Functionalization of Piperidine Derivatives for the Site‐Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate

Rhodium‐catalyzed C−H insertions and cyclopropanations of donor/acceptor carbenes have been used for the synthesis of positional analogues of methylphenidate. The site selectivity is controlled by the catalyst and the amine protecting group. C−H functionalization of N‐Boc‐piperidine using Rh(2)(R‐TCPTAD)(4), or N‐brosyl‐piperidine using Rh(2)(R‐TPPTTL)(4) generated 2‐substitited analogues. In contrast, when N‐α‐oxoarylacetyl‐piperidines were used in combination with Rh(2)(S‐2‐Cl‐5‐BrTPCP)(4), the C−H functionalization produced 4‐susbstiuted analogues. Finally, the 3‐substituted analogues were prepared indirectly by cyclopropanation of N‐Boc‐tetrahydropyridine followed by reductive regio‐ and stereoselective ring‐opening of the cyclopropanes.