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.

Non-Directed β- or γ-C(sp3)–H Functionalization of Saturated Nitrogen-Containing Heterocycles

“…In 2020, Davies reported the site-and stereoselective γ-C(sp 3 )-H functionalization of piperidines catalyzed by rhodium complex (Scheme 32). 42 This reaction yields the γ-functionalized product 137a from piperidine 135a and aryldiazoacetate 136. They managed to alter the selectivity from the αposition to the γ-position by use of the catalyst A, favoring the electronically deactivate sites, 43 and the substituent which deactivated the α-position to the nitrogen by electron-withdrawing properties.…”

Antimicrobial action of arylsulfonamides bearing (aza)norbornane and related motifs: evaluation of new promising anti-MRSA agents

“…NaOH in Et 2 O (Scheme 1, A). In addition, derivatives of non-cage-like morpholine and piperidine (compounds VP-4604 [50,51] and VP-4605 [50] respectively) were obtained for comparison and control. The target azanorbornane acid VP-4563 was synthesized based on hetero-Diels-Alder cycloaddition followed by hydrolysis of the ester 2 (Scheme 1, B).…”

Enantioselective Synthesis of N-Alkylamines through β-Amino C–H Functionalization Promoted by Cooperative Actions of B(C6F5)3 and a Chiral Lewis Acid Co-Catalyst

“…Enantioselective synthesis of N -alkylamines through the transformations of amino C­(sp 3 )–H bonds has emerged as a powerful strategy to access key building blocks of N-based natural products, drugs and catalysts for stereoselective synthesis. − A plethora of organometallic catalysts have been introduced that can promote reaction at an α-amino C–H bond by conversion of an amine substrate to appropriately reactive intermediate (e.g., α-amino radical, iminium ion), − metal–carbenoid insertion, , or heteroatom-directed metalation. − More remote γ-amino C–H bonds may be activated by L n Pd-catalyzed and N-directed cyclometalation. − However, development of methods for synthesis of enantiomerically enriched amines by β-amino C–H functionalization is a major challenge that remains to be addressed. − α-Amino C–H activation by hydrogen atom or hydride transfer is facilitated by stabilization of the resulting species through hyperconjugation with the nitrogen lone pair. Nonetheless, such processes do not readily occur at the β position of amines.…”

“…Enantioselective synthesis of N-alkylamines through the transformations of amino C(sp 3 )−H bonds has emerged as a powerful strategy to access key building blocks of N-based natural products, drugs and catalysts for stereoselective synthesis. 1−18 A plethora of organometallic catalysts have been introduced that can promote reaction at an α-amino C− H bond by conversion of an amine substrate to appropriately reactive intermediate (e.g., α-amino radical, iminium ion), 19−31 metal−carbenoid insertion, 32,33 or heteroatom-directed metalation. 34−36 More remote γ-amino C−H bonds may be activated by L n Pd-catalyzed and N-directed cyclometalation.…”