Sequential Heterolytic Carbon‐Halide and Carbon–Carbon Bond Activation in Unactivated Piperidines

The thermodynamic stability of unactivated Csp³─F and Csp³─Csp³ bonds remains a major challenge in organic synthesis as methods that achieve effective cleavage and high-yielding functionalization under mild conditions are rare. Herein, we introduce a cascade reaction involving heterolytic activation of 4-halopiperidines with organoaluminum reagents which is followed by fast ring opening toward a thermodynamically favored iminium ion that undergoes C─C bond formation via aryl or alkyl transfer from a concomitantly generated fluoroaluminate counteranion. Fluoropiperidines were found to be more reactive than other halides and are smoothly transformed into tertiary homoallyl amines with good to excellent yields. This reaction occurs at room temperature with high functional group tolerance and without noticeable by-product formation. Similarly, Csp³─F bond scission is observed with 4,4-difluoropiperidines, giving rise to monofluorinated alkene products as the Csp²─F bond generated during this process does not react. X-ray crystallographic analysis of two cationic reaction intermediates simultaneously isolated in a single crystal provides a snapshot of the ring-opening process and together with chemical trapping and control experiments is in agreement with an ionic mechanism and a three-step reaction sequence. By contrast, defluorinative halide exchange leaving the piperidinyl ring intact prevails when 4-fluoro- and 4,4-difluoropiperidines are treated with aluminum trihalide Lewis acids.