Benzylic functionalisation of phenyl all-cis-2, 3, 5, 6-tetrafluorocyclohexane provides access to new organofluorine building blocks
MetadataShow full item record
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 23 – 26 and the preferred conformations of these α‐fluoroamides were explored by DFT, X‐ray structure and 1H–19F HOESY NMR analysis.
Bykova , T , Al-Maharik , N , Slawin , A M Z , Buehl , M , Lebl , T & O'Hagan , D 2018 , ' Benzylic functionalisation of phenyl all- cis -2, 3, 5, 6-tetrafluorocyclohexane provides access to new organofluorine building blocks ' Chemistry - A European Journal , vol. Early View . https://doi.org/10.1002/chem.201802166
Chemistry - A European Journal
© 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. This work has been made available online in accordance with the publisher’s policies. This is the author created accepted version manuscript following peer review and as such may differ slightly from the final published version. The final published version of this work is available at https://doi.org/10.1002/chem.201802166
DescriptionThe Royal Society is thanked for support through its Wolfson Research Merit Award Scheme (DO’H).
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.