Prolinamides water aldol reaction

Scheme 8.14 Recoverable prolinamides for aldol reactions in water.

Several reports deal with aqueous media. Acid-base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) - a series of meta- and para-substituted 2-arylpyrrolidines - as catalysts of an aqueous aldol reaction shows p = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127... 

Catalyst 10 was introduced for reactions in aqueous systems in the presence of surfactant Brdnsted acids, and 13 promotes the aldol reaction in the presence of a base, whereas prolinamide 4, prepared by click stra-tegy, has been used for the first aldol reaction of thiazolecarbaldehyde with methyl-isopropyl ketone on water with excellent results. Phthalimido-prolinamide 12 is also effective in promoting aldol reactions in neat conditions. 

In the last year, an impressive number of highly efficient enantioselective aldolisations have been catalysed by variously substituted prolinamides. As an example, Chimni et ctl. have demonstrated that very simple protonated (5)-prolinamide derivatives efficiently catalysed aldol reactions of ketones with aromatic aldehydes in water. The best results concerning a range of cyclohexanones are collected in Scheme 2.11. When applied to aliphatic ketones, the protocol provided the aldol adducts in good yields, albeit with lower diastereo-and enantioselectivities (<63% de and <48% ee, respectively). 

Monge-Marcet, A., Cattoen, X., Alonso, D.A., Najera, C, Man, M.W.C., and Pleixats, R. (2012) Recyclable silica-supported prolinamide organocatalysts for direct asymmetric aldol reaction in water. Green Chem, 14 (6), 1601-1610. 

BF4] or [bmim][PF6] (Scheme 22.8). Bis-amide 19-catalyzed aldol reactions performed in [bmimllBFJ required a much lower excess of donor ketone 21 (3 equiv. instead of 30 equiv. in proline-catalyzed reactions) and allowed a synthesis of chiral compounds 22 bearing heterocyclic, prenyl, or metallocene units [43], The improved catalytic performance of prolinamide derivatives in ionic liquids might be due to a stabihzation of the iminium intermediate formed from the ketone and the catalyst or because of the enhanced nucleophilicity of the enamine [42]. Notably, IL dilution with water (1 1 by volume) accelerated the enamine/iminium ion hydrolysis and raised reaction rates and product yields, with the enantioselec-tivity being retained or even becoming somewhat higher than under water-free conditions [45], Furthermore, the catalyst/lL/water system could be easily recycled five times without aldol yield, dr, and ee losses. 

One of the simplest stractures is prolinamide 37 (Figure 24.13), which catalyzed the direct aldol reaction of acetone with 4-nitrobenzaldehyde in water in 50% ee. In the absence of water no reaction took place [59]. Further experiments were carried out using proline-thioamide 38 (Figure 24.13). Brine was found to be a suitable reaction medium for the aldol reaction of several cyclic ketones with electron-deficient aldehydes catalyzed by 38 (5mol%) and in the presence of CI2CHCOOH as additive [60]. 

In addition to pyrrolidine-based structure, prolme-based catalysts were also investigated. Two examples of supported prolinamide-based catalysts for the Michael reaction are 86 and 87 (Figure 24.29). Prolinamide-bridged silsesquioxane 86 was prepared from a bis-sUylated prolinamide by sol-gel methodology and used in water. This catalytic material was also used in aldol reactions [108]. The prolyl-prolinol catalyst 87 was anchored to a polystyrene backbone and used in a dichloromethane/water mixture [22a]. 

The efficacies of prolinamide bearing a carbohydrate group on nitrogen, six / -cyclodextrin conjugates with proline, and two with the enantiomers of proline-derived 2-aminomethylpyrrolidine have been reported for aldol reactions in water. The performance of new pyrrolidine-based organocatalysts derived from tartaric and glyceric... 

In 2008, Gruttadauria and coworkers synthesised prolinamide derivatives 54a and 54b, in which prolinamide units were anchored to a polystyrene support via thiol-ene coupling reactions. In the presence of these heterogeneous catalysts, cyclic ketones or acetone 8 reacted with atyl aldehydes 9 to afford corresponding chiral aldols 10 (Scheme 10.l). The best yields of 10 and stereoselectivity of the reactions (dr antilsyn) 96 4-98 2 and 89-99% ee) were attained in a 1 2 (v/v) water/chloroform solvent system, in which water pushed reagents to the concentrated organic phase where asymmetric reactions occurred, meanwhile chloroform ensured swelling of the polymer chain. However, the activity of catalysts 54a and 54b became... 

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