Oxo-Thiolation of Cationically Polymerizable Alkenes Using Flow Microreactors

Article abstract of DOI:10.1002/chem.201903426

The present study describes the cationic oxo-thiolation of polymerizable alkenes by using highly reactive cationic species generated by anodic oxidation. These highly reactive cations were able to activate alkenes before their polymerization. Fast mixing in flow microreactors effectively controlled chemoselectivity, enabling higher reaction temperatures.

Full text of DOI:10.1002/chem.201903426

A Journal of
Accepted Article
Title: Oxo-Thiolation of Cationically Polymerizable Alkenes Using Flow
Microreactors
Authors: Aiichiro Nagaki, Jun-ichi Yoshida, Yosuke Ashikari, Kodai
Saito, and Toshiki Nokami
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To be cited as: Chem. Eur. J. 10.1002/chem.201903426
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Oxo-Thiolation of Cationically Polymerizable Alkenes Using Flow
Microreactors
Yosuke Ashikari,[a] Kodai Saito,[b] Toshiki Nokami,[c] Jun-ichi Yoshida,*[d] and Aiichiro Nagaki*[a]
Abstract: The present study describes the cationic oxo-thiolation of
polymerizable alkenes using highly reactive cationic species
generated by anodic oxidation. These highly reactive cations were
able to activate alkenes before their polymerization. Fast mixing of
flow microreactors effectively controlled chemoselectivity, enabling
higher reaction temperatures.
electrochemical reactions[2][3]
, and we have described the
electrochemical generation and accumulation of organic cations
(cation pool method).[4][5] In this system, low-temperature anodic
oxidation irreversibly generates cationic species, which can react
with nucleophiles following the end of electrolysis. As an
extension, we have developed heteroatom cation pools that
undergo alkene difunctionalization with high efficiency.[6] Using
this method, diaryl disulfide, for example, is electrochemically
oxidized in the presence of dimethyl sulfoxide (DMSO) to
generate the O-arylsulfenyl alkoxysulfonium ion (ArS–OS+Me2).
The latter reacts with alkenes, yielding the corresponding three-
membered ring cationic intermediates (thiiranium ions). DMSO
attacks the cyclic intermediates, opening the ring and generating
-substituted alkoxysulfonium ions, an intermediate of DMSO
oxidation reactions, such as Swern oxidation and Kornblum
oxidation).[7] Treatment of these intermediates with an amine base
resulted in their oxidization to the corresponding carbonyl
Alkene difunctionalization is a class of reactions that involves the
forming of bonds with nucleophiles and/or electrophiles at two
adjacent sp2 carbons of alkenes.[1] Because it results in the rapid
construction
of
complex
structures,
alkene
vicinal
functionalization plays a crucial role in modern organic synthesis.
The ability of cationic three-membered ring intermediates to react
in a stereo- and regioselective manner results in the rapid and
selective transformation of these intermediates. These reactions,
however, have
a potential limitation; as cationic alkene
difunctionalization is not applicable to polymerizable alkenes such
as styrenes. Because of their cationic properties, intermediates
may react with unreacted alkenes as nucleophiles, yielding
polymers. Because the generation of cationic species is often
reversible, gradually generated cations activate alkenes
sequentially, enabling abundant surrounding alkenes to react and
form polymers, despite the number of nucleophiles being
sufficient. Thus, cationic difunctionalization of polymerizable
alkenes is generally challenging.
One possible solution may be the irreversible generation and
accumulation of cationic species in the absence of alkenes. The
high reactivity of cationic species results in the rapid conversion
of alkenes to three-membered intermediates prior to the start of
polymerization. Cationic species may be generated irreversibly by
compounds
(Figure
1a).
Although
this
integrated[8]
difunctionalization reaction is applicable to a range of alkenes, it
is especially applicable to the polymerization of polymerizable
alkenes such as styrenes. Because this arylsulfenium cation is
stabilized by DMSO, its reactivity is milder than that of bare cation,
thus preventing the wholesale conversion of styrenes to
thiiranium ions. Gradually generated thiiranium ions may
accumulate at the growing ends of polymers (Figure 1b). A similar
problem may occur during the general cationic oxo-thiolatioin of
styrenes, suggesting that these transformations are generally
performed using radical mechanisms.[9]
To address this challenge, we hypothesized that highly
reactive cationic species may enable the rapid conversion of
polymerizable alkenes to thiiranium ions, which can react with
DMSO to yield -thiocarbonyl products before polymerization.
We have described the anodic generation of arylsulfonium ions
coordinated by diaryl disulfide (ArS(ArSSAr)+) and the reactions
of these ions.[10] In particular, sulfonium cation can react with
carbon–carbon unsaturated compounds to generate three-
membered ring intermediates, which react with nucleophiles in a
manner resulting in alkene difunctionalization.[11] This reactive
cation pool may prevent polymerization. The present study
reports the cationic difunctionalization of polymerizable alkenes
using electrochemically generated sulfur cations (Figure 1c).
[a]
Dr. Y. Ashikari, Prof. Dr. A. Nagaki
Department of Synthetic and Biological Chemistry
Graduate School of Engineering, Kyoto University
Nishikyo-ku, Kyoto, 615-8510 (Japan)
E-mail: anagaki@sbchem.kyoto-u.ac.jp
Dr. K. Saito
[b]
[c]
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Prof. Dr. T. Nokami
Department of Chemistry and Biotechnology and Center for
Research on Green Sustainable Chemistry, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-
8552, Japan
[d]
Prof. Dr. J.-i. Yoshida
National Institute of Technology, Suzuka College
Shiroko-cho, Suzuka, Mie. 510-0294 (Japan)
E-mail: j-yoshida@jim.suzuka-ct.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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After finding that the concept was feasible, we started to
optimize the reaction conditions (Table 1). We attempted to
shorten the time required for the reaction by increasing the
reaction temperature when adding cation to the solution
containing alkene and DMSO. We found, however, that
increasing the reaction temperature reduced the reaction yields
(entries 1-5). In contrast, yields were increased when
Bu4NB(C6F5)4 was used instead of Bu4NBF4 as a supporting
electrolyte for anodic oxidation (entry 6), presumably because the
softer counter anion made the sulfur cation more reactive. We
assumed that this condition was optimal, and we started
investigating the scope of the alkenes that could be used in these
reactions. Unsubstituted styrene (entry 7), electron-deficient
substituted styrene (4-bromostyrene, entry 8), and 1,3-diene (1,3-
cyclohexadiene, entry 9) were converted to their corresponding
-thiocarbonyl compounds at high yields, whereas their reactions
with DMSO-stabilized sulfenium ion (method 1) resulted in low
yields. Non-polymerizable alkenes were also found to be good
reactants for transformation using the same reaction conditions
(entries 10-13). Because the intermediates were positively
charged, dienes were selectively mono-reacted (entries 9 and 13).
Although the yield of the reaction with vinylether was low (entry
14), this yield was slightly increased by using 3 equiv. of DMSO,
The very high reactivity of vinylethers may have interfered with
this transformation even at −78 °C.
Figure 1. (a) Alkene difunctionalization with DMSO-stabilized cation pool.
The first step consisted of oxo-thiolation of 4-methoxystyrene,
a good monomer for cationic polymerization (Scheme 1). Using a
DMSO-stabilized monovalent sulfur cation, the corresponding
product was, as expected, obtained at low yield (Method 1).
Therefore, we used arylsulfonium ions (ArS(ArSSAr)+, Ar = 4-F-
C6H4), which were generated from anodic oxidation of diaryl
disulfide (ArSSAr), using Bu4NBF4 as a supporting electrolyte, at
−78 °C. Stepwise addition to the solution of 4-methoxystyrene of
the cation pool, DMSO (1.3 equiv.), and trimethylamine at 5
minute intervals generated the desired product, but at lower yields
(Method 2). This disappointing result suggested that 4-
methoxystyrene polymerizes within minutes, or possibly seconds.
After determining the reaction time scale, we arranged the
reaction conditions. Specifically; DMSO was added to 4-
methoxystyrene solution, followed by the addition of the cation
pool, trapping the thiiranium ion with DMSO prior to
polymerization of the intermediate (Method 3). This trial provided
a good result, with the desired -thiocarbonyl product being
obtained at a yield of 74%. To our knowledge, this is the first
successful example of cationic oxo-thiolation of styrenes.[12]
Table 1. Reactions of anodically generated surfonium ions with alkenes[a]
Scheme 1. Initial trials of 4-methoxystyrene oxo-thiolation with 3 different
methods. “Ar” means 4-fluorophenyl group.
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Figure 2. (a) GPC trace of crude products on the reaction of ArS(ArSSAr)+ with
4-methoxystyrene. (b) bar: Area of polymer peak on GPC (elution time from 6
min to 8.5 min), line: product yields on the reaction temperature.
A flow microreactor system may allow transformation at
higher temperatures. Flow microreactors have been shown to
enable highly chemoselective reactions by fast mixing and
precise control of residence (reaction) times.[13-15] To evaluate this
hypothesis, cation flow syntheses were performed (Table 2).[16]
Anodically generated arylsulfonium ion solution was mixed with a
solution of polymerizable alkenes and DMSO in a micromixer 1
(M1,  = 500 m). After 17 seconds of residence, the mixed
solution was allowed to flow into M2 ( = 500 m), where it reacted
with Et3N solution. The solution was subsequently allowed to flow
into a round-bottomed-flask, and the contents of the flask were
stirred at room temperature for 1 hour to complete the
deprotonation reaction.[17] The -thiocarbonyl product of 4-
methoxystyrene was obtained at 95% yield at a reaction
temperature of −50 °C, whereas the batch reaction at the same
temperature resulted in a 32% yield. These findings indicate that
the flow microreactor plays a vital role in the reaction. Fast mixing
prevented localization of the chemicals, allowing alkenes to react
with the arylsulfonium cation pool prior to polymerization. Using
the same flow microreactor system, 4-bromostyrene was
converted to the corresponding product at a higher temperature
(0 °C). Surprisingly, this system was effective with vinylether, in
that the reaction of cyclohexyl vinyl ether produced a good yield
of the corresponding ester product, whereas the batch reaction
yielded only 17% of the product. These results indicate that rapid
mixing by the flow microreactor enabled highly efficient reactions
that require low temperatures in a batch reactor.
[a] Reactions were carried out 1.3 eq. of cations generated from anodic
oxidation using Bu4NB(C6F5)4 as a supporting electrolyte. Ar = 4-F-C6H4. [b]
Isolated yield. [c] Yields were determined by 1H NMR. [d] Bu4NBF4 was used as
a supporting electrolyte. [e] 3 equiv. of DMSO was used.
Although styrene underwent cationic difunctionalization, this
transformation required extremely low temperatures (−78 °C),
ruining the utility of this concept. To overcome this limitation, we
again examined the effects of the reaction temperature (entries 1-
5), observing that higher temperatures yielded greater amounts of
polymers, as indicated by GPC analyses (Figure 2a). This
tendency correlated with the lower product yields at higher
temperatures (Figure 2b), suggesting that higher temperatures
result in poorer chemoselectivity and unselective reactions
(polymerization). Polymerization of 4-methoxystyrene took place,
was observed, even at −78 °C, with non-negligible amounts of
polymers generated (Fig. 3). This finding suggested that
sufficiently rapid mixing of ArS(ArSSAr)+ with styrenes (and
DMSO) allowed the oxo-thiolation to proceed effectively, even at
higher temperatures.
Table 2. Flow Syntheses of -thiocarbonyl compounds[a].
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to their polymerization. The method described in the present study
is applicable to non-polymerizable alkenes and can be used to
constructing complex cyclized frameworks. This improvement
may result in novel reaction control methods and may also open
a new aspect of cationic chemistry.
Acknowledgements
This work was partially supported by the Grant-in-Aid for Scientific
Research on Innovative Areas 2707 Middle molecular strategy
from MEXT (no. 15H05849), Scientific Research (B) (no.
26288049), Scientific Research (S) (no. 26220804), Scientific
Research (S) (no. 25220913), Scientific Research (C) (no.
17865428), AMED (no. 18061567), the Japan Science and
Technology Agency’s (JST) A-step program (no. 18067420), and
the Ogasawara Foundation for the Promotion of Science &
Engineering. The authors are grateful to NIPPON SHOKUBAI Co.,
Ltd., for providing NaB(C6F5)4 as a precursor of Bu4NB(C6F5)4.
[a] Anodic generation of ArS(ArSSAr)+ (Ar = 4-F-C6H4) at −78 °C using Bu4NBF4
as a supporting electrolyte. In a flow reactor, the reaction required 1.3 eq of
ArS(ArSSAr)+, 1.3 eq of DMSO, and 5 eq of Et3N. [b] Obtained yields. [c] Yield
when 3 equiv. of DMSO was used.
Keywords: anodic oxidation • cationic species • flow
microreactor • polymerizable alkenes • electrochemistry
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Figure 3. Cyclization reaction using anodically generated thionium ions..
In conclusion, this study demonstrated the cationic
difunctionalization of polymerizable alkenes using anodically
generated highly reactive cationic species. These findings
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styrenes. Moreover, fast mixing using a flow microreactor system
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Chemistry - A European Journal
COMMUNICATION
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COMMUNICATION
Dr. Yosuke Ashikari, Dr. Kodai Saito,
Prof. Dr. Toshiki Nokami, Prof. Dr. Jun-
ichi Yoshida,* and Prof. Dr. Aiichiro
Nagaki*
Page No. – Page No.
Oxo-Thiolation of Cationically
Polymerizable Alkenes Using Flow
Microreactors
Highly reactive arylsulfonium ions generated by anodic oxidation provide oxo-
thiolation of polymerizable alkenes such as styrenes prior to their polymerization.
Fast mixing based on flow mixcoreactor systems enables this transformation at a
higher temperature.
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