DOI: 10.1002/anie.201105380
Arene Functionalization
Friedel–Crafts Benzylation of Activated and Deactivated Arenes**
Gabriel Schꢀfer and Jeffrey W. Bode*
The Friedel–Crafts alkylation of aromatic compounds is a
improvements both reduce the reliance on toxic organo-
halides and decrease the environmental impact of Friedel–
Crafts reactions. In most cases, however, these advances are
limited to highly activated primary or secondary benzylic
substrates, the use of electron-rich nucleophiles, such as
anisoles, or intramolecular reactions. The textbook Friedel–
Crafts benzylation of even simple arenes, such as chloroben-
zene or benzoic esters, has seen little improvement in its 135
year history.
À
versatile method for C C bond formation from unactivated
À
C H bonds.[1] Despite the power and historical importance of
Friedel–Crafts reactions, the poor reactivity of deactivated
aromatic compounds, the difficultly of employing even
modestly deactivated alkyl halides, and complications from
the aluminum by-products have encouraged the development
of new aromatic transformations. In the current era, new
reactions for regio- and chemoselective direct functionaliza-
À
tion of arenes through C H bond activation, largely based on
The key to our improvement of the Friedel–Crafts
alkylation is the selective activation of a N-methyl hydroxa-
mic acid[13] leaving group with BF3·OEt2, an inexpensive and
easily handled Lewis acid. Friedel–Crafts reactions using this
approach are cleaner, more selective, and more easily
executed than traditional methods. This research stemmed
from our recent finding that mixed hydroxamate acetals are
superior substrates for BF3·OEt2-promoted cross-coupling
reactions with organotrifluoroborates to give dialkyl ethers
with outstanding regioselectivity.[14] Our mechanistic studies
suggested that the improved reactivity and conditions were
achieved by the ability of the boron-chelated hydroxamate to
serve as a reversible leaving group—a process that allows
controlled generation of the reactive oxonium cation. We
anticipated that this strategy would be applicable to other
reactions proceeding via carbocation intermediates and
selected the Friedel–Crafts alkylation for initial investiga-
tions.
transition metal catalysis, have revolutionized the preparation
of aromatic derivatives.[2,3] Despite these advances, there
remains an unmet synthetic need for refinements to the more
economical Friedel–Crafts reaction to improve its substrate
scope, operational simplicity, and sustainability, particularly
for substitutions of electron-deficient substrates.[4] Herein we
document a new approach to Friedel–Crafts benzylations that
operates with both electron-deficient electrophiles and nucle-
ophiles, proceeds under mild, simple conditions, and does not
require the use of aluminum or other metal reagents or
catalysts (Scheme 1). Importantly, this method allows for the
selective mono-meta-functionalization of electron-deficient
nucleophiles with electron-poor electrophiles.[5]
Our studies began with a survey of reactions and
conditions for the alkylation of toluene with para-chloroben-
zyl hydroxamate 1.[15] As desired, the use of BF3·OEt2
(4 equiv) at room temperature gave the benzylation product
3 as a mixture of regioisomers in excellent yield (Table 1,
entry 1). Similar results were obtained using only 2 equiv-
alents of BF3·OEt2 (Table 1, entry 2). The reaction workup
was operational friendly; aqueous extraction removed the
BF3·OEt2 and hydroxamic acid without difficulty to obtain the
pure product after evaporation of the organic solvent. As
expected, catalytic reactions were not effective, likely due to
chelation of the BF3·OEt2 by released hydroxamate, an effect
that sequesters the BF3·OEt2 after the reaction. This is
beneficial under non-catalytic conditions, as it prevents the
formation of side products. In contrast, a number of other
Lewis or protic acids including HBF4 (Table 1, entry 5),
B(OH)3 (Table 1, entry 6), ZnCl2 (Table 1, entry 7), Mg-
(acac)2 (Table 1, entry 8), and Cu(OAc)2 (Table 1, entry 10)
proved ineffective. FeCl3 and AlCl3 were viable reagents but
led to more complicated workup and the formation of side
products (Table 1, entries 11 and 12).[16] Experiments in the
absence of additive (Table 1, entry 14) and with 0.1 equiv-
alents of FeCl3 (Table 1, entry 13) did not afford product and
confirmed that the reactions were not promoted by trace
metal impurities. The reactions could also be performed with
Scheme 1. BF3·OEt2-promoted Friedel–Crafts benzylation.
A recent advance in Friedel–Crafts alkylations[6] of
aromatic substrates is the discovery that metal salts including
[11]
TeCl4,[7] Sc(OTf)3,[8] FeCl3,[9] Bi(OTf)3,[10] and HAuCl4
promote the coupling of activated benzyl alcohols and halides
with arenes. Other researchers have employed heterogeneous
catalysts, such as zeolites, to Friedel–Crafts reactions.[12] These
[*] G. Schꢀfer, Prof. Dr. J. W. Bode
Laboratorium fꢁr Organische Chemie
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology (ETH) Zꢁrich
Wolfgang Pauli Strasse 10, 8093 Zꢁrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
[**] This work was supported by ETH Research Grant ETH-12 11-1. We
thank the ETH Zꢁrich Mass Spectrometry Service for spectroscopic
data, Aaron Dumas for helpful discussions, and Cam-Van Thi Vo for
a preliminary study.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 10913 –10916
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10913