Aldol Condensations with Aromatic Aldehydes

Mixed Aldol Condensations with Aromatic Aldehydes 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

There is a pronounced preference for the formation of a trans double bond in the Claisen-Schmidt condensation of methyl ketones. This stereoselectivity arises in the dehydration step. In the transition state for elimination to a cis double bond, an unfavorable steric interaction between the ketone substituent (R) and the phenyl group occurs. This interaction is absent in the transition state for elimination to the trans double bond. 

Additional insight into the factors affecting product structure was obtained by study of the condensation of 2-butanone with benzaldehyde.2 

PhCH= CCCH3 - --- PhCH=0 + CH3CCH2CH3 ------ PhCH= CHCCH2CH3 

The results indicate that the product ratio is determined by the competition between the various reaction steps. Under base-catalyzed conditions, 2-butanone reacts with benzalde-hyde at the methyl group to give l-phenylpent-l-en-3-one. Under acid-catalyzed conditions, the product is the result of condensation at the methylene group, namely, 3-methyl-4-phenylbut-3-en-2-one. Under the reaction conditions used, it is not possible to isolate the intermediate ketols, because the addition Step is rate-limiting. These intermediates can be 

Addition of Enolates and Enols to Carbonyl Compounds The Aldol Addition and Condensation Reactions 

The dehydration reactions require somewhat higher activation energies than the addition step. Detailed studies have provided rate and equilibrium constants for the individual steps in a few cases. The results for the acetone-benzaldehyde system in the presence of hydroxide ion are given below. Note that Kj is sufficiently large to drive the first equilibrium forward. 

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Mixed Aldol Condensations with Aromatic Aldehydes... 

Methyl-3,6-diacetylcarbazole undergoes a double aldol condensation with aromatic aldehydes. The cyclic ketone 197 (R = Hj) condenses with... 

At a lower oxidation level, orffto-hydroxy-acyl-arenes undergo base-catalysed aldol condensations with aromatic aldehydes to give chalcones, °° which can be cyclised to 2,3-dihydro-chromones via an intramolecular Michael process the dihydro-chromones can in turn be dehydrogenated to produce chromones by a variety of methods, for example by bromination then dehydrobromination or by oxidation with the trityl cation, iodine, dimethyldioxirane or iodobenzene diacetate. ° ... 

Saturated heterocyclic ketones are also good substrates for mixed aldol condensations with aromatic aldehydes. Again, a selection of high-yielding examples is presented in equations (76)-(80). These... 

Alternatively, 2-aryl-4-quinolones (124, R =Ar) are obtained from (2-amino)aceto-phenones 125 by base-induced aldol condensation with aromatic aldehydes (—>-126), Lewis acid-promoted cyclization to the 2,3-dihydro-4-quinolones 127, and their dehydrogenation with PhI(OAc)2 (127 -> 124, R=Ar) [186],... 

Aldol condensations.1 Under usual conditions, 1 is not useful for crossed-aldol condensation because of predominant self-condensation. However in the presence of pyridine and acetic acid 1 undergoes aldol condensation with aromatic and a,p-unsaturated aldehydes. Yields are moderate to high if the concentration of 1 is kept low (inverse addition). This reaction can be used to obtain all-trans-19,19,19- and 20,20,20-trifluororetinal (2). 

Most of the examples in this chapter have been of molecules without selectivity. They have indeed all been self condensations. We hope this has established the basic disconnections and the chemistry but we must now turn to examples where selectivity is needed. So the ketone 46 was made to study aldol reactions with aromatic aldehydes.13 They found that, in acid or base, the enone 52 was the main product with the best yield from HCI in EtOH. The product 52 was isolated as its HCI salt. In this case it is easy to see that only the ketone can enolise, that the aldehyde is more electrophilic than the ketone and that the geometrical isomer shown is the more stable. Such considerations are the substance of the next chapter. 

A methodology has been developed for preparation of either trans- or cis-3-substituted prolines from 4-oxoprolines by aldol reactions of the corresponding enolate. The enolate of an A-(9-phenylfluoren-9-yl)-4-oxoproline ester (34) undergoes aldol condensation with aromatic and aliphatic aldehydes by preferential... 

The a-ionization of 7-methylpteridines can also be utilized in aldol-type condensation reactions. 7-Methyl-pterin and -lumazine and 2,4-diaminopteridine condense readily in aqueous base with aromatic aldehydes to afford 7-alkylidenepteridines (77JOC2951). A Claisen condensation requires the protection of the acidic hydrogens of the amide bonds. 

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

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) ... 

Kinetic Aldol Condensations of Cyclohexanone Enolates with Aromatic Aldehydes (eq. [18])... 

In general, the product ratio of a mixed aldol condensation will depend upon the individual reaction rates. Most ketones show a pattern similar to butanone in reactions with aromatic aldehydes. Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference. 

Properties. Vanillin is a colorless crystalline solid mp 82-83 °C) with a typical vanilla odor. Because it possesses aldehyde and hydroxyl substituents, it undergoes many reactions. Additional reactions are possible due to the reactivity of the aromatic nucleus. Vanillyl alcohol and 2-methoxy-4-methylphenol are obtained by catalytic hydrogenation vanillic acid derivatives are formed after oxidation and protection of the phenolic hydroxyl group. Since vanillin is a phenol aldehyde, it is stable to autoxidation and does not undergo the Cannizzarro reaction. Numerous derivatives can be prepared by etherification or esterification of the hydroxyl group and by aldol condensation at the aldehyde group. Several of these derivatives are intermediates, for example, in the synthesis of pharmaceuticals. 

Aromatic and aliphatic aldehydes can be oxidized after careful and individual optimization of the reaction conditions to carboxylic acids (Eq. (7), Table 12). With aromatic aldehydes yields are excellent, with aliphatic aldehydes good to satisfactory. The electrolyte has to be less alkaline than normal to suppress the aldol condensation. 2-Phenylpropanol is best oxidized at low temperatures to render the cleavage to benzoic acid more difficult, at 70 °C benzoic acid becomes main product (47 %). Double bonds in y,8- or even a,P-position are not touched in the oxidation. 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

Aldol condensation of the zinc enolate of resin-bound alkyl ester 29 with aromatic aldehyde or ketone forms a P-hydroxy ester, which upon treatment with DIBAL-H leads to simultaneous reduction and cleavage of the ester moiety from the resin to give a soluble 1,3-diol 31 [31], Parallel synthesis utilizing three ester and nine carbonyl building blocks afforded a library of 27 analogs which was screened for antioxidative efficiency using a ferric thiocyanate assay. 

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