Urea-amine bifunctional catalyst

2 Bifunctional Catalysts Possessing Both Acidic and Basic Organic Croups 3 Catalyst (20 mg) 

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Thioureas (and less often ureas) as organocatalysts were introduced into synthetic practice by Jacobsen and Schreiner. Further development included the design of bifunctional catalysts combining two thiourea subunits or a thiourea group and chiral amines. ... 

The extension of the thiourea-tertiary amine concept to the cinchona alkaloids was reported by several groups independently in 2005. The general usefulness of cinchona alkaloids as bifunctional catalysts was recognized by several groups even before this date [9]. The focus herein is on (thio)urea and squaramide catalysts since they are prototypes of more efficient catalysts. The Chen and the Dixon groups screened cinchonine and cinchonidine-derived thiourea catalysts for conjugate... 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

In 2012, the first polymer supported bifunctional primaiy amine-ureas were developed by Portnoy and coworkers. This heterogeneous catalytic system was tested in the Michael addition of acetone, cyclic ketones and aldehydes to aromatic nitro-olefins leading to activities and selectivities unprecedented for immobilised catalysts. Catalyst 41 based on (ll ,2f )-diphenylethylene-1,2-diamine and a L-valine spacer provided the Michael products in yields ranging from 23 to 99% and in high enantioselectivity (up to 99% enantiomeric excess) (Scheme 19.43). Unfortunately, recovery of the polymer-catalyst and reuse was only tested for 3 cycles, maintaining the high levels of enantioselectivity, but with a significant loss in the yield. 

The employment of bifunctional urea-tertiary amine 104 or monothiourea 105 catalysts selectively promotes either the Michael addition or cycloaddition process, respectively, [60]. As depicted in Scheme 2.30, the tertiary amine group would activate the in situ formed a-amino esters to produce azomethine ylides A (or enolates), whereas the nitroalkene counterparts would be activated by the thiourea (urea) moiety through a double H bonding interaction (B). 

On the other hand, Chen et al. have reported an asymmetric three-component reaction of aldehydes, diethyl a-aminomalonate and nitroalkenes. The Michael adducts were obtained in excellent yields and enantioselectivities of up to 98% ee by using a chiral bifunctional urea-tertiary amine as the organo-catalyst (Scheme 1.64). 

The majority of the organocatalysts that are commonly employed are chiral Lewis or Brpnsted bases, and the catalytic potential of base functionalities has been referred to in previous chapters to some extent already. As discussed before, the use of chiral primary or secondary amines for enamine or iminium activation belongs to the most important applications of asymmetric organocatalysts nowadays. In addition, also the interplay between an acidic (thio)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such bifunctional thiourea-containing acid-base catalysts, chiral catalysts containing a (Lewis or... 

Despite the prevalence of amine/metal or Brpnsted acid/metal binary catalysis, bifunctional (thio)urea/metal binary catalysis finds only limited applications in in cascade or tandem reactions and is much less well developed. This may be due partially to deactivation of the Lewis acidic metal catalysts by coordinative (thio)urea catalysts. The examples reported often adopted the strategy of sequential additions of catalysts and substrates to solve the problans mentioned above. 

Very recently. Barber et al. reported a tandem reaction combining bifunctional urea and Au(I) salt for the asymmetric synthesis of valuable tetrahydropyridine derivatives [80]. This reaction consisted of a urea-promoted nitro-Mannich reaction of an alkyne-tethered secondary nitroalkane to N-Boc-protected imines and an Au(I) complex-catalyzed intramolecular hydroamination and isomerization (Scheme 9.75). Notably, since the inherent Lewis basic tertiary amine-tethered urea would deactivate the Au catalyst, the reaction system was acidified by additional DPP before addition of an Au catalyst to ensure the success of the overall process. 

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