Cascade reactions bifunctional catalysts

In 2010, Zhong and co-workers [32] tried a similar approach using nitrotyrenes and cyclic ketoesters. The reaction occurs through a Michael-Henry cascade reaction catalyzed by bifunctional thiourea catalysts derived from cinchona alkaloids. The reaction furnished the desired bicyclic products 43 in good yields and excellent stereoselectivities (Scheme 10.14). 

As shown in Figure 9.13, sulfonic of PPAF, which is characterized by a 9,9 -spiro-bisfluorene unit, is another example. Further grafting with amine makes PPAF-SO3H-NH2, which may be used as a bifunctional catalyst in a model cascade reaction. In particular, this catalyst can be used several times without obvious loss of the activity. 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Among all the possible approach to polysubstimted cyclohexane derivatives, Dixon et al. proposed a further and very elegant alternative approach wherein the asymmetric organocatalytic cascade reaction reties on the synergic action of a bifunctional base/Br0nsted acid catalyst 158 and a cyclic secondary amine (5)-76 (Scheme 2.49) [77]. 

With this new methodology in hands, Hu et al. [166] explored the trapping of the 1,4-addition intermediate with a different electrophile for the development of a new MCR. RhjCOAc) was again the most active catalyst in the 1,4-addition/aldol-type intramolecular cascade reaction. Under the optimized reaction conditions, this three-component reaction worked well with a broad family of bifunctional substrates 135 bearing different substituents on the aryl group next to the enone moiety and a variety of alcohols 136 (Scheme 3.63). In all cases, 1-indanols 137 were obtained in 60-83% yield and with complete diastereoselectivity. Enantiopure 1-indanol was obtained employing a L-menthol-derived diazo compound. The intermolecular four-component version was also attempted, but the formation of the desired product was not observed. 

Wang and coworkers made a similar approach using isocyanoesters [25]. The reaction was catalyzed by bifunctional tertiary amine-thiourea catalysts and afforded the pyrrolidinyl spirooxindoles in good yields and excellent enantioselectivities but low diastereoselectivities. Later, Yan and coworkers developed a similar reaction involving the three-component cascade reaction of isatin, isocyanoesters, and malononitrile [26]. First, the Knoevenagel reaction between isatin and malononitrile afforded the... 

Phosphoric acid 25a was successfully employed for mediating enantioselective synthesis of 1,3-disubstituted isoindolines from electrophilic bifunctional substrates (containing an imine and a Michael acceptor site) and indoles [33]. Catalyst 7a was used effectively in an organocatalytic asymmetric F-C alkylation/cyclization cascade reaction between 1-naphthols and a,(i-unsaturated aldehydes to give chro-manes in good yields and select vities (Scheme 3 5.18) [ 10]. Furthermore, 2-naphthols and p,y-unsaturated a-keto ester also reacted in a F-C alkylation/dehydration sequence, in the presence of a thiourea catalyst and a catalytic amount of concentrated sulfuric acid, affording optically active naphthopyran derivatives [54]. 

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

The organocatalyzed asymmetric synthesis of bicylco[3.2.1]octan-8-ones 214 was described independently by Rueping et al. [84a] and Ding et al. [84b] respectively (Scheme 2.58). The bifunctional thioureas were found to be optimal catalysts to promote the Michael-Henry cascade reaction of cyclohexa-l,2-dione 177 with the P-nitrostyrenes 165, which afforded the bicycles desired, 214 in good yields and stereoselectivities. 

Nazarov reagents 238, which possess both a nucleophiUc carbon and an electron-deficient C—C double bond, have been employed in the synthesis of enantioenriched spiro[4-cyclohexanone-l,3 -oxindoUne] derivatives 239 by Wei and Gong. The Michael-Michael cascade reaction of 238 and methyleneindolinones 55 proceeded smoothly in the presence of the bifunctional urea catalyst 140 h and 4-A molecular sieves, which afforded structurally diverse spirooxindole derivatives 239 with excellent enantioselectivities (Scheme 2.64) [93],... 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

The ability of A -heterocyclic carbenes to activate a,p-unsaturated carbonyl compounds via the formation of the corresponding Breslow intermediate, which plays the role of a homoenolate nucleophile, has also been applied to a cascade process involving a formal intramolecular Michael reaction/oxidation/ lactonization, leading to the formation of complex tricyclic carbon frameworks starting from a bifunctional substrate containing an enone and an a,p-unsa-turated aldehyde side chain linked to each other via a benzene tether (Scheme 7.82). The reaction involved a complex multistep mechanism which started with the activation of the enal by the catalyst, forming the Breslow intermediate, which subsequently underwent intramolecular Michael reaction and next the generated enol-type intermediate reacted intramolecularly with the... 

The proposed reaction mechanism is shown in Scheme 6.75. The nitroalkene moiety of bifunctional ortAo-alkyne-substituted nitrostyrenes 159 is activated through hydrogen bonding with catalyst 160 to incorporate the stereoehemieal information in the first AFC reaction. Then the alkyne is activated under gold catalysis to affect the seeond AFC/ring expansion cascade. 

Barluenga, J., Fernandez, M.A., Aznar, R and Valdes, C. (2005) Cascade alkenyl amina-tion/Heck reaction promoted by a bifunctional palladium catalyst a novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides. Chem. Eur. 11, 2276-83. 

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. 

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