Aldol reactions prolinamides

In direct nitroso aldol reactions of a-branched aldehydes, an L-prolinamide (50) catalyses to give a-hydroxyamino carbonyl compounds which are otherwise dis- favoured ees up to 64% were found.149 Another prolinamide derivative gives similar results in a nitrosobenzene reaction.150 For proline-catalysed cases involving highly substituted cyclohexanones, DFT calculations have highlighted the roles of electro- static and dipole-dipole interactions in the level of de achieved.151 (g)... 

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... 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

Scheme 8.14 Recoverable prolinamides for aldol reactions in water.

Chiral 3-hydroxyoxindoles can he synthesized from isatin hy an asymmetric aldol reaction. The prolinamide 68 possesses just the right attrihutes of a catalyst to meet the demand. 

Prolinamides featuring additional chiral elements and functional groups may find special utilities, for example to deal with more complicated substrates. There is a report of aldol reaction between a-methylthio acetone and aldehydes which relies on 7b.For promoting reactions of ethyl glyoxylate, the dipeptide 10 has been employed. 

Fteproduced from GuiSena G, del Carmen Hita M. Nijera C, Vidzquez SF Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (SJ-binam-L-prolinamide. Tetrahedron Asymm 2007 18 2300-4. Copyright (2007). with permission from Elsevier. 

Reproduced with permission from Alma D, Alonso DA, N jera C. Prolinamides versus proiine-thioamides as recyclable catalysts in the enantbselective solvent-free inter- and intramolecular aldol reactions. Adv Synth Catal 2008 350 2467-72. Copyright (2008), Wiley. 

Guillena G, del Carmen Hita M, Nijera C, Viozquez SF. A highly efficient solvent-free asymmetric direct aldol reaction organocatalyzed by recoverable (5)-Binam-L-Prolinamides. ESI-MS evidence of the enamine-iminium formation. 1 Org Chem 2008 73 5933-43. 

The most widely accepted hypothesis to explain the regio- and stereo outcome of the prolinamide-catalysed aldol reactions supposes the formation of the most stable enamine (generally E-anti) by reaction of the donor carbonyl compound with the pyrrolidine nucleus, and simultaneous activation of the acceptor by hydrogen-bond formation with the carboxamide substituent. Then, the major product is formed by preferential attack of the enamine re-face to the re-face of the carbonyl, as summarised in the ternary complex A (Scheme 6.1). 

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. 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

Owing to the increased acidity of an NH group of thioamide relative to the parent amide, proline-thioamide 25a behaves as an excellent catalyst. It has been demonstrated that the reaction occurs in a biphasic medium. Najera" and Li independently synthesised thioamides 25b and 25c,d for enantioselective direct aldol reactions. These ligands were found to be better alternatives to L-prolinamides and provided excellent levels of enantio-seiectivity as compared to their parent ligands. 

To extend the operation period of prolinamide-derived IL-supported catalysts, bis-amides 58a-e were synthesised from (25, 4R)-4-hydro yproline and various diamines. C2-Symmetric compounds 58c-e bearing p-phenyle-nediamine, l,2-diaminocyclohexane or 1,2-diphenyl ethylenedia-mine ° structural units exhibited excellent catalytic performance in asymmetric cross-aldol reactions between ketones 8 and aldehydes 9 in the aqueous medium and could be recycled 15 times without any decrease of activity or loss of enantiocontrol. Furthermore, bis-amide 58e efficiently catalysed aldol reactions of acetone with a-ketoesters 62 to afford a-hydrojqr-y-ketoesters 63 in a nearly quantitative yield, yet with moderate enantioselectivity (Scheme 10.14). 

Prolinamides are probably the most large group of (5)-proline (1) derivatives used in the intermolecular aldol reaction, due to their easy preparation, stability of the amide linkage and the enough acidity of the NH-moiety able to activate electrophiles by hydrogen bonding. 

Other prolinamides derived from chiral diamines have been synthesized and employed as catalyst in the intermolecular aldol reaction. Thus, diamide 59a (20 mol%. Fig. 4.5) containing only one unit of proUne has been used in the aldol reaction of cyclohexanone (19.2 equiv.) with different aromatic aldehydes. The use of 20 mol% of acetic acid is required to enhance the catalytic activity [118a, b]. It seems that both NH group of diamide stabilized the transition state, activating the electrophile. Changing the R group in catalyst 59, would influence the acidity of the... 

Fig. 4.6 Other prolinamides used as catalysts in the aldol reaction...

Although prolinamides have shown their versatility in the aldol reaction between ketones and aldehydes, their application towards the reaction between the cross or homo-aldol reaction between aldehydes have been scarcely studied. The homo-aldol dimerization reaction between neat propionaldehyde (5, R =Me and 2, R =Et in Scheme 4.23) catalyzed by (S)-prolinamide (40, 20 mol%) in the presence of... 

Scheme 4.23 Cross aldol reaction catalyzed by prolinamide 74...

The cross-aldol reaction between propionaldehyde (5, R =Me) and several aromatic aldehydes (2, R =Ar) under dry or wet solvent-free conditions has been accomplished using BINAM-prolinamides 62 (5 mol%) or 63 (10 mol%) in the presence of benzoic acid as catalyst (10 and 5 mol%, respectively). After reduction... 

The attachment of proline and proline derivatives to dendrons was a further strategy used to attempt their recycling (Fig. 4.37). Thus, compact and expanded dendrimers functionalized with prolinamide units at the periphery such as system 189 were used in the aldol reaction of cyclopentanone and cyclohexanone with p-nitrobenzaldehyde, with a possible dendritic effect that inaeased the stereoselectivities observed with simple A -benzylproUnamide and G1 dendron 189 [271]. 

Kokotos and coworkers investigated the use of prolinamide-based thioureas as bifunctional organocatalysts for the direct aldol reaction. The amide and the thiourea functionalities, tethered by a chiral diamine motif, offered multiple hydrogen bonding sites for electrophile activation, while the pyrrolidine skeleton served to activate the nucleophile via enamine catalysis. Thiourea 61 proved to provide the best catalyst in the presence of 4-nitrobenzoic acid as cocatalyst at low temperature and delivered the anti-aXAoX products in moderate to high yields and in high to excellent... 

Scheme 19.69 Prolinamide-based thiourea catalyst developed for the direct aldol reaction.

Scheme 19.70 Direct aldol reaction of ketones with perfluoroaUg l ketones catalysed by a prolinamide-thiourea.

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