Aldehyde self-aldolization

The netv reaction conditions effectively suppressed aldehyde self-aldolization. The main side product vas now the corresponding acetone cross aldol condensation product, typically formed in comparable yields vrith the desired aldol addition product. 

Proline-mediated aldehyde self-aldolizations have been mentioned by F. Orsini, F. Pelizzoni, M. Forte,/. Heterocycl. Chem. 1989, 26, 837. 

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. 

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... 

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... 

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. 

Cyclohexyl carbaldehyde is also a good substrate [70a, 71]. Tertiary aldehydes, e.g. pivaldehyde, are excellent substrates, furnishing the aldol products, e.g. (R)-38f, with >99% ee and in high yield [70a], Aliphatic a-unsubstituted aldehydes, e.g. pentanal, which usually undergo self-aldolization, can also yield optically active cross-aldol products [71, 73]. A prerequisite for efficient reaction is, however, that the reaction is conducted in neat acetone. Thus, a yield of 75% with 73% ee was achieved in the reaction of pentanal as acceptor and acetone as donor [71]. 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

Self-aldolization of acetaldehyde provided one-step enantioselective syntheses of (5R)- and (5S)-Hydroxy-(2E)-hexenal using either (R) or (S)-proline as catalysts of the homologation of three acetaldehyde units ee-values of up to 90% were obtained [25]. Using this methodology, a series of triketides was prepared by slow addition of propionaldehyde into acceptor aldehyde and (S)-proline in DMF, and the isolated lactols were converted to the corresponding d-lactones [26]. The product enantiomeric purity was typically moderate because of the isomerization... 

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... 

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 lower yield may be explained by the fact that linear aldehydes also undergo self-aldol condensation, which is in direct competition with the crossed-aldol reaction. Aromatic aldehydes as the carbonyl component led to reduced diastereoselectivity. For example, the (.S )-prolinc-catalyzed aldol reaction of 4 with ort/tochlorobenzaldehyde proceeded with a good yield of 73%, but with an anti/syn ratio of only 4 1 and enantiomeric excesses of 86% ee (anti) and 70% ee (syn). 

Problem 17.25 Which of the following alkanes can be synthesized from a self-aldol condensation product of an aldehyde [see Problem 17.24(a)] or a symmetrical ketone (a) CH3CH2CH2CH2CH(CH3)CH2CH2CH3, (b) CH3CH2CH2CH2CH(CH3)CH2CH3, (c) (CH3)2CHCH2CH2CH3, ([Pg.390]

This newly developed heteropolymetallic catalyst system was applied to a variety of direct catalytic asymmetric aldol reactions, giving aldol products 48-64 in modest to good ee, as shown in Table 16. It is worthy of note that even 62 can be produced from hexanal 54 in 55% yield and 42% ee without the formation of the corresponding self-aldol product (-50 °C). This result can be imderstood by considering that aldehyde enolates are not usually generated by the catalyst at low temperatme, an assumption which was confirmed by several experimental results. It is also worthy of note that the direct catalytic asymmetric aldol reaction between 46 and cyclopenta-none 55 also proceeded smoothly to afford 64 in 95% yield synlanti = 93 7, syn = 76% ee, anti = 88% ee). 

The self-aldol condensation of unmodified aldehydes in toluene catalyzed by propylamines supported on mesoporous silica FSM-16 (surface area 881 iirg has been reported.The aminopropyl groups (propylamine, N-methylpropylamine and A. A -diciliylpropylaiiiinc) were anchored on FSM-16 silica by post-modification methodology by using 3-aminopropyl-, A -methyl-3-aminopropyl- and A, A -diethyl-3-aminopropyltriethoxysilane respectively (Scheme 3.3). ... 

Nucleophilic reactions of unmodified aldehydes are usually diiScult to control, affording complex mixture of products, often due to the high reactivity of the formyl group under either basic or acidic reaction conditions. The activity order of the supported amines was secondary > primary > tertiary, which may suggest the intervention of an enamine pathway the enals were exclusively obtained as ( ) isomers. Notably, FSM-16-(CH2)3-NHMe exhibited higher activity than conventional solid bases such as MgO and Mg-Al-hydrotalcite [hexanal self-aldol condensation FSM-16-(CH2)3-NHMe 97% conversion and 85% yield in 2h, MgO 56% conversion and 26% yield in 20 h, Mg-Al-hydrotalcite 22% conversion and 11% yield in 24 h]. 

Lithium enolates do not even solve all problems of chemoselectivity most notoriously, they fail when the specific enolates of aldehydes are needed. The problem is that aldehydes self-condense so readily that the rate of the aldol reaction can be comparable with the rate of enolate formation by proton removal. Fortunately there are good alternatives. Earlier in this chapter we showed examples of what can go wrong with enamines. Now we can set the record straight by extolling the virtues of the enamines 96 of aldehydes.17 They are easily made without excessive aldol reaction as they are much less reactive than lithium enolates, they take part well in reactions such as Michael additions, a standard route to 1,5-dicarbonyl compounds, e.g. 97.18... 

The enol ester or silyl enol ether route to enolates has advantages over direct deprotonation in certain cases. If direct deprotonation provides a mixture of regio- or stereo-isomers, it is often possible to trap the enolate mixture by esterification or silylation, separate the desired enol ester or silyl enol ether and regenerate the enolate by reaction with methyllithium. It is also useful for preparation of enolates from substances that are so electrophilic that direct deprotonation is complicated by self-aldolization. For example, aldehyde enolates have been prepared in this manner (equation 14). ... 

When a ketone and an aldehyde are condensed in a cross-aldol reaction, excess ketone must be used to avoid aldehyde self-condensation, and even so the surface is essentially saturated with aldehyde at low temperature. Exceptions are reactions of easily enolizable ketones at ambient and lower temperatures. Therefore increasing the temperature often increases selectivity as well, a situation reminiscent of decarboxylative condensation, by allowing for greater ketone adsorption. 

In the same study, a range of related amino acid derivatives were applied as catalysts, hut clearly failed to reach similar results compared to proline, both in terms of yield and enantioselectivity. It was shown already at that point that both the pyrrolidine ring as well as the carbo>ylate in the unique structure of proline are crucial for its activity. The scope of aldehydes was extended to several branched, aromatic aldehydes, with moderate yields and enantioselectivities. Nonbranched aldehydes were naturally excluded from the method due to aldehyde self-aldolisation and aldol condensation. List et al. were able to address this problem by modifying the conditions, temperature and solvent in particular. The revisited method applies to a range of aliphatic, nonbranched aldehydes, moderate yields but good enantioselectivities are obtainable. The approach was shortly after extended to the valuable, asymmetric synthesis of, 2-diols (Scheme 5.5). 

Barbas and coworkers disclosed the first example of diastereo- and enantioselctive aldol reactions of fluoroacetone with aromatic and aliphatic aldehydes catalysed by simple prolinol Ic. Notable advances in substrate scope and convenient procedures for the aldol reaction have been illustrated by Hayashi and coworkers, who demonstrated the ability of diatyl prolinols to catalyse the highly challenging self-aldol and cross-aldol reactions of acetaldehyde (Scheme 7.19). ... 

The cross-aldol reaction between two aldehydes is a very difficult transformation. Since ahphatic aldehydes can act both as nucleophiles and as electrophiles, a successful cross-reaction requires two aldehydes with a significant difference in the rate of enamine formation (Scheme 3.20). (3-Hydroxy-aldehydes can be easily synthesized in an amine-catalyzed direct asymmetric cross-aldol reaction between two aldehydes only when one enolizable aldehyde is used and self-aldolization is somehow prevented. 

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]. 

CHART 3.13. Dimers of aliphatic aldehydes obtained via self-aldolization. 

MacMillan developed imldazolidinones 114 as new catalysts for the self-aldolization (Scheme 3.23) [143]. Notably, it is also suitable for the reaction between two non-equivalent aldehydes, but the slow addition of donor was still required. 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

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