Reactions related to the aldol condensation

Condensation reactions of the aldol type play an important part in heterocyclic chemistry. There are a large number of condensation reactions that are closely related to the aldol condensation. Each of these reactions has its own name Claisen, Dieckmann, Doebner, Knoevenagel, Perkin, to mention a few, but the chemistry is essentially the same as that of the aldol condensation. 

The reaction of triphenyl-/ -phosphanes with carbonyl compounds, the Wittig olcfmation reaction, involves addition to the carbonyl carbon in a reaction closely related to the aldol condensation. Triphenyl-2 -phosphanes, derived from alkyltriphenylphosphorus salts, react with 1,1,1-trifluoroacetonc or other trifluoromethyl ketones " - to give products 29. 

This reaction is related to the Aldol Condensation and Michael Reaction. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

The pioneer work in this field was carried out on polystyrene-supported acid catalysts [161]. Thereafter, several works on the use of sulfonic, strong acidic cation exchangers as acid catalysts were reported for alkylation, hydration, etherification, esterification, cleavage of ether bonds, dehydration, and aldol condensation [162,168-171], Besides, industrial applications of these materials were evaluated with reactions related to the chemistry of alkenes, that is, alkylation, isomerization, oligomerization, and acylation. [163,169], Also, Nation, an acid resin which has an acid strength equivalent to concentrated sulfuric acid, can be applied as an acid catalyst. It is used for the alkylation of aromatics with olefins in the liquid or gas phases and other reactions however, due to its low surface area, the Nation resin has relatively low catalytic activity in gas-phase reactions or liquid-phase processes where a nonpolar reactant or solvent is employed [166],... 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

Kinetics (Section 8.8) The study of the rates of reactions. Knoevenagel condensation (Section 19.6) Any of a number of condensation reactions related to the crossed aldol condensation. A stabilized anion, often an enolate, is first formed and then adds to the carbonyl group of another molecule. Dehydration usually leads to the formation of the final product. 

With simpler, less stabilized, enols and enolates, the same selectivity issues arise in this addition process as we saw for aldol and related reactions—these reactions are related to the aldols, but a double bond simply intervenes as an electron relay. Consider the example shown in Figure 17.68. We have chosen a nucleophile that can enolize readily and an a,p-unsaturated aldehyde that can t enolize. The enal is more electrophilic than the ketone, so self-condensation of the ketone is not... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Kambe and Yasuda19 discovered the effectiveness of the fluoride as a Henry reaction catalyst. Since then, the use of diverse fluorides is a common method to catalyze nitro aldol condensations, since they provide mild conditions that are particularly convenient for sensitive products as carbohydrates. The most common fluorides are potassium fluoride20 and tetrabutyl ammonium fluoride.21 A recent example relates to the TBAF catalyzed addition of nitroethanol to the D-glucose derivative 18, to give nitro sugars 19 (Scheme 8).22... 

R3 R2 and R2 Ri gauche interactions however, for the same set of substituents, an increase in the steric requirements of either Rj or R3 will influence only one set of vicinal steric interactions (Rj R2 or R3 R2). Some support for these conclusions has been cited (eqs. [6] and [7]). These qualitative arguments may also be relevant to the observed populations of hydrogen- and nonhydrogen-bonded populations of the aldol adducts as well (see Table 1, entries K, L). Unfortunately, little detailed information exists on the solution geometries of these metal chelates. Furthermore, in many studies it is impossible to ascertain whether the aldol condensations between metal enolates and aldehydes were carried out under kinetic or thermodynamic conditions. Consequently, the importance of metal structure and enolate geometry in the definition of product stereochemistry remains ill defined. This is particularly true in the numerous studies reported on the Reformatsky reaction (20) and related variants (21). 

In contrast to the "classical solution" we have just discussed, we will now consider the aldol condensation -one of the most important carbon-carbon bond formation reactions [3], in both the laboratory and Nature l - as an example of the "contemporary solution" to the problem of acyclic stereoselection. As a reversible reaction, the design of highly stereoselective aldol and related reactions demands that all the stereochemical aspects involved in the C-C bond formation are kinetically controlled. 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

Moving from rearrangements, condensation reactions were also presented. Condensation reactions occur when two reactive species condense with one another forming a new compound. The first was the aldol condensation (Scheme 8.9). Later, a more complex application of the aldol condensation was presented in the form of the Robinson annula-tion (Scheme 8.10). For both of these reactions, the underlying lessons relate to the ability to induce reactions and incorporate substitutions at carbon atoms adjacent to carbonyl groups. Similar reactivities of such carbon atoms can be utilized for alkylation (SN2) and acylation (addition-elimination) reactions as illustrated in Scheme 8.11. 

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