Silyl enol ethers Lewis acid catalysed aldol reaction

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). 

On the other hand, we have found that the Mukaiyama aldol reaction of benzalde-hyde with silyl enol ether 1 was catalysed by ytterbium triflate (YbfOTOj) in water-THF (1/4) to give the corresponding aldol adduct in high yield (Equation (1)). When this reaction was carried out in dry THE (without water), the yield of the aldol adduct was very low (ca. 10%). Thus, this catalyst is not only compatible with water but also activated by water probably because of dissociation of the counteranions from the Lewis acidic metal. Furthermore, these catalysts can be easily recovered and reused. 

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form -ketoalcohols, have been promoted by new chiral lanthanide-containing complexes and a chiral Fe(II)-bipyridine complex with 0 outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselec-tivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the a-carbon of the silyl ether, and the aldehyde. The relative steric effects of the Lewis acid and 0 trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with /-unsaturated a-ketoesters has been reported for the first time and studied extensively. ... 

Silyl enol ethers also combine with aldehydes and ketones in efficient aldol reactions catalysed by Lewis acids such as SnCl4, ZnCl2, A1C13, and TiCl4, the last being the most popular.13 Thus each of the silyl enol ethers 25 and 22 derived from the unsymmetrical ketone 23 gives a different aldol product 34 and 35 with benzaldehyde.11,14... 

The true extended aldol reaction, the combination of an extended enolate in the y-position, with an aldehyde or ketone, can best be realised by combining a silyl enol ether 54 with an acetal 70 under Lewis acid catalysis.20 The Lewis acid, usually TiCl4, catalyses the formation of the oxonium ion 71 which adds in the y-position to the silyl enol ether [cf. 64] to give the adduct 72 from which the remaining OMe group can be removed with base to give the dienal 73, the extended aldol product. 

The air stable and storable zirconium catalyst, formed from Zr(0 Bu)4, 3,3 -diiodo-l,l -binaphthalene-2,2 -diol (3,3 -l2-BINOL), -propanol and water, with the putative dimeric structure (7.33) also catalyses auft -selective asymmetric aldol reactions. While this process is beheved to proceed through an acyclic transition state, as depicted in Figure 7.2, it is postulated that the greatest steric interaction is now between the silyl enol ether substituent R3 and the bulky Lewis acid resulting in the formation of the fluft -diastereomer predominantly. 

Gd(OTf)3 is prepared by the general method described above. If suspect, then add aqueous triflic acid (50% vA) and proceed as above. It catalyses the aminolysis of epoxides in an extraordinarily efficient manner in aprotic solvents (e.g. toluene, CH2CI2) with complete trans stereoselectivity and high regioselectivity [Chini et al. Tetrahedron Lett 35 433 1994]. It also catalyses the reactions between nitriles and amines to yield a variety of amidines which, depending on the amine, can be used to prepare cyclic amidines, pyrimidines and x-triazines [Forsberg et al. J Org Chem 52 1017 79S7]. It is a water-tolerant Lewis acid used in aldol reactions of silyl enol-ethers and aldehydes in -79-89% yields (see below) [Kobayashi Hachiya J Org Chem 59 3590 1994]. 

A number of Lewis acids such as PhsCOTf and TiCp2(OT02 which apparently catalyse Mukaiyama cross-aldols actually proceed via catalysis by trimethyl triflate, due to exchange with the silyl enol ether under the influence of adventitious moisture. The range of mechanisms operating in this reaction is also reviewed (23 references). 

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