Benzylation of arenes through FeCl3-catalyzed Friedel-Crafts reaction via C-O activation of benzyl ether

Article abstract of DOI:10.1016/j.tetlet.2008.04.117

Various benzyl ethers were converted to benzyl arenes via a FeCl₃-catalyzed Friedel-Crafts alkylation reaction under mild condition in good yields. This method also offered a simple and practical approach to synthesize di- or tri-aryl methanes and aryl heteroaryl methanes through the activation of C-O bonds.

Full text of DOI:10.1016/j.tetlet.2008.04.117

Tetrahedron Letters 49 (2008) 4310–4312
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Benzylation of arenes through FeCl3-catalyzed Friedel–Crafts reaction
via C–O activation of benzyl ether
Bi-Qin Wang a,b, Shi-Kai Xiang a,b, Zuo-Peng Sun a,b, Bing-Tao Guan b, Ping Hu a,
b,
Ke-Qing Zhao a, , Zhang-Jie Shi
*
*
a College of Chemistry and Material Sciences, Sichuan Normal University, Chengdu, Sichuan 610066, China
b College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Various benzyl ethers were converted to benzyl arenes via a FeCl3-catalyzed Friedel–Crafts alkylation
reaction under mild condition in good yields. This method also offered a simple and practical approach
to synthesize di- or tri-aryl methanes and aryl heteroaryl methanes through the activation of C–O bonds.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 January 2008
Revised 17 April 2008
Accepted 22 April 2008
Available online 24 April 2008
Friedel–Crafts alkylation is one of the most powerful methods
in organic synthesis, which has been broadly applied to the con-
struction of C–C bonds for a long history. Originally, Friedel–Crafts
reactions took place between alkyl halides and electron rich arenes
in the presence of different Lewis Acids.1 In the past several dec-
ades, Friedel–Crafts reactions have been widely investigated and
various reagents were introduced to those transformations, such
as alkenes and acyl chlorides.2 Other developments realized the
alkylation of arenes with alcohols3 and esters4 as the alkylating
reagents. Generally, large amount of Lewis acids or Brönsted acids
was required to facilitate those Friedel–Crafts reactions.5 Herein,
we reported a new methodology to carry out the benzylation of
electron rich arenes and substituted thiophenes through benzylic
sp3 C–O activation of benzyl methyl ether.
Recently, much attention has been paid to the utilization of iron
complexes in catalytic organic transformations due to their readily
availability, inexpensiveness, and environmentally friendliness.6
Many efforts have been made to construct C–C and C–X bonds
(X = N, O, etc.) by coupling reactions catalyzed by iron complexes.7
Among those developments, a noteworthy progress was the iron-
catalyzed Friedel–Crafts alkylation of arenes with low catalyst
loading under relatively mild conditions.8 In those reactions, benz-
ylic alcohol and its acetate have been utilized to conduct the benz-
ylation of arenes.9 Different from esters and alcohols, ethers are
among the most stable organic compounds, which were broadly
used as the solvent. Under relatively harsh conditions, ethers could
react with different reagents.10 Due to their commercial availabil-
ity, much attention has been drawn to the activation of etheric C–O
bonds through transition-metal catalyzed coupling reactions to
construct C–C bonds.11 However, most studies in this field were
focused on the aryl/alkenyl C–OMe.12 Various transition-metal cat-
alysts, such as palladium and nickel complexes, have been
exploited effectively and efficiently in this field.13 In contrary, the
activation of sp3 C–O in saturated ether is much more challenging,
Table 1
Benzylation of benzene with benzyl methyl ether (1a) under different conditionsa
catalyst (10%)
OMe
benzene, 90 oC, 12 h
2a
Conversionb (%)
1a
Catalyst
Entry
Yieldc (%)
1
2
3
4
5
—
0
0
0
0
0
0
0
CuCl
CuCl2
CuBr2
Cu(OAc)2
ZnCl2
<5
<5
<5
<5
0
6
7
8
9
AlCl3
<5
<5
<5
<5
<5
<5
>99
<5
12
<5
<5
<5
<5
<5
0
0
<5
0
0
83
<5
12
<5
0
MgCl2
Fe(OAc)2
FeCl2
Fe(NO2)3 Á 9H2O
Fe(acac)3
FeCl3
InCl3
AuCl3
AuCl
CoCl2
10
11
12
13d
15
16
17
18
19
20
HOTf
HCl
0
0
a
Reaction condition: benzyl methyl ether (1a) (0.5 mmol), benzene (1 mL), and
catalyst (10 mol %) were mixed and heated to 90 for 12 h.
b
Conversion was determined by GC with n-dodecane as an internal standard.
Yield was determined by GC with n-dodecane as an internal standard if without
c
* Corresponding authors. Tel./fax: +86 10 6276 0890 (Z.-J.S.).
E-mail addresses: zhaokeqing@yahoo.com.cn (K.-Q. Zhao), zshi@pku.edu.cn
(Z.-J. Shi).
further note.
d
Isolated yield.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.117

B.-Q. Wang et al. / Tetrahedron Letters 49 (2008) 4310–4312
4311
which is arising from not only the high bond energy, but also the
selectivity issue between two different C–O bonds in unsymmetri-
cal ethers. Since benzylic sp3 C–O bond is relatively active, we fo-
cused on the reaction of benzyl methyl ether. Actually, direct
application of benzyl ether through sp3 C–O activation is rarely re-
ported. In our recent studies, the methylation of benzylic sp3 C–O
bonds via Ni-catalyzation was demonstrated.14 This report showed
the good reactivities of benzyl methyl ethers in Friedel–Crafts
alkylation via FeCl3 catalyzation.
Our attempt was started by investigating the traditional
Friedel–Crafts reaction with benzene as the reaction partner.
Under different conditions, we observed only a very small amount
of diphenyl methane by GC as the desired product with some com-
mon Lewis acids as the catalysts (Table 1). Afterward, we started
searching for the possibility to activate the sp3 C–O bond with iron
salts. To our delight, the Friedel–Crafts reaction performed well in
the presence of commercially available iron(III) chloride (FeCl3)
(entry 13). This reaction took place under mild condition (90 °C)
and was compatible with both air and moisture. The desired
product was obtained with a complete conversion and an excellent
isolated yield. When the temperature was lowered to 60 °C, the
transformation also took place very smoothly but with longer time.
However, some other iron salts, such as FeCl2 and Fe(acac)3 were
not suitable for this transformation.
Table 2
Benzylation of different arenes with benzyl methyl ethera
FeCl3 ( 10. 0 mol%)
90-130 oC, 12 h
OMe
+
Ar
Ar-H
Other than benzene, different arenes were systematically inves-
tigated under the standard condition (Table 2). We observed that:
(1) various methyl-substituted benzenes showed high reactivities,
including those with two or more methyl groups equipped on the
1a
2
Entry
1
Arenes
Main product
T (°C)
Yieldb (%) (regioselectivity)
90
83
2a
Table 3
Benzylation of benzene with different benzyl methyl ethersa
R
R
2
3
4
90
90
90
90 (58:42)
86 (65:35)
88 (79:21)
FeCl3 ( 10. 0 mol%)
2b
2c
Ar
+
Ar
OMe
90 oC, 12 h
2
1
Entry
1
1
Product 2
Yieldb (%)
83
OMe
2a
1a
2d
2e
OMe
2
3
4
5
6
7
90
33
35
67
48
5
90
90
1b
2k
2l
Ph
OMe
1c
6
7
130
130
75
86
2f
Ph
OMe
1d
MeO
2m
2n
2g
Ph
1e
8c
130
72
2h
OMe
S
2o
2a
2a
1f
9
100
100
75 (94:6)
S
2i
27
68
O
O
1g
10
80
S
S
2j
a
Reaction condition: arene (1 mL), benzyl methyl ether (0.5 mmol), no solvent,
FeCl3 (10.0 mol %) at the proper temperature for 12 h.
8
1h
Isolated yields and the ratio of the isomers were determined by 1H NMR.
b
a
c
Reaction condition: benzyl ether 1 (0.5 mmol), benzene (1 mL), FeCl3 (10.0
mol %) at 90 for 12 h.
The reaction was carried out with pentamethylbenzene (0.5 mmol), benzyl
methyl ether (1a, 0.5 mmol), and FeCl3 (10.0 mol %) under solvent-free condition at
130 °C for 12 h.
b
Isolated yields.

4312
B.-Q. Wang et al. / Tetrahedron Letters 49 (2008) 4310–4312
phenyl ring (entries 2–8). The selectivity of this benzylation was
controlled by both electronic effect and steric effect. For example,
with toluene as the substrate, benzylation occurred at para and
ortho position with a 58:42 ratio in high efficiency (entry 2). With
polysubstituted substrates, such as mesitylene, 1,2,4,5-tetramethyl
benzene, and pentamethylbenzene, the benzylation took place at
higher temperature and lower yields were obtained, which may
arise from the severe steric hindrance of methyl groups (entries
6–8). It is of importance to note that the benzylation could run un-
der solvent-free condition with 1:1 ratio of pentamethylbenzene
and benzyl methyl ether, which illustrated that the transformation
could be realized in high atomic economy (entry 8). (2) Thiophene
and 2,5-dimethylthiophene were also submitted to this transfor-
mation and the corresponding products formed in good efficiency
and high selectivity (entries 9 and 10).
We further tested different benzyl ethers in this transformation
(Table 3). The results indicated that: (1) both benzyl methyl ether
and diphenylmethyl methyl ether were suitable for this transfor-
mation (entries 1 and 2); (2) para- and meta-phenyl substituted
benzyl ether showed poor reactivity (entries 3 and 4), while
ortho-substituted substrate performed much better in this trans-
formation (entry 5). The reason for the different reactivities of
those substrates is still obscure; (3) compared with diphenyl-
methyl methyl ether, secondary benzyl methyl ether showed rela-
tively poor reactivity, since the substrate also went through
elimination pathway to form styrene derivative as the byproduct
(entry 6); (4) benzyl phenyl ether was submitted to this transfor-
mation and the desired product 2a was isolated in a relatively
low yield (entry 7), but highly regioselectivity was observed that
only benzylic sp3 C–O bond was cleaved and phenyl sp2 C–O bond
was kept untouched; (5) dibenzyl ether also showed good reactiv-
ity and desired biphenyl methane was obtained in good yield, and
both benzyl groups could be transformed into the final products
(entry 8).
method to construct the useful structural units and functional
groups in target molecules are underway.
Acknowledgments
We are pleased to acknowledge the financial support from
Peking University and NSFC (Nos. 20542001 and 20521202).
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In summary, we first developed a cleavage of benzylic sp3 C–O
bonds in benzyl ethers, fulfilling the Friedel–Crafts benzylation of
arenes via FeCl3-catalyzation. Various benzyl ethers and arenes
were systematically studied. This study offered a simple and prac-
tical method to synthesize di- or tri-aryl methane and arylhetero-
aryl methane under mild condition. Further studies to use this
14. Guan, B.; Xiang, S.; Sun, Z.; Shi, Z. J. Am. Chem. Soc. 2008, 130, 3268.