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

Abstract

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 Rh₂ (R-TCPTAD)₄ , or N-brosyl-piperidine using Rh₂ (R-TPPTTL)₄ generated 2-substitited analogues. In contrast, when N-α-oxoarylacetyl-piperidines were used in combination with Rh₂ (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.

Keywords: C−H functionalization; diastereoselectivity; piperidines; regioselectivity; rhodium.