Angewandte
Communications
Chemie
Friedel–Crafts Reactions
Catalytic Friedel–Crafts Reactions of Highly Electronically
Deactivated Benzylic Alcohols
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Abstract: Highly electronically deactivated benzylic alcohols,
including those with a CF3 group adjacent to the OH-bearing
carbon, undergo dehydrative Friedel–Crafts reactions upon
exposure to catalytic Brønsted acid in 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) solvent. Titration and kinetic experiments
support the involvement of higher order solvent/acid clusters in
catalysis.
T
he Friedel–Crafts reaction is a transformation of central
importance for the synthesis of industrially relevant arenes
and heteroarenes.[1,2] The classical version requires stoichio-
metric quantities of Lewis acid and uses alkyl halides as
starting materials, which are often generated in a separate
step from alcohol precursors. Variants developed recently by
Bode and Stephan have expanded the scope of the Friedel–
Crafts reaction to include electronically deactivated benzylic
electrophiles through the use of benzylic N-methylhydroxa-
mic acids and fluorides, respectively (Figure 1a).[3] However,
like the classical version, these reactions require additional
steps for substrate preactivation and use stoichiometric
activating agents. The need to improve the step- and atom-
economy of the Friedel–Crafts reaction prompted the ACS
Green Chemistry Pharmaceutical Roundtable to designate the
development of catalytic versions starting directly from
alcohols, which produce water as the only stoichiometric by-
product, as a top priority for green chemistry.[4] Accordingly,
the past years have witnessed numerous reports of Lewis or
Brønsted acid catalyzed Friedel–Crafts reactions of electroni-
cally activated benzylic alcohols,[5–7] but the inability of the
reaction to accommodate electronically deactivated alcohols
remains a striking limitation. For example, the ferrocenium
hexafluoroantimonate boronic acid catalyst developed by
Hall and McCubbin—arguably the most active catalytic
system described to date—reaches its limits at primary
benzylic alcohols bearing modestly deactivating substituents,
and restricts access to highly fluorinated molecules of
potential interest to the pharmaceutical and agrochemical
industries (Figure 1b).[6i] Recently, we observed that hydro-
gen bonding interactions between Brønsted acid catalysts and
cocatalysts or solvents can have profound accelerating effects
and even change the kinetic concentration dependence in
catalytic substitution reactions of alcohols.[8] Herein, we
Figure 1. Friedel–Crafts reactions of highly electronically deactivated
benzylic electrophiles.
report that interactions between Brønsted acid catalysts and
solvents of low nucleophilicity known to form H-bond
clusters, such as hexafluoroisopropanol (HFIP),[9–11] can be
exploited to surpass current limitations of the catalytic
dehydrative Friedel–Crafts reaction by enabling reactivity of
highly electronically deactivated benzylic alcohols; including
those bearing a geminal CF3 group. This new method grants
access to deactivated, often highly fluorinated, diaryl-
methanes and diaryltrifluoroethanes from the corresponding
alcohol in a single catalytic step (Figure 1c). Mechanistic
experiments support the involvement of higher order solvent/
acid clusters and point to an SN1-type mechanism.
Initial experiments targeted Friedel–Crafts reactivity of
m-xylene with alcohol 1a, which was too deactivated for
catalysis by ferrocenium hexafluoroantimonate boronic
acid.[6i] To our delight, the simple conjugate acid,
HSbF6·6H2O, furnished modest yields of 2a under otherwise
identical conditions (Table 1, entry 1). Reactivity was
improved slightly using HFIP exclusively as the solvent
(Table 1, entry 2). TfOH furnished higher yields because of its
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[*] V. D. Vukovic, Dr. E. Richmond, Dr. E. Wolf, Dr. J. Moran
University of Strasbourg, CNRS, ISIS UMR 7006
67000 Strasbourg (France)
E-mail: moran@unistra.fr
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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