Electrochemical Synthesis of β-Ketosulfones from Switchable Starting Materials

Article abstract of DOI:10.1021/acs.orglett.9b04221

A synthesis of β-ketosulfones via sulfination of aryl methyl ketones and aryl acetylenes with sodium sulfinates under mild electrochemical conditions, in moderate to good chemical yields, is described. In particular, an electrochemical sulfination reaction of alkynes with sulfinate salts has never been explored. An environmentally friendly characteristic of this reaction is that it uses electricity as a valuable energy source for electrochemical synthesis of β-ketosulfones. This strategy is more convenient and practical compared to previous approaches.

Full text of DOI:10.1021/acs.orglett.9b04221

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Synthesis of β‑Ketosulfones from Switchable
Starting Materials
Issa Yavari* and Sina Shaabanzadeh
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran 14117-13116, Iran
S
* Supporting Information
ABSTRACT: A synthesis of β-ketosulfones via sulfination of
aryl methyl ketones and aryl acetylenes with sodium sulfinates
under mild electrochemical conditions, in moderate to good
chemical yields, is described. In particular, an electrochemical
sulfination reaction of alkynes with sulfinate salts has never
been explored. An environmentally friendly characteristic of
this reaction is that it uses electricity as a valuable energy
source for electrochemical synthesis of β-ketosulfones. This
strategy is more convenient and practical compared to
previous approaches.
ynthesis of sulfone derivatives with broad application in
bioactive compounds is a quest in organic chemistry.1−3
Scheme 1. (a) Reported Protocols for Synthesis of β-
Ketosulfones and (B) Our Method Based on
Electrochemical Sulfination of Aryl Methyl Ketones or Aryl
Acetylenes
S
Innovative routes for the preparation of β-ketosulfones have
always been an interesting issue in organic chemistry, especially
with developing photochemistry. The growth of published
articles based on a photoinduced radical sulfonylation for the
formation of C−S bond is significant.4
In 2013, Lu and co-workers reported a novel protocol for
achieving β-ketosulfones with direct aerobic difunctionalization
of terminal alkynes.5 In the same year, Wang and co-workers
developed a new technique for copper-catalyzed oxysulfony-
lation of alkenes with dioxygen and sulfonylhydrazides to
prepare β-ketosulfones.6 In 2016, Yang and co-workers found a
visible-light-catalyzed method for direct oxysulfonylation of
alkenes with sulfinic acids that lead to β-ketosulfones.7
Later in 2017, Li and co-workers developed an efficient
route for obtaining β-ketosulfones via photoinduced rearrange-
ment of vinyl tosylates (see Scheme 1a).8
Visible-light promoted reactions for sulfination of various
kinds of C−H bonds just for their lower cost and less toxicity
in comparison with metal catalysts have been increased.
However, this method has some defects such as the need to
use organic dyes or transition-metal catalysts, like ruthenium
and iridium complexes, as a photosensitizer.9 Defects such as
utilizing transition metals, odd sensitizers, exerting strong base,
and using high temperatures could vanish with electro-
chemistry. Herein, we report a switchable protocol for the
synthesis of β-ketosulfones by sulfination of aryl methyl
ketones and aryl acetylenes under mild electrochemical anodic
oxidation conditions (Scheme 1b).
In recent decades, electro-organic synthesis, as a practical
method, has grown dramatically.10 Iodide salts, for their safety
and availability, have been used as useful and efficient species
in electrosynthesis.11 They have served as an oxidation agent
and as a supporting electrolyte, but in a few cases they played
both roles. The anodic oxidation product of iodide ion for its
availability under electrochemical conditions has always been a
good candidate for carbon−hydrogen bond activation in
electro-organic synthesis.12 Herein, we introduce an innovative
approach for synthesis of β-ketosulfones via anodic oxidation
product of iodide ion under environmentally benign electro-
chemical conditions by activation of aryl methyl ketones or aryl
acetylenes in MeOH at room temperature.
After initial tests to prove product formation, acetophenone
(1a, 0.2 mmol) and sodium p-toluenesulfinate (2a, 0.4 mmol)
Received: November 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04221
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were chosen as model substrates to optimize the reaction
conditions. Our initial investigation focused on finding the best
solvent for obtaining the optimum amount of product (3a). As
shown in Table 1 (entries 1−5), when H2O was used as
Similar reaction conditions used for the synthesis of β-
ketosulfones by sulfination of aryl methyl ketones (1) under
electrochemical conditions were screened for conversion of
aryl acetylenes (4) to β-ketosulfones (3). As shown in Table 2,
Table 1. Optimization of the Reaction Conditions for
Acetophenone
Table 2. Optimization of the Reaction Condition for
Phenylacetylene (4a)
a
a
b
b
entry anode−cathode electrolyte (M) solvent (5 mL) yield (%)
entry anode−cathode electrolyte (M) solvent (5 mL) yield (%)
1
2
3
4
5
6
7
8
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
PG-PG
PG-St
PG-St
PG-St
PG-St
PG-St
KI (0.25)
KI (0.25)
KI (0.25)
KI (0.25)
H2O
MeCN
DMF
nd
1
2
3
4
5
6
PG-St
PG-St
PG-St
PG-St
PG-St
PG-St
KI (0.25)
KI (0.25)
KI (0.25)
KI (0.25)
KI (0.25)
KI (0.25)
H2O
MeCN
DMF
EtOH
MeOH
MeOH
nd
trace
trace
66
82
63
trace
trace
45
58
nd
EtOH
KI (0.25)
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
c
NaI (0.25)
NH4I (0.25)
NH4Cl (0.25)
TBAB (0.25)
TBAF (0.25)
LiClO4 (0.25)
Na2SO4 (0.25)
a
27
Optimal reaction conditions: 4a (0.5 mmol), 2a (1 mmol), KI (0.25
trace
trace
trace
nd
nd
nd
70
trace
85
trace
30
n.d
M), TBHP 70% in H2O (2 equiv), solvent (5 mL), St (stainless steel)
as a cathode, and PGE as a anode electrolyzed at constant current of
40 mA for 10 h (29.85 F/mol) in an undivided cell at rt. nd = not
9
10
11
12
13
14
15
16
17
18
19
b
c
detected. Isolated yields. In the absence of TBHP 70% in H2O.
MeOH was found to be the best solvent among the those
tested, by affording product (3a) in 58% yield (entry 5), and
the reaction did not go well in the absence of TBHP (entry 6).
When the optimized reaction conditions were established,
we sought to find the scope of derivatives that could tolerate
the electrochemical conditions. As shown in Scheme 2, a good
range of derivatives were found to be compatible with the
reaction condition. By using acetophenone derivatives bearing
substituents in ortho positions with sodium p-toluenesulfinate,
products (3b, 3c, and 3d) were obtained in good yields of 80,
86, and 76%, respectively. Productivities increased when
acetophenone derivatives bearing halides substituent in para
positions were used (products 3e, 3f, and 3g). Using electron-
rich para-substituted derivatives of acetophenone, namely (3i)
and (3o), the yields slightly decreased. Surprisingly, 2-
acetylpyridine and 4′-nitroacetophenone showed difficulty for
producing products (3h and 3k) under electrochemical
conditions. As shown in Scheme 2, sodium benzenesulfinate
was found to be as effective as sodium p-toluenesulfinate for
conversion of acetophenones (1) to β-ketosulfones (3). Thus,
products (3l−3p) were achieved in comparative yields (see
Scheme 2). Our attemts to prepare 2-(methylsulfonyl)-1-
phenylethan-1-one (3q), using sodium methanesulfinate as a
sulfonating agent, were unproductive (Scheme 2).
KI (0.25)
KI (0.05)
KI (0.5)
KI (0.25)
KI (0.25)
KI (0.25)
c
d
e
a
Optimal reaction conditions: 1a (0.5 mmol), 2a (1 mmol), KI (0.25
M), solvent (5 mL), St (stainless steel) as cathode and PGE as anode
electrolyzed at constant current of 40 mA for 5 h (14.92 F/mol) in an
undivided cell at rt. nd = not detected. Isolated yields. Constant
current of 10 mA (3.73 F/mol). Constant current of 20 mA (7.46 F/
b
c
d
e
mol). Two equiv of TEMPO was added.
solvent, 3a vanished (entry 1), but in MeCN and DMF it
appeared in trace amounts (entries 2 and 3). When the
reaction was carried out in EtOH, the yield of (3a) was raised
to 66% (entry 4). Finally, MeOH was found to be the best
solvent by affording (3a) in 82% yield (entry 5). After utilizing
various electrolytes, we found that the halide salts have a direct
influence on product formation (entries 6−12). Among halide
salts, the iodide salt has a superior effect on the reaction
outcome, and KI with 82% yield was found to be the best
electrolyte (entry 5). The reaction was quenched in the
absence of the iodide salt (entry 13). The other factors that
could influence the reaction outcomes were carefully
examined. To facilitate the reaction, stainless steel and pencil
graphite (PG), as accessible and cheap electrodes, were used in
this approach. PG as the anode and stainless steel for the
cathode, showed the best capacity to produce (3a) (entry 5).
However, when the stainless steel cathode was replaced by PG,
the yield of (3a) diminished to 70% (entry 14). The optimal
concentration of supporting electrolyte was found to be 0.25 M
(see entry 5). Attempts to decrease (entry 15) or increase
(entry 16) the concentration of supporting electrolyte were
found to be fruitless. Fortunately, 40 mA as initially applied
current was the best choice. Some efforts to change the current
(entries 17 and 18) for increasing the yield were unsuccessful.
Because of our restricted access to arylalkynes, we examined
only a limited range of compounds (4). As shown in Scheme 3,
phenylacetylene, 4-bromophenylacetylene, and 4-ethynylto-
luene, as alkyne sources, were used. Thus, six derivatives of
(3) were obtained in moderate yields of 51−62% (see Scheme
3).
Electrochemical formation of β-ketosulfones 3a from
acetophenone and sodium p-toluenesulfinate in a gram-scale
synthesis show excellent compatibility of this aryl methyl
ketone for the formation of 1-phenyl-2-tosylethanone (Scheme
4).
By relying on previous paradigms, related reports,13 and
cyclic voltammetry experiments, offering a plausible mecha-
nism (see Scheme 5) was not a difficult task. Starting keys in
B
DOI: 10.1021/acs.orglett.9b04221
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Substrate Scope of Aryl Methyl Ketones
Scheme 3. Substrate Scope of Aryl Alkynes
a
Optimal reaction conditions: 4 (0.5 mmol), 2 (1 mmol), KI (0.25
M), TBHP 70% in H2O (2 equiv), MeOH (5 mL), St (stainless steel)
as a cathode, and PGE as a anode electrolyzed at constant current of
40 mA for 10 h (29.85 F/mol) in an undivided cell at rt.
Scheme 4. Gram-Scale Synthesis of 1-Phenyl-2-
tosylethanone
Scheme 5. Possible Mechanism for the Formation of β-
Ketosulfones
a
Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), KI (0.25 M),
MeOH (5 mL), St (stainless steel) as cathode, and PGE as anode
electrolyzed at constant current of 40 mA for 5 h (14.92 F/mol) in an
undivided cell at rt.
our electrochemical reaction were the anodic oxidation of
iodide ion14 and 1a.15 At first, although the formation of 5′ was
well proven by previous reports,16 but for ensuring its
formation in our applied potential, cyclic voltammetry (CV)
experiments were performed (Figures 9 and 10). In the second
step, by considering the ability of iodide ion for oxidation to
11, that can play the role of oxidant in the reaction, CV
experiments of iodide ion were performed (Figure 6). Hence,
in our suggested mechanism iodide ion is converted to radical
11 on the anode surface, which can abstract a H• from
acetophenones to produce 6 that be stabilized by resonance to
6′.17 Intermediate 6′ can attach upon 5′ to afford 3a. Also in
the reaction of 4a, it can attach to 5′ to form 7 which
subsequently combine with 10 to generate 8. Because of 3a is
much more stable than 8, it is readily interconverting to 3a by
tautomerization. For ensuring the existence of radical
intermediates in the reaction, we used a radical scavenger.
When 2 equiv of TEMPO (2,2,6,6-tetramethylpiperidin-1-
oxyl) was added to the reaction mixture, the reaction was
totally quenched (Table 1, entry 19). During the anodic
oxidation of species, the cathodic reduction of MeOH releases
hydrogen gas and MeO−.
In conclusion, we have developed an electrochemical
synthesis of β-ketosulfones from switchable starting materials.
The sulfination occurred between aryl methyl ketones or aryl
acetylenes with sodium sulfinates. A broad substrate scope and
moderate to good yields were observed, but aliphatic sulfinates
did not work for this transformation. The reaction in a gram
scale synthesis make this strategy to be convenient and
C
DOI: 10.1021/acs.orglett.9b04221
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
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Detailed experimental procedure of electrochemistry
reaction and spectral data of all the products (PDF)
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■
Corresponding Author
*E-mail: yavarisa@modares.ac.ir
ORCID
Issa Yavari: 0000-0001-7896-9282
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Partial support of this work by the Research Council of Tarbiat
Modares University is gratefully acknowledged.
■
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DOI: 10.1021/acs.orglett.9b04221
Org. Lett. XXXX, XXX, XXX−XXX