Room-temperature Swern oxidations by using a microscale flow system

Article abstract of DOI:10.1002/anie.200462466

(Equation Presented) Residence time controlled reaction: The Swern oxidation of alcohols has been accomplished by using a microscale flow system, consisting of micromixers and microscale tube reactors (see schematic representation ; DMSO = dimethylsulfoxide, TFAA = trifluoroacetic anhydride), at higher temperatures (-20 to 20°C) than those for conventional macroscale batch systems (-50°C or below).

Full text of DOI:10.1002/anie.200462466

Angewandte
Chemie
Microreactors
Room-Temperature Swern Oxidations by Using a
Microscale Flow System**
Tatsuya Kawaguchi, Hiroyuki Miyata, Kikuo Ataka,
Kazuhiro Mae, and Jun-ichi Yoshida*
Microreactors (microstructured chemical reactors)[1] are
expected to make a revolutionary change in chemical syn-
thesis[2] from both the academic and industrial viewpoints.[3]
Microreactors exhibit numerous practical advantages, includ-
ing safety, easy modulation, and easy scale-up for industrial
production, when compared with conventional macroscale
batch reactors.[4] It is also advantageous that highly exother-
mic reactions can be conducted on the basis of efficient mass
and heat transfer.[5] Microreactors also enable the precise
control of reactive intermediates and thereby facilitate highly
selective reactions that are difficult to achieve in conventional
reactors.[6] Herein, we report that the Swern oxidation can be
accomplished by using a microreactor at temperatures
between À20 and 208C, much higher temperatures than
those required for conventional macroscale batch reactors
(À508C or below).
[*] Prof. J.-i. Yoshida
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering
Kyoto University, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2727
E-mail: yoshida@sbchem.kyoto-u.ac.jp
Dr. T. Kawaguchi
Micro Chemical Process Technology Research Association (MCPT)
in Kyoto
Kyoto University, Kyoto 615-8510 (Japan)
H. Miyata, Dr. K. Ataka
Corporate Research and Development
Ube Industries, Ltd., Ube, Yamaguchi, 755-8633 (Japan)
Prof. K. Mae
Department of Chemical Engineering
Graduate School of Engineering
Kyoto University, Kyoto 615-8510 (Japan)
[**] We thank Technology Japan and the Project of Micro-Chemical
Technology for Production, Analysis, and Measurement Systems of
NEDO, Japan, for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 2413 –2416
DOI: 10.1002/anie.200462466
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
The oxidation with dimethyl sulfoxide (DMSO), known as
We examined the Swern oxidation by using a microscale
flow system consisting of multilamination-type micromix-
ers[10] and stainless tube reactors, as represented in Figure 1. A
the Moffatt–Swern type oxidation, is one of the most versatile
and reliable methods for the oxidation of alcohols into
carbonyl compounds and is widely utilized in organic syn-
thesis.[7] Various methods for the activation of DMSO have
been developed so far, and activation with trifluoroacetic
anhydride (TFAA) is frequently employed in modern organic
synthesis.[8] It is well known that activation of DMSO leads to
an inevitable side reaction, the Pummerer rearrangement.
Therefore, the reaction is usually carried out at low temper-
atures (À508C or below) at which the side reaction is very
slow. However, the requirement for such low temperatures
causes severe limitations in the industrial use of this highly
useful reaction.
solution of DMSO (4.0m) in CH2Cl2 (flow rate: 1 mLminÀ1
,
The Swern oxidation with TFAA generally proceeds as
depicted in Scheme 1. In the first step, DMSO (usually in
Figure 1. Schematic diagram of the microscale flow system for the
Swern oxidation.
4 mmolminÀ1) and a solution of TFAA (2.4m) in CH2Cl2 (flow
rate: 1 mLminÀ1, 2.4 mmolminÀ1) were introduced to the first
micromixer (M1) by using syringe pumps.[11] The resulting
solution was passed through reactor R1 and was mixed with a
solution of the alcohol (1.0m) in CH2Cl2 (flow rate:
2 mLminÀ1, 2 mmolminÀ1) in the second micromixer (M2).
The resulting solution was passed through reactor R2 and was
mixed with a solution of triethylamine (1.45m) in CH2Cl2
(flow rate 4 mLminÀ1, 5.8 mmolminÀ1) in the third micro-
mixer (M3). The solution was then introduced to tube reactor
R3 before being passed through reactor R4. The three mixers
(M1–3) and three of the reactors (R1–R3) were dipped in a
cooling bath. Reactor R4 was dipped in a bath maintained at
308C. The outlet solution was collected and was analyzed by
GC with an internal standard. The residence time in each
reactor was as follows: R1: 0.01–2.4 s, R2: 1.2 s, R3: 1.2 s, R4:
5.9 s. After a steady state was reached, an aliquot of the
product solution was taken over a period of 1.0 min and
analyzed by GC.
As indicated in Table 1, the oxidation of primary, secon-
dary, cyclic, and benzylic alcohols took place smoothly to give
the corresponding carbonyl compounds in good yields and
with good selectivity at À208C (R1: 2.4 s). It is noteworthy
that the reactions with a conventional macroscale batch
reactor (a 30 mL flask with magnetic stirring) at the same
temperature led to the formation of significant amounts of
trifluoroacetates VII and the yields of the carbonyl com-
pounds V were low. Significant amounts of substrate alcohols
III also remained unchanged in the macroscale batch system.
The dramatic effect of the microscale flow system seems to be
attributable to precise temperature control (small local
deviation of temperature in the reactor) and extremely fast
and efficient mixing by virtue of a short diffusion path in the
micromixer. Short residence time also seems to play a crucial
role because fast transfer of the reactive intermediate to the
next reactor seems to be essential for the present trans-
formation.
Scheme 1. The proposed mechanism of the Swern oxidation with
TFAA.
excess) reacts with TFAA to form cationic intermediate I,
which is known to be stable only below À308C.[9] Therefore,
the first step is usually carried out below À508C. At higher
temperatures, the rearrangement of I takes place to give II.
Therefore, I is immediately allowed to react with an alcohol
III at or below À508C to obtain intermediate IV (the second
step).
In the third step, IV is treated with a base (usually
triethylamine) to obtain the corresponding carbonyl com-
pound Vand dimethyl sulfide. However, upon treatment with
a base, IV may also undergo the Pummerer rearrangement to
give a methylthiomethyl ether (MTM ether) VI. Another
important byproduct is the trifluoroacetate (TFA ester) VII,
which is formed by the reaction of II with an alcohol III upon
treatment with a base. In fact, the reaction of DMSO with
TFAA at or above À308C mainly led to the formation the
Pummerer rearrangement product II, and a significant
amount of VII is therefore eventually formed in the final
stage.
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Angew. Chem. Int. Ed. 2005, 44, 2413 –2416

Angewandte
Chemie
Table 1: Swern oxidation of alcohols by using the microscale flow system and macroscale batch
Another important point is that
system.[a]
microsystems serve as a quick
means for scale-up, because the
quality of the product does not
change during the course of
scale-up, although batch methods
suffer from such a problem.
In conclusion, the present
observations demonstrate a strik-
ing example of the effectiveness
of the microscale flow system for
a reaction involving highly unsta-
Alcohol III
System
Residence time T [8C] Conversion Yield
Yield
Yield
in R1 [s]
[%]
of V [%] of VI [%] of VII [%]
1-decanol
microscale flow
2.4
0.01
0.01
À20 95
75
70
71
11
95
86
89
20
88
89
88
19
83
91
78
75
49
8
6
6
1
5
4
3
2
6
7
5
2
10
19
22
22
90
2
3
2
75
5
1
0
94
20 96
À20 73
À20 92
macroscale batch
microscale flow
2-octanol
2.4
0.01
0.01
0
91
20 88
À20 51
À20 88
macroscale batch
cyclohexanol microscale flow
2.4
0.01
0.01
ble
intermediates.
Further
0
90
20 81
À20 86
À70 88
À20 97
2
70
5
improvement of the reaction
system and applications to the
synthesis of various carbonyl
compounds are in progress.
macroscale batch
benzyl alcohol microscale flow
2.4
0.01
0.01
n.d.[b]
n.d.[b]
n.d.[b]
n.d.[b]
8
0
100
14
16
50
20 100
À20 80
Received: October 29, 2004
Published online: March 10, 2005
macroscale batch
[a] Yields were determined by GC withan internal standard and are based upon the amount of the alcohol
consumed. [b] n.d.=not determined.
Keywords: alcohols ·
microreactors · oxidation ·
Swern oxidation ·
.
synthetic methods
The success of the Swern oxidation by using the micro-
scale flow system at À208C prompted us to examine further
increases in the reaction temperature. The reaction at 08C
[1] a) Microreaction Technology (Ed.: W. Ehrfeld), Springer, Berlin,
1998; b) W. Ehrfeld, V. Hessel, H. Lꢀwe, Microreactors, Wiley-
VCH, Weinheim, 2000; c) Microsystem Technology in Chemistry
and Life Sciences (Eds.: A. Manz, H. Becker), Springer, Berlin,
1999; d) V. Hessel, S. Hardt, H. Lꢀwe, Chemical Micro Process
Engineering, Wiley-VCH, Weinheim, 2004.
resulted in a significant decrease in the yield of carbonyl
compounds V (32% for cyclohexanol; results not shown).
Presumably Pummerer rearrangement of intermediate I took
place to give II at this temperature. However, we found that
by shortening the residence time (R1: 0.01 s) the desired
carbonyl compounds V were obtained in good yields even at
08C. More outstanding is the fact that the reaction can be
conducted even at room temperature (208C) to obtain V in
good yields. This success of the Swern oxidation at room
temperature seems to be attributable to the extremely short
residence time, which ensures very fast transfer of the highly
unstable intermediate I to the next reactor before decom-
position.
[2] a) H. Salimi-Moosavi, T. Tang, D. J. Harrison, J. Am. Chem. Soc.
1997, 119, 8716 – 8717; b) C. de Bellefon, N. Tanchoux, S.
Caravieilhes, P. Grenouillet, V. Hessel, Angew. Chem. 2000,
112, 3584 – 3587; Angew. Chem. Int. Ed. 2000, 39, 3442 – 3445;
c) H. Hisamoto, T. Saito, M. Tokeshi, A. Hibara, T. Kitamori,
Chem. Commun. 2001, 2662 – 2663; d) C. Wiles, P. Watts, S. J.
Haswell, E. Pombo-Villar, Chem. Commun. 2002, 1034 – 1035;
e) T. Fukuyama, M. Shinmen, S. Nishitani, M. Sato, I. Ryu, Org.
Lett. 2002, 4, 1691 – 1694; f) E. Garcia-Egido, V. Spikmans,
S. Y. F. Wong, B. H. Warrington, Lab Chip 2003, 3, 73 – 76; g) M.
Ueno, H. Hisamoto, T. Kitamori, S. Kobayashi, Chem. Commun.
2003, 936 – 937; h) S. M. Lai, R. Martin-Aranda, K. L. Yeung,
Chem. Commun. 2003, 218 – 219; i) J. Kobayashi, Y. Mori, K.
Okamoto, R. Akiyama, M. Ueno, T. Kitamori, S. Kobayashi,
Science 2004, 304, 1305 – 1308; j) T. Wu, Y. Mei, J. T. Cabral, C.
Xu, K. L. Beers, J. Am. Chem. Soc. 2004, 126, 9880 – 9881.
[3] Example reviews: a) S. H. DeWitt, Curr. Opin. Chem. Biol. 1999,
3, 350 – 356; b) H. Okamoto, J. Syn. Org. Chem. Jpn. 1999, 57,
805 – 812; c) T. Sugawara, Pharmacia 2000, 36, 34 – 38; d) O.
Wꢀrz, K. P. Jꢁckel, T. Richter, A. Wolf, Chem. Eng. Sci. 2001, 56,
1029 – 1033; e) S. J. Haswell, R. J. Middleton, B. OꢂSullivan, V.
Skelton, P. Watts, P. Styring, Chem. Commun. 2001, 391 – 398;
f) K. F. Jensen, Chem. Eng. Sci. 2001, 56, 293 – 303; g) A.
de Mello, R. Wootton, Lab Chip 2002, 2, 7N – 13N; h) K.
Jꢁhnisch, V. Hessel, H. Lꢀwe, M. Baerns, Angew. Chem. 2004,
116, 410 – 451; Angew. Chem. Int. Ed. 2004, 43, 406 – 446. .
[4] S. Taghavi-Moghadam, A. Kleemann, K. G. Golbig, Org. Process
Res. Dev. 2001, 5, 652 – 658.
It is important to check the durability of the process for
scale-up. So, we ran the reaction of cyclohexanol for 3 h
(0.36 mol scale) at 208C and found that the alcohol con-
version and product selectivity did not change (Table 2).
Table 2: Continuous Swern oxidation of cyclohexanol by using the
microscale flow system at 208C.[a]
t [h]
Conversion
[%]
Yield
of V [%]
Yield
of VI [%]
Yield
of VII [%]
0
83
84
85
81
86
87
85
92
92
89
89
91
91
91
5
5
5
4
5
5
5
4
4
4
4
3
3
4
0.5
1.0
1.5
2.0
2.5
3.0
[5] a) R. D. Chambers, R. C. H. Spink, Chem. Commun. 1999, 883 –
884; b) M. T. Janicke, H. Kestenbaum, U. Hagendorf, F. Schꢃth,
M. Fichtner, K. Schubert, J. Catal. 2000, 191, 282 – 293; c) M. W.
[a] Yields were determined by GC with an internal standard and are based
upon the amount of the alcohol consumed.
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Communications
Losey, M. A. Schmidt, K. F. Jensen, Ind. Eng. Chem. Res. 2001,
40, 2555 – 2562.
[6] For example, a) S. Suga, M. Okajima, K. Fujiwara, J. Yoshida, J.
Am. Chem. Soc. 2001, 123, 7941 – 7942; b) J. Yoshida, S. Suga,
Chem. Eur. J. 2002, 8, 2651 – 2658; c) S. Suga, A. Nagaki, J.
Yoshida, Chem. Commun. 2003, 354 – 355; d) S. Suga, A. Nagaki,
Y. Tsutsui, J. Yoshida, Org. Lett. 2003, 5, 945 – 947; e) A. Nagaki,
K. Kawamura, S. Suga, T. Ando, M. Sawamoto, J. Yoshida, J.
Am. Chem. Soc. 2004, 126, 14702 – 14703.
[7] For example, T. T. Tidwell, Org. React. 1990, 39, 297 – 572.
[8] a) K. Omura, A. K. Sharma, D. Swern, J. Org. Chem. 1976, 41,
957 – 962; b) K. Omura, D. Swern, Tetrahedron 1978, 34, 1651 –
1660.
[9] a) A. K. Sharma, D. Swern, Tetrahedron Lett. 1974, 1503 – 1506;
b) A. K. Sharma, T. Ku, A. D. Dawson, D. Swern, J. Org. Chem.
1975, 40, 2758 – 2764.
[10] The IMM (Institut fꢃr Mikrotechnik Mainz GmbH) single
mixer, version 2, (http://www.imm-mainz.de/) was used. The
inlay is made of silver and the channel width is 40 mm.
[11] The Harvard PHD2000 Programmable syringe pump, Harvard
Pump11 (http://www.harvardapparatus.com/), and kdScientific
model 100 syringe pump (http://www.kdscientific.com/) were
used.
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