Development of a [3+3] cycloaddition strategy toward functionalized piperidines.
This paper describes a novel route to functionalized piperidines via a formal [3+3] cycloaddition reaction of activated aziridines and palladium-trimethylenemethane (Pd-TMM) complexes. The cycloaddition reaction generally proceeds enantiospecifically with ring opening at the least hindered site of the aziridine. Therefore, readily available enantiomerically pure 2-substituted aziridines can be utilized to prepare enantiomerically pure 2-substituted piperidines in good to excellent yield. The N-substituent on the aziridine proved to be crucial to the success of this reaction with only 4-toluenesulfonyl (Ts) and 4-methoxybenzenesulfonyl (PMBS) aziridines permitting smooth cycloaddition to take place. Additionally, spirocyclic aziridines have been found to participate in the [3+3] cycloaddition reaction, whereas 2,3-disubstituted aziridines can be applied to provide fused bicyclic piperidines, albeit in low yield.
Hedley
Simon J
SJ
Department of Chemistry, University of Sheffield, United Kingdom.
Moran
Wesley J
WJ
Price
David A
DA
Harrity
Joseph P A
JP
D001388:Aziridines / Q000737:chemistry; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D007202:Indicators and Reagents; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D010880:Piperidines / Q000032:analysis / Q000138:chemical synthesis*
D001388:Aziridines; D007202:Indicators and Reagents; D010880:Piperidines; D010165:Palladium