Crossed aldol reactions products

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... 

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). 

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. 

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. 

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) ... 

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 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]. 

Several cross-aldol condensations have been performed with alkaline earth metal oxides, including MgO, as a base catalyst. A general limitation of the cross-aldol condensation reactions is the formation of byproducts via the self-condensation of the carbonyl compounds, resulting in low selectivities for the cross-aldol condensation product. For example, the cross-condensation of heptanal with benzalde-hyde, which leads to jasminaldehyde (a-K-amylcinnamaldehyde), with a violet scent... 

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). 

It is thus possible to look at a molecule such as A below and recognize that it is a ft-hydroxy ketone and thus could be formed in a crossed-aldol reaction between enolate B and aldehyde C. Likewise D could potentially be produced by dehydration of the aldol product of cyclohexanone... 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

Significant for cross-aldol reactions, when an aldehyde was mixed with (S)-proline in a reaction solvent, the dimer (the self-aldol product) was the predominant initial product. Formation of the trimer typically requires extended reaction time (as described above). Thus, it is possible to perform controlled cross-aldol reactions, wherein the donor aldehyde and the acceptor aldehyde are different. In order to obtain a cross-aldol product in good yield, it was often required that the donor aldehyde be slowly added into the mixture of the acceptor aldehyde and (S)-proline in a solvent to prevent the formation of the self-aldol product of the donor aldehyde. The outcome of these reactions depends on the aldehydes used for the reactions. Slow addition conditions can sometimes be avoided through the use of excess equivalents of donor or acceptor aldehyde - that is, the use of 5-10 equiv. of acceptor aldehyde or donor aldehyde. In general, aldehydes that easily form self-aldol products cannot be used as the acceptor aldehydes in... 

S)-Proline-catalyzed cross-aldol reaction of aldehydes followed by Mukaiyama aldol reaction sequence was used for the synthesis of prelactone B [27]. The products of the aldol reactions of O-protected a-oxyaldehydes are protected carbohydrates, and were also transformed to highly enantiomerically enriched hexose derivatives, again through a second Mukaiyama aldol reaction (Scheme 2.5) [28]. The products of the aldol reactions of N-protected a-aminoaldehyde donor were easily converted to the corresponding highly enantiomerically enriched /Miydroxy-a-amino acids and their derivatives (Scheme 2.6) [24]. (For experimental details see Chapter 14.1.1). 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

Predict the products of aldol and crossed aldol reactions before and after dehydra- Problems 22-62, 64, 67, 68, 69, tion of the products. Give mechanisms for the acid-catalyzed and base-catalyzed 72, 73, 76, 79, 80, and 81... 

A simple example from the first report of this reaction by Gilbert Stork and his group in 1974 is the condensation of pentan-2-one with butanal to give the aldol and then the enone oct-4-en-3-one by acid-catalysed dehydration. The yields may seem disappointing, but this was the first time anyone had carried out a crossed aldol reaction like this with an unsymmetrical ketone and an enolizable aldehyde and got just one aldol product in any reasonable yield at all. 

When one carbonyl compound has no a hydrogens, a crossed aldol reaction often leads to one product. Two common carbonyl compounds with no a hydrogens used for this purpose are formaldehyde (CH2=0) and benzaldehyde (C HsCHO). 

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. 

Problem 24.8 Draw the products formed in the crossed aldol reaction of phenylacetaldehyde (C6H5CH2CHO) with each compound (a) CH2(COOEt)2 (b) CH2(COCH3)2 (c) CH3COCH2CN. 

The p-hydroxy carbonyl compound formed from the crossed aldol reaction can be reduced with NaBH4, CH3OH (Section 20.4A) to form a 1,3-diol (Reaction [1]) or dehydrated to form an a,p-unsaturated carbonyl compound (Reaction [2]). Reduction of the c(,p-unsaturated carbonyl compound forms an allylic alcohol with NaBHi (Reaction [3]), or a ketone with H2 and Pd-C (Reaction [4]) see Section 20.4C. Reaction of the a,p-unsaturated carbonyl compound with an organometalllc reagent forms two different products depending on the choice of RM (Reaction [5]) see Section 20.15. 

In addition to enol silyl ethers, other derivatives of aldehydes and ketones, i.e. enol ethers (Eq. 8) [48] and enol esters (Eq. 9) [49, 50], serve as a partners for the cross aldol reaction, although the lower reactivity of these compounds compared with enol silyl ethers often makes the reaetion more complicated. For example, the products isolated in Eq. (8) were ether derivatives or a,y8-unsaturated carbonyl compounds rather than the expected aldol itself. 

Cross aldol reaction between two different aldehydes and/or ketones without prior activation or protection should provide a straightforward methodology for the synthesis of aldols, Mahrwald recently reported that treatment of aldehydes with TiCU and NEta (or TMEDA) gives rise to syn- do reaction in good yields (Eqs 38 and 39) [141], This method was extended to the aldehyde-ketone cross aldol reaction catalyzed by TiCU [142], an advantage of which is that reaction occurs at the more encumbered a-position of unsymmetrical ketones, as illustrated in Eqs (40) and (41) [143], The use of aliphatic aldehydes instead of PhCHO usually reduced stereoselectivity. When TiCU was replaced by a catalytic amount of BuTi(0-/-Pr)4Li, the aldol reaction was followed by the Tischenko reaction [144], Methyl vinyl ketone trimerized to give a chlorinated cyclic product with TiCU [145],... 

Reaction between Two Different Aldehydes. In the most general case, this will produce a mixture of four products (eight, if the alkenes 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. The crossed aldol is readily accomplished using amide bases in aprotic solvent. The first aldehyde is treated with LDA in THF at —78°C, for example, to form the enolate anion. Subsequent treatment with a second aldehyde leads to the mixed aldol product. The crossed aldol of two aldehydes has been done using potassium ferf-butoxide and Ti(OBu)4. ... 

Aldol reactions between two different carbonyl compounds are called mixed or crossed aldol reactions. With aqueous bases, these reactions are of little synthetic value if both reactants have a-hydrogens because they afford mixtures of products. However, under carefully controlled conditions, it is possible to condense ketones with aldehydes in the presence of dilute sodium hydroxide to furnish P-hydroxyke-tones, provided that the aldehyde is added slowly to the ketone. 

Corey, Enders and Bock were among the first to describe the utility of lithium dimethylhydrazone anions for crossed aldol reactions. In the reaction shown in equation (14), an azaallyllithium reagent derived from an aldehyde dimethylhydrazone was first silylated with trimethylsilyl chloride to yield a silyl aldehyde dimethylhydrazone. Subsequent lithiation using lithium diethylamide at -20 C for 1 h generated the silylated azaallyllithium reagent (29). Subsequent addition of one equivalent of an aldehyde or ketone at -78 C and warming to -20 C then yielded the product a,p-unsaturated aldehyde dimethylhydrazone in yields of 85-95%. Hydrolysis produced the unsaturated aldehyde in 75% overall yield. 

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