Multicomponent cascade

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. 

Method Cis based on intramolecular cyclization of 2-aminothiophenes containing a substituent with the electrophilic y-carbon atom at position 3. This class of compounds, for example, amines 50, can be prepared by multicomponent cascade heterocyclization of phenyl isothiocyanate, CH-acids, and alkylating agents (1991SL229, 1992G147, 1992M341, 2001PS215). Cyclization of compounds 50 affords 6-oxo(imino)-6,7-dihydrothieno[2,3-Z>]pyridines 51 as the final products. 

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... 

Analysis of the data on the chemistry of isomeric thienopyrimidines published over the last 10-15 years shows that this class of heteroaromatic compounds, which are structural analogs of natural compounds of the purine class, attracts increasing interest of chemists and biochemists. In the first half of the 21st century, new approaches to the synthesis of derivatives of these fused heterocyclic systems will be, undoubtedly, extensively developed. These derivatives are not only of theoretical interest but also possess a broad spectrum of practical use, primarily, due to various biological activities. Of the approaches to their synthesis, multicomponent cascade heterocyclization, which allows one to construct various functionalized thienopyrimidines and their fused analogs in one technologically and ecologically safe step, holds the most promise. 

Multicomponent cascade heterocyclization as a route to directed syntheses of polyfunctionalized pyridines 03UK75. 

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. 

In a more speculative and intuitive way, 3 and 4 should react in the presence of a base to give intermediates of type 15 (9 compounds), which similarly to entry c should react with 2 to give intermediates 16 (27 compounds) followed by cyclodehydration to yield 17 (27 compounds). Whereas a five component one-pot condensation would maximally yield 243 compounds with one single core structure, the decribed multicomponent cascade approach using reactive building blocks... 

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. 

A facile access to A-sulfonylimidates and their synthetic utility for the transformation to amidines and amides, (b) E. J. Yoo, S. H. Park, S. H. Lee, S. Chang, Org. Lett. 2009, 11, 1155-1158. A new entry of copper-catalyzed four-component reaction facile access to a-aryl P-hydroxy imidates. (c) R. Husmann, Y. S. Na, C. Bohn, S. Chang, Chem. Commun. 2010, 46, 5494—5496. Copper-catalyzed one-pot synthesis of a-functionalized imidates. (d) W. Song, W. Lu, J. Wang, P. Lu, Y. Wang, J. Org. Chem. 2010, 75, 3481-3483. A facile route to y-nitro imidates via four-component reaction of alkynes with sulfonyl azides, alcohols, and nitroolefins. (e) G. Murugavel, T. Punniyamurthy, Org. Lett. 2013, 15, 3828—3831. Novel copper-catalyzed multicomponent cascade synthesis of iminocoumarin aryl methyl ethers. 

L. Zhang, H. C. Malinakova, J. Org. Chem. 2007, 72,1484— 1487. Copper-catalyzed multicomponent cascade process for the synthesis of hexahydro-lH-isoindolones. 

K. Inanaga, K. Takasu, M. lhara, J. Am. Chem. Soc. 2004,126, 1352-1353. Rapid assembly of polycyclic substances by a multicomponent cascade [4 + 2]-[2+2] cycloadditions total synthesis of the proposed stmcture of paesslerin A. 

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