In(OTf)3-Catalyzed Friedel-Crafts Reaction of Aromatic Compounds with Methyl Trifluoropyruvate in Water

Article abstract of DOI:10.1055/s-2004-815430

In the presence of In(OTf)₃ as a catalyst, aniline derivatives 1a-c, 1e-h and anisole derivatives 2a-c, 2e reacted with methyl trifluoropyruvate 3 in water at room temperature to give the corresponding Friedel-Crafts reaction products 4a-g and

Full text of DOI:10.1055/s-2004-815430

LETTER
555
In(OTf)3-Catalyzed Friedel–Crafts Reaction of Aromatic Compounds with
Methyl Trifluoropyruvate in Water
I
n(OTf) -Catalyz
u
e
d
Friedel–C
i
r
afts Reaction
D
of Aromatic Com
i
pound
n
s
g,a Hai Bo Zhang,a Yong Jun Chen,a Li Liu,a Dong Wang,*a Chao Jun Li*b
3
a
Center for Molecular Science, Institue of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. China
E-mail: dwang210@iccas.ac.cn
b
Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montreal, QC, H3A 2K6, Canada
Received 5 November 2003
Abstract: In the presence of In(OTf)3 as a catalyst, aniline deriva-
tives 1a–c, 1e–h and anisole derivatives 2a–c, 2e reacted with me-
thyl trifluoropyruvate 3 in water at room temperature to give the
corresponding Friedel–Crafts reaction products 4a–g and 5a–d in
good yields, respectively.
Key words: In(OTf)3 catalyst, Friedel–Crafts reaction, methyl trif-
luoropyruvate, water, CF3-substituted compound
Scheme 1
Recently, aqueous organic reactions have received con-
siderable attention in view of their synthetic efficiency
and environmental friendliness.1 Accordingly, Lewis acid
catalyzed carbon-carbon bond forming reactions in aque-
ous media becomes one of the most challenging topics in
organic synthesis.2 Among the C-C bond forming reac-
tions, Friedel–Crafts alkylation is an important reaction,
which provides an effectively synthetic route to numerous
functionalized aromatic compounds with special proper-
ties.3 The development of aqueous Friedel–Crafts reac-
tions should be very interesating to organic chemists. It
was found that lanthanide triflates effectively catalyzed
the reaction of indole with imines using aqueous ethanol
(ethanol–water: 4:1) as solvent.4 Recently, Kobayashi5 re-
ported that in the presence of Lewis acid-surfactant-com-
bined catalyst (LASC), Friedel–Crafts type conjugate
addition of indoles with a,b-unsaturated carbonyl com-
pounds can be carried out in water. Jørgensen6 developed
reactions of indoles and pyrroles with ethyl glyoxylate in
aqueous NaHCO3 solution without the use of the tradi-
tional Lewis acid catalyst to give Friedel–Crafts addition
adducts in good yields. It was noteworthy that all three ex-
amples on aqueous Friedel–Crafts reaction have to in-
volve the use of more activated heteroaromatic
compounds, indole and pyrrole derivatives. There has
been no example of aqueous Friedel–Crafts reaction of
other type of aromatic compounds reported, probably due
to the lower reactivity of aromatic compounds in water
than that of activated heteroaromatic compounds under
the reaction conditions mentioned above. On the other
hand, organofluorine compounds are important in both
organic synthesis and the development of novel drugs. In
particular, the synthesis of biologically active CF3-substi-
tuted compounds have attracted considerable attention.7
A chiral Cu-Lewis acid-catalyzed asymmetric addition re-
action of heteroaromatics to trifluoropyruvate was carried
out in organic solvent,8 which provided a new synthetic
route to Mosher’s acid analogs.9 More recently, Olah10 re-
ported a superacid-catalyzed reaction of highly activated
heteroaromatic or substituted benzene with trifluoropyru-
vate in suitable organic solvent and under inert atmo-
sphere. Herein, we wish to report an In(OTf)3-catalyzed
Friedel–Crafts reaction of amino- and methoxy-substitut-
ed aromatic compounds with methyl trifluoropyruvate in
water for the synthesis of methyl a-CF3-a-hydroxy phenyl
acetate with amino and methoxy substituents on the phe-
nyl ring.
To start the investigation, N,N-dimethylaniline (1a) was
reacted with methyl 3,3,3-trifluoropyruvate (3) in the
presence of various Lewis acids (5 mol%) in water at
room temperature (Scheme 1). For screening purposes,
Sc(OTf)3, Ce(OTf)3, Nd(OTf)3, Gd(OTf)3, Yb(OTf)3 and
Y(OTf)3 were selected as catalysts; however, in all cases
no reaction product was detected by TLC. The addition of
a surfactant (SDS) is not efficient to catalyze the reaction
in water either (Table 1, entry 6). In the presence of triflic
acid (TfOH) as catalyst, the reaction of 1a with 3 in water
gave the product N,N-dimethyl-4-(hydroxy trifluorometh-
yl ester)aniline (4a) in only 18% yield (entry 7). More-
over, the reaction of 1a with 3 in saturated NaHCO3
aqueous solution without the use of Lewis acid catalyst
only gave a trace of 4a (entry 8). Cu(OTf)2 and Ga(OTf)3
showed a catalytic ability for the reaction of 1a with 3 in
water, giving the product 4a in 55% and 58% yields with
5 mol% catalyst loading, and 88% and 78% yields with 20
mol% catalyst loading, respectively (entries 1–4). How-
ever, Cu(OTf)2 could not catalyze the reaction of anisole
2a with 3 in water (entry 9). The lower yields in the case
of Ga(OTf)3 (entries 3 and 10) would be attributed to
slight decomposition of the catalyst in water. Fortunately,
SYNLETT 2004, No. 3, pp 0555–0557
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8.
0
2.
2
0
0
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Advanced online publication: 26.01.2004
DOI: 10.1055/s-2004-815430; Art ID: U23203ST.pdf
© Georg Thieme Verlag Stuttgart · New York

556
R. Ding et al.
LETTER
Table 1 Lewis Acid-Catalyzed Friedel–Crafts Reaction of 1a or 2a
with 3 in Water
the derivatives of Mosher’s acid with substitutions on the
phenyl ring, which are not easily accessible by the
conventional method employing phenyl trifluoromethyl
ketones. Since the reaction is the nucleophilic attack of
electron-rich aromatic moiety to a carbonyl group, the in-
troduction of electron-withdrawing group into the phenyl
ring would retard the reaction. The good regioselectivities
are consistent with Jørgenson’s observation8a for the reac-
tion in organic solvent. Although aniline 1d and phenol 2d
could not react with 3 in water in the presence of In(OTf)3
(entries 4 and 13), it is found that their derivatives 1e and
2e have enough activity to react with 3 in water by using
5 mol% In(OTf)3 as a catalyst to afford the products 4d
and 5d in good yields (entries 5 and 14). The aqueous
Friedel–Crafts reaction provides a convenient method for
the synthesis of the products with mono-N-substituent and
free amino groups, for example, 4e and 4d, which are
usually prepared by the deprotection of N,N-dialkyl
compounds, such as 4f.11 It can be noted from the investi-
gations that the Lewis acid-catalyzed Friedel–Crafts addi-
tion of aromatic moiety with carbonyl group in water is an
atom-economic reaction, according with the principle of
green chemistry.
Entry Substrate Catalyst (mol%)
Time Product
(h)a
Yield
(%)b
1
Cu(OTf)2, (5)
24
55
1a
4a
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
Cu(OTf)2, (20)
Ga(OTf)3, (5)
Ga(OTf)3, (20)
In(OTf)3, (5)
12 4a
88
58
78
89
12 4a
12 4a
6
4a
Sc(OTf)3/SDS, (20) 12 NR
TfOH (5)
12 4a
12 4a
12 NR
18
<5
c
NaHCO3
Cu(OTf)2, (20)
OMe
Table 2 In(OTf)3-catalyzed Friedel–Craft Reactions of Aromatic
Compounds with 3 in Watera
2a
10 2a
Entry
Substrate
Time (h)b Productc
Yield (%)d
Ga(OTf)2, (5)
12
52
1
2
1a
6
6
4a
89
91
5a
12 5a
1b
11 2a
12 2a
Ga(OTf)3, (20)
In(OTf)3, (5)
72
88
4b
NMe2
3
6
87
6
5a
NMe2
a Reaction temperature: r.t.
b Isolated yield.
Me
Me
R
c Sat. aq solution of NaHCO3.
1c
4c
NR
4
5
6
by using 5 mol% In(OTf)3 as catalyst, the reaction of 1a
with 3 in water proceeded smoothly to give the product 4a
in 89% yield (entry 5). For the reaction of 2a with 3 in wa-
ter, In(OTf)3 also showed the same catalytic ability, giv-
ing the product 4-(hydroxy trifluoromethyl ester)anisole
(5a) in 88% yield (entry 12). The 4-substituted products
4a and 5a were the only isomer formed in the reaction of
1a and 2a with 3, which demonstrates that the Friedel–
Crafts reaction in water has excellent para-regioselectivi-
ty. Subsequently, In(OTf)3 was selected as a Lewis acid
catalyst for the following Friedel–Crafts reactions in wa-
ter.
1d
NH2
12
65
NH2
OMe
OMe
R
1e
1e
4d
4d
6
7
12
12
75e
75
NHMe
OMe
Based on these experimental results, various aniline deriv-
atives 1a–h and anisole derivatives 2a–e were used in the
In(OTf)3-catalyzed Friedel–Crafts reactions with 3 in wa-
ter and air at room temperature. The reactions proceeded
smoothly to give addition products 4a–g and 5a–d in good
yields (Table 2). The reaction provides a synthetic route to
1f
4e
Synlett 2004, No. 3, 555–557 © Thieme Stuttgart · New York

LETTER
In(OTf)3-Catalyzed Friedel–Crafts Reaction of Aromatic Compounds
557
Table 2 In(OTf)3-catalyzed Friedel–Craft Reactions of Aromatic
Compounds with 3 in Watera (continued)
A Typical Experimental Procedure is as follow:
A mixture of 1a (84 mg, 0.7 mmol), 3 (108 mg, 0.7 mmol) and
In(OTf)3 (20 mg, 0.035 mmol) in water (4 mL) was stirred at r.t. Af-
ter the reaction was completed (monitored by TLC), diethyl ether
(15 mL) was added. The organic phase was separated and aqueous
phase was extracted with diethyl ether (3 × 10 mL). The combined
organic layer was dried over MgSO4, filtered and concentrated in
vacuo. The crude material was purified by a flash chromatography
on silica gel (eluent: petroleum ether–EtOAc = 15:1) to give the
product 4a (171 mg, 89%).
Entry
8
Substrate
Time (h)b Productc
12
Yield (%)d
76
1g
4f
9
12
71
NHMe
NHMe
OMe
OMe
Acknowledgment
We gratefully acknowledge financial support by NSFC (No
20332030 and 20232010) and CAS.
R
1h
2a
4g
5a
10
11
6
88
84
References
12
OMe
OMe
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OH
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OMe
OH
OH
R
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Synlett 2004, No. 3, 555–557 © Thieme Stuttgart · New York