Iron(iii)-based ionic liquid-catalyzed regioselective benzylation of arenes and heteroarenes

Article abstract of DOI:10.1039/c1gc15056a

An easily prepared Fe(iii)-derived Lewis acid ionic liquid ([C ₄mim][FeCl₄]), being comprised of 1-butyl-3-methyl imidazolium cation and tetrachloroferrate anion, was found to be an efficient, recyclable catalyst for benzylation of various arenes/heteroarenes into the diarylmethanes derivatives under mild reaction conditions without utilization of additional organic solvent. Interestingly, the acidity of [C ₄mim][FeCl₄] could account for its catalytic activity in promoting the Lewis acid-catalyzed alkylation. Notably, this type of Fe(iii)-based ionic liquid (IL) shows excellent stability, and could be easily recovered, and reused for five times without significant loss of its catalytic activity.

Full text of DOI:10.1039/c1gc15056a

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Green Chemistry
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PAPER
Iron(III)-based ionic liquid-catalyzed regioselective benzylation of arenes
and heteroarenes†
a
b
a
a
Jian Gao, Jin-Quan Wang, Qing-Wen Song and Liang-Nian He*
Received 14th January 2011, Accepted 11th March 2011
DOI: 10.1039/c1gc15056a
An easily prepared Fe(III)-derived Lewis acid ionic liquid ([C
4
mim][FeCl
4
]), being comprised of
1
-butyl-3-methyl imidazolium cation and tetrachloroferrate anion, was found to be an efficient,
recyclable catalyst for benzylation of various arenes/heteroarenes into the diarylmethanes
derivatives under mild reaction conditions without utilization of additional organic solvent.
Interestingly, the acidity of [C
4
mim][FeCl ] could account for its catalytic activity in promoting the
4
Lewis acid-catalyzed alkylation. Notably, this type of Fe(III)-based ionic liquid (IL) shows
excellent stability, and could be easily recovered, and reused for five times without significant loss
of its catalytic activity.
Introduction
It is well known that fine chemicals, pharmaceuticals, agrochem-
icals, dyes, commonly contain an aromatic and/or heteroaro-
matic framework structure. Most aromatic and/or heteroaro-
matic compounds are conventionally prepared on a large scale
by employing classic transformations like Friedel–Crafts alkyla-
1
tions, Friedel–Crafts acylations, nitrations, and halogenations.
Although these methods work reliably for a variety of substrates,
they often pose major drawbacks such as drastic reaction condi-
tions (high temperature, strong acidic conditions in conjunction
with the use of stoichiometric amounts of Lewis acid such
as AlCl ), low regioselectivity along with formation of large
3
amounts of salt by-products. Due to increasing demand for
efficient, cost-effective and environmentally friendly processes to
prepare the aforementioned aromatic compounds, development
of direct catalytic carbon-carbon bond forming reactions of
arenes and heteroarenes is of great significance, and has become
an important topic in organometallic chemistry and catalysis. In
this regard, considerable progress has been made in the metal-
catalyzed Friedel–Crafts type alkylation of arenes to prepare
the desired products containing a diarylmethane motif, com-
Scheme 1 Selected biologically active compounds containing diaryl-
methane moiety.
monly showing biological activity (Scheme 1). Recently, various
2
3
3
late-transition-metal salts, such as FeCl
3
, IrCl
3
, RhCl
3
, or
3
4
5
6
a
H PtCl , AuCl , Bi(OTf) and [IrCp*(OTf) (NHC)] com-
State Key Laboratory and Institute of Elemento-Organic Chemistry,
2
6
3
3
2
Nankai University, Tianjin, 300071, People’s Republic of China.
plexes were found to catalyze the addition reaction of benzyl
acetates to arenes and heteroarenes in high yield and selectivity.
However, high catalyst loadings and difficulties in recovering
the transition-metal catalysts in these processes could lead to
high corrosion and increased cost to some extent. Therefore,
developing greener protocol would still be highly appealing.
Ionic liquids (ILs) have been attracting rising interest in the
last decades with a diversified range of applications because of
their potential advantages including negligible vapor pressure,
E-mail: heln@nankai.edu.cn; Fax: +86 22 2350 1493; Tel: +86 22-2350
4
216
b
Key Laboratory of Green Process and Engineering, Institute of Process
Engineering, Chinese Academy of Sciences, P.O. Box 353, Beijing,
1
00190, People’s Republic of China.
†
Electronic supplementary information (ESI) available: General exper-
imental methods, experimental procedures, characterization for ionic
liquids, iron-containing ionic liquids, benzylating reagents and products
and copies of the NMR spectra, thermal gravimetric analysis and Raman
scattering spectra. See DOI: 10.1039/c1gc15056a
1
182 | Green Chem., 2011, 13, 1182–1186
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good thermal stabilities, wide liquid temperature ranges and
so on. In this aspect, ILs have been successfully used as
Table 1 Fe(III) based IL-catalyzed coupling reaction of o-xylene with
a
7
1-phenylethyl acetate
immobilizing reagents for transition-metal catalysts, offering
advantages of both homogeneous and heterogeneous catalysis
and thus leading to improved catalyst performance. Recently,
Conversion Yield Regioselectivity
b
c
d
Entry Catalyst
(%)
(%)
(%)
7
1
2
3
4
5
6
7
8
9
1
FeCl
3
98
0
0
0
0
0
4
97
—
—
—
—
—
4
95 : 5
—
—
—
—
—
—
synthesis and application of specific-task ILs containing transi-
tion metals have drawn much attention in this thriving research
field. The functionalized ILs are regarded as promising materials
which would favorably combine spectroscopic, and/or mag-
netic properties with catalytic activity, presumably originating
from incorporated metals. In this context, ILs containing
metals such as Fe(II), Fe(III), Zn(II) and Al(III) have been
successfully used as catalysts in organic transformations, e.g.
C
C
C
[C
[C
4
4
4
mimCl
mimBr
mimBF
4
e
4
mim][FeCl
mim][FeCl
3
Br] (1 : 1)
] (1 : 1)
4
4
f
C
[C
4
mimBF
4
FeCl
] (1 : 1.2)
3
4
mim][FeCl
4
99
99
20
69
98
98
14
64
96 : 4
96 : 4
94 : 6
95 : 5
[C mim][FeCl ] (1 : 2.0)
4
4
4
4
4
4
g
h
0
[C
[C
mim][FeCl
mim][FeCl
] (1 : 1.2)
] (1 : 1.2)
8
9
11
Friedel–Crafts type alkylation /acylation and hydroxymethy-
10
a
lation of b-ketoesters. In particular, the Fe(III)-based IL, e.g.
mim][FeCl ] which combines the attractive properties of both
ionic liquid and FeCl was found to have great application in
Reaction conditions: 1-phenylethyl acetate, 1 mmol; o-xylene, 8.4 mmol
◦
(
1 mL); catalyst, 10 mmol% relative to 1-phenyl acetate, 80 C, 12 h. All
[C
4
4
the reactions were performed two times, and the data were the average
3
b
c
d
of both results. Determined by GC. Total yield of 1 and 2. Molar
11
catalysis. As one of the most inexpensive and non-pollutant
metals, iron catalysis would be of great interest and is constantly
e
f
4 3 4 4
ratio of 1 to 2. Molar ratio of C mimX/FeCl . C mimBF was used
g
◦
h
4
instead of C mimCl. 50 C. 6 h.
12
growing from a standpoint of sustainable catalysis.
As part of our continuous efforts to develop ILs and
13
transition metal-based ILs for catalytic transformations, we
envisioned that the Fe(III)-derived Lewis acid IL could catalyze
an electrophilic substitution, for instance, Friedel–Crafts type
we used acetonitrile as a basic probe molecule to determine the
17
acidity of the iron-containing ILs mentioned above. As can
be seen from Fig. 1, acetonitrile itself shows two characteristic
alkylation. Indeed, [C
4
mim][FeCl
4
] proved to be an efficient
-1
n
CN stretching vibrations at 2254 and 2293 cm (Fig. 1a).
catalyst for regioselective benzylation of arenes and heteroarenes
affording functionalized diarylmethane motif which is an inte-
gral part of a number of biologically active compounds and
pharmaceuticals such as piritrexim, trimethoprim, avrainvilleol,
When acetonitrile was mixed with the iron-containing IL with
a FeCl /C mimCl molar ratio of 1 : 1, no change in the nCN
stretching frequencies was observed (Fig. 1b). This indicates
that there is no interaction between this relatively weak acidic
IL and acetonitrile, a weak Lewis base. Interestingly, when the
3
4
2,14
papaverine, beclobrate, or letrozole (Scheme 1). In addition,
the catalyst can be successfully recovered and reused for five
times without any loss of its catalytic activity. The protocol
presented here provides an alternative and efficacious strategy
to achieve both regioselective benzylation and transition-metal
recycling and would be particularly promising from a viewpoint
of green chemistry.
molar ratio of FeCl
3
/C
4
mimCl is more than 1 : 1, a third band
-1
appeared at around 2355 cm (Fig. 1c and d), being indicative
of Lewis acid–base interactions between the iron-containing
ILs and acetonitrile. Moreover, the intensity of the IR band
-1
around 2355 cm becomes stronger with the increase of the
molar fraction of FeCl
3
, implying that the increased fraction of
FeCl leads to a stronger Lewis acid–base interaction between
3
Results and discussion
the ILs and acetonitrile. Those results indicate that the Lewis
acidity of the iron-containing ILs can be modified by varying
The Fe(III)-based Lewis acidic ILs are comprised of 1-butyl-3-
the fraction of FeCl
FeCl could lead to stronger Lewis acidity of the FeCl
IL, i.e. [C mim][FeCl ].
3
. In other words, a higher molar fraction of
-
methylimidazolium cation and different anions such as FeCl
4
3
3
-based
-
or FeCl
3
X (X = Br) as depicted in Scheme 2. Those ILs were
4
4
easily prepared from commercially available anhydrous FeCl
3
and an imidazolium salt such as C mimCl. They were charac-
4
terized by Raman scattering spectroscopy (see Supplementary
Information†) and proved to be identical with authentic material
15
-
reported in the literature. The results indicated that FeCl
4
would be the dominating anion species. Furthermore, a small
-
quantity of Fe
results.
2
Cl
7
species also exists in the IL as published
15b
Scheme 2 Iron-containing ionic liquids used in this study.
Fig. 1 IR spectra of mixtures of acetonitrile and [C
acetonitrile; (b) molar ratio of FeCl to C mimCl = 1 : 1; (c) molar ratio
of FeCl to C mimCl = 1.2 : 1; (d) molar ratio of FeCl to C mimCl =
4 4
mim][FeCl ]: (a)
It was reported that the Lewis acidic strength of this kind
of metal-containing ILs could be adjusted by varying the molar
3
4
3
4
3
4
8d,16
fraction of the metal halide.
Based on the reported principles,
2.0 : 1.
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a
4 4
Table 2 [C mim][FeCl ]-catalyzed benzylation reaction of different arenes with various benzylating reagents
b
c
Entry
1
(Hetero)Arenes
Benzylating reagent
Main product
Yield (%)
Regioselectivity (%)
21
—
f
2
3
4
5
55
98
76 : 11 : 3
96 : 4
100
d
86
97
98
84
80 : 20
e
6
67 : 33
94 : 6
e
7
e
8
65
87
78 : 22
100
e
9
1
1
1
0
1
2
92
87
96
98 : 2
98 : 2
96 : 4
1
1
3
4
56
93
95 : 5
97 : 3
a
c
◦
b
Reaction conditions: 1-phenylethyl acetate, 1 mmol; (hetero)arenes, 1 mL; [C
4
mim][FeCl
4
] (1 : 1.2), 10 mmol%; 80 C; 12 h. Determined by GC.
f
d
e
Molar ratio of p-:o-isomer. 30 mmol% C
4
mim-FeCl
4
(1 : 1.2). 4 mmol of arenes or heteroarenes, 2 mL CH NO . Molar ratio of p-:o-:m-isomer.
3 2
1
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a
Then the catalytic application of the task-specific ILs for
benzylation of arenes was further investigated. In the initial
study, the reaction of o-xylene and 1-phenylethyl acetate was
selected as a model reaction for preliminary study, as shown in
Scheme 3. The results are summarized in Table 1.
Table 3 Catalyst repetition
b
c
d
Run
Conversion (%)
Yield (%)
Regioselectivity (%)
1
2
3
4
5
99
99
99
99
99
97
97
96
97
96
96 : 4
95 : 5
95 : 5
95 : 5
96 : 4
a
Reaction conditions: 1-phenylethyl acetate, 1 mmol; o-xylene, 8.4 mmol
◦
b
(
1 mL); catalyst, 0.1 mmol; [C mim][FeCl ] (1 : 1.2); 80 C; 12 h. Based
4
4
c
on 1-phenylethyl acetate, determined by GC. Total yield of 1 and 2.
d
Scheme 3 Benzylation reaction of o-xylene with 1-phenylethyl acetate.
Molar ratio of 1 to 2.
On one hand, FeCl
fording the corresponding p-benzylated product 1 [1,2-dimethyl-
-(1-phenylethyl)benzene] quantitatively under the given reac-
tion conditions (entry 1, Table 1). On the other hand, the
native ILs, viz. C mimCl, C mimBr and C mimBF were inactive
3
showed high activity for the reaction, af-
alcohol, benzyl acetate, 1-phenylethanol, 1,1-diphenylmethanol
and benzyl chloride were found to be active benzylating reagents.
O-xylene could react with the tested benzylating reagents in the
4
4
4
4
4
presence of C
4
mim/FeCl (1 : 1.2) to give the corresponding
4
at all (entries 2-4). Furthermore, only starting materials were
recovered when the reaction was carried out in the presence
benzylated products in good to excellent yields with high
regioselectivity. (entries 3, 10–14).
of 10 mmol% of the FeCl
3
-based IL, i.e. [C
Br] with 1 : 1 molar ratio of C
entries 5, 6). Additionally, the catalyst system comprising FeCl
mimBF
% conversion (entry 7), suggesting that the neutral FeCl
study could not be the actual catalytic species. To our delight,
-phenylethyl acetate was almost quantitatively converted to the
desired p-benzylated products 1 with an excellent regioselectivity
when the molar ratio of FeCl to C mimCl was increased
to 1 : 1.2 and 1 : 2.0 (entries 8, 9), respectively. This could be
understandable because the catalyst activity of [C mim][FeCl
4
mim][FeCl
4
] or
[C
4
mim][FeCl
3
4
mimX/FeCl
3
(
3
and the non-complexing IL, viz. C
5
4
4
only gave less than
in this
Catalyst recycling
3
ILs have been proven to be an excellent medium for the
7
immobilization of transition metal catalysts. One feature of this
1
IL-catalyzed benzylation reaction would be facile separation of
the catalyst. Although FeCl
its hydrolysis easily, the results in this study showed that the
catalyst FeCl /C mimCl is stable to air and moisture. To test
3
alone is sensitive to moisture since
3
4
]
3
4
4
4
catalyst reusability, the initially surveyed benzylation reaction
of o-xylene and 1-phenylethyl acetate was carried out under
for the Lewis acid-catalyzed alkylation reactions could be
depended on its acidity as mentioned before in Fig. 1. As a
identical reaction conditions in the presence of [C
4
mim][FeCl ].
4
consequence, the Fe(III)-based IL with a FeCl
3
/C mimCl molar
4
The products can be simply separated by decantation from the
reaction mixture while the catalyst trapped in the IL phase was
then subjected to a subsequent run of the reaction by charging
ratio of 1.2 : 1 was chosen as the catalyst for further investigation.
It is also worth mentioning that either decreasing the reaction
temperature or shortening the reaction time caused a sharp
decrease in the conversion while regioselectivity was almost
unchanged (entries 10, 11).
The utility and generality of this approach for various
aromatics using 1-phenylethyl acetate as the benzylating reagent
were also investigated by performing the reaction under the
given conditions. The results are summarized in Table 2.
As expected, a variety of electron-rich aromatic substrates
such as o-xylene, anisole, phenol, and b-naphthol gave the
corresponding benzylated products in excellent yields (entries
fresh substrate. As listed in Table 3, the catalyst [C
4
mim][FeCl ]
4
could be reused for five times without significant loss of its cat-
alytic activity with the retention of high regioselectivity (entries
1
–5, Table 3). In addition, determination of the iron content
of both fresh and recovered catalyst by using ICP method
also confirmed the stability of the catalyst (see Supplementary
Information†).
3
, 5, 6, 7, Table 2). However, toluene was shown to be less
Conclusions
active for this reaction (entry 2). In the case of p-xylene as a
substrate, higher catalyst loading up to 30 mmol% is required
to perform the reaction smoothly (entry 4). On the other hand,
benzene as a non-activated substrate gave poor results under
the reaction conditions (entry 1), and further increasing the
reaction temperature or prolonging the reaction time can not
improve the reaction. In addition, several heteroarenes such
as thiophene and furan could work very well affording the
corresponding benzylated products in good to excellent yields
In conclusion, we have established an efficient approach to
Friedel–Crafts-type benzylation of various arenes and het-
eroarenes using an iron-containing IL, viz. [C
4
mim][FeCl ] as
4
the catalyst. The mild reaction conditions, operational simplicity
and practicability render this protocol an attractive approach to
diarylmethane derivatives. Furthermore, it is worth noting that
this procedure is especially attractive because of its cheap, easy
to handle and recyclable catalyst from the point of view of green
and sustainable chemistry. When benzyl alcohols are used as the
benzylated reagents, it would become a state-of-the-art green
access to diarylmethane derivatives because water is the only
side-product in this reaction.
(
entries 8, 9). It is particularly noteworthy that furan showed the
best regioselectivity specifically furnishing the corresponding p-
benzylated product. The scope of benzylating reagents was also
investigated as shown in Table 2. 1-Phenylethylacetate, benzyl
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Acknowledgements
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This work was supported by the National Natural Science Foun-
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Fellowship for International Young Scientists from NSFC
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7 Determination of the acidity of ionic liquids: acetonitrile was refluxed
over, and distilled from P . All IR samples were prepared by mixing
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