Spiro-pyrrolidine-oxindoles

A spiro[pyrrolidine-2,3 -oxindole] library <1998TL2235> has been synthesized via a three-component 1,3-dipolar cycloaddition in the solution phase. Isatins 432 were treated with L-proline or L-thiaproline and chalcone 433 in a MeOH-H20, CH3CN-H20, or dioxane-H20 solution. Spiropyrrolidines 49 (Scheme 96) were obtained as the sole products in good yield and high purity (Table 15). 

An Example Synthesis of a Spiro[Pyrrolidine-2,3 -Oxindole] Library... 

TABLE 8.1 Spiro [pyrrolidine-2,3-oxindole] Discrete Library L5 Chemistry Assessment and Monomer Rehearsai... 

A fhree-component reaction of isatin 58, a-amino acids 59, and dipolarophiles 60 in aqueous alcoholic environ-menf forming spiro-pyrrolidine-oxindoles 61 (Scheme 19) is reporfed by Rehn and coworkers [54]. Bofh N-unsubsti-fufed and N-substituted a-amino acids have been employed in the study. 

SCHEME 19 A three-component reaction of isatin, a-amino acids, and dipolarophiles in aqueous alcoholic environment forming spiro-pyrrolidine-oxindoles. 

There are several examples in literature on cycloaddition of alkenes to azomethine ylides, generated in situ by decarboxylative condensation of isatins with an a-amino acid, sarcosine (MeNHCH2C02H), for architecture of pyrrolidine ring in spiro-pyrrolidine-oxindoles [55]. The cycloaddition of ylide 62 from N-methylisatin 58 and sarcosine to 3,4-diphenylcyclobutene-l,2-dione 63 proceeded smoothly to afford the product 64 (Scheme 20) [56]. 

The isolation and synthesis of indole alkaloids containing a non-rearranged monoterpenoid unit have been reviewed <03NPR216>, as has the synthesis of spiro[pyrrolidine-3,3 -oxindoles] as building blocks for oxindole alkaloids <03EJ02209>. 

Spiro[pyrrolidine-3,3,-oxindoles] construction in the synthesis of oxindole alkaloids 03EJ02209. 

Alper, RB., Meyers, C., Lerchner, A., Siegel, D.R., and Carreira, E.M., Eacile, novel methodology for the synthesis of spiro[pyrrolidin-3,3 -oxindoles] catalyzed ring expansion reactions of cyclopropanes by aldimines, Angewandte Chemie-Intemational Edition 38 (21), 3186, 1999. 

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]... 

F. Shi, S. Tu, Z. Tao, S. Luo, L. Gong, Chem. Eur. J. 2012, 18, 6885-6894. Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2 -oxindoles] with stiuctural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions. 

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... 

An asymmetric one-pot sequential Mannich/hydroamination sequence involves a three-catalyst system a chiral organocatalyst, BF3 and a gold complex. It converts an indole-imine into privileged spiro[pyrrolidin-3,2 -oxindole] structures in up to 91/97% yield/ee. 

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... 

Spiro compounds. For example, Gong and coworkers combined 17 and in situ generated azomethine ylides derived from the condensation of aminomalonate 33 and aldehydes 15 to afford spiro[pyrrolidin-3,3 -oxindoles] 34 in good yields and excellent stereoselectivities when the binaphthol phosphoric acid derivative IV was used as catalyst (Scheme 10.8) [16]. 

Chen, X.-H., Wei, Q., Luo, S.-W., Xiao, H., Gong, L.-Z. (2009). Organocatalytic synthesis of spiro[pyrrolidin-3,3 -oxindoles] with high enantiopurity and structural diversity. 

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... 

The imidazoline-aminophenol-ligand complex (34) has been developed for the 3 + 2-cycloaddition reaction of methyleneindolinones (32) with iminoesters (33) to produce exo-spiro[pyrrolidin-3,3 -oxindole]s (35) as stable isomers. The reaction proceeds in a stepwise Michael-Mannich reaction sequence (Scheme 12). ... 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

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. 

SCHEME 16.21. Synthesis of spiro(oxindole-3,3 -pyrrolidines) using an asymmetric 1,3-dipolar cycloaddition. 2005 American Chemical Society. All rights reserved. 

---