MoO2Cl2 as a novel catalyst for Friedel-Crafts acylation and sulfonylation

Article abstract of DOI:10.1016/j.tetlet.2009.01.039

The use of MoO₂Cl₂ as a novel catalyst for Friedel-Crafts acylation and sulfonylation is described. A series of aromatic ketones and sulfones were prepared in moderate to good yields using acyl chloride or sulfonyl chloride in the presence of MoO₂Cl₂ (20 mol %), under solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2009.01.039

Tetrahedron Letters 50 (2009) 1407–1410
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Tetrahedron Letters
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MoO2Cl2 as a novel catalyst for Friedel–Crafts acylation and sulfonylation
a
Rita G. de Noronha a, Ana C. Fernandes b, , Carlos C. Romão
*
a Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República - EAN, 2781-157 Oeiras, Portugal
b Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of MoO2Cl2 as a novel catalyst for Friedel–Crafts acylation and sulfonylation is described. A series
of aromatic ketones and sulfones were prepared in moderate to good yields using acyl chloride or sulfo-
nyl chloride in the presence of MoO2Cl2 (20 mol %), under solvent-free conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 5 November 2008
Revised 9 December 2008
Accepted 9 January 2009
Available online 15 January 2009
Keywords:
Friedel–Crafts acylation
Sulfonylation
Aromatic ketones
Aromatic sulfones
Dioxomolybdenum dichloride
Friedel–Crafts acylation and sulfonylation provide fundamental
and useful methods for the synthesis of aromatic ketones and sulf-
ones, which are important intermediates for preparing fine chem-
icals in the field of pharmaceuticals, agrochemicals, and fragrances.
Typically, these reactions are performed using acyl chloride (for
acylation) or sulfonyl chloride (for sulfonylation) in the presence of
a little more than one equivalent of Lewis acids, such as anhydrous
AlCl3, TiCl4, and FeCl3. These methods are limited by high amounts,
toxicity and corrosion of the catalysts, which are non-recoverable
materials after aqueous work-up, generation of a large amount of
waste, and difficult purification of the desired products.
Over the last years, a variety of catalysts such as metal halides,
zeolites, or mesoporous aluminosilicates have been reported to
catalyze Friedel–Crafts acylation and sulfonylation.1 However,
due to the high importance of the Friedel–Crafts reactions in indus-
try, a search for new catalysts is still in demand.
High valent dioxomolybdenum (VI) complexes are known for
their abilities to catalyze oxygen-transfer reactions to sulfides,
phosphines, and olefins,2–5 and also as models of molybdoenzymes
active sites, such as dimethyl sulfoxide reductases.6–8
Recently, we have demonstrated a new reactivity of the high va-
lent oxo-molybdenum complex MoO2Cl2 as excellent catalyst for
Si–H bond activation and for hydrosilylation of aldehydes and ke-
tones.9,10 The system silane/MoO2Cl2 proved to be also very effi-
cient for the reduction of imines,11 amides,12 esters,13
sulfoxides,14 and pyridine N-oxides14 to the corresponding amines,
alcohols, sulfides, and pyridines. We also found that MoO2Cl2 acti-
vates the B–H bond of boranes and catalyzes the reduction of aro-
matic sulfoxides with boranes in excellent yields.15
Other applications of dioxomolybdenum (VI) dichloride com-
plexes as catalysts in organic chemistry include transformation of
epoxides to b-alkoxy alcohols, acetonides, and
a
-alkoxyketones,16
thioglycosylation of O-acetylated glycosides,17 thioacetalization
of heterocyclic, aromatic, and aliphatic compounds,18 nucleophilic
acyl substitution of anhydrides with a variety of alcohols, amines,
and thiols,19 reductive cyclization of nitro-aromatic compounds,20
reduction of sulfoxides21 and pyridine N-oxides.22
As part of our continuing studies on the development of new
methods catalyzed by high valent oxo-complexes, in this work,
we report novel Friedel–Crafts acylation and sulfonylation meth-
ods for the synthesis of aromatic ketones and sulfones catalyzed
by MoO2Cl2.
To optimize the reaction conditions, we first studied the reac-
tion of anisole with p-toluoyl chloride catalyzed by MoO2Cl2 in dif-
ferent solvents as summarized in Table 1. This reaction was also
performed without solvent, using an excess of liquid aromatic
compound. The best yields were obtained when the acylation
was performed without solvent or in bromobenzene, inert under
these conditions (Table 1, entries 1 and 2). The reactions carried
out in acetonitrile and dichloromethane gave moderate yields of
ketone (Table 1, entries 3 and 4). In THF, a chloroester was isolated
as result of THF ring cleavage by reaction with acyl chloride (Table
1, entry 5).23
The Friedel–Crafts acylation catalyzed by MoO2Cl2 (20 mol %)
was explored with a variety of aromatic compounds to evaluate
the scope and limitations of this method. The results summarized
in Table 2 show that this novel method affords aromatic ketones in
* Corresponding author. Tel.: +351 218419388; fax: +351 218464457.
E-mail address: anacristinafernandes@ist.utl.pt (A.C. Fernandes).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.039

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R. G. de Noronha et al. / Tetrahedron Letters 50 (2009) 1407–1410
Table 1
Friedel–Crafts acylation of anisole in different solventsa
Entry
Solvent
Yield (para/ortho)b
1
2
3
4
5
Neat
85 (1:0)c
82 (1:0)
62 (20:1)
50 (50:1)
Esterification
Bromobenzene
CH3CN
CH2Cl2
THF
a
The reactions were carried out with 1 mmol of acyl chloride, 3 mmol of aromatic compound, and 20 mol % of MoO2Cl2.
Isolated yields. The ratio of para/ortho-isomers was determined by 1H NMR.
The reaction was carried out with 1 mmol of acyl chloride, 30 mmol of aromatic compound, and 20 mol % of MoO2Cl2.
b
c
moderate to good yields. The reactions were carried out without
and 81%, respectively (Table 2, entries 2 and 3), indicating a high
selectivity with these acyl chlorides. The presence of the strong
electron-withdrawing group NO2 in the acyl chloride reduced
drastically the yield of the acylation (34% yield, Table 2, entry
4), and produced a high amount of the corresponding carboxylic
acid.
solvent, using an excess of liquid aromatic substrates at reflux tem-
perature under inert atmosphere.24
The acylation of anisole was investigated with different acyl
chlorides. The reaction with 4-chlorobenzoyl chloride produced
a mixture of para/ortho-isomers in 80% yield with a ratio of
17:1 (Table 2, entry 1). Similar acylation with p-toluoyl and p-
anisoyl chlorides afforded exclusively the para-isomer in 85
The Friedel–Crafts acylation of thioanisole afforded the aro-
matic ketones in 56–64% yield. The reaction of thioanisole with
Table 2
a
Friedel–Crafts acylation catalyzed by MoO2Cl2
Entry
Acyl chloride
Aromatic compound
Product
Yieldb (%) (para/ortho)
1
2
3
4
R1 = Cl
R1 = CH3
Anisole
Anisole
Anisole
Anisole
80 (17:1)
85 (1:0)
81 (1:0)
34 (9:1)
R
1 = OCH3
R1 = NO2
5
6
7
R
1 = Cl
Thioanisole
Thioanisole
Thioanisole
64 (10:1)
57 (1:0)
56 (1:0)
R1 = CH3
R1 = OCH3
8
9
10
R
R
1 = Cl
1 = CH3
p-Xylene
p-Xylene
p-Xylene
58
54
31
R1 = OCH3
11
12
13
R
1 = Cl
Toluene
Toluene
Toluene
54 (4:1)
50 (13:1)
9 (2:1)
R1 = CH3
R1 = OCH3
14
15
16
R
R
1 = Cl
1 = CH3
Thiophene
Thiophene
Thiophene
61
66
66
R1 = OCH3
a
All the reactions were carried out with 1 mmol of acyl chloride, 30 mmol of aromatic compound, and 20 mol % of MoO2Cl2.
b
Isolated yields. The ratio of para/ortho-isomers was determined by 1H NMR.

R. G. de Noronha et al. / Tetrahedron Letters 50 (2009) 1407–1410
1409
Table 3
a
Friedel–Crafts sulfonylation catalyzed by MoO2Cl2
Entry
Aromatic compound
Product
Yieldb (%) (para/ortho)
1
Anisole
89 (2:1)
2
3
4
5
n-Butyl phenyl ether
66 (8:1)c
1,4-Dimethoxy-benzene
66c
Toluene
55 (8:1)
p-Xylene
44
6
1,2,4,5-Tetra-methylbenzene
45
a
The reactions were carried out with 1 mmol of sulfonyl chloride, 30 mmol of aromatic compound, and 20 mol % of MoO2Cl2.
Isolated yields. The ratio of para/ortho-isomers was determined by 1H NMR.
The reaction was carried out with 1 mmol of sulfonyl chloride, 3 mmol of aromatic compound, and 20 mol % of MoO2Cl2 in bromobenzene.
b
c
4-chlorobenzoyl chloride gave a mixture of para/ortho-isomers
The analysis of the results showed that the best yields were ob-
tained with substrates bearing electron-donating groups, such as
alkoxy substituents in the aromatic ring.
Ring closure is another important application of the Friedel–
Crafts acylation. The high valent oxo-molybdenum complex
MoO2Cl2 was successfully applied in the synthesis of 3,4-dime-
with a ratio of 10:1 (Table 2, entry 5). In contrast, the reactions
with p-toluoyl and p-anisoyl chlorides were regioselective, yielding
only the para-isomers (Table 2, entries 6 and 7).
The acylation of alkyl-substituted benzenes such as toluene is
more difficult, and some of the methods reported in the litera-
ture are not applied to this substrate or gave poor yields of ke-
tone.1k,n Under our catalytic conditions, acylation of p-xylene
gave the corresponding ketones in moderate yields (Table 2, en-
tries 8–10), and the acylation of toluene afforded a mixture of
para/ortho-regioisomers with a high para-selectivity (Table 2, en-
tries 11–13). Finally, the deactivated bromobenzene did not
react.
The Friedel–Crafts acylation of thiophene with different acyl
chlorides was also investigated in the presence of MoO2Cl2. These
reactions were regioselective, producing only the 2-acyl products
in 61–66% yields (Table 2, entries 14–16).
thoxy-a-tetralone by intramolecular Friedel-Crafts acylation with
an overall yield of 90% (Eq. 1).
ð1Þ
The reusability of MoO2Cl2 was evaluated using anisole as test sub-
strate. We carried out five successive reactions by sequential addi-
tion of fresh substrate and p-toluoyl chloride to the reaction

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R. G. de Noronha et al. / Tetrahedron Letters 50 (2009) 1407–1410
mixture. The results obtained showed that the catalytic activity of
MoO2Cl2 did not decrease with successive uses.
References and notes
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The catalytic activity of MoO2Cl2 was also investigated in the
sulfonylation of a variety of aromatic compounds with p-toluene-
sulfonyl chloride and methanesulfonyl chloride.24 Table 3 shows
that MoO2Cl2 catalyzes the synthesis of aromatic sulfones in mod-
erate to good yields. The reaction of anisole with p-toluenesulfonyl
chloride afforded a mixture of para/ortho-isomers (2:1) in 89%
yield (Table 3, entry 1). However, similar reaction with methane-
sulfonyl chloride gave also a mixture of para/ortho-isomers (1:1)
in low yield (4%).
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sulfones in 44–55% yields (Table 3, entries 4, 5, and 6).
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ride or the sulfonyl chloride by the coordinatively unsaturated
and strongly acidic Lewis acid MoO2Cl2. This activation can occur
by two different addition modes. One possibility involves the car-
bonyl or sulfonyl group coordination to the molybdenum vacant
sites, or MoO2Cl2 can also activate the C(O)–Cl or S(O)2–Cl bonds
through their addition across Mo@O multiple bond, similar to the
activation of anhydrides reported by Chen.19 In the next step, the
complex formed reacts with the aromatic compound, yielding the
corresponding acylated product and HCl.
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sulfonylation methods for the synthesis of aromatic ketones and
sulfones in moderate to good yields. We also demonstrated that
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sults extend the scope of the use of high valent oxo-molybdenum
complexes as effective catalysts for organic reactions, and open a
new area of catalysis for these complexes, since C–C bond-forming
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Further mechanistic studies of these catalytic processes as well
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24. In a typical experiment, to a solution of MoO2Cl2 (20 mol %) and the aromatic
compound (30 mmol) under inert atmosphere, was added the acyl chloride
(1.0 mmol) or sulfonyl chloride (1.0 mmol). The reaction mixture was stirred at
reflux temperature during 20 h. Upon completion, the reaction mixture was
evaporated and purified by silica gel column chromatography with the
appropriate mixture of n-hexane and ethyl acetate to afford the aromatic
ketones or sulfones, which are all known compounds.
Acknowledgments
This research was supported by FCT through Project PTDC/QUI/
71741/2006. RGN thanks FCT for a postdoctoral Grant (SFRH/BPD/
27215/2006).