A Convenient Synthesis of Sulfones via Light Promoted Coupling of Sodium Sulfinates and Aryl Halides

Article abstract of DOI:10.1002/adsc.201801390

A convenient and e?cient synthesis of sulfones from sulfinates and aryl halides was developed. The reaction occurred under UV irradiation without transition metal catalyst or photocatalyst. A radical pathway via single-electron transfer (SET) of electron donor-acceptor (EDA) complex was proposed based on UV-vis spectroscopy, radical inhibiting and trapping experiments. (Figure presented.).

Full text of DOI:10.1002/adsc.201801390

Title: A convenient synthesis of sulfones via light promoted couplings
of sodium sulfinates and aryl halides
Authors: Lei Chen, Jie Liang, zhenyu chen, Jie Chen, Ming Yan, and
Xue-jing Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801390
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10.1002/adsc.201801390
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A convenient synthesis of sulfones via light promoted coupling
of sodium sulfinates and aryl halides
Lei Chen, Jie Liang, Zhen-yu Chen, Jie Chen, Ming Yan*, Xue-jing Zhang*
The Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences,
Sun Yat-sen University, Guangzhou 510006, China
E-mail: zhangxj33@mail.sysu.edu.cn; yanming@mail.sysu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Recently, Melchiorre group found that electron-rich
enamines could become strong reductants upon light
excitation and trigger the formation of radicals through the
SET reduction of electron-deficient organic halides.[20] It
was believed that an electron donor-acceptor (EDA)
complex is formed to promote the electron transfer.[21-22]
Using the similar strategy, Miyake group reported a mild,
efficient, visible-light promoted protocol for the C-S cross-
coupling of thiols and aryl halides.[23] Wang group
developed a new synthetic method of vinyl sulfones via
light-promoted formation of EDA complex from
arylsulfinic acid and biaryl isocyanide. In the latter two
reactions, the anions were proposed as the electron
donors.[24] As an effort to the green and sustainable
construction of sulfone motif, we wondered whether the
readily-available sodium arylsulfinates can be used as
electron donators in an EDA reaction. Herein, we report a
new strategy for the synthesis of sulfones via the formation
of EDA complexes from sodium sulfinates and aryl halides.
Abstract: A convenient and efficient synthesis of
sulfones from sulfinates and aryl halides was
developed. The reaction occurred under UV
irradiation without transition metal catalyst or
photocatalyst. A radical pathway via single-electron
transfer (SET) of electron donor−acceptor (EDA)
complex was proposed based on UV-vis
spectroscopy, radical inhibiting and trapping
experiments.
Keywords: Sulfone; Sulfinate; Aryl halides; EDA
complex; single-electron transfer (SET)
Due to their unique chemical, biological and
pharmaceutical activities, sulfone groups are prevalently
present in many bioactive compounds[1], such as antibiotics
thiamphenicol[1a]
and
dapsone[1b]
,
antipsychotics
amisulprode[1c] (Figure 1), agrochemicals[2] and functional
materials.[3] These compounds also have great synthetic
potentials in Julia olefination,[4] Ramberg-Backlund
reaction[5] and Smiles rearrangement[6] for the preparation
of
organic
building
blocks,
biologically
and
pharmaceutically active molecules.
Considering their versatile applications, efficient and
sustainable methodologies for sulfone synthesis are highly
demanded. Classical methods for the preparation of
sulfones[7] include the oxidation of sulfides, [8] electrophilic
aromatic sulfonylation with sulfonyl chlorides,[9] transition
metal catalyzed cross coupling of arylsulfinates and aryl
Figure 1. Representative sulfones with biological activities
Initially, a model reaction of sodium toluenesulfinate (1a)
and 4-iodobenzonitril (2a) was investigated. The reaction
did not occur without light irradiation (Table 1, entry 1).
Under the irradiation of 365 nm light, the reaction gave the
sulfone 3a in 40% yield (entry 2). In addition, blue LED
and white LED were proved to be inefficient (entries 3-4).
The effect of various solvent was then investigated, but no
improvement was observed (entries 5-11). To our delight,
when Cs2CO3 was added, the yield of 3a was increased to
80% (entry 12). Other bases such as K2CO3, Na2CO3 and
CsF were also applicable and 3a was obtained in moderate
to good yields (entries 13-15). Organic base Et3N led to a
poor yield (entry 16). When 3.0 equivalents of 1a was used,
the yield was increased to 87% (entry 17). The reaction
was also inefficient with Cs2CO3, but without light
irradiation (entry 1).
[13]
halides,[10-12] and the insertion of sulfur dioxide.
Recently, the reactions of sulfonyl radicals have received
significant consideration in terms of synthetic efficiency
and atom economy. [14] The sulfonyl radicals are usually in-
situ generated from sulfinic acid,[15] sodium sulfinate,[16]
[19]
sulfonyl chloride,[17] sulfonyl hydrazide,[18] and SO2
promoted by photo-catalysts or oxidants. Most of these
methods encounter certain limitations including over-
stoichiometric amounts of oxidants, harsh acid conditions,
high reaction temperatures, and extra addition of metal-
catalyst or photo-catalyst. To overcome these limitations,
green and sustainable synthesis of sulfones is still desirable.
1
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10.1002/adsc.201801390
Advanced Synthesis & Catalysis
Table 1. Optimization of Reaction Conditions[a]
Entry Solvent Light
Additive
Yield
(%)[b]
n.d.
40
3
n.d.
15
1[c]
2
DMSO
DMSO
DMSO
DMSO
DMA
dark
-
-
-
-
-
-
365 nm
blue LED
white LED
365 nm
365 nm
3
4
5
6
DMF
16
7
8
9
Toluene 365 nm
CH3CN 365 nm
Dioxane 365 nm
CH3OH 365nm
-
-
-
-
n.d.
n.d.
n.d.
9
n.d.
80
79
54
48
10
11
12
13
14
15
16
17[d]
H2O
365nm
365 nm
365 nm
365 nm
365 nm
365 nm
365 nm
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Cs2CO3
K2CO3
Na2CO3
CsF
Et3N
Cs2CO3
13
87(86[e])
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), additive (0.2
mmol) and solvent (2.0 mL) at RT under a nitrogen atmosphere.
[b] Yield determined by GC using n-dodecane as internal standard.
[c] The reaction was conduct with or without Cs2CO3.
[d] 1a (0.6 mmol).
[e] Yield of isolated product.
With the optimized reaction conditions in hands, a
number of aryl halides were examined and the results are
summarized in Scheme 1. Various iodides, bromides, and
chlorides were successfully coupled with sodium toluene-
sulfinate. 4-CN-phenyl halides gave the product 3a in
moderate to good yields. Among them, 4-CN-phenyl iodide
showed the best reactivity. The steric hindrance did not
exert obvious influence on the reaction since 2-CN-phenyl
iodide gave 86% yield of 3c. However, the electronic
property of the substituent significantly influenced the
reactivity of aryl iodides. The substrates with electron-
withdrawing groups such as ketone (3d-3e), ester (3f),
amide (3g), aldehyde (3h), halide (3i), CF3 (3j-3k) and
NO2 (3l) provided the products in moderate to good yields.
When the phenyl group was replaced by electron-deficient
heteroaryl groups such as pyridinyl (3m), pyrimidinyl (3n)
and quinolinyl (3o), good to excellent yields were achieved.
On the contrary, lower yields were obtained for electron-
rich aryl iodides (3p-3r) after a longer reaction time. To
explore the synthetic potential of this method, the reaction
of 1a on a gram scale was examined. The product 3a was
obtained with a 78% yield.
Scheme 1. Scope of halides.Reaction conditions: 1a (0.6 mmol),
2 (0.2 mmol), Cs2CO3 (0.2 mmol) and DMSO (2.0 mL) at RT under a
nitrogen atmosphere with the irradiation of 365 nm light. Isolated yields.
[a] Reaction performed on a 5.0 mmol scale. [b] Detected by GC-MS.
We then investigated the cross-couplings of various
sodium sulfinates with 4-CN-phenyl iodide (Scheme 2).
The arylsulfinates such as 4-methoxylbenzenesulfinate,
benzenesulfinate, 4-F-benzenesulfinate, 4-CF3-benzenesul-
finate and pyridinylsulfinate gave the sulfones 3s-3w with
good yields. Alkylsulfinates were also applicable. Sulfones
3x-3z were obtained with moderate to good yields.[25]
Scheme 2. Scope of sodium sulfinates. Reaction condition: 1s-
1z (0.6 mmol), 2a (0.2 mmol), Cs2CO3 (0.2 mmol) and DMSO (2.0 mL) at
RT under a nitrogen atmosphere with the irradiation of 365 nm light for 24
h. Isolated yields. [a] Reaction time is 48 h.
To gain insights into the reaction mechanism, we firstly
performed UV-vis spectroscopic measurements on various
combinations of 1a, 2d and Cs2CO3 in DMSO (Scheme 3,
eq. a). Color change and red shift of UV absorption peaks
were observed when Cs2CO3 was added to the mixture of
1a and 2d. The result implicated the formation of an
2
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10.1002/adsc.201801390
Advanced Synthesis & Catalysis
electron donor-acceptor (EDA) complex. To confirm the
eff ect of photoirradiation, a turn-on/off light experiment
was also carried out (see SI for details). The reaction
proceeded or stop depending on light on/off. The fact
excluded the radical chain reaction mechanism.
The control experiments with free radical scavengers
such as TEMPO, DPPH (1,1-diphenyl-2-picrylhydrazyl
radical) and oxygen were also carried out. The reactions
with TEMPO and oxygen were inhibited and the yields of
3a were largely reduced. When DPPH was added, the
reaction was totally inhibited (Scheme 3, eq. b). To further
understand the reaction mechanism, the trapping of the
radical intermediate with 1,1-diphenylethylene was
attempted (Scheme 3, eq. c). To our delight, compounds 4,
5, 6 were detected by GC-MS or HRMS. All the data
proved the generation of the sulfonyl radical, 4-methyl-
phenyl radical, and 4-CN-phenyl radical in the reaction.
Scheme 4. Proposed mechanism.
In summary, we have developed a simple and efficient
synthesis of sulfones via UV-light promoted coupling of
sodium sulfinates and aryl halides. A series of sulfones
were obtained in moderate to good yields. The reaction
may proceed via the formation of the EDA complex and
subsequent light-induced SET process.
Experimental Section
Typical procedure for the synthesis of 3a-3z:
To a dried quartz test tube (25 mL) was added 4-
iodobenzonitrile (45.8 mg, 0.2 mmol, 1.0 equiv.), sodium
4-methylbenzenesulfinate (106.9 mg, 0.6 mmol, 3.0 equiv.),
Cs2CO3 (65.2 mg, 0.2 mmol, 1.0 equiv.) and DMSO (2.0
mL) under a nitrogen atmosphere. The reaction mixture
was then stirred at room temperature under the irradiation
of UV LED (365 ± 5 nm, 40W) for 24 h. The reaction was
then quenched by water (15 mL) and the mixture was
extracted with CH2Cl2 (20 mL × 3). Then the combined
organic phases were washed with saturated brine, dried
over anhydrous Na2SO4 and concentrated in vacuum. The
crude product was purified by flash chromatography
(petroleum ether/ethyl acetate = 12/1) to give the sulfone
3a (44.0 mg, 86%) as a white solid.
Acknowledgements
We acknowledge the National Natural Science Foundation
of China (no. No. 21472248, 21772240), the National
Science and Technology Major Project of the Ministry of
Science and Technology of China (2018ZX09735010), and
the Guangzhou Science Technology and Innovation
Commission (201707010210) for the financial support of
this study.
Scheme 3. Control experiments
References
On the basis of these analyses, we propose the following
mechanism (Scheme 4). A sulfinate anion and an aryl
halide form an EDA complex. This complex is then
activated by UV irradiation to induce a single electron
transfer (SET) from the sulfinate anion to the aryl halide. A
sulfonyl radical, an aryl radical and a halide anion are
generated. The subsequent coupling of the sulfonyl radical
and the aryl radical provides the sulfone product.
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10.1002/adsc.201801390
Advanced Synthesis & Catalysis
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4
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10.1002/adsc.201801390
Advanced Synthesis & Catalysis
COMMUNICATION
A convenient synthesis of sulfones
via light promoted coupling of
sodium sulfinates and aryl
halides
Adv. Synth. Catal. Year, Volume,
Page – Page



Transition metal- and photo-catalyst free
Mild reaction conditions
Broad substrate scope
Lei Chen, Jie Liang, Zhen-yu Chen,
Jie Chen, Ming Yan*, Xue-jing
Zhang*
5
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