Hf[N(SO2C8F17)2] 4-catalyzed Friedel-Crafts acylation in a fluorous biphase system

Article abstract of DOI:10.1016/j.tetlet.2005.02.065

In a fluorous biphase system, Hf[N(SO₂C₈F ₁₇)₂]₄ complex (1 mol %) catalyzes Friedel-Crafts acylation of aromatic compounds such as anisole, toluene and chlorobenzene, and the corresponding aromatic ketones are obtained in satisfactory to high yields. The catalyst is selectively soluble in lower fluorous phase and can be easily recovered by simple phase separation. Furthermore, the catalyst can be reused without decrease of activity in most cases.

Full text of DOI:10.1016/j.tetlet.2005.02.065

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2697–2700
Hf[N(SO2C8F17)2]4-catalyzed Friedel–Crafts acylation in a
fluorous biphase system
Xiuhua Hao, Akihiro Yoshida and Joji Nishikido*
The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo 173-0003, Japan
Received 3 December 2004; revised 31 January 2005; accepted 4 February 2005
Abstract—In a fluorous biphase system, Hf[N(SO2C8F17)2]4 complex (1 mol%) catalyzes Friedel–Crafts acylation of aromatic com-
pounds such as anisole, toluene and chlorobenzene, and the corresponding aromatic ketones are obtained in satisfactory to high
yields. The catalyst is selectively soluble in lower fluorous phase and can be easily recovered by simple phase separation. Further-
more, the catalyst can be reused without decrease of activity in most cases.
Ó 2005 Elsevier Ltd. All rights reserved.
Friedel–Crafts acylation is one of the most common and
useful synthetic routes for introducing functional sub-
stituents to aromatic rings, and industrially important
as well.1 The reaction is generally performed by using
aluminum trichloride (AlCl3) as a Lewis acid. A com-
mon problem, particularly in an industrial process, is
that at least stoichiometric quantities of the Lewis acid
are required and are destroyed upon work-up leading
to serious environment concerns with strongly acidic
waste streams. The development for truly catalytic Frie-
del–Crafts acylation with recoverable and recyclable cat-
alysts is strongly in demand.
geneous catalysis and can be shown to be one of envi-
ronmentally benign techniques for phase separation
and catalyst immobilization.4 Our recent works in FBS
have found that metal (e.g., Hf, Sc and Yb) complexes
with bis(perfluorooctanesulfonyl)amide ligands are
excellent active and recyclable catalysts in the fluorous
immobilized phase for Baeyer–Villiger oxidation,5
Diels–Alder reaction6 and esterification,7 far superior
to the corresponding metal trifluoromethanesulfonates.
In this letter a mild and effective method for fluorous
biphase Friedel–Crafts acylation was performed by
Hf[N(SO2C8F17)2]4. It was found that under mild condi-
tions the catalyst can function efficiently at low catalytic
loadings (1 mol%) and can be easily recovered and
reused.
In an effort to procure an effective catalyst for Friedel–
Crafts acylation, much research has been performed.2
KobayashiÕs group has reported the catalytic use of
metal trifluoromethanesulfonates (e.g., Hf(OSO2CF3)4
and Sc(OSO2CF3)3) for excellent Friedel–Crafts acyla-
tion and has shown that the catalyst may be recycled
in selected instances.3 In most cases, however, high cata-
lyst loadings and/or extended reaction time were
required for satisfactory yields. Thus, the search for
milder and more environmentally benign conditions is
still in demand especially for industrial applications.
Friedel–Crafts acylation of anisole with acetic anhydride
was carried out in FBS to investigate the potential of
Hf[N(SO2C8F17)2]4 at low catalytic loading (1 mol%)
under mild conditions. As shown in Table 1, with
respect to HfIV-based catalysts (entries 1 and 2),
Hf[N(SO2C8F17)2]4 showed significantly higher activity
than Hf(OSO2CF3)4, even though the latter gave a rela-
tively higher activity than the other listed metal trifluo-
romethanesulfonates. This result can be attributed to
the presence of the powerfully electron-withdrawing
–N(SO2C8F17)2 ligand bearing the higher fluorine load.8
As for M(OSO2CF3)n (n = 3,4) catalysts, yield (from
On the other hand, a fluorous biphase system (FBS)
brings about potential advantages over classical homo-
moderate to low) followed the order of HfIV > ScIII
>
Keywords: Lewis acid catalyst; Fluorous biphase system; Perfluori-
nated ligand; Friedel–Crafts acylation; Regioselectivity.
GaIII > BiIII ꢀ YbIII > AlIII (entries 2–7), and there was
no significant difference in the regioselectivity (p-regio-
isomer > 97%) except for GaIII catalyst (o/p = 19/81).
*
Corresponding author. Tel.: +81 3 5248 3596; fax: +81 3 5248
3597; e-mail: nishikido.jb@om.asahi-kasei.co.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.065

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X. Hao et al. / Tetrahedron Letters 46 (2005) 2697–2700
Table 1. Effect of catalystsa
OMe
OMe
Cat. (1 mol%)
O
+
Ac2O
chlorobenzene 1.5 mL
SV 135
1.5 mL
1.0 mmol
2.0 mmol
100 °C, 1 h
Entry
1
Catalyst
Yieldb,c (%)
Isomer distribution/a:bd
Hf[N(SO2C8F17)2]4
80
92e
49
45
42
39
16
8
0:100
<1:99e
3:97
2
3
4
5
6
7
8f
9
Hf(OSO2CF3)4
Sc(OSO2CF3)3
Ga(OSO2CF3)3
Bi(OSO2CF3)3
Yb(OSO2CF3)3
Al(OSO2CF3)3
AlCl3
2:98
19:81
2:98
3:97
3:97
0:100
—
2
None
0
a Reaction conditions: see typical procedure.
b Acylation products: o-(1a), p-methoxyacetophenone (1b).
c Isolated yield after chromatography, with respect to anisole.
d Determined by GC–MS and NMR analysis.
e 3 mol% of Hf[N(SO2C8F17)2]4 was used.
f 10 mol% of AlCl3 was used.
In addition, the activity of AlCl3 (entry 8), a well-
known industrially used catalyst for Friedel–Crafts
acylation, was significantly low under the present mild
reaction conditions. No product was obtained in the ab-
sence of the catalyst (entry 9). Accordingly, Hf[N(SO2-
C8F17)2]4 was considered to be an excellent catalyst in
terms of good yield of 80% and p-regioselectivity of
using acetic, n-butyric and benzoic anhydride, or n-butyr-
yl and benzoyl chloride as an acylating agent. The results
are summarized in Table 2. In all cases,
Hf[N(SO2C8F17)2]4 showed a relatively higher activity
than Hf(OSO2CF3)4. As expected, acylation of more elec-
tron rich aromatic compounds (o-, m-dimethoxybenzene
of entries 6–15, mesitylene of entry 16) proceeded more
smoothly than anisole (entries 1–5), and produced a sin-
gle regioisomer in excellent yields. On the other hand, less
electron rich toluene (entry 17) underwent acylation
more slowly than anisole. These conditions allowed the
acylation of anisole, o-, m-dimethoxybenzene with anhy-
drides, similarly to acid chlorides, even though they were
less regioselective in a few cases (entries 3 and 5).
, à
100%.
Several aromatic compounds were subjected to the
Hf[N(SO2C8F17)2]4-catalyzed Friedel–Crafts acylation
Typical procedure (Table 1, entry 1): to a mixture of GALDENÒ SV
135 (1.5 mL; a suitable fluorous solvent for FBS5c) and chlorobenzene
(1.5 mL) were added Hf[N(SO2C8F17)2]4 (41 mg, 0.01 mmol), anisole
(108 mg, 1.0 mmol) and acetic anhydride (204 mg, 2.0 mmol). The
reaction mixture was stirred continuously at 100 °C for 1 h. Once the
stirring was stopped, the reaction mixture settled down at room
temperature and turned into two liquid phases within 5 min, that is,
an upper toluene and a lower SV 135 phase. Pure p-methoxyace-
tophenone product was obtained from the upper phase after silica gel
chromatography and reduced pressure evaporation (120 mg, 80%
isolated yield). The lower fluorous phase containing the catalyst was
reused in the subsequent recycling reactions, to which chlorobenzene
(1.5 mL), anisole (108 mg, 1.0 mmol) and acetic anhydride (204 mg,
2.0 mmol) were added, respectively. The other operations and
procedure (e.g., stirring at 100 °C for 1 h, product separation) were
the same as described above for the first cycle. Such a procedure was
repeated a further two times. Substantially, the yields of p-methoxy-
acetophenone were 81% and 79% in the succeeding two times,
respectively.
Furthermore,
the
recycling
performance9
of
Hf[N(SO2C8F17)2]4 for all of the reactions in Table 2 ex-
cept benzoylation of toluene (entry 17) was also investi-
gated. The operation (see footnote ) was quite similar
to that we have reported for Baeyer–Villiger oxidation,5
that is, the lower fluorous catalytic phase was directly re-
used in the next reaction by combining with another
mixture of reactants more than three times without de-
crease in catalytic activity. Typical results are shown in
Scheme 1.
The benzoylation of less reactive substrates such as
xylene, toluene and chlorobenzene catalyzed by
1 mol% Hf[N(SO2C8F17)2]4 were examined with excess
of substrates. The results are summarized in Table 3.
Although the benzolyation of chlorobenzene (entry 5)
was slow, the elongation of reaction time led to the mid-
dle yield of 45% as well. The benzoylation of o-, m- and
p-xylene (entries 2–4) proceeded fast to afford the corre-
sponding 3,4-, 2,4- and 2,5-dimethylbenzophenone in
92%, 96% and 98% yields, respectively. With respect to
toluene (entry 1), it reacted also smoothly to produce
methylbenzophenone (o/m/p = 10/2/88) in 96% yield.
à Synthesis of Hf[N(SO2C8F17)2]4 complex: to anhydrous methanol
(10.0 mL) were added HN(SO2C8F17)2 (5.89 g, 6.0 mmol) and HfCl4
(0.48 g, 1.5 mmol), which was stirred continuously at 50 °C for 15 h.
After being cooled to room temperature, the mixture was evaporated
and dried at 80 °C/0.01 mmHg for 16 h to give white powders of
hafnium(IV) bis(perfluorooctanesulfonyl)amide complex in 97% yield
(5.96 g). Hf[N(SO2C8F17)2]4 elemental analysis: calcd C, 18.75; Hf,
4.35. Found: C, 18.65; Hf, 4.33. 19F NMR d À126.2, À121.1, À114.2,
À81.5.

X. Hao et al. / Tetrahedron Letters 46 (2005) 2697–2700
Table 2. Hf[N(SO2C8F17)2]4–catalyzed Friedel–Crafts acylation reactions
2699
Hf[N(SO2C8F17)2]4
(1 mol%)
ArH
+
Acylating Agent
2.0 mmol
ArCOR
chlorobenzene 1.5 mL
SV 135
1.5 mL
1.0 mmol
Entry
ArH
Acylating agent
Conditions (°C, h)
Producta
Yieldb,c (%)
Isomer distribution/a:bc,d
1
2
3
4
5
Anisole
Ac2O
100, 1
90, 4
90, 1
1b
80 (49)
90 (46)
88 (57)
89 (43)
90 (35)
0:100 (3:97)
4:96 (13:87)
18:82 (23:77)
0:100 (11:89)
3:97 (14:86)
n-C3H7COCl
(n-C3H7CO)2O
PhCOCl
2a,b
2a,b
3a,b
3a,b
120, 2
120, 2
(PhCO)2O
6
o-Dimethoxybenzene
m-Dimethoxybenzene
Ac2O
90, 1
110, 1
90, 1
4
5
5
6
6
91 (39)
94 (70)
97 (66)
92 (67)
94 (56)
7
n-C3H7COCl
(n-C3H7CO)2O
PhCOCl
8
9
10
110, 1
110, 2
(PhCO)2O
11
12
13
14
15
Ac2O
70, 1
70, 2
70, 2
90, 4
90, 4
7
8
8
9
9
93 (35)
94
96
n-C3H7COCl
(n-C3H7CO)2O
PhCOCl
90
92
(PhCO)2O
16
Mesitylene
Toluene
PhCOCl
110, 3
10
96
17
PhCOCl
110, 5
11c
35
a Acylation products: o-(2a), p-methoxybutyrophenone (2b); o-(3a), p-methoxybenzophenone (3b); 3,4-dimethoxyacetophenone (4); 3,4-dimeth-
oxybutyrophenone (5); 3,4-dimethoxybenzophenone (6); 2,4-dimethoxyacetophenone (7); 2,4-dimethoxybutyrophenone (8); 2,4-dimethoxybenzo-
phenone (9); 2,4,6-trimethylbenzophenone (10); o-(11a), m-(11b), p-methylbenzophenone (11c).
b Isolated yield after chromatography, with respect to aromatic compound.
c Figures in parentheses refer to results using 1 mol% Hf(OSO2CF3)4.
d Determined by GC–MS and NMR analysis.
Table 3. Hf[N(SO2C8F17)2]4–catalyzed benzoylation of aromatic com-
pounds with benzoyl chloride
O
Hf[N(SO2C8F17)2]4
(1 mol%)
MeO
MeO
MeO
MeO
+
n-C3H7COCl
n-C3H7
chlorobenzene 1.5 mL
Hf[N(SO2C8F17)2]4
(1 mol%)
SV 135
1.5 mL
ArH
+
PhCOCl
ArCOPh
1.0 mmol
2.0 mmol
110 °C, 1 h
SV 135 1.5 mL
0.5 mL
2.0 mmol
Yield/%
1st Cycle: 94
2nd Cycle: 90
3rd Cycle: 93
4th Cycle: 92
Entry ArH
Conditions Producta
Yieldb (%)
(isomer distri-
(°C, h)
bution/a:b:c)c
1
2
3
4
5
Toluene
o-Xylene
m-Xylene
p-Xylene
110, 8
120, 3
120, 3
120, 3
11a,b and c 96 (10:2:88)
O
12a
12b
12c
13
92
96
98
45
Hf[N(SO2C8F17)2]4
(1 mol%)
MeO
MeO
MeO
MeO
+
(PhCO)2O
2.0 mmol
Ph
chlorobenzene 1.5 mL
SV 135
1.5 mL
Chlorobenzene 130, 16
1.0 mmol
110 °C, 2 h
a Acylation products: 3,4-(12a), 2,4-(12b), 2,5-dimethylbenzophenone
(12c); p-chlorobenzophenone (13).
b Isolated yield after chromatography, with respect to PhCOCl.
c Determined by GC–MS and NMR analysis.
Yield/%
1st Cycle: 94
2nd Cycle: 92
3rd Cycle: 93
4th Cycle: 90
Scheme 1. Recycles of Hf[N(SO2C8F17)2]4 catalyst under the condi-
tions in Table 2.
cation. (1) The catalyst has an excellent accelerating
effect superior to the well-known trifluoromethanesulf-
onates; (2) high yields and regioselectivity of the
desired aromatic ketones can be obtained at low
catalytic loadings (1 mol%); (3) the catalyst, completely
immobilized in the fluorous phase, can be recovered
and reused. Further experiments are still under
progress.
In conclusion, Hf[N(SO2C8F17)2]4 in FBS has proved
to be a favorable catalyst for Friedel–Crafts acylation.
We believe that the following results endow the cata-
lytic approach with great potential for industrial appli-

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X. Hao et al. / Tetrahedron Letters 46 (2005) 2697–2700
Mikami, Y.; Matsumoto, Y.; Mikami, K. Synlett 1999,
Acknowledgments
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This work was partially supported by a Grant-in-Aid for
Scientific Research (No. 16750087) from the Ministry of
Education, Culture, Sports, Science and Technology,
Government of Japan.
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