Simple and improved procedure for the regioselective acylation of aromatic ethers with carboxylic acids on the surface of graphite in the presence of methanesulfonic acid

Article abstract of DOI:10.1055/s-2004-831162

Friedel-Crafts acylation of aromatic compounds such as anisole has been successfully carried out using the combination of graphite with MeSO ₃H. Both aromatic and aliphatic carboxylic acids reacted smoothly under the conditions to afford the corresponding aromatic ketones in high yield.

Full text of DOI:10.1055/s-2004-831162

PAPER
2165
Simple and Improved Procedure for the Regioselective Acylation of Aromatic
Ethers with Carboxylic Acids on the Surface of Graphite in the Presence of
Methanesulfonic Acid
Regioselective
Acylati
o
onof
A
roma
n
tic
E
ther
s
w
i
a
thCarboxylic
Aci
H
ds osseini Sarvari, Hashem Sharghi*
Department of Chemistry, Faculty of Science, Shiraz University, Shiraz 71454, Iran
E-mail: sharghi@chem.susc.ac.ir
Received 29 March 2004; revised 1 June 2004
11
version of aldehydes into nitriles were effected using
such conditions.
Abstract: Friedel–Crafts acylation of aromatic compounds such as
anisole has been successfully carried out using the combination of
graphite with MeSO3H. Both aromatic and aliphatic carboxylic ac-
ids reacted smoothly under the conditions to afford the correspond-
ing aromatic ketones in high yield.
As a part of our continued efforts to utilize surface-medi-
ated reactions for useful synthetic transformations,12 we
wish to disclose here a very simple and highly efficient
method for regioselective acylation of aromatic ethers
with carboxylic acids in the presence of MeSO3H on the
surface of graphite (Scheme 1).
Keyword: Friedel-Crafts acylation, acylations, graphite, regiose-
lectivity, carboxylic acids
The Friedel–Crafts acylation of aromatic compounds is
one of the most fundamental and useful reactions in or-
ganic synthesis.1 The disadvantages associated with the
classical procedures include the use of toxic acid chloride
as the acylating agent and stoichiometric amounts of alu-
minium trichloride as a Lewis acid, which entails environ-
ment pollution. In order to minimize this problem, some
catalytic Friedel–Crafts acylations have been developed
recently.2 In addition, acylations involving carboxylic ac-
ids and less toxic Lewis acids3 or apparently non-hazard-
ous acid catalysts4 have been studied, although these
procedures are not quite successful as practical and gener-
al synthetic methods. For instance, a methodology4b of
acylation of anisole with carboxylic acids over HZSM-5
zeolite, although environmentally safe, has limitations
with regard to generality (no reaction with higher acids)
and efficiency (reaction time of 48 h and concomitant O-
acylation). Recently, it was also shown that alumina pro-
motes the acylation of reactive aromatics such as anisole
and thiophene with carboxylic acid in the presence of tri-
fluoroacetic anhydride.5 Thus, a reliable general method
for this useful reaction involving non-hazardous reagents
is in demand.
Scheme 1
To exploit a simple and suitable condition for the Friedel–
Crafts acylation of aromatic ethers, the reaction of anisole
with acetic acid was chosen as a model, and its behavior
was studied under a variety of conditions via TLC and 1H
NMR spectroscopy (Table 1).
According to Table 1, the best results were obtained using
a mixture of graphite and MeSO3H in a 2:1 molar ration,
when carried out at 80 °C for 20 min. The results also
show that the importance of using both graphite and
MeSO3H. In the absence of graphite (entry 3) or MeSO3H
(entry 4), the attempted acylation did not afford the corre-
sponding product.
In a typical reaction, carboxylic acid and aromatic ether
were added to a mixture of graphite and MeSO3H and
mixed uniformly with shaking. The mixture was kept at
80 °C in an oil bath with occasional shaking for a certain
period of time until the reaction was completed. The prod-
uct was isolated by simple extraction of the solid mass by
diethyl ether followed by usual work-up. Several structur-
ally varied aromatic ethers underwent acylations with a
wide range of carboxylic acids including cyclic, acyclic,
and aromatic ones. The results are presented in Table 2.
One of the most important objectives now is to adapt clas-
sical processes so that pollution effects are kept to a min-
imum, with both a reduction in energy and consumption
of raw materials. In this respect, dry-media reactions are
promising, and a new approach has been undertaken using
graphite chemistry. The exceptional ability of graphite to
adsorb organic molecules is well known.6 Diels–Alder
and ene reactions,7a–g decarboxylations,7a,b decomposi-
tions,8 rearrangements,7a,b,9 keto carboxylation 10 and con-
The reactions are remarkably clean, and no chromato-
graphic separation is necessary to get the spectra-pure
compounds. Acylation occurs exclusively para to the
OMe group for all of the ethers studied, in high yields.
However, in cases where the para position is blocked
(Table 2, entry 11), the acyl group is introduced ortho to
the ether moiety. This procedure is also good enough for
SYNTHESIS 2004, No. 13, pp 2165–2168
x
x.
x
x
.
2
0
0
4
Advanced online publication: 13.08.2004
DOI: 10.1055/s-2004-831162; Art ID: Z06804SS
© Georg Thieme Verlag Stuttgart · New York

2166
M. Hosseini Sarvari, H. Sharghi
PAPER
Table 1 Friedel Crafts Acylation of Anisol (1 mmol) with Acetic
Acid (1 mmol) under Various Reaction Conditions
high yields, without any of the environmental disadvan-
tages of using toxic homogeneous reagents such as anhy-
drous AlCl3.
Another interesting behaviour of graphite lies in the fact
that it can be re-used after simple washing with ethyl ace-
tate and water, rendering thus process more economic.
The results of this study are shown in Figure 1.
Entry Conditions
Time (min) Yield (%)a
1
2
3
4
5
H2SO4, 80 °C
120
60
10
PPA, 80 °C
10
MeSO3H (1 mL), 80 °C
graphite (0.1 g), 80 °C
60
trace
120
10
No reaction
80
graphite (0.1 g);
MeSO3H (1.5 mL), 100 °C
6
7
graphite (0.1 g);
MeSO3H (0.5 mL), 100 °C
5
10
10
60
20
75
82
85
70
98
graphite (0.1 g);
MeSO3H (0.3 mL), 100 °C
8
graphite (0.1 g);
MeSO3H (1.5 mL), 80 °C
Figure 1 Re-use studies on the graphite-mediated synthesis of 4-
methoxyacetophenone using anisol (1 mmol) and acetic acid (1
mmol). The reaction was carried out in an oil bath at 80 °C. In paren-
thesis reaction time is given.
9
graphite (0.1 g);
MeSO3H (0.5 mL), 60 °C
10
graphite (0.1 g);
MeSO3H (0.3 mL), 80 °C
In conclusion, the present method provides a very conve-
nient and efficient procedure for acylation of aromatic
ethers. The notable advantages of this methodology are
direct use of a wide variety of carboxylic acids, fast reac-
tion, operational simplicity, generality, excellent regiose-
lectivity, no side reaction, and quantitative yields, and
thus it offers significant improvements over other proce-
dures involving Friedel–Crafts acylation of aromatic
ethers.2–4,14,15
a Isolated yields.
the acylation of heterocyclic compounds such as furan
(Table 1, entry 9), producing the corresponding 2-acylat-
ed product in excellent yield. The reactions are reasonably
fast even with the higher acids and cyclohexanecarboxylic
acid; however, aromatic carboxylic acids with electron-
withdrawing groups (Table 2, entries 6, 7, 8) react rather
slowly. The reaction conditions are mild enough not to in-
duce any dealkylation of an ether residue ortho to the in-
troduced acyl group (Table 2, entry 11) as observed in the
acylation reaction with carboxylic acid catalyzed by BF3.3
Starting materials were obtained from Fluka Company. Melting
points were determined using a Büchi 510 apparatus and are uncor-
rected. IR spectra were measured on a Perkin-Elmer spectrometer.
NMR [1H (250 MHz), 13C (62.9 MHz)] spectra were recorded on a
Bruker Advance DPX FT 250 MHz instrument in CDCl3 with TMS
as the internal standard.
Although the use of graphite for acylation of active aro-
matic compounds has been reported previously,13 our new
method, using a mixture of graphite and MeSO3H, offers
significant improvements over the earlier method, reduc-
ing the reaction time considerably (20 minutes compared
to eight hours), minimizing the amount of graphite from 1
g to 0.1 g, increasing the yield remarkably, and above all,
using both electron donating and specially withdrawing
substituted carboxylic acids instead of using the expen-
sive and polluting acid halides that require special proce-
dures in handling and working up.
Acylation of Aromatic Ethers (Table 2); Typical Procedure
To a mixture of graphite (powder type; 0.1 g, 8 mmol) and MeSO3H
(0.3 mL, 4 mmol) at 80 °C in an oil bath, aromatic ether (1 mmol)
and carboxylic acid (1 mmol) were added. The reaction mixture was
kept at 80 °C with occasional shaking for a certain period of time
(Table 2) as required to complete the reaction (monitored by TLC).
The reaction mixture was extracted with CHCl3 (2 × 20 mL). The
organic layer was washed with sat. aq NaHCO3, dried (Na2SO4).
Evaporation of solvent furnished practically pure product. This was
further purified by recrystallization with suitable solvent (Et2O or
MeOH).
Therefore, graphite–MeSO3H has been shown to have a
remarkable high activity for the acylation of aromatic
compounds with both aromatic and aliphatic carboxylic
1
The structure of the products was confirmed by H NMR, IR and
comparison with authentic samples obtained commercially or pre-
acids to give the corresponding acylated compounds in pared by reported methods.
Synthesis 2004, No. 13, 2165–2168 © Thieme Stuttgart · New York

PAPER
Regioselective Acylation of Aromatic Ethers with Carboxylic Acids
2167
Table 2 Acylation of Aromatic Ethers with Carboxylic Acids Using Graphite–MeSO3H in Molar Ratio of 2:1
Entry
1
Substrate
Acid
Product
Time (min)
20
Yield (%)a
MeCO2H
98
95
98
90
85
85
80
2
3
4
5
6
7
20
5
Me(CH2)8CO2H
20
60
120
180
8
240
85
9
MeCO2H
MeCO2H
20b
50
98
90
10
11
12
MeCO2H
MeCO2H
30
30
95
90
a Yields are the isolated compounds.
b The reaction was carried out at r.t., and better at 0–10 °C.
Acknowledgment
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We gratefully acknowledge the support of this work by the Shiraz
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