Multicomponent cascade reactions

As indicated in Section I.C, we focused on convergent multigeneration strategies employing multicomponent one-pot or multicomponent cascade reactions. Multi-component one-pot reactions offer the possibility to introduce several elements of diversity in one reaction and one reaction vessel.93 Performed in solution or on solid supports, these reactions allow one to synthesize the products in the same format used for screening without having to resort to reaction vessel transfers. 

The usefulness of palladium-based chemistry is highlighted by the multicomponent cascade reaction sequence that uses o-ethylanilines, aryl iodides, primary amines, and carbon monoxide (Equation 99) <2005JOC6454>. 

This new multicomponent cascade reaction can also be performed with a large variety of aryl halides, most favorably iodides (Scheme 7). The yields in this coupling-cycloaddition sequence are particularly high with the parent... 

By using a multicomponent cascade reaction. Parsons et al. [88] achieved one-pot sequential [1+4] and [3+2] cycloadditions to synthesize highly substituted iso-xazolines via nitrile oxides (Scheme 11.28). These five-component reactions proceed by initial formation of isonitriles 109 that react with nitroalkenes 110 to form unstable N-(isoxazolylidene)alkylamines, which in turn fragment to generate the nitrile oxides 111. Cycloaddition then occurs with methyl acrylate, chosen for its expected reactivity with nitrile oxide dipoles, to generate the isoxazolines 112. Reactions using standard thermal conditions and microwave irradiation were com-... 

Blechert et developed a multicomponent cascade reaction for the synthesis of indole derivatives as depicted in Scheme 1.8.5.17. The first step of the sequence involves formation of a nitrone derivative starting from phenylhydroxylamines and aldehydes. The resulting nitrones were not isolated but captured by a cyanoallene in a 1,3-dipolar cycloaddition reaction followed by hetero-Cope rearrangement, ring-opening and condensation to yield an indole derivative. 

We were especially interested in reactive building blocks that would allow to carry out multicomponent-cascade reactions giving rise to different core structures depending on the sequence of mixing ( combinatorics of building blocks ). Ultimately, this excercise can lead into the discovery of novel multicomponent reactions. 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

SCHEME 10.29. Multicomponent cascade reaction leading to cyclohexanes. 

A one-pot multicomponent cascade reaction of arylamines, aldehydes, and electron-deficient dienophiles on a soluble support under microwave conditions has been reported to involve a base-catalysed Povarov reaction and a [l,3]-sigmatropic rearrangement leading to 4,10-dihydropyrimido[l,2-fl]benzimidazoles (Scheme 17). ... 

Multicomponent cascade reactions of methyl/ethyl acetoacetate, phenyl hydrazine, and Baylis-Hillman adducts 23 and 24 give access to tetracyclic... 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

D.-F. Yu, Y. Wang, P.-F. Xu, Tetrahedron 2011,67, iXl i-iTn. Organocatalytic enantioselective multicomponent cascade reaction facUe access to tetrahydropyridines with C3 all-carbon quaternary stereocenters. 

L. Tian, X.-Q. Hu, Y.-H. Li, P.-F. Xu, Chem. Commun. 2013, 49, 7213-7215. Organocatalytic asymmetric multicomponent cascade reaction via 1,3-proton shift and [3-t2] cycloaddition an efficient strategy for the synthesis of oxindole derivatives. 

J. Barluenga, A. Mendoza, E Rodriguez, F. J. Fanands, Angew. Chem. Int. Ed. 2009, 48, 1644-1647. A palladium(II)-cata-lyzed synthesis of spiroacetals through a one-pot multicomponent cascade reaction. 

Barluenga, J., Mendoza, A., Rodriguez, F., Fanands, F.-J. (2008). Synthesis of spiroquino-lines through a one-pot multicatalytic and multicomponent cascade reaction. Angewandte Chemie International Edition, 47, 7044-7047. 

Kriis, K., Ausmees, K., Pehk, T., Lopp, M., Kanger, T. (2010). A novel diastereoselective multicomponent cascade reaction. Organic Letters, 12, 2230-2233. 

Finally, Han, Huang, and Peng reported a multicomponent cascade reaction for the synthesis of the spirooxindole pyranone scaffold [38]. The reaction started with the addition of aliphatic aldehydes 15 to nitrostyrenes 64 catalyzed by chiral secondary amine catalyst I. Next, the resulting adduct reacted with A-benzyl isatin (54b) by a Henry-hemiacetal formation cascade followed by pyridinium chlorochromate (PCC) oxidation to afford the corresponding spirooxindoles 70 in good yields and stereoselectivities (Scheme 10.24). 

Xie, X., Peng, C., He, G., Leng, H.-J., Wang, B., Huang, W., Han, B. (2012). Asymmetric synthesis of a structurally and stereochemicaUy complex spirooxindole pyran scaffold through an organocatalytic multicomponent cascade reaction. Chemical Communications, 48, 10487-10489. 

The first organocatalytic sulfa-Michael reaction of enals was reported by j0rgensen in 2005 [68]. In this report aliphatic and aromatic aldehydes reacted with several thiols in good yields and enantioselectivities under catalysis of 28. The products must be reduced immediately due to their fast epimerization at room temperature (Scheme 33.21). In this work, j0rgensen and coworkers also developed several multicomponent cascade reactions with good to excellent results. 

A further small tweaking of the reaction conditions involves great changes a further new cascade channel is breaking. This is accomplished by modulation of the nucleophilicity of the activated methylene compounds applied. When used with isocyanoacetate 87 instead of cyanoacetates 86 as a methylene-activated component, an Ugi-like multicomponent cascade reaction is observed. This reaction was first detected by deployment of ethyl isocyanoacetate 87 in reactions of ribose and proline. In these experiments, proline—once the catalyst in the Knoevenagel condensation/ketalization/oxa-Michael cascade reactions—is directly incorporated into the product. As a result of that, seven-membered lactone 89 is formed. This sharp difference is demonstrated in Scheme 2.18 [40]. 

Several multicomponent cascade reactions involving a critical Diels-Alder cycloaddition have been recently described by Huang and Xu. Thus, a one-pot preparation of isoindoles such as 172 involves an Ugi four-component coupling of furfural (167a) with benzyl amine (168a), 2-(phenylselanyl)acrylic acid (169a), and benzylisonitrile... 

Scheme 4.44 Multicomponent cascade reaction for regiospecific synthesis of 1,5-disubstituted 1,2,3-triazoles.

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