Aldehydes aldol reactions with silyl enol ethers

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

In addition to rare earth triflates, copper triflate was also found to be a stable Lewis acid in aqueous media. In a mixed aqueous solvent system (H20-EtOH-toIuene = 1 7 4), allylation of various aldehydes with tetraallyltin and aldol reactions with silyl enol ethers proceeded smoothly in the presence of Cu(OTf)2 (20 mol%) to give homoallylic alcohols and aldol adducts, respectively, in high yields (Schemes 3.9 and 3.10). 

Reductive aldol reaction of a,(5-unsaturated esters and enones with aldehyde mediated by a transition metal hydride complex and a hydride source, such as hydrosilane, is a versatile process to produce p-hydroxy carbonyl compounds (Scheme 15a) [21]. This reaction is thought to be an alternative transformation of Lewis acid-catalyzed Mukaiyama-type aldol reaction with silyl enol ethers or silyl ketene acetals (Scheme 15b). 

Evans et al. applied the Mukaiyama aldol reaction to the total synthesis of the squalene synthase inhibitor zaragozic acid C (Scheme 8.23). ° Di-f-butyl tartrate 135 was protected as acetal 137, which was converted into silyl enol ether 138. The partner aldehyde 141 was synthesized by the Evans aldol reaction (139 —> 140). The Mukaiyama aldol reaction with silyl enol ether 138 and aldehyde 141 in the presence of (i-PrO)TiCl3 gave adduct 142 as a single isomer. These transformations gave the desired stereochemistry at the C3 to C7 positions. 

In 1991, Kobayashi el al. prepared novel chiral S/N ligands for the tin-mediated aldol reaction of silyl enol ethers with aldehydes. As an example, the reaction of benzaldehyde afforded the expected syn aldol product as the major product with a good yield and an enantioselectivity of up to 92% ee (Scheme 10.26). Moreover, other aldehydes such as substituted benzaldehydes or aliphatic unsaturated aldehydes were converted into their corresponding aldol products with enantioselectivities of more than 90% ee. It was checked that the corresponding diamine ligands provided less active complexes for the same reactions. 

Sc(OTf)3 is an effective catalyst in aldol reactions of silyl enol ethers with aldehydes.49 Compared with other typical rare-earth-metal (Y, Yb) trifiates, Sc(OTf)3 has the strongest activity in the reaction of 1-trimethylsiloxycyclohexane with benzaldehyde in dichloromethane. Although the reaction scarcely proceeded at —78°C in the presence of Y(OTf)3 or Yb(OTf)3, the aldol adduct was obtained in 81% yield in the presence of Sc(OTf)3 (Scheme 9). 

S. Kobayashi, L Hachiya, The Aldol Reaction of Silyl Enol Ethers with Aldehydes in Aqueous Media Tetrahedron Lett. 1992,1625-1628. 

S. Kobayashi, T. Wakabayashi, S. Nagayama, H. Oya-mada, Lewis Add Catalysis in MiceUar Systems. Sc(OTf)3-Catalyzed Aqueous Aldol Reactions of Silyl Enol Ethers with Aldehydes in the Presence of a Surfactant Tetrahedron Lett. 1997,38, 4559-4562... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

Recently it was found that the aldol reaction of silyl enol ethers with acetals or aldehydes is effectively promoted by a catalytic amount of trityl perchlorate to give the corresponding aldols in good yields (44,45). Polymer-bound trityl perchlorate also successfully catalyzed the aldol reaction (45). 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Silyl enol ethers react with aldehydes at -78°C, and with ketones near CTC. Note that the aldol reaction of silyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

The blend SnC -ZnCli is an effective catalyst in the aldol reaction of silyl enol ethers with aldehydes (Eq. 87), acetals (Eq. 88), or ketones [122]. Product antilsyn ratios vary (32 69 to 89 11). The blend also catalyzes the Michael addition of silyl enol ethers with a,/3-unsaturated ketones (Eq. 89), yielding alkylation products (84-100 %) with anti selectivity antilsyn = 55 45 to 87 23). 

Sc(OTf)3-catalyzed aldol reactions of silyl enol ethers with aldehydes have recently been successfully performed in micellar systems [60]. Although the reaction proceeded sluggishly in water (without organic solvents), reactivity was remarkably enhanced by the presence of a small amount of a surfactant. In these systems, versatile carbon-carbon bond-forming reactions proceeded smoothly in water without the use of organic solvents. 

Suzuki, T., Hirama, M. Asymmetric aldol reaction of silyl enol ethers with aldehydes promoted by the combined use of chiral diamine coordinated tin(ll) triflate and tribulyltin fluoride. Chemtracts Org. Chem. 1989, 2, 268-270. 

The use of Ln(OTf)3 in the activation of aldehydes other than formaldehyde was also investigated [18], Several examples of the present aldol reaction of silyl enol ethers with aldehydes are listed in Table 14-1. In every case, the aldol adducts were obtained in high yields in the presence of a catalytic amount of Yb(OTf)3, Gd(OTf)3, or Lu(OTf)3 in aqueous media. Diastereoselectivities were generally good to moderate. One feature in the present reaction is that water-soluble aldehydes, for instance, acetaldehyde, acrolein, and chloroacetaldehyde, can be reacted with silyl enol ethers to afford the corresponding cross aldol adducts in high yields (entries 5-7). Some of these aldehydes are commercially supplied as water solutions and are appropriate for direct use. Phenylglyoxal monohydrate also worked well (entry 8). It is known that water often interferes with the aldol reactions of aldehydes with metal enolates and that, in the cases where such water... 

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). 

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 demand for environmentally friendly chemistry and its widespread applicability have made water an increasingly popnlar solvent for organic transformations. Mixtures of water and other solvents snch as tetrahydrofnran are now commonly anployed for a number of organic transformations. For instance, the Lewis acid catalysed aldol reaction of silyl enol ethers, commonly known as the Mnkaiyama aldol reaction, which was firstly reported in the early seventies, can be carried ont in snch media. With titanium tetrachloride as the catalyst this reaction proceeds regioselectively in high yields, but the reaction has to be carried ont strictly nnder non-aqneons conditions in order to prevent decomposition of the catalyst and hydrolysis of the sUyl enol ethCTS. In the absence of the catalyst it was observed that water had a beneficial influence on this process (Table 4, entry D) . Nevertheless, the yields in the nncatalysed version WCTe still unsatisfactory. Improved results were obtained with water-tolerant Lewis acids. The first reported example for Lewis acid catalysis in aqueous media is the hydroxymethylation of silyl enol ethers with commercial formaldehyde solution using lanthanide trillates. In the meantime, the influence of several lanthanide triflates in cross-aldol reactions of various aldehydes was examined " " ". The reactions were most effectively carried out in 1 9 mixtures of water and tetrahydrofnran with 5-10% Yb(OTf)3, which can be reused after completion of the reaction (Table 19, entry A). Although the realization of this reaction is quite simple, the choice of the solvent is crucial (Table 20). 

The aldol reactions of silyl enol ethers with aldehydes also proceed smoothly in water/ethanol/toluene [17]. The reactions proceed much faster in this solvent than in water/THF (Eq. 2). Furthermore, the new solvent system involves continuous use of the catalyst by a very simple procedure. Although the water/ethanol/toluene (1 7 4) system is one phase, it easily becomes two phases by adding toluene after the reaction is completed. The product is isolated from the organic layer by a usual work-up. On the other hand, the catalyst remains in the aqueous layer, which is used directly in the next reaction without removing water. It is noteworthy that the yields of the second, third, and fourth runs are comparable with that of the first run. 

Lubineau reported the water-promoted aldol reactions of silyl enol ethers with aldehydes, but the yields and the substrate scope were not yet satisfactory ... 

The pinwheel shape of a f-butyl propionate derived silylketene acetal (see Section 2.4.2.1) was revealed by a single-crystal X-ray diffraction analysis. Several different catalysts were reported to promote the aldol-type condensation of alkyl enol ethersand silyl enol ethers with aldehydes, acetals and various other electrophiles. In some cases the reaction proceeded with high simple stereoselection. The mechanism of the Lewis acid mediated additions to acetals (see Section 2.4.2.3) was investigated in detail, as well as the uncatalyzed aldol reaction of silyl enol ethers with aldehydes promoted by the hydrophobic effect (see Section 2.4.2.1). 

The aldol reactions of silyl enol ethers with aldehydes were also found to proceed smoothly in water-ethanol-toluene [20]. Some reactions proceeded much faster in this solvent system than in THF-water. Furthermore, the new solvent system realized continuous use of the catalyst by a very simple procedure. 

Several examples of the present aldol reactions of silyl enol ethers with aldehydes in water-ethanol-toluene are listed in Table 6.3-Pyridinecarboxaldehyde as well as 2-pyridinecarboxaldehyde, salicylaldehyde, and formaldehyde water... 

---