Spiro-oxindole derivatives

R = H, Me, Ph, 4-CF3-C6H4, 3-CN-C6H4, 4-MeO-CgH4, 2-Br-CeH4, 2-thienyl Scheme 8.27 Synthesis of spiro-oxindole derivatives. 

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. " ... 

Dandia, A., Jain, A. K., and Laxkar, A. K. (2013). Ethyl lactate lactate as a promising bio based green solvent for the synthesis of spiro-oxindole derivatives via 1,3 dipolar cycloaddtion reaction. Tetrahedron Lett., 54, 3929-3932. 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

Beckwith and Storey have developed a tandem translocation and homolytic aromatic substitution sequence en route to spiro-oxindoles [95CC977]. Treatment of the bromoaniline derivative 122 with tin hydride at 160 °C generated the aryl radical 123 which underwent a 1,5-hydrogen atom transfer to give intermediate 124. Intramolecular homolytic aromatic substitution and aromatization gave the spiro-oxindole 125. Intramolecular aryl radical cyclization on to a pyrrole nucleus has been used to prepare spirocyclic heterocycles [95TL6743]. 

The key step remaining involved the conversion of the ketone functionality in 260 to a spiro-oxindole. The conversion of a sterically hindered ketone to an oxindole by applying most of the conventional methods for the creation of a quaternary center at the spiro position was not an easy process. A process involving C—C bond formation by combination of two radical centers generated by photolysis of the alkoxy-substituted-1-alkenylbenzotriazole was then investigated (Scheme 35). By applying Wender s procedure (102), the benzotriazole derivative 261 was converted to 262 by metallation-silylation, and then the trimethylsilyl derivative was... 

The Yao group disclosed an NHC-catalyzed oxidative y-addition of a,p-unsaturated aldehydes to isatins, providing a facile access to a highly efficient synthesis of spiro oxindole-dihydropyranones. " An efficient construction of the spiro oxindole-dihydropyranone scaffold via the NHC-catalyzed oxidative y-functionalization of a,p-unsaturated aldehydes bearing y-H with isatin derivatives was achieved. Preliminary study on the asymmetric version of this methodology was also carried out. However, only moderate enantiose-lectivity was realized (up to 33% ee) (Scheme 7.117). 

Scheme 3.81 1,3-Dipolar cycloaddition reactions for synthesis of spiro[pytrolidin-3,3 -oxindole] derivatives...

The proposed mechanism (Scheme 11) of the asymmetric epoxidation of a-ylideneoxindoles (97) by TBHP to cis- and frani-spiro[oxirane-oxindole] derivatives (101 and 102) had TBHP react with the catalyst (5)-a,a-diphenylprolinol (95) in the initial step forming a tight ion pair (96), which attacks the Cp carbon of the substfate (97) to give a transitory intermediary complex (98) as precursor of a long-living intermediate (99) from which (101) and (102) are derived. " 0... 

An efficient, one pot, atom-economic and simple method for the synthesis of Spiro dihydrofuran oxindole derivatives was realized using InBr3 as catalyst and EtsN as base (13TL6991). 

In the same context, azomethine ylides derived from imino esters were reacted by Arai and Awata with methyleneindolinones in the presence of an in situ generated chiral nickel catalyst derived from their original chiral imid-azoline-aminophenol ligand 11. Remarkably, the process afforded the corresponding chiral spiro[pyrrolidine-3,3 -oxindoles] in excellent yields and exo selectivities, as well as enantioselectivities in almost all cases of substrates studied, as summarised in Scheme 1.11. Since the spiro-oxindole skeleton is... 

Basavaiah developed a convenient, one-pot stereoselective synthesis of spiro-oxindoles via TiCU catalyzed coupling of 2-acetyl-6-methyl-2,3-dihydro-4H-pyran with various isatin derivatives [328]. The reaction involves a tandem construction of C-C and C-0 bonds and its catalytic asymmetric version remained to be developed (Scheme 14.145). 

XPhos and the complex of (Tf2N)Au and XPhos (186), has been reported to produce the spiro[pyrrolidin-3,2 -oxindole] derivatives (184) in <97% ee and with >20 1 exolendo selectivity from their precursors (182) and (183) (Scheme 12). ... 

XPhos = 2-(dicyclohe3g lphosphino)-2, 4, 6 -triisopropylbiphenyl), to promote the following hydroamination reaction. As shown in Scheme 7.65, the corresponding chiral spiro[pyrrolidin-3,2 -oxindole]derivatives were obtained in good yields and good to excellent enantioselectivities of up to... 

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. 

V. Nair, K.C. Sheela, N.R Rath, Dipolar cycloaddition reactions of isatin derived azomethine yKde with 3,4-diphenylcyclobutene-l,2-dione synthesis of novel spiro[oxindole-3,2-pyrrolidine] derivatives, Chem. Lett. (2000) 980-981. 

The same group also demonstrated an efficient asymmetric construction of spiro[pyrrolidin-3,3 -oxindole] derivatives 55 via a three-component 1,3-dipolar cycloaddition of methyleneindolinones 54 with aldehydes 3 and amino esters 49 in... 

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