Organophotoredox-Catalyzed Formation of Alkyl-Aryl and -Alkyl C-S/Se Bonds from Coupling of Redox-Active Esters with Thio/Selenosulfonates

Article abstract of DOI:10.1021/acs.orglett.0c03624

A mild organophotoredox synthetic protocol for forming a Csp3-S/Se bond by reacting widespread redox-active esters with thio/selenosulfonates has been developed. The power of the synthetic manifold is fueled by an unprecedented broad substrate scope and wide functional group tolerance.

Full text of DOI:10.1021/acs.orglett.0c03624

pubs.acs.org/OrgLett
Letter
Organophotoredox-Catalyzed Formation of Alkyl−Aryl and −Alkyl
C−S/Se Bonds from Coupling of Redox-Active Esters with Thio/
Selenosulfonates
Yue Dong, Peng Ji, Yueteng Zhang, Changqing Wang, Xiang Meng, and Wei Wang*
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ABSTRACT: A mild organophotoredox synthetic protocol for forming a Csp −S/Se bond by reacting widespread redox-active
esters with thio/selenosulfonates has been developed. The power of the synthetic manifold is fueled by an unprecedented broad
substrate scope and wide functional group tolerance.
espite the fact that the C−O ether bond is dominant in
organic and biologically active molecules, the C−S
been made in the preparation of alkyl−aryl sulfides with
photochemical approaches (Scheme 1c). The Ru/Ni dual-
catalytic thioarylation of native peptides and other biomole-
cules with visible light has been nicely realized by Molander
and coworkers.10 In addition to the use of aryl halides,
abundant carboxylic acids and their derivatives11 have been
demonstrated as versatile radical coupling partners in the
thioetherification. These processes have been efficiently
achieved by Fu, Zheng, and Xu (Scheme 1c). Fu and
colleagues developed an impressive photocatalyst free visible-
light photoredox decarboxylative coupling of redox-active ester
(RAE) N-(acetoxy)phthalimides (NHPIs) with aryl thiols.12 A
similar approach using disulfides and a Ru complex as a
photocatalyst (PC) was attained by Zheng.13 Xu et al. reported
an efficient nickel/photoredox cooperative decarboxylative
thioetherification of amino acids with arylthiosuccinimide.14
These methods have offered new efficient approaches for the
synthesis of sulfides. However, they are limited to the synthesis
of aryl−aryl or −alkyl thioethers. Strategies capable of
accessing alkyl−alkyl sulfides remain elusive. Recently, Ji
D
thioether linkage is also an important functionality and is
broadly distributed in numerous biologically active synthetic
substances, natural products, and functional materials.1 It is of
particular note that more than 30 drugs, such as lincomycin,
cimetidine, and retapamulin, contain the thioether function-
ality (Scheme 1a).2 Therefore, the thioether has constituted a
long-standing interest in organic synthesis.
The classic substitution reaction between alkyl halides and
mercaptans offers a stalwart approach to thioether synthesis;
however, harsh alkaline reaction conditions limit the functional
group tolerance and in many cases give low reaction yields.
Transition-metal-catalyzed C−S bond-forming reactions have
been the mainstay of the contemporary thioether synthesis.3
The field has advanced from precious4 to base metal catalysis.5
Furthermore, transition-metal (TM)-promoted C−S bond
processes have been transformed from a 2e− into single-
electron transfer (SET) strategy.6 In this context, radical-
engaged diarylsulfide synthesis was achieved (Scheme 1b). Fu
and Peters pioneered the field by uncovering a copper-
catalyzed coupling of aryl thiols with aryl halides with a Hg
lamp (Scheme 1b).7 The mild visible-light photoredox Ir- and
Ir/Ni-catalyzed formation of C−S bond from thiols with aryl/
heteroaryl iodides was independently developed by Oderinde
and Johannes and Fu.8 A rose-bengal-promoted diaryl sulfide
formation with arylhydrazines was unveiled by Hajra et al.9 In
addition to diarylsulfide synthesis, significant advances have
Received: October 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03624
© XXXX American Chemical Society
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A

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a
Scheme 1. Thioether-Containing Drugs and Radical-
Engaged Thiother Synthesis
Table 1. Exploration and Optimization
b
entry
derivation from standard conditions
yield (%)
1
2
3
4
5
6
7
8
none
85
81
82
65
19
0
Ir[dF(CF3)ppy]2(dtbpy)PF6 as PC
(Ru(bpy)3(BF4)2 as PC
eosin Y as PC
DCM as solvent
DMF as solvent
DMSO as solvent
2a1 as reagent
2a2 as reagent
2a3 as reagent
2a4 as reagent
2a5 as reagent
no DIPEA
0
5
5
c
c
9
10
11
12
13
14
15
30
60
45
0
0
0
no light
no PC
a
Reaction conditions: Unless otherwise specified, a mixture of 1a
(0.15 mmol), 2a (0.1 mmol), 4CzIPN (0.002 mmol), and DIPEA
(0.15 mmol) in MeCN was irradiated by 40 W Kessil blue LEDs in a
b
c
1
N2 atmosphere at rt for 12 h. Isolated yield. Yield based on H
NMR.
Scheme 2. Proposed Mechanism
cross-coupling of 4-alkyl-1,4-dihydropyridines with thio-/
selenium sulfonates (Scheme 1e).17 Whereas the technique
provides a viable approach for the synthesis of alkyl−aryl or
−alkyl thioethers,18 it employs 4-alkyl-1,4-dihydropyridines as
radical precursors and with that carries an inherent substrate
scope limitation.
Herein we report an alternative mild organophotoredox
thiolation reaction using NHPI-derived RAEs as radical
precursors with thio/seleno sulfonates (Scheme 1e). The
easy accessibility and high radical-producing liability of the
RAEs19 enable the generation of structurally diverse radicals
for efficient coupling to electrophilic thio/seleno-sulfonates. As
demonstrated, 1, 2, and 3° radicals can effectively participate in
the process. Furthermore, biologically relevant molecules such
as amino acids, peptides, saccharides, and steroids are versatile
substrates for the reaction. Therefore, a broad substrate scope
and a variable functional group tolerance of the mild process is
achieved.
The exploration of developing the organophotoredox visible-
light-mediated thiolation of RAEs19 with thiosulfonates20 was
inspired by our recent studies of thiosulfonates as radical
acceptors in the synthesis of thioesters21 and RAEs as versatile
radical progenitors in C-glucosylation.22 We hypothesized that
coupling of the radicals R• 4 produced from the corresponding
reported a Ni(II)-catalyzed thiolation of alkyl bromides with
thiosulfonates using Mn(0) as a reducing reagent by affording
both alkyl−aryl and −alkyl thioethers (Scheme 1d).15
A
strategy using the Mn(0)-mediated reductive decarboxylation
and deamination of respective RAEs and Katritzky’s N-
alkylpyridinium salts with disulfides was revealed by Wang
and colleagues.16 It is noted that a stoichiometric amount
(1.5−5 equiv) of Mn(0) is used for the reductive generation of
radicals in both studies. During our investigation, Ji and
coworkers have reported a more efficient organophotocatalytic
B
https://dx.doi.org/10.1021/acs.orglett.0c03624
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a
a
Scheme 3. Scope of Carboxylic-Acid-Derived RAEs
Scheme 4. Scope of Thiosulfonates
a
Reaction conditions: Unless otherwise specified, see Table 1 and the
experimental section in the Supporting Information (SI). Yields are
calculated based on isolated products.
a
Reaction conditions: Unless otherwise specified, see Table 1 and the
experimental section in the SI. Yields are calculated based on isolated
products.
RAEs 1 with thiosulfonates 2 could deliver a new method for
the synthesis of thioethers (Scheme 2).
acids (3e, 3f) could participate in the process with good yields
(60−86%). Moreover, this study was further expanded to
primary (3j−m) and tertiary carboxylate RAEs (3m−s) as
alkyl radical precursors. It is noted that there is limited success
in the method with 4-alkyl-1,4-dihydropyridines as radical
progenitors.17 As shown, the protocol worked smoothly for the
cases of 3j−m with different lengths of primary chain.
Furthermore, the radical-engaged process offers an unrivaled
power for accessing sterically hindered tertiary thioethers 3n−
s, whose synthesis has been an unmet challenge.
Next, we probed the structural alternation of thiosulfonate S-
esters under the optimized reaction conditions (Scheme 4).
Again, this strategy serves as a general approach for the
synthesis of structurally diverse thioethers. Notably, satisfying
results for the synthesis of aliphatic thioethers (3t−ah), whose
access was previously limited, are obtained. In particular, the
successful modification of cysteine and dipeptide (3af, 3ag,
3ah) offers a useful chemical tool for biochemistry study. It is
noteworthy that under the mild reaction conditions, this
radical-based method exhibits broad functional group toler-
ance, as demonstrated for protected amines (3s), free hydroxyl
(3u), alkene (3x), alkyne (3y), ester (3g−i, 3k−m, 3p−s, and
3aa), ether (3v, 3w, 3ae), and cyano (3z). Aromatic iodide is
not affected by the reaction conditions (3ad), whereas it is
The validation of the feasibility of this proposal commenced
with a model reaction of THF-derived, NHPI-derived RAE 1a
with S-benzyl 4-methylbenzenesulfonothioate (2a) (Table 1
and Table S1). To our delight, the irradiation of a solution of
1a (0.15 mmol), 2a (0.1 mmol), and DIPEA (0.15 mmol) in
the presence of the PC 4CzIPN (0.002 mmol) in MeCN using
40 W Kessil blue LEDs led to the formation of the desired
thioether 3a in 83% yield (entry 1). Among the PCs probed,
Ir[dF(CF3)ppy]2(dtbpy)PF6 and (Ru(bpy)3(BF4)2 are also
effective promoters by delivering similar reaction efficiencies
(entries 2 and 3). Inferior results were observed with eosin Y,
presumably because it is a weaker reductant compared with
4CzIPN (entry 4).6j A survey of reaction media (DCM, DMF,
and DMSO, entries 5−7) and S precursors 2a−a5 (entries 1
and 8−12) revealed that they had pronounced effects on the
process. The control experiments confirmed that the base,
light, and PC were prerequisites for this transformation
(entries 13−15).
With the optimized reaction conditions in hand, we explored
the strategy for the synthesis of structurally diverse thioethers
(Scheme 3). We first probed the structural variation of RAEs 1.
We found that other secondary alkyl carboxylic-acid-derived
RAEs such as cyclic (3a,b, 3g−i), acyclic (3c, 3d), and amino
C
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Scheme 5. Thiolation of Bioactive Structures and Gram-
Scale Reaction
ASSOCIATED CONTENT
* Supporting Information
■
a
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03624.
Experiment details and spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wei Wang − Departments of Pharmacology and Toxicology
and Chemistry and Biochemistry and BIO5 Institute,
University of Arizona, Tucson, Arizona 85721, United
States; orcid.org/0000-0001-6043-0860;
Email: wwang@pharmacy.arizona.edu
Authors
Yue Dong − Departments of Pharmacology and Toxicology
and Chemistry and Biochemistry and BIO5 Institute,
University of Arizona, Tucson, Arizona 85721, United States
Peng Ji − Departments of Pharmacology and Toxicology and
Chemistry and Biochemistry and BIO5 Institute, University
of Arizona, Tucson, Arizona 85721, United States
Yueteng Zhang − Departments of Pharmacology and
Toxicology and Chemistry and Biochemistry and BIO5
Institute, University of Arizona, Tucson, Arizona 85721,
United States
a
Reaction conditions: See Table 1 and the experimental section in the
SI. Yields are calculated based on isolated products.
Changqing Wang − Departments of Pharmacology and
Toxicology and Chemistry and Biochemistry and BIO5
Institute, University of Arizona, Tucson, Arizona 85721,
United States
Xiang Meng − Departments of Pharmacology and Toxicology
and Chemistry and Biochemistry and BIO5 Institute,
University of Arizona, Tucson, Arizona 85721, United States
generally not compatible with transition-metal catalysis.
Furthermore, the protocol also works smoothly in the
formation of alky−aryl thioethers (3ai−al) and selenides
(3am−ao).
The success in the application of this mild synthetic protocol
for a wide array of NHPI esters and thiosulfonate S-esters
encouraged us to explore the synthetic methodology for more
challenging targets of complex biologically active molecules
including clinically used therapeutics (Scheme 5). Marketed
drug captopril-derived thiosulfonate S-esters can be efficiently
modified to give the desired product in a good yield of 71%
(3ap).23 In addition to peptides, saccharide-derived thioethers
3aq and 3ar are efficiently assembled. It is of particular note
that methylsulfide is a common functionality in many
pharmaceuticals (Scheme 1a).2 Estrone, chlorambucil, and
biotin-derived RAE esters were selectively thioesterificated to
give the products 3as, 3at, and 3au in 55, 75, and 62%,
respectively. These examples demonstrate the potential of this
approach for the selective decorating of complex molecules
under benign reaction conditions. A gram-scale reaction was
conducted using NHPI ester 2a under the same reaction
conditions, as used in the small-scale process to give 3g in a
similar yield.
In conclusion, we have developed a new, efficient method
for the construction of a C−S/Se bond via the visible-light
organophotoredox catalysis of redox-active esters with thio-/
seleno sulfonates. The mild process serves as a viable strategy
for the synthesis of both alkyl−alkyl and alkyl−aryl sulfides
with outstanding functional group tolerance. Furthermore, an
unrivaled feature of the process is to employ the feedstock
carboxylic-acid-derived RAEs as radical progenitors, and an
unprecedented broad substrate scope is achieved. These merits
make this protocol a promising strategy for the construction of
C−S bonds in widespread applications within organic
synthesis.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03624
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH (5R01GM125920-
04 and 3R01GM125920-03S1) and the NSF MRI for the
acquisition of the 500 MHz NMR spectrometer (1920234).
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