isomerization of the formed adducts and (iii) with a reversed synlanti stereoselectivity compared with that of the TiCU-catalysed reactions. ... 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

Several examples of the Sc(OTf)3-catalyzed aldol reactions of silyl enolates with aldehydes were examined, and it was found that silyl enolates derived from ketones, thioesters, and esters reacted smoothly with aldehydes in the presence of 5mol% Sc(OTf)3 to afford the aldol adducts in high yields. Sc(OTf)3 was also found to be an effective catalyst in the aldol-type reaction of silyl enolates with acetals. The reactions proceeded smoothly at -78°C or room temperature to give the corresponding aldol-type adducts in high yields without side reaction products. It should be noted that aldehydes were more reactive than acetals (Noyori et al. 1981, Mukai et al. 1990, Mukaiyama et al. 1991). For example, while 3-phenylpropionealdehyde reacted with the ketene silyl acetal of methyl 2-methylpropionate (3) at -78°C to give the aldol adduct in 80% yield, no reaction occurred at —78°C in the reaction of the same ketene silyl acetal with 3-phenylpropionealdehyde dimethylacetal. The acetal reacted with the ketene silyl acetal at 0°C to room temperature to give the aldol-type adduct in 97% yield (scheme 3). 

Scandium triflate-catalyzed aldol reactions of silyl enol ethers with aldehyde were successfully carried out in micellar systems and encapsulating systems. While the reactions proceeded sluggishly in water alone, strong enhancement of the reactivity was observed in the presence of a small amount of a surfactant. The effect of surfactant was attributed to the stabiMzation of enol silyl ether by it. Versatile carbon-carbon bondforming reactions proceeded in water without using any organic solvents. Cross-linked Sc-containing dendrimers were also found to be effective and the catalyst can be readily recycled without any appreciable loss of catalytic activity.Aldol reaction of 1-phenyl-l-(trimethylsilyloxy) ethylene and benzaldehyde was also conducted in a gel medium of fluoroalkyl end-capped 2-acrylamido-2-methylpropanesulfonic acid polymer. A nanostmctured, polymer-supported Sc(III) catalyst (NP-Sc) functions in water at ambient temperature and can be efficiently recycled. It also affords stereoselectivities different from isotropic solution and solid-state scandium catalysts in Mukaiyama aldol and Mannich-type reactions. 

CAB 3a is also an excellent catalyst (20 mol%) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. Furthermore, the reactivity of aldol-type reactions can be improved without reducing the enantioselec-tivity by using 10-20 mol% of 3c. Enantioselectivity can also be improved without reducing the chemical yield by using 20 mol% of 3b. The 3-catalyzed aldol process allows for the formation of adducts in a highly diastereo- and enantioselective manner (up to 99% ee) under mild reaction conditions [41a, cj. These reactions are catalytic, and the chiral source is recoverable and reusable (Equation 41). The observed high syn selectivities, together with their lack of dependence on the stereoselectivity of the silyl enol ethers, in 3-catalyzed reactions are fully consistent with Noyori s TMSOTf-catalyzed aldol reactions of acetals, and thus may reflect the acyclic extended transition state mechanism postulated in the latter reactions. 

While several resin- or polymer-supported Sc(OTf)3 catalysts have been developed and some of them are commercially available, a drawback of these catalysts is that their catalytic ability and reusability are still not satisfactory. Conceptually new methods, polymer incarcerated (PI) method and polymer-micelle incarcerated (PMI) have been developed to immobilize Sc(OTf)3 [100]. PMI Sc(OTf)3 is highly effective in several fundamental carbon-carbon bond-forming reactions, including Mukaiyama aldol, Mannich-type and Michael reactions. It is noted that the high catalytic activity in terms of TON (>7500) has been attained in Michael reaction. The catalyst was recovered quantitatively by simple filtration and reused several times without loss of catalytic activity, and no Sc leaching was observed in all the reactions (<0.1 ppm). 

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama aldol) was first studied by Lubineau and coworkers in aqueous solvents. Without any acid catalyst, these reactions took several days to complete. A major development was the use of water-tolerant Lewis acids for such reactions, pioneered by Kobayashi and coworkers. ... 

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