Radical Cation Diels-Alder Reactions of Non-Conjugated Alkenes as Dienophiles by Electrocatalysis

Article abstract of DOI:10.1002/cjoc.201900054

Radical cation Diels-Alder reactions provide a powerful method for the construction of six-membered ring systems between both electron-rich dienes and dienophiles. However, the most recent examples of this class have been limited to β-methylstyrenes as di

Full text of DOI:10.1002/cjoc.201900054

radical cation, Diels-Alder reaction, non-conjugated alkene,
electrochemistry, single electron transfer
中
国 化 学
Radical Cation Diels-Alder Reactions of Non-Conjugated Alkenes as
Dienophiles by Electrocatalysis†
Atsushi Ozaki,a Yusuke Yamaguchi,a Yohei Okada,b and Kazuhiro Chiba*,a
a Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
b Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
Cite this paper: Chin. J. Chem. 2019, 37, 561—564. DOI: 10.1002/cjoc.201900054
Summary of main observation and conclusion Radical cation Diels-Alder reactions provide a powerful method for the construction of six-membered
ring systems between both electron-rich dienes and dienophiles. However, the most recent examples of this class have been limited to -methylstyrenes
as dienophiles; the use of non-conjugated alkenes remains challenging. The present study describes the serendipitous development of novel radical cati-
on Diels-Alder reactions by electrocatalysis that use non-conjugated alkenes as dienophiles. The key to successful transformation involves highly substi-
tuted cyclohexenyl radical cations that are stable enough to be reduced by intermolecular single electron transfer.
tween the carbon-centered radical cation and carbon nucleophile.
Background and Originality Content
The reactions are designed based on a redox tag strategy,[14]
Diels-Alder reactions are recognized as a first option to con-
which highlights the importance of an intramolecular SET. For
example, trans-anethole (1) has also been shown to be a suc-
cessful dienophile for radical cation Diels-Alder reaction by elec-
trocatalysis, while β-methylstyrene (5) is non-productive (Figure
1). This can be understood by considering the efficacy of intra-
molecular SET, i.e., an electron-rich methoxyphenyl ring can im-
struct six-membered ring systems in synthetic organic chemistry.[1]
Concerted bond formations between diene and dienophile occur
to form cyclohexenes usually with good stereo- and regio-selec-
tivity. Electronic matching of the substrates is required, with the
typical combination of an electron-rich diene and electron-poor
dienophile. The opposite combination, an electron-poor diene
mediately reduce transient cyclohexnyl radical cations through
and electron-rich dienophile, can also be productive, and is re-
intramolecular SET, while this is not true for a non-substituted
ferred to as an inverse electron-demand Diels-Alder reaction.
phenyl ring. We also demonstrated that some aryl vinyl ethers
However, the reaction between an electron-rich diene and elec-
tron-rich dienophile is less effective, even under harsh conditions.
For such an electronically-mismatched Diels-Alder reaction to be
successful, polarity inversion, more commonly called as “um-
polung,” has been highly effective. Single electron transfer (SET) is
the simplest and most straightforward umpolung, which can be
induced by chemical redox reagents, and by electrochemical[2]
and photochemical[3] approaches. Oxidative SET can produce a
radical cation of an electron-rich diene or dienophile, which is
then trapped by the other component, referred to as a radical
cation Diels-Alder reaction.[4] A typical example of this class is
reaction of trans-anethole (1) as the electron-rich dienophile
(Scheme 1),[5] which is possible using various photocatalysts, in-
cluding Ru,[6] Cr,[7] and Fe[8] complexes, graphitic carbon nitride,[9]
and organic dye.[10] Although radical cation Diels-Alder reactions
by photocatalysis can be complementary to normal and inverse
electron-demand versions, most recent examples have been lim-
ited to β-methylstyrenes as dienophiles, except for aryl vinyl
ethers (3)[6] and aryl vinyl sulfides (4) (Scheme 2).[11]
Scheme 2 Radical cation Diels-Alder reactions of aryl vinyl ether (2) and
aryl vinyl sulfide (3)
Scheme 1 Radical cation Diels-Alder reaction of trans-anethole (1)
We have been developing radical cation Diels-Alder reactions
by electrocatalysis[12] in lithium perchlorate (LPC)/nitromethane
(NM) electrolyte solution,[13] which facilitates the reaction be-
Figure 1 Radical cation Diels-Alder reactions by electrocatalysis.
*E-mail: chiba@cc.tuat.ac.jp
For submission: https://mc.manuscriptcentral.com/cjoc
For articles: https://onlinelibrary.wiley.com/journal/16147065
† Dedicated to the Special Issue of “Organic Electrochemistry”.
Chin. J. Chem. 2019, 37, 561－564
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
561

Ozaki et al.
Concise Report
could be used as a dienophile;[15] however, the use of non-con-
jugated alkenes remains challenging. We questioned whether the
redox tag strategy could be applied to overcome this limitation.
Described herein is the serendipitous development of novel radi-
cal cation Diels-Alder reactions of non-conjugated alkenes as
dienophiles by electrocatalysis.
Scheme 4 Unsuccessful radical cation Diels-Alder reactions
Results and Discussion
The present work began with the synthesis of alkenes (6—9)
that could be used as dienophiles in radical cation Diels-Alder
reactions (Scheme 3). We hypothesized if alkenyl radical cations
(A˙+) are generated by anodic oxidative SET, they can be trapped
by a diene to form cyclohexnyl radical cations (B˙+), which are
then transformed into aryl radical cations (C˙+) through intramo-
lecular SET (Figure 2). Reductive SET to aryl radical cations (C˙+)
provided the desired cycloadducts (C). However, reactions of the
alkenes (6—8) in combination with 2,3-dimethyl-1,3-butadiene (2)
were unsuccessful and no significant amounts of cycloadducts
(10—12) were obtained, even after a stoichiometric amount of
electricity was passed (Scheme 4), likely due to the electron den-
sity of the alkenes. Since di- and tri-substituted alkenes are not
electron-rich enough, anodic oxidative SET generated aryl radical
cations (D˙+) rather than alkenyl radical cations (A˙+). Although
alkenyl radical cations (A˙+) were recognized as electron-poor
dienophiles that could be trapped by electron-rich dienes, aryl
radical cations (D˙+) could not be trapped. However, eventually
the tetrasubstituted alkene (9) was found to be productive for the
reaction, affording the desired cycloadduct (13) in excellent yield
with a catalytic amount of electricity (Figure 3). This result
Scheme 3 Synthesis of the alkenes (6—9)
Figure 3 Radical cation Diels-Alder reaction of the alkene (9) and ex-
pected mechanism.
suggested that a radical cation chain mechanism was involved, in
which the aryl radical cation (13˙+) oxidized the starting alkene (9)
during an electrocatalytic cycle.
As a control experiment, an alkene with a non-substituted
phenyl ring (14) was synthesized and used in the reaction instead
of alkene (9). The cyclohexnyl radical cations (E˙+) were not ex-
pected to be transformed into the aryl radical cations (F˙+)
through intramolecular SET, since a non-substituted phenyl ring is
not an effective electron donor (Scheme 5). However, the reac-
tion between alkene (14) and 2,3-dimethyl-1,3-butadiene (2) gave
cycloadduct (15) in moderate yield. Furthermore, competitive
intramolecular cyclization was found to occur during the reaction,
producing a significant amount of undesired byproduct (16)
(Scheme 6). Better results were obtained when the reaction was
conducted at 0 °C. Under these conditions, little intramolecular
Scheme 5 Radical cation Diels-Alder reaction of alkene (14)
Figure 2 Working hypothesis for novel radical cation Diels-Alder reactions.
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Chin. J. Chem. 2019, 37, 561－564

Radical Cation Diels-Alder Reactions of Non-Conjugated Alkenes
Chin. J. Chem.
Scheme 6 Competitive reactions
take place separately from aryl rings. These observations are in
sharp contrast to the synthetic outcome using β-methylstyrene (5)
as a dienophile, which was an unsuccessful substrate for the reac-
tion.
Conclusions
In conclusion, we have serendipitously found that radical cat-
ion Diels-Alder reactions of non-conjugated alkenes as dieno-
philes are possible by electrocatalysis. Since highly substituted
cyclohexenyl radical cations are stable enough to be reduced by
intermolecular SET, the contribution of an aryl ring as an electron
donor is not required. The reactions complete using a catalytic
amount of electricity and therefore, a radical cation chain mecha-
nism is likely to be involved. A cyclohexenyl radical cation can
oxidize the starting tetrasubstituted alkenes, running an electro-
catalytic cycle. These results will expand the utility of radical cat-
ion Diels-Alder reactions in the field of synthetic organic chemis-
try. Further development of this reaction by electrocatalysis and
photocatalysis is under investigation.
cyclization occurred and the cycloadduct (15) was obtained in
excellent yield, although a slightly larger amount of electricity was
needed to complete the reaction. These results can be explained
in two ways: the non-substituted phenyl ring may immediately
reduce the transient cyclohexnyl radical cation through intramo-
lecular SET to form the aryl radical cation (F˙+), or the cyclo-
hexneyl radical cation (E˙+) itself is stable enough to be reduced by
intermolecular SET.
To gain further mechanistic insights into the reaction, an al-
kene with a cyclohexane ring (17) was synthesized and used for
the reaction instead of alkene (14) because no contribution of an
aryl radical cation is possible. Surprisingly, alkene (17) was also
productive in the reaction, affording cycloadduct (18) in good
yield (Scheme 7). Furthermore, alkenes (19, 20) were also found
to be successful substrates for the reactions to give cycloadducts
(21, 22) in good yields, respectively (Scheme 8). These results
indicate that the cyclohexneyl radical cation composed of a
tetrasubstituted alkene and 2,3-dimethyl-1,3-butadiene (2) was
stable enough to be reduced by intermolecular SET (Figure 4).
Although the involvement of intramolecular SET cannot be ruled
out for reaction involving alkenes (9, 14) instead of alkene (17), it
is perhaps fair to say that the six-membered ring formations can
Experimental
General procedure for radical cation Diels-Alder reactions.
To a solution of LiClO4/CH3NO2 (1.0 mol∙L–1, 2 mL) stirred at room
temperature, were added the respective alkenes (0.16 mmol) and
dienes (2 equiv.). The resulting reaction mixture was electrolyzed
at 1.2 V vs. Ag/AgCl using carbon felt electrodes in an undivided
cell with stirring until the starting material was consumed (moni-
tored by TLC and GC-MS). The reaction mixture was diluted with
brine and extracted with EtOAc. The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
Scheme 7 Radical cation Diels-Alder reaction of alkene (17)
1
Yields were determined by H NMR analysis using benzaldehyde
as an internal standard. Silica gel column chromatography (Hex/
EtOAc) gave the corresponding cycloadducts.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.201900054.
Scheme 8 Radical cation Diels-Alder reaction of alkenes (19, 20)
Acknowledgement
This work was partially supported by JSPS KAKENHI Grant
Numbers 15H04494, 17K19222 (to K.C.), 16H06193, and
17K19221 (to Y.O.).
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Manuscript received: February 2, 2019
Manuscript revised: March 25, 2019
Manuscript accepted: March 28, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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