Aromatic aldehydes aldol condensation

Purpose. We prepare the first of three intermediates on the synthetic pathway to our target molecule, a photochromic imine. A base-catalyzed aldol reaction is carried out in which an aromatic aldehyde is condensed with an aryl alkyl ketone. This addition reaction is followed by dehydration to form an a,p-unsaturated ketone this particular product is commonly called a chalcone. This intermediate is isolated and purified for use as the starting material in the next stage of the synthesis. You will carry out a semimicroscale reaction to gain experience at conducting larger-scale organic reactions. 

The most efficient variant of this combination is based on reaction of an enolizable ketone with a non-enolizable aldehyde, so that self-condensation of the latter cannot occur. Several examples of this type of combination in aldol reactions are given in Scheme 1.2. Usually in situ elimination occurs, so a,j5-unsaturated ketones result, in particular when aromatic aldehydes are condensed with ketones ( Claisen-Schmidt reaction ) [18-21]. 

Clalsen aldol condensation. This consists in the condensation of an aromatic aldehyde and an ester R—CHjCOOCjHj in the presence of finely divided sodium and a trace of alcohol at a low temperature. The catalyst is the alkoxide ion aqueous alkalis caimot be employed since they will hydrolyse the resulting ester. The product is an ap-unsaturated ester, for example ... 

The mechanism of the reaction between aromatic aldehydes and esters probably involves the intermediate formation of an aldol (hence the name— Claisen aldol condensation) ... 

Indeed formaldehyde is so reactive toward nucleophilic addition that it suppresses the self condensation of the other component by reacting rapidly with any enolate present Aromatic aldehydes cannot form enolates and a large number of mixed aldol con densations have been carried out m which an aromatic aldehyde reacts with an enolate... 

Mixed aldol condensations in which a ketone reacts with an aromatic aldehyde are known as Claisen-Schmidt condensations... 

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. 

In Robinson s now well-known suggestions, regarding the processes by which alkaloids may be produced in plants, two main reactions are used j the aldol condensation and the similar condensation of carbinol-amines, resulting from the combination of an aldehyde or ketone with ammonia or an amine, and containing the group. C(OH). N., with substances in which the group, CH. CO. is present. By these reactions it is possible to form the alkaloid skeleton, and the further necessary changes postulated include oxidations or reductions and elimination of water for the formation of an aromatic nucleus or of an ethylene derivative. 

Aromatic aldehydes cannot fonn enolates, and a large number of mixed aldol condensations have been cariied out in which an aromatic aldehyde reacts with an enolate. 

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). ... 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

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) ... 

A combination of a Heck reaction with an aldol condensation is observed on treatment of aromatic aldehydes or ketones as 6/1-151 with allylic alcohols as 6/1-152, as described by Dyker and coworkers [83]. The Pd-catalyzed reaction led to 6/1-154 via 6/1-153, in 55% yield (Scheme 6/1.40). 

The Cannizzaro reaction is by no means confined to aromatic aldehydes. Formaldehyde undergoes the same change, yielding formic acid and methyl alcohol. That the aliphatic aldehydes from acetaldehyde upwards do not undergo the reaction is due to the fact that the aldol condensation (mentioned above), in virtue of its much greater velocity, takes precedence over the Cannizzaro reaction. 

The reason why the acyloin synthesis is especially characteristic of aromatic aldehydes, depends on the circumstance that in the aromatic series the tertiary carbon atom in the ring does not allow of the aldol condensation, a reaction for which conditions are otherwise much more favourable. The simplest example of the acyloin condensation, moreover, was already encountered in the case of formaldehyde (p. 218) glycollic aldehyde is the simplest acyloin. Acyloin compounds are also produced, in the aliphatic series, by the action of sodium or potassium on esters, and hence are also formed as by-products in the acetoacetic ester synthesis (Bouveault, Scheibler). 

Zirconium tetrachloride promotes a tandem nucleophilic addition and aldol-type condensation reaction of methyl propynoate, or /V,/V-dimethylpropynamidc, with aldehydes, or ketones, in the presence of tetra-n-butylammonium iodide (Scheme 6.13) [8] with a high selectivity towards the formation of Z-isomers. A similar reaction occurs between aliphatic and aromatic aldehydes and penta-3,4-dien-2-one to yield 1-substituted 2-acetyl-3-iodobut-3-enols (50-75%) [9]. 

In contrast with the reactions of the imino esters, the aldol condensation of imino nitriles and aromatic aldehydes in dichloromethane produces azabutadienes (Scheme 6.17), with the Z-isomers predominating often to the exclusion of the E-isomers [43, 44], Yields generally tend to be at least 10% lower when the reaction is conducted in acetonitrile. 

Aromatic and a-substituted aliphatic aldehydes react with oxiranes under neutral conditions to yield 1,3-dioxoIanes [35] whereas a-unsubstituted aldehydes undergo a simple aldol condensation under such conditions. In a somewhat similar manner, perfluorocarboxylic esters react with oxiranes to produce cyclic orthoesters (-50%) [36]. The corresponding reaction with non-fluorinated esters fails. 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

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

Ex situ formation of (33) followed by addition to a mixture of CHCI3 and aldehyde (aliphatic or aromatic) in DMF at low temperature leads to deprotonation of CHCI3 but not of the aldehyde, and formation of the trichlorocarbinol takes place without formation of side products by aldol condensation, Scheme 21 [99]. The reaction could also be carried out (75-86% yield for butanal) using polymeric amides as a PB and with similar conditions [74]. 

The scope of the aldehyde inputs includes a wide range of (hetero)aromatic aldehydes as well as a,(3-unsaturated aldehydes. With the use of aliphatic aldehydes, side products due to aldol condensations could be observed. Allowed ot-substituents at the isocyano acetate (1) includes R" = Ph, H, Me, Et, Bn, iBu, iPr. The scope according to the nitrile input includes aromatic, heteroaromatic, and aliphatic nitriles. However, the use of primary aliphatic nitriles should be avoided. 

The activated Ba(OH)2 was used as a basic catalyst for the Claisen-Schmidt (CS) condensation of a variety of ketones and aromatic aldehydes (288). The reactions were performed in ethanol as solvent at reflux temperature. Excellent yields of the condensation products were obtained (80-100%) within 1 h in a batch reactor. Reaction rates and yields were generally higher than those reported for alkali metal hydroxides as catalysts. Neither the Cannizaro reaction nor self-aldol condensation of the ketone was observed, a result that was attributed to the catalyst s being more nucleophilic than basic. Thus, better selectivity to the condensation product was observed than in homogeneous catalysis under similar conditions. It was found that the reaction takes place on the catalyst surface, and when the reactants were small ketones, the rate-determining step was found to be the surface reaction, whereas with sterically hindered ketones the adsorption process was rate determining. 

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 are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen-Schmidt condensation. Scheme 2.2 presents some representative examples. 

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. 

Polyquinolines (PQ) are obtained by the Friedlander reaction of a bis-o-aminoaromatic aldehyde (or ketone) with an aromatic hisketomethylene reactant [Concilio et al., 2001 Stille, 1981]. The quinoline ring is formed hy a combination of an aldol condensation and imine formation (Eq. 2-221). Polymerization is carried out at 135°C in m-cresol with poly (phosphoric acid) as the catalyst. The reaction also proceeds under base catalysis, but there... 

Formylfuran behaves in a very similar manner to benzaldehyde and undergoes the usual reactions of an aromatic aldehyde, e.g. (i) the Cannizzaro reaction with cone, sodium hydroxide to give furan-2-ylmethanol and the sodium salt of furoic acid, (ii) the Perkin reaction with acetic anhydride and sodium acetate to yield an aldol product that dehydrates to 3-(furan-2-yl)propenoic acid, and (iii) a condensation with potassium cyanide in alcoholic solution to form furoin (under these conditions, benzaldehyde undergoes the benzoin condensation) (Scheme 6.32). 

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