Pentanidium catalyzed enantioselective hydroperoxidation of 2-oxindole using molecular oxygen

Article abstract of DOI:10.1016/j.catcom.2016.04.016

Pentanidium catalyzed enantioselective 3-hydroperoxidation of 2-oxindoles with molecular oxygen has been established. Various 3-hydroperoxy-2-oxindoles were achieved in good ee and yield.

Full text of DOI:10.1016/j.catcom.2016.04.016

Catalysis Communications 82 (2016) 29–31
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
Pentanidium catalyzed enantioselective hydroperoxidation of 2-oxindole
using molecular oxygen
a,
Shun Zhou a,b, Lin Zhang a, Chun Li a, Yuanhu Mao a, Jianta Wang a, Ping Zhao a, Lei Tang a, , Yuanyong Yang
⁎
⁎
a
Department of Pharmacy, Guizhou Medical University, Guizhou 550004, China
b
Environmental Monitor Station, Anshun 561000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pentanidium catalyzed enantioselective 3-hydroperoxidation of 2-oxindoles with molecular oxygen has been
established. Various 3-hydroperoxy-2-oxindoles were achieved in good ee and yield.
© 2016 Elsevier B.V. All rights reserved.
Received 29 January 2016
Received in revised form 7 April 2016
Accepted 20 April 2016
Available online 22 April 2016
Keywords:
Hydroperoxidation
Phase-transfer catalysis
Molecular oxygen
Pentanidium
Asymmetric catalysis
Numerous peroxy natural products and metabolites have been iso-
lated, and many of them are found to be highly potent antimalarial, an-
tibacterial, and antitumor compounds (Fig. 1) [1]. Artemisine, as the
most widely used antimalarial drug, the peroxy fragment is demon-
strated to be essential for the therapeutic action [2]. This in turn stimu-
late the development of new methods to access chiral peroxy
compounds with broad structure diversity. To date, the generation of
optically active peroxy compounds dominantly depends on singlet oxy-
gen and peroxy precursors [3], and little study was conducted on the
peroxidation of compounds with molecular oxygen [4]. It is known
that many carbonyl compounds react rapidly with molecular oxygen
under basic conditions to yield α-hydroxy carbonyl products [5], some-
times reductant such as triethyl phosphite was required to reduce the
hydroperoxy intermediates. [5f] As the most cheap and abundant
green oxidant, molecular oxygen have numerous advantages over
other oxidant, such as higher atom efficacy and less byproduct [6].
Therefore, enantioselective methods of useful generality for the incor-
poration of molecular oxygen into optically active peroxides are urgent-
ly needed.
synthesis of 3-hydroperoxy-2-oxindole derivatives. Previously, We
had already succeeded in establishing a general and practical syn-
thetic method for the hydroxylation of 2-oxindoles with air using
pentanidium as catalyst in the absence of reductant [7]. During our
study, noticeable amount of hydroperoxy intermediate was detected
in each run so we proposed a two step pathway under air limited
condition. The first step generate hydroperoxy intermediate and
the second step is the hydroperoxy intermediate got reduced by an-
other molecular of 2-oxindole. To probe the reaction mechanism and
verify our proposed reaction pathway, further research was conduct-
ed in hope of generate hydroperoxy as the major product by tuning
the reaction conditions (Fig. 2).
With our previous established procedure, pentanidium catalyst
could be synthesized from commercial available (1S, 2S)-1,2-
diphenylethane-1,2-diamine in few steps [8]. With pentanidium in
hand, we began our investigation by employing 2a as the model sub-
strate for hydroperoxidation under phase-transfer catalysis. As we
know base have dominate effect on the reaction rate for phase-
transfer catalysis, a variety of base were screened first (Table 1). It
is encouraging to find this reaction will not proceed under base
free condition (Table 1, entry 1), as background reaction will always
reduce the ee of the final product. Besides, organic base such as
triethyl amine cannot promote this reaction (Table 1, entry 2) and
inorganic base was tested. Weak inorganic base such CsF and K2CO3
are inefficient in promote this reaction, b20% conversion was ob-
served by TLC analysis after 24 h, so the ee was not measured
(Table 1, entries 3–4). With LiOH as base, 50% conversion was
Recently, Nakamura group reported the reaction of hydroperox-
ides with ketimines derived from isatins (Fig. 2), after deprotection
chiral α-amino peroxides were achieved in excellent yield and
enantioselectivities [3e]. This is the only known report on the
⁎
Corresponding authors.
E-mail addresses: 2317972657@qq.com (L. Tang), yangyuanyong@gmc.edu.cn
(Y. Yang).
http://dx.doi.org/10.1016/j.catcom.2016.04.016
1566-7367/© 2016 Elsevier B.V. All rights reserved.

30
S. Zhou et al. / Catalysis Communications 82 (2016) 29–31
Table 1
Optimizing conditions for pentanidium-catalyzed α-hydroperoxidation of 3-methyl-2-
oxindole 2a.
Entry
Base
Time/h
Conv. (%)a,b
4a ee (%)c
Ratio 3a:4ac
1
2
3
4
5
6
7
8
9
\
24
24
24
24
24
6
5
2
2
2
b5
b5
b5
b20
50
100
100
100
100
100
\
\
\
\
\
\
\
\
Et3N
CsF
K2CO3
LiOH·H2O
NaOH (50%)
RbOH (50%)
CsOH (50%)
KOH solid
KOH (50%)
Fig. 1. Selected examples of bioactive peroxy compounds.
\
N95:5
85:15
76:24
71:29
65:35
67:33
30
39
45
56
60
observed after 24 h (Table 1, entry 5), however, no hydroperoxy
product 4a was detected. Stronger inorganic base such as NaOH,
KOH, RbOH and CsOH favor the generation of hydroperoxy product
along with higher ee (Table 1, entries 6–10). Conceivably, stronger
inorganic base promote the hydroperoxidation of 2a more efficiently
than the hydroperoxide 4a reduction step as air is not a limited re-
agent in this reaction. Therefore, KOH (50%) was considered to be
optimal base for further optimization.
10
a
Reactions were run on a 0.05 mmol scale with 5 mol% PTC in 3 ml solvent, air.
Conversion determined by TLC.
Determined by HPLC analysis.
b
c
Then, the effect of solvent parameter on the product distribution and
ee was screened and summarized in Table 2. The solvent was found to
have significant effect on the product distribution and ee. Non-polar sol-
vent such toluene, mesitylene and ether give lower ratio of hydroperoxy
4a but higher ee (Table 2, entries 1–3), while polar solvent such as THF,
anisole and fluorobenzene give higher ratio of hydroperoxy 4a but
lower ee (Table 2, entries 4–6). When isopropanol was applied as sol-
vent, hydroperoxy 4a was obtained as dominant product but in almost
racemic form, so toluene was considered to be optimal solvent for fur-
ther optimization.
Finally, the effect of reaction temperature and oxygen parameter
was screened and summarized in Table 3. With the decrease of tem-
perature, the ratio of hydroperoxy 4a increased steadily along with
the enantioselectivity (Table 3, entries 1–4) and becomes the major
product when the temperature reached −60 °C. When oxygen bal-
loon was used instead of air, the ratio of hydroperoxy 4a increased
from 55% to 68%, and further increased to 87% when solvent mixture
was used under oxygen balloon condition (Table 3, entries 5–7).
Moreover, the catalyst loading could be reduced to 1 mol% in main-
taining the product ratio and enantioselectivity (Table 3, entry 8), al-
beit longer reaction time. The absolute configuration of 4a was
designated as R by comparing with an example in the literature
after reduction to 3a.
Table 2
Optimizing conditions for pentanidium-catalyzed α-hydroperoxidation of 3-methyl-2-
oxindole 2a.
Entrya
Solvent
Conv. (%)b
4a ee(%)c
Ratio 3a:4ac
1
2
3
4
5
6
7
Toluene
Et2O
Mesitylene
THF
Anisole
PhF
IPA
100
100
100
100
100
100
80
60
57
58
50
42
38
5
67:33
68:32
73:27
57:43
43:57
31:69
12:88
a
Run on a 0.05 mmol scale with 5 mol% PTC in 3 ml solvent, air.
Conversion determined by TLC.
Determined by HPLC analysis.
b
c
group of oxindoles has little affect on ee and product ratio (Table 4,
entries 1–3). While the substituent at C3-position of 2 have signifi-
cant effect on ee and product ratio (Table 4, entries 4–6). Moreover,
lower ratio of 4 always resulting lower ee of 4. These results suggest
that R-4 was preferentially reduced to R-3 leading to 4 with lower
yield along with lower ee, which indicates kinetic resolution may in-
volved in the second step.
With the optimized reaction condition on hand, the
hydroperoxylation could be applied to a variety of 3-substituted-2-
oxindoles to give 3-hydroperoxy-2-oxindoles (Table 4). Studies
showed that introduction of various substituents onto the phenyl
Fig. 2. Enantioselective synthesis of 3-hydroperoxy-2-oxindole derivatives.

S. Zhou et al. / Catalysis Communications 82 (2016) 29–31
31
Table 3
converted into (R)-3a with 76% ee, and the remaining hydroperoxy
oxindole was determined to be (S)-4a with 51% ee (Fig. 3). The selec-
tivity factor S (or Krel) was determined to be 5 on the basis of this re-
sult [9]. This result demonstrated that the pentanidium catalyst
preferentially consume (R)-4a to form (R)-3a, and that is why
lower ratio of 4a always resulting lower ee 4a.
Optimizing conditions for pentanidium-catalyzed α-hydroperoxidation of 3-methyl-2-
oxindole 2a.
In summary, an enantioselective α-hydroperoxidation of 2-oxindoles
with molecular oxygen has been established using pentanidium as the
chiral phase-transfer catalyst. Several 3-hydroperoxy-2-oxindoles with
good enantioselectivities (47%–83% ee) were obtained. Partial lower
yield and ee of hydroperoxide is due to pentanidium catalyzed selective
(R)-4a consumption.
Entrya
Temp °C
Time
5 min
30 min
2 h
Conv. (%)b
4a ee(%)c
Ratio 3a:4ac
1
2
3
4
5
rt
0
100
100
100
100
100
100
100
100
NA
NA
60
67
75
79
81
80
N95:5
N9:1
−20
−40
−60
−60
−60
−60
67:33
60:40
45:55
32:68
13:87
11:89
6 h
12 h
12 h
12 h
48 h
6d
7e
8def
Acknowledgment
a
Reactions were run on a 0.05 mmol scale with 5 mol% PTC in 3 ml solvent, air.
Conversion determined by TLC.
Determined by HPLC analysis.
O2 balloon was used instead of air.
Toluene:THF 10:1 was used as solvent.
1 mol% PTC was used.
Financial support from GMU (J[2014]015 to Y.Y.), Office of Science &
Technology of Guizhou ([2015]7343 to Y.Y.), Office of Science & Tech-
nology of Guiyang ([20151001]06 to Y.Y.), Office of Science & Technol-
ogy of Guiyang ([2011204]48 to P.Z.) and Ministry of Education
(NCET-12-0656 to L.T.) are greatly appreciated.
b
c
d
e
f
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