Synthesis of 7′-Arylidenespiro[indoline-3,1′-pyrrolizines] and 7′-Arylidenespiro[indene-2,1′-pyrrolizines] via [3 + 2] Cycloaddition and β-C–H Functionalized Pyrrolidine

Abstract

The acetic acid catalyzed three-component reaction of pyrrolidine, aromatic aldehydes, and 3-arylideneoxindolin-2-ones in refluxing toluene afforded functionalized 7′arylidenespiro[indoline-3,1′-pyrrolizines] in good yields and with high diastereoselectivity. The similar three-component reaction with 2-arylidene-1,3-indanediones also gave 7′arylidenespiro[indene-2,1′-pyrrolizines] in good yields. However, the reaction with 3-phenacylideneoxindoles resulted in a mixture of spiro[indoline-3,1′-pyrrolizines] and 7′-arylidenesubstituted spirooxindoles in moderate yields. The reaction mechanism included generation of azomethine ylides, β-C−H functionalization of pyrrolidine, and sequential [3 + 2] cycloaddition. The obtained spirooxindole derivatives were investigated by in vitro evaluation against mouse colon cancer cells CT26 and human liver cancer cells HepG2 by MTT assay.

Domino β‐C−H Functionalization and [3+2] Cycloaddition for Efficient Synthesis of Diverse Spiro and Polycyclic Compounds

“…According to the previously established reaction conditions for the 7′‐arylidenespiro[indoline‐3,1′‐pyrrolizines], [12g] a mixture of pyrrolidine, benzaldehyde, and 4‐benzylidene‐5‐methyl‐2‐phenylpyrazol‐3‐one was refluxed in toluene in the presence of acetic acid for about sixteen hours. TLC monitoring showed that the reaction resulted in a major product with several byproducts in very low yields.…”

“…Very recently, we also reported the domino generation of conjugated azomethine ylides between pyrrolidine and aromatic aldehydes and [3+2] cycloaddition reaction with 3‐arylideneoxindoline‐2‐ones or 2‐arylidene‐1,3‐indanediones for convenient synthesis of novel functionalized spiropyrrolidine derivatives [12g] . In order to further develop the synthetic values of the conjugated azomethine ylides and with our continuous object on developing efficient synthetic methods for heterocyclic spiro compounds, [13] herein we wish to report the three‐component reactions of pyrrolidine, aromatic aldehydes and various cyclic dipolarophiles such as 4‐arylidene‐5‐methyl‐2‐phenylpyrazol‐3‐ones, 2‐arylidene‐ N,N’ ‐dimethylbarbiturates and N ‐phenylmaleimide for the synthesis of diverse spiropyrrolidine and pyrrolo[3,4‐ a ]pyrrolizine derivatives.…”

Spiro‐2‐oxindoles via 1,3‐dipolar cycloadditions. A decade update

“…The reaction mechanism included β‐C−H functionalization of pyrrolidine, generation of the azomethine ylide intermediate and subsequent 1,3‐dipolar cycloaddition (Scheme 5). [44] The resulting spirooxindole derivatives were investigated by evaluation against mouse colon cancer cells CT26 and human liver cancer cells HepG2 by MTT assay.…”

Condensation-Based Methods for the C–H Bond Functionalization of Amines

“…In 2019-2020, Yan and co-workers reported transformations resembling reactions shown in Scheme 76, with the modification that N-methylmaleimide is replaced by other electron-deficient alkenes. 133,134 Several other research groups have reported condensation-based reactions involving the -C-H bond functionalization of cyclic amines. Wu, Wu, and co-workers reported a process in which a mixture of pyrrolidine, an -ketoaldehyde, and an acrylate undergo a reaction that leads to simultaneous -and -C-H bond functionalization of the amine to furnish bicyclic 2,3-dihydro-1H-pyrrolizines 166 (Scheme 78).…”