Green diacetoxylation of alkenes in a microchemical system

Article abstract of DOI:10.1021/ol3026445

The palladium-catalyzed diacetoxylation and trifluoromethanesulfonic acid-catalyzed diacetoxylation using inexpensive and environmentally friendly hydrogen peroxide and peracetic acid were successfully conducted with the help of microchemical technology.

Full text of DOI:10.1021/ol3026445

ORGANIC
LETTERS
2013
Vol. 15, No. 4
752–755
Green Diacetoxylation of Alkenes
in a Microchemical System
Jeong Hyeon Park,† Chan Yi Park,† Hyun Seung Song,† Yun Suk Huh,‡
Geon Hee Kim,§ and Chan Pil Park*,†,§
Graduate School of Analytical Science and Technology (GRAST), Chungnam National
University, Daejeon 305-764, Korea, Department of Biological Engineering,
Inha University, Incheon 402-751, Korea, and Korea Basic Science Institute (KBSI),
Daejeon 305-806, Korea
chan@cnu.ac.kr
Received December 3, 2012
ABSTRACT
The palladium-catalyzed diacetoxylation and trifluoromethanesulfonic acid-catalyzed diacetoxylation using inexpensive and environmentally
friendly hydrogen peroxide and peracetic acid were successfully conducted with the help of microchemical technology. Excellent yield and
selectivity were achieved in significantly shortened reaction times without the decomposition of explosive oxidants and further transformation of
unstable products, offering a safe and efficient alternative to traditional methods for alkene diacetoxylation.
The vicinal difunctionalization of alkenes plays an im-
portant role in organic chemistry. The transformation
is generally achieved using osmium catalysts or
m-chloroperbenzoic acid (m-CPBA) on a laboratory-scale.1
However, the catalyst and oxidant pose inherent problems
such as high toxicity and cost or formation of troublesome
byproducts. The requirements for good chemical processes
include minimizing waste, designing safe control, and
diminishing energy consumption.2 Accordingly, alterna-
tive oxidants and catalytic systems have been challenging
areas of research. Hydrogen peroxide and peracetic acid
are obviously cheap and clean oxidants because they only
release water or acetic acid, which can be easily removed by
distillation in the purification step.3 However, these ideal
reagents are very unstable and may lead to highly exother-
mic explosion in the presence of heat or infinitesimal
amounts of metallic impurities.4 Oxidations under extre-
mely mild conditions were certainly preferred because hot
spots caused by self-decomposition can instantly spoil the
entire reaction.5
† Graduate School of Analytical Science and Technology.
‡ Department of Biological Engineering.
§ Korea Basic Science Institute
(1) Selected references for vicinal difunctionalization of alkenes:
(a) Christie, S. D. R.; Warrington, A. D. Synthesis 2008, 1325–1341.
(b) Donohoe, T. J.; Harris, R. M.; Butterworth, S.; Burrows, J. N.;
Cowley, A.; Parker, J. S. J. Org. Chem. 2006, 71, 4481–4489. (c)
Crispino, G. A.; Ho, P. T.; Sharpless, K. B. Science 1993, 259, 64–66.
(d) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483–2547. (e) Donohoe, T. J.; Blades, K.; Winter, J. J. G.;
Stemp, G. Tetrahedron Lett. 2000, 41, 4701–4704. (f) Schultz, M. J.;
Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 1460–1463. (g) Thiery, E.;
Chevrin, C.; Le Bras, J.; Harakat, D.; Muzart, J. J. Org. Chem. 2007, 72,
1859–1862. (h) Zhang, Y.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129,
3076–3077. (i) Kang, Y.-B.; Gade, L. H. J. Am. Chem. Soc. 2011, 133,
3658–3667. (j) Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett.
2005, 7, 5071–5074. (k) Fujita, M.; Yoshida, Y.; Miyata, K.; Wakisaka,
A.; Sugimura, T. Angew. Chem., Int. ed 2010, 49, 7068–7071. (l) Giglio,
B. C.; Schmidt, V. A.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133,
13320–13322. (m) Bataille, C. J. R.; Donohoe, T. J. Chem. Soc. Rev.
2011, 40, 114–128.
Microchemical technology offers noticeable innovation
compared with traditional batch reactions.6 The ease with
which reaction parameters can be controlled is manifested
in improved selectivity and reaction yield. Scaling out can
(3) (a) Sato, K.; Aoki, M.; Ogawa, M.; Hashomoto, T.; Noyori, R.
J. Org. Chem. 1996, 61, 8310–8311. (b) Sanderson, W. R. Pure Appl.
Chem. 2000, 72, 1289–1304.
(4) (a) Swern, D. Organic Peroxides; John Wiley & Sons: Toronto,
1970; Vol. 1.. (b) Ebrahimi, F.; Kolehmainen, E.; Oinas, P.; Hietapelto,
V.; Turunen, I. Chem. Eng. J. 2011, 167, 713–717.
(5) (a) Schwalbe, T.; Autze, V.; Wille, G. Chimia 2002, 56, 636–646.
(b) Chambers, R. D.; Fox, M. A.; Holling, D.; Nakano, T.; Okazoe, T.;
Sandford, G. Lab Chip 2005, 5, 191–198.
(2) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M.
Angew. Chem., Int. Ed. 1995, 34, 259–281.
r
10.1021/ol3026445
Published on Web 01/31/2013
2013 American Chemical Society

also be achieved by systems arranged in a row. Further-
more, hazardous and unstable chemicals can be applied in
various reactions without safety hazards.4b,7 Recently,
Yoshida’s research group serialized various reactions via
flash chemistry using reactive organic lithium reagents.8
The reactions involving unstable short-lived reactive inter-
mediates are perfectly controlled under the sophisticated
regulations of residence time and temperatures.
Excellent microchemical reactions for alkene diacetoxyla-
tion are summarized in Scheme 1. Although use of mild
reaction conditions has been the most important issue in
previous studies because of explosive oxidants and
unstable products, this is not the case in this microchem-
istry. Fastand selective reaction conditions werepreferable
in our study, providing the diacetoxylation products in
good yields and selectivities within 5 min residence time.
Table 1. Pd-Catalyzed Diacetoxylation of 2-Methylallyl Acetate
in a Microreactora
Scheme 1. Diacetoxylation of Alkenes
reaction A
reaction B
ratio (AcO2H/ time (min), time (min), convc yieldc
entry
Ac2O)b
temp (°C)
temp (°C)
(%)
(%)
1
2
1:0
À, À
À, À
À, À
5, rt
5, rt
5, 50
5, 65
5, rt
8
1:0
38 9.5
59 19.5
15 6.75
80 38.4
78 46.8
73 59.9
83 66.4
88 80.1
99 95.0 (93.0)
99 92.7
99 86.0
35 19.6
3
1:0
4
1:3
5
1:3
5, 50
5, 50
5, 50
5, 50
5, rt
5, 50
5, 50
5, 50
5, 60
5, 60
5, 60
10, 60
15, 60
5, 60
6
1:5
7
1:10
1:10
1:20
1:20
1:20
1:20
1:20
8
9
Herein, we report safe microchemical processes for the
diacetoxylation of several alkenes which showed advan-
tage of shortened and optimal reaction time. High heat-
exchange efficiency in the microchemical system allowed
highly exothermic reactions to be performed under iso-
thermal conditions, and the formation of hot spots and
accumulation of reaction heat were suppressed. It afforded
high yields and selectivities at elevated temperature.
10
11
12
13d
5, 50
5, rt
5, 50
5, 50
a Reagents: 1.00 M 2-methylallyl acetate in AcOH, 5 mol %
Pd(OAc)2 (0.05 M in AcOH), 1.2 equiv AcO2H (solution of 35.5% AcO2H,
6.5% hydrogen peroxide, 17% H2O, 40% AcOH). b Wt/wt ratio of 35.5%
AcO2H solution/Ac2O. c Conversion (%) and yield (%) were determined
by GC/MSD analysis. The number in parentheses is the isolated yield.
d No catalyst.
(6) Selected examples of microchemical systems: (a) Mason, B. P.;
Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107, 2300–2318. (b) Whitesides, G. M. Nature 2006, 442, 368–
373. (c) Park, C. P.; Kim, D.-P. Angew. Chem., Int. Ed. 2010, 49, 6825–
6829. (d) Park, C. P.; Kim, D.-P. J. Am. Chem. Soc. 2010, 132, 10102–
10106. (e) Park, C. P.; Van Wingerden, M. M.; Han, S.-Y.; Kim, D.-P.;
Grubbs, R. H. Org. Lett. 2011, 13, 2398–2401. (f) Park, C. P.; Maurya,
R. A.; Lee, J. H.; Kim, D.-P. Lab Chip 2011, 11, 1941–1945. (g) Wiles, C.;
Watts, P.; Haswell, S. J. Lab Chip 2007, 7, 322–330. (h) Baxendale, I. R.;
Ley, S. V.; Mansfield, A. C.; Smith, C. D. Angew. Chem., Int. Ed. 2009,
48, 4017–4021. (i) Kobayashi, J.; Mori, Y.; Okamoto, K.; Akiyama, R.;
Ueno, M.; Kitamori, T.; Kobayashi, S. Science 2004, 304, 1305–1308. (j)
Fukuyama, T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151–163.
(7) (a) Maurya, R. A.; Park, C. P.; Lee, J. H.; Kim, D.-P. Angew.
Chem., Int. Ed. 2011, 50, 5952–5955. (b) O’Brien, M.; Baxendale, I. R.;
Ley, S. V. Org. Lett. 2010, 12, 1596–1598. (c) van den Broek, B. A. M.
W.; Becker, R.; Kossl, F.; Delville, M. M. E.; Nieuwland, P. J.; Koch,
K.; Rutjes, F. P. J. T. Chem. Sus. Chem. 2012, 5, 289–292. (d) Hartung,
A.; Keane, M. A.; Kraft, A. J. Org. Chem. 2007, 72, 10235–10238.
(8) (a) Nagaki, A.; Matsuo, C.; Kim, S.; Saito, K.; Miyazaki, A.;
Yoshida, J. Angew. Chem., Int. Ed. 2012, 51, 3245–3248. (b) Tomida, Y.;
Nagaki, A.; Yoshida, J. J. Am. Chem. Soc. 2011, 133, 3744–3747.
(c) Nagaki, A.; Yamada, S.; Doi, M.; Tomida, Y.; Takabayashi, N.;
Yoshida, J. Green Chem. 2011, 13, 1110–1113. (d) Kim, H.; Nagaki, A.;
Yoshida, J. Nat. Commun. 2011, 2, 264.
Recently, Jung et al. reported palladium-catalyzed di-
acetoxylation in the presence of peracetic acid and acetic
anhydride.9 Even though the reaction has the significant
advantage of mild reaction conditions, the reaction had to
be conducted slowly for higher selectivity and safety. We
began our study by investigating the diacetoxylation in the
microchemical system which was made of a commercial
polytetrafluoroethylene (PTFE) tube (i.d.: 500 μm, length:
6 m); details are described in the Supporting Information.
We regulated reaction parameters including temperature,
reagents, and residence time; the results are summarized in
Table 1. Because the commercially available peracetic acid
solution (35.5%) always contains acetic acid (40%), hy-
drogen peroxide (6.5%), and water (17%) to stabilize the
(9) Park, C. P.; Lee, J. H.; Yoo, K. S.; Jung, K. W. Org. Lett. 2010, 12,
2450–2452.
Org. Lett., Vol. 15, No. 4, 2013
753

peracid, the region for the first reaction (A) was intended
for the reaction of acetic anhydride with peracetic acid,
hydrogen peroxide, and water. In the absence or lack of
acetic acid anhydride, the reactions resulted in complicated
mixtures. WackerÀTsuji-type oxidation was dominant,
which was detected by GC/MSD analysis (entries 1À8).10
In the presence of increased amounts of acetic anhydride
(35.5% AcO2H solution/Ac2O = 1/20), diacetoxylation
became the exclusive reaction (entries 9 and 10). Even
though the reactions in entries 10 and 11 showed similar
results, it can be inferred from the result in entry 9 that the
reaction pathway may be different. This indicates that
hydrogen peroxide and water should be removed before
beginning the palladium-catalyzed reaction. Yield was
increased up to 95% because of the use of perfectly
controlled conditions with a rapid mixing and homoge-
neous ratio of reagents and the avoidance of hot spots.
Unlike batch reactions, which take several hours, diace-
toxylation in the microchemical system was completed
within 5 min when the temperature was increased to
60 °C. However, reaction temperature over 65 °C resulted
in sharp self-decomposition of the oxidant and formation
of oxygen bubbles, which resulted in a situation of gas
bubbles and liquid slugs as in a droplet microreactor. The
bubble formation disturbed the steady flow and resulted in
an incomplete reaction. Entry 12 emphasized the need for
optimized reaction conditions; the microchemical reaction
should be regulated according to the stability of product.
To further explore the Pd-catalyzed diacetoxylation, we
screened three alkenes including a nonconjucated alkene
Scheme 2. TfOH-Catalyzed Diacetoxylation of Alkenesa
a Reagents: 1.00 M alkene in AcOH, 1 mol % of TfOH (0.05 M in
AcOH), 2.5 equiv of AcO2H (solution of 35.5% AcO2H, 6.5% hydrogen
peroxide, 17% H2O, 40% AcOH). b Yields (%) were determined by GC/
MSD analysis. The numbers in parentheses are the isolated yields.
c 20 min in acetylation; main side products were triacetates.
Scheme 3. Plausible Pathway in Transformation of Product 4
Pd-catalyzed reaction (Scheme 3). Two reactions were
finished within only 5 min, when the temperature was
increased to 60 °C. 2-Methylallyl acetate successfully
generated compound 1 (96% isolated yield); allylbenzene
was efficiently converted to product 4 (90% isolated yield).
However, further transformation of product 4into triacetates
were significant at the elevated temperature, it may include
dehydroacetoxylation and second diacetoxylation (Figure 1).
Diacetoxylation by peracetic acid generated in situ
from much cheaper and stable hydrogen peroxide4b was
achieved using the system shown in Scheme 4. 2-Methyl-
allyl acetate and 3-methylbut-3-enyl acetate successfully
generated compounds 1 and 3, respectively (94% and 92%
yields). The method was also very efficient in the oxidative
lactonization; but-3-enoic acid and pent-4-enoic acid were
perfectly transformed to five-membered lactones 2 and 5,
respectively (92% and 97% yields). Allylbenzene was con-
verted to product 4 with slightly lowered 89% yield (side
product 4c, 4% yield; see the Supporting Information);
propen-2-ylbenzene was transformed to product 7 with
90% yield. Internal alkenes gave only syn addition product
6 and 8 in 93% and 89% yields, respectively (side product
8b, 6% yield; see the Supporting Information), which were
Figure 1. Products of the Pd-catalyzed diacetoxylation of al-
kenes. Reagents: 1.00 M alkene (in AcOH), 5 mol % of Pd-
(OAc)2 (0.05 M in AcOH), 1.2 equiv of AcO2H (solution of
35.5% AcO2H, 6.5% hydrogen peroxide, 17% H2O, 40%
AcOH). Reaction conditions, see Table 1, entry 10.
and two terminal aliphatic alkenes (Scheme 2). Cyclization
of but-3-enoic acid gave five-membered lactone 2 in 91%
isolatedyield. 3-Methylbut-3-enyl acetateandallylbenzene
successfully generated compound 3 (91% isolated yield)
and compound 4 (the slightly lower yield of 86%). All
reactions were finished within a residence time of only 5 min.
Trifluoromethanesulfonic acid (TfOH)-catalyzed diace-
toxylation reported by Gade et al. is a metal-free, clean,
and cheap method.12 We used their method to perform
microchemical reactions using the system applied in the
(10) (a) Cornell, C. N.; Sigman, M. S. Org. Lett. 2006, 8, 4117–4120.
(b) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481–485.
(11) Zhong, W.; Liu, S.; Yang, J.; Meng, X.; Zhongjun, L. Org. Lett.
2012, 14, 3336–3339.
(12) Kang, Y.-B.; Gade, L. H. J. Org. Chem. 2012, 77, 1610–1615.
754
Org. Lett., Vol. 15, No. 4, 2013

Because of the many-sided functions of TfOH, the system
was significantly simplified, and might be useful in industrial
applications. However, the TfOH carried out unexpected
catalytic function in dehydroacetoxylation and rearrange-
ment, it should be considered to minimize the decomposi-
tion of desired products. The daily output of microreactor
with reaction volume of 1.178 mL (0.25 mm Â0.25 mm Â
π Â 6 m) was calurated. Compound 8 of 4.12 g (14.9 mmol)
was generated through the continuous running of 3 h, the
obtainable product from the 1.178 mL volume was 32.96 g
in one day. We also tested the reaction of a hypervalent
iodine species (PhI(OAc)2) in the presence of peroxide; the
result was not impressive.11
Scheme 4. TfOH-Catalyzed Diacetoxylation by Peracetic Acid
Generated in Situa
In conclusion, we have described three types of microche-
mical reactions conducted using clean and cheap hydrogen
peroxide and peracetic acid. The diacetoxylation reactions of
alkenes were very fast, safe, and highly selective without
rearrangement of diaceotoxylated products. Overall, our
processes provide convenient and practical methods that we
believe can be used not only for laboratory-scale synthesis, but
on the industrial scale as well. Currently, another diacetoxyla-
tions involving heterogeneous catalysts and catalyst-free con-
ditions are underway and will be reported in due course.
Acknowledgment. We acknowledge generous financial
support from the National Research Foundation of Korea
Grant funded by the Korean Government (MEST) (2012,
University-Institute cooperation program and NRF-2012-
1012596).
a Reagents: 1.00 M alkene in AcOH, 1 mol % of TfOH (0.05 M in
AcOH), 2.5 equiv of H2O2 (50 wt % in H2O). Yields (%) were
determined by GC/MSD analysis. b The diastereomeric ratios were
determined by 1H NMR analysis.
determined by 1H NMR analysis. All reactions were com-
pleted within only 5 min residence time. Herein, catalyst
TfOH might perform multiple roles in peracetic acid for-
mation, vicinal difunctioanlization, and/or ring-opening of
epoxide, as well as acetylation of the hydroxyl group.12
Supporting Information Available. Experimental pro-
cedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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