Aldols self-aldol reactions

E. Westerlund, Formation of 3-octuloses by a self-aldol reaction of D-erythrose, Carbohydr. Res., 91 (1981) 21-30. 

A basic amine catalyst may promote the self-aldol reaction of the aldehyde, having an enolizable carbonyl. This reaction can be particularly important in the case of slowly reacting hindered aldehydes. In order to avoid this secondary reaction, a number of trialkylphosphines were tested and, in non-asymmetric reactions, tributylphosphine was generally found to be the most effective [32, 33],... 

The 2-oxopropanoate of 5-methyl-2-(l-methyl-l-phenylcthyl)cyclohcxanol undergoes mainly self-aldol reactions rather than ene reactions in the presence of Lewis acids and alkenes (the original report was incorrect92). Nonetheless, ene reactions between the 2-oxopropanoate of franj-2-phenylcydohexanol and both 1-hexene and 3-trimethylsilylpropene (see Table 4, entries 11,12) proceed with good yield and good to excellent absolute stereochemical control93. 

Heintz AS, Gonzales JE, Fink Ml, Mitchell BS. Catalyzed self-aldol reaction of valeral-dehyde via a mechanochemical method. J Mol Catal A Chem 2009 304 117-20. 

The self-aldolization reaction of protected a-oxoaldehydes would be a valuable tool in carbohydrate synthesis [132]. Interestingly, even dimers of sterically hindered aldehydes such as /iobutyraldehyde (2n) can be formed, though with moderate enantioselectivity (Chart 3.13) [124, 126, 128, 132]. 

Firstly, we have the acetone aldol self-condensation reaction over basic sites to give diacetone alcohol (DAA). Dehydration of this alcohol yeilds mesityl oxide (MSO) winch, in turn, can be selectively hydrogenated over reduced metal sites to finally give methyl isobutyl ketone (MIBK). In addition to the aldol condensation route, the acetone carbonyl functional group can also be directly hydrogenated over reduced metal sites yielding 2-propanol. Other reaction by-products such as methane, propane, diisopropyl ether and diisobutyl ketone have been detected in some experiments, but in very low amounts, lower than 2% of the total reaction products. 

The self-aldol reaction of aldehydes and ketones gives either P-hydroxy carbonyl or a,P-unsaturated carbonyl products. When the same reaction mechanism is applied to esters, the reaction is called the Claisen condensation. Like the aldol reaction, the Claisen condensation involves the attack of an enolate (or enol) nucleophile on a carbonyl electrophile. However, subsequent elimination of the leaving group creates a P-keto ester product. If this 1,3-dicarbonyl pattern is present in a TM, it is an indication that the TM might be the product of a Claisen condensation, and a Claisen disconnection will be one option for retrosynthesis. 

The direct application of unmodified aldehydes in catalytic Michael additions can be severely hindered due to the presence of undesirable intermolecular self-aldol reactions (Hagiwara, Komatsubara et al. 2001 Hagiwara, Okabe et al. 2001). Barbas and co-workers achieved the first direct catalytic asymmetric Michael reaction between unmodified aldehydes and nitroolefins. The usage of an (S)-2-(morphohnomethyl) pyrrolidine catalyst in 20 % furnished the Michael addition products in 72 % enantioselectivity, 12 1 diastereoselectivity and 78 % yield (Betancort and Barbas 2001 Betancort, Sakthivel et aL 2004 Mosse, Andrey et al. 2006). The utilization of the ionic hquid tagged catalysts 25 and 26 in the Michael reactions of frans- -nitrostyrenes to aldehydes resulted in high yields but... 

Antibody 38C2-catalyzed self-aldol reactions. 

C2-catalyzed self-aldol reactions (Section 6.3.1), deuterium-exchanged aldehydes accumulated in the presence of 38C2 in D2O. 

Dicarbonyl compounds condense with aldehydes and ketones that do not undergo self-aldol reaction. The products are afi-unsaturated dicarbonyl compounds, and the process goes by the colorful name of Knoevenagel condensation, (a) An example of a Knoevenagel condensation is given below. Propose a mechanism. 

The two (i )-isomers have lower, comparable energies, suggesting these are the predominant catalytic intermediates. The computational findings are further supported by X-ray studies on model substrates by Seebach et al. [7]. Moreover, NMR spectroscopic studies by Gschwind et al. of the similar proline-catalyzed self-aldol reaction of propionaldehyde in DMSO verify the presence of an [E-s-trans]-enamine as the only observable intermediate [8]. 

As briefly discussed above, another approach for the modiflcation of the proline structure is its transformation into a prolinamide bearing an appropriate subshtu-ent. Apart from simple prolinamide, which catalyzed the self-aldol reaction of... 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

Derivatization of the optically active aldehydes to imines has been used for determination of their enantiomeric excess. Chi et al.3 have examined a series of chiral primary amines as a derivatizing agent in determination of the enantiomeric purity of the a-substituted 8-keto-aldehydes obtained from catalysed Michael additions. The imine proton signals were well resolved even if the reaction was not completed. The best results were obtained when chiral amines with —OMe or —COOMe groups were used [2], The differences in chemical shifts of diastereo-meric imine proton were ca. 0.02-0.08 ppm depending on amine. This method has been also used for identification of isomers of self-aldol condensation of hydrocinnamaldehyde. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

D-Erythrose undergoes self-aldolization in alkali solution, to form d- / co-L- /3 C6 TO-3-octulopyranose by combination of the 1,2-enediol and aldehyde forms. In weak alkali at 105°, syrupy D-erythrose yields d- /ycero-tetrulose, jS-D-a/tro-L-g/ycero-l-octulofuranose, and a-Ti-gluco-i -g/ycero-3-octulopyranose. At 300° in alkali, the major products from syrupy D-erythrose were 1-5% of butanedione (biacetyl) with smaller proportions of pyrocatechol, 33, 2,5-dimethyl-2,5-cyclohexadiene-l,4-dione (2,5-dimethylbenzoquinone), and 2,5-dimethyl-1,4-benzenediol (2,5-dimethylhydroquinone). It was assumed that D-erythrose is reduced to erythritol by a Cannizzaro type of reaction, followed by dehydration of erythritol to form biacetyl. However, very low proportions (<1%) of biacetyl are formed from erythritol compared with D-erythrose itself. Apparently, some other mechanism predominates in the formation of biacetyl. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

Several NaOH-treated ionic liquids for self- and cross-aldol condensation reactions of propanal provide an interesting example illustrating improved product selectivity in a system in which competing reactions take place (109). In the self-aldol condensation reaction of propanal, 2-methylpent-2-enal is formed. The reaction progresses through an aldol intermediate and produces the unsaturated aldehyde. The NaOH-treated ionic liquid [BDMIM]PF gave the highest product... 

II reaction under similar conditions at temperatures between 80 and 100°C and with a four-fold excess of 2-methylpentanal (to compensate for the low solubility), the selectivity for the Aldol II product (80%) was 20% higher in [BMIMJEF NaOH than in the water/NaOH system, both at 100% propanal conversion. The increased selectivity was attributed to the higher solubility of the reactant 2-methylpentanal in the ionic liquid phase than in the water phase. The higher solubility of 2-methylpentanal effectively suppressed the self-aldol condensation in the ionic liquid. 

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. 

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