Solvent-enabled radical selectivities: Controlled syntheses of sulfoxides and sulfides

Article abstract of DOI:10.1002/anie.201508729

Controlling selectivity is of central importance to radical chemistry. However, the highly reactive and unstable radical intermediates make this task especially challenging. Herein, a strategy for taming radical redox reactions has been developed, in which solvent-bonding can alter the reactivity of the generated radical intermediates and thereby drastically alter the reaction selectivity at room temperature. Various β-oxy sulfoxides and β-hydroxy sulfides can be facilely obtained, some of which are difficult to synthesize by existing methods. Notably, neither a metal catalyst nor any further additives are necessary in these processes. Solvent selection alters the reactivity of the generated reaction intermediate and drastically switches the reaction selectivity under simple and mild conditions. Various β-oxy sulfoxides and β-hydroxy sulfides could be facilely obtained from readily available starting materials. Importantly, neither a metal catalyst nor an additional additive was necessary in these transformations.

Full text of DOI:10.1002/anie.201508729

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201508729
German Edition: DOI: 10.1002/ange.201508729
Radical Reactions
Solvent-Enabled Radical Selectivities: Controlled Syntheses of
Sulfoxides and Sulfides
Huamin Wang+, Qingquan Lu+, Chaohang Qian, Chao Liu, Wei Liu, Kai Chen, and Aiwen Lei*
Abstract: Controlling selectivity is of central importance to
radical chemistry. However, the highly reactive and unstable
radical intermediates make this task especially challenging.
Herein, a strategy for taming radical redox reactions has been
developed, in which solvent-bonding can alter the reactivity of
the generated radical intermediates and thereby drastically alter
the reaction selectivity at room temperature. Various b-oxy
sulfoxides and b-hydroxy sulfides can be facilely obtained,
some of which are difficult to synthesize by existing methods.
Notably, neither a metal catalyst nor any further additives are
necessary in these processes.
ing process for preparation of b-hydroxy sulfides and b-
hydroxy sulfoxides.[7] However, the diversity of these trans-
formations is often constrained to electron-rich olefins and
suffers from low regioselectivity, chemical inefficiency, and
requires assistance in the form of UV irradiation, peroxides,
and/or transition metals.[1b,d,5e, 7,8] Until now, only a handful of
methods have been developed for the synthesis of b-hydroxy
sulfides, and the efficient approach towards b-oxy sulfoxides
from simple starting materials is still very limited.[5,6] Herein,
a method to control radical selectivity through solvent-
bonding is presented, which can dictate reaction selectivity
without outside assistance. Various b-oxy sulfoxides and b-
hydroxy sulfides can be facilely obtained featuring switchable
selectivity, mild conditions, and gram-scale synthesis
(Scheme 1).
R
adical chemistry has been vibrant and alive for more than
one century, yet controlling selectivity in radical reactions has
always been an essential issue. The fast reaction rates, highly
reactive and unstable radical intermediates make this task
especially challenging.[1] Recently, attention has been shifted
towards the use of milder radical initiators, such as transition
metal catalysts and photosensitizers, to tune the reaction
selectivity.[1,2] Despite the significance of these developments,
the successful application of these strategies often relies on
creative substrate design. Until now, switching product
selectivity from the same starting materials still remains
a fundamental challenge.[3] Seeking efficient and sustainable
alternatives to achieve this goal is an appealing, yet difficult,
task.
Scheme 1. Switchable synthesis of b-oxy sulfoxides and b-hydroxy
b-Oxy sulfoxides and b-hydroxy sulfides are widely
featured in natural products, pharmaceuticals, and biologi-
cally active compounds.[4] They are also important building
blocks and have versatile synthetic applications in asymmetric
synthesis and total synthesis of natural products.[4] Despite the
intriguing properties of the sulfoxide and sulfide groups, facile
synthesis of these molecules from simple starting materials is
still underdeveloped,[5] especially for the valuable b-oxy
sulfoxides.[6] In this regard, thiol–oxygen co-oxidation
(TOCO) reactions, which are traditionally free-radical-medi-
ated hydroxysulfenylation reactions, have provided a promis-
sulfides.
Radical redox reactions of thiols and alkenes in the
presence of dioxygen have been a fundamental research area
in synthetic community, and the final products obtained from
these reactions largely depend on the reaction concentration,
temperature, structure of reactant, solvent, initiator, catalyst,
and other conditions.[1b,d,7,8] Consequently, the product dis-
tribution remains difficult to predict, even today. In principle,
the H-abstraction products or the oxygenation products,
hydroperoxy sulfides, can be generated after the reversible
addition of the thiyl radical to the alkene (Scheme 2).
However, hydroperoxy sulfides are simultaneously a combi-
nation of an oxidant and reductant, which can easily undergo
rearrangement to sulfoxides, sulfides, hemithioacetals, alde-
hydes, and ketones, resulting in low reaction selectivity.[9] As
shown in Scheme 2, the redox reactivity of the hydroperoxy
sulfide may directly determine the self- or intermolecular
redox processes, leading to the b-hydroxy sulfoxide or b-
hydroxy sulfide, respectively. Accordingly, the ability to tune
the redox reactivity of the unstable hydroperoxy sulfide
would be the key to achieve high reaction selectivity. Spurred
by the unique structure of the hydroperoxy sulfide, we
envisioned that the solute–solvent interaction might have an
[*] H. Wang,[+] Dr. Q. Lu,[+] C. Qian, C. Liu, W. Liu, K. Chen, Prof. A. Lei
College of Chemistry and Molecular Sciences
The Institute for Advanced Studies (IAS)
Wuhan University
Wuhan 430072, Hubei (P.R. (China))
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
National Research Center for Carbohydrate Synthesis
Jiangxi Normal University
Nanchang 330022, Jiangxi (P.R. (China))
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508729.
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Table 1: Synthesis of b-hydroxy sulfoxides.[a]
Scheme 2. Solvent bonding for selectivity control in radical redox
processes.
impact on the redox reactivity of the hydroperoxy sulfide
through solvent-bonding, thus providing a possible way to
steer the redox processes to the corresponding sulfoxide or
sulfide under metal-free conditions.
To test whether the solvent-bonding could influence the
redox selectivity, we chose the abundant and commonly used
1,1-diphenylethylene (1a) and p-toluenethiol (2a) as the
starting materials to test different solvents (Supporting
Information, Table S1). Indeed, b-hydroxy sulfoxide 3a
could be furnished in good to excellent yields (up to 90%
NMR yield) at room temperature in weakly hydrogen-
bonding solvents, including CHCl3, dichloroethane (DCE),
and toluene. Conversely, when DMSO was used as the
solvent, the selectivity was reversed, as expected, and 89%
NMR yield of b-hydroxy sulfide 4a was obtained after PPh3
workup. Notably, no 3a or 4a was observed when the reaction
was carried out under N2 atmosphere, which was also
consistent with proposed reaction routes in Scheme 2.
Furthermore, 18O2-labeling experiments were conducted
to elucidate the origin of the oxygen atom of the b-hydroxy
sulfoxide and b-hydroxy sulfide. The corresponding 18O-
labeled 3a and 4a could be isolated in 90% and 89% yields
under optimized conditions, which confirmed that dioxygen
took part in this transformation and was incorporated into the
final products (Supporting Information).[10]
Subsequently, the substrate scope for the highly selective
synthesis of tertiary b-hydroxy sulfoxides was investigated
(Table 1), this substrate class was selected because they are
normally difficult to synthesize by existing methods. Thio-
phenols bearing not only electron-donating groups, such as
methoxy and methyl, but also electron-withdrawing groups,
such as F, Cl, and Br, could react smoothly with 1a, affording
the corresponding products in 84–87% yields (3a–e and 3g).
To our delight, non-terminal styrene derivatives, such as 2-
methyl-1,1-diphenylethylene, were amenable to this method
(3 f). 2-Naphthalenethiol also reacted efficiently with 1a to
give the product in 76% yield (3h). Furthermore, a variety of
a-substituted styrene derivatives were suitable partners in this
procedure, and an array of tertiary b-hydroxy sulfoxides could
be facilely obtained in moderate to excellent yields (3i–o).
Encouraged by these promising results, we further applied
this method to prepare secondary b-hydroxy sulfoxides using
[a] Unless otherwise specified, all of the reactions were carried out using
1 (0.2 mmol) and 2 (0.2 mmol) in DCE (0.1 mL) at room temperature for
2 h under O2. Isolated yield (%). [b] 3 h.
styrene derivatives as substrates. As exemplified by styrene
and p-methoxystyrene, the desired secondary b-hydroxy
sulfoxides (3p–q), were furnished in 61% and 45% yields,
respectively. Importantly, activated aliphatic alkene also
performed well, generating 3r in 71% yield with high
selectivity, probably owing to the directional selectivity from
the steric hindrance. Nevertheless, non-activated aliphatic
alkenes, such as 1-butene, were not amenable to this
procedure, probably owing to the lower stability of the
corresponding radical intermediates.
Additionally, a series of tertiary and secondary b-hydroxy
sulfides could be obtained in good to excellent yields from the
corresponding alkenes and thiophenols (Table 2). Notably, a-
cyclopropylstyrene reacted smoothly with 2a without ring
opening rearrangement, providing the desired product 4j in
86% yield. Secondary b-hydroxy sulfides, exemplified by 4l,
could also be readily prepared by using styrene as reactant.
Pleasingly, non-terminal and cyclic styrene derivatives with
steric hindrance, such as trans-anethole and 1-phenyl-1-cyclo-
hexene, were able as well to give the expected products 4m
and 4n in good yields, respectively. Furthermore, ethyl
methacrylate, a widely used Michael acceptor, effectively
outcompeted the Michael addition of thiophenol to the
electron-deficient alkene, generating 4o in 82% yield.
The efficiency of this method on a larger scale was next
investigated. It is noteworthy that this procedure can be
scaled up to gram quantities of the desired b-hydroxy
sulfoxides and b-hydroxy sulfides without sacrificing yield.
For instance, 1.39 g of 3a and 1.41 g of 4a could be isolated in
83% and 88% yields, highlighting the synthetic utility of this
method (Supporting Information).
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Table 2: Synthesis of b-hydroxy sulfides.[a]
Scheme 3. Switchable synthesis of b-hydroxy sulfoxide 3b.
Scheme 4. Proposed mechanism.
[a] Unless otherwise specified, all of the reactions were carried out using
1 (0.2 mmol) and 2 (0.2 mmol) in DMSO (2.0 mL) at room temperature
for 2 h under O2. Isolated yield after PPh3 workup (%). [b] 3 h.
react quickly with dioxygen and be transformed into peroxyl
radical III. Subsequently, an intermolecular hydrogen
abstraction process occurs between 2a and III, delivering
arenethiyl radical I and the key intermediate, hydroperoxy
sulfide IV. Finally, IV undergoes a redox process with or
without assistance of solvent-bonding, providing b-hydroxy
sulfoxides and b-hydroxy sulfides, respectively.
On the basis of this mechanistic proposal, we further
attempted to apply the present method in the synthesis of b-
keto sulfoxides by introducing a good leaving group at the a-
position of the alkene. As shown in Table 3, a range of b-keto
sulfoxides could be successfully synthesized in moderate
yields by employing a-substituted alkenes. Intriguingly, these
reactions were also performed at room temperature under
metal-free conditions, highlighting the practical utility of this
method. Furthermore, because the reaction intermediate, b-
hydroperoxy sulfide, easily undergoes decomposition, a thio-
phenol-catalyzed radical cleavage of 1,1-diphenylethylene
was further developed under irradiation by a 3 W Blue LED,
in which benzophenone could be selectively obtained in 78%
yield (Supporting Information).[12,13]
In summary, we have developed a practical strategy for
the highly selective construction of b-oxy sulfoxides and b-
hydroxy sulfides from readily available starting materials.[14]
This reaction features simple operation, switchable selectivity,
green reagents, and gram-scale synthesis. Crucially, neither
metal catalyst nor any additional additive was necessary in
these transformations. Mechanistic investigations demon-
strated that hydroperoxy sulfide might be the same inter-
mediate for both of the redox processes, and solvent-bonding
enables tuning of the redox reactivity of the unstable hydro-
peroxy sulfide, which is the key to achieve switchable
selectivity. Ongoing research, including further mechanistic
details and expanding the substrate scope, are currently
underway.
To gain insight into the reaction mechanism, radical
trapping experiments were conducted. The reaction between
1a and 2a was extremely inhibited by the radical scavenger,
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), either using
DCE or DMSO as the solvent (Supporting Information),
supporting the proposed radical pathway for this reaction.
Additionally, the reaction of 1a and 2a in DCM was
monitored by in situ IR. The signal of 3a increased gradually
in intensity with the consumption of 2a, and no inductive
period and obvious reaction intermediate were observed
(Supporting Information). In contrast, the hydroperoxy
sulfide could be confirmed as the vital reaction intermediate
for b-hydroxy sulfide formation. The consumption of 2a and
1a, generation of hydroperoxy sulfide IV and 4a could all be
well tracked in sequence (1H NMR experiments; Supporting
Information).
With these results in hand, we wondered whether the b-
hydroxy sulfoxide also originates from the hydroperoxy
sulfide under the current conditions. Interestingly, 3b can be
isolated in 70% yield by reacting the hydroperoxy sulfide
(generated in DMSO without isolation; Supporting Informa-
tion) in DCE for 1.5 h (Scheme 3). These results suggested
that the hydroperoxy sulfide might be formed predominantly
in both transformations. This result also indirectly demon-
strated that solvent-bonding stabilizes the unstable hydro-
peroxy sulfide and induces an intermolecular redox, whereas
a self-rearrangement would occur easily.[11]
Based on these results and on previous works,[7,10]
a mechanism for this reaction is proposed in Scheme 4.
Firstly, arenethiyl radical I is generated from autoxidation of
4-methylthiophenol (2a). Then, radical addition of I to alkene
(1a) affords carbon-centered radical II, which would further
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Acknowledgements
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21520102003, 21272180, 21302148), the Hubei Province Nat-
ural Science Foundation of China (2013CFA081), the
Research Fund for the Doctoral Program of Higher Education
of China (20120141130002), and the Ministry of Science and
Technology of China (2012YQ120060). The Program of
Introducing Talents of Discipline to Universities of China
(111 Program) is also appreciated.
[11] Self-rearrangement was shown to mainly occur through an
intramolecular redox (Supporting Information).
À
[12] For oxidative cleavage of C C bonds from the Jiao group, see:
Keywords: dioxygen activation · metal-free · oxygenation ·
radical coupling · switchable selectivity
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Received: September 17, 2015
Revised: November 5, 2015
Published online: December 7, 2015
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