Bifunctional organocatalysts

In contrast to monofunctional (thio)urea organocatalysts, bifunctional catalyst structures enable simultaneous coordination, activation, and suitable relative orientation of both reaction components (the electrophile and the nucleophile) resulting in high... 

Takemoto and co-workers communicated that bifunctional organocatalyst 166 would promote aza-Henry reactions of phosphinoyl imines with nitroalkanes (Scheme 52) [104]. The catalytic additions provided high selectivities and yields... 

Pratt RC, Lohmeijer BGG, Long DA, Waymouth RM, Hedrick JL (2006) Triazabicyclodecene a simple bifunctional organocatalyst for acyl transfer and ring-opening polymerization of cyclic esters. J Am Chem Soc 128 4556-4557... 

Takemoto et al. were the first to report that bifunctional organocatalysts of the thiourea-tert-amine type efficiently promote certain Michael reactions, for example, the addition of 5-dicarbonyl compounds to nitro olefins [29-31]. 

Scheme 6.55 Design principle of amine-functionalized bifunctional thiourea organocatalysts derived from privileged monofunctional thiourea 9 cooperating with an amine base additive (A) and basic bifunctional mode of action of chiral amine...

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

In 2005, Nagasawa and co-workers developed a new catalyst design concept leading to novel hydrogen-bonding bifunctional organocatalysts, which incorpo-... 

Compared to the chemo-catalyzed kinetic resolution of alcohols, there are few reports of similar reactions for amines. Building on other work, one elegant example from Berkessel uses bifunctional organocatalysts to enantioselectively hydrolyze a racemic azlactone, and the dynamic kinetic resolution (DKR) is achieved by in-situ acid-catalyzed racemization of the azlactone under mild conditions to give product N-acylarnino esters in, for example, 72% ee and 96% conversion with phenylalanine [6]. 

Sterically and electronically tuneable and bifunctional organocatalysts based on diamides derived from proline are particularly selective in reactions of heterocyclic ketones with aldehydes.109... 

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/r/c/ee. Alkyl chains of (40) make an organic microphase likely. 

A diastereomeric guanidine-bisthiourea bifunctional organocatalyst gives high ees (g) and des in nitroaldols in a biphasic system toluene-water at 0°C.146... 

Chiral BINOL (60) is a bifunctional organocatalyst in addition to the phenolic Brpnsted acid groups, it has a Lewis base unit attached via a spacer moiety.167 This particular combination holds the groups in a conformational lock, where they can doubly activate a substrate while giving a high level of stereocontrol. For this example of an aza-Morita-Baylis-Hillman reaction of an enone and an imine, yields up to 100% and ees up to 96% have been achieved. 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

S)-3-(A-Isopropyl-A-3-pyridinylaminomethyl)BINOL (4) has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction.23 The acid-base functionalities cooperate in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantiocontrol. 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

Hydroxyaldehydes, with an intervening quaternary centre, have been synthesized enantioselectively by direct aldol reactions of oqa-dialkylaldehydes with aromatic aldehydes, using a chiral bifunctional pyrrolidine sulfonamide organocatalyst.118... 

Organocatalyst (56), a pyrrolidine sulfonamide derived from L-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid-base) nature.220 ... 

Another class of bifunctional organocatalysts for the enantioselective aza-Morita-Baylis-Hillman reaction of imines (112) with enones (113) (Scheme 6) is based on BINOL (115). The efficiency of the catalysts proved to be mainly influenced by the position of the Lewis basic moiety attached to the BINOL scaffold. The activation of the substrate by acid-base functionalities and the fixing of conformation of the catalyst (115) are apparently harmonized to maximize the enantiocontrol (<95% ee) 52... 

Scheme 1. Diastereo- and/or enantioselective aminoalkylation of ketones catalyzed by a chiral bifunctional organocatalyst [8a].

Fig. 3 Possible bifunctional approach to Michael components of the organocatalyst 145a...

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