Cross-aldol type reaction

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Ruthenium hydride-catalyzed carbon-carbon double bond migration is applicable to isomerization of allylic acetals and ketals 31 to vinylic ones 32, which undergo selective cross-aldol type reaction by treatment with Bp3-Et20 to yield 33 (Eq. 12.12) [18]. 

Cross aldol-type reactions are catalyzed by Rh4(CO),2 The trimethylsi-lyl enolether 87 reacts with hexanal to give 88... 

The Claisen-Schmidt Reaction. When aromatic aldehydes are treated with aliphatic ketones in the presence of base, three reactions might be expected a Cannizzaro reaction of the aromatic aldehyde an aldol-type reaction of the ketone or a crossed aldol reaction between the ketone and the aromatic aldehyde. In either of the last two possibilities dehydration might also occur. Undoubtedly all these reactions will take place in strong base, but by employing about 10 per cent aqueous sodium hydroxide, good yields are often obtained of j3-unsaturated carbonyl conipounds derived from a crossed aldol reaction between the aldehyde and the ketone. This reaction, generally called a Claisen-Schmidt reaction, can be illustrated by the synthesis of benzalacetophenone.16... 

Fluoroacetonitrile condenses with carbon disulfide in an interesting aldol-type reaction (Scheme 3.14). The carbanion for ethyl fluoroacetate reacts readily with benzaldehyde in a cross-aldol reaction to give the fluorinated alcohol. a-Fluorinated carbonyl compounds are often very toxic materials because biologically they are converted into fluoroacetate, which is toxic to the Krebs cycle. Thus, extreme care is needed during the use of these compounds. 

Tables 1 and 2 show some examples of self- or cross-aldol condensation reactions followed by dehydration to obtain a,/3-unsaturated carbonyl compounds. Also in Table 1, a review of methyl isobutyl ketone (a saturated ketone) synthesis in the presence of hydrogen is included (10). In Table 2, some examples of fine chemicals obtained by aldol-type reactions are shown.

The aldol or aldol-type reaction is well recognized as one of the most important carbon-carbon bond forming reactions in organic synthesis. As shown in Scheme 8.1, two stereogenic centers could be generated in this aldol reaction. The classical aldol condensation between an aldehyde and a ketone is often catalyzed by a base or an acid. Another approach is the acid-catalyzed cross-aldol reaction of silyl enol ethers with carbonyl compounds, the so-called Mukaiyama reaction. 

The aldol reaction has long been recognized as one of the most useful synthetic tools. Under classical aldol reaction conditions, in vhich basic media are usually employed, dimers, polymers, self-condensation products, or a,j5-unsaturated carbonyl compounds are invariably formed as byproducts. The lithium enolate-mediated aldol reaction is regarded as one useful synthetic means of solving these problems. Besides the vell-studied aldol reaction based on lithium enolates, very versatile regio- and stereoselective carbon-carbon bond forming aldol-type reactions have been established in our laboratory by use of boron enolates (1971), silicon enolates-Le vis acids (1973), and tin(II) enolates (1982). Here we describe the first t vo topics, boron and silicon enolate-mediated crossed aldol reactions, in sequence. 

Stannous triflate is an efficient catalyst for aldol-type condensations [ 23, 124, 125 Under conditions of kinetic control, it provides excellent diastereo-selectivity in various cross-aldol reactions (equation 61)... 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

Cerium enolate complexes of type Cl2Ce(OCR=CHR) achieve higher yields in stoichiometric cross-aldol reactions of sterically crowded substrates than the corresponding lithium enolates (Scheme 26). The larger cerium is assumed to be more effective in the inital aldol chelate formation. Formation of oc-bromo-/ -hydroxyketones is also catalyzed [249]. 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

Much the same type of arguments applies here as applied in the crossed aldol reaction (Chapter 27). We must be quite sure that we know which compound is going to act as the enol partner and which as the acylation partner. 

As we learned in Section 23.3, the a hydrogens between two carbonyl groups are especially acidic, and so they are more readily removed than other a H atoms. As a result, the p-dicarbonyl compound always becomes the enolate component of the aldol reaction. Figure 24.2 shows the steps for the crossed aldol reaction between diethyl malonate and benzaidehyde. In this type of crossed aldol reaction, the initial P-hydroxy carbonyl compound always loses water to form the highly conjugated product. 

Cross-coupling between allylic alcohol and aldehyde is efficiently catalyzed by RuCl2(PPh3)3 in water to form an aldol-type product 48 [22], This reaction has limitations in the substituents of the aldehydes, and the use of aliphatic aldehydes provides complicated mixtures. Cross-coupling of imines with allylic alcohols under similar conditions generates Mannich-type reaction products 50 as major products, together with aldol-type products 48 [22], The selectivity of the reaction was improved by using methanol as the solvent, whereupon no aldol-type product was observed (Eqs. 12.19 and 12.20). 

Proline is a stable, nontoxic, cyclic, secondary pyrrolidine-based amino acid with an increased pK value. Thus, proline is a chiral bidentate compound that can form catalytically active metal complexes (Melchiorre et al. 2008). Bidentate means that proline has not only one tooth but also a second one to bite and react. The greatest difference to other amino acids is a Lewis-base type catalysis that facilitates iminium and enamine-based reactions. It is especially noteworthy that cross-aldol condensations of unprotected glycoladehyde and racemic glyceralde-hyde in the presence of catalytic amounts of the Zn-(proline)2 gave a mixture of pentoses and hexoses (Kofoed et al. 2004). Again, proline seems to play the decisive role. The conditions are prebiotic the reaction proceeded in water for seven days at room temperature. It is remarkable that the pentose products contained ribose (34%), lyxose (32%), arabinose (21%), and xylose (12%) and that all are stable under the conditions. Thus, the diastereomeric and enantiomeric selection observed support the idea that amino acids have been the source of chirality for prebiotic sugar synthesis. 

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