Single-pass reaction column system with super br?nsted acid-loaded resin

Article abstract of DOI:10.1055/s-2002-32964

Various acid-promoted reactions gave the desired products in high yields by passing a solution of reactants through a reaction column packed with polystyrene-bound super Br?nsted acid (1) just once. Polar and nonpolar organic solvent-swellable 1 is much superior to Nafion SAC-13 (2) as a Br?nsted acid-loaded resin packed in the column.

Full text of DOI:10.1055/s-2002-32964

1296
LETTER
Single-Pass Reaction Column System with Super Brønsted Acid-loaded Resin
Single-Pass
Reacti
a
on
C
olumn
z
S
yste
m
uaki Ishihara, Aiko Hasegawa, Hisashi Yamamoto*
Graduate School of Engineering, Nagoya University, SORST, Japan Science and Technology Corporation (JST), Furo-cho, Chikusa,
Nagoya 464-8603, Japan
Fax +81(52)7893222; E-mail: yamamoto@cc.nagoya-u.ac.jp
Received 9 May 2002
ter was used as a reaction column. A mixture of 1 [1.05
Abstract: Various acid-promoted reactions gave the desired prod-
mmol H+/g resin: polystyrene, 2% cross-linked with divi-
ucts in high yields by passing a solution of reactants through a reac-
nylbenzene cross-linker, 38-75 m (200-400 mesh)] and
tion column packed with polystyrene-bound super Brønsted acid (1)
just once. Polar and nonpolar organic solvent-swellable 1 is much
Celite® 545 (17 m) was packed in a 2 mL syringe, and a
superior to Nafion® SAC-13 (2) as a Brønsted acid-loaded resin solution of reactants was passed through the reaction col-
packed in the column.
umn. Super Brønsted acid-loaded resin 1 could be easily
isolated from a mixture of 1 and Celite® based on the dif-
Key words: Brønsted acid, reaction column, flow system, resin,
catalyst
ference in their specific gravity: while 1 floats on water,
Celite® sinks.
1 cm
Resin-bound catalysts offer several advantages in prepar-
ative procedures. Simplification of product workup, sepa-
ration, and isolation as well as reuse of the catalyst could
lead to an economical automation system. Although the
use of immobilized homogeneous catalysts is of interest,
there are few known examples of polymer-bound super
Brønsted acids.1,2 Recently, we succeeded in preparing
polystyrene-bound super Brønsted acid (1).1 It has been
ascertained that 1 is effectively swollen by both polar and
nonpolar organic solvents, and its catalytic activity for
various organic reactions is superior to that of Nafion®-H/
silica nanocomposite [Nafion® SAC-13 (2)],3 which has a
104-fold higher surface area than Nafion®-H beads
(Nafion® NR50) (Scheme).1 However, as 1 is repeatedly
reused in a batch system, it becomes more difficult to re-
cover 1 by filtration, since vigorous agitation degrades the
resin beads. To avoid physical degradation of the resin
beads, we applied 1 to a flow reaction system.4,5 In this
Letter, we demonstrate that various acid-promoted reac-
tions proceed to afford the desired products in high yields
by passing a solution of reactants through a reaction col-
umn packed with 1 just one time (‘single-pass reaction
column system’).
Plunger
Reaction column
[2-mL syringe]
A solution of reactants
1 (1.05 mmol H+/g resin)
+ Celite® 545
Syringe filter
Product elution
Figure Single-pass reaction column assembly.
We tested the reaction column packed with 9.5 mg of 1
(0.01 mmol) and 500 mg of Celite® 545 in acetylation re-
action (1 mmol-scale) of alcohols with acetic anhydride
(Table 1).6 First, the column was flushed with 2 mL of ac-
etonitrile under air. An ambient-temperature solution of L-
menthol (1 mmol) and acetic anhydride (1.5 mmol) in ac-
etonitrile (2 mL) was added to the column. The reaction
was initiated by allowing the reactant mixture to percolate
through the reaction column. Additional acetonitrile (10
mL) was added to allow complete elution of the column
contents. After passing through the reaction column over
1 h (flow rate, 0.2 mL/min), the eluted reaction mixture
was concentrated to afford L-menthyl acetate in quantita-
tive yield. 2,4,6-Trimethylphenyl acetate was also ob-
tained in quantitative yield in a similar manner.
Acetylation of 2,6-di-tert-butyl-4-methylphenol was rela-
tively slow, but the corresponding ester was obtained in
73% yield by allowing the eluents to flow under gravity
without pressurization (0.8 mL/h). It was noted that 1 was
much more effective than 2.4
F
F
[(CF2CF2)nCFCF2]x
(OCF2CF)mOCF2CF2SO3H
Tf
H
Tf
CF3
F
F
Polystyrene-bound
Nafion® SAC-13 (2)
super Brønsted acid (1)
Scheme
Figure shows the column catalysis assembly we designed
for this purpose. A 2-mL syringe attached to a syringe fil-
The reaction column with 1 was effective for the esterifi-
cation of carboxylic acids with methanol.7 For instance,
methyl 3-phenylpropionate was obtained in 53% yield by
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1296,1298,ftx,en;G12602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Single-Pass Reaction Column System
Table 2 Preapartion of Cyclic Acetals
1297
Table 1 Acetylation of Alcohols with Acetic Anhydride
Reaction column
Reaction column
[1 (9.5 mg, 1 mol%)
+Celite (500 mg)]
[1 (9.5 mg, 1 mol%)+Celite® (500 mg)]
O
+
ROH
Ac2O
ROAc
+
+
HC(OMe)3
(1.2 equiv)
O
O
1 mmol
1.5 mmol
MeCN, rt, flow
R1
R2
HO
OH
toluene or MeCN, rt,
flow
R1 R2
(1.2 equiv)
ROH
Flow rate
Yield (%)a
R1R2C=O
Diol
Solvent Flow rate Yield
(mL/min) (%)a
OH
0.2 mL/min
99 [6]
O
i-Pr
MeCN 0.2
87 [17]
R1
0.1 mL/min
0.8 mL/h
>99 [12]
73 [<5]
Ph
OH OH
OH
toluene 0.2
MeCN 0.07
88 [11]
88 [12]
O
O
R1
Ph
Ph
HO
OH
R1=Me
R1=t-Bu
OH OH
H
a Yield in using 2 (9.5 mg) in place of 1 is indicated in brackets.
a Yield in using 2 (9.5 mg) in place of 1 is indicated in brackets.
passing through 1 (5 mol%) just once. On the other hand,
2 was much less effective for this esterification (Equation
1).
pared with those of Nafion® SAC-13 (Equations 3–6).
The reaction column containing 1 was highly active and
reusable for all of the reactions examined: the Mukaiyama
aldol reaction (Equation 3), the Sakurai–Hosomi allyla-
tion reaction (Equation 4), the Mukaiyama–Michael addi-
tion reaction (Equation 5), and the Mukaiyama aldol-type
reaction of benzaldehyde dimethylacetal (Equation 6).
The catalytic activity of 1 in the flow system as well as in
the batch system1 was superior to that of 2, which may be
the strongest Brønsted acid among the known solid acids.
Hydrolysis of trimethylsilyl ethers obtained in Equations
3–5 was also carried out by passing a solution of crude
products in H2O–THF [1:5 (v/v)] through the same reac-
tion column containing 1.
Reaction column
[1 (48 mg, 5 mol%) +Celite® (460 mg)]
PhCH2CH2CO2H
1 mmol
PhCH2CH2CO2Me
MeOH, rt, flow (0.1 mL/min)
21% yield (53% yield (0.8 mL/h)); cf. 2 (48 mg) in place of 1: <1% yield
Equation 1
Acetalization with trialkyl orthoformates also proceeded
very well by passing through 1.8 In particular, trimethyl-
orthoformate is very reactive, and 2,2-dimethoxy-4-phen-
ylbutane was obtained quantitatively by passing through 1
(1 mol%) just once (Equation 2).
Reaction column
[1 (14 mg, 3 mol%) + Celite® (500 mg)]
OSiMe3
+
PhCHO
Reaction column
O
RO OR
Ph
Ph
Toluene, rt, flow (0.2 mL/min)
[1 + Celite® (500 mg)]
0.5 mmol
0.6 mmol
+
HC(OR)3
(1.2 equiv)
Reaction column
Toluene, rt, flow
[1 (14 mg, 3 mol%) + Celite® (500 mg)]
Ph
Me3SiO
Ph
O
HO
O
Ph
R=Me: 98% yield (1 (9.5 mg), 1 mol%), flow (0.3 mL/min);
cf. 46% yield (2 (9.5 mg) in place of 1)
R=Et: 85% yield (1 (28.5 mg), 3 mol%), flow (0.15 mL/min);
cf. 21% yield (2 (28.5 mg) in place of 1)
Ph
Ph
THF:H2O (5:1), rt, flow (0.2 mL/min)
crude
96% yield; cf. 2 (14 mg) in place of 1: 12% yield
Equation 3
Equation 2
Reaction column
The single-pass reaction column system was used for an
in situ acetal exchange reaction of benzylacetone or 3-
phenylpropionaldehyde with diols in the presence of tri-
methylorthoformate (Table 2).8 Most cyclic acetals were
obtained in good yield by passing through 1 (1 mol%).
Acetonitrile was useful as a solvent to dissolve diols.
[1 (57 mg, 3 mol%) + Celite® (450 mg)]
SiMe3
+
PhCHO
2 mmol
Toluene, rt, flow (0.08 mL/min)
3 mmol
Reaction column
® (450 mg)]
Me3SiO
Ph
[1 (57 mg, 3 mol%) + Celite
OH
Ph
THF:H2O (5:1), rt, flow (0.2 mL/min)
To demonstrate the usefulness and effectiveness of the
single-pass reaction column system, its catalytic activities
in several other important synthetic reactions were com-
crude
78% yield; cf. 2 (57 mg) in place of 1: <10% yield
Equation 4
Synlett 2002, No. 8, 1296–1298 ISSN 0936-5214 © Thieme Stuttgart · New York

1298
K. Ishihara et al.
LETTER
Reaction column
ture is likely to be more generally useful for possible
small-scale applications such as the preparation of analy-
tical samples.9
O
OSiMe3
[1 (14 mg, 3 mol%) + Celite® (500 mg)]
+
OEt
Toluene, rt, flow (0.1 mL/min)
0.5 mmol
0.6 mmol
References
OSiMe3
O
Reaction column
[1 (14 mg, 3 mol%) + Celite® (500 mg)]
(1) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem.
Int. Ed. 2001, 40, 4077.
(2) Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis 1986,
513.
CO2Et
CO2Et
THF:H2O (5:1), rt,
flow (0.2 mL/min)
crude
(3) (a) Purchased from Aldrich. (b) Török, B.; Kiricsi, I.;
Molnár, A.; Olah, G. A. J. Catal. 2000, 193, 132.
(4) For examples of reaction columns with Nafion®, see:
(a) Olah, G. A.; Kaspi, J.; Bukala, J. J. Org. Chem. 1977, 42,
4187. (b) Beltrame, P.; Beltrame, P. L.; Carniti, P.; Nespoli,
G. Ind. Eng. Chem. Prod. Res. Dev. 1980, 19, 205.
(c) Hahn-Hägerdal, B.; Skoog, K.; Mattiasson, B. Ann. N. Y.
Acad. Sci. 1984, 434, 161. (d) Olah, A.; Ip, W. M. New J.
Chem. 1988, 12, 299. (e) Bucsi, I.; Olah, G. A. J. Catal.
1992, 137, 12.
80% yield; cf. 2 (14 mg) in place of 1: 3% yield
Equation 5
Reaction column
[1 (14 mg, 3 mol%)
+ Celite® (500 mg)]
OMe
OMe
O
OSiMe3
+
Ph
Toluene, rt,
Ph
Ph
Ph
OMe
0.5 mmol
flow (0.1 mL/min)
0.6 mmol
(5) For recent examples of reaction columns, see:
(a) Mukaiyama, T.; Kobayashi, S. Carbohydr. Res. 1987,
171, 81. (b) Kobayashi, S.; Nagayama, S. J. Org. Chem.
1996, 61, 2256. (c) Kamahori, K.; Ito, K.; Itsuno, S. J. Org.
Chem. 1996, 61, 8321. (d) Annis, D. A.; Jacobsen, E. N. J.
Am. Chem. Soc. 1999, 121, 4147. (e) Hafez, A. M.; Taggi,
A. E.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 2001, 123,
10853.
(6) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J.
Org. Chem. 1996, 61, 4560.
(7) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290,
1140.
99% yield; cf. 2 (14 mg) in place of 1: 44% yield
Equation 6
In conclusion, a single-pass reaction column system was
realized based on the extremely high catalytic activity of
1.1 Although the present system can be applied to a con-
tinuous-flow reaction system, in most cases products can
be obtained in high yield by passing through the reaction
column with 1 just once. The use of the reaction column
greatly simplifies the purification of the crude reaction
mixture, allowing for shorter production times and thus
lower costs under certain circumstances. In particular, a
single-pass reaction column system at ambient tempera-
(8) Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett
1996, 839.
(9) It was ascertained that Celite® 545 itself did not catalyze any
reactions which were demonstrated in this paper by blank
experiments without 1.
Synlett 2002, No. 8, 1296–1298 ISSN 0936-5214 © Thieme Stuttgart · New York