Regio- and Stereoselective Synthesis of Spiropyrrolizidines and Piperazines through Azomethine Ylide Cycloaddition Reaction

• Published in: Journal of organic chemistry 2015-09, Vol.80 (18), p.9064-9075
• Main Authors: Haddad, Saoussen, Boudriga, Sarra, Porzio, François, Soldera, Armand, Askri, Moheddine, Knorr, Michael, Rousselin, Yoann, Kubicki, Marek M, Golz, Christopher, Strohmann, Carsten
• Format: Article
• Language: English
• Subjects: Azo Compounds - chemical synthesis; Azo Compounds - chemistry; Chemical Sciences; Cyclization; Cycloaddition Reaction; Isatin - chemical synthesis; Isatin - chemistry; Kinetics; Piperazines - chemical synthesis; Piperazines - chemistry; Pyrrolizidine Alkaloids; Quantum Theory; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Stereoisomerism; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; X-Ray Diffraction
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.5b01399

A series of original spiropyrrolizidine derivatives has been prepared by a one-pot three-component [3 + 2] cycloaddition reaction of (E)-3-arylidene-1-phenyl-pyrrolidine-2,5-diones, l-proline, and the cyclic ketones 1H-indole-2,3-dione (isatin), indenoquinoxaline-11-one and acenaphthenequinone. We disclose an unprecedented isomerization of some spiroadducts leading to a new family of spirooxindolepyrrolizidines. Furthermore, these cycloadducts underwent retro-1,3-dipolar cycloaddition yielding unexpected regioisomers. Upon treatment of the dipolarophiles with in situ generated azomethine ylides from l-proline or acenaphthenequinone, formation of spiroadducts and unusual polycyclic fused piperazines through a stepwise [3 + 3] cycloaddition pathway is observed. The stereochemistry of these N-heterocycles has been confirmed by several X-ray diffraction studies. Some of these compounds exhibit extensive hydrogen bonding in the crystalline state. To enlighten the observed regio- and stereoselectivity of the [3 + 2] cycloaddition, calculations using the DFT approach at the B3LYP/6-31G­(d,p) level were carried out. It was found that this reaction is under kinetic control.