Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif

This paper reports the synthesis of three amine stereoisomers 5a–c of the tetrafluorocyclohexyl ring system, as building blocks for discovery chemistry programmes. The synthesis starts from a Birch reduction of benzonitrile, followed by an in situ methyl iodide quench. The resultant 2,5-cyclohexadiene was progressed via double epoxidations and then hydrofluorination ring opening reactions. The resultant fluorohydrin moieties were then converted to different stereoisomers of the tetrafluorocyclohexyl ring system, and then reductive hydrogenation of the nitrile delivered three amine stereoisomers. It proved necessary to place a methyl group on the cyclohexane ring in order to stabilise the compound against subsequent HF elimination. The two all-cis tetrafluorocyclohexyl isomers 5a and 5b constitute facially polarized cyclohexane rings, with fluorines on the electronegative face and hydrogens on the electropositive face.

[1]  A. Slawin,et al.  Multicomponent reactions of methyl substituted all-cis tetrafluorocyclohexane aldehydes. , 2016, Organic & biomolecular chemistry.

[2]  A. Slawin,et al.  Selectively fluorinated cyclohexane building blocks: Derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane , 2015, Beilstein journal of organic chemistry.

[3]  A. Slawin,et al.  Synthesis of selectively fluorinated cyclohexanes: The observation of phenonium rearrangements during deoxyfluorination reactions on cyclohexane rings with a vicinal phenyl substituent , 2015 .

[4]  D. Philp,et al.  All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane. , 2015, Nature chemistry.

[5]  A. Slawin,et al.  Fluorine containing amino acids: synthesis and peptide coupling of amino acids containing the all-cis tetrafluorocyclohexyl motif. , 2015, Organic & biomolecular chemistry.

[6]  A. Slawin,et al.  Stepwise preparation of all-cis 1,3,4-trifluoro-2-phenylcyclohexane, avoiding a phenonium intermediate. , 2014, The Journal of organic chemistry.

[7]  Rodrigo A. Cormanich,et al.  Synthesis and elaboration of all-cis-1,2,4,5-tetrafluoro-3-phenylcyclohexane: a polar cyclohexane motif. , 2014, Chemistry.

[8]  A. Börner,et al.  Selective catalytic transfer hydrogenation of nitriles to primary amines using Pd/C , 2014 .

[9]  A. Slawin,et al.  Fluorocyclohexanes: synthesis and structure of all-syn-1,2,4,5-tetrafluorocyclohexane. , 2012, Chemical communications.

[10]  G. Khan,et al.  Synthesis of benzoic acids and polybenzamides containing tertiary alkylamino functionality , 2012 .

[11]  A. Slawin,et al.  Synthesis and structure of all-syn-1,2,3,4-tetrafluorocyclohexane. , 2011, Chemical communications.

[12]  David O'Hagan,et al.  Understanding organofluorine chemistry. An introduction to the C-F bond. , 2008, Chemical Society reviews.

[13]  F. Diederich,et al.  Fluorine in Pharmaceuticals: Looking Beyond Intuition , 2007, Science.

[14]  M. Ruiz,et al.  Stereocontrolled access to orthogonally protected anti,anti-4-aminopiperidine-3,5-diols through chemoselective reduction of enantiopure beta-lactam cyanohydrins. , 2007, The Journal of organic chemistry.

[15]  K. Kirk,et al.  Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules , 2006 .

[16]  S. Kojima,et al.  Stereoselectivity control by oxaspiro rings during Diels-Alder cycloadditions to cross-conjugated cyclohexadienones: the syn oxygen phenomenon. , 2004, Journal of the American Chemical Society.

[17]  T. Widlanski,et al.  Facile deprotection of O-Cbz-protected nucleosides by hydrogenolysis: an alternative to O-benzyl ether-protected nucleosides. , 2004, Organic letters.

[18]  Justin C. Biffinger,et al.  The Polar Hydrophobicity of Fluorinated Compounds , 2004, Chembiochem : a European journal of chemical biology.

[19]  A. Birch.  The Birch reduction in organic synthesis , 1996 .

[20]  E. Scriven.  4-Dialkylaminopyridines: super acylation and alkylation catalysts , 1983 .

[21]  Nicholas A. Cortese,et al.  Palladium catalyzed reductions of halo- and nitroaromatic compounds with triethylammonium formate , 1977 .

[22]  N. Schwartz,et al.  Epoxidations with m-Chloroperbenzoic Acid , 1964 .

[23]  N. Prileschajew.  Oxydation ungesättigter Verbindungen mittels organischer Superoxyde , 1909 .

[24]  Juyoung Yoon,et al.  Chem Soc Rev , 2020 .

[25]  Alexander Dömling,et al.  Recent developments in isocyanide based multicomponent reactions in applied chemistry. , 2006, Chemical reviews.