Visible-Light-Driven Silver-Catalyzed One-Pot Approach: A Selective Synthesis of Diaryl Sulfoxides and Diaryl Sulfones

Article abstract of DOI:10.1021/acs.orglett.7b03901

An efficient one-pot approach for the synthesis of diaryl sulfoxides and diaryl sulfones using aryl thiols and aryl diazonium salts was developed. The use of a visible-light-driven silver catalysis and the subsequent singlet-oxygen-induced oxidation enabled selective synthesis of sulfoxides and sulfones in the absence of a photocatalyst. The reactions were carried out under mild reaction conditions; the desired products were obtained under air atmosphere at room temperature.

Full text of DOI:10.1021/acs.orglett.7b03901

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Driven Silver-Catalyzed One-Pot Approach: A Selective
Synthesis of Diaryl Sulfoxides and Diaryl Sulfones
Dong Hyuk Kim,† Juyoung Lee,† and Anna Lee*,†,‡
‡
†Department of Chemistry and Department of Energy Science and Technology, Myongji University, Yongin 17058, Republic of
Korea
S
* Supporting Information
ABSTRACT: An efficient one-pot approach for the synthesis
of diaryl sulfoxides and diaryl sulfones using aryl thiols and aryl
diazonium salts was developed. The use of a visible-light-
driven silver catalysis and the subsequent singlet-oxygen-
induced oxidation enabled selective synthesis of sulfoxides and
sulfones in the absence of a photocatalyst. The reactions were
carried out under mild reaction conditions; the desired
products were obtained under air atmosphere at room temperature.
ryl sulfoxides and aryl sulfones are useful building blocks1 of
Scheme 1. Synthetic Approaches to Sulfoxides and Sulfones
2
Anumerous organic compounds and drug candidates and
have exhibited many significant biological activities.2,3 They can
act as prostaglandin D2 antagonists, proton pump inhibitors,
antidepressants, as well as anti-inflammatory and antibacterial
agents (Figure 1).3c,d,4 What is more, diaryl sulfoxides and diaryl
sulfones have shown promising antitumor and antifungal
properties as well as HIV-1 reverse transcriptase inhibitor
activity.3a,b,4a,5
Figure 1. Bioactive molecules containing an aryl/diaryl sulfoxide/
sulfone moiety.
use of organometallic reagents, in combination with iodonium
salts,4a or palladium catalysts (Scheme 1, I, b).12 Thiol−ene type
Given the significance of these moieties, their synthesis has
drawn a great deal of attention from the synthetic community.
The most conventional method for the synthesis of sulfoxides
reactions have also been reported for the direct synthesis of β-
hydroxy, β-oxy, β-peroxy, β-keto sulfides, sulfoxides, and sulfones
using olefins and thiols (Scheme 1, I, b).13 In spite of the
availability of various approaches to the synthesis of these
important bioactive moieties, there are many limitations that
could pose a problem. The use of stoichiometric amounts of
oxidants and toxic/sensitive catalysts or reagents in the reactions,
as well as the limited functional group tolerance and operational
control difficulties of these methods imply the ongoing demand
and sulfones is through the oxidation of sulfides.1,4a,6 This could
be accomplished by either using stoichiometric amounts of
peracid or inorganic oxidants (Scheme 1, I, a)7 or, as very recent
studies show, through a photocatalytic oxidation process.8,9
Many other synthetic approaches to the formation of these
moieties have been developed. These include the sulfonylation of
arenes using strong acids,1,4a,6 nucleophilic substitution of
electrophilic sulfoxide derivatives,10 and transition-metal-cata-
lyzed arylation of sulfenate anions.11 Moreover, one-pot methods
for the synthesis of aryl sulfones have been established, with the
Received: December 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03901
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
for a novel and efficient approach. Herein, we report a new one-
pot method for the selective synthesis of diaryl sulfoxides and
diaryl sulfones via visible-light-induced silver catalysis under air
(Scheme 1, II).
sulfone 4a decreased over time. When pyridine was added,
however, a mixture of sulfoxide 3a and sulfone 4a (3a: 19%, 4a:
51%) was obtained (entry 8). Control reactions were performed
in the absence of light, the silver catalyst, or the oxidant
(K2S2O8), which did not give any of the desired products (entries
9, 13, and 14). Changing the light source, in contrast, diminished
the reaction yields, giving sulfoxide 3a in moderate yields (entries
10−12). The atmosphere under which the reaction takes place
seemed to play an important role. While the synthesis under Ar
atmosphere gave only trace amounts of the desired product
(entry 15), under O2 atmosphere, sulfoxide 3a was obtained in
77% yield (entry 16). Following these results, we concluded that
any further studies on this reaction should be conducted with the
silver catalyst, oxidant (K2S2O8), under visible light, and air (O2).
With the optimized reaction conditions in hand, the scope of
the synthesis of the diaryl sulfoxides and diaryl sulfones was
explored. The synthesis of the diaryl sulfoxides proved to be
tolerant to various aryl thiol starting materials (Scheme 2). The
The initial studies of the one-pot reaction conditions began
with a reaction of thiols and diazonium salts, catalyzed by both
silver and photoredox catalysts. The silver catalyst was expected
to generate a thiyl radical from the thiol14 and the photoredox
catalyst was anticipated to form aryl radicals from the aryl
diazonium salts.9 The desired sulfoxides could then be formed
through oxidation. To test this hypothesis, thiophenol (1a) and
4-methoxybenzenediazonium tetrafluoroborate (2a) were re-
acted in the presence of eosin Y (5 mol %) and AgNO3 (20 mol
%) at room temperature under green LED light irradiation (530
nm) in air, which yielded sulfoxide 3a in 48% yield. However,
control experiments without eosin Y generated the desired
product with the same yield (48%) (Table 1, entry 1). One
a
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Substrate Scope: Diaryl Sulfoxides
b
b
entry
1
AgNO3 (mol %)
solvent
3a yield (%)
4a yield (%)
20
20
10
30
20
20
20
20
20
20
20
20
0
DMSO
DMSO
DMSO
DMSO
CH3CN
DCM
48
82
60
72
0
0
0
c
2
c
3
0
c
4
0
5
6
7
0
0
0
DMF
0
78
51
0
c
8
DMF
19
0
c,d
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
c
c
c
c
c
c
c
,
,
,
e
f
10
11
12
13
14
15
16
55
47
37
0
0
0
g
0
0
,
,
,
h
i
20
20
20
0
0
trace
77
0
j
0
a
Conditions: 1a (0.5 mmol, 1.0 equiv), 2a (1.2 equiv), catalyst,
K2S2O8 (3.0 equiv), solvent (0.25 M) under air at 23 °C for 15 h.
b
c
Isolated yield after column chromatography. Pyridine (3.0 equiv)
d
e
f
was added. In the dark. Under blue LED light irradiation. Under
white LED light irradiation. Under sunlight irradiation. In the
absence of K2S2O8. Under Ar atmosphere. Under O2 atmosphere.
a
g
h
Reactions conducted on a 0.5 mmol scale. Yields are of the isolated
i
j
product after column chromatography. For details, see the Supporting
Information.
possible explanation of these results could be the generation of an
aryl radical from the diazonium ions15 under UV or visible-light
irradiation in the absence of photocatalyst.16 Following these
results, we investigated various reaction conditions, of which
selected examples are summarized in Table 1.
As can be observed from the optimization studies, a significant
improvement in the yield was observed when pyridine was added
to the reaction, giving the desired product 3a in 82% yield (Table
1, entry 2). Varying the amount of AgNO3, in contrast, did not
improve the reaction yields (entries 3 and 4). Solvent screening
showed that the reaction does not take place in either acetonitrile
or dichloromethane (entries 5 and 6), while DMF allows the
formation of sulfone 4a in 78% after 15 h (entry 7). Careful TLC
monitoring over the time of this reaction (entry 7) was
performed, which showed that the ratio of sulfoxide 3a to
desired sulfoxides were obtained in moderate to high yields (52−
84%) in the presence of both electron-withdrawing (3g−j, 3n)
and electron-donating (3d−f, 3k and 3m) substituents. The
products derived from the ortho-substituted aryl thiols (3d and
3i) were obtained with lower reaction yields, compared to those
obtained with meta- and para-substituted ones. However, a
noticeable electronic effect of these substituents was not
observed. Heteroaromatic thiols also proved to be suitable
substrates under these reaction conditions, giving sulfoxide 3o in
good yield (71%). Additionally, the scope of aryl diazonium salts
2 in the reaction was investigated. Substituents at all positions
(ortho-, meta- and para-) were tolerated, affording the desired
products (3a−c) in moderate to high yields (52−82%).
Moreover, the use of naphthyl diazonium salts gave the desired
products in good yields (3m: 76%, 3n: 74%).
B
DOI: 10.1021/acs.orglett.7b03901
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Organic Letters
Letter
Next, the substrate scope of the synthesis of diaryl sulfones was
explored (Scheme 3). Both the aryl thiols and diazonium salts
Considering the optimization studies performed earlier (Table 1,
entry 16), it is possible that a singlet oxygen (1O2) is involved in
the oxidation process. To test this hypothesis, NaN3, a well-
1
b
known strong O2 quencher, was added to the reaction. As
Scheme 3. Substrate Scope: Diaryl Sulfones
expected, the desired product was not obtained (Scheme 4, II),
which suggests that the reaction mechanism includes a radical
1
pathway and a O2-mediated oxidation process. Furthermore,
diaryl sulfide C, a possible intermediate for further oxidation
reactions, was detected by GC−MS during the reaction. To
investigate this matter further, the synthesized (4-
methoxyphenyl)(phenyl)sulfane (C), was subjected to the
standard reaction conditions. As a result, the desired sulfoxide
3a and sulfone 4a were obtained in DMSO and DMF,
respectively. In contrast, when NaN3 was added to the mixture,
no reaction was observed (Scheme 4, III). In addition, potassium
persulfate (K2S2O8) does not promote the oxidation process.
(Scheme 4, IV). These results indicate that after the formation of
diaryl sulfide C as an intermediate, a singlet-oxygen-induced
oxidation process takes place to give the desired products. The
selective formation of sulfoxides in DMSO and sulfones in DMF
could be due to the dependence of the rate of singlet oxygen
deactivation on the chemical environment such as solvents or
additional radical sources.17 Amines such as pyridine are well-
known single electron donors or acceptors in many radical-
mediated reactions.9 The sulfoxide group of DMSO could also be
18
1
involved in the O2 quenching process. These effects could
affect the oxidative environment and cause the selective oxidation
process.
A proposed reaction pathway based on the present results and
previous reports13b,c,19 is shown in Scheme 5. Initially, thiol 1 and
b
Reactions conducted on a 0.5 mmol scale. Yields are of the isolated
Scheme 5. Proposed Reaction Pathway
product after column chromatography. For details, see the Supporting
Information.
were varied, giving the desired sulfones in moderate to high
yields (61−85%). Similar to the results of the diarylsulfoxides
(3b, 3d, and 3i in Scheme 2), the products derived from the
ortho-substituted aryl thiols or diazonium salts (4b and 4g) were
obtained in decreased yields, which could be due to the steric
effect at the ortho-position.
To gain a mechanistic insight into this one-pot synthesis,
several control experiments were carried out (Scheme 4). First,
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was employed
as a radical inhibitor, which did not afford the desired product
(Scheme 4, I). Next, the oxidation source was investigated.
diazonium salt 2 are excited through visible light irradiation.
Then, thiyl radical A, generated by the silver catalyst from thiol 1
reacts with aryl radical B, generated from diazonium salt 2, to
afford sulfide C as an intermediate. Subsequent oxidation by
1O219a−c would provide the desired sulfoxide 3 or sulfone 4.
To demonstrate the utility of this one-pot synthetic method,
bioactive compounds containing a diaryl sulfoxide/sulfone
moiety were synthesized (Figure 2).20 The desired sulfones 5
and 7 and sulfoxide 6 were obtained in good to high yields under
the reaction conditions (see the Supporting Information for
details).
Scheme 4. Control Experiments
Figure 2. Synthesis of bioactive compounds via the one-pot approach.
C
DOI: 10.1021/acs.orglett.7b03901
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03901.
Experimental details, characterization data for the
products, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: annalee@mju.ac.kr.
ORCID
Anna Lee: 0000-0002-3450-7024
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education
(2016R1D1A1B03931335) and the Korea Institute of Energy
Technology Evaluation and Planning (KETEP) and the Ministry
of Trade, Industry & Energy (MOTIE) of the Republic of Korea
(No. 20174010201160).
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