Synthesis of Spirooxindoles

Wang and coworkers reported the highly enantioselective domino reaction between isatin derivatives 54c and a-isothiocyanato imides 102 catalyzed by a 

Gong and coworkers reported the 1,3-dipolar cycloaddition between the in situ formed azomethine precursors and electron-deficient olefins [60]. The reaction 

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Recently, Curran described a procedure using triethylborane for the synthesis of spirooxindoles and spirodihydroquinolones through intramolecular addition of aryl radicals at the ipso position 4-alkoxy-substituted aromatic rings [15]. The key step for a formal synthesis of the vasopressin inhibitor SR121463A is described in Scheme 5. The initiation was performed with Et3B in an open to air reaction vessel. 

Scheme 36 Three-component synthesis of spirooxindole-containing tetrahydrochromene derivatives...

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

Zhu SL, Ji SJ, Zhang Y (2007) A simple and clean procedure for three-component synthesis of spirooxindoles in aqueous medium. Tetrahedron 63 9365-9372... 

Nair et al. (87,88) achieved a synthesis of spirooxindole-containing molecules by adding isatins to various carbonyl ylides (Scheme 4.46). There has been relatively little research regarding the efficiency of C=0 of 1,2-dicarbonyl compounds as dipolarophiles relative to their olefinic counterparts. As anticipated, Nair found that the more electrophilic carbonyl of the isatin 187 (non-amide carbonyl) reacted smoothly with the carbonyl ylide formed from diazoketone 186 to give the spirocyclic adduct 188. Nair s yields were moderate to good (44—83%), but were based on recovered isatin. 

Scheme 35 Samarium iodide-promoted synthesis of spirooxindoles related to welwitin-dolinone A...

The spirooxindole system is the core unit of many natural products such as spirotryprostatin A, isopeteropodine, etc. Perumal and co-workers have developed a fast, clean and simple method for the synthesis of spirooxindoles and spiroindenoquinoxaline derivatives catalyzed by silica gel impregnated indium(in) chloride under solvent-free microwave irradiation (Scheme 5.36). 

Likewise, the intramolecular oxidative coupling of substituted 4-hydroxyphenyl-A(-phenylbenzamides 72 has been realized in a catalytic manner by using iodobenzene as catalyst and mCPBA or urea-H202 as terminal oxidant (Scheme 4.37). This reaction constitutes an efficient method for the synthesis of spirooxindoles 73 [69],... 

Abehnan, M.M., Oh, T. and Overman, L.E. (1987) Intramolecular alkene arylations for rapid assembly of polycyclic systems containing quaternary centers. A new synthesis of spirooxindoles and other fused and bridged ring systems. J. Org. Chem., 52, 4130-3. 

The same research group developed a similar cascade leading to the synthesis of spirooxindoles bearing four stereogenic centers. The starting material this time was a-methylene oxindoles (90) instead of 2-cyanoacrylate derivative. The reaction renders the spirooxindole derivatives 110 in excellent yields and enantioselectivities [59]. In 2011, Rios and co-workers [70] expanded the scope of the reaction using a-methylene pyrazolones 111, leading to spiropyrazolones 112 with excellent results (Scheme 10.29). 

Scheme 13 Takemoto s synthesis of spirooxindoles and order of reactivity experiments...

Tsukano C, Okuno M, Takemoto Y (2013) Synthesis of spirooxindoles from carbamoyl chlorides via cyclopropyl methine C(sp )-H activation using palladium catalyst. Chem Lett 42(7) 753-755... 

Ort/io-selectivity is generally observed in the reactions of 2,4-dichloro- and 2,4-difluoro-nitrobenzene with alkoxide and thiophenoxide ions [199]. Also in less activated systems, nucleophiles generated from phenols and thiophenols with potassium fluoride-alumina and 18-crown-6-polyether will react in DMSO with cyano- or nitro-substituted fluoro- or chloro-benzenes [200]. Interestingly, the reaction of difluorobenzenes with two diffoent alcohols can occur sequentially. Introduction of the first etho" function deactivates the ring, and use of more forcing conditions allows substitution of the second fluorine [201]. Consecutive displacements of fluorine and nitro groups have been observed in the reaction of ort/io-fluoronitrobenzene with chiral acyl bicyclic lactones in a highly enantioselective synthesis of spirooxindoles [202]. 

F. Macaev, N. Sucman, F. Shepeli, M. Zveaghintseva, V. Pogrebnoi, Symmetry 2011, 3, 165-170. Facile and convenient one-pot process for the synthesis of spirooxindole derivatives in high optical purity using (-)-(5)-brevicolline as an organocatalyst. 

SCHEME 6.32 MCR strategy used in the synthesis of spirooxindole pyrans... 

SCHEME 633 CAN-catalyzed synthesis of spirooxindole derivatives 235 via three-component reaction in aqueous media. 

P. H. Yang, C. T. Qu, W. Z. Wang, Res. Chem. Intermed. 2013, 39, 463 68. AcOH catalyzed three-component synthesis of spirooxindole derivatives. 

Zhao LQ, Zhou B, Li YQ (2011) An efficient one-pot three-component reaction for synthesis of spirooxindole derivatives in water media under catalyst-free condition. Heteroat Chem... 

Microwave-Assisted Synthesis of Spirooxindoles via Three-Component Reaction. 76... 

Silica-bonded A -propyl sulfamic acid (SBNPSA) is employed as a solid acid catalyst for the synthesis of spirooxindoles via three-component reaction in good yields and short reaction times in ethanol under irradiation MW conditions. Irradiation of the combination of isatin or acenaphthoquinone, an activated metltylene reagent, and 1,3-dicaiboityl compounds in the presence of catalytic SBNPSA was found to be a suitable and efficient method for the synthesis of the biologically important spirooxindoles (Schemes 3.4 and 3.5) [48]. 

Scheme 3.4 Synthesis of spirooxindoles (4a-g) via three-component reaction with isatin (2) in the presence of silica-bonded Af-propyl sulfamic acid (SBNPSA) as catalyst under irradiation microwave conditions...

Gharib A, Jahangir M, Roshani M, Scheeren JHW (2014) Silica-bonded N-Propyl sulfamic acid a recyclable catalyst for microwave-assisted synthesis of spirooxindoles via three-component reaction. Bulg Chem Commun (In press)... 

Dandia et al. [68] described a novel and highly efficient protocol for the synthesis of structurally complex and diverse spirooxindole derivatives catalyzed effectively by ZnS NPs in aqneons medinm (Scheme 5.23). ZnS NPs were well characterized by TEM and XRD techniqnes. Greenness of the process was well instituted as water was exploited both as a reaction medium as well as a medium for synthesis of catalyst (ZnS NPs). The particle size was determined by TEM and XRD. Compared with other methods for synthesis of spirooxindole derivatives, satisfactoiy resnlts were obtained with high yields, short reaction time, with simple experimental pro-cednre. After reaction conrse, the ZnS NPs can be recycled and rensed withont aiy apparent loss of activity. 

Scheme 21 FeCls-catalyzed synthesis of spirooxindole tetrahydroquinoUnes...

Shintani, R., Hayashi, S.-Y., Murakami, M., Takeda, M., Hayashi, T. (2009). Stereoselective synthesis of spirooxindoles by palladium-catalyzed decarboxylative cyclization of Y-methylidene-5-valerolactones with isatins. Organic Letters, 11, 3754-3756. 

This chapter is not intended to provide comprehensive details, but rather to summarize the organocatalytic multiple-bond forming reactions from the last 10 years in the context of their utility in the synthesis of spirocycles with emphasis on the different strategies. The chapter will be structured according to the nature of the spiroatom synthesized and the nature of the spirocycle formed. First, we will discuss the synthesis of all-carbon spirocenters, focusing on the synthesis of spirooxindoles and other heterocycles. Next, we will focus on the synthesis of spirocenters with at least one heteroatom. 

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