Spiro-fused 2-oxindoles

A four-component domino reaction of isatin 58, phenylhydrazine, 3-aminocrotononitrile 117, and cyclic 3-diketones/amide/thioamide 118 in an aqueous medium in the presence of ( )-camphor-10-sulfonic acid on heating at 100 °C for 2-3 h afforded the spiro-fused 2-oxindoles 119 (Scheme 39) [94]. The reaction was successfully extended to 5-chloro- and 5-nitroisatins. According to the proposed mechanism, an acid-catalyzed reaction of phenylhydrazine with nitrile 117 affords the 5-amino-3-methyl-l-phenyl pyrazole 111 that adds to the carbonyl carbon of isatin giving rise to an intermediate product 120. The acid-catalyzed reaction of this intermediate (that has been isolated) with carbonyl compounds 118 affords another intermediate compound 121, which eventually furnishes the final products 119 by cyclodehydration forming tetrahydropyridine ring followed by subsequent dehydration (Scheme 40). 

SCHEME 40 Mechanism of formation of dihydropyridine spiro-fused 2-oxindoles. 

In another early application to natural product synthesis, Fleming and coworkers utilized this approach in the efficient formation of the gelsemine model (47) from 45 according to Scheme 8. The cyclization step to form the spiro-oxindole (46) proceeded in 85% yield and provided a means of generating the spiro-fused quaternary carbon without the need for carbenium ion or carbanion chemistry. 

In 2008, Ruck et al. developed a novel and efficient synthetic route to spiro-fused indance-oxindoles 9 by a palladium-catalyzed tandem Heck/C—H functionalization reaction [8] (Schone 6.2). Oxidative addition of the aryl bromide 8 to the palladium complex is followed by the intramolecular Heck insertion process through 5-exo-trig cycUzation to afford primary alkylpaUadium species 11. Reaction at the highlighted C—H bond provides six-monbered paUadacycle 12, and subsequent reductive elimination generates spiro-fused iudauce-oxindoles 9. 

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). ... 

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

K. Jiang, Z.-J. Jia, X. Yin, L. Wu, Y.-C. Chen, Org. Lett. 2010, 12, 2766-2769. Asymmetric quadruple aminocatalytic domino reactions to fused carbocycles incorporating a spiro-oxindole motif. 

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