Spirooxindoles cascades

The first formed chroman-2-ols were, after work-up, oxidised with PCC to naturally widespread 3,4-dihydrocoumarins, in high yield, diastereo- and enantioselectivity. Recently, a powerful Michael/Michael cascade reaction catalysed by prolinol lb via dienamine activation of a, 3-unsaturated aldehydes combined with ethyleneindolinones has been reported. Complex 3,3 -spirooxindoles fused with a cyclobutane bearing four stereogenic centres were obtained in good yield and high diastereo- and enantioselectivity (Scheme 7.18). Surprisingly, catalyst 10 proved to be less active and... 

In the second case, Melchiorre and co-workers [59] used a Michael—Michael cascade reaction between an unsaturated spirocycle and an enone. This reaction is efficiently catalyzed by a primary amine derived (XIII) in a single step from the cinchona alkaloid hydroquinine. The reaction afforded the final spirooxindoles in... 

The same research group developed a similar cascade leading to the synthesis of spirooxindoles bearing four stereogenic centers. The starting material this time was a-methylene oxindoles (90) instead of 2-cyanoacrylate derivative. The reaction renders the spirooxindole derivatives 110 in excellent yields and enantioselectivities [59]. In 2011, Rios and co-workers [70] expanded the scope of the reaction using a-methylene pyrazolones 111, leading to spiropyrazolones 112 with excellent results (Scheme 10.29). 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Based on a rare example of asymmetric 1,6-addition to linear 2,4-dienals proceeding with high 6-site and stereoselectivity, a novel aminocatalytic vinylogous cascade reaction was also developed to yield valuable tetrahy-drofuran spirooxindole derivatives (13AGE10780). 

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]... 

Alkylideneindolones are particularly good electrophiles, especially toward Michael additions, and therefore constitute excellent starting materials for the synthesis of spirooxindoles by multiple bond-forming approaches. The general strategy of the cascade reactions consists of an initial Michael reaction followed by a nucleophilic addition of the in situ formed enolate intermediate to various electrophiles. In the last years, several electrophilic partners with different scaffolds that lead to formal cyclizations, such as [3+2] cycloadditions [8a], Diels-Alder reactions [8b], and cyclopropanation [8c], have been used to afford a plethora of new spirooxindole scaffolds with excellent stereocontrol. 

In the second reaction, a Michael-Michael cascade between an unsaturated oxin-doles 17 and enones 22 was shown to be catalyzed by a primary amine-derived catalyst (II) (Scheme 10.3). The reaction afforded the spirooxindoles 23 in excellent yields and diastereo and enantioselectivities. Wang used a similar approach in the reaction of isatylidene malononitriles and enones [12]. The reaction was catalyzed by the dual combination of cinchona-based chiral primary amine and BINOL phosphoric acids to afford the spirocycles in excellent yields (88-99%), diastereo (up to 99 1 dr), and enantioselectivities (95-99% ee). 

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... 

Domino Sequences Involving Oxindoles as Pronucleophiles Another commonly used approach for the synthesis of spirooxindoles relies on the use of simple oxindoles as pronucleophiles with several Michael acceptors. For example, we developed a highly enantioselective methodology for the synthesis of spirooxindoles by a Michael-Michael-aldol cascade (Scheme 10.19) [30]. Simple 2-oxindole (58) undergoes two consecutive Michael reactions with enals 16 catalyzed by the Jprgensen-Hayashi catalyst I. Next, an intramolecular aldol reaction catalyzed by the same catalyst takes place to afford, after dehydration, the corresponding spirooxindoles 59. 

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). 

Albertshofer, K., Anderson, K. E., Barbas 111, C. R (2012). Assembly of spirooxindole derivatives via organocatalytic iminium-enamine cascade reactions. Organic Letters, 14, 5968-5971. 

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. 

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],... 

Chen et al. reported that oxindole-type a-isothiocyanato imides 271 had high activities in the aldol-cyclization reaction with inactive simple ketones. With the promotion of thiourea catalyst 1401, the cascade process of either aromatic or aliphatic ketones 206 with 3-isothiocyanato oxindoles 271 proceeded smoothly to afford spirooxindoles 272 bearing a quaternary stereogenic center with perfect stereoselectivity (Scheme 2.72) [102],... 

Considering the rapid growth of asymmetric construction of oxindoles, Sun et al. recently reported their assembly of chiral spirooxindoles by combining secondary amine and palladium catalysis in a cascade reaction [55]. The reaction was initiated by the reversible Michael addition of 3-substituted oxindole to enal, which was followed by a metal/organic-cocatalyzed carbocyclization of the aUcyne tether (Scheme 9.60). Similar to the aforementioned dynamic kinetic asymmetric transformations, this chemistry highlighted the cooperative effects of the two catalysts in the same reaction vessel, while either catalyst could not solely promote the overall reaction, and unsatisfactory results were observed when this reaction was conducted in a two-step mode. 

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