Visible-light-promoted cross-coupling reactions of aryldiazonium salts with S-methyl-D3 sulfonothioate or Se-methyl-D3 selenium sulfonate: Synthesis of trideuteromethylated sulfides, sulfoxides, and selenides

Article abstract of DOI:10.1021/acs.orglett.0c03562

A novel visible-light-photocatalytic deuterated thiomethylation/methylselenation of aryldiazonium salts utilizing S/ Se-methyl-d₃ sulfonothioate has been developed. The mild conditions and the various functional groups provide a green protocol for the efficient and rapid introduction of the S-CD₃ or Se-CD₃ group with useful levels of deuterium content (>91% D). Trideuteromethyl sulfoxides have also been successfully chemoselectively observed by simple atmospheric changes under photocatalytic conditions.

Full text of DOI:10.1021/acs.orglett.0c03562

pubs.acs.org/OrgLett
Letter
Visible-Light-Promoted Cross-Coupling Reactions of Aryldiazonium
Salts with S‑Methyl‑d3 Sulfonothioate or Se-Methyl‑d3 Selenium
Sulfonate: Synthesis of Trideuteromethylated Sulfides, Sulfoxides,
and Selenides
Cheng-Mi Huang, Jian Li, Jing-Jing Ai, Xin-Yu Liu, Weidong Rao, and Shun-Yi Wang*
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ABSTRACT: A novel visible-light-photocatalytic deuterated thiomethylation/methylselenation of aryldiazonium salts utilizing S/
Se-methyl-d3 sulfonothioate has been developed. The mild conditions and the various functional groups provide a green protocol for
the efficient and rapid introduction of the S-CD3 or Se-CD3 group with useful levels of deuterium content (>91% D).
Trideuteromethyl sulfoxides have also been successfully chemoselectively observed by simple atmospheric changes under
photocatalytic conditions.
sulprofos,10 an insecticide to worms, thiocolchicine,11
a
euterium is a stable nonradioactive isotope of hydrogen
Dand is well-known to medicinal chemists for its wide proliferative disease drug, thioridazine,12 an antipsychotic
drug, and sulmazole,13 a cardiovascular drug. Therefore, it is
meaningful and attractive to develop trideuteromethylated
analogues of aryl methyl sulfide and methyl sulfoxide.
However, there are limited reports on the synthesis of
trideuteromethylated analogues of aryl methyl sulfide and
methyl sulfoxide compounds.14 We developed a new method
for the preparation of S-methyl-d3 sulfonothioate
(PhSO2SCD3) and Se-methyl-d3 selenium sulfonate
(PhSO2SeCD3) as new deuterated methylthiolation/methyl-
selenation reagents. On the basis of Wang’s work,14c
trimethylsulfoxonium iodide reacted efficiently with less toxic
DMSO-d6 to generate trideuteromethylsulfoxonium iodide,
which further reacted with PhSO2SNa to afford PhSO2SCD3
with a deuteration rate of up to 97% (Figure 1). In addition,
application in drug discovery and development.1 The
important feature of deuterium is that the C−D bond length
is shorter and the vibrational frequency is lower, so it is
stronger than the C−H bond, which can directly affect the
absorption, distribution, metabolism, and excretion of some
drug molecules, thereby improving the efficacy, tolerance, and
safety of those drugs.2,3 Deuterium-labeled compounds are
pivotal diagnostic tools in research determination of the
products and mechanistic investigations of organic reactions.4
Notably, deutetrabenazine was approved by the FDA for the
treatment of dyskinesia associated with Huntington’s disease as
the first deuterated drug in 2017.5 It also means that
deuterated drugs have entered a new era with a promising
future.
The methyl group is one of the most common functional
groups in biologically active compounds, and methyl groups
are usually introduced to improve the biological activity and
physical properties of molecules.6 Among them, aryl methyl
sulfide and methyl sulfoxide are important building blocks in
medicinal chemistry and widely exist in biological molecules,7
agrochemicals,8 and pharmaceuticals.9 Examples include
Received: October 25, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03562
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
PhSO2SeCD3 was also synthesized with a deuteration rate of
up to 91%, as shown in Figure 1.
Table 1. Screening of Reaction Conditions
b
yield (D inc.)
entry
additive
solvent (mL)
3a
4a
1
2
3
4
5
6
7
8
9
−
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMF (1)
48% (97%)
65% (97%)
54% (97%)
57% (97%)
49% (97%)
36% (97%)
37%(97%)
42% (97%)
76% (97%)
52% (97%)
72% (97%)
33% (97%)
0
0
0
0
0
0
0
0
0
0
0
0
0
K3PO4
NaHCO3
KOAc
CsF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Figure 1. Preparation of PhSO2SCD3 and PhSO2SeCD3.
With the deuterated methylation reagents PhSO2SCD3 and
PhSO2SeCD3 in hand, we envisioned that trideuteromethyl
sulfides, sulfoxides, and selenides could be synthesized by the
reaction of readily available aryldiazonium salts with these
reagents via a radical pathway. Herein we report visible-light-
promoted cross-coupling reactions of aryldiazonium salts with
PhSO2SCD3 and PhSO2SeCD3 to afford trideuteromethyl
sulfides, sulfoxides, and selenides (Figure 2).
MeCN (1)
DCM (1)
MeOH (1)
MeOH (1)
MeOH (1)
MeOH (1)
MeOH (1)
MeOH (3)
d
10
11
12
13
e
f
c
51% (97%)
76% (97%)
c
14
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), PC (5 mol %),
and additive (0.2 mmol) in the solvent at 30 °C for 22 h under N2
b
with 40 W purple LED irradiation (λ = 395 nm). Isolated yields.
Deuterium incorporation levels were determined by 1H NMR
c
d
e
spectroscopy. Under air. 40 W white LEDs. 40 W blue LEDs.
f
Figure 2. Visible-light photoredox construction of trideuteromethyl
sulfides, sulfoxides, and selenides.
40 W orange LEDs.
products (3b, 3c, 3o) in excellent yields with 97% D
incorporation while retaining the C−X bond intact, which
can be useful for further modification. Notably, substrates with
condensed aromatic rings, such as indane and fluorene, were
compatible with the optimized reaction conditions as well,
furnishing the corresponding products 3l and 3r with 97% D
incorporation. Heteroaryldiazonium salts could also be
adapted to the reaction under the optimized conditions to
provide the desired products 3s−u, respectively.
On the other hand, through only transforming the
atmosphere to air, a wide range of diazonium salts bearing
electron-withdrawing or electron-donating groups at the para
position were transformed well into the corresponding
sulfoxide products (4a−j) in yields ranging from 27% to
76% (Scheme 2). Moreover, disubstituted and trisubstituted
aryldiazonium salts also reacted smoothly under the standard
conditions to give the desired products 4k, 4l, and 4n in 48,
34, and 52% yield, respectively.
Initially, a model reaction of 4-ethoxyphenyldiazonium
tetrafluoroborate (1a) with S-methyl-d3 sulfonothioate 2a in
DMSO catalyzed by eosin Y under irradiation with 40 W
purple LED light was investigated. To our delight, the desired
deuterated product 3a was isolated in 48% yield (Table 1,
entry 1). Furthermore, a series of additives such as K3PO4,
NaHCO3, KOAc, and CsF were explored (Table 1, entries 2−
5). Among the above examined additives, K3PO4 was the most
efficient one. Next, we screened a range of solvents such as
MeOH, MeCN, DMF, and DCM, and the yield of 3a increased
to 76% when the reaction was carried out in MeOH (Table 1,
entries 6−9). We used white, blue, and orange LEDs, leading
to the corresponding products in 52, 72, and 33% yield,
respectively (Table 1, entries 10−12).
Notably, 1-ethoxy-4-((methyl-d3)sulfinyl)benzene (4a) in-
stead of 3a was obtained in 51% isolated yield when the
reaction was performed under an air atmosphere (Table 1,
entry 13). We further carefully investigated the reaction
concentration. It was found that 3 mL of MeOH was the ideal
quantity for the reaction, and the yield of 4a could be increased
to 76% (Table 1, entry 14).
Furthermore, Se-methyl-d3 sulfonoselenoate (PhSO2SeCD3)
could be successfully coupled with various of diazonium salts.
The (methyl-d3)(phenyl)selanes (5a−c) were successfully
observed in moderate to good yields (Scheme 3).
With the optimized reaction conditions in hand, a variety of
diazonium salts 1 were explored, and the results are
summarized in Scheme 1. Aryldiazonium salt derivatives
bearing electron-donating groups reacted smoothly to afford
the desired products (3a, 3d, 3f, 3g, 3h) in good yields with
97% D incorporation. Aryldiazonium salt derivatives with
functional groups such as cyano (1e), phenyl (1i), ester (1j),
amide (1k), ketone (1m, 1n), nitro (1p), and α,β- unsaturated
lactone (1q) were well-tolerated in this transformation to
afford the desired products with 97% D incorporation.
Moreover, the reactions of halogen (Cl, Br, I)-substituted
aryldiazonium salts proceeded well, affording the desired
To further reveal the practicability of the visible-light-
promoted cross-coupling protocol, late-stage modifications of
drug candidates were further conducted. Sulfonamides are an
important class of drugs15 that have a variety of pharmaco-
logical effects, including antibacterial, antitumor, anticarbonic
anhydrase, and diuretic.16 p-Sulfide sulfonamide also shows
important biological activity.17 We explored the late-stage
deuterothiomethylation of sulfonamide pharmaceuticals. Sulfa-
methazine and sulfamethoxazole were converted to trideuter-
omethyl sulfides or trideuteromethyl sulfoxides (6a, 6b, 7a) in
good yields with 97% D incorporation from the corresponding
diazonium salt substrates (Scheme 4).
B
https://dx.doi.org/10.1021/acs.orglett.0c03562
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a b
,
Scheme 1. Substrate Scope of Trideuteromethyl Sulfides
Scheme 2. Substrate Scope of Trideuteromethylated
a b
,
Sulfoxides
a
Standard conditions: 1 (0.2 mmol), 2a (0.3 mmol), PC (5 mol %),
and K3PO4 (0.2 mmol) in MeOH at 30 °C for 22 h under air with 40
b
W purple LED irradiation (λ = 395 nm). Isolated yields are shown.
Deuterium incorporation levels were determined by 1H NMR
spectroscopy.
Scheme 3. Substrate Scope of Trideuteromethyl
Selenides
a
Standard conditions: 1 (0.2 mmol), 2a (0.3 mmol), PC (5 mol %),
and K3PO4 (0.2 mmol) in MeOH at 30 °C for 22 h under N2 with 40
a b
,
b
W purple LED irradiation (λ = 395 nm). Isolated yields are shown.
Deuterium incorporation levels were determined by 1H NMR
c
spectroscopy. 1 mL of DMSO was used.
To further reveal the practicability of this protocol, a gram-
scale reaction of 1h (4 mmol) with 2a (6 mmol) in the
presence of 2 mol % eosin Y and K3PO4 was investigated
(Scheme 5a). The desired product 3h was obtained in 74%
yield with 97% D incorporation. To investigate the possible
mechanism of the reaction, several control experiments were
conducted (Scheme 5b,c). When 2,2,6,6-tetramethylpiperidin-
1-oxyl (TEMPO) or butylated hydroxytoluene (BHT) was
added to the reaction system under the standard reaction
conditions, the reaction was completely suppressed. Further-
more, the LC−ESI-MS analysis of the reaction mixture
indicated the formation of the TEMPO−PhOEt adduct,
which confirmed that a radical pathway might be involved.
a
Standard conditions: 1 (0.2 mmol), 2b (0.3 mmol), PC (5 mol %),
and K3PO4 (0.2 mmol) in MeOH at 30 °C for 22 h under N2 with 40
b
W purple LED irradiation (λ = 395 nm). Isolated yields are shown.
Deuterium incorporation levels were determined by 1H NMR
spectroscopy.
On the basis of the above results and literature reports,18
a
radical cation of the photocatalyst to furnish a sulfonyl cation
and regenerate the photocatalyst (EY). On the other hand, the
energy transfer between 3O2 and EY* generates 1O2, which can
oxidize the trideuteromethyl sulfide to the corresponding
trideuteromethyl sulfoxide 4.
In summary, we prepared two novel and bench-stable
deuterated reagents: PhSO2SCD3 and PhSO2SeCD3. These
two deuterated methylthiolation/methylselenation reagents
plausible reaction mechanism is proposed in Scheme 6. EY* is
generated from EY under visible-light irradiation and
subsequently assists with the reaction of aromatic diazonium
salt 1 through a single electron transfer (SET) process to
generate aryl radical 8. Subsequently, aryl radical 8 reacts with
PhSO2SCD3 to afford trideuteromethyl sulfide 3 and sulfone
radical 9. Then sulfone radical 9 undergoes SET with the
C
https://dx.doi.org/10.1021/acs.orglett.0c03562
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a b
,
Scheme 4. Late-Stage Modification of Pharmaceuticals
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03562.
Detailed experimental procedures (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Shun-Yi Wang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China; orcid.org/0000-0002-8985-8753;
Email: shunyi@suda.edu.cn
a
Standard conditions: 1 (0.2 mmol), 2a (0.3 mmol), PC (5 mol %),
and K3PO4 (0.2 mmol) in MeOH at 30 °C for 22 h under air or N2
b
with 40 W purple LED irradiation (λ = 395 nm). Isolated yields are
shown. Deuterium incorporation levels were determined by 1H NMR
spectroscopy.
Authors
Scheme 5. Gram-Scale Reactions and Control Experiments
Cheng-Mi Huang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Jian Li − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Jing-Jing Ai − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Scheme 6. Proposed Mechanism
Xin-Yu Liu − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, and Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, China
Weidong Rao − Nanjing Forest University, Nanjing 210037,
China; orcid.org/0000-0002-6088-7278
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03562
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21971174 and 217721375), PAPD,
the Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions
(16KJA150002), the Project of Scientific and Technologic
Infrastructute of Suzhou (SZS201708), Soochow University,
and the State and Local Joint Engineering Laboratory for
Novel Functional Polymeric Materials for financial support.
were successfully applied to reactions with diazonium salts
under visible-light catalysis for the construction of trideuter-
omethyl sulfides, sulfoxides, and selenides. The reactions were
carried out under mild conditions, and various functional
groups were compatible. The application of this method in late
modification of bioactive molecules further proves the
superiority of this method. Thus, this strategy provides an
alternative and attractive method for the synthesis of
trideuteromethyl sulfides, sulfoxides, and selenides.
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