Michael reaction oxindoles

In a related example, the desired rhodium carbenoid could be generated from 3-substituted indole or oxindole derivatives, which are readily accessible by ytterbium triflate-catalyzed Michael reactions, but several problems were... 

Scheme 3.12 Michael reaction of oxindoles to o,p-unsaturated aldehydes.

Scheme 5.20 Enantioselective Michael reaction of 3-aryl oxindoles with enones catalyzed by phosphonium salt 110.

Finally, it should also be pointed out that enantioselective Michael reactions to enones under PTC conditions do not exclusively rely on the use of chiral ammonium salts as catalysts and, for example, chiral phosphonium salts can also be successfully employed in this context. This is the case of binaphthyl-containing phosphonium salt 110, which was demonstrated to be an outstanding catalyst in the conjugate addition of oxindoles to enones under PTC conditions (Scheme 5.20). The Michael adducts were obtained in excellent yields and enantioselectivities for a wide variety of differently substituted 3-aryl oxindoles tested as Michael donors. Remarkably, the high acidity of the 3-aryloxindoles employed as Michael donors allowed the use of a very mild base such as potassium benzoate for the activation of the nucleophile. 

For this reason, the only literature example regarding the use of nitroalkenes as Michael acceptors in enantioselective Michael reactions under PTC conditions is related to the use of oxindoles as pro-nucleophiles (Scheme 5.31). In this context, using deuterium labeling experiments, it was found that oxindoles underwent fast deprotonation in neutral aqueous media only in the... 

Scheme 5.31 Enantioselective 107b-catalyzed Michael reaction of a-aryl oxindoles with nitroalkenes.

Similar to oxindole derivatives, benzofuranones are also suitable donors in Michael reactions. Recently, Luo and Cheng fulfilled the successful application of benzofuranones in the conjugated addition to chalcones [95] and malemides [96] utilizing bifunctional amine thiourea 75 and 90, respectively (Scheme 5.46). These reactions provide powerful methods for the synthesis of chiral benzofuranone derivatives with different functional groups. 

A similar approach was reported by Wang et al. [60] a year later, consisting of a double Michael reaction of simple oxindoles with dienones. The reaction was simply catalyzed by a cinchona-based primary amine catalyst (XIII). The reaction afforded the final spirocyclic oxindoles in good yields and excellent enantioselectivities when diaryldienones were used. The only limitation of the reaction was the need to use carbamate-protected oxindoles thus, the use of unprotected or benzylated oxindoles is ineffective for this transformation. In 2010, the same research group proposed a similar approach [61]. They performed a reaction with an oxindole derivative decorated with a ketone in position 3 of the oxindole and acyclic enones. This reaction was catalyzed by chiral primary amines, affording the final spirooxindoles in good yields and enantioselectivities. 

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). 

In 2011, Wang et al disclosed a highly enantioselective domino double Michael reaction of dienones with 3-nonsubstituted oxindoles to access chiral spirocyclic oxindoles in high yields of up to 98% and excellent dia-stereo- and enantioselectivities of up to >90% de and 98% ee, respectively. This novel reaction was performed in the presence of a cinchona-based... 

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. 

Zheng W, Zhang Z, Kaplan MJ, Antilla JC. Chiral calcium VAPOL phosphate mediated asymmetric chlorination and Michael reactions of 3-substituted oxindoles. J. Am. Chem. Soc. 2011 133(10) 3339-3341. 

Knoevenagel adduct 239 of oxohomophthalimide 240 with malononitrile 27a in reactions with CH-acids behaves ambiguously (82CPB1215). Reactions of 239 with acetylacetone, ethyl esters of acetoacetic and ben-zoylacetic acids, as well as methyl pyruvate led to the formation of the desired spiropyrans 241. However, benzoylacetone, dibenzoylmethane, cyanacetamide, and oxindole always gave the same 242. Authors explain this feature in terms of a retro-cleavage of adducts of Michael product 239... 

An all organic catalyst system 38 has been reported by the Maruoka group for directing asymmetric additions of oxindole enolates derived from 36 to nitro-aUcenes 37 under phase-transfer conditions [26] (Scheme 10). The methodology was extended to the synthesis of a tetrahydropyrroloindole scaffold bearing two chiral centers. Asymmetric Michael and Mannich reactions of 3-aryloxindoles directed by chiral phosphonium salt phase-transfer catalysts have been described by the same group [27]. 

Racemic 3-alkyl oxindoles have also been found to be useful pro-nucleophiles in this context (Scheme 4.IS)." For this transformation, a modified version of Takemoto s catalyst was identified as the most efficient promoter of the reaction, which was found to have a remarkably wide substrate scope, allowing many different substitution patterns both at the oxindole and at the nitroalkene reagent, and even tolerating well the use of p-alkyl substituted nitroalkenes as Michael acceptors. Yields, diastereo- and enantioselectivities were found to be excellent in almost all the cases studied. The reaction also accepted very well the use of the simple nitroethene, another very challenging... 

Scheme 7.18 Stereoselective Michael/Michael cascade reaction to 3 -spiro-oxindoles fused with cyclobutane catalysed by prolinol lb.

Recently, there has been considerable progress in the synthesis of nitrogen-containing heterocycles based on (ox)indole skeleton. Oxindole derivatives serve as useful reaction partners in various domino transformations. Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral intermediates, which were further combined with diverse activated olefins or imines to afford spirocyclic oxindoles with high molecular complexity (Scheme 8.27). Spiro-oxindole derivatives were also assembled by a Michael/Michael/aldol cascade of oxindole and two equivalents of enal. " ... 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

Scheme 19.33 Organocatalytic asymmetric vinylogous Michael (AVM) reaction of 3-alkylidene oxindoles with nitro-olefins promoted by thiourea 17.

Scheme 19.62 Organocatalysed domino Michael-aldol reaction for the construction of bispiro-oxindoles.

S. Oxindole Derivatives. Most recently, Curti et al. [140] disclosed the first example of a direct, organocatalytic asymmetric vinylogous Michael addition of 3-alkylidene oxindole to nitroalkenes. Bifunctional cinchona alkaloid/thiourea catalyst 69 could effectively promote the reaction, solely aHbrding the 7-substituted 3-alkylidene oxindoles 146 with excellent regio-, diastereo-, and enantioselectivities (Scheme 5.71). Importantly, both aromatic and aliphatic substituted nitroalkenes were applicable for such a reaction. 

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