The Friedel-Crafts acylation of aromatic compounds with carboxylic acids by the combined use of perfluoroalkanoic anhydride and bismuth or scandium triflate

Article abstract of DOI:10.1016/j.tetlet.2004.04.089

Aromatic ketones were synthesized by solventless Friedel-Crafts acylation of anisole, mesitylene, xylenes, and toluene with acetic acid and benzoic acid in the presence of trifluoroacetic anhydride by use of bismuth or scandium triflate at 30°C. Toluene, benzene, and even deactivated substrate such as chlorobenzene were benzoylated by the combined use of heptafluorobutyric anhydride and bismuth triflate at 75-100°C. The catalyst could be easily recovered and reused repeatedly for the reaction.

Full text of DOI:10.1016/j.tetlet.2004.04.089

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4723–4727
The Friedel–Crafts acylation of aromatic compounds with
carboxylic acids by the combined use of perfluoroalkanoic
anhydride and bismuth or scandium triflate
Yoh-ichi Matsushita,* Kazuhiro Sugamoto and Takanao Matsui
Faculty of Engineering, University of Miyazaki, Gakuen-Kibanadai-Nishi, Miyazaki 889-2192, Japan
Received 23 February 2004; revised 14 April 2004; accepted 15 April 2004
Abstract—Aromatic ketones were synthesized by solventless Friedel–Crafts acylation of anisole, mesitylene, xylenes, and toluene
with acetic acid and benzoic acid in the presence of trifluoroacetic anhydride by use of bismuth or scandium triflate at 30 ꢀC.
Toluene, benzene, and even deactivated substrate such as chlorobenzene were benzoylated by the combined use of heptafluoro-
butyric anhydride and bismuth triflate at 75–100 ꢀC. The catalyst could be easily recovered and reused repeatedly for the reaction.
ꢁ 2004 Elsevier Ltd. All rights reserved.
The Friedel–Crafts acylation of aromatic compounds
with acyl halides, which is an important process for the
preparation of pharmaceuticals, perfumes, and poly-
mers, has been performed with at least a stoichiometric
amount of Lewis acids.1;2 Aromatic ketones have been
also prepared by dehydrative acylation reactions of
aromatic compounds with carboxylic acids catalyzed by
various types of acid such as methanesulfonic acid,3
trifluoromethanesulfonic acid (TfOH),4 Nafion-H,5
zeolite,6 and heteropoly salt.7 However the acid catalysts
are generally used in excess of molar amounts. Recently,
Kobayashi et al. reported the direct acylation of phenol
and naphthol derivatives with carboxylic acids using a
catalytic amount of metal triflate such as Hf(OTf)4,
Zr(OTf)4, or Sc(OTf)3.8 Furthermore, Shimada’s group
reported both the intramolecular reaction of 3-aryl-
the direct dehydration reactions. On the other hand, the
Friedel–Crafts acylation via mixed anhydrides prepared
in situ from carboxylic acids has been achieved by the
combined use of an activating agent and a catalyst, for
example, p-trifluoromethylbenzoic anhydride and SiCl4–
AgClO4,11 trifluoroacetic anhydride (TFAA) and
H3PO4,12;13 or TFAA and AlPW12O40.14 The mixed
anhydride methods are advantageous in terms of the
mild conditions employed and the easily availability of
carboxylic acids, however, the substrates are limited to
activated benzenes such as anisole, xylene, and toluene.
Development of more efficient activating agents and/or
catalysts is still demanded. In this paper we report an
facile and efficient method for preparation of aromatic
ketones by solventless Friedel–Crafts acylation of aro-
matic compounds with carboxylic acids in the presence
of perfluoroalkanoic anhydride such as TFAA or hepta-
fluorobutyric anhydride (HFBA) by use of Bi(OTf)3 or
Sc(OTf)3 as a catalyst (Scheme 1).
9
propionic acids in the presence of Tb(OTf)3 and the
intermolecular reaction of anisole and alkylbenzenes
with carboxylic acids in the presence of Eu(NTf2)3.10
However, drastic conditions at high temperature are
needed and/or applicable substrate range is limited on
We first examined the effect of catalysts such as Nafion-
16
Bi(OTf),3 and
17
H15 (Nafion NR-50beads), TfOH,
18
Sc(OTf)3 on the Friedel–Crafts acetylations of aro-
matic compounds with acetic acid in the presence of
1.5 equiv of TFAA at 30 ꢀC (Scheme 2). The time
courses for production of acetophenones 1–5 were fol-
lowed by GC.
Keywords: Friedel–Crafts acylation; Trifluoroacetic anhydride; Hepta-
fluorobutyric anhydride; Bismuth triflate; Scandium triflate; Mixed
anhydride.
Figure 1 shows the results for m-xylene. The acetylation
of m-xylene proceeded very slowly without the catalyst.
* Corresponding author. Tel.: +81-985-58-7389; fax: +81-985-58-7323;
e-mail: matusita@cc.miyazaki-u.ac.jp
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.089

4724
Y. Matsushita et al. / Tetrahedron Letters 45 (2004) 4723–4727
Scheme 1.
the reaction of toluene with benzoyl chloride and the
real catalyst was TfOH formed from the metal triflates
by ligand exchange reaction.19b The present activity
tendency of the catalysts coincides with that described
by them. Since Nafion-H, Bi(OTf)3, and Sc(OTf)3 can be
more easily recovered than TfOH from the reaction
mixture, we decided to use these catalysts on the fol-
lowing reactions.
Next, acetic acid was allowed to react with several
benzenes (Table 1). In the absence of the catalyst, the
acetylations of anisole and mesitylene proceeded faster
than that of m-xylene: Acetophenones 2a,b and 3 were
obtained in 86% and 95% yields after 24 h, respectively.
Although Nafion-H, Bi(OTf)3, and Sc(OTf)3 promoted
the acetylation of anisole, the elongation of the reaction
time led to the decrease in the yield of 2a,b. Hydroxy-
acetophenones were isolated as minor products in the
reaction mixture after 24 h, and are probably produced
from 2a,b by cleavage of O–Me bond. Bi(OTf)3 and
Sc(OTf)3 were more effective than Nafion-H on the
acetylation of mesitylene. The acetylation of toluene
using 10mol % Bi(OTf) 3 or 10mol % Sc(OTf) 3 gave
4a,b, while no reaction took place without the catalyst.
Bi(OTf)3 was more effective than Sc(OTf)3. No or little
acetylation of benzene occurred both in the absence and
in the presence of Bi(OTf)3. Bi(OTf)3 and Sc(OTf)3 are
found to be more active on the TFAA-mediated acetyl-
Scheme 2.
14
ation than AlPW12O4 as the catalyst, and be almost
comparable with H3PO4.12;13
The acetylations of aromatic compounds at higher
temperature were carried out in the presence of HFBA
(bp 108–109 ꢀC) instead of TFAA (bp 39.5–40 ꢀC) and
the results are shown in Table 2. Under the conditions at
100 ꢀC without the catalyst, both anisole and mesitylene
gave the corresponding acetophenones in high yields for
3 h, and m-xylene gave 3 in 60% yield for 24 h. The
reaction of m-xylene using 3.3 mol % Bi(OTf)3 was
complete in 3 h. The reaction of toluene at 100 ꢀC
without the catalyst was very slow, while that with
10mol % Bi(OTf) 3 gave 4a,b in 32% yield. Decreasing
yield of 4a,b with the elapse of the reaction time suggests
that 4a,b gradually decompose during the reaction. (The
decomposed products was not yet determined.) Benzene
could be acetylated in low yield in the presence of
10mol % Bi(OTf) 3 at 75 ꢀC.
Figure 1. Time courses of the Friedel–Crafts acetylation of m-xylene
(2 mmol) with acetic acid (1 mmol) in the presence of TFAA
(1.5 mmol) at 30 ꢀC by use of several catalysts: none (·), 10mol %
Nafion-H (}), 10mol % TfOH ( n), 3.3 mol % Bi(OTf)3 (s), 3.3 mol %
Sc(OTf)3 (h), 10mol % Bi(OTf) 3 (d), and 10mol % Sc(OTf) 3 (j).
Yield of 1 was determined based on acetic acid by GC: conditions;
detector, FID; column: OV-17 (3.2 mm, 2 m); carrier gas, N2; temp
100–280 ꢀC (10 ꢀC/min); internal standard, tridecane.
The addition of 10mol % Nafion-H (Nafion NR-50
beads) or 10mol % TfOH promoted the reaction, and
the yield of 1 was 70% for Nafion-H and 86% for TfOH
after 24 h. The catalytic activity of 10mol % TfOH was
almost equal to those of 3.3 mol % Bi(OTf)3 and
3.3 mol % Sc(OTf)3. When using 10mol % Bi(OTf) 3 or
10mol % Sc(OTf) 3, the reaction was complete in 6 h.
Dubac’s group already elucidated that metal triflates
had the same activity as triplicate amount of TfOH on
The benzoylations of aromatic compounds were
attempted in the presence of TFAA or HFBA (Scheme
3). Table 3 summarizes the results. The TFAA-mediated
benzoylations of anisole and mesitylene without the
catalyst at 30 ꢀC afforded 6 and 7, respectively, in 41%
and 36% yields after 12 h. When HBFA was used at

Y. Matsushita et al. / Tetrahedron Letters 45 (2004) 4723–4727
4725
Table 1. The Friedel–Crafts acetylations of aromatic compounds with acetic acid in the presence of TFAA at 30 ꢀCa
Entry
Substrate
Catalyst (mol %)
Product
Yield/% (isomer distribution/a:b)b
6 h 24 h
71 (96:4)
3 h
51 (96:4)
1
Anisole
Anisole
None
2a,b
2a,b
2a,b
2a,b
3
86 (98:2)
75 (99:1)
65 (98:2)
68 (98:2)
95
2
Nafion-H (10)
Bi(OTf)3 (3.3)
Sc(OTf)3 (3.3)
None
84 (98:2)
73 (96:4)
76 (98:2)
17
82 (98:2)
72 (98:2)
71 (98:2)
28
3
Anisole
Anisole
4
5
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Toluene
6
Nafion-H (10)
Bi(OTf)3 (3.3)
Sc(OTf)3 (3.3)
None
3
4063 0
92
10
7
3
100
100
8
3
100
100
0
100
0
9
10Toluene
4a,b
4a,b
4a,b
5
0
38 (94:6)
25 (96:4)
Bi(OTf)
(10)
Sc(OTf)3 (10)
None
43 (94:6)
27 (96:4)
46 (95:5)
30(96:4)
3
11
12
13
14
Toluene
Benzene
Benzene
Benzene
0
1
0
0
1
0
0
1
0
Bi(OTf)3 (10)
Sc(OTf)3 (10)
5
5
a Acetic acid (1 mmol) was allowed to react with aromatic compounds (2.0mmol) in the presence of TFAA (1.5 mmol) by use or no use of the catalyst
(3.3 or 10mol %) at 30 ꢀC.
b Determined by GC using decane for toluene, tridecane for mesitylene, or tetradecane for anisole and benzene as an internal standard under the same
conditions as described in Figure 1.
Table 2. The Friedel–Crafts acetylations of aromatic compounds with acetic acid in the presence of HFBAa
Entry
Substrate
Catalyst (mol %)
Temp/ꢀC
Product
Yield/% (isomer distribution/a:b)b
3 h
89 (93:7)
6 h
24 h
1
2
3
4
5
6
7
8
Anisole
None
None
100
100
100
100
100
100
75
2a,b
3
85 (95:5)
––c
33
73 (98:2)
––
Mesitylene
m-Xylene
m-Xylene
Toluene
Toluene
Benzene
Benzene
100
19
None
Bi(OTf)3 (3.3)
None
1
60
––
1
100
––
4a,b
4a,b
5
1 (100:0)
32 (86:14)
2 (100:0)
22 (84:16)
0
6 (86:14)
16 (78:22)
0
Bi(OTf)3 (10)
None
Bi(OTf)3 (10)
0
12
75
5
2023
a Acetic acid (1 mmol) was allowed to react with aromatic compounds (2.0mmol) in the presence of HFBA (1.5 mmol) by use or no use of the catalyst
(3.3 or 10mol %) at 75 or 100 ꢀC.
b Determined by GC under the same conditions as described in Table 1.
c Not examined.
30 ꢀC instead of TFAA for the reactions of anisole and
mesitylene, the yields of 6 and 7 were 24% and 10%,
respectively (data not shown in Table 3): A reason of the
low yields is likely that the reaction mixture is hetero-
geneous because neither anisole nor mesitylene is soluble
in HBFA at 30 ꢀC. On the other hand, when HFBA
alone was used at 100 ꢀC, anisole and mesitylene were
rapidly converted into the corresponding ketones in high
yields. Bi(OTf)3 was effective not only for the TFAA-
mediated benzoylations at 30 ꢀC of anisole, mesitylene,
xylenes, and toluenes but also for the HFBA-mediated
acylations at 75 ꢀC of toluene and benzene with benzoic
acid, m-chlorobenzoic acid, or p-chlorobenzoic acid.
Chlorobenzene, one of the deactivated benzenes, was
also benzoylated by the combination use of Bi(OTf)3
and HFBA at 100 ꢀC. It has been reported that less
reactive substrates such as toluene, benzene, and chlo-
robenzene were acylated with acyl chlorides or acyl
anhydrides by a catalytic amount of metal perflu-
oroalkylsufonates, for example, Bi(OTf)3,19 Hf(OTf)4–
TfOH,20 Hf(OTf)4 in LiClO4–MeNO2,21 Cu(OTf)2,22
B(OTf)3,23 Al(OTf)3,23 Ga(OTf)3,23 and Ga(OSO2CF2
CF2CF2CF3)3.24 However, the catalytic acylation of
benzene and chlorobenzene with free carboxylic acid via
mixed anhydride generated in situ was not reported, as
far as we know. It is noteworthy that toluene, benzene,
and especially deactivated substrate such as chlorobenz-
ene are benzoylated in the present conditions.
Finally, we tried recovery and reuse of the catalyst on
the Bi(OTf)3-catalyzed benzoylation of m-xylene with
benzoic acid in the presence of TFAA (Table 4). The

4726
Y. Matsushita et al. / Tetrahedron Letters 45 (2004) 4723–4727
Scheme 3.
Table 3. The Friedel–Crafts acylations of aromatic compounds with benzoic acids in the presence of TFAA or HFBAa
Carboxylic acid
Yield/%b (isomer
distribution/a:b)c
Entry
Substrate
Anhydride
Catalyst (mol %)
Temp/ꢀC
Time/h
Product
X1 ¼
X2 ¼
1
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
Anisole
Anisole
Anisole
TFAA
TFAA
HFBA
TFAA
TFAA
HFBA
TFAA
TFAA
TFAA
None
3012
3012
100
3012
30
6
41
98
2
Bi(OTf)3 (3.3)
None
None
6
3
3
6
95
36
4
Mesitylene
Mesitylene
Mesitylene
o-Xylene
m-Xylene
Toluene
7
5
Bi(OTf)3 (10)
None
12
3
7
99
98
6
100
30
7
7
Bi(OTf)3 (10)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
12
12
12
12
12
12
12
12
12
8a,b
9
98 (97:3)
98
8
30
30
9
10a,b
10a,b
11
72 (88:12)
96 (86:14)
12
10H
11
12
13
14
15
Toluene
HFBA
Bi(OTf)
(10)
75
30
3
H
H
Cl
H
H
Benzene
Benzene
Benzene
Benzene
TFAA
HFBA
HFBA
HFBA
Bi(OTf)3 (10)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
Bi(OTf)3 (10)
75
75
11
12
90
86
75
100
13
14a,b
54
65 (94:6)
Chlorobenzene HFBA
a Benzoic acid, m-chlorobenzoic acid, or p-chlorobenzoic acid (1 mmol) was allowed to react with aromatic compounds (2.0mmol) in the presence
of TFAA or HFBA (1.5 mmol) by use or no use of Bi(OTf)3 (3.3 or 10mol %) at 75 or 100 ꢀC.
b Isolated yield.
c Determined by 1H NMR.
Table 4. Repeated use of Bi(OTf)3 for the benzoylation of m-xylenea
aqueous layer after aqueous work-up, Bi(OTf)3 is more
easily recovered without post-treatment in our method.
Run
Isolated yield of 9/%
Recovery of Bi(OTf)3/%
1
2
3
4
98
96
97
96
95
96
96
95
In a typical procedure, to a mixture of benzoic acid
(610mg, 5.0mmol), m-xylene (1.06 g, 10 mmol), and
Bi(OTf)3Æ4H2O (364 mg, 0.5 mmol) in glass vial with
Teflon-lined screw cap was added TFAA (1.06 cm3,
7.5 mmol) at 0 ꢀC, and the vial was sealed with the cap.
The mixture was magnetically stirred at 30 ꢀC for 12 h.
After the reaction mixture has been evaporated in
vacuo, 10cm3 of hexane was added to the gummy residue.
The resulted solution was treated with ultrasonic cleaner
bath (200 W) for 5 min: pale yellowish solid of Bi(OTf)3
precipitated. The precipitate was filtered with suction,
washed with hexane, and dried briefly in vacuo. Thus,
345 mg (95%) of Bi(OTf)3 was recovered and reused on
second run. On the other hand, the filtrate was evapo-
a Benzoic acid (5 mmol) was allowed to react with m-xylene (10mmol)
in the presence of TFAA (7.5 mmol) and Bi(OTf)3 (0.5 mmol) at 30 ꢀC
for 12 h.
reaction mixture was evaporated in vacuo in order to
remove volatile TFAA, trifluoroacetic acid, and m-xyl-
ene. Hexane was added to the residue and the precipitate
of Bi(OTf)3 was collected by filtration. Bi(OTf)3 was
recycled and used repeatedly without loss of activity.
Although metal triflates are usually recovered from the

Y. Matsushita et al. / Tetrahedron Letters 45 (2004) 4723–4727
4727
8. Kobayashi, S.; Morikawa, M.; Hachiya, I. Tetrahedron
Lett. 1996, 37, 4183–4186.
9. Cui, D.-M.; Zhang, C.; Kawamura, M.; Shimada, S.
Tetrahedron Lett. 2004, 45, 1741–1745.
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rated under the reduced pressure to give the almost pure
9 as colorless oil. Further purification was done by flash
column chromatography on silica gel (25 g) with hexane/
Et2O ¼ 20/1 to give 9 (1.03 g, 4.90 mmol) in 98% yield.
In conclusion, the Friedel–Crafts acylation of aromatic
compounds with carboxylic acids was successfully car-
ried out by using Bi(OTf)3 or Sc(OTf)3 as the catalyst in
the presence of perfluoroalkanoic anhydrides such as
TFAA and HFBA under solventless and mild condi-
tions, less reactive substrates such as benzene and
chlorobenzene could be converted into the correspond-
ing benzophenones. Further investigation to clarify the
scope and limitation of the present reaction and to apply
for synthesis of fine chemicals is now in progress.
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