High-Throughput Synthesis of Alkylbenzophenones with Indium Triflate in the Absence of Solvents Using Microwave

Article abstract of DOI:10.1081/SCC-120026324

A series of alkylbenzophenones were rapidly and efficiently prepared from alkylbenzenes and benzoyl chlorides by Friedel-Crafts acylation catalyzed with indium triflate under solvent-free conditions by microwave heating.

Full text of DOI:10.1081/SCC-120026324

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High-Throughput Synthesis of Alkylbenzophenones
with Indium Triflate in the Absence of Solvents Using
Microwave
Hideko Koshima a & Masashi Kubota a
a Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama,
Japan
Version of record first published: 19 Aug 2006.
To cite this article: Hideko Koshima & Masashi Kubota (2003): High-Throughput Synthesis of Alkylbenzophenones with
Indium Triflate in the Absence of Solvents Using Microwave, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:22, 3983-3988
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 22, pp. 3983–3988, 2003
High-Throughput Synthesis of
Alkylbenzophenones with Indium Triflate in the
Absence of Solvents Using Microwave
*
Hideko Koshima and Masashi Kubota
Department of Applied Chemistry, Faculty of
Engineering, Ehime University, Matsuyama, Japan
ABSTRACT
A series of alkylbenzophenones were rapidly and efficiently prepared
from alkylbenzenes and benzoyl chlorides by Friedel-Crafts acylation
catalyzed with indium triflate under solvent-free conditions by
microwave heating.
Key Words: Microwave-assisted synthesis; Friedel-Crafts acyla-
tion; Alkylbenzophenones; Indium triflates; Solvent-free synthesis.
High-throughput synthesis is one of the goals in organic synthesis.
Decrease of reaction time as well as simplification of separation process is
required in high-throughput synthesis. Microwave heating brings the
*Correspondence: Hideko Koshima, Department of Applied Chemistry, Faculty
of Engineering, Ehime University, Matsuyama 790-8577, Japan; E-mail:
koshima@eng.ehime-u.ac.jp.
3983
DOI: 10.1081/SCC-120026324
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3984
Koshima amd Kubota
technical solutions because of dramatic decrease of reaction time.[1–5]
Friedel-Crafts acylation is fundamental and important reaction in
organic synthesis.[6–8] Lewis acid catalysts such as AlCl3 and BF3 have
been commonly used in more than a stoichiometric amount. However,
recently metal triflates such as Sc(OTf )3 and Yb(OTf )3 have been known
to be efficient catalysts for Friedel-Crafts acylation in small or catalytic
amount.[9–14] Microwave assisted Friedel-Crafts acylations have been
[15]
already reported, but an over stoichiometric excess of AlCl3
and
FeCl3,[16] and large excess of polyphosphoric acid[17] were needed to
complete the reactions. We would like to decrease amounts of catalysts
and not to use organic solvents in our microwave assisted Friedel-Crafts
acylation, because chemical wastes should be as little as possible from the
environmental and economic requirements. Initially we intended to use
water-compatible Sc(OTf )3 and Yb(OTf )3. However, preliminary tests
revealed that moisture sensitive Ga(OTf )3 was more efficient than
Sc(OTf )3 to lead us to use 3b metal triflates such as Ga(OTf )3,
In(OTf )3, and Tl(OTf )3. In this synthesis, microwave heating was applied
for main Friedel-Crafts reaction and then decomposition of unreacted
acid chloride as well as preparation of the three metal triflates.
Finally products were simply separated only by filtration of the water
slurries of reaction mixtures, achieving high-throughput synthesis of
alkylbenzophoenones.
First, Ga(OTf )3, In(OTf )3, and Tl(OTf )3 were rapidly prepared
by microwave irradiation of the corresponding metal oxides in
trifluoromethanesulfonic acid only for 10 min, then complete drying
under reduced pressure at elevated temperature to afford the three triflates
in 97, 94, and 96% yield, respectively. On the other hand, conventional
heating needed long refluxing time at 140ꢀC for 15 h, giving the three
triflates quantitatively. Herein, the catalysts prepared by microwave
heating were submitted to Friedel-Crafts reactions.
In the context of our work on the Friedel-Crafts acylation of alkyl-
benzenes with benzoyl chlorides in the absence of solvent, we first
examined to what extent triflate should be used as a catalyst. A reaction
vessel was put into alumina powder bath and irradiated intermittently
MW
O
O
In(CF3SO3)3
+
Cl
R
R
CO2Me
solvent-free
CO2Me
2
3
1
Scheme 1. Friedel-Crafts acylation.

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High-Throughput Synthesis of Alkylbenzophenones
3985
Table 1. Rapid preparation of benzophenones (3) from various benzenes (1) and
the acid chloride (2) with metal triflates by microwave heating.
In(OTf )3
Ga(OTf )3
Tl(OTf )3
Benzene
compound 1
Irrad. time Yield of Irrad. time Yield of Irrad. time Yield of
3 (%)
(min)
3 (%)
(min)
3 (%)
(min)
a
b
c
d
e
8
5
2
5
2
23
20
91
68a
91
10
10
2
15
6
8
10
3
10
0
Cl
OMe
85
47b
86
81
25b
70
10
2
8
OMe
OMe
3
f
5
5
6
8
5
84
95
77
89
95
10
6
73
83
76
81
90
10
10
10
8
61
81
48
77
78
g
h
i
10
10
10
j
8
k
l
5
3
95
95
10
6
70
87
10
10
61
84
m
n
6
7
25
58
10
3
18
27
10
5
12
19
ap-: o- ¼ 5:1.
bp-: o- ¼ 10:1.
with 200 W microwave to be kept at around 100ꢀC, typically 1 min
irradiation and 30 s stopping. For 1:1 mixture of pentamethylbenzene
(1l) and terephthalic acid monomethyl ester chloride (2), presence of
0.01, 0.03, 0.05, and 0.10 equiv. In(OTf )3 completed the reaction by
decreasing irradiation time for 10, 5, 3, and 2 min to give the correspond-
ing benzophenone (3l) in 87, 92, 95, and 95% yield, respectively.
Thereafter 1:1:0.05 mixture of 1:2:triflate catalyst was applied.
Table 1 summarizes the results of reactions of various benzenes (1)
and 2 with each metal triflate. Microwave irradiation accelerated and

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completed all the reactions within 10 min. In(OTf )3 revealed to be the best
catalyst of the three, because giving the highest yields of every benzophe-
none (3), second Ga(OTf )3. Tl(OTf )3 was immediately decomposed in
air. The lowest efficiency of Tl(OTf )3 as a catalyst is probably due to the
low stability with moisture.
In the presence of In(OTf )3, anisole (1c), and several alkylbenzenes
(1e–l) gave almost quantitative yields of the corresponding benzo-
phenones (3c, e–l). Reactivities with toluene (1d) and 1,3,5-triisopropyl-
benzene (1n) were moderate. Because of low reactivities with benzene
(1a), chlorobenzene (1b), and 1,4-diisopropylbenzene (1m), correspond-
ing products 3a, 3b, and 3m were separated by silica gel column chroma-
tography from the reaction mixtures. p-Substituted benzophenones (3b
and 3c) alone were selectively obtained from chlorobenzene (1b) and
anisole (1c) with the three triflates. On the other hand, toluene (1d)
gave mixture of p- (3d) and o-substituted products in 5:1 with In(OTf )3
1
and 10:1 with Ga(OTf )3 and Tl(OTf )3 by H NMR measurement. 1,2-
Disubstituted benzenes (1e, f ), 1,3-dimethylbenzene (1g), and 1,2,4-tri-
methylbenzene (1i) gave selectively sole products of 3e, 3f, 3g, and 3i,
respectively.
O
O
O
O
R
R
CO2Me
R
CO2Me
CO2Me
CO2Me
3b; R = Cl
3c; R = OMe
3d; R = Me
3e; R = OMe
3f; R = Me
3g
3i
Reactivities with other acid chlorides were also examined by using
1,3,5-trimethylbenzene (1j) as a reactant in the presence of In(OTf )3.
Benzoyl chloride, p-toluoyl chloride, and 4-nitrobenzoyl chloride
revealed good reactivities to afford corresponding benzophenones in
95, 88, and 95% yield by microwave irradiation for 5, 4, and 5 min,
respectively. However, isonicotinoyl chloride and benzoic acid anhydride
had no reactivity even by irradiation for more than 10 min.
For a comparison, conventional heating was performed for the
reaction of anisole (1c) and trimethylbenzene (1j) with 2 in the presence
of In(OTf)3; heating for each 3 h at 100ꢀC was needed to complete the
reactions, giving 3c and 3j in 83 and 89% yield, respectively. The
reactions proceeded at room temperature; standing on for 30 and 40 h
completed the reactions to result in the formation of 3c and 3j in 91 and
92% yield. Furthermore, we compared with traditional Friedel-Crafts
acylation by using AlCl3 as a catalyst. Equimolar mixtures of 1a, 1m,
and 1n with 2 were refluxed in the presence of a stoichiometric amount of
AlCl3 in CS2 for 60, 60, and 14 h by conventional heating, resulting in

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High-Throughput Synthesis of Alkylbenzophenones
3987
nothing product of 3a, and giving 3m and 3n in low yield of 3 and 30%,
respectively. In contrast, the present method afforded the higher yields of
23, 25, and 58% by the short microwave irradiation time for only 8, 6,
and 7 min (Table 1).
In conclusion, the solvent-free microwave assisted Friedel-Crafts
acylation with In(OTf )3 achieved practically useful high-throughput
synthesis of alkylbenzophenones.
EXPERIMENTAL
A mixture of each metal oxide (Ga2O3, In2O3, or Tl2O3, 15.0 mmol)
and large excess of trifluoromethanesulfonic acid (180 mmol) was
irradiated in a vessel with a cooling condenser and dry tube (CaCl2 and
Na2CO3) by microwave oven (2.45 GHz, 200 W) for 10 min. Then the
reaction mixture was completely dried under reduced pressure of
25 mm Hg at 180ꢀC, giving Ga(OTf )3, In(OTf )3, and Tl(OTf )3,
respectively. Then a 1:1:0.25 mixture of alkylbenzene (5.0 mmol), acid
chloride (5.0 mmol), and metal triflate (0.25 mmol) was transferred in a
vessel with a dry tube (CaCl2 and Na2CO3). The vessel was put into alu-
mina powder bath and submitted to intermittent microwave irradiation at
200 W for appropriate minutes to be kept at around 100ꢀC of alumina. To
the reaction mixture, Na2CO3 (15 mmol) and a few mL of water were
added and the paste was irradiated for 1 min in order to decompose the
unreacted acid chloride. Then water was added to the reaction paste and
the water slurry was filtered off, giving product. When necessary, product
was separated by silica gel column chromatography.
ACKNOWLEDGMENT
This work was supported by grants from the Ministry of Education,
Science, Sports, and Culture of Japan.
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3988
Koshima amd Kubota
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Received in Japan May 12, 2003