Radical Cation Cycloadditions Using Cleavable Redox Auxiliaries

Article abstract of DOI:10.1021/acs.orglett.6b03545

The incorporation of an easily oxidized arylsulfide moiety facilitates the photocatalytic generation of alkene radical cations that undergo a variety of cycloaddition reactions with electron-rich reaction partners. The sulfide moiety can subsequently be reductively cleaved in a traceless fashion, affording products that are not otherwise directly accessible using photoredox catalysis. This approach constitutes a novel oxidative “redox auxiliary” strategy that offers a practical means to circumvent a fundamental thermodynamic limitation facing photoredox reactions.

Full text of DOI:10.1021/acs.orglett.6b03545

Letter
pubs.acs.org/OrgLett
Radical Cation Cycloadditions Using Cleavable Redox Auxiliaries
Shishi Lin, Shane D. Lies, Christopher S. Gravatt, and Tehshik P. Yoon*
Department of Chemistry, University of Wisconsin−Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: The incorporation of an easily oxidized
arylsulfide moiety facilitates the photocatalytic generation of
alkene radical cations that undergo a variety of cycloaddition
reactions with electron-rich reaction partners. The sulfide
moiety can subsequently be reductively cleaved in a traceless
fashion, affording products that are not otherwise directly accessible using photoredox catalysis. This approach constitutes a novel
oxidative “redox auxiliary” strategy that offers a practical means to circumvent a fundamental thermodynamic limitation facing
photoredox reactions.
lkene radical ions are open-shell reactive intermediates that
applied to facilitate photooxidatively initiated organic trans-
Acan participate in a wide variety of organic transformations. formations. We imagined that installation of an electron-rich
Many features of these reactions are synthetically attractive: they
often proceed with very low activation barriers, and their
regiochemical outcomes generally complement those involving
closed-shell neutral alkenes.1 In the past several years, there has
been a renewed interest in the application of radical ion
chemistry to synthesis, due in part to the recognition that
photoredox catalysis offers a convenient means to access the
distinctive reactivity of these odd-electron intermediates under
relatively mild and convenient conditions.2 Recent reports of
synthetic transformations involving photogenerated alkene
radical cations have included a variety of cycloaddition reactions3
and anti-Markovnikov hydrofunctionalization reactions,4 each of
which would be challenging to accomplish using alternate
synthetic strategies.
redox auxiliary onto an otherwise unactivated alkene would
facilitate its one-electron oxidation; the resulting radical cations
could subsequently be induced to undergo a number of
characteristic alkene radical cation reactions, including Diels−
Alder3b,f,g and [2 + 2] cycloadditions.3a,d Subsequent cleavage of
the redox auxiliary group would afford the products of formal
cycloadditions involving unactivated alkene substrates (Figure
1).8,9
One limitation common to all photoredox reactions is that the
scope of a given method is dictated by the thermodynamic
feasibility of the initial photoinduced electron-transfer step;
substantially endergonic photoredox steps result in poor overall
reactivity. On the one hand, the availability of a large number of
structurally varied photocatalysts spanning a range of excited
state redox potentials can be exploited to broaden the scope of
these reactions.5 Nevertheless, a substrate’s redox potential
remains a fundamental thermodynamic constraint on the success
of photoredox methods. For instance, simple mono- and
disubstituted aliphatic alkenes have proven too difficult to
oxidize (>+2.5 V vs SCE)6 using even the most powerfully
oxidizing photoredox catalysts in common usage and have not
successfully been engaged in photooxidatively triggered trans-
formations.
We recently described the concept of a “redox auxiliary,” which
we defined as an easily removable moiety that can be temporarily
installed on a substrate to enable its activation by single-electron
transfer processes.7 Our initial demonstration of this concept was
a radical anion [2 + 2] photoredox cycloaddition using 2-
acylimidazoles as readily reducible analogues of enoate esters that
would otherwise be resistant toward photoreductive activation.
We wondered if a similar redox auxiliary strategy might be
Figure 1. Traceless redox auxiliary strategy for radical cation reactions.
Very recently, Cooke and co-workers described an intriguing
first step toward an alternate oxidative redox auxiliary strategy.
They demonstrated that vinyl ferrocene is powerfully activated
toward Diels−Alder and hydrothiolation reactions upon one-
electron chemical oxidation.10 This study verified that the
incorporation of a reversibly oxidizable moiety onto an alkene
can indeed be used to facilitate redox-promoted transformations.
However, this strategy involves a separate activation step using
stoichiometric chemical oxidant rather than an in situ redox
Received: November 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03545
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalyst, and the requisite ferrocenyl moiety is not removable in a
traceless fashion.
addition reactions of electron-rich styrenes can typically be
conducted open to air, we observed diminished yields and poor
mass balance when this Diels−Alder reaction was run under
ambient atmosphere rather than in degassed solvent (entry 8), an
observation we attribute to the sensitivity of sulfides toward
reactive oxygen species.14 Finally, consistent with the photo-
catalytic nature of this reaction, control experiments indicated
that no product is formed either in the absence of Ru(bpz)32+ or
in the dark (entries 9 and 10).
We imagined a different strategy utilizing a reversibly
oxidizable sulfide moiety as a redox auxiliary (Figure 1). We
were attracted to the use of vinyl sulfides in this context for a
number of reasons. First, aryl vinyl sulfides generally possess
oxidation potentials ranging from +1.1 V to +1.4 V vs SCE,11
which are readily accessible using the well-characterized Ru(II)
polypyridyl photoredox catalysts that are increasingly being
utilized in synthetic chemistry. Second, Bauld has studied radical
cation Diels−Alder cycloadditions of aryl vinyl sulfides using
triarylaminium salts as chemical oxidants or aromatic nitriles as
PET sensitizers.11 This valuable precedent demonstrates that
vinyl sulfide radical cations are indeed activated toward
cycloaddition reactions. Finally, C−S bonds are relatively weak,
and a variety of mild, operationally facile methods for their
cleavage have been utilized in the synthesis of complex
molecules.12 We imagined that successful development of this
sequence would enable the preparation of formal cycloaddition
products of simple alkenes that are not amenable to direct
activation by photoredox catalysis and would also be challenging
to engage in classical thermal cycloaddition methods.
Studies examining the scope of the radical cation Diels−Alder
cycloaddition of vinyl sulfides under optimized photocatalytic
conditions are summarized in Scheme 1. A range of simple cyclic
Scheme 1. Scope Studies for Photocatalytic Vinyl Sulfide
a
Radical Cation Diels−Alder Cycloadditions
As a starting point for our investigations, we optimized
conditions for the radical cation Diels−Alder cycloaddition of
vinyl sulfide 1 with isoprene (2) (Table 1).13 We first examined
Table 1. Optimization Studies for Vinyl Sulfide Radical Cation
a
Diels−Alder Cycloadditions
entry
solvent
light source
additive
yield (%)
1
2
3
4
5
6
7
8
9
MeCN
CH2Cl2
DMF
blue LED
blue LED
blue LED
blue LED
blue LED
blue LED
23 W CFL
blue LED
40
22
0
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
H2O (10 mol %)
MgSO4
11
84
44
24
0
MgSO4
MgSO4, air
MgSO4
a
Reactions were conducted using 5 mol % Ru(bpz)3(BArF)2, 1 equiv
b
of vinyl sulfide, 3 equiv of diene, and 2 weight equiv of MgSO4 in
degassed MeCN. A 15 W blue LED was used as the irradiation source.
10
blue LED
MgSO4
0
a
Unless otherwise noted, reactions were conducted using 5 mol %
Ru(bpz)3(BArF)2, 1 equiv of 1, and 3 equiv of 2 in solvent degassed
using three freeze/pump/thaw cycles. A 15 W blue LED was used as
the irradiation source. Reaction conducted without Ru(bpz)3(BArF)2.
and acyclic dienes participate readily in this process (3−7),
though sterically bulky dienes require longer reaction times (5),
and electron-rich dienes provide somewhat lower yields (6).
Simple cyclic dienes (7), however, work well in this reaction. The
structure of the vinyl sulfide partner can also be modified. An
examination of simple alkyl-substituted dienophiles reveals a
sensitivity to steric bulk; larger vinyl substituents result in
substantially slower Diels−Alder reactions (10 and 11), and β,β-
disubstituted vinyl sulfides do not provide any observable
cycloadducts. However, the reaction tolerates various functional
groups including esters, silyl ethers, and phthalimides (12−14).
These conditions were also found to be applicable to
intramolecular cycloadditions (15).15
b
conditions adapted from our previous study of photocatalytic
radical cation Diels−Alder cycloadditions with styrenic dien-
ophiles, utilizing Ru(bpz)3(BArF)2 as a strongly oxidizing,
organic-soluble photocatalyst. The yield of this model cyclo-
addition, however, was disappointingly low in a variety of
solvents (entries 1−4). A study of additives quickly revealed a
sensitivity of the reaction to the presence of water (entry 5). This
observation led us to investigate the effect of dessicants such as
MgSO4, which resulted in a significant increase in the yield of the
cycloaddition (entry 6), along with improved reproducibility.
Intense blue LEDs are not required; the photocatalytic reaction
proceeds using a less-intense CFL light bulb, albeit with slower
rates (entry 7). Interestingly, although radical cation cyclo-
These studies were premised on the hope that sulfide redox
auxiliaries might be broadly applicable not only to Diels−Alder
cycloadditions but also to a range of useful transformations
B
DOI: 10.1021/acs.orglett.6b03545
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
involving alkene radical cations. As a first attempt to investigate
the generality of this strategy, we studied the use of vinyl sulfides
in intermolecular [2 + 2] cycloaddition reactions.3d We had
previously investigated the factors controlling the crossed
selectivity of such reactions involving electron-rich styrenes
and were pleased to observe that similar considerations are
applicable to [2 + 2] radical cation cycloadditions of vinyl sulfides
(Scheme 2). Thus, when 1 is irradiated in the presence of
Scheme 3. Reductive Cleavage of the Redox Auxiliary Group
Scheme 2. Scope Studies for Photocatalytic Vinyl Sulfide
a
Radical Cation [2 + 2] Cycloadditions
(eq 3), and the diastereomer ratio of the resulting cyclobutane
(26) is identical to that of the starting material, indicating that
epimerization does not occur under these conditions. The
desulfurization of functionalized cycloadduct 16 occurs without
observable cleavage or elimination of the alkoxy substituent.
Thus, removal of these sulfide auxiliary groups can be
accomplished under relatively mild conditions that tolerate a
variety of common functional groups.
In conclusion, vinyl sulfides are easily activated by visible-light-
promoted photooxidation and subsequently undergo cyclo-
addition reactions characteristic of alkene radical cations. The
activating sulfide moiety can be tracelessly removed after the
photoredox reaction to afford cycloadducts that could not be
directly synthesized by reactions of simple unfunctionalized
alkenes. These results, along with the reductive redox auxiliary
strategy our group reported several years ago,7 suggest that the
use of redox auxiliary groups present a practical strategy to
circumvent a fundamental limitation on the feasibility of
photoredox reactions and could be used to significantly increase
the scope of products that are available using this powerful mode
of activation.
a
Unless otherwise noted, reactions were conducted using 5 mol %
Ru(bpz)3(BArF)2, 1 equiv of vinyl sulfide, 3 equiv of alkene reaction
partner, and 2 weight equiv of MgSO4 in degassed MeCN. A 15 W
blue LED was used as the irradiation source. Reaction conducted
using 10 equiv of N-vinylacetamide.
b
electron-rich monosubstituted alkenes, the corresponding
unsymmetrical cyclobutanes are produced in good yield. Vinyl
ethers were excellent reaction partners in this reaction, affording
good yields and excellent selectivities regardless of the steric bulk
of the ether substituent (16−20).16 An enamide also provided
synthetically useful yields of the corresponding acetamide-
substituted cyclobutane (21). Finally, although simple aliphatic
olefins and vinyl esters did not participate in this reaction,
styrenes are successful reaction partners (22 and 23), consistent
with the stepwise radical mechanism expected for this cyclo-
addition.
The concluding step in this redox auxiliary strategy requires
the cleavage of the sulfide moiety, which can readily be
accomplished using various reductive protocols (Scheme 3).
First, treatment of [4 + 2] cycloadduct 3 with freshly prepared
lithium naphthalenide rapidly affords the corresponding
desulfurized product without competitive reduction of the
alkene moiety (eq 1). Importantly, the resulting cyclohexene
24 would not be directly accessible using alternate thermal or
redox-promoted Diels−Alder methods. Similarly, cycloadduct
13 bearing a TBS-protected primary alcohol undergoes
desulfurization to afford 25 without cleavage of the silyl
protecting group (eq 2). The reduction of [2 + 2] cycloadduct
23 can readily be accomplished by treatment with Raney nickel
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03545.
Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tyoon@chem.wisc.edu.
ORCID
Tehshik P. Yoon: 0000-0002-3934-4973
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the NIH (GM098886) for financial
support and to Sigma−Aldrich for a generous gift of RuCl3.
Analytical instrumentation at UW−Madison is supported in part
C
DOI: 10.1021/acs.orglett.6b03545
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
P.; Font, J.; Bayon
1534−1543.
(13) Both (E) and (Z) linear vinyl sulfides provide identical reaction
rates and diastereomer ratios. Thus, the studies described herein were
conducted using a mixture of geometric isomers arising from the
synthesis of the substrates via photoinduced radical thiol-ene addition.
See the Supporting Information for details.
(14) (a) Schenck, G. O.; Krauch, C. H. Angew. Chem. 1962, 74, 510−
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vinyl ethers, presumably because their redox potentials (ca. +1.67 V vs
́
, P.; Figueredo, M. Eur. J. Org. Chem. 2011, 2011,
by the NIH (1S10 OD020022-1) and by a generous gift from the
Paul J. Bender fund.
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