Development of a Continuous-Flow Microreactor for Asymmetric Sulfoxidation Using a Biomimetic Manganese Catalyst

Article abstract of DOI:10.1002/adsc.201501023

Asymmetric sulfoxidation catalyzed by a biomimetic manganese complex under continuous-flow microreactor is described. The reaction is conducted in microreactor, it can rapidly (<4 min) oxidize a wide scope of sulfides with high yield (up to 91%) and excel

Full text of DOI:10.1002/adsc.201501023

UPDATES
DOI: 10.1002/adsc.201501023
Very Important Publication
Development of a Continuous-Flow Microreactor for Asymmetric
Sulfoxidation Using a Biomimetic Manganese Catalyst
Wen Dai,+a Yuan Mi,+a Ying Lv,a Bo Chen,a Guosong Li,a Guangwen Chen,a,*
and Shuang Gaoa,*
a
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences and Dalian National Laboratory for Clean
Energy, Dalian 116023, Peopleꢀs Republic of China
Fax: (+86)-411-8437-9248 or (+86)-411-84379327; phone: (+86)-411-8437-9248 or (+86)-411-84379031;
e-mail: gwchen@dicp.ac.cn or sgao@dicp.ac.cn
+
These authors contributed equally to this work.
Received: November 7, 2015; Revised: November 25, 2015; Published online: January 22, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501023.
Abstract: Asymmetric sulfoxidation catalyzed by
a biomimetic manganese complex under continu-
ous-flow microreactor is described. The reaction is
conducted in microreactor, it can rapidly (<4 min)
oxidize a wide scope of sulfides with high yield (up
to 91%) and excellent enantioselectivity (up to
99% ee), and allows shorter reaction times, easier
scale-up and lower catalyst loadings than its batch-
wise counterpart. Additionally, a convenient num-
bering-up strategy for the scale-up of asymmetric
sulfoxidation has been developed which enables
a direct scaling of the reaction to 5 g affording the
corresponding sulfoxides within 20 min.
proaches. Consequently, the pursuit of new methods
for the synthesis of enantiopure sulfoxides is desira-
ble.
Over the past decade, interest has grown in contin-
uous-flow microreactors due to their potential in ac-
celerating reactions, facilitating scale-up and allowing
safe handling of hazardous reactions.[4] Owing to
these attributes, the microreactors are becoming an
ideal alternative to traditional batch reactors for syn-
thetic chemistry and have been applied to many stan-
dard transformations in organic synthesis. However,
only a few examples on homogeneous enantioselec-
tive catalysis performed in microreactors have been
described to date.[4a–d,o,5] In addition, we recently de-
veloped a new type of porphyrin-inspired N4 ligands
which fulfilled the structural requirements of the por-
phyrin ligand in some way.[6] The biomimetic ligands
possessing excellent tolerance have been successfully
applied in the asymmetric sulfoxidation.[6e,f] With this
background in mind, it was envisioned that we could
develop an asymmetric sulfoxidation method conduct-
Keywords: asymmetric sulfoxidation; biomimetic
process; continuous flow conditions; microreactor;
porphyrin-inspired catalyst
Optically active sulfoxides are extremely useful and ed in continuous-flow microreactor exploiting the por-
versatile building blocks, chiral auxiliaries and orga- phyrin-inspired manganese catalyst which could allow
nocatalysts in organic synthesis.[1] They have also shorter reaction times, easier scale-up and lower cata-
been extensively applied in the manufacture of phar- lyst loading than its batchwise counterpart
maceuticals such as modafinil and esomeprazole.[2] In (Scheme 1). Herein we present the, to the best of our
view of the importance of optically pure sulfoxides, knowledge, first example of homogeneous asymmetric
intensive effort has been devoted to expand the meth- sulfoxidation conducted in a microreactor which can
ods towards sulfoxides with high enantiomeric rapidly (<4 min) oxidize a wide range of sulfides with
purity.[3] Among the available approaches, it is widely low catalyst loading (0.35 mol%) using environmen-
appreciated that the asymmetric sulfoxidation is the tally friendly hydrogen peroxide which provides a val-
most straightforward and reliable route. Nevertheless, uable approach to circumvent the known drawbacks
despite the general success story of this approach, of asymmetric sulfoxidation in traditional batch reac-
some problems such as long reaction times, high cata- tors. Moreover, direct scaling of the reaction to 5 g af-
lyst loading and/or difficult scale-up still remain that forded the corresponding sulfoxides in good yield and
can rarely be addressed by conventional batch ap- enantioselectivity within 20 min.
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Wen Dai et al.
Table 1. Optimization of the asymmetric sulfoxidation under
continuous-flow conditions.[a]
Entry
t [min][b]
Yield [%][c]
ee [%][d]
1
2
3
4
8
6
5
4
2
4
4
4
94
93
95
96
95
92
91
93
89
88
88
86
82
90
90
88
5
6[e]
7[f]
8[g]
Scheme 1. Strategy for the development of asymmetric sul-
foxidation under continuous-flow microreactor conditions.
[a]
Reaction conditions: 1a (0.4 mmol), L1 (0.5 mol%),
Mn(OTf)2 (0.5 mol%), aca (0.08 mmol), 45% H2O2
(0.6 mmol), microreactor: 0.8 mm inner diameter,
1989 mm length.
Residence time.
Isolated yield.
Determined by chiral HPLC analysis.
45% H2O2 (2.0 equiv.).
L1 (0.35 mol%), Mn(OTf)2 (0.35 mol%), 45% H2O2
(2.0 equiv.).
L1 (0.25 mol%), Mn(OTf)2 (0.25 mol%), 45% H2O2
(2.0 equiv.).
A microfluidic system was initially assembled as
shown in Scheme 1. The asymmetric sulfoxidation was
carried out in a 1-mL reactor made of PTFE (polyte-
trafluoroethylene) tubing (0.8 mm inner diameter,
1989 mm length). Homogeneous solutions of 1a
(0.4 mmol), 0.08 mmol adamantinecarboxylic acid
(aca) and 0.5 mol% of catalyst which was generated
from Mn(OTf)2 (0.5 mol%) and L1 (0.5 mol%) as
well as 45% H2O2 (1.5 equiv.) in the mixed solvent
CH3CN and isopropyl alcohol (IPA) were loaded into
syringes and introduced into microfluidic systems
[b]
[c]
[d]
[e]
[f]
[g]
With the optimal conditions in hand, exploration of
through syringe pumps. First, to obtain an insight into the substrate scope was carried out under flow condi-
the features of the reaction, reactions with varying tions, and the results are summarized in Table 2. A
residence times were carried out. We found that sul- wide variety of aryl methyl sulfides could be efficient-
fides could be converted into their corresponding sulf- ly oxidized within short reaction times, providing the
oxides in the microreactor within shorter times than corresponding sulfoxides in high yields with excellent
in batch reactions while maintaining yield and enan- enantioselectivities regardless of the position of the
tioselectivity (Table 1). The result is probably attribut- substituent on the aromatic ring (entries 1–5). Good
ed to the improved mass transfer as well as mixing. yields and excellent enantioselectivities were pre-
Interestingly, almost identical ee values could be ob- served even when extending the alkyl chain linearly
tained when the residence time was shortened from from methyl to pentyl (entries 6–10).
8 min to 4 min (entries 1–4). Further shortening the
Presumably as result of electronic effects, use of
residence time to 2 min resulted in an obvious de- substrates containing electron-withdrawing halogen
crease in enantioselectivity, albeit with no obvious de- substituents at the meta-position of the phenyl groups
crease of yield (entry 5). Subsequently, the oxidant could significantly shorten the residence time when
loading was examined (entry 6). The enantioselectivi- compared with ortho- and para- positions. This situa-
ty was significantly increased when the oxidant load- tion is largely attributed to the transition state of the
ing was raised to 2 equiv. which might be attributed to reaction being electron-demanding and the active oxi-
the oxidative kinetic resolution. Eventually, the cata- dant being electrophilic.[6] Encouraged by these re-
lyst loading was investigated. It is noteworthy that the sults, we next turned our attention to the aryl benzyl
catalyst loading was successfully lowered to sulfides. High yields and excellent enantioselectivities
0.35 mol% without erosion of yield and enantioselec- could also be achieved (entries 11–16). In order to
tivity, and even a catalyst loading of 0.25 mol% gave extend the substrate scope further, a cyclic sulfide
a good result (entries 7 and 8).
was subjected to the continuous-flow reactor. Gratify-
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Development of a Continuous-Flow Microreactor for Asymmetric Sulfoxidation
Table 2. Substrate scope.
ment is small, but high-throughput rates can be realiz-
ed by having many microreactors working in paral-
lel.[4t] Therefore, we developed a novel continuous-
flow microreactor system containing 4 microreactors
in parallel (see the Supporting Information Figure 2).
This change corresponds to an approximately 4 times
enlargement of the reactor volume when compared to
the set-up used in Scheme 1. First the reaction using
aryl benzyl sulfides as the substrate was tested. Direct
scaling of the reaction to 5 g, and collecting for
20 min, afforded the corresponding sulfoxides in 84–
86% yield and 92–98% ee (Table 3, entries 1–3). Then
the scope of the scale-up reaction was further extend-
ed to aryl methyl sulfides. Good yield and excellent
enantioselectivity were also achieved (Table 3,
entry 4).
Moreover, it is well-known that the primary diffi-
culty in the use of hydrogen peroxide as the oxidant
is the extremely explosive nature of the compound.
Due to the microreactor possessing superior heat and
Table 3. Scale-up of asymmetric sulfoxidation under continu-
ous-flow microreactor conditions.
[a]
Reaction
conditions:
substrate
(0.4 mmol),
L1
(0.35 mol%), Mn(OTf)2 (0.35 mol%), aca (20 mmol%),
45% H2O2 (1.5 equiv.).
Residence time.
Isolated yield.
Determined by chiral HPLC analysis.
45% H2O2 (0.6 mmol).
[b]
[c]
[d]
[e]
ingly, good yield and high enantioselectivity were also
obtained (entry 17).
To further evaluate the practical utility of the cur-
rent microreactor system, the application of the pro-
tocol towards scale-up was investigated. The volume
output per unit time from a single microreactor ele-
[a]
Reaction conditions: substrate (5.0 g), L1 (0.35 mol%),
Mn(OTf)2 (0.35 mol%), aca (20 mmol%), 45% H2O2
(1.5 equiv.).
Residence time.
Isolated yield.
Determined by chiral HPLC analysis.
[b]
[c]
[d]
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UPDATES
Wen Dai et al.
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Experimental Section
General Procedure
The asymmetric sulfoxidation was conducted in a 1-mL re-
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(0.8 mm inner diameter, 1989 mm length).The L1
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This work was financially supported by the NSFC (21502187,
21225627) and the dedicated grant for new technology of
methanol conversion from Dalian Institute of Chemical and
Physics, Chinese Academy of Science is gratefully acknowl-
edged.
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