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-catalysed dearomatization-hydrogenation 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 dearomatization-hydrogenation process.

Figure 1. The preparation of all-cis-(multi)fluorinated piperidines by the DAH process.

a, Merging common elements of drugs. The goal is the incorporation of fluorine into piperidine derivatives. The basicity of kinesin spindle protein (KSP) inhibitor was affected by the orientation of the fluorine atom. The more basic axial isomer (MK-0731) was selected for clinical evaluation. b, Known retrosynthetic routes for the preparation of monofluorinated piperidines. LG: leaving group. c, The multistep synthesis of cis-3,5-difluoropiperidine hydrochloride. A 1,3-diaxial behavior of the fluorine atoms was observed. d, Our proposed DAH process is a combined dearomatization and hydrogenation that gives access to all-cis-(multi)fluorinated piperidine building blocks.

Figure 2. Selected mechanistic experiments for the DAH process.

a, Complete hydrodefluorination of 2-fluoropydrine was observed. b, The amount of HBpin was determined after the reaction by NMR analysis using benzene as internal standard. c, Deuterium scrambling was observed by employing molecular deuterium. The structure of 4-D was confirmed by NMR and ESI-MS studies. d, The D-incorporation for HBpin was observed under the reaction conditions. For more details concerning additional mechanistic studies, see Supplementary Section 6.

Figure 3. Application of the all-cis-(multi)fluorinated piperidines building blocks.

a, The preparation of fluorinated analogues of commercial drugs starting from fluoropiperidine hydrochloride derivatives. b, Fluorinated analogues of additional commercial drugs. For reaction conditions, see Supplementary Section 7. c, The preparation of fluorinated analogues of PipPhos and ionic liquids. For detailed reaction conditions, see Supplementary Section 7. Et₃N: triethylamine; MeCN: acetonitrile; DMF: dimethylformamide; (R)-BINOL-PCl: (R)-1,1'-binaphthyl-2,2'-dioxychlorophosphine; LiTFSI: bis(trifluoromethane) sulfonimide lithium salt; AgOTf: silver trifluoromethanesulfonate.