Aliphatic aldehydes self-aldol reactions

Class I aldolase-like catalysis of the intermolecular aldol reaction with amines and amino acids in aqueous solution has been studied sporadically throughout the last century. Fischer and Marschall showed in 1931 that alanine and a few primary and secondary amines in neutral, buffered aqueous solutions catalyze the self-aldolization of acetaldehyde to give aldol (11) and crotonaldehyde (12) (Scheme 4.3, Eq. (1)) [41]. In 1941 Langenbeck et al. found that secondary amino acids such as sarcosine also catalyze this reaction [42]. Independently, Westheimer et al. and other groups showed that amines, amino acids, and certain diamines catalyze the retro-aldolization of diacetone alcohol (13) and other aldols (Scheme 4.3, Eq. (2)) [43-47]. More recently Reymond et al. [48] studied the aqueous amine catalysis of cross-aldolizations of acetone with aliphatic aldehydes furnishing aldols 16 (Scheme 4.3, Eq. (3)) and obtained direct kinetic evidence for the involvement of enamine intermediates. 

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... 

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]. 

A series of aldehydes was examined with this stannane (Table 30). These reactions were conducted neat with a twofold excess of stannane at 100-140 °C. The anti, (Z) adducts were always formed exclusively via a proposed chair transition state in which the OMOM substituent adopts an axial orientation to avoid interactions with the adjacent stannane substituents, as previously seen with alkylstannanes (Eq. 9). Unbranched aliphatic aldehydes gave the adducts in low yield because of a competing aldol self-conden-sation reaction. Pivaldehyde also proved unsatisfactory. 

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 first example of this reaction, the acid-catalyzed self-condensation of acetone to give mesityl oxide, was reported more than one and a half centuries ago by Kane [4]. The condensation of an aromatic aldehyde with an aliphatic aldehyde or ketone, obviously the first example of an aldol condensation under basic conditions, was reported by Schmidt [5] and by... 

Hitchcock and covrorkers developed ephedrine-derived 3,4,5,6-tetrahydro-21-f-l,3,4-oxadiazin-2-one-based chiral auxiliary 141 and demonstrated its utility in aldol reactions [50]. It vas discovered that the aldehyde had to be present during enolization for reaction to occur, because of difficulties in enolization. Use of aromatic aldehydes resulted in good yield and good to excellent selectivity, as did aliphatic aldehydes vithout a-hydrogen atoms. This method is not useful for aldehydes bearing a-hydrogen atoms, because of self-condensation. 

Simple aldol processes do not seem to have been undertaken by PTC in any serious way. Some of the papers reporting alkylations of ketones, or the Horner-Wittig reactions mentioned above, describe aliphatic aldehydes and ketones as undergoing undesired self-condensations, and it is presumably a lack of control over such processes that has deterred researchers. 

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