Catalysts prolinamide

In the first approach, prolinamides have been supported on micelleforming species, dendrimers (32a-c), polystyrene (26, 31a-d), poly-vinylidene chloride, phenolic polymers, ionic liquids, silica (28, 29), other inorganic supports (30), ° and polymer-modified small peptides. Supported prolinamide catalysts have also been prepared by acrylic and styrene (27) copolymerisation. 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

In this context, prolinamide 2 [5-8] and its aryl-substituted homologs such as 3-5 have been developed [9-14]. Analogous to these examples, binaphthyldiamine-derived compounds such as 6 and 7 have been introduced for use in aqueous systems and as recoverable catalysts [15-18]. For example, Benaglia and coworkers reported that the prolinamide catalyst 7 with a UpophiUc side chain showed efficient catalytic activity in water [16b]. Chiral spiro diamine-derived catalysts have also been designed, albeit in moderate enantioselectivity [19]. Owing to the increased acidity of an NH group of thioamide relative to a normal amide, proline-thioamide catalysts such as 8 have been shown to be more effective [20-23]. 

With regard to aldol chemistry, Mannich or domino-Mannich-Michael reactions can also be promoted by N-arylsulfonyl-substituted prolinamide catalysts such as 17 with high levels of enantioselectivity [82, 83). 

Importantly, prolinamide catalysts work well in Michael addition reactions using nitroolefins as acceptors [58, 64, 84-95], For example, Najera and coworkers used bifunctional catalyst 20 by virtue of the synergistic effect of double hydrogenbonding activation, as depicted in the transition state model 21 (Scheme 1.3) [90]. For the same purpose, prolinamides containing a heteroaromatic system like 14 have also been reported [96]. 

In addition to organometaUic dendrimers for asymmetric catalysis, a number of dendritic organocatalysts have been developed and successfully applied in different asymmetric reactions in the absence of any metal [63]. In 2009, Parquette and coworkers [64] reported a new kind of folded pyridine-2,6-dicarboxamide dendrons (36) for direct aldol reaction. These dendritic prolinamide catalysts were tested for the aldol reactions of various acycUc and cydic ketones with 4-nitrobenzaldehyde (Figure 4.33). Remarkable dendritic effects on both the enantioselectivity and... 

Figure 4.33 Folded dendritic prolinamide catalysts for asymmetric aldol reactions.

Encapsulated rhodium complexes were prepared from Rh-exchanged NaY zeolite by complexation with (S)-prolinamide or M-tert-butyl-(S)-prolinamide [73,74]. Although these catalysts showed higher specific activity than their homogeneous counterparts in non-enantioselective hydrogenations, the hydrogenation of prochiral substrates, such as methyl (Z)-acetamidocinnamate [73] or ( )-2-methyl-2-pentenoic acid [74], led to low... 

A range of prolinamides, some bearing one or more additional amino groups, have been developed as catalysts in water 107 o-hydroxyaromatic substituents likewise give high selectivity in this solvent (and in neat ketone solution) for direct aldols of aralde-hydes with ketones.108... 

BINAM - the diamino analogue of BEMOL - has been converted to its C2-symmetric bis(prolinamide).116 The latter acts as a recoverable catalyst of direct aldols in DMF-H2O at 0 °C, giving high des and ees. Butan-2-one showed significant regioselectivity, giving predominantly the iso product. 

L-Prolinamides (71) with a pendant alcohol act as recoverable bifunctional catalysts of direct nitro-Michael addition of ketones to -nitrostyrenes, giving syn-de s up to 94% and ees up to 80%.204 The pyrrolidine provides enamine catalysis, and the side-chain donors can hydrogen-bond the nitro oxygens. 

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. 

The same method, using Co(acac)2 and the chiral diamines has also been applied to several other stabilized carbanions and enones with up to 100% yield, however, the asymmetric inductions did not exceed 40% ee59. Similarly, a catalyst derived from Ni(acac), and (+ )-(S)-2-(anili-nomethyl)pyrrolidine, (—)-(5)-prolinamide or (—)-(S)-prolinol catalyzes the conjugate addition of nitromethane to benzalacetone, chalcone and 2-cyclohexenone with up to 59% ee62,67. 

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. 

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. 

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. 

Organocatalysed asymmetric Michael addition has been extensively studied because of the interest in the adducts as valuable intermediates in organic synthesis. The use of a carbonyl compound as donor and prolinamides as catalysts supposes the formation of the corresponding enamine which adds to the a,p-unsaturated compound activated by formation of hydrogen bonds with the carboxamide substituent. In general, the major diastereoisomer has syn configuration because the enamine attacks from its re-face to the re-face of the double bond (Scheme 6.2). 

Various i-prolinamides, derived from chiral p-amino alcohols, are active hifunctional catalysts for nitro-Michael additions of ketones to p-nitrostyr-enes. In particular, catalyst 25e exhibits the highest catalytic performance working in polar aprotic solvents. 

Sugar-hased prolinamide 16m has also been employed as catalyst for the asymmetric Michael addition of cyclohexanones to p-nitroslyrenes. During optimisation of the reaction conditions, the authors found that the polarity of the solvent does not modify the yield or stereoselectivity, but the best ee was obtained under neat conditions at -20 °C. Ammonium ionic liquids 41a,b are also efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitro-olefins giving the adducts with excellent yields and enantioselectivities and modest to high diastereoselectivities. 

A Toluensulfonyl-L-prolinamide 15b was used as catalyst in the enan-tioselective Michael addition of carbonyl compounds to (B)-nitrostyrene in ionic liquids under different reaction conditions. The best yields (up to 98%) and enantioselectivity (70% ee) were obtained in a basic ionic liquid [bmim]BF4 at room temperature. 

The simplest L-Prolinamide 1 is an effective catalyst for a-phenyl-selenylation reactions of aldehydes with Al-(phenylseleno)-phthalimide, although no mention of the enantioselectivity of the process has been reported (eqn. (3) in Scheme 6.4). 

In spite of the plethora of prolinamide-derived catalysts developed until now, some problems, such as the high catalyst loading or long reaction times, remain unresolved. The search for catalysts that improve the reactivity of both the donor or acceptor will continue to be an area of development in the future. 

Heterofunctionalisation of carbonyl compounds in the a-position has become an important facet of oiganocatalytic enamine-mediated reactions. In 2005, the Jorgensen group described asymmetric a-sulfenylation of aliphatic aldehydes using TMS-protected prolinol catalysts. The best sulfenylating agent was M-benzylsulfanyl-1,2,4-triazole. Other catalysts, such as proline, prolinol, prolinamide or other secondary amide were less effective. The catalyst with bulkier aromatic groups (C2a) afforded the most enantioselective reaction (Scheme 8.39). 

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... 

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). 

---