Polysulfide Anions as Visible Light Photoredox Catalysts for Aryl Cross-Couplings

Article abstract of DOI:10.1021/jacs.0c11968

Polysulfide anions are endowed with unique redox properties, attracting considerable attentions for their applications in alkali metals-sulfur batteries. However, the employment of these anionic species in redox catalysis for small molecule synthesis remains underdeveloped due to their moderate-poor electrochemical potential in the ground state, whereas some of them are characterized by photoabsorptions in visible spectral regions. Herein, we disclose the use of polysulfide anions as visible light photoredox catalysts for aryl cross-coupling reactions. The reaction design enables single-electron reduction of aryl halides upon the photoexcitation of tetrasulfide dianions (S42-). The resulting aryl radicals are engaged in (hetero)biaryl cross-coupling, borylation, and hydrogenation in a redox catalytic regime involving S4?-/S42- and S3?-/S32- redox couples.

Full text of DOI:10.1021/jacs.0c11968

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Article
Polysulfide Anions as Visible Light Photoredox Catalysts for Aryl
Cross-Couplings
Haoyu Li, Xinxin Tang,§ Jia Hao Pang,§ Xiangyang Wu, Edwin K. L. Yeow, Jie Wu,
and Shunsuke Chiba*
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ABSTRACT: Polysulfide anions are endowed with unique redox
properties, attracting considerable attentions for their applications in
alkali metals−sulfur batteries. However, the employment of these
anionic species in redox catalysis for small molecule synthesis remains
underdeveloped due to their moderate−poor electrochemical potential
in the ground state, whereas some of them are characterized by
photoabsorptions in visible spectral regions. Herein, we disclose the
use of polysulfide anions as visible light photoredox catalysts for aryl
cross-coupling reactions. The reaction design enables single-electron
reduction of aryl halides upon the photoexcitation of tetrasulfide
dianions (S42−). The resulting aryl radicals are engaged in (hetero)-
2−
2−
biaryl cross-coupling, borylation, and hydrogenation in a redox catalytic regime involving S4• −/S4 and S3• −/S3 redox couples.
versus saturated calomel electrode (SCE) in dimethylforma-
mide (DMF)5 (Scheme 1 A). However, the employment of
these homoatomic sulfide anions in redox catalysis that
engages organic electrophores in the radical-mediated
reactions remains an unmet challenge. Nonetheless, their
electrochemical potentials dictate that they are incapable of
inducing the single-electron reduction of unactivated organic
electrophores of highly negative reduction potentials such as
aryl halides [Ered <1.9 V (vs SCE)].6 On the contrary, these
species show a characteristic absorbance in the ultraviolet−
visible (UV−vis) spectroscopy and some of them are observed
in the visible spectral regions. For example, a degassed solution
of cheap and readily available potassium polysulfide (K2Sx, US
$0.12 per gram) in dimethyl sulfoxide (DMSO) shows a blue
color and its steady-state UV−vis absorption spectrum
INTRODUCTION
■
Visible light photoredox catalysis has advanced in the state-of-
the-art chemical synthesis, enabling us to harness lower energy
visible light to productively drive various types of useful
molecular transformations.1 Homogeneous photocatalysts such
as ruthenium-/iridium-based polypyridyl complexes or organic
dyes could be excited under irradiation with visible light,
inducing a single-electron transfer (SET) to or from organic
substrates to provide reactive open-shell radical intermediates.
The employment of heterogeneous semiconductors as a redox
active chromophore for the synthesis of complex molecules has
recently offered another contemporary trend in photoredox
catalysis.2 Nonetheless, the further development of new
photocatalysts based on inexpensive and abundant elements
that can perform productive bond formation processes in a
highly efficient fashion is of prominent interest.
• −
indicates the presence of persistent S3 (λmax at 618 nm
2−
with a wide bandwidth ranging from 450 to 800 nm), S4
Sulfur is known to form various catenated homoatomic
(λmax at 436 and 333 nm), and S32− (λmax at 273 nm) (Scheme
2−
polysulfide dianions Sx (typically, x = 2−8) and a persistent
1 B). We posited that on the basis of the redox potentials and
radical anion S3• −, which is known as a blue chromophore in
ultramarine blues.3 In seeking the development of alkali
metals−sulfur batteries, the chemical reactivity and redox
characters of polysulfide anions have been elucidated in detail.4
Polysulfide anions undergo complicated redox, dissociative,
and disproportionation processes in the solution states to
afford an equilibrium mixture of multiple polysulfide anions,
and their steady states depend majorly on the solvents. The in
situ spectroelectrochemical studies on the reduction of
octasulfur (S8) identified the ground state redox couples of
2−
• −
visible photon absorptions of S4 and S3 in their ground
2−
state, oxidizible S4 could potentially serve as a photoexcited
• −
reductant whereas reducible S3
could function as a
photoexcited oxidant.1f Therefore, we anticipated that these
Received: November 15, 2020
2−
S3• −/S3 and S4• −/S42−, and their electrochemical potentials
are estimated at around −1.35 and −0.85 V, respectively,
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A

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Scheme 1. Redox Potential and UV−vis Absorption of
Polysulfide Anions
Scheme 2. Photoredox Biaryl Cross-Coupling Catalyzed by
K2Sx
a
Reaction conditions: 1 (0.5 mmol), 2 (20 equiv), K2Sx (12.5 mol %
per S) with H2O (2 equiv), K2CO3 (1.5 equiv), DMSO (2.5 mL), 440
nm light (Kessil lamp), < 30 °C. Isolated yield of 3 was recorded.
polysulfide anions could be engaged seamlessly in SET-driven
radical-mediated processes in a redox catalytic manifold under
visible light irradiation. Herein, we report the use of polysulfide
a
Table 1. Screening of Precatalysts for Polysulfide Anions
2−
• −
anions S4 and S3 as photoredox catalysts for aryl cross-
coupling reactions. The reaction design leverages the photo-
2−
excitation of S4 to induce the single-electron reduction of
aryl halides, having reduction potentials (Ered) as low as −2.4 V
(vs SCE). The resulting aryl radicals are engaged in
(hetero)biaryl cross-coupling, borylation, and hydrogenation
in a redox catalytic regime where the redox interplay between
yield of 3
b
2−
2−
S4• −/S4 and S3• −/S3 redox couples enables the redox-
entry
precatalysts
time (h)
(%)
c
neutral catalytic turnover.
1
2
3
4
K2Sx (12.5 mol %/S) + H2O (2 equiv)
S8 (10 mol %/S) + NaOt-Bu (10 mol %)
Li2S (10 mol %)
1.5
3
2
92 (86)
85
RESULTS
88
82
■
i-Pr3SiSH (10 mol %)
2
Development of Biaryl Cross-Coupling. At the outset of
a
the project, we explored if the DMSO solution of K2Sx
Reaction conditions: 1 (0.5 mmol), 2 (20 equiv), precatalysts,
containing S3• −, S42−, and S3 could engage aryl halides in
2−
K2CO3 (1.5 equiv), DMSO (2.5 mL), 440 nm light (Kessil lamp), <
b
c
30 °C. 1H NMR yields based on the internal standard. Isolated
radical coupling reactions under visible light irradiation. We
selected to investigate a heterobiaryl coupling of 4′-
bromoacetophenone (1, Ered = −1.89 V vs SCE)6 as an
electrophore with N-methylpyrrole (2) as a radical acceptor.
The current state-of-the-art strategies for such a radical-based
biaryl cross-coupling7 leverage highly reducing photoexcited
radical anions of polyaromatic hydrocarbons as a photoexcited
yield.
440 nm) to the mixture of 1 and 2 in the presence of K2Sx
(12.5 mol % per S atom), potassium carbonate (K2CO3, 1.5
equiv), and water (H2O, 2 equiv) in DMSO enabled an
efficient coupling to afford heterobiaryl 3 in 86% yield within
1.5 h (Scheme 2A). The control experiments indicated that
K2Sx, the irradiation with blue light, and a buffer (K2CO3) are
all essential for the process, and the reaction is hampered
under an air atmosphere (see the Supporting Information (SI),
Table S1). The following synergistic catalytic cycle involving
reductant. In particular, consecutive photoelectron-transfer
8
̈
processes shown by Konig and electrophotocatalytic strategies
detailed by Lambert and Lin9a and Wickens9b have successfully
generated excited radical anions. The leveraging of readily
accessible α-aminoalkyl radicals for hydrogen−atom transfer
agents was recently proven useful to promote aryl cross-
coupling by Leonori,10a while the inherent net-oxidative nature
of the process necessitates the use of a stoichiometric amount
of the oxidant. More recently, the same group revealed that α-
aminoalkyl radicals serve as an initiator and a chain carrier for
the aryl cross-coupling between aryl halides (especially aryl
iodides) and pyrroles.10b Our optimization of the reaction
S42−/S4 and S32−/S3 redox couples is proposed (Scheme
2B). Photoexcitation by 440 nm light endows S42− with highly
reducing potential in its excited state,11 allowing for single-
electron reduction of 1 to form arene radical anion I along with
generation of S4• −. The single-electron reduction of reducible
S4 by concomitant ground-state oxidizable S3 allows for
the regeneration of ground-state S42−. Meanwhile, the resulting
arene radical anion I undergoes mesolysis of the carbon−
• −
• −
• −
2−
conditions revealed that the irradiation with blue light (λmax
=
B
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been utilized as a hydrogen−atom transfer catalyst,15 could
also perform as a promising precatalyst (entry 4).
Scheme 3. Bottom-up Generation of Polysulfide Anions
from Mono-Sulfides Li2S and i-Pr3SiSH
These monosulfides (Li2S and i-Pr3SiSH) neither showed
absorption at the visible region nor facilitated the cross-
coupling reaction under the dark conditions due to an
insufficient oxidation potential of monosulfide ions (Eox of
S2− = −0.76 V vs SCE)16 (see the SI, Figures S13−S15). On
the contrary, a charge-transfer absorption band was observed
from the mixture of 1 and Li2S (Scheme 3A) and the
irradiation with blue light (440 nm) to a mixture of 1 and Li2S
(in 1:1 molar ratio) in DMSO formed acetophenone (4),
biaryl 5, and diaryl sulfide 6, all of which could be derived from
the corresponding aryl radical (Scheme 3B and Figure S4). We
propose that Li2S triggers the cross-coupling process through
the formation of electron−donor−acceptor (EDA) complex V
with 1, which induces single-electron transfer upon the
irradiation with visible light to produce a radical ion pair
(Scheme 3C).17 The resulting radical anion of 1 undergoes
cleavage of the C−Br bond to form the aryl radical, whereas a
simultaneously formed monosulfide anion radical (S• −
undergoes dimerization to form a disulfide dianion (S2
)
)
2−
and its subsequent disproportionation generates the higher
order photoredox active polysulfides,18 which promote the
photocatalytic turnover further. Interestingly, i-Pr3SiSH might
initiate the bottom-up formation of polysulfide anions in a
different manner. We observed that the treatment of i-Pr3SiSH
with K2CO3 in DMSO immediately stains the solution blue,
and the UV−vis absorption spectroscopy unambiguously
2−
indicated the generation of polysulfide anions (S3• −, S4
,
and S32−) (Figure S16). The nuclear magnetic resonance
(NMR) spectroscopy showed the formation of disulfide (i-
Pr3SiS)2 VI in the solution (Figure S5). Therefore, we
postulated that DMSO functions as an oxidant19 to promote
the desilylative oligomerization of i-Pr3SiSH to the higher
order polysulfides via disulfide VI (Scheme 3D). The capability
of disulfide VI as the catalyst was ascertained as it performed
the productive cross-coupling (Table S2).
Substrate Scope on Biaryl Cross-Coupling. We found
that this photoredox protocol with polysulfide anions is
capable of engaging a wide range of aryl halides for the
(hetero)biaryl coupling (Scheme 4A). We first studied the
reactivity of 4′-chlolroacetophenone (7), having a reductively
inert C−Cl bond.20 We observed a diminished efficiency in the
reaction with K2Sx (12.5 mol % per S atom), resulting in an
incomplete conversion of 7 (60%) even after irradiation for 22
h (Table S3). We found that the use of Li2S and i-Pr3SiSH
results in the completion of the process within 4 h to give
coupling product 3 in 80% and 75% yields, respectively. These
outcomes suggested that a bottom-up preparation of the
polysulfide anions from mono sulfides would provide more
productive reactivity especially for reductively recalcitrant aryl
halides. The method allows for the installation of various polar-
π electron-withdrawing groups susceptible to reductive
reaction conditions, such as ketone (7−10), aldehyde (11−
13), nitrile (14), and ester (15). The protocol could
successfully engage five-membered ring heteroaryl halides
based on furan (16), thiophene (17, 18), and thiazole (19).
The chemistry was also extended to functionalize six-
membered ring heteroaryl halides such as pyridine (20, 21),
quinoline (22), and pyrazine (23). We also found that
nonactivated aryl halides having a highly negative reduction
potential (Ered > −2.4 V vs SCE)21 are suitable substrates (24−
27). In these cases, the employment of Li2S or i-Pr3SiSH (10
halogen bond to afford aryl radical II,12 which adds onto 2 to
form the radical intermediate III. Single-electron oxidation of
III by photoexcited S3• − followed by deprotonation liberates 3
13
2−
and ground-state S3
.
We measured the quantum yield for
the formation of 3 under the optimized reaction conditions,
which was determined as Φ = 0.07. This implicates that a
possibility of the radical chain process10b is less likely and
supports the proposed photoredox catalytic cycle.
Evaluation of Precatalysts. We next screened the
precatalysts of the polysulfide anions in the cross-coupling
between 1 and 2 (Table 1). The top-down generation of
polysulfide anions through the reductive fragmentation of
octasulfur (S8)14 in the presence of sodium tert-butoxide
(NaOt-Bu) in DMSO was amenable for the productive cross-
coupling (entry 2). We also found that the bottom-up
generation of polysulfide anions from monosulfide species is
suitable for the catalysis. For example, the use of dilithium
sulfide (Li2S, 10 mol %) as a precatalyst led to a full conversion
of 1 within 2 h to afford 3 in 88% yield (entry 3). Similarly,
neutral triisopropylsilylthiol (i-Pr3SiSH), which has commonly
C
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Scheme 4. Reaction Scope on (Hetero)biaryl Cross-Coupling
a
Reaction conditions: substrates (0.5 mmol), coupling partners (20 equiv), K2Sx (12.5 mol % per S) with H2O (2 equiv), K2CO3 (1.5 equiv),
b
c
DMSO (2.5 mL), 440 nm light (Kessil lamp), < 30 °C. Isolated yields of the products were recorded. Precatalyst: Li2S (10 mol %). Precatalyst: i-
Pr3SiSH (10 mol %). 390 nm light. Ten equiv of 3-methylindole was used. The reaction was run with 5 equiv of 4-methoxyphenol and 5 equiv of
d
e
f
NaOt-Bu.
mol %) as a precatalyst was optimal. However, the reaction of
reductively more inert 4-bromoanisole (28) (Ered = −2.72 V vs
SCE)22 was sluggish. This protocol was found to be capable in
the functionalization of nicergoline (29) and indomethacin
D
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a
Scheme 5. Borylation and Hydrodehalogenation
Scheme 6. Scale-up in Flow
a
O′D′ = outer diameter; I′D′ = inner diameter; TR = residence time;
V = volume of the micro-tubing reactor; BPR = back pressure
regulator.
Electron-rich benzenes (40, 41) were also found to be
compatible as a coupling partner.
Development of Borylation and Hydrodehalogena-
tion. The synthetic utility of this polysulfide anions-based
photoredox catalysis was further extended to the dehalo-
borylation reaction by employing bis(pinacolato)diboron (B2
pin2) as the radical trapping reagents (Scheme 5A and Table
S4).24,25 The optimization for the borylation of 4′-
bromoacetophenone (1) with K2Sx as a precatalyst led to the
identification of tetramethylguanidine (TMG) and acetonitrile
(CH3CN) as the optimal base and solvent, respectively,
delivering pinacol arylboronate 42 in 84% yield within 1.5 h.
This protocol was found to be applicable to the borylation of
various functionalized haloarenes (43−47). We also found that
the protocol is amenable to hydrodebromination of 1 using
diisopropylethylamine (i-Pr2NEt) as a hydrogen donor,
providing acetophenone (4) in 96% yield within 2 h (Scheme
5B and Table S5).22,26,27 The identified reaction conditions
were capable of reductive radical cyclization of 48 to
dihydrobenzofuran 49 and hydrodeiodination of secondary
alkyl iodide 50 (Ered = −2.35 V)10a to 51.
Scale-up in Flow. These batch photoredox processes
catalyzed by the polysulfide anions stimulated us to explore the
scalability of the heterobiaryl cross-coupling and borylation in
flow (Scheme 6). The cross-coupling between 1 and 2 was
efficiently promoted in a homogeneous system using i-Pr3SiSH
as a precatalyst and tetramethylguanidine (TMG) as a base in
an operationally simple microtubing continuous-flow reactor28
(Figure S8). The desired product 3 was delivered at a 1.75 g/
hour production rate (78%) with 30 min as the residence time
(Scheme 6A). The debromo-borylation of 1 could also be
performed in the same flow reactor to afford 42 at a 6.9 g/hour
production rate (83%) with 20 min as the residence time
(Scheme 6B).
a
Reaction conditions: substrates (0.5 mmol), B2 pin2 (2 equiv), K2Sx
(12.5 mol % per S), TMG (1.5 equiv), CH3CN (5 mL), 440 nm light
(Kessil lamp), < 30 °C. Isolated yields of the products were recorded.
b
c
Precatalyst: i-Pr3SiSH (10 mol %). substrates (0.5 mmol), i-Pr2NEt
(2 equiv), i-Pr3SiSH (10 mol %), H2O (20 equiv), CH3CN (5 mL),
440 nm light (Kessil lamp), < 30 °C.
methyl ester (30) without damaging the other functional
groups in these substrates. Finally, we explored if polyhalo-
genated aromatic substrates could be engaged in chemo-
selective cross-coupling processes. We were pleased to observe
that 2-bromo-4-chlorobenzaldehyde (31) was selectively
functionalized on the C−Br bond. Similarly, the coupling
reaction of 4-bromo-2-fluoro-1,1′-biphenyl (32) occurs
selectively at the C−Br bond. A more reactive C−I bond23
could be functionalized selectively in the reactions of methyl 3-
bromo-5-iodobenzoate (33) and 1-bromo-4-iodobenzene
(34). Moreover, 3,5-dibromobenzonitrile (35) was found to
undergo single functionalization at one of the C−Br bonds.
The scope with respect to the trapping (hetero)arenes was
next evaluated (Scheme 4B). The use of N−H pyrrole (36)
and indole (37) was found to be optimal, while the coupling
with thiophene (38) resulted in moderate efficiency. The
protocol enables the Minisci type-coupling with pyrazine (39).
E
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Notes
CONCLUSION
■
The authors declare no competing financial interest.
The key enabling advance in the present method takes
advantage of unique reactivity of the polysulfide anions as
photoredox catalysts, which are capable of engaging a wide
range of aryl halides in productive radical cross-coupling
chemistry. We anticipate that the broad scope with wide
functional group compatibility, operational simplicity, and
scalability in flow would bring useful and practical applications
of this catalysis strategy in various fields.
ACKNOWLEDGMENTS
■
Financial support was provided by Pharma Innovation
Programme Singapore (A*STAR, SERC A19B3a0014). The
authors would like to thank Han Sen Soo (NTU Singapore),
Rei Kinjo (NTU Singapore), Joel M. Hawkins (Pfizer),
́
Thomas Knauber (Pfizer), Franco̧ is Levesque (Merck), Lee
Edwards (GSK), and Jean-Philippe Krieger (Syngenta) for
helpful discussion.
ASSOCIATED CONTENT
■
sı
* Supporting Information
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Shunsuke Chiba − Division of Chemistry and Biological
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Nanyang Technological University, 637371, Singapore;
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Authors
Haoyu Li − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, 637371, Singapore
Xinxin Tang − Department of Chemistry, National University
of Singapore, 117543, Singapore
Jia Hao Pang − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 637371, Singapore
Xiangyang Wu − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 637371, Singapore
Edwin K. L. Yeow − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 637371, Singapore;
orcid.org/0000-0003-0290-4882
Jie Wu − Department of Chemistry, National University of
Singapore, 117543, Singapore; orcid.org/0000-0002-
9865-180X
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11968
Author Contributions
§X.T. and J.H.P. contributed equally.
F
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