Oxindoles Michael addition

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... 

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

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. " ... 

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). 

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. 

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 stereoselective vinylogous Michael addition-cyclization cascade of alkylidene malononitriles and 3-alkylideneoxindoles was effectively catalyzed by rosin-derived thiourea 36 to give spirocyclic oxindoles with excellent stereoselectivity (Scheme 35) [61]. Although simple thiourea 20 (see Scheme 16) provided low stereoselectivity (dr = 3 1, 29% ee), introduction of the rosin unit into the thiourea core significantly improved the diastereoselectivity to >20 1 the pyrrolidine structure was essential for high enantioselectivity. The effect of the chirality of the rosin component on the absolute stereocontrol was negligible and, thus, the major proposed role of this structural unit was to increase the steric hindrance of the catalyst. One of the salient features of this protocol is the... 

Scheme 35 Vinylogous Michael addition-cyclization cascade reaction to form spiro-oxindoles...

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... 

The Michael addition/cyclization of isothiocyanato oxindoles (296), catalysed by the quinine-derived thiourea (288b) and its analogues, has been employed for the preparation of a variety of 3,2 -pyrrolidinyl spirooxindoles (297) and bis-spirooxindoles (298) with <98% ee and >20 1 dr (Scheme 15). " ... 

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. 

Based on the enantioselective Michael addition/ISOC (intramolecular silyl nitronate olefin cycloaddition)/lragmentation sequence previously developed by the group of Rodriguez [33a], Shao and coworkers proposed an extrapolation for the construction of spirooxindoles catalyzed by a bifunctional tertiary amine-thiourea catalyst XV between 4-allyl-substituted oxindoles 63 and nitrostyrenes 64 (Scheme 10.21) [33b]. After the addition of TMSCl and EtgN at -30 C, the Michael adduct underwent an ISCX3 to afford the spiro oxime derivatives 65 in very good yields (85-85%), and excellent diastereo (up to >30 1) and enantioselectivities (94-99% ee) after the treatment with TBAF. 

Noteworthy is also the organocatalyst directed, enantioselective Michael addition to a monosubstituted oxindole, affording the sterically encumbered adduct 540 at room temperature in 90 and 93% ee [189]. 

Benzo-annulated heterocyclic compounds such as oxindole and benzofuran derivatives were prepared in high yields by a novel cy-clization reaction of ethenetricarboxylate derivatives of aromatic compounds via Friedel-Crafts intramolecular Michael addition... 

Oxindoles and benzofuranones have been used as nucleophiles in the Michael addition to cyclic enones using as a catalyst primary amines derived from cinchona... 

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... 

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%... 

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