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.

Figure 1

Synthetic strategies towards C−H functionalization of piperidines at C2, C3 and C4. C2−H: electronically activated but sterically hindered; C3−H: electronically deactivated through inductive effect of NPg, indirect approach through regio‐ and stereoselective cyclopropane ring opening; C4−H: accessible if the electronic preference for C2 can be overridden by steric shielding of catalyst and NPg.

Scheme 1

Catalyst structures.

Scheme 2

Substrate scope of C2 functionalization. The N‐Boc‐piperidine (1 a) functionalization was catalyzed by Rh₂(R‐TCPTAD)₄ to form 5 b–e and N‐Bs‐piperidine (1 b) functionalization was catalyzed by Rh₂(R‐TPPTTL)₄ to form 6 b–e. [a] Boc group was removed through trifluoroacetic acid treatment before analysis. [b] reaction conducted in refluxing CH₂Cl₂ (39 °C).

Scheme 3

C4‐Analog from N‐Boc‐dihydropyridine.

Scheme 4

Substrate scope of C4 functionalization.