Michael addition of oxindoles

Scheme 19.51 Asymmetric Michael addition of oxindoles to enals.

Oxindoles with an all-carbon quaternary center at the C3 position are privileged structural motifs found in many pharmaceuticals and alkaloid natural products [90]. The asymmetric Michael addition of oxindoles proved to be an efficient method for the construction of these structural motifs and a wide range of electrophiles such as a,(3-unsaturated aldehydes [91], ketones [92], sulfones, nitroalkenes [93], and 2-chloroacrylonitrile [94] have been weU studied in recent years (Scheme 5.45). 

SCHEME 5,71. Direct vinylogous Michael addition of oxindole derivatives to nitroalkenes. 

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). 

The group of Enders recently disclosed an original use of prolinol TMS ether as organocatalyst to promote the Michael addition of oxindoles to nitroolefins (Scheme 34.25) [65]. The reaction proceed through Bronsted base activation despite the fact that such a catalyst structure, chiral pyrrolidine, was usually employed in... 

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]. 

Scheme 4.15 Enantioselective Michael addition of racemic 3-alkyl oxindoles to nitroalkenes and application to the total synthesis of ( + )-physostigmine.

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. 

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. " ... 

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. 

Calcium VAPOL (2,2 -diphenyl-(4-biphenanthrol)) phosphate (150) has been reported as an efficient catalyst for the enantioselective Michael addition of 3-aryloxindoles to CH2=CHCOMe (<95% ee) and for chlorination of 3-substituted oxindoles with A-chlorosuccinimide (<99% ee). ... 

An enantioselective Michael addition of 3-aryloxindole to PhCH=CHS02Ph, catalysed by the quinine-derived amine-thiourea (205) as a multiple hydrogen-bonding donor, has been developed. The resulting adducts, containing a chiral quaternary carbon centre at the 3-position of the oxindole, were obtained with <98% eeP" An... 

Michael addition of 3-benzyl-substituted oxindoles to 2-cyclopentenone, catalysed by the chiral guanidine (322), produced 3,3-disubstituted oxindoles (323) at -10 C with 73-98% ee and 9 1 to >20 1 dr ... 

Various thiourea-based bifunctional organocatalysts (e.g. 289a and 372a,b) have been successfully applied for the Michael addition of nitroalkanes RCH2NO2 to 3-ylidene oxindoles (373). The resulting enolate intermediates (374) were then trapped by electrophiles, such as enones, maleimide, and sulfone CH2=C(S02Ph)2. The products were obtained with <99% ee and >95 5... 

Taking the advantage of the reactivity of alkylideneindolones, Bencivenni and Bartoli developed the nitrocyclopropanation of oxindoles (Scheme 10.15) [21]. The reaction of 1-bromonitromethane (47) with 17c was catalyzed by the bifunctional Bronsted acid-Lewis base cinchona derivative IX. The reaction required 1 equiv of Na2C03 to trap the bromhydric acid released during the last cyclization step. The reaction started with Michael addition of the nitromethane, which was followed by intramolecular alkylation to afford the spirocyclic nitropropanes 48. 

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. 

The Michael additions of 3-benzyl-substituted oxindoles to M-substituted maleimides has been reported to proceed with <99% ee in the presence of the C2-symmetric bicyclic guanidine (302) as a basic organocatalyst in toluene at -50 C over 48 h. A plausible transition state has been proposed4 ... 

The analogue of 0-TMS prolinol (325) with CH3(CH2)n groups instead of the typical aryls, activated by a Brpnsted base, has been employed as catalyst for the Michael addition of N-Boc-protected oxindoles to nitroalkenes and exhibited >98 2 dr and 82 to >99% 0... 

A vinylogous Michael addition of 3-alkylidene oxindoles (441), normally regarded as good Michel acceptors, to nitroalkenes, has been attained in the presence of the cinchona-derived thiourea catalyst (372). This rare example of organocatalytic umpol-ung, presumably proceeding via the hydrogen-binding stabilized enol (442), afforded the adducts (443) in a >99 1 y.a ratio with 10 1 to >20 1 Z/E) selectivity and 97 to >99%... 

The highly enantioselective calcium phosphate (392) catalysed chlorination of 3-substituted oxindoles (387) with A -chlorosuccinimide (NCS, 388) in the catalytic enantioselective Michael addition of (387) to methyl vinyl ketone (389) to afford the product (390) and (391) in quantitative yields, with high enantioselectivities, has been described by Antilla et al. (Scheme 102). ... 

Aziridine-2-phosphonates spiro-fused with 2-oxindole (790) have been prepared by a straightforward Horner-Wadsworth-Emmons reaction of ethyl 7V- [(4-nitrophenyl)sulfonyl]oxy -carbamate (791) and 3-(phosphoryl-methylene)oxindoles (792) in the presence of calcium oxide. Oxindoles (792) were also transformed into novel oxirane-2-phosphonates (793), as oxygen analogues of (790), by reaction with H202/Na0H (Scheme 201). " Cinchonine-based thiourea (797) catalysed asymmetric Michael addition of simple p-oxo-alkyl phosphonates (794) to nitro olefins (795), which afforded valuable a-substituted p-oxo phosphonates (796) in satisfactory yields with good to excellent enantioselectivities (up to 98% ee) (Scheme 202). ... 

Asyimnetric catalytic method to generate C-C bond with adjacent quatemaiy-tertiary stereocenters ranains a challenging synthetic task. In this regard, the use of 3-substituted oxindoles as carbon-nucleophiles has attracted intensive interests due to their relevance in synthesizing bioactive indole alkaloids. Melchiorre recently reported asymmetric Michael addition of 3-substituted oxindoles to a,P-unsaturated aldehydes catalyzed by a primary amine thiourea catalyst 114 (Scheme 5.29). Good diasteieoselectivity and enantioselectivity have been achieved in most cases. However, the reactions were generally sluggish [56]. 

The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2-vinylindoles from A-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an A-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. 

Chlorophenylmagnesium bromide attacked only the ketonic carbonyl group of isatin (426) to give the oxindole (427). Michael addition to acrylonitrile followed by reduction gave the saturated primary amine (428) which in refluxing xylene containing 4-toluene sulphonic acid cyclized to ciclazindol (429) Scheme 5.101.). The intermediate (428) can also be... 

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-... 

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