Benzylic functionalisation of phenyl all-cis-2, 3, 5, 6-tetrafluorocyclohexane provides access to new organofluorine building blocks

Tetiana Bykova, Nawaf Al-Maharik, Alexandra M. Z. Slawin, Michael Buehl, Tomas Lebl, David O'Hagan

Research output: Contribution to journalReview articlepeer-review

6 Citations (Scopus)

Abstract

Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all cis-2, 3, 5, 6–tetrafluoro- cyclohexane 2 as a key reaction for accessing building blocks Selectively fluorinated hydrocarbons continue to attract attention for tuning pharmacokinetic properties in agrochemical and pharmaceutical discovery programmes. This study identifies benzylic bromination of phenyl all‐cis‐2,3,5,6‐tetrafluorocyclohexane 2 as a key reaction for accessing building blocks containing the all‐cis‐2,3,5,6‐tetrafluorocyclohexane ring system. These cyclohexanes are of interest as the fluorines are only on one face of the cyclohexane, and this imparts an unusual polar aspect, very different to an otherwise hydrophobic cyclohexane. Ritter type reactions of benzyl bromide 4 with DMF and acetonitrile generated the corresponding benzyl alcohol 6 and benzylacetamide 7 respectively. Benzylacetamide 7 was hydrolysed to benzyl amine 8 and syn‐amino‐alcohol 9, and separately the phenyl ring was oxidatively cleaved to furnish carboxylic acid acetamide 10, which after hydrolysis gave the tetrafluorocyclohexyl amino acid 11. A trans‐halogenation of benzylbromide 4 with AgF2 gave benzyl fluoride 13. Oxidative cleavage of the aryl ring then gave pentafluorocyclohexyl carboxylic acid 14. This carboxylic acid was readily converted to amides 2326 and the preferred conformations of these α‐fluoroamides were explored by DFT, X‐ray structure and 1H–19F HOESY NMR analysis.
Original languageEnglish
JournalChemistry - A European Journal
VolumeEarly View
Early online date31 Jul 2018
DOIs
Publication statusE-pub ahead of print - 31 Jul 2018

Keywords

  • Organofluorine
  • Hydrocarbons
  • Fluorinated building blocks
  • Ritter reaction
  • Conformational analysis

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