The formation of all-cis-(multi)fluorinated piperidines by a dearomatization–hydrogenation process

Abstract

Piperidines and fluorine-substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalyzed dearomatization–hydrogenation (DAH) of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine-substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this DAH process.

Understanding the Conformational Behavior of Fluorinated Piperidines: The Origin of the Axial‐F Preference

“…[2] We recently describedastraightforward process for the preparation of fluorinated piperidines. [9] In this reaction, fluoropyridine precursors underwent ac atalytic dearomatization-hydrogenation sequence to furnish ap lethora of substituted, allcis-(multi)fluorinated piperidinesi nahighly diastereoselective fashion.W ithin the course of this study we became interested in the conformational behavioro ft he newly accessed fluorinated piperidines( 1-12), obtained as the trifluoroacetamide (1A-12A)o rHCls alts (1B-12B). Analysis of the 3 J( 19 F, 1 H) coupling in NMR experimentsa llowed us to determine the relative orientation of the fluorine atom(s), whichw ere often found to adopte ither axial or equatorial orientations exclusively.…”

Selective Arene Hydrogenation for Direct Access to Saturated Carbo‐ and Heterocycles

“…7). [9] The former motif (6)isofinterest in materials science for its high polarity;t he latter (7)c ombines two abundant design elements of medicinal chemistry.T he chemo-and enantioselective hydrogenation of pyridines is the key step within aconcise,multikilogram synthesis (7 steps,38%overall yield) of ap romising therapeutic against Ty pe 2d iabetes (8). [10] However,the implementation of this transformation towards ag iven target must satisfy three important conditions: 1) Reactivity:incontrast to the established hydrogenation of other unsaturated moieties such as alkenes, [11] ketones, [12] and imines/enamines, [13] the hydrogenation of arenes is hindered by the added kinetic barrier resulting from the aromatic stabilization energy.…”

Die selektive Arenhydrierung bietet einen direkten Zugang zu gesättigten Carbo‐ und Heterocyclen

“…[3] Weiterhin ist die Arenhydrierung ein wichtiger Schritt in der Verwertung von Plattformchemikalien aus Biomasse wie Furfural [4] und, zusammen mit der Dehydrierung,z entral beim Betrieb von flüssigen organischen Wasserstoffträgern (LOHCs). [9] Das erstgenannte Motiv (6)ist wegen der hohen Polaritätvon Interesse fürd ie Materialwissenschaft;d as zweite (7)k ombiniert zwei zentrale Motive der medizinischen Chemie.A ußerdem ist die chemo-und enantioselektive Hydrierung von Pyridinen der Schlüsselschritt der effizienten Synthese (7 Stufen, 38 %G esamtausbeute) eines Wikstoffkandidaten gegen Ty p-2-Diabetes (8). [6] Die von der Stoltz-Gruppe entwickelte Synthese von (À)-Jorunnamycin Aund (À)-Jorumycin (5)ist ein beeindruckendes aktuelles Beispiel.…”

“…7)e rmçglicht. [9] Das erstgenannte Motiv (6)ist wegen der hohen Polaritätvon Interesse fürd ie Materialwissenschaft;d as zweite (7)k ombiniert zwei zentrale Motive der medizinischen Chemie.A ußerdem ist die chemo-und enantioselektive Hydrierung von Pyridinen der Schlüsselschritt der effizienten Synthese (7 Stufen, 38 %G esamtausbeute) eines Wikstoffkandidaten gegen Ty p-2-Diabetes (8). [10] Allerdings muss jede Anwendung der Transfor-mation auf ein bestimmtes Zielmoleküld rei wichtige Bedingungen erfüllen: 1) Reaktivität: Im Unterschied zur etablierten Hydrierung von anderen ungesättigten Einheiten wie Alkenen, [11] Ketonen [12] und Iminen/ Enaminen [13] weist die Hydrierung von Arenen eine durch die aromatische Stabilisierungsenergie hervorgerufene,zusätzliche kinetische Barriere auf.…”