Spirocyclic oxindole

Spirocyclic oxindole 60 was synthesized by [3,3]-sigmatropic rearrangement of the Af-phenyl-O-acylhydroxamic acid 58 (equation 19). The potassium enolate formed by treatment of 58 with potassium hexamethyldisilazide at low temperature rearranged to 59, which easily cyclized to the spirocyclic oxindole 60. Spirooxindoles were previously synthesized by Wolff and Taddei. The spirooxindole 60 was formed in 51% yield from cyclohexanecarboxylic acid after heating the preformed lithium salts of phenyl hydrazide 61 to 205-210 °C. 

The intramolecular Heck reaction is valuable for elaborating the spirocyclic oxindole system related to gelsemine. 

Pummerer-like cyclization reactions were utilized to prepare spirocyclic oxindole derivatives <04OL1869, 04OL2849>. For example, treatment of 2-sulfenylindole 215 with an iodonium reagent in the presence of 2,6-lutidine produced thioimidate 216. Oxidation of the latter with cerium ammonium nitrate (CAN) gave spirooxindole 217. 

An independent synthesis of the spirocyclic oxindole-lactone (20) constitutes a second formal synthesis of ( )-trypto-... 

Feldman KS, Karatjas AG (2006) Extending Pummaer reaction chtanistry. Asymmetric synthesis of spirocyclic oxindoles via chiral mdole-2-sulfoxides. Organic Lett 8 4137-4140... 

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. " ... 

On the other hand, the Chi group reported NHC-catalyzed homoeno-late additions of a,p-unsaturated aldehydes to isatin-derived Boc-protected ketimines to afford spirocyclic oxindole-y-lactams with high diastereo- and enantioselectivity (up to 83% yield, 99% ee, and 20 1 dr) (Scheme 7.49). ... 

In 2012, the Chi group demonstrated a diastereoselective NHC-catalyzed access to p-lactam fused spirocyclic oxindoles with an all-carbon quaternary stereogenic center, employing oxindole-derived p,p-disubstituted a,p-unsaturated imines and enals as substrates. The p-lactam products, stable at room temperature, were easily converted to cyclopentenes at 50 °C. An asymmetric example of the annulation reaction was presented with moderate enantioselectivity (89% yield and 51% ee by using the amino indanol derived catalyst), which is probably due to the sterical hindrance of p,p-disubstituted a,p-unsaturated imines (Scheme 7.58). 

Ruck and coworkers [2] developed an efficient method for synthesizing spirocyclic oxindoles 2 from acrylamides 1 (Scheme 3.1a). The key event in... 

In 2011, Ye and coworkers found that N-heterocyclic carbene C7 was an efficient catalysts for the cyclisation reaction of a,p-unsaturated p-methylacyl chloride with activated trifluoromethyl ketones or isatin. The spirocyclic oxindole-dihydropyrones 198 and trifluoromethyldihydropyrones 199 were obtained in good yield with good to high enantioselectivity (Scheme 20.84). 

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. 

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... 

In a similar mode, spirocyclic oxindole derivatives such as 40 can be formed from the corresponding relevantly substituted indoles in good yield. " These transformations can be carried out using either the sulphide (38) and Stang s reagent or the sulfoxide (39) and acetic anhydride. 

On the wave of such impressive results, other notable research groups addressed their efforts to the development of alternative and complementary triple cascade procedures. For instance, amazing contributes have been published, over the years, by Melchiorre et al. that successfully suggested a practical synthesis of several spirocyclic oxindoles and then-analogues [72]. Exploiting the enamine-iminium-enamine activation mode of aminocatalysis, the organocatalytic triple cascade process disclosed by the Spanish group provided the stereoselective construction of all-carbon quaternary... 

The synthetic and kinetic regularities of the amino-Claisen rearrangement were studied for the transformation of 2,5-dimethyl-Af-(pent-3-en-2-yl)aniline." The products are obtained via conversion of a binary r-complex formed by the reaction of N-alkenylaniline hydrochloride with the hydrochloride of the solvent (2,5-dimethylaniline). Spirocyclic oxindoles have been prepared from iodoindoles via a sequential intramolecular Ullmann coupling and Claisen rearrangement." Nucleophilic ort/io-propargylation of aryl sulfoxides has been reported to occur by intermolecular delivery of the nucleophile to sulfur followed by an intramolecular relay to carbon in a... 

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... 

In 2013, Li et al. reported a novel synthesis of chiral six-memhered spir-ocyclic oxindoles bearing five consecutive stereocentres on the basis of an enantioselective three-component domino Michael-Michael-aldol reaction catalysed hy a combination of a chiral diphenylprolinol silyl ether and a chiral bifunctional quinine thiourea. " As shown in Scheme 2.26, the reaction between iV-substituted oxindoles, nitrostyrenes, and enals led to the corresponding highly substituted spirocyclic oxindoles in high yields, moderate diastereoselectivities of up to 44% de, and enantioselectivities of up to >99% ee. A large variety of substrates could be used well in this... 

Scheme 9.3 Synthesis of spirocyclic oxindoles via an UUman coupling/Claisen rearrangement sequence.

Miyamoto, J., Okawa, Y., Nakazaki, A., Kobayashi, S. (2006). Highly diastereoselective one-pot synthesis of spirocyclic oxindoles through intramolecular Ullmann coupling and Claisen rearrangement. Angewandte Chemie International Edition, 45, 2274-2277. 

Later, Ye and coworkers developed a highly enantioselective synthesis of spiro-cyclic oxindole-p-lactones by a [2-1-2] cycloaddition reaction between isatins and ketenes catalyzed by A-heterocyclic carbenes (NHCs) [57]. TheA-methyl isatin 54c reacted with various aromatic ketenes 100 in the presence of an NHC precursor XXVI at -40 °C to afford the corresponding spirocyclic oxindole-p-lactones 101 in good yields and enantioselectivities, as shown in Scheme 10.36. 

Bencivenni, G., Wu, L.-Y., Mazzanti, A., Giannichi, B., Pesciaioli, R, Song, M.-R, Bar-toli, G., Melchiorre P. (2009). Targeting structural and stereochemical complexity by organocascade catalysis construction of spirocyclic oxindoles having multiple stereocenters. Angewandte Chemie International Edition, 48, 7200-7203. 

Jiang, K., Jia, Z.-J., Chen, S., Wu, L., Chen, Y.-C. (2010). Organocatalytic tandem reaction to construct six-membered spirocyclic oxindoles with multiple chiral centres through a formal [2-I-2-I-2] annulation. Chemistry — A European Journal, 16, 2852—2856. 

Wang, X.-N., Zhang, Y.-Y, Ye, S. (2010). Enantioselective synthesis of spirocyclic oxindole-(3-lactones via n-heterocyclic carbene-catalyzed cycloaddition of ketenes and isatins. Advanced Synthesis Catalysis, 352, 1892-1895. 

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