Recovering from aldol reactions

When trimethylorthoformate is utilized as the dehydration agent (Equation 8.), heavies due to Aldol condensation are eliminated. Methyl formate can be easily recovered from the reaction products, but synthetic routes to regenerate trimethylorthoformate are very involved and costly. An advancement to improve trimethylorthoformate synthesis would enhance the attractiveness of the homogeneous oxycarbonylation route to adipic acid. 

On the other hand, rare-earth trifluoromethanesulfonates (rare earth triflate, RE(OTf)3) have been found to work efficiently as Lewis acids even in aqueous media or in the presence of amines [4], A catalytic amount of RE(OTf)3 enables several synthetically useful reactions, for example aldol, Michael, allylation, Mannich, Diels-Alder reactions, etc., to proceed. It has also been demonstrated that a small amount of RE(OTf)3 is enough to complete the reactions and that RE(OTf)3 can easily be recovered from the reaction mixture and can be reused. A key to accomplishing the catalytic processes was assumed to be the equilibrium between Lewis acids and Lewis bases, for example water, carbonyl compounds, and amines, etc. A similar equilibrium was expected between Lewis adds and aromatic ketones, and, thus, RE(OTf)3-catalyzed Friedel-Crafts acylation was investigated [5]. 

The (0)-reagent (91) is formed almost exclusively from S-3-(3-ethyl)pentyl propanethioate (92) and borolanyl triflate (90). Despite its apparent steric demand, (91) still retains a high degree of reactivity towards aldehydes (in Scheme 21 the interaction between R and Me is not exceedingly large). Summarized in Table 6 are the results obtained from aldol reactions of representative aldehydes with (91 Scheme 38). All reactions proceed smoothly at -78 °C and the major products have the 2,3-anti stereochemistry (antiisyn > 30 1). With (2 ,55)-(90) the aldehydes examined provide, in most cases, the (2R) aldol products with more than 98% ee. It is important to note that the external chiral moiety can be recovered as its 2,2-dimethylaminoethanol complex, and that the aldol products are equipped with a versatile thioate functionality for further synthetic transformation. 

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 trans addition of indole (at position 3) to epoxides (e.g. to phenoxymetltyloxirane) in >50% yields at 60° (42 hours) under pressure (10 Kbar) and was successfully applied for an enantioselective synthesis of (+)-diolmycin A2 [Kotsuki Tetrahedron Lett 37 3727 799(5]. Of the ten lanthanide triflates, Yb(OTf)3 gave the highest yields (> 90%, see above) of condensation products by catalytically activating formaldehyde, and a variety of aldehydes, in hydroformylations and aldol reactions, respectively, with trimethylsilyl enol-ethers in THF at room temperature. All the lanthanide triflates can be recovered from these reactions for re-use. [Kobayashi Hachiya J Org Chem 59 3590 1994.]... 

Besides these experimental achievements, the authors have discussed the reaction pathway thoroughly their reaction network is in fine with the reaction scheme in Fig. 5. Thermodynamics were calculated and DFT calculations suggested that the coordination of Pb with three oxygen atoms of fructose increases the positive charge of the C4-OH, facilitating its proton transfer to C2 = O, and thus the retro-aldol of fructose. Apart from this, Pb(ll)-OH was postulated to be the active species in solution. Although Pb " could be completely recovered from the reaction, it is a very toxic cation. Nevertheless, this research demonstrates the potential of chemocatalysis to convert cellulose to LA and should therefore motivate the search for more environmentally friendly catalysts [146]. 

Bisprolindiamide 13a proved to be a good catalyst for the aldol reaction of cyclohexanone (57) with 4-nitrobenzaldehyde (2a) (Chart 3.6) [86, 33, 34] Carter et al. designed a proline sulfonamide-derivative possessing a long alkyl chain and applied it to the synthesis of 263 g of the aldol product anti-SSa [87]. Disappointingly, only 63% of the catalyst was recovered. To avoid this drawback, fluorous sulfonamide was synthesized and could be easily recovered from the reaction mixture by fluorous solid-phase extraction [88]. 

Excess of ketone was recovered after reaction. 6 The yield from aldol product. Conditions SnCl4 (cat.), (TMSO)2,... 

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. 

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. 

Evans and coworkers have developed chiral oxazolidinone auxiliaries such as 10 and 11 that are easily obtainable from (5)-vanilol or from (liS, 2R)-norephedrine. As well as the excellent selectivities obtained in aldol reactions, ease of attachment and removal of these auxiliaries has made this method widely popular. The auxiliary may be recovered and reused after cleavage from the aldol product. 

Kobayashi et al. discovered that Yb(OTf)3 and other lanthanide triflates (l,ri(() lf)(, Ln=La, Pr, Nd, Sm, Eu, Gd, Dy, Ho, and Er) are excellent catalysts of hydroxymefhylation of propiophenone TMS enolate with aqueous formaldehyde solution at room temperature (Scheme 10.22) [70, 71]. The Yb(OTf) j-catalyzed hydroxymefhylation of a variety of SEE, including sterically hindered compounds, proceeds regiospecifically in high yield. In addition, almost 100% of Yb(OHf). is quite easily recovered from fhe aqueous layer and can be reused. Yb(OTf)3 also has high catalytic activity in fhe aqueous aldol reaction of other aldehydes. Interestingly, the catalytic activity is rather low in the absence of water. In aqueous media water would coordinate to ytterbium to form active ytterbium cations. 

Lanthanide triflates and Sc(OTf)3 effectively catalyze conjugate addition of SEE, KSA, and ketene silyl thioacetals under mild conditions (0°C to room temperature, 1-10 mol% catalyst) (Scheme 10.86) [69, 238]. After an aqueous work-up these Lewis acids can be recovered almost quantitatively from the aqueous layer and can be re-used without reduction of fheir catalytic activity. Eu(fod)3 also is effective in not only aldol reactions but also Michael addition of KSA [239]. The Eu(fod)3-catalyzed addition of KSA is highly chemoselective for enones in the presence of ketones. 

Acyl-1,3-thiazolidines-2-ones 1.123 (X = S, R = COOMe), obtained from cysteine methyl ether [261], have been introduced by Mukaiyama and coworkers for use in asymmetric aldol reactions [261, 433, 434, 435], In reactions of related //-acyl-1,3-oxazolidines-2-thiones 1.123 (X = O, R = COOMe), each enantiomer can be obtained either from L- or D-serine [434] and the auxiliaries can easily be recovered by methanolysis. Similarly, //-acyl derivatives of 1.121 (X = S) have been used in asymmetric aldol reactions [429, 436], and //-acyl- 1,3-thiazo-lidinethiones 1.123 (X = S, R = r -Pr) are useful in asymmetric acylation [437] and aldol and related reactions [437, 438], Cleavage of the chiral auxiliary is accomplished by aminolysis with O-benzylhydroxylamine or by reduction with LiAlH.,. ... 

To improve the yields and therefore the scope of this aqueous aldolization, the use of lanthanide triflates as water-tolerant Lewis acids was recommended [9, 60]. After completion of the reaction nearly 100% of the catalyst is recovered from the aqueous layer and can be re-used quite easily. Other water-tolerant Lewis acids, including indium chloride [61] and tris(pentafluorophenyl) boron [62], were proposed as catalysts in the aqueous aldol reaction. 

Silyl enolates derived from not only esters but also thioesters and ketones reacted with aldehydes to give the corresponding adducts in high yields (Scheme 2) [22]. 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. 

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). 

Huorous compounds are also potentially useful as additives to promote organic reactions in carbon dioxide. For example, a fluorous alcohol RfCH20H assists asymmetric hydrogenations with non-fluorous ruthenium BINAP catalysts, and a fluorous aryl alkyl ether (C8F17C6H4-P-OC12H25) does so in scandium-triflate-catalyzed aldol and Friedel-Crafts reactions. These additives are presumed to act as solubilizers or emulsifiers to promote contact among the various reaction components. Since they are fluorous, they can be readily recovered from the otherwise organic reaction mixtures for reuse. 

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