Direct C-H Methylsulfonylation of Alkenes with the Insertion of Sulfur Dioxide

Article abstract of DOI:10.1021/acs.joc.9b01729

The direct C-H methylsulfonylation of alkenes using inorganic sodium metabisulfite as the sulfur dioxide surrogate is described. This method provides convenient access to (E)-2-methyl styrenyl sulfones in good yields. In general, the in situ generated met

Full text of DOI:10.1021/acs.joc.9b01729

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Direct C-H Methylsulfonylation of Alkenes with the Insertion of Sulfur Dioxide
Fu-Sheng He, Xinxing Gong, Pornchai Rojsitthisak, and Jie Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01729 • Publication Date (Web): 05 Sep 2019
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The Journal of Organic Chemistry
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Direct C-H Methylsulfonylation of Alkenes with the Insertion of Sul-
fur Dioxide
Fu-Sheng He,† Xinxing Gong,‡ Pornchai Rojsitthisak,§ and Jie Wu*†
,‡,
¶
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† School of Pharmaceutical and Materials Engineering & Institute for Advanced Studies, Taizhou University, 1139 Shifu Ave-
nue, Taizhou 318000, China. Email: jie_wu@fudan.edu.cn
‡ Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, China
§ Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 254
Phayathai Road, Patumwan, Bangkok 10330, Thailand.
¶ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Scienc-
es, 345 Lingling Road, Shanghai 200032, China
KEYWORDS: C-H bond functionalization, methylsulfonylation, sulfur dioxide, radical reaction, sodium metabisulfite
FeCl3 (1.0 equiv)
Me
O
O
O
H
quinoline (50 mol %)
+
Na2S2O5
+
O
Ar
S
MeCN, N2, 130 oC, 5 h
Ar
Me
ABSTRACT: The direct C-H methylsulfonylation of alkenes using inorganic sodium metabisulfite as the sulfur dioxide surrogate
is described. This method provides convenient access to (E)-2-methyl styrenyl sulfones in good yields. In general, the in situ gener-
ated methyl radical from di-tert-butyl peroxide (DTBP) undergoes a methylsulfonylation process with the combination of sulfur
dioxide.
In recent years, the direct C–H functionalization of organic
molecules has become a powerful strategy for the formation of
new C-C or C-X bonds.1 As a result, great achievements for
the functionalization of C–H bonds have been constantly ac-
complished under transition metal catalysis or through a radi-
cal process.2 Among them, the methylsulfonylation of C-H
bonds to produce methylsulfonyl-containing compounds is one
of important transformations in organic synthesis, attributing
to the broad applications of methylsulfonyl-containing com-
pounds in many bioactive molecules and drugs.3 When it
comes to methyl group, the popular “magic methyl effect” has
to be mentioned, offering driving force for the design of new
molecular entities in drug discovery.4 Meanwhile, sulfonyl
compounds also play an important role in pharmaceuticals and
material science.5 Prompted by these results, continuous ef-
forts have been made for the preparation of methylsulfonyl-
containing compounds.6,7 The traditional approaches for the
construction of such methyl fragments mainly involved the
oxidative sulfonylation of the corresponding thioethers or uti-
lized toxic methylation reagents, which often required harsh
reaction conditions and limited to narrow substrate scope.
Therefore, it’s highly desirable to develop efficient methods
for the synthesis of methylsulfonyl-containing compounds.
reaction of boronic acids, sodium metabisulfite, and dimethyl
carbonate to generate aryl methyl sulfones.11a In this transfor-
mation, dimethyl carbonate served as the methylated rea-
gent.11a Earlier this year, we disclosed a radical relay strategy
for the generation of 3-(methylsulfonyl)benzo[b]thiophenes
through
a
photoinduced
reaction
of
methyl(2-
alkynylphenyl)sulfanes with sodium metabisulfite.11b During
the reaction process, the in situ generated methyl radical12 was
found to be the key intermediate that combined with sulfur
dioxide through a radical relay. Interestingly, DTBP was also
applicable in this transformation to give methyl radical. In our
continuous studies on the insertion of sulfur dioxide, we envi-
sioned that the formation of methylsulfonyl radical from in
situ generated methyl radical and sulfur dioxide might undergo
C(sp2)-H methylsulfonylation of alkenes, leading to (E)-2-
methyl styrenyl sulfones. Considering the significance of vi-
Recently, using DABCO·(SO2)2 or inorganic sulfites as the
source for the installation of sulfonyl group into organic mole-
cules has received considerable attention.8 With this strategy, a
variety of sulfones, sulfonamides and sulfonate esters were
successfully accomplished.9,10 Despite the great achievements
of this area, only few examples with respect to methyl-
sulfonyl-containing compounds have been reported.11 For in-
stance, Jiang and co-workers developed a three-component
Scheme 1. A proposed route for the generation of (E)-2-methyl
styrenyl sulfones.
nylsulfones and methyl group in medicinal chemistry, it would
be an attractive strategy to construct molecules that have both
scaffolds through methyl radical. Herein, we report the direct
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C-H methylsulfonylation of alkenes for the generation of (E)-
Page 2 of 7
Scheme 2. Substrate scope of the reaction of alkenes 1 with sodium
1
2
3
4
5
6
7
8
2-methyl styrenyl sulfones by employing sodium metabisulfite
as the sulfur dioxide surrogate and DTBP as the methyl radical
source (Scheme 1).
metabisulfite and DTBP a
FeCl3 (1.0 equiv)
Me
O
O
O
H
quinoline (50 mol %)
+
Na2S2O5
+
O
Ar
S
MeCN, N2, 130 oC, 5 h
Ar
Me
1
2
Table 1. Initial studies for the reaction of styrene 1a with sodium
O
O
O
O
O
O
O
O
metabisulfite and DTBPa
S
S
S
S
Me
Me
tBu
Me
Me
2b, 80%
2a, 80%
2c, 67%
2d, 62%
O
O
O
O
O
O
9
S
S
S
Me
Me
Me
10
11
12
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60
Entry
1
Variation from standard condition
None
Yield (%)b
68
F
Cl
Br
2e, 58% (DTBP)
55% (TBPB)
2f, 64%
2g, 70%
2
3
DABSO instead of Na2S2O5
No FeCl3
65
n.d.
trace
41
O
S
O
O
O
O
O
S
Br
S
Me
Me
Me
F3C
4
No quinoline
2h, 57%
2i, 73%
O
2j, 60%
5
75 mol % of FeCl3
O
O
O
O
O
O
S
O
S
S
S
6
FeCl2 instead of FeCl3
CuCl2, Fe(acac)3 or FeSO4 instead of FeCl3
50 mol % of quinoline
1,10-Phen instead of quinoline
43
Me
Me
Me
Me
7
n.d.
66
Cl
Br
2k, 68%
2n, 72%
2l, 77%
2m, 66%
8
O
S
O
O
O
9
50
S
Me
Me
10
11c
12
<30
80
80 C
130 C
toluene instead of MeCN
S
2o, 55%
2p, n.d.
35
a Reaction conditions: Alkene 1 (0.2 mmol), sodium metabisulfite (0.4 mmol),
DTBP (0.6 mmol), FeCl3 (0.2 mmol), quinoline (0.1 mmol), MeCN (2.0 mL),
sealed tube, N2, 130 oC, 5 h, isolated yields based on alkene 1.
a
Reaction conditions: styrene 1a (0.2 mmol), sodium metabisulfite (0.4
mmol), DTBP (0.6 mmol), FeCl3 (0.2 mmol), quinoline (0.2 mmol), solvent
(2.0 mL), sealed tube, N2, 110 C, 5 h. b Isolated yield based on styrene 1a.
c
Quinoline (50 mol%) was used.
withdrawing groups proceeded smoothly, leading to the de-
sired products 2 in good yields. Several functional groups
were tolerated in this reaction, including fluoro, chloro, bromo
and trifluoromethyl. For example, the bromo-containing prod-
uct 2g was isolated in 70% yield. Moreover, the steric hin-
drance of alkenes had subtle effect on the reaction efficiency.
Substrates with substituents in meta- and ortho-positions
worked well to provide the corresponding products 2i-2n in
60-72% yields. Notably, the thiophenyl group was also suita-
ble in this transformation, affording the methyl sulfonated
product 2o in 55% yield. However, no desired product was
obtained when prop-1-en-2-ylbenzene, 1-phenylpropene, al-
lylbenzene or chalcone was employed in this reaction, proba-
bly due to the low reactivity.
We began our investigation with the reaction of styrene 1a,
sodium metabisulfite, and DTBP in MeCN under N2 at 110 C
in the presence of FeCl3 and quinoline. The reaction condtions
were shown in Table 1. To our delight, the desired (E)-(2-
(methylsulfonyl)vinyl)benzene 2a was isolated in 68% yield
(Table 1, entry 1). We next examined the variation impact of
reaction conditions on the reaction efficiency. By replacing
sodium metabisulfite with DABCO·(SO2)2, the yield slightly
decreased to 65% (Table 1, entry 2). The control experiments
revealed that no reaction took place without the addition of
FeCl3 or quinoline (Table 1, entries 3-4). It was found that the
amount of FeCl3 has notable influence on the reaction outcome,
with 41% yield of 2a was produced when 75 mol % of FeCl3
was used (Table 1, entry 5). Subsequently, other metal salts
such as FeCl2, CuCl2, Fe(acac)3 and FeSO4 were examined,
however, no better results were obtained (Table 1, entries 6-7).
The corresponding (E)-(2-(methylsulfonyl)vinyl)benzene 2a
was delivered in 66% yield when 50 mol % of quinolone was
employed in the reaction (Table 1, entry 8). Instead, 1,10-
phen could not give better result compared to quinoline (Table
1, entry 9). Additionally, the reaction temperature was evalu-
ated. A low yield was observed when the reaction was per-
formed at 80 C (Table 1, entry 10). This transformation at
130 C was found to be more suitable, providing compound 2a
in 80% yield (Table 1, entry 11). The solvent of the reaction
was then changed, and the yield of compound 2a was de-
creased to 35% (Table 1, entry 12).
Scheme 3. Control Experiments
To gain more insights to the reaction mechanism, some con-
trol experiments were carried out. Firstly, radical trapping
experiment was conducted by adding 4.0 equiv of TEMPO
into the model reaction under standard conditions, and no de-
sired product 2a was detected. Then, 1, 1-diphenylene was
employed in the reaction of styrene 1a, sodium metabisulfite,
and DTBP, affording 2a in 26% yield and (2-
(Methylsulfonyl)ethene-1,1-diyl)dibenzene 3 in 35% yield.
The scope for the direct C-H methylsulfonylation of alkenes
1 was subsequently investigated under the above optimized
reaction conditions (Scheme 2). It was found that reactions
with a range of styrenes 1 with both electron-donating and
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3.04 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
1
2
3
4
5
6
7
8
144.1, 142.1, 129.9, 128.6, 125.0, 110.0, 43.4, 21.6.
(E)-2-(2-(Methylsulfonyl)vinyl)naphthalene (2c)13
o
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Yellow solid; m. p.: 130-134 C; 30.9 mg; 67% yield; H
NMR (400 MHz, CDCl3): 7.95 (s, 1H), 7.90 – 7.75 (m,
4H),7.61 – 7.54 (m, 3H), 7.02 (d, J = 15.4 Hz, 1H), 3.07 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): 144.1, 134.6, 133.2,
131.1, 129.6, 129.1, 128.8, 127.9, 127.9, 127.1, 126.3, 123.4,
43.4.
(E)-1-(tert-Butyl)-4-(2-(methylsulfonyl)vinyl)benzene (2d)13
9
Scheme 4. A plausible mechanism for the direct C-H methyl-
sulfonylation of alkenes.
These results indicated that methylsulfonyl radical generated
in situ was involved in this transformation (Scheme 3).
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60
White solid; m. p.: 79-83 C; 29.4 mg; 62% yield; H NMR
(400 MHz, CDCl3): 7.63 (d, J = 15.4 Hz, 1H), 7.47 (m, 4H),
6.90 (d, J = 15.4 Hz, 1H), 3.05 (s, 3H), 1.35 (s, 8H). 13C{1H}
NMR (100 MHz, CDCl3): 155.2, 144.0, 129.3, 128.5, 126.2,
125.2, 110.0, 43.4, 31.1.
Based on the control experimental observations in Scheme 3
and previous reports,11b,12 a plausible mechanism is illustrated
in Scheme 4. Initially, a tert-butyl radical was generated
through the homolytic cleavage of DTBP, which would be
converted to methyl radical by the loss of acetone. Subse-
quently, the methyl radical would be trapped by sulfur dioxide,
giving rise to the methylsulfonyl radical. The addition of me-
thylsulfonyl radical to alkene would produce carbon radical
species A, which would be oxidized to cation intermidiate B in
the presence of Fe(III) via a single electron transfer (SET).
The subsequent deprotonation of intermediate B would pro-
vide the final product 2.
(E)-1-Fluoro-4-(2-(methylsulfonyl)vinyl)benzene (2e)13
o
1
Pale yellow solid; m. p.: 110-114 C; 23.1 mg; 58% yield; H
NMR (400 MHz, CDCl3): 7.61 (d, J = 15.5 Hz, 1H), 7.56-7.52
(m, 2H), 7.14 (t, J = 8.3 Hz, 2H), 6.88 (d, J = 15.4 Hz, 1H),
3.06 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): 164.5 (d, J =
253.0 Hz), 142.7, 130.6 (d, J = 9.4 Hz), 126.0, 116.5 (d, J =
22.6 Hz), 110.0, 43.3. 19F NMR (400 MHz, CDCl3): δ -107.42.
(E)-1-Chloro-4-(2-(methylsulfonyl)vinyl)benzene (2f)13
Colorless oil; 27.6 mg; 64% yield; 1H NMR (400 MHz,
CDCl3): 7.60 (d, J = 15.5 Hz, 1H), 7.49-7.41 (m, 4H), 6.92 (d,
J = 15.5 Hz, 1H), 3.06 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): 142.6, 137.5, 129.8, 129.5, 126.8, 110.0, 43.3.
In conclusion, we have disclosed an approach for the syn-
thesis of (E)-2-methyl styrenyl sulfones via a direct C-H me-
thyl sulfonylation of alkenes. By using sodium metabisulfite
as the sulfur dioxide surrogate and DTBP as the methyl source,
a variety of (E)-2-methyl styrenyl sulfones are obtained in
good yields. A plausible mechanism is proposed, revealing
that the methyl radical generated from DTBP is the key inter-
mediate in the transformation. In general, the in situ generated
methyl radical from di-tert-butyl peroxide (DTBP) undergoes
a methylsulfonylation process with the combination of sulfur
dioxide.
(E)-1-Bromo-4-(2-(methylsulfonyl)vinyl)benzene (2g)13
White solid; m. p.: 110-114 oC; 36.3 mg; 70% yield; 1H NMR
(400 MHz, CDCl3): 7.58-7.55 (m, 3H), 7.38 (d, J = 8.3 Hz,
2H), 6.93 (d, J = 15.5 Hz, 1H), 3.04 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): 142.7, 132.5, 130.0, 126.9, 125.9, 43.2.
(E)-1-(2-(Methylsulfonyl)vinyl)-4-(trifluoromethyl)benzene
(2h)13
White solid; m. p.: 139-141 oC; 28.5 mg; 57% yield; 1H NMR
(400 MHz, CDCl3): 7.71-7.63 (m, 5H), 7.02 (d, J = 15.5 Hz,
1H), 3.07 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): 142.2,
135.5, 128.9, 128.8, 126.2 (q, J = 4.0 Hz), 123.6 (q, J = 272.3
Hz), 43.1. 19F NMR (400 MHz, CDCl3): δ -63.02.
Experiment Section
General experimental procedure for the direct C-H methyl-
sulfonylation of alkenes 1:
Alkene 1 (0.20 mmol) in MeCN (1.0 mL) was added to a mix-
ture of sodium metabisulfite (0.40 mmol) and FeCl3 (0.2 mmol)
at N2 atmosphere. Then di-tert-butyl peroxide (DTBP) (0.60
mmol) in MeCN (0.5 mL) and quinoline (0.1 mmol) in MeCN
(0.5 mL) were added to the seal tube. The mixture was stirred
(E)-1-Methyl-3-(2-(methylsulfonyl)vinyl)benzene (2i)13
Yellow oil; 28.6 mg; 73% yield; 1H NMR (400 MHz, CDCl3):
7.62 (d, J = 15.4 Hz, 1H), 7.37 – 7.28 (m, 4H), 6.92 (d, J =
15.4 Hz, 1H), 3.05 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): 144.3, 139.0, 132.3, 129.2, 129.7, 126.0, 125.8,
110.0, 43.3.
o
at 130 C in oil bath for 5 hours. After cooling to room tem-
perature, the solvent was evaporated under reduced pressure.
The residue was purified directly by flash column chromatog-
raphy (n-hexane/EA= 4:1) to give the corresponding product 2.
(E)-(2-(Methylsulfonyl)vinyl)benzene (2a)13
(E)-1-Bromo-3-(2-(methylsulfonyl)vinyl)benzene (2j)14
Yellow oil; 31.0 mg; 60% yield; 1H NMR (400 MHz, CDCl3):
7.69 (s, 1H), 7.60 (s, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7.35-7.28
(m, 2H), 6.95 (d, J = 15.4 Hz, 1H), 3.06 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 142.3, 134.2, 134.1, 131.2, 130.7,
127.9, 127.3, 123.2, 43.2.
1
Yellow oil; 28.9 mg; 80% yield; H NMR (400 MHz, CDCl3):
7.64 (d, J = 15.4 Hz, 1H), 7.53 – 7.52 (m, 2H), 7.45 – 7.43 (m,
3H), 6.92 (d, J = 15.5 Hz, 1H), 3.04 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): 144.1, 132.0, 131.4, 129.2, 128.6, 126.3,
43.3.
(E)-1-Methyl-2-(2-(methylsulfonyl)vinyl)benzene (2k)13
o
1
Yellow solid; m. p.: 68-71 C; 26.7 mg; 68% yield; H NMR
(400 MHz, CDCl3): 7.93 (d, J = 15.3 Hz, 1H), 7.53 (d, J = 7.7
Hz, 1H), 7.36-7.27 (m, 3H), 6.87 (d, J = 15.3 Hz, 1H), 3.06 (s,
3H), 2.47 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): 141.7,
138.3, 131.2, 127.2, 126.9, 126.6, 110.0, 43.3.
(E)-1-Methyl-4-(2-(methylsulfonyl)vinyl)benzene (2b)13
o
1
Yellow solid; m. p.: 104-106 C; 31.1 mg; 80% yield; H
NMR (400 MHz, CDCl3): 7.61 (d, J = 15.4 Hz, 1H), 7.43 (d, J
= 7.8 Hz, 2H), 7.28 – 7.24 (m, 2H), 6.88 (d, J = 15.4 Hz, 1H),
(E)-1-Chloro-2-(2-(methylsulfonyl)vinyl)benzene (2l)
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o
1
Financial support from National Natural Science Foundation of
China (Nos. 21672037 and 21532001) is gratefully acknowledged.
Yellow solid; m. p.: 70-74 C; 33.2 mg; 77% yield; H NMR
(400 MHz, CDCl3): δ 8.04 (d, J = 15.5 Hz, 1H), 7.58 (d, J =
7.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.40-7.31 (m, 2H), 6.98
(d, J = 15.5 Hz, 1H), 3.06 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): 140.0, 135.4, 132.1, 130.5, 129.1, 128.4, 127.3, 43.2.
HRMS (ESI) calcd for C9H10ClO2S+: 217.0085 (M+H+), found:
217.0086.
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(E)-1-Bromo-2-(2-(methylsulfonyl)vinyl)benzene (2m)
Yellow oil; 34.2 mg; 66% yield; 1H NMR (400 MHz, CDCl3):
8.01 (d, J = 15.4 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.57 (d, J =
7.5 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H),
6.93 (d, J = 15.4 Hz, 1H), 3.06 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3): 142.5, 133.8, 132.3, 129.8, 129.2, 128.3, 128.0,
125.6, 43.2. HRMS (ESI) calcd for C9H10BrO2S+: 260.9579
(M+H+), found: 260.9582.
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(E)-1,4-Dimethyl-2-(2-(methylsulfonyl)vinyl)benzene (2n)13
Yellow oil; 30.2 mg; 72% yield; 1H NMR (400 MHz, CDCl3):
7.89 (d, J = 15.3 Hz, 1H), 7.32-7.26 (m, 2H), 7.14 (d, J = 2.9
Hz, 2H), 6.83 (d, J = 15.3 Hz, 1H), 3.04 (s, 3H), 2.40 (s, 3H),
2.34 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): 141.9, 136.1,
135.3, 132.0, 131.1, 127.4, 126.8, 110.1, 43.3, 20.9, 19.2.
(E)-2-(2-(Methylsulfonyl)vinyl)thiophene (2o)13
1
Brown oil; 20.6 mg; 55% yield; H NMR (400 MHz, CDCl3):
7.73 (d, J = 15.2 Hz, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.33 (d, J =
2.9 Hz, 1H), 7.10 (d, J = 3.9 Hz, 1H), 6.71 (d, J = 15.2 Hz,
1H), 3.03 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 136.6,
132.7, 130.2, 128.4, 124.3, 110.0, 43.5.
(2-(Methylsulfonyl)ethene-1,1-diyl)dibenzene (3)
1
Pale yellow solid; 54.1 mg; 35% yield; H NMR (400 MHz,
Rev. 2017, 117, 9163-9227, and references cited therein.
CDCl3): δ 7.49 – 7.34 (m, 8H), 7.29 (d, J = 7.5 Hz, 2H), 6.87
(s, 1H), 2.69 (s, 3H).13C{1H} NMR (100 MHz, CDCl3): δ
154.9, 139.0, 135.7, 130.4, 129.8, 129.6, 128.7, 128.3, 128.0,
125.9, 43.3.
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AUTHOR INFORMATION
Corresponding Author
jie_wu@fudan.edu.cn
F.-S. He and X. Gong contributed equally.
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The authors declare no competing financial interests.
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