Development of fluorous lewis acid-catalyzed reactions

Article abstract of DOI:10.3390/11080627

Organic synthetic methodology in the 21st century aims to conform to the principles of green sustainable chemistry (GSC) and we may expect that in the future, the realization of GSC will be an important objective for chemical industries. An important aim of synthetic organic chemistry is to implement waste-free and environmentally-benign industrial processes using Lewis acids as versatile as aluminum choride. A key technological objective of our work in this area has been to achieve a "catalyst recycling system that utilizes the high activity and structural features of fluorous Lewis acid catalysts". Thus, we have developed a series of novel fluorous Lewis acid catalysts, namely the ytterbium(III), scandium(III), tin(IV) or hafnium(IV) bis(perfluoroalkanesulfonyl)amides or tris(perfluoro- alkanesulfonyl)methides. Our catalysts are recyclable and effective for acylations of alcohols and aromatics, Baeyer-Villiger reactions, direct esterifications and transesterifications in a fluorous biphasic system (FBS), in supercritical carbon dioxide and on fluorous silica gel supports.

Full text of DOI:10.3390/11080627

Molecules 2006, 11, 627-640
molecules
ISSN 1420-3049
http://www.mdpi.org
Review
Development of Fluorous Lewis Acid-Catalyzed Reactions
1
,†
1
2
2,
Akihiro Yoshida , Xiuhua Hao , Osamu Yamazaki and Joji Nishikido *
1
2
†
The Noguchi Institute, Itabashi-ku, Tokyo 173-0003, Japan; e-mail: ayoshida@noguchi.or.jp
Asahi Kasei Corporation, Fuji, Shizuoka 416-8501, Japan
*
Author to whom correspondence should be addressed; e-mail: nishikido.jc@om.asahi-kasei.co.jp
Received: 5 July 2006; in revised form: 26 July 2006 / Accepted: 26 July 2006 / Published: 23 August
006
2
Abstract: Organic synthetic methodology in the 21st century aims to conform to the
principles of green sustainable chemistry (GSC) and we may expect that in the future, the
realization of GSC will be an important objective for chemical industries. An important aim
of synthetic organic chemistry is to implement waste-free and environmentally-benign
industrial processes using Lewis acids as versatile as aluminum choride. A key
technological objective of our work in this area has been to achieve a “catalyst recycling
system that utilizes the high activity and structural features of fluorous Lewis acid catalysts”.
Thus, we have developed a series of novel fluorous Lewis acid catalysts, namely the
ytterbium(III), scandium(III), tin(IV) or hafnium(IV) bis(perfluoroalkanesulfonyl)amides or
tris(perfluoro- alkanesulfonyl)methides. Our catalysts are recyclable and effective for
acylations of alcohols and aromatics, Baeyer-Villiger reactions, direct esterifications and
transesterifications in a fluorous biphasic system (FBS), in supercritical carbon dioxide and
on fluorous silica gel supports.
Keywords: Fluorous chemistry, Lewis acid, sulfonimide, biphasic system, aqueous reaction.
Contents
1
2
3
4
. Introduction
. Fluorous Lewis Acid Catalysts
. Fluorous Biphasic Catalysis by Fluorous Lewis Acids
. Fluorous Biphasic Reactions Containing Water

Molecules 2006, 11
628
5
6
7
8
. Continuous-flow Reaction in FBS
. Fluorous Silica Gel-Supported Lewis Acid Catalysts
. Supercritical Carbon Dioxide as a Reaction Medium
. Conclusions
Introduction
Lewis acid-mediated reactions using aluminum chloride typically yield large amounts of acidic
wastes along with the desired product(s). With this in mind, we sought to develop novel reaction
processes catalyzed by highly active, selective and recyclable Lewis acids that would significantly
reduce these acidic wastes and could thus be used to replace existing aluminum chloride processes. So-
called “fluorous chemistry” [1] has been studied since 1994, when Horváth and Rábai first reported
fluorous biphasic catalysis [2]. Lively discussions on this topic occurred at the 1st International
Symposium on Fluorous Technologies (ISoFT), held in Bordeaux (France) in July 2005, which was
attended by chemists from 15 countries and highlighted by Chemical & Engineering News [3]. We
review herein a series of fluorous biphasic reactions catalyzed by fluorous Lewis acids containing a
large number of fluorine atoms, heterogeneous Lewis acid-catalyzed reactions using fluorous silica
gel-supported fluorous Lewis acids and fluorous Lewis acid-catalyzed reactions in supercritical carbon
dioxide.
Fluorous Lewis Acid Catalysts
Kobayashi and co-workers have recently reported that lanthanide(III) triflates can be used as water-
stable Lewis acid catalysts [4]. In 1994, Koppel, Taft et al. predicted that perfluorobutanesulfonimide
[
(n-C F SO ) NH] and tris(perfluorobutanesulfonyl)methane [(n-C F SO ) CH] would have much
4 9 2 2 4 9 2 3
3 2
higher acidity than trifluoromethanesulfonic acid (CF SO OH) [5]. Thus, it was expected that Lewis
acid bearing conjugate bases of these compounds as ligands could be more active than the
corresponding metal triflates.
Meanwhile, we have been actively involved in the discovery and development of stronger and
water-stable Lewis acid catalysts, and have successfully prepared and developed novel fluorous Lewis
2 8 17 2 3 2 8 17 3 3
acid catalysts [(Ln[N(SO -n-C F ) ] and Ln[C(SO -n-C F ) ] )], like those described above, using
ytterbium(III) and scandium(III) as central metals, which can be highly active catalysts in Friedel-
Crafts acylation, Diels-Alder, Meerwein-Ponndorf-Verley reduction and esterification reactions [6].
Whereas metal triflate catalysts are generally water-soluble, our catalysts are water-repellent and
highly “fluorous” due to the perfluoroalkyl chains surrounding the central metal. The next topic of
interest was recycling of these catalysts, which is an important feature for industrial processes. Thus,
we examined various reactions under fluorous biphasic catalysis, heterogeneous reactions catalyzed by
fluorous silica gel-supported fluorous Lewis acid catalysts and fluorous Lewis acid-catalyzed reactions
in supercritical carbon dioxide.

Molecules 2006, 11
629
Fluorous Biphasic Catalysis by Fluorous Lewis Acids
Fluorous solvents such as perfluoroalkanes are sparingly soluble in general organic solvents and
water. On the other hand, fluorous catalysts bearing highly fluorinated ligands are also sparingly
soluble in general organic solvents, but they are soluble in fluorous solvents. As mentioned above,
Horváth and Rábai introduced the concept of a fluorous biphasic system (FBS, Figure 1) in 1994,
when they reported hydroformylation in organic and fluorous solvents catalyzed by a rhodium(I)
catalyst bearing fluorous ligands [2]. Since then, a number of fluorous catalysts have been prepared,
although almost all of these catalysts were transition metal complexes bearing perfluoroalkyl group
ligands connected through hydrocarbon spacers. In contrast, we were the first to develop lanthanide(III)
tris(perfluoroalkanesulfonyl)methides (Ln[C(SO -n-C F ) ] ) and bis(perfluoroalkanesulfonyl)amides
2
8 17 3 3
(
Ln[N(SO -n-C F ) ] ) bearing no hydrocarbon spacers for fluorous biphasic catalysis.
2 8 17 2 3
Figure 1. Fluorous biphasic catalysis.
substrates
products
organic
organic
catalytic
reactions
catalyst
catalyst
fluorous
fluorous
stirring
(
high temperature)
recycling
Considering that lanthanide complexes with fluorous ligands with long-chain fluorous ponytails and
no hydrocarbon spacers would be both strongly Lewis acidic and highly fluorous for use in FBS, we
prepared several fluorous Lewis acids (such as Hf(IV), Sn(IV), Bi(III)) and examined their utilities in
fluorous biphasic reactions [7].
Initially, we studied acetylation reactions of cyclohexanol in toluene/perfluoro(methylcyclohexane)
2 8 17 3 3 2 8 17 3 3
catalyzed by 1 mol% of Yb[C(SO -n-C F ) ] or Sc[C(SO -n-C F ) ] (Table 1). These reactions
proceeded quantitatively in the heterogeneous solution under vigorous stirring. After the reaction, the
reaction mixture separated into two phases upon standing. The lower fluorous phase, containing the
fluorous catalyst, was recovered and reused up to five times without any loss of catalytic activity. On
the other hand, the upper organic phase was shown by ICP analysis to contain <2 ppm of metal. Thus,
the fluorous catalyst was almost completely immobilized in the fluorous phase.

Molecules 2006, 11
630
Table 1. Fluorous biphasic acetylation.
Cat. (1 mol%)
OH
+
Ac
2
O
OAc
toluene 5 mL
CF -c-C F 5 mL
3
6 11
2
mmol
2 mmol
3
0 °C, 20 min
b,c
%
yield
a
cycle Yb[C(SO
2
-n-C
8
F
17
)
3
]
3
2 8 17 3 3
Sc[C(SO -n-C F ) ]
1
2
3
4
5
99
99 (98)
100 (98)
99
99 (96)
98
99
99
99 (96)
100 (98)
a
b
The catalyst in the lower phase was recycled; Calculated by
c
GC analysis using n-nonane as an internal standard; Values in
parentheses refer to the isolated yields.
We have also reported that fluorous Lewis acid catalysts were both useful and recyclable in carbon-
carbon bond forming reactions such as the Diels-Alder reaction, the Mukaiyama aldol reaction [8] and
Friedel-Crafts acylations [9]. In particular, classical Friedel-Crafts acylation generally requires the use
of an equimolar or greater amount of a catalyst such as aluminum chloride, whereas on the contrary,
Friedel-Crafts acylation of anisole and related aromatic compounds proceeded smoothly in
®
chlorobenzene/GALDEN SV135 [10] using only 1 mol% of Hf[N(SO
2
-n-C
8
F
17
)
2
]
4
, which was more
4
active than Hf(OTf) (Table 2). As expected, this catalyst was also recyclable. Toluene and even
chlorobenzene could be used as both nucleophilic aromatics and solvents [9].
Table 2. Fluorous biphasic Friedel-Crafts acylation.
Cat. (1 mol%)
O
MeO
+
Ac
2
O
MeO
+
MeO
O
chlorobenzene 1.5 mL
GALDEN® SV135 1.5 mL
1
mmol
2 mmol
100 °C, 1 h
a
a
catalyst
% yield
80
ratio (p / o)
100 : 0
>99 : <1
97 : 3
Hf[N(SO
Hf[N(SO
Hf(OTf)
Sc(OTf)
2
-n-C
8
F
17
)
2
]
4
b
2
-n-C
8
F
17
)
2
]
4
92
4
49
3
45
98 : 2
Yb(OTf)
3
16
97 : 3
c
AlCl
3
2
100 : 0
a
b
Calculated by GC analysis using n-nonane as an internal standard; 3
c
mol% of fluorous Hf(IV) catalyst was used; 10 mol% of AlCl was used.
3
2 3 2
Recently, we have clarified that lanthanide(III) with N(SO -C10HF20O ) ligands, including ether
oxygen atoms, also behave as highly active fluorous Lewis acids [11].

Molecules 2006, 11
631
Fluorous Biphasic Reactions Containing Water
Our fluorous Lewis acid catalysts, which catalyze several reactions at the organic/fluorous interface,
are stable to water due to their highly water-repellent properties. It was therefore considered that
fluorous Lewis acid catalysts could be used even in water-containing reaction systems.
At first, we examined direct esterification reactions [12] using Hf[N(SO -n-C F ) ] as catalyst.
2
8 17 2 4
The catalytic reactions of an equimolar amount of carboxylic acid and alcohol proceeded under mild
conditions (<100 °C) without distilling off the water formed as a by-product (Table 3) [13]. The
hafnium(IV) catalyst was recyclable, as expected. It was thought that water rapidly moved out of the
reactive site at the organic/fluorous interface, since water is inmiscible in both the organic and fluorous
phases.
Table 3. Direct esterification of carboxylic acid and alcohol.
Hf[N(SO -n-C F ) ]
8 17 2 4
2
(
5 mol%)
1
2
1
2
R CO H
+
R OH
R CO R
2
2
ClCH CH Cl 3 mL
2
2
CF -c-C F 3 mL
3
6 11
1
mmol
1 mmol
1
2
a
b
R CO
2
H
R OH
c-C
n-C
PhCH
c-C
conditions
50 °C, 8 h
70 °C,15 h
50 °C,24 h
50 °C,24 h
90 °C,15 h
60 °C, 8 h
% yield
% selectivity
AcOH
6
H
11OH
82
92
89
55
85
86
98
97
98
98
96
98
c-C
c-C
c-C
6
6
6
H
H
H
11CO
2
2
2
H
4
H
9
OH
11CO
11CO
H
H
2
OH
6
H
11OH
c
PhCO
2
H
n-C
4
H
9
OH
d
CH
2
=CH(CH
3
)CO
2
H
3
CH OH
a
b
Calculated by GC analysis using n-nonane as an internal standard; Molar ratio of formed
c
d
ester / converted acid; In ClCH CH Cl (3 mL) / perfluorodecalin (3 mL); 5 mmol of
2
2
methanol were used.
The Baeyer-Villiger reaction is a useful method for synthesis of esters or lactones from ketones. It
was also known that to carry out this reaction ketones typically have to be treated with a stoichiometric
amount of a potentially explosive concentrated organic peracid such as peracetic acid or perbenzoic
acid. As a result we developed an environmentally benign Baeyer-Villiger oxidation with
commercially available and less explosive 35% aqueous hydrogen peroxide solution, using our
fluorous catalysts. From an examination of various catalysts, it was found that Sn[N(SO
was the most effective catalyst for lactonization of cyclic ketones such as 2-adamantanone (Table 4)
14].
The fluorous tin(IV) catalyst was recyclable and even after the 4th cycle reaction, the high yields
2 8 17 2 4
-n-C F ) ]
[
and selectivity were maintained. It was also found that the FBS reaction displayed better selectivity
than a single phase system. Furthermore, fluorous amide catalysts were more active than the
corresponding triflate catalysts. The fluorous tin(IV) catalyst was also effective for transesterification
[14].

Molecules 2006, 11
632
Table 4. Baeyer−Villiger reactions with aqueous H O .
2
2
O
O
Cat. (1 mol%)
O
+
H O aq.
2 2
(
35%)
ClCH CH Cl 3 mL
2
2
CF -c-C F 3 mL
3
6 11
2
mmol
2 mmol
rt, 2 h
a
b,c
d
catalyst
Sn[N(SO -n-C
Sn[N(SO -n-C
cycle
% yield
% selectivity
1
4
1
1
1
1
1
1
1
93 (91)
93
99
99
80
83
87
92
91
69
66
2
8
F
17
)
2
]
4
e
2
8
F
17
)
2
]
4
68
48
37
82
41
53
Sn[N(SO -n-C
Sn(OTf)
Hf[N(SO -n-C
Hf(OTf)
Sc[N(SO -n-C F ) ]
2
8
F
17
)
2
]
2
4
2
2
8
F
17
)
2
]
4
2
8
17 2 3
Sc(OTf)
3
31
a
b
The catalyst in the lower phase was recycled. Calculated by GC
c
analysis using n-nonane as an internal standard. Values in parentheses
d
refer to the isolated yields. Molar ratio of formed lactone / converted
e
adamantanone. In CF C H (single phase).
3
6
5
Continuous-flow Reaction in FBS
The density of fluorous solvents is higher than that of common organic solvents. Based on this fact
we designed novel continuous-flow reaction apparatus, which consisted of a reactor equipped with a
mechanical stirrer and a decanter (Figure 2). The fluorous solvent is poured into the reactor, followed
2 3 2 3
by addition of a fluorous catalyst such as Yb[N(SO -C10HF20O ) ] , which is immobilized in the
fluorous solution because of its insolubility in general organic solvents. The organic solution
containing organic substrates and reagents as the mobile organic phase flows continuously into the
reactor where it is vigorously stirred with the stationary fluorous phase. The reactions proceed in the
resultant emulsion. After the reaction, the emulsion mixture is automatically introduced to the decanter
where the organic-fluorous phases are separated. The upper organic phase containing the product(s)
overflows and is collected while the lower fluorous phase is recycled and thus, the substrates can be
readily converted to the products through this continuous-flow system. This technique is of importance
for application to industrial processes. We performed the acetylation of cyclohexanol with acetic
®
anhydride catalyzed by Yb[N(SO -C HF O ) ] in a biphasic toluene/GALDEN SV135 system
2
10
20 3 2 3
using the bench-scale apparatus (Figure 2) [10]. The reaction proceeded successfully for about 400 h
to give cyclohexyl acetate in >90% yield. A high turnover number (TON) of >9000 was attained for
the Lewis acid catalysis [11] After 400 h, yields of cyclohexyl acetate decreased due to leaching of the
fluorous catalyst into the mobile organic phase. Consequently, we performed the continuous-flow
2 3 2 3
acetylation of cyclohexanol using a one-tenth amount of Yb[N(SO -C10HF20O ) ] (Figure 3). After
4
9 h and 77 h, the leached fluorous catalyst was recovered from the organic phase in the product tank
by extraction with SV135. When the recovered catalyst (which was confirmed to be as active as the
fresh catalyst) was poured back into the reactor, the reaction again proceeded smoothly to give

Molecules 2006, 11
633
cyclohexyl acetate in high yield. After 107 h, a TON of >21000 was attained [15]. It is expected that a
much higher TON could be attained by continuous recovery of the leached fluorous catalysts.
Figure 2. Bench-scale continuous-flow reaction system.
product in organic solvent
.
. . . .
. . . .
. . . .
.
.
.
.
emulsion
.
organic phase
fluorous phase
. . . .
.
. . . .
.
. . . .
.
.
decanter
substrate
in organic solvent
phase separation
reactor
stirre
decanter
reactor
substrate tank
product
tank
feed pump
Figure 3. Continuous-flow acetylation of cyclohexanol.
1
00
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
conversion of CyOH
yield
The recovered catalyst was added!
0
20
40
60
80
100
120
time /h

Molecules 2006, 11
634
We also applied this method to a Sn[N(SO -n-C F ) ] -catalyzed Baeyer-Villiger reaction with
2
8 17 2 4
aqueous hydrogen peroxide. As a result, a TON of 2200 was attained [11].
Fluorous Silica Gel-Supported Lewis Acid Catalysts
Fluorous silica gel has a perfluoroalkyl bonding phase and high affinity towards fluorous
compounds. We therefore considered that our fluorous Lewis acid catalysts could be immobilized on
fluorous silica gel, and this type of solid catalyst would be recoverable by simple filtration (Figure 4).
It was expected that the catalytic reaction was taking place not only in an organic solvent but also in
water [16]. In addition, we have previously reported aqueous reactions catalyzed by cyclodextrin-
epichlorohydrin copolymer-supported Ln[C(SO -n-C F ) ] , due to the affinity of cyclodextrin for the
2
4 9 3 3
perfluorobutyl groups [17]. We examined the Baeyer-Villiger oxidation at a low-concentration (<5
wt%) of aqueous hydrogen peroxide catalyzed by fluorous silica gel-supported Sn[N(SO -n-C F ) ]
8 17 2 4
2
(
Table 5).
Figure 4. Fluorous silica gel-supported Lewis acid catalyst model.
sub-
strate
H O
2
F
F
F
F
catalyst
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F F
F
F
F
F
F
F
F
F
F
F
F
F
F F
F
F
F
Si
O
Si
O
Si
O
OH
HO
silica gel
Fluorous silica gel-supported Sn[N(SO -n-C F ) ] is a more active catalyst than any other silica
2
8 17 2 4
2 8 17 2 4
gel-supported Sn[N(SO -n-C F ) ] . Additionally, it was found that octadecyl (ODS)-silica gel and
normal silica gel-supported tin(IV) catalysts were not effective for recycling, while fluorous silica-gel-
supported catalyst was recyclable; i.e. catalytic activity was maintained even after the 4th cycle
reaction. Electron probe microanalysis (EPMA) confirmed that the fluorous tin(IV) catalyst was
strongly immobilized on fluorous silica gel [7a], whereas, on the other hand, it was not effectively
immobilized on either ODS-silica gel or on normal silica gel.

Molecules 2006, 11
635
Table 5. Baeyer−Villiger reactions catalyzed by silica gel-supported Sn[N(SO -n-C F ) ] .
2
8 17 2 4
various silica gel-Sn[N(SO C F ) ]
O
2
8
17 2 4
O
O
(5 mol%)
+
H O
2 2
H O
2
(
1.1 equiv., 0.44 wt%)
35 °C, 16 h
a
b,c
c,d
catalyst
fluorous SiO
cycle
% yield
% selectivity
100 (89)
97 (92)
96 (90)
91 (93)
88
2
-
1
2
3
4
1
2
3
1
2
3
79 (87)
75 (89)
73 (86)
71 (88)
60
Sn[N(SO
2
-n-C
8
F
17
)
2
]
4
ODS SiO
Sn[N(SO -n-C
2
-
2
8
F
17
)
)
2
2
]
4
4
41
28
43
34
84
82
93
100
SiO
2
-
Sn[N(SO -n-C
2
8
F
17
]
24
86
a
b
The catalyst was recycled by simple filtration; Calculated by GC analysis
c
using n-nonane as an internal standard; Values in parentheses were the results
d
of the reactions at 25 °C using 10 equiv. of H O (4 wt%); Molar ratio of
2
2
formed lactone / converted 2-adamantanone.
Fluorous silica gel-supported fluorous Lewis acid catalysts were also effective for Diels-Alder
reactions in water and direct esterification reactions in organic media. While our study was underway
Bannwarth and co-workers reported the use of a fluorous silica gel-supported fluorous palladium(0)
catalyst for the Sonogashira coupling [18].
Supercritical Carbon Dioxide as a Reaction Medium
The replacement of reaction media for homogeneous catalysis has been known to provide an
opportunity to control reactions in terms of reactivity and selectivity due to the high gas miscibilities,
greater diffusivities, clustering effects, and tunable solvent power by changing their density along with
the pressure [19]. Supercritical carbon dioxide has been used as an environmentally benign reaction
medium for transition metal-catalyzed hydroformylation [20], hydrogenation [21] and so on. On the
other hand, the use of supercritical carbon dioxide for Lewis acid catalysis in terms of design and
recyclability of Lewis acid catalysts is an important research topic [22].
We have developed fluorous Lewis acid catalysts bearing long perfluoroalkyl group chains such as
perfluorooctyl groups as highly active catalysts. Since typical fluorous compounds are soluble in
supercritical carbon dioxide [20-22], a homogeneous phase with the fluorous solvent is expected to
immobilize fluorous catalysts. After the reaction, the fluorous solvent with the fluorous catalyst
remains in the reaction vessel after releasing liquid carbon dioxide. Thus, the fluorous phase is
expected to be recyclable (Figure 5a). Moreover, we examined another method for recycling Lewis
acid catalysts that are insoluble in liquid carbon dioxide, even in the presence of reaction substrates
and products (Figure 5b). We describe herein a method for recycling our fluorous Lewis acid catalysts
in supercritical carbon dioxide [23].

Molecules 2006, 11
636
Figure 5. Recycle methods for fluorous lanthanide catalysts using scCO as a reaction
2
media: (a) fluorous/scCO
2
biphasic reaction; (b) without fluorous solvent.
supercritical state
scCO2
liq. CO2
product
product
in liq. CO
phase
scCO2
after
(a)
2
substrate
the reaction
homogeneous
phase
fluorous media
Cat.
fluorous media
Cat.
reuse of fluorous Cat. in fluorous phase
supercritical state
substrate
scCO2
liq. CO
2
product
in liq. CO2
phase
scCO2
after
the reaction
(b)
product
homogeneous
phase
substrate
Cat.
Cat.
reuse of fluorous Cat.
substrate
(
a) Supercritical carbon dioxide/fluorous solvent system
We examined the catalytic activities of the fluorous Lewis acids using alcohol acylation in
supercritical carbon dioxide/perfluorooctane as a probe reaction. The acetylation of cyclohexanol with
.1 equiv. of acetic anhydride proceeded in the homogeneous phase involving a soluble fluorous phase
1
immobilized fluorous catalyst above the critical point (Table 6).
2 8 18
Table 6. Fluorous biphasic acetylation in scCO /C F .
Yb[N(SO -n-C F ) ]
2
8
17 2 3
(
1 mol%)
OH
+
Ac
2
O
OAc
scCO / C F
2
8
18
20 MPa
2
mmol
2.2 mmol
4
0 °C, 15 min
a
b,c
cycle
% yield
1
2
3
4
5
99 (98)
99
99
99
99
a
b
The catalyst in the fluorous phase was recycled; Calculated
c
by GC analysis using n-nonane as an internal standard; Value
in parenthesis refers to the isolated yield.

Molecules 2006, 11
637
After the reaction, the catalyst was soluble in the fluorous phase and the product was separated
from the fluorous phase by extracting with an organic solvent. The isolated yield of the product was
9
8%, whereas the yield of acetylation in supercritical carbon dioxide without the fluorous catalyst was
only 3%. Therefore, we may conclude that the fluorous catalyst is effective in supercritical carbon
dioxide. The fluorous phase immobilized lanthanide catalyst was recyclable five times and no loss of
catalytic activity was observed for the recovered catalyst.
(
b) Supercritical carbon dioxide system
We also examined the acetylation of cyclohexanol in supercritical carbon dioxide catalyzed by the
fluorous catalyst without a fluorous solvent. It was observed that Yb[N(SO -n-C F ) ] catalyst was
2
8 17 2 3
soluble in supercritical carbon dioxide (40 °C, 10 MPa) (Figure 6a). In contrast, the catalyst was
deposited in liquid carbon dioxide below the critical point by lowering temperature and pressure (−20
°
C, 6 MPa) even in the presence of the products (Figure 6b). Using this temperature-dependent
solubility advantage of the fluorous catalyst, we examined its reuse [24].
Figure 6. Esterification in: (a) homogeneous phase under supercritical carbon dioxide;
(
b) heterogeneous phase under liquid carbon dioxide.
(a)
(b)
2 8 17 2 3
The acetylation of cyclohexanol with acetic anhydride catalyzed by Yb[N(SO -n-C F ) ] or
Sc[N(SO
2
-n-C
8
F
17
)
2
]
3
was performed in supercritical carbon dioxide (Table 7).
Table 7. Fluorous biphasic acetylation in scCO2.
Cat. (1 mol%)
OH
+
Ac
2
O
OAc
scCO2
1
0 MPa
2
mmol
2.2 mmol
4
0 °C, 10 min
b,c
%
yield
a
cycle Yb[N(SO
2
-n-C
8
F
17
)
2
]
3
2 8 17 3 3
Sc[C(SO -n-C F ) ]
1
2
3
99 (98)
99
98
99 (98)
100 (98)
99
a
b
The residual catalyst was recycled; Calculated by GC
c
analysis using n-nonane as an internal standard; Values in
parentheses refer to the isolated yields.

Molecules 2006, 11
638
After the reaction, the reaction vessel was cooled to −20 °C to deposit the fluorous catalyst. The
resultant liquid carbon dioxide was evacuated with products. The residual catalyst remained in the
reaction vessel and was reused without isolation. The isolated yield was 98% using Yb(III) or Sc(III)
catalyst. The lanthanide catalyst was recyclable three times and no loss of catalytic activity was
observed with the recovered catalyst.
Next, the catalytic activities and recyclable use of the fluorous catalysts were examined for C-C
bond forming reactions. The Friedel-Crafts acylation reaction is one of the most useful processes in
organic synthesis. The reaction of anisole with 2 equiv. of acetic anhydride was also carried out in the
presence of Yb(III) or Sc(III) catalyst (Table 8). As a result, it was noted that both catalysts were
effective for the Friedel-Crafts acylation. After the reaction, the remaining catalyst was completely
recovered and reused in supercritical carbon dioxide without isolation.
Table 8. Fluorous biphasic Friedel-Crafts acylation in scCO2.
Cat. (3 mol%)
scCO2
O
MeO
2
+
Ac
2
O
MeO
1
0 MPa
mmol
2.2 mmol
8
0 °C, 2 h
b,c
%
yield
2 8 17 3 3
Sc[C(SO -n-C F ) ]
a
cycle Yb[N(SO
2
-n-C
8
F
17
)
2
]
3
1
2
3
79 (77)
77
82 (79)
80
77
79
a
b
The residual catalyst was recycled; Calculated by GC
c
analysis using n-nonane as an internal standard; Values in
parentheses refer to the isolated yields.
Conclusions
We have developed various useful reactions catalyzed by novel fluorous Lewis acids M[N(SO
2
-n-
8 17 2 n
C F ) ] in a fluorous biphasic system, immobilized on fluorous silica gel, and in supercritical carbon
dioxide. The catalysts were recyclable in many cases and this enables reduction of acidic wastes. We
have established a continuous-flow reaction system based on the fluorous biphasic system for
industrial processes. The fluorous catalytic reaction processes can be applied to synthesis of various
products such as fine chemicals, pharmaceutical and pesticide intermediates, that are expected to come
into practical use as useful technology for reduction of acidic wastes.
Acknowledgements
This work was mainly supported by New Energy and Industrial Technology Development
Organization (NEDO) through the R&D program for Process Utilizing Multi-Phase Catalytic Systems.
This work was partially supported by Grant-in-Aid for Scientific Research (No. 16750087) from the
Ministry of Education, Culture, Sports, Science and Technology, Government of Japan.

Molecules 2006, 11
639
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