Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation

Abstract

Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general synthetic access remains out of reach. Herein, we describe a simple and robust cis -selective hydrogenation of abundant and cheap fluoropyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoropyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated derivatives of important drug compounds are prepared, and a straightforward strategy for the synthesis of enantioenriched fluorinated piperidines is disclosed.

Fluorinated Rings: Conformation and Application

“…[77] Similar interactions are revealed to tip the conformational balance towards the axial preference in the trifluoroacetyl (TFA)-protected fluoropiperidine 55 and 56, and presumably for 3-fluoro-2-phenylpiperidine 57. [80] In addition to electrostatic and hyperconjugative interactions, steric forces are found to contribute to the stabilization of the equatorial conformations of 58 and 59. The same forces are also found to stabilize the axial conformation of 60 in both gas phase and chloroform.…”

Recent developments in enantio- and diastereoselective hydrogenation of N-heteroaromatic compounds

“…Very recently, Glorius et al reported a simple, cis -selective hydrogenation of multi-substituted fluorinated pyridine derivatives using a heterogeneous Pd catalyst (Scheme 60). 153 Initially, the hydrogenation of 3-fluoropyridine was studied using various heterogeneous catalysts in a variety of organic solvents. In these conditions, the catalyst was not found to be active enough.…”

Haptophilicity and Substrate-Directed Reactivity in Diastereoselective Heterogeneous Hydrogenation

“…The low reactivity of arenes necessitates high catalyst loading, hydrogen pressure, and temperature in order to achieve reasonable reactivity, and very few molecular catalysts are stable under these conditions. − As a result, heterogeneous noble metal catalysts remain the dominant catalysts in arene hydrogenation. ,− Significant work on diastereoselective arene hydrogenation has focused on the cis–trans selectivity of hydrogen addition to achiral aromatic substrates. Heterogeneous catalysts favor hydrogenation of simple arenes in an all- cis configuration because the substrate does not readily desorb from the catalyst surface during the reaction. − However, arenes with relatively weaker surface interactions can proceed through mechanisms that include an intermediate desorption and readsorption step; in which case, the binding properties of the partially hydrogenated intermediate dictate the trans selectivity. − For more complex aromatic substrates that contain a chiral center from the outset, diastereoinduction relative to the existing stereocenter arises from steric differentiation of the two molecular faces. − …”