Angewandte
Chemie
DOI: 10.1002/anie.201406088
Benzylation
Friedel–Crafts Reaction of Benzyl Fluorides: Selective Activation of
À
C F Bonds as Enabled by Hydrogen Bonding**
Pier Alexandre Champagne, Yasmine Benhassine, Justine Desroches, and Jean-FranÅois Paquin*
Abstract: A Friedel–Crafts benzylation of arenes with benzyl
fluorides has been developed. The reaction produces 1,1-diaryl
alkanes in good yield under mild conditions without the need
for a transition metal or a strong Lewis acid. A mechanism
À
involving activation of the C F bond through hydrogen
bonding is proposed. This mode of activation enables the
À
selective reaction of benzylic C F bonds in the presence of
other benzylic leaving groups.
À
T
he substitution of C F bonds has been a subject of intensive
research for a number of years.[1] Part of the interest in this
process is the fundamental prospect of being able to activate
the strongest single bond with carbon.[2] Potential applications
in synthetic organic chemistry and in environmental sciences
have also stimulated research in this area. In line with our
efforts in designing new synthetic methodology involving the
À
activation of C F bonds, we recently reported a new strategy
toward this goal on the basis of hydrogen bonding.[3]
Specifically, we showed that activated alkyl fluorides could
undergo a bimolecular nucleophilic substitution reaction with
various nucleophiles in the presence of water as a hydrogen-
bond donor (HBD; Scheme 1a). Calculations demonstrated
that in this system, stabilization of the transition state
occurred through hydrogen bonding between the fluorine
atom and water molecules. The possibility that the fluorine
Scheme 1. A previous study, an unexpected result, and the goal of this
study.
and hence an acceleration of the reaction. To test this
hypothesis, we selected 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP),[9] one of the strongest HBD solvents (a = 1.96), as
a potential replacement for water. When benzylic fluoride
1 was treated with morpholine in HFIP, none of the benzylic
amine 2 was observed; rather, an insoluble polymer with
À
atom of a C F bond could act as a hydrogen-bond acceptor
has been a subject of debate for some time,[4] as the analysis of
crystal-structure databases generated only a few examples of
[5]
À
structures consistent with a C F···H bond. However,
spectroscopic and computational evidence now convincingly
support the existence of this interaction in solution.[6] Thus,
although water is a good hydrogen-bond donor (a = 1.17),[7]
we wondered what would happen with stronger HBDs, such
as fluorinated alcohols.[8] Our hypothesis was that the use of
a stronger HBD would result in stronger hydrogen bonds,
which themselves would correlate with a stronger activation,
a
1,1-diaryl methane backbone was isolated (Sche-
me 1b).[10–12] We hypothesized that the stronger HBD capa-
bility of HFIP could favor direct ionization of the benzyl
fluoride to generate a benzyl carbocation,[13,14] which poly-
merized through a Friedel–Crafts reaction.
On the basis of this result, we envisioned that the
treatment of benzylic fluorides with nucleophilic arenes in
the presence of HFIP could provide facile access to 1,1-diaryl
methanes (Scheme 1c). Herein, we document Friedel–Crafts
benzylation[15,16] with benzylic fluorides as enabled by hydro-
gen bonding. This method is notable on a number of grounds:
It provides access to 1,1-diaryl alkanes, which are valuable
synthetic building blocks in medicinal and agrochemistry; it
does not require a transition metal or a strong Lewis acid; and
it expands the use of benzylic fluorides[17] as building blocks in
organic synthesis, exploiting a new type of reactivity.
[*] P. A. Champagne, Y. Benhassine, J. Desroches, Prof. J.-F. Paquin
Canada Research Chair in Organic and Medicinal Chemistry
CCVC, PROTEO, Dꢀpartement de chimie, Universitꢀ Laval
1045 Avenue de la Mꢀdecine, Pavillon Alexandre-Vachon
Quꢀbec, Quꢀbec, G1V 0A6 (Canada)
E-mail: jean-francois.paquin@chm.ulaval.ca
[**] This research was supported by the Canada Research Chair
Program, the Natural Sciences and Engineering Research Council of
Canada, the Canada Foundation for Innovation, FQRNT Centre in
Green Chemistry and Catalysis (CCVC), and the Universitꢀ Laval.
We thank Jelier Bensen and Prof. Chad Friesen from Trinity Western
University for MALDI-TOF analysis.
À
Under optimized conditions [Ar H (5 equiv), HFIP/
CH2Cl2 (1:9), room temperature, 18 h],[10] we evaluated the
reactivity of arene nucleophiles with benzyl fluoride 3
(Scheme 2). Various electron-rich or electron-neutral aro-
matic compounds[18] could be used, and the corresponding 1,1-
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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