Cross aldol reactions

Butyraldehyde undergoes stereoselective crossed aldol addition with diethyl ketone [96-22-0] ia the presence of a staimous triflate catalyst (14) to give a predominantiy erythro product (3). Other stereoselective crossed aldol reactions of //-butyraldehyde have been reported (15). 

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)... 

A different situation is found in the case of crossed aldol reactions, which are also called Claisen-Schmidt reactions. Here the problem arises, that generally a mixture of products might be obtained. 

If only one of the two aldehydes has an a-hydrogen, only two aldols can be formed and numerous examples have been reported, where the crossed aldol reaction is the major pathway. For two different ketones, similar considerations do apply in addition to the unfavorable equilibrium mentioned above, which is why such reactions are seldom attempted. 

An analogous reaction has been carried out using malononitrile and different products derived by a Cross-Aldol reaction of acetone (Scheme 32). The cyclic furanimide 91 was then reacted under microwave irradiation in the presence of NaOEt with a second molecule of malononitrile to give the furanone 92 [66]. The NLO chromophore 93 was prepared using this procedure. 

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... 

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama-aldol) was studied by Lubineau and co-workers... 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

TiIV compounds also work well at promoting cross-aldol reactions between two different aldehydes and/or ketones without prior activation or protection (Scheme 19).74 Claisen condensation and Knoevenagel condensation are promoted by TiX4, an amine, and trimethylsilyl triflate.75-77... 

In the Mukaiyama cross-aldol reaction, an aldehyde and a ketene silyl acetal [e.g. (43)] react via Lewis acid catalysis to give a jS-silyloxy ester (44). The reaction... 

Ketones can also be used as one component in the cross aldol reactions. 

The aldol reaction as formulated above involves two molecules of the starting substrate. However, by a consideration of the mechanism, one can see that different carbonyl compounds might be used as nucleophile or electrophile. This would be termed a mixed aldol reaction or crossed aldol reaction. However, if one merely reacted, say, two aldehydes together under basic conditions, one would get a... 

A nondirect enantioselective cross-aldol reaction between two discrete aldehyde components has been achieved see Denmark, S. E. Ghosh, S. K. Angew. Chem. Int. Ed. 2001, 40, 4759 762. 

As demonstrated by MacMillan and coworkers, a-oxygenated aldehydes are very good reaction partners in the aldehyde-aldehyde crossed-aldol reaction. The products are tetroses, and one further aldol step affords a range of hexoses, i.e. differentially protected monosaccharides, in a two-step synthesis (Scheme 20) [203],... 

The simplest possible aldehyde donor, acetaldehyde, can also be used as the donor Very recently, Hayashi and coworkers discovered how to use acetaldehyde in crossed-aldol reactions - the trick is to use diarylprohnol as the catalyst and to optimize the reaction conditions carefully to prevent oligomerization of acetaldehyde. However, so far the acetaldehyde aldol reactions appear to be limited to aromatic aldehyde acceptors [205],... 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

An aldol reaction/condensation occurs when the enolate ion from an aldehyde or ketone attacks a molecule of the parent compound. If, however, two different carbonyl compounds are present, a crossed aldol reaction/ condensation occurs. 

Cross aldol reactions of silyl enol ethers with acetals (25 - 26, and 27 - 28) are also mediated by EGA. The reaction runs smoothly at —78 °C in a CH2CI2— —LiClO —Et NClO —(Pt) system. At an elevated temperature protonation of both enol ether and acetal occurs competitively to give 28 in a poor yield. Table 5 summarizes yields and diastereoselectivities of 28 obtained by EGA, TiCl TMSOTf and TrtClO 5 . The EGA method is superior to TiCl with regard to the stereocontrol, and comparable with TMSOTf and TrtClO in both stereocontrol and yield. 

Reaction between two different aldehydes. In the most general case, this will produce a mixture of four products (eight, if the olefins are counted). However, if one aldehyde does not have an a hydrogen, only two aldols are possible, and in many cases the crossed product is the main one. The crossed aldol reaction is often called the Claisen-Schmidt reaction. 

On the other hand, a remarkable difference between catalysis by Y and 13 zeolites has been found for the Claisen-Sohmidt condensation of acetophenone and benzaldehyde (Table 5). When the cross aldolic reaction is carried out in the presence of HY, together with the expected trans and ois chalcones 5, the 3,3-diphenylpropiophenone 6 is also formed, this product being not detected on 13 zeolites. A likely explanation for the absence of 6 using zeolite beta is that the crystalline structure of this zeolite exerte a spatial constraint making difficult the formation of a big size molecule like 6, especially in the smaller channel. Similar effects due steno limitations on 6 catalysis have been found for the formation of multi-branched products during the cracking of alkanes (ref 8). 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

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