Arene hydrogenation provides direct access to saturated carbo‐ and heterocycles and thus its strategic application may be used to shorten synthetic routes. This powerful transformation is widely applied in industry and is expected to facilitate major breakthroughs in the applied sciences. The ability to overcome aromaticity while controlling diastereo‐, enantio‐, and chemoselectivity is central to the use of hydrogenation in the preparation of complex molecules. In general, the hydrogenation of multisubstituted arenes yields predominantly the cis isomer. Enantiocontrol is imparted by chiral auxiliaries, Brønsted acids, or transition‐metal catalysts. Recent studies have demonstrated that highly chemoselective transformations are possible. Such methods and the underlying strategies are reviewed herein, with an emphasis on synthetically useful examples that employ readily available catalysts.

All-c-multifluorinated cycloalkanes exhibit intriguing electronic properties. In particular, they display extremely high dipole moments perpendicular to the aliphatic ring, making them highly desired motifs in material science. Very few such motifs have been prepared, as their syntheses require multistep sequences from diastereoselectively prefunctionalized precursors. Herein we report a synthetic strategy to access these valuable materials via the rhodium-cyclic (alkyl)(amino)carbene (CAAC)-catalyzed hydrogenation of readily available fluorinated arenes in hexane. This route enables the scalable single-step preparation of an abundance of multisubstituted and multifluorinated cycloalkanes, including all--1,2,3,4,5,6-hexafluorocyclohexane as well as cis-configured fluorinated aliphatic heterocycles.

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.

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The introduction of fluorine atoms into molecules and materials across many fields of academic and industrial research is now commonplace, owing to their unique properties. A particularly interesting feature is the impact of fluorine substitution on the relative orientation of a C−F bond when incorporated into organic molecules. In this Review, we will be discussing the conformational behavior of fluorinated aliphatic carbo‐ and heterocyclic systems. The conformational preference of each system is associated with various interactions introduced by fluorine substitution such as charge‐dipole, dipole‐dipole, and hyperconjugative interactions. The contribution of each interaction on the stabilization of the fluorinated alicyclic system, which manifests itself in low conformations, will be discussed in detail. The novelty of this feature will be demonstrated by presenting the most recent applications.

Scheme2.The conformational preferences of 3-fluoropiperidine (1)and 3,5-difluoropiperidine (2)a nd their TFA-(A), HCl-(B), and NH-(C)-analogues.T he free enthalpydifferences between the equatorial conformer to the axial conformer (DG)are presenteda sf ollows: DG Solvent( DG Gas Phase). The DG valuesfor TFA-, and for both HCl-, and NH-analoguesa re given in chloroform andwater,r espectively. All values are given in kcal mol À1 .Experimentally,a ll analogues of 1 and 2 showed high axialpreference. In NH-analogues 1C and 2C,wew ere unable to determine the orientation of the NÀHb ond becauseofafast H/D exchange in solution.[a] Both computationala nalysis and experimental observation were carriedo ut in toluene.

Transfer hydrogenation reactions are of great interest to reduce diverse molecules under mild reaction conditions. To date, this type of reaction has only been successfully applied to alkenes, alkynes and polarized unsaturated compounds such as ketones, imines, pyridines, etc. The reduction of benzene derivatives by transfer hydrogenation has never been described, which is likely due to the high energy barrier required to dearomatize these compounds. In this context, we have developed a catalytic transfer hydrogenation reaction for the reduction of benzene derivatives and heteroarenes to form complex 3‐dimensional scaffolds bearing various functional groups at room temperature without needing compressed hydrogen gas.

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