Organocatalysts hydrogen-bond-donor

The roles of the catalytic functions are not necessarily opposite or limited to Lewis acid/base pairs. For example, amine thiourea derivatives like Takemoto s catalyst 4 merge the hydrogen bond donor capability of the thiourea moiety with Bronsted base functionality of the amine function and revealed itself particularly efficient organocatalysts for Michael reactions of various 1,3-dicarbonyl compounds with nitroolefins (Scheme 3) [17-19]. 

FIGURE 2.42. Dual activation of electrophile and nucleophile by a bifunctional hydrogen-bond donor/Lewis base organocatalyst. 

The diastereoselectivities observed in aldol reactions of cyclic ketones catalysed by di- and tri-amino-organocatalysts is strongly influenced by the nature, size, and hydrogen-bond-donor ability of the Brpnsted acid additives employed. ... 

A new class of organocatalyst, pyrroUdinyl-sulfamides (106), bearing strong hydrogen-bond donors, gives yields/dc/cc up to 96/98/95% in Michael additions of cyclohexanone to nitroalkenes. ... 

Two new series of bifunctional hydrogen-bond-donor asymmetric organocatalysts have been described, based on 2-aminoquinazol-4-(l//)-one (111a) or 3-amino-benzothiadiazine-1,1-dioxide (111b) skeletons. Both types catalyse Michael additions (e.g. nitrostyrene and diethyl malonate), hydrazinations of the a-carbon of ketones and /3-ketoesters, and isomerizations of alkyne esters to aUene esters (mainly... 

Since the discovery of proline-catalyzed enantioselective aldol reactions, an extensive research program to explore chiral secondary amine catalysts has been pursued. Several polymer-supported chiral amines have been synthesized for aldol, Mannich, and related reactions. Polystyrene is a popular solid phase for use in place of silica gel in the proline-based organocatalysis. In contrast, silica gel displays a slightly acidic character and has a hydrogen-bond donor or acceptor, which may change the catalytic activity and chiral space of the organocatalyst. Flow enantioselective aldol [158-161], Mannich [162], Michael [163], and related reactions... 

By now, thiourea derivatives and other hydrogen-bond donors are well established as non-covalent organocatalysts for the activation of neutral substrates or for anion-binding-based transformations, and numerous further examples have been reported for both variants [13-15, 24, 25]. 

As outlined in the previous paragraph, chiral Brpnsted base organocatalysts appear to be most effective when equipped with an additional Brpnsted acidic moiety, for example, hydrogen bond donors like (thio)urea. Apparently, both functionalities catalyze the asymmetric Mannich reaction in a cooperative fashion, that is, simultaneous activation of both the nucleophile and the electrophile. However, activation of the electrophile can also be accomplished with a single, enantiomerically pure Brpnsted acid. In this respect, readily available chiral phosphoric acids are most commonly applied [88-90]. In 2004, the groups of Akiyama and Terada independently from each other reported the first asymmetric Mannich reaction of silyl ketene acetals or acetyl acetone with imines utilizing chiral phosphoric acid catalysts, which... 

H. (2007) Enantioselective Strecker reaction catalyzed by an organocatalyst lacking a hydrogen-bond-donor function. Angew. Chem. Int. Ed., 46, 9339-9341. 

While these organocatalysts comprise a considerably broad stractural/functional spectrum, a common requirement for them to work efficiently in the Henry reaction appears to be the presence of (i) a basic unit to generate the nucleophilic nitronate species and (ii) some hydrogen bond donor sites capable of interacting with the acceptor carbonyl group. 

Organocatalysts To date, the main classes of organocatalysts that have been used are [42] imidazolidinone, diarylprolinol silyl ether, cinchona alkaloid, and phosphoric acid and thiourea derivatives. Essentially, two modes of activation can be considered the reversible formation of iminiums/enamines (covalent activation) with a,P-unsaturated aldehydes and ketones in the presence of primary or secondary chiral amines (Figure 35.1), and activation via hydrogen-bond formation (non-covalent activation) when chiral catalysts bearing hydrogen-bond donors are used (Figure 35.2). 

The reported organic bifunctional catalysts possessing both hydrogen bond donor and acceptor moieties are often derived from the cinchona alkaloids. Tan and coworkers developed the simple and readily available amino-indanol 95 as an efficient bifunctional organocatalyst for the enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones 94 (Scheme 38.26) [40]. Besides maleimides 80, alkyl vinyl ketones were also suitable dienophiles for this catalytic system. 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

Abstract Acid-base catalysis with bifunctional catalysts is a very prominent catalytic strategy in both small-molecule organocatalysts as well as enzyme catalysis. In both worlds, small-molecule catalysts and enzymatic catalysis, a variety of different general acids or hydrogen bond donors are used. In this chapter, important parallels between small molecule catalysts and enzymes are discussed, and a comparison is also made to the emerging field of frustrated Lewis pair catalysis. 

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