Pyrrolidines spiro

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

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). 

Several pyrrole-ring syntheses have been developed that utilize an intramolecular Heck reaction, but, since these transformations involve C-N bond formation, they are covered in Section 2.7. Grigg has employed the intramolecular Heck reaction to craft a series of spiro-pyrrolidines (147)... 

Other spiro pyrrolidine derivatives can be prepared from 2-oxoindolin-3-ylidine derivatives. Even the nitro derivative which is known to be extremely sensitive to base and heat, has been obtained in good yield.421,422 The spiro-indolenine framework is frequently encountered in alkaloids such as horsfilline.423... 

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... 

Applications of MCR-Derived Heterocycles in Drug Discovery Table 16 Antimycobacterial activities of spiro pyrrolidines... 

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>. 

The anion derived from furobenzopyrandione 28 reacts with Michael acceptors regiospecifically to yield xanthones and various annulated derivatives <03OL3753> and intramolecular trapping of the anion by a carbamate side-chain leads to spiro- pyrrolidine and piperidine 9-xanthene derivatives <03TL9291>. 

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. 

The spiro-pyrrolidine 180 and piperidine 181 containing the dioxinopyridine heterocyclic system were synthesized from 2-chloro-3-pyridinol via Smiles rearrangement. ... 

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. 

Santia reported a microwave-promoted, chemodiveigent four-component reaction that afforded either spiro pyrrolidines 13 or 2,5-diketopiperazines 14 from the reaction of ethyl hydrogen fumarate, aldeltydes, benzylamine derivatives and isonitriles. The product selectivity of this reaction depends mainly on the substituent on the amine component, since it affords compounds 13 for the case X=OH and 14 for X=OMe [10], Its mechanism involves an initial Ugi four-component reaction that gives intermediate 15, which undergoes either an intramolecular Michael reaction to give 13 (pathway a) or, for less reactive aromatic rings, an intramolecular aza-Michael reaction that affords 14 (pathway b Scheme 1.6). 

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... 

Cl3H13N3O3, Methyl 1,2,3,4-tetrahydro-1-methyl-2-oxo-pyrimido[1,2-a]benzimidazol-4-carboxylate, 4OB, 249 Cl3H14N4OS, 6,6-Dimethyl-3-methylthio-6,7-dihydro-as-triazino[1,6-c]quinazolin-5-ium-1-olate, 4IB, 343 Cl3H15NO2, trans-1 -Hydroxy-spiro[pyrrolidine-2,2 -tetralin]-5-one, 45B, 311... 

Spiropentane ring 27, 873 Spiro [pyrrolidin-3,1 - (pyrroli-dino[3,4-c]pyrrolidines)], 2,4, 5,6 -tetraoxo-... 

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. 

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. 

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