Highly selective catalytic Friedel-Crafts acylation and sulfonylation of activated aromatic compounds using indium metal

Article abstract of DOI:10.1016/j.tetlet.2006.06.099

The Friedel-Crafts acylation of activated benzenes with various aromatic and aliphatic acid chlorides was studied in the presence of indium metal. The reaction was accomplished in high isolated yields under solvent or solvent-less conditions. The method is also applicable for preparing diaryl sulfones from aromatic compounds and aryl sulfonyl chlorides.

Full text of DOI:10.1016/j.tetlet.2006.06.099

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Tetrahedron Letters 47 (2006) 6063–6066
Highly selective catalytic Friedel–Crafts acylation and
sulfonylation of activated aromatic compounds using indium metal
a
a
c
Doo Ok Jang,a,b, Kyung Soo Moon, Dae Hyan Cho and Joong-Gon Kim
*
aDepartment of Chemistry, Yonsei University, Wonju 220-710, Republic of Korea
bCenter for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, Republic of Korea
cBiotechnology Division, Hanwha Chemical R&D Center, Daejeon 305-345, Republic of Korea
Received 8 May 2006; revised 14 June 2006; accepted 20 June 2006
Available online 10 July 2006
Abstract—The Friedel–Crafts acylation of activated benzenes with various aromatic and aliphatic acid chlorides was studied in the
presence of indium metal. The reaction was accomplished in high isolated yields under solvent or solvent-less conditions. The
method is also applicable for preparing diaryl sulfones from aromatic compounds and aryl sulfonyl chlorides.
Ó 2006 Elsevier Ltd. All rights reserved.
Aromatic ketones are important intermediates for
preparing fine chemicals in the field of pharmaceuticals,
fragrances, and agrochemicals. Aromatic ketones have
been prepared conventionally by Friedel–Crafts acyl-
ation of aromatic compounds with acid chlorides using
more than stoichiometric amounts of anhydrous strong
Lewis acids such as AlCl3, TiCl3, FeCl3, or SnCl4.1
However, these Lewis acids are very sensitive to mois-
ture. Hence moisture-free reaction conditions are
required to attain the optimal yields of the desired prod-
ucts. Moreover, the Friedel–Crafts acylations based on
the use of above mentioned Lewis acids have other
problems including high toxicity, corrosion, generation
of a large amount of waste, and difficulty in purifying
the desired products. Thus, the need for developing Fri-
edel–Crafts acylation of aromatic compounds with
moisture insensitive catalysts remains strong. Varieties
of catalysts for Friedel–Crafts acylation of aromatic
compounds have been reported.2
prompted us to apply it in organic synthesis.4 Herein
we report a method of Friedel–Crafts acylation and sulf-
onylation of aromatic compounds in the presence of
indium metal.
The activity of indium metal as a promoter of Friedel–
Crafts acylation of anisole with various acid chlorides
was examined (Table 1). Anisole was allowed to react
Table 1. The Friedel–Crafts acylation of anisole under various
reaction conditions
O
O
O
In
R
+
neat, 100 oC
R
Cl
O
Entry
R
In (equiv)
Time (h)
Isolated
yield (%)a
1
2
3
4
5
6
7
8
9
Cyclohexyl
Cyclohexyl
Adamantyl
C6H5
p-NO2–C6H4
tButyl
tButyl
tButyl
1
0
1
1
1
1
3
1
4
4
4
2
2.5
6
2
4
2
98
0
In recent years, indium-mediated reactions have re-
ceived considerable attention owing to the unique prop-
erties of indium metal.3 Indium metal is stable in air or
in oxygen at ambient temperature, and it is practically
inert even in boiling water. In addition, its toxicity is
low. These special properties inherent to indium metal
70
76
78
76
78
80b
83
C6H5
0.2
a The reaction was carried out under the conditions of 1:6 molar ratio
of acid chlorides and anisole, and the yield was calculated based on
acid chlorides.
Keywords: Friedel–Crafts acylation; Sulfonylation; Indium; Aromatic
ketones; Acid chlorides.
*
Corresponding author. Tel.: +82 337602261; fax: +82 337602208;
e-mail: dojang@yonsei.ac.kr
b The reaction was carried out in dioxane.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.099

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D. O. Jang et al. / Tetrahedron Letters 47 (2006) 6063–6066
Table 2. Indium-mediated Friedel–Crafts acylation of various aro-
matic compounds with benzoyl chloride
with cyclohexanecarbonyl chloride in the presence of
indium metal in boiling dioxane for 4 h affording the
acylated product in 98% yield (entry 1). The same reac-
tion without indium metal did not proceed, implying
that indium metal is the active promoter in the reaction
(entry 2). 1-Adamantanecarbonyl chloride, benzoyl
chloride, and p-nitro benzoyl chloride were good sub-
strates for the present process (entries 3–5). The reaction
proceeded efficiently even with highly sterically hindered
pivalolyl chloride affording high yields of the acylated
product (entry 6). An increase in the amount of indium
was found to shorten the reaction time (entry 6 vs 7).
The reaction was accomplished in dioxane without
detrimental effects on the yield of the product (entry
8). We also found it possible to accomplish the reaction
with a catalytic amount of indium metal. The reaction of
anisole with benzoyl chloride with 0.2 equiv of indium
metal produced the corresponding aryl ketone without
affecting the yield of the product (entry 9). The Fri-
edel–Crafts acylation of anisole under the present reac-
tion conditions produced a para isomer as the sole
product with no detection of ortho and/or meta isomers,
indicating a high selectivity in the acylation of anisole.
However, when toluene was allowed to react with
p-nitrobenzoyl chloride under the reaction conditions,
the corresponding aromatic ketones were produced
in 69% yield with an ortho:para ratio of 3.4:1 (Scheme 1).
O
O
In (0.2 equiv)
Ar
Entry
H
+
Ph
Cl
dioxane, 100 oC
Ph
Ar
Ar–H
Time (h)
Isolated
yield (%)a
1
2
3
N,N-Dimethylaniline
1,3,5-Trimethoxybenzene
1,4-Dimethoxybenzene
Thioanisole
0.75
1.5
2
92
91
87
90
4
2
5
6
7
8
9
10
Toluene
p-Xylene
Mesitylene
Mesitylene
Chlorobenzene
Bromobenzene
2.5
2.5
1.5
0.5
5
21c
40c
60c
77b,c
0c
5
0c
a The reaction was carried out under the conditions of 1:6 molar ratio
of benzoyl chloride and aromatic compounds, and the yield was
calculated based on benzoyl chloride.
b The reaction was carried out at 150 °C.
c The reaction was performed with 1 equiv of indium under solvent-less
conditions.
sole with a ratio of 1:1 was allowed to react with benzoyl
chloride in the presence of indium metal at 100 °C for
1 h, and the products were analyzed. Since 4-methoxy-
acetophenone was obtained as a sole product in 81%
yield, a high selectivity was found between alkoxy and
alkyl groups on the benzene ring.
The benzoylations of various aromatic compounds were
attempted in the presence of a catalytic amount of
indium metal to examine the scope and limitations of
the reaction. The results are summarized in Table 2.
The indium-mediated benzoylations of benzene with
electron-donating groups such as N,N-dimethylaniline,
1,3,5-trimethoxybenzene, 1,4-dimethoxybenzene, and
thioanisole gave high yields of the corresponding aryl
ketones with a catalytic amount of indium metal in boil-
ing dioxane (entries 1–4). In the case of alkyl benzenes
such as toluene and xylene, the benzene ring is less
activated; hence it is more difficult to accomplish the
acylation of alkyl benzenes (entries 5 and 6). With mesi-
tylene, the yield of the product was 58% at 100 °C and
77% at 150 °C (entries 7 and 8). Deactivated benzenes
such as chlorobenzene and bromobenzene were inac-
tive under the reaction conditions (entries 9 and 10).
These results show that the indium-mediated Friedel–
Crafts acylation is favored by the presence of electron-
donating groups such as alkyl, alkoxy, or alkyl amine
in the aromatic compounds whereas it is inhibited by
the presence of electron withdrawing groups such as
halo functionality.
The present reaction was applied to the preparation of
an intermediate for the synthesis of a tamoxifen deriva-
tive which is a good candidate for the treatment of estro-
gen-dependent breast tumors (Scheme 2).5 When the
reaction mixture of benzoyl chloride (1 equiv), 2-chloro-
ethoxybenzene (2 equiv) and In (1 equiv) in dioxane was
stirred at 100 °C for 1 h, the desired product, 4-(2-chloro-
ethoxy)benzophenone, was obtained in 87% isolated
yield.
Next, we utilized our method in preparing diaryl sulf-
ones, which are important intermediates for synthesizing
medicines.6 Conventionally, diaryl sulfones are prepared
using strong Lewis acids.1a A variety of activated aro-
matic compounds were transformed into the corre-
sponding diaryl sulfones in excellent yields under the
present reaction conditions. The results are summarized
in Table 3. The reaction of activated benzenes with
p-toluenesulfonyl chloride in the presence of a catalytic
amount of indium metal furnished the corresponding
diaryl sulfones in high yields (entries 1–5). With moder-
ately activated alkyl benzenes such as xylenes, low yields
were obtained (entries 6 and 7). In the case of mesityl-
ene, the corresponding diaryl sulfone was obtained in
82% yield (entry 9).
We carried out a competitive experiment to study the
selectivity of the reaction. A mixture of toluene and ani-
O
O
It was observed that the presence of a radical scavenger
such as BHT (butylated hydroxytoluene) and TEMPO
(2,2,6,6-tetramethylpiperidine oxide) showed no effects
on the reaction in terms of the reaction rate and the yield
of the product. This implied that the reaction did not
proceed via a radical pathway. We also observed a
In (1 equiv)
Cl
5 h, 100 o
C
+
NO2
O2N
69 % (para
:
ortho = 3.4:1)
Scheme 1.

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D. O. Jang et al. / Tetrahedron Letters 47 (2006) 6063–6066
6065
O
O
O
Cl
In (1 equiv)
dioxane, 1 h, 100 oC
+
Cl
Cl
O
(1 equiv)
(2 equiv)
87%
Scheme 2.
Table 3. Indium-mediated sulfonylation of various aromatic com-
pounds with p-toluenesulfonyl chloride
Acknowledgements
This work was supported by the Center for Bioactive
Molecular Hybrids and Yonsei University.
SO2Ar
SO2Cl
In (0.2 equiv)
dioxane, 100 oC
Ar
H
+
Entry
Ar–H
Time (h)
Isolated
Yield (%)a
References and notes
1
2
3
4
5
6
7
8
Anisole
2
1.5
3
2
2
2
1
1.5
76
84
71
77
N,N-Dimethylaniline
1,3,5-Trimethoxybenzene
1,4-Dimethoxybenzene
Thioanisole
p-Xylene
m-Xylene
1. (a) Olah, G. A. In Friedel–Crafts and Related Reactions;
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82
23b
40b
82b
Mesitylene
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conditions.
metallic shiny species during the reaction, which might
be the regenerated indium. At present, although the
possibility of the participation of indium chloride gener-
ated in situ as a promoter for the reaction cannot be ex-
cluded,7 we suggest that the reaction is likely to proceed
by an ionic pathway involving an indium complex hav-
ing an alkyl or aryloxocarbenium ion character,8 which
reacts with aromatic compounds to generate the Fri-
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with HCl.
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aryl ketones and diaryl sulfones by means of indium-
mediated Friedel–Crafts acylation and sulfonylation of
aromatic compounds, which showed a good selectivity
for the activated aromatic compounds. The present pro-
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advantages such as low toxicity and no pretreatment
of the reagents.
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A typical experimental procedure is as follows: Anisole
(0.48 mL, 4.42 mmol), benzoyl chloride (84 lL,
0.73 mmol), indium powder (16.8 mg, 0.15 mmol) and
dioxane (0.5 mL) were placed in a two-necked flask,
and the resulting mixture was stirred at 100 °C for 2 h
under nitrogen. The mixture was then quenched with
saturated NaHCO3 and extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4
and purified by column chromatography on silica gel,
eluting with hexane: EtOAc (20:1) to give the corre-
sponding aryl ketone (129 mg, 83%).
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D. O. Jang et al. / Tetrahedron Letters 47 (2006) 6063–6066
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