Spirooxindole pyrans

In a separate investigation by Porco, Jr. and coworkers, the isatin derivative 134 (R = H) was converted to spirooxindole pyran 141 in 13 1 dr and 99% ee by means of a Prins-type cyclization involving homoaUyhc alcohol 140 [79]. The diastereos-electivity of the transformation has been proposed to arise from a preferred chairlike transition state with the benzenoid ring of oxindole in a pseudoequatorial orientation. Spirooxindole oxepenes also were prepared via diastereoselective spiro-annulation of isatins with bis-homoallyhc alcohols. 

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

Xie, X., Peng, C., He, G., Leng, H.-J., Wang, B., Huang, W., Han, B. (2012). Asymmetric synthesis of a structurally and stereochemicaUy complex spirooxindole pyran scaffold through an organocatalytic multicomponent cascade reaction. Chemical Communications, 48, 10487-10489. 

Two independent reports have appeared that detail methodology for the introduction of pyran or oxepene spirocychc moieties onto oxindole scaffolds by means of a Prins cyclization (Scheme 35). In one study by Zhang and Panek, treatment of isatin dimethylketal 134 with sUyl alcohol (S )-135 afforded predominately c -137 or trans-Vi9 depending on reaction time and solvent polarity [78]. A mechanism involving epimerization of the cis-product to the trans adduct was put forward to explain the observed frans-selectivity with increased reaction time in polar solvents. A cyclic transition state involving a (Z)-oxonium intermediate formed via condensation of silyl alcohol 135 with isatin 134 was invoked to rationalize the preferential formation of the cis-spirocycle under kinetic control. Further optimization led to the formation of spirooxindoles 138, e.g., R, = Me, as single... 

The iron-catalyzed synthesis of dihydro-2H-pyrans, 2H- and 4H-chromenes, chromones, isocoumarins and xanthenes were described in a broad review on the synthesis of heterocycles (14T4827), while the synthesis of 2H-pyran and chroman derivatives, coumarins and xanthone-type compounds was described in a review of recent progress on the chemistry of dimethyl acetylenedicarboxylate (14S537). The synthesis of several polysubstituted spirooxidole-2-amino-4H-pyrans, mainly through three-component reactions, was also described in a review on the synthesis of biologically active spirooxindoles (14T9735). 

A metal-firee oxidative spirocyclization of hydroxy methylacrylamide with 1,3-dicarbonyl compounds provides a range of spirooxindole 3,4-dihydro-2H-pyrans, in moderate to good yields. This strategy involves the formation of two C-C bonds and one C-O bond in one step (Scheme 7) (130L5254). 

Indole-fused pyran-4-ones are prepared in one-pot two-step synthesis. In the first there is the acylation of 1-substituted 3-acetyl-lH-indol-2-ols with acid chlorides using triethylamine as base, in dichloromethane at room temperature. The second consists in the 4ff-pyran-4-one ring formation firom the in situ-obtained 3-acetyl-2-acyloxy-lF/-indole derivatives (13S1235).A highly diastereo- and enantioselective organocatalytic formal hDA reaction of enones with isatins occurs in the presence of amine 34, acid 35, and thiourea 36 to produce spirooxindole tetrahydro-4ff-pyran-4-ones (Scheme 59) (13CEJ6213). 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

On replacing 2-hydroxynaphthalene-l,4-dione (21) by 4-hydroxy-6-methyl-2H-pyran-2-one (11), Bazgir and his group obtained another series of spiro[indole-3,4 -pyrano[4,3-li]pyran]-3 -carbonitriles (23) under the same reaction conditions they even synthesized these scaffolds using magnetically recoverable and reusable CuFe204 nanoparticles as well in aqueous media (Scheme 12) [112,113], Besides, sodium stearate was also efficiently used in S5mthesiz-ing this spirooxindole scaffold in aqueous micellar media [114],... 

P. Saluja, K. Aggarwal, J.M. Khurana, One-pot synthesis of biologically important spiro-2-amino-4H-pyrans, spiroacenaphthylenes, and spirooxindoles using DBU as a green and recyclable catalyst in aqueous medium, Synth. Commun. 43 (2013) 3239-3246. 

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