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

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Date
31/07/2018
Author
Bykova, Tetiana
Al-Maharik, Nawaf
Slawin, Alexandra M. Z.
Buehl, Michael
Lebl, Tomas
O'Hagan, David
Keywords
Organofluorine
Hydrocarbons
Fluorinated building blocks
Ritter reaction
Conformational analysis
QD Chemistry
NDAS
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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 23 – 26 and the preferred conformations of these α‐fluoroamides were explored by DFT, X‐ray structure and 1H–19F HOESY NMR analysis.
Citation
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
Publication
Chemistry - A European Journal
Status
Peer reviewed
DOI
https://doi.org/10.1002/chem.201802166
ISSN
0947-6539
Type
Journal item
Rights
© 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
Description
The Royal Society is thanked for support through its Wolfson Research Merit Award Scheme (DO’H).
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/18207

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