Reduction of CO2 with NaBH4/I2 for the Conversion of Thiophenols to Aryl Methyl Sulfides

Article abstract of DOI:10.1021/acs.joc.9b01180

We report a tandem reaction to realize reduction of carbon dioxide with thiophenols to generate aryl methyl sulfides under the NaBH₄/I₂ system with 18-crown-6 as the solvent. Thiophenols bearing electron-donating and electron-withdrawing groups are feasible in this reaction. Controlled experiment results indicate that 18-crown-6 plays a critical role in six-electron reduction of carbon dioxide.

Full text of DOI:10.1021/acs.joc.9b01180

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Article
Reduction of CO2 with NaBH4 /I2 for the
Conversion of Thiophenols to Aryl Methyl Sulfides
Bo Zhang, Zhengning Fan, Zhiqiang Guo, and Chanjuan Xi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01180 • Publication Date (Web): 06 Jun 2019
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The Journal of Organic Chemistry
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Reduction of CO with NaBH /I for the Conversion of Thiophenols
to Aryl Methyl Sulfides
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a
a
b
a,c
Bo Zhang , Zhengning Fan , Zhiqiang Guo , and Chanjuan Xi *
aMOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua
University, Beijing 100084, China.
bScientific Instrument Center, Shanxi University, Taiyuan 030006, China
cState Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
NaBH / I2
4
S
Ar SH + CO2
Ar
CH3
18-crown-6
yield up to 99%
ABSTRACT: We report a tandem reaction to realize reduction of carbon dioxide with thiophenols to generate aryl methyl sulfides
under NaBH /I system in 18-crown-6 as solvent. Thiophenols bearing electron-donating and electron-withdrawing groups are
4
2
feasible in this reaction. Controlled experiment results indicate that the 18-crown-6 plays critical role in six-electron reduction of
carbon dioxide.
cancerogenic.17 A sustainable, nonhazardous and efficient
method to synthesize aryl methyl sulfide is in great demanding.
INTRODUCTION
1
Organosulfur molecules are ubiquitous in agrochemicals,
biological molecules, and pharmaceuticals as well as
compounds widely exist in nature. Thereinto, aryl methyl
sulfides, sulfoxides, and sulfones are significant building blocks
in pharmaceutical chemistry and commonly exist in different
small molecule drugs and bioactive molecules (Scheme 1A).
Different oxidative state of sulfur atoms in the counterpart
2
3
A. Methylsulfide-containing bioactive molecules
4
Me
S
O
S
H
N
O
N
N
Me
S
n
S
S Pr
N
Me
P
N
N
H
N
N
O
MeO
OEt
H
Simetryn
Herbicide
Sulprofos
Insects on Cotton and Tobacco
Sulmazole
cardiovascular
5
NH2
Me
S
backbones can lead to versatile bioactivities, such as Simetryn,
N
N
an effective and selective herbicide for paddy rice species,
N
O
6
Me
Sulprofos, an insecticide to worms on cotton and tobacco,
N
N
S
OMe
HO
7
8
H
N
OMe
OMe
Sulmazole, a cardiovascular, Thioridazine, an antipsychotic
O
N
S
S
Me
H
H
H
O
9
drug, Thiocolchicine, the proliferative diseases drug, and
H
H
OH
1
0
adenosine, an important motif in both DNA and RNA.
Besides, methylmercaptoarenes are also combined with other
electrophiles or nucleophiles through cross-coupling reaction to
Thioridazine
antipsychotic
Thiocolchicine
proliferative diseases
Adenosin
B. Previous methods
O
S
11
12
Ar
CH3
H]
deliver products with C-C, C-N or other carbon-heteroatom
[
1
3
bonds. Therefore, construction of C-S bonds and “MeS”
functional group are of vital importance in organic synthesis.
Numerous synthesis approaches can produce aryl methyl
sulfides, which could be summarized in four major methods
O
CH3SH or CH3SNa
CH SCH
3
3
[Pd] or [Cu]
[Cu]
S
+
Ar
CH3
+
Ar-X
Ar-H or Ar-X
Base
1
4
(Scheme 1B): one is deoxygenation of sulfoxides. The second
Ar-SH + CH3I or (CH3)2SO4
C. Our strategy
H
approach is utilizing aryl halides to react with methanethiol
1
5
(
MeSH) or sodium methyl mercaptide (MeSNa) as well as
one-pot three-component
1
6
ArS
C
H
H
ArSH
CO2 NaBH4
+ +
their alternatives such as DMSO with transitional metal
catalysts. However, there are several inevitable problems
including catalysts poison, environment pollution, intractable
operation of MeSH and low yields with electron-deficient
substrates. Another common approach is based on methylation
of thiophenol with methylating reagents such as methyl iodide
a
b
Scheme 1. Significance of methylsulfides and preparation
Carbon dioxide (CO
2
) is a recyclable, abundant source of
2 4
(MeI) and dimethyl sulfate (Me SO ), both are volatile and
carbon and has been employed as an appealing C1 building
1
8
block to construct carboxylic acid derivatives, formaldehyde
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1
9
derivatives, and methyl compounds. With the development of
reductive amination of CO , the “diagonal approach” was
reactivity and selectivity in the 18-crown-6, a series of gradient
solvents mixed with 18-crown-6 and 1,4-dioxane were used and
these experiments confirmed our proposals. (See Figure S1 in
Supporting Information (SI)). Notably, the reaction was carried
out in one-pot two-step within addition of reagents.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
0
elaborated by Cantat et al. to classify the hierarchical
reduction of CO in organic synthesis, such as two-electron
reduction products formamides, four-electron reduction
products aminals, and six-electron reduction products
methylamines. In the circumstances, different catalytic systems
2
Table 1. Optimization for reductive functionalization of
a
2
CO with thiophenols
2
1
22
23
have been employed: metal catalysts such as Ru, Co, Fe,
1) NaBH4
2
4
25
26
27
S
S
Cu, Zn, Ni, and organocatalysts such as TBD, NHCs,
TBAF, Ionic liquids, B(C and proazaphosphatrane
superbases have shown capacity to yielding formamides and
0 oC, 0.5 h H3C
C
8
H3C
SH + CO2
~1 atm
SCH3
+
H
2
6
F
5
)
3
2) I2, temp.
H3C
CH3
1a
2a
temp.( C) time(h)
3a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27b
27g
NaBH4
equiv) (equiv)
I2
methylamines. In 2017, Han and He reported hierarchical
reduction of CO with amines and hydrosilane independently
and simultaneously, proved that CO reduction stage could be
tuned by the reaction conditions. However, hierarchical
reduction of CO combined with C-S bonds construction is still
scarce. Recently our group successfully achieved the first
catalyst-free selective reduction of CO with aryl thiophenols
and alkyl hydrosulfides using NaBH as a mild reductant to
generate dithioacetals with wide substrates scope and high
o
2a yieldb (%) 3a yieldb (%)
entry
solvent
(
2
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
1
1
1
1
1
1
140
140
140
140
140
140
24
24
24
24
24
24
1,4-Dioxane
THF
13
13
-
40
-
2
Ph2O
-
2
PhCF3
Tol.
17
-
-
-
2
3
CH CN
-
-
3
3
3
3
4
5
6
1
1
140
140
140
140
140
140
140
24
24
24
24
24
24
24
DEGDME
DME
40
26
34
50
56
98
99
16
25
23
20
23
-
4
2
8c
1
15-crown-5
18-crown-6
efficiency. To gain more insight into the reduction of CO
well as C-S bond formation, herein, we report a selective
methylation of aryl thiophenols using CO and NaBH . This
protocol realized the six-electron reduction of CO to the methyl
2
as
10
11
12
1
1.3
1.6
2
18-crown-6
18-crown-6
18-crown-6
18-crown-6
2
4
2
13
14
-
with the formation of the C-S bond (Scheme 1C).
5
1.6
120
24
46
23
15
16
17
18
5
5
1.6
1.6
100
140
24
12
18-crown-6
18-crown-6
40
22
-
95 (90)
RESULTS AND DISSCUSION
5
5
1.6
1.6
140
140
10
6
18-crown-6
18-crown-6
93
83
-
-
The initial optimization studies of the reaction conditions were
conducted using p-toluenethiol (1a, 0.5 mmol) as a model
a
Reaction conditions: 1) p-thiocresol 1a (0.5 mmol), NaBH
4
(2.5 mmol), 1 atm
substrate in the presence of NaBH
of our approach to generate dithioactals with CO
we tried to use NaBH /I as the reductive system in ethers to
achieve our goal, which are easy to handle and stable to air and
4
(Table 1). In consideration
o
2
CO , solvent (1 mL) or 18-crown-6 (0.6 g), 80 C, 0.5 h; 2) iodine (0.8 mmol),
1
internal standard, isolated yield is given in parenthesis.
in 1,4-dioxane,
40 oC, 12 h. Yield determined by H NMR using trichloroethylene as an
b
1
2
4
2
2
8b,c
moisture.
However, only 13% methyl (p-tolyl) sulfide 2a
Adopting the optimal conditions, we sought to extend the
scope of this methylation with various thiophenols as listed in
Table 2. The alkyl substituted thiophenol proceeded smoothly
to deliver aryl methyl sulfides (2a-2e) in high to excellent yields.
Naphthalene-2-thiol also gave out the corresponding product
was detected in 1,4-dioxane using three equivalents of NaBH
4
o
and one equivalent of I
low selectivity (entry 1). In tetrahydrofuran (THF) and diphenyl
ether (Ph O), the reaction didn’t perform well either (entries 2-
3). The reaction did not proceed well in solvents with different
polarity such as toluene, acetonitrile and
trifluoromethyl)benzene (entries 4-6). And 2a was observed in
2
as an additive at 140 C for 24 h with
2
(
8
2f) in 95% yield while naphthalene-1-thiol yield product (2g)
1%. Notably, hydroxy group and sulflydryl group were
(
selected in this reaction and only sulfhydryl group was
methylated (2h). Furthermore, when 4-aminobenzenethiol was
used and the reaction led to the formation of complex, inseparable
mixture. The substrates bearing different functional groups with
oxygen atom such as 4-methoxybenzenethiol (1i), 3,4-
4
0% yield in diethylene glycol dimethyl ether (DEGDME)
(entry 7). When DEGDME was replaced by 1,2-
dimethoxyethane (DME), the yield of 2a decreased apparently
and the yield of 3a increased (entry 8), which indicates that the
number of constitutional unit -OCH CH O- in solvent might
2 2
dimethoxybenzenethiol
(1j),
and
3-(tert-
affect reactivity and selectivity of this reaction. In order to
confirm this indication, crown ethers such as 15-crown-5 and
18-crown-6 were used as solvents. 18-Crown-6 demonstrated
higher reactivity and selectivity than 15-crown-5 (entries 9-10).
butyldimethylsilyl)benzenethiol (1k) were well tolerated and
the corresponding products (2i-2k) were obtained in 93%, 78%,
and 72%, respectively. Halogen groups at the para- and ortho-
position of the aromaticring also yielded methyl aryl sulfides
2
9
It was reported by Warchhold et al. that the reducibility of
NaBH is higher in 18-crown-6. Our result is consistent with
(
2l-2o) in good yields. Additionally, heteroaromatic ring can
also proceed in this reaction and yield 2-(methylthio)pyridine
2p) in 51% yield. The congesting 2,6-dimethylbenzenethiol
4
reported. Although the DEGDME and the 18-crown-6 used as
solvents gave out similar yield and selectivity, isotopic labelling
experiments demonstrated that nearly half amount of methyl
group in 1a comes from DEGDME when the DEGDME was
used as solvent. Scaling up the amount of NaBH and I , yield
4 2
of 2a was further improved (entries 11-13). Hence, the reaction
was performed in the 18-crown-6 as solvent with five
4
equivalents of NaBH and 2a could be generated nearly
quantitatively. With the decrease of temperature and reaction
time, poor yields of 2a were observed (entries 14-18) and the
reaction could not proceed without iodine. To verify the
(
only afford 2q in 31% yield. Thiophenols with strong electron-
withdrawing groups, such as 4-trifluoromethylbenzenethiol (1r)
and 3,5-bis(trifluoromethyl)benzenethiol (1s), could undergo
this reaction smoothly and afford the corresponding
methylation product (2r and 2s) in 75% and 41%, respectively.
Benzene-1,2-dithiol could produce two methyl group
4 2
simultaneously with double amount NaBH and I to afford 1,2-
bis(methylthio)benzene (2t) in 48% yield. Unfortunately, alkyl
thiol such as (4-(tert-butyl)phenyl)methanethiol only get
product 2u in trace. To verify the applicability of current
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method, the reaction was amplified to 5 mmol scale with a yield
of methyl (p-tolyl) sulfide 2a in 60% (413 mg) under the
standard conditions in 6 g of 18-crown-6.
bis(boryl)acetal (II) are minor intermediates (see Figure S2-S3).
To further confirm the reaction pathway, the reaction of
B(OMe) and thiophenol 1a was treated under the conditions
3
and product 2a was obtained in 78% yield (Eq. 1). These results
indicated that the methoxyborane (III) is major intermediate in
the reaction.
1
2
3
4
5
6
7
8
9
Table 2. Substrate scope for reductive functionalization of
a
CO
2
1
) 18-crown-6
R
0 oC, 0.5 h
R
8
SH
SH
+
NaBH4
+
CO2
SCH3
SCH3
2) I2, 140 oC, 12 h
1
2
1
8-crown-6
SCH3
SCH3
SCH3
Me
SCH3
SCH3
+
NaBH4 + B(OCH3)3
(Eq. 1)
I2 0.5 eq
o
1
eq.
1 eq
1a
Me
140 C, 12 h
2a
Me
Me
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
78%
Me
a 90%
2c 75%
iPr
2d 82%
tBu
2e 93%
2b 68%
2
SCH3
SCH3
SCH3
Furthermore, two control experiments were conducted. First,
an isotope-labelling NaBD was employed in the reaction to
afford 2a' (Eq. 2) and the result demonstrated that H atom on
SCH3
SCH3
4
OMe
OMe
2f 95%
OH
h 81%
OMe
the -SCH3 group are from NaBH . When the reaction of
2
g 81%
4
2
2i 93%
2j 78%
SCH3
N
4 2 2
thiophenol 1a with NaBH was operated in N (without CO )
SCH3
SCH3
SCH3
Cl
SCH3
Br
SCH3
under the conditions and no product 2a generated as well as the
thiophenol 1a remained after hydrolysis (Eq. 3), which
confirmed that the reaction did not work without CO2.
OTBS
Cl
l 85%
Br
2m 76%
2n 61%
2o 74%
2p 51%
2
k 72%
2
SH
SCD3
SCH3
SCH3
1) 18-crown-6
SCH3
SCH3
Me
SCH3
SCH3
0 oC, 0.5 h
8
Me
NaBD4 + CO2
5 eq.
+
(Eq. 2)
2) I2 1.6 eq
F3C
CF3
1a
Me
2tb 48%
2a'
CF3
o
2
q 31%
tBu
2u trace
140 C, 12 h
2
s 41%
2
r 75%
Me
D > 94%
90%
a
Reaction conditions: 1) Thiophenols (0.5 mmol), NaBH
4
(2.5 mmol), CO
2
1
4
SH
SCH3
SH
o
o
b
1) 18-crown-6
atm, 18-crown-6 (0.6 g); 80 C, 0.5 h; 2) iodine (0.8 mmol), 140 C, 12 h. NaBH
5.0 mmol), iodine (1.6 mmol).
80 oC, 0.5 h H3O+
(
+
N2
+
(Eq. 3)
+
NaBH4
eq.
2
) I2 1.6 eq
5
1
Me
a
o
140 C, 12 h
The current approach also provided a synthetic shortcut for
the Fensulfothion precursor, which was used as insecticide to
worms on corn and sugar cane. As shown in Figure 1, the
Fensulfothion precursor could be efficiently produced through
highly selective methylation of 1h followed by phosphorylation
reaction with O, O-diethyl phosphorochloridothioate.
Me
Me
2a: N.D.1a: recoverd
30
On the basis of the above results, a plausible mechanism for
this reductive CO with thiolation under NaBH /I system was
illustrated as follows (Scheme 3). NaBH would be oxidized by
iodine and release more reactive species BH accompanied with
. The BH reacts with carbon dioxide to produce boryl
2
4 2
4
3
S
CO2 ~1 atm
NaBH4/I2
8-crown-6
H
2
3
SH
SCH3
SCH3
EtO
P
OEt
28a,28b
formate I.
B-OCH (III) in 18-crown-6. The methoxyborane (III) could
be attacked by Na[BH
thiophenol 1 and NaBH
3
The boryl formate I reacts with BH to give out
1
Cl
3
o
1
40 C, 12 h
DABCO
90%
3
SAr] generated by the reaction of
4
and finally transfer methyl group to
8
1%
OEt
OH
OH
O
P
1h
S
the sulfur atom to afford aryl methyl sulfides 2. When the
reaction was performed in 1,4-dioxane, the boryl formate I first
2
h
EtO
3
h: Fensulfothion precursor
reacts with Na[BH
with the BH to generate intermediate B. The intermediate B
reacts with Na[BH SR] to release dithioacetal 3.
3
SR] to afford thioformate A, which reacts
Figure 1. Late-stage diversification
The net consequence of this reductive functionalization of
is cleavage of two C=O bonds and the formation of three
C-H bonds and one C-S bonds, which is rare to form aryl methyl
sulfides via the complete deoxygenation of CO . Hydroboration
of CO is of interest from a fundamental reactivity perspective.
Stepwises hydroboration of CO to boryl formate (I),
bis(boryl)acetal (II), and methoxyborane (III) species (Scheme
). The methoxyborane (III) species could react with
3
28b
3
CO
2
ArSH + NaBH4
NaBH4 + I2
1
H2
H
O
2
H2 + NaI
CO2
BH3
C
O
[ArSBH3]Na
S
CH3
2
BH3
H2B
O
Ar
CH3
2
H B
I
III
2
2
In 18-crown-6
2
[
RSBH3]Na
thiophenols to finally afford methyl aryl sulfides.
BH3
O
C
[
RSBH3]Na
O
RS-CH2-OBH2
RS-CH -SR
H2
RS
H
2
B
H
C
B
H
C
B
H
CH3
A
B
3
CO2
B
O
H
B
O
O
B
B
O
28b
In 1,4-dioxane
I
II
III
Scheme 3. Plausible selective reduction of CO
2
with thiophenol
Scheme 2. Stepwises hydroboration of CO
In order to investigate the intermediates of CO
this process, the reaction of NaBH , CO , and I was monitored
2
2
reduced in
CONCLUSION
4
2
2
In summary, we have developed a transition-metal-free
system to achieve reduction thiolation of CO utilizing
NaBH /I system into methyl aryl sulfides. The reaction
1
by NMR. H NMR revealed that methoxyborane (III) is major
intermediate appeared at 3.26 ppm while boryl formate (I) and
2
4
2
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features highly reductive selectivity, 18-crown-6 as solvent and
(101 MHz, CHLOROFORM-D) δ 137.7, 135.9, 129.9, 126.6,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
broad functional groups tolerance with moderate to excellent
yields. This work offers not only a protocol to produce methyl
aryl sulfides, but also provides a guide for selective reduction
of CO . Subsequent research is currently undergoing, including
2
further mechanism and application.
124.7, 20.1, 15.4. GC-MS: 138.
3
2
Methyl(o-tolyl)sulfane (2c) . Yield 75% (52 mg), colorless oil;
H NMR (400 MHz, CHLOROFORM-D) δ 7.16 (t, J = 7.6 Hz,
1
1
H), 7.06 (dd, J = 6.3, 5.3 Hz, 2H), 6.94 (d, J = 7.4 Hz, 1H), 2.46
1
3
1
(
s, 3H), 2.32 (s, 3H). C{ H} NMR (101 MHz, CHLOROFORM-
D) δ 138.7, 138.2, 128.80, 127.4, 126.0, 123.8, 21.5, 16.0. GC-MS:
38.
(4-Isopropylphenyl)(methyl)sulfane (2d) . Yield 82% (68 mg),
1
EXPERIMENTAL SECTION
General Information
3
3
1
colorless oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.21 (d,
J = 8.2 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 2.87 (m, 1H), 2.47 (s,
All solvents were dried and distilled before use according to the
standard methods. Unless otherwise noted, the starting materials
were commercially available and used without further purification.
1
3
1
2
H), 1.23 (d, J = 6.9 Hz, 6H). C{ H} NMR (101 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CHLOROFORM-D) δ 146.2, 135.2, 127.3, 127.1, 33.8, 24.1, 16.5.
GC-MS: 166.
2
CO comes from tank directly. Thin layer chromatography (TLC)
34
(4-(tert-Butyl)phenyl)(methyl)sulfane (2e) . Yield 93% (84
employed glass 0.25 mm silica gel plates. Flash chromatography
columns were packed with 200-300 mesh silica gel in hexane and
1
mg), colorless oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.32
(d, J = 1.9 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.22 (d, J = 2.0 Hz,
1
13
1
19
31
ethyl acetate. H NMR, C{ H} NMR, F NMR, P NMR data
were recorded with 600 MHz, 400 MHz spectrometers with
tetramethylsilane as an internal standard. All chemical shifts (δ) are
reported in ppm and coupling constants (J) in Hz. All chemical
shifts are reported relative to tetramethylsilane and d-solvent peaks
1
3
1
1
H), 7.21 (d, J = 2.1 Hz, 1H), 2.47 (s, 3H), 1.30 (s, 9H). C{ H}
NMR (101 MHz, CHLOROFORM-D) δ 148.5, 134.9, 127.0,
26.0, 34.51, 31.4, 16.4. GC-MS: 180.
1
3
5
Methyl(naphthalen-2-yl)sulfane (2f) . Yield 95% (83 mg),
1
white solid; H NMR (400 MHz, CHLOROFORM-D) δ 7.73 (dd,
J = 17.4, 8.2 Hz, 3H), 7.58 (d, J = 1.5 Hz, 1H), 7.47 – 7.33 (m, 3H),
(77.16 ppm, chloroform), respectively. Unless otherwise indicated,
all reagents and solvents were used as obtained commercially.
HRMS were obtained with APCI in positive ion mode on IT-TOF
instrument.
1
3
1
2.55 (s, 3H). C{ H} NMR (101 MHz, CHLOROFORM-D) δ
1
1
36.2, 134.0, 131.4, 128.3, 127.8, 126.9, 126.6, 125.8, 125.3,
23.4, 15.9. GC-MS: 174.
General procedure for (2a-2t). To a 25 mL Schlenk tube
3
1
Methyl(naphthalen-1-yl)sulfane (2g) . Yield 81% (70 mg),
equipped with a magnetic stir bar was added NaBH
mmol), the tube was evacuated and filled CO for three times. Then
the thiophenols (0.5 mmol) and 18-crown-6 (0.6 g) were added to
the tube under CO atmosphere. The reaction tube was sealed and
stirred at 80 C (heating mantle temperature) for 30 min, then the
reaction mixture allowed to room temperature, I (203.1 mg 0.8
mmol) was added under CO atmosphere, the reaction tube was
4
(94.6 mg, 2.5
1
yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ 8.31 – 8.22
2
(
m, 1H), 7.87 – 7.78 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58 – 7.46
13
1
(m, 2H), 7.44 – 7.33 (m, 2H), 2.56 (s, 3H). C{ H} NMR (101
2
o
MHz, CHLOROFORM-D) δ 135.9, 133.7, 131.7, 128.6, 126.4,
1
26.2, 125.9, 125.8, 124.4, 123.6, 16.3. GC-MS: 174.
2
3
6
4
-(Methylthio)phenol (2h) . Yield 81% (57 mg), white solid;
2
1
o
H NMR (400 MHz, CHLOROFORM-D) δ 7.25 – 7.19 (m, 2H),
sealed again and stirred for 12 h at 140 C (heating mantle
temperature). After completion, the residue was carefully quenched
with water and the mixture was extracted with ethyl acetate (3 x 10
1
3
1
6
.82 – 6.74 (m, 2H), 5.03 (s, 1H), 2.44 (s, 3H). C{ H} NMR (101
MHz, CHLOROFORM-D) δ 154.2, 130.5, 129.0, 116.2, 18.2. GC-
1
MS: 140.
mL). The yields were determined by H NMR technique using
3
1
(4-Methoxyphenyl)(methyl)sulfane (2i) .Yield 93% (72 mg),
yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.26 (m,
trichloroethylene (45 μL, 0.5 mmol) as an internal standard. The
reaction mixture was purified by silica gel column chromatography
with hexane/ethyl acetate as the eluent to afford the desired methyl
aryl sulfides. All of the products were characterized by NMR
techniques.
1
1
3
1
2
H), 6.86 (m, 2H), 3.79 (s, 3H), 2.45 (s, 3H). C{ H} NMR (101
MHz, CHLOROFORM-D) δ 158.3, 130.3, 128.9, 114.7, 77.5, 77.2,
6.8, 55.5, 18.2. GC-MS: 154.
3,4-Dimethoxyphenyl)(methyl)sulfane (2j) . Yield 78% (72
7
3
7
(
Experimental Procedure for large-scale reaction for the
synthesis of compound 2a. To a 250 mL Schlenk tube equipped
1
mg), colorless oil; H NMR (400 MHz, CHLOROFORM-D) δ 6.88
(m, 2H), 6.83 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.47 (s, 3H).
with a magnetic stir bar was added NaBH
tube was evacuated and filled CO for three times. Then the
thiophenol 1a (621 mg, 5 mmol) and 18-crown-6 (6 g) were added
to the tube under CO atmosphere. The reaction tube was sealed
and stirred at 80 C (heating mantle temperature) for 30 min, then
the reaction mixture allowed to room temperature, I (2.03 g, 8
mmol) was added under CO atmosphere carefully and slowly, the
reaction tube was sealed again and stirred for 12 h at 140
heating mantle temperature). After completion, the residue was
4
(946 mg, 25 mmol), the
1
3
1
C{ H} NMR (101 MHz, CHLOROFORM-D) δ 149.2, 147.8,
2
1
29.4, 120.8, 112.4, 111.9, 56.1, 56.0, 18.0. GC-MS: 184.
tert-Butyldimethyl(3-(methylthio)phenoxy)silane (2k). Yield
2
1
o
72% (91 mg), colorless oil; H NMR (400 MHz, CHLOROFORM-
D) δ 7.13 (t, J = 8.0 Hz, 1H), 6.85 (ddd, J = 7.8, 1.8, 0.9 Hz, 1H),
2
6
.74 (t, J = 2.1 Hz, 1H), 6.61 (ddd, J = 8.1, 2.3, 0.9 Hz, 1H), 2.46
2
13
1
o
(s, 3H), 0.98 (s, 9H), 0.20 (s, 6H). C{ H} NMR (101 MHz,
C
CHLOROFORM-D) δ 156.1, 139.6, 129.6, 119.5, 118.2, 116.9,
(
+
2
5.8, 18.3, 15.8, -4.3. HRMS (APCI), m/z: [M+H] calcd. for
carefully quenched with water and the mixture was extracted with
ethyl acetate (3 x 50 mL). The reaction mixture was purified by
silica gel column chromatography with hexane/ethyl acetate as the
eluent to afford the 2a (413 mg, 60% yield).
+
13
C H23OSSi 255.1239; found 255.1236.
3
8
(
4-Chlorophenyl)(methyl)sulfane (2l) . Yield 85% (67 mg),
yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.25 (dd, J
= 7.1, 1.5 Hz, 2H), 7.20 – 7.15 (m, 2H), 2.47 (s, 3H). C{ H} NMR
(101 MHz, CHLOROFORM-D) δ 137.1, 131.0, 129.0, 128.0, 16.2.
GC-MS: 158.
(4-Bromophenyl)(methyl)sulfane (2m) . Yield 76% (77 mg),
white solid, M.p. 32-34 C; H NMR (400 MHz, CHLOROFORM-
D) δ 7.42 – 7.36 (m, 2H), 7.11 (d, J = 8.6 Hz, 2H), 2.46 (s, 3H). C
{ H} NMR (101 MHz, CHLOROFORM-D) δ 137.8, 131.9, 128.2,
1
13
1
3
1
Methyl(p-tolyl)sulfane (2a) . Yield 90% (62 mg), colorless oil;
H NMR (400 MHz, CHLOROFORM-D) δ 7.18 (d, J = 6.3 Hz,
1
13
1
2
H), 7.08 (d, J = 7.9 Hz, 2H), 2.45 (s, 3H), 2.30 (s, 3H). C{ H}
3
9
NMR (101 MHz, CHLOROFORM-D) δ 137.7, 135.9, 129.9,
o
1
126.6, 124.7, 20.0, 15.4. GC-MS: 138.
1
3
3
2
Methyl(m-tolyl)sulfane (2b) . Yield 68% (43 mg), colorless
1
1
oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.22 – 7.11 (m,
1
3
1
118.7, 16.1. GC-MS: 202.
3
H), 7.08 – 7.02 (m, 1H), 2.45 (s, 3H), 2.33 (s, 3H). C{ H} NMR
33
(
2-Chlorophenyl)(methyl)sulfane (2n) . Yield 61% (48 mg),
1
yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.34 (dd, J
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The Journal of Organic Chemistry
=
7.9, 1.3 Hz, 1H), 7.27 – 7.22 (m, 1H), 7.16 (dd, J = 7.9, 1.4 Hz,
ACKNOWLEDGMENT
1
3
1
1
2
3
4
5
6
7
8
9
1H), 7.08 (td, J = 7.7, 1.5 Hz, 1H), 2.47 (s, 3H). C{ H} NMR
101 MHz, CHLOROFORM-D) δ 137.83, 131.95, 129.48, 127.29,
25.67, 125.61, 15.30. GC-MS: 158.
2-Bromophenyl)(methyl)sulfane (2o) . Yield 74% (75 mg),
We are grateful for the financial support from the National Natural
Science Foundation of China (Nos. 91645120, 21871163, and
21911530097).
(
1
4
0
(
1
yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.51 (dd, J
7.9, 1.3 Hz, 1H), 7.29 (td, J = 7.9, 1.3 Hz, 1H), 7.12 (dd, J = 8.0,
REFERENCES
=
13
1
1. (a) Jacob, C.; Battaglia, E.; Burkholz, T.; Peng, D.; Bagrel, D.;
Montenarh, M. Control of Oxidative Posttranslational Cysteine
Modifications: From Intricate Chemistry to Widespread Biological and
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Action. J. Agric. Food Chem. 2016, 64, 4471-4477.
1
.4 Hz, 1H), 7.03 – 6.94 (m, 1H), 2.46 (s, 3H). C{ H} NMR (101
MHz, CHLOROFORM-D) δ 139.8, 132.8, 127.9, 125.8, 125.5,
121.9, 15.8. GC-MS: 202.
3
1
2
-(Methylthio)pyridine (2p) . Yield 51% (32 mg), yellow oil;
1
H NMR (400 MHz, CHLOROFORM-D) δ 8.46 – 8.41 (m, 1H),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.51 – 7.44 (m, 1H), 7.18 (dd, J = 8.2, 0.6 Hz, 1H), 7.00 – 6.93 (m,
13
1
1
H), 2.56 (s, 3H). C{ H} NMR (101 MHz, CHLOROFORM-D)
δ 160.1, 149.6, 135.9, 121.6, 119.2, 13.4. GC-MS: 125.
4
1
2. (a) Delhotal Landes, B.; Petite, J. P.; Flouvat, B. Clinical
Pharmacokinetics of Lansoprazole. Clin. Pharmacokinet. 1995, 28, 458-
(2,6-Dimethylphenyl)(methyl)sulfane (2q) . Yield 31% (21
1
mg), yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.10
4
70. (b) Fontecave, M.; Ollagnier-de-Choudens, S.; Mulliez, E. Biological
s, 3H), 2.56 (s, 6H), 2.23 (s, 3H). 13C{ H} NMR (101 MHz,
1
(
Radical Sulfur Insertion Reactions. Chem. Rev. 2003, 103, 2149-2166. (c)
Dayan, A. D. Albendazole, Mebendazole and Praziquantel. Review of Non-
clinical Toxicity and Pharmacokinetics. Acta Trop. 2003, 86, 141-159.
3. (a) Smith, B. R.; Eastman, C. M.; Njardarson, J. T. Beyond C, H, O,
and N! Analysis of the Elemental Composition of U.S. FDA Approved
Drug Architectures. J. Med. Chem. 2014, 57, 9764-9773. (b) Wu, Z.;
Tucker, I. G.; Razzak, M.; Medlicott, N. J. Stability of Ricobendazole in
Aqueous Solutions. J. Pharm. Biomed. Anal. 2009, 49, 1282-1286.
CHLOROFORM-D) δ 142.8, 135.3, 128.2, 128.2, 21.9, 18.4. GC-
MS: 152.
3
1
Methyl(4-(trifluoromethyl)phenyl)sulfane (2r) . Yield 75%
1
(72 mg), yellow oil; H NMR (400 MHz, CHLOROFORM-D) δ
7
.50 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 2.49 (s, 3H).
1
3
1
C{ H} NMR (101 MHz, CHLOROFORM-D) δ: 144.0, 126.8 (q,
C-F
C-F
2
J
= 32.6 Hz), 124.4 (q, 1 J = 271.5 Hz), 125.6, 125. 7 (q, 3
4
. For selected reviews, see: (a) Davis, B. G. Synthesis of Glycoproteins.
C-F
19
J
= 3.7 Hz), 15.0. F NMR (565 MHz, CHLOROFORM-D) δ -
Chem. Rev. 2002, 102, 579-601. (b) Davis, B. G. Mimicking
Posttranslational Modifications of Proteins. Science 2004, 303, 480-482. (c)
Jiang, C. S.; Muller, W. E.; Schroder, H. C.; Guo, Y. W. Disulfide- and
Multisulfide-Containing Metabolites from Marine Organisms. Chem. Rev.
2012, 112, 2179-2270.
6
2.19. GC-MS: 192.
3,5-Bis(trifluoromethyl)phenyl)(methyl)sulfane (2s). Yield
(
1
4
1% (53 mg), colorless oil; H NMR (400 MHz, CHLOROFORM-
13
1
D) δ 7.61 (s, 3H), 2.57 (s, 3H). C{ H} NMR (101 MHz,
CHLOROFORM-D) δ 142.5, 132.4, 132.0, 125.7, 124.6, 121.9,
5
. Gianessi, L. P. Benefits of Triazine Herbicides. In Triazine
1
9
Herbicides: Risk Assessment; Ballantine, L. G., McFarland, J. E., Eds.; ACS
Symposium Series, Vol. 683; American Chemical Society: Washington,
DC, 1998, Chapter 1, pp 1-8.
6. Dailey, O. D., Jr.; Bland, J. M.; Trask-Morrell, B. J. Preparation and
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Substituted Sulmazole and Isomazole Analogues. J. Med. Chem. 1990, 33,
2231-2239.
1
18.5, 15.4. F NMR (565 MHz, CHLOROFORM-D) δ -62.98.
+
+
HRMS(APCI), m/z: [M+H] calcd. for C
61.0168.
,2-Bis(methylthio)benzene (2t) . Yield 48% (41 mg),
9 7 6
H F S 261.0173; found
2
3
7
1
1
colorless oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.23 –
13
1
7
.19 (m, 2H), 7.16 (m, 2H), 2.47 (s, 6H). C{ H} NMR (101 MHz,
CHLOROFORM-D) δ 137.5, 126.8, 126.0, 16.4. GC-MS: 170.
Methyl deuterated methyl(p-tolyl)sulfane (2a'). Yield 88% (62
mg), colorless oil; H NMR (400 MHz, CHLOROFORM-D) δ 7.19
1
8
. De Keijzer, J.; Mulder, A.; de Haas, P. E.; de Ru, A. H.; Heerkens, E.
(d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.47 – 2.43 (s, 1H),
M.; Amaral, L.; van Soolingen, D.; van Veelen, P. A. Thioridazine Alters
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10. Selected articles, see: (a) Liu, J.; Robins, M. J. S Ar Displacements
N
with 6-(Fluoro, Chloro, Bromo, Iodo, and Alkylsulfonyl)purine
Nucleosides: Synthesis, Kinetics, and Mechanism. J. Am. Chem. Soc. 2007,
1
3
1
2
1
.33 (s, 3H). C{ H} NMR (151 MHz, CHLOROFORM-D) δ
35.1, 134.8, 129.7, 127.4, 21.0, 16.1 (m). GC-MS: 141.
30
O,O-Diethyl O-(4-(methylthio)phenyl) phosphorothioate (3h) .
1
Yield 72% (105 mg), colorless oil; H NMR (600 MHz,
CHLOROFORM-D) δ 7.23 (d, J = 8.7 Hz, 2H), 7.14 – 7.09 (m,
2
H), 4.27 – 4.18 (m, 4H), 2.46 (s, 3H), 1.36 (t, J = 7.2 Hz, 6H).
1
3
1
C{ H} NMR (151 MHz, CHLOROFORM-D) δ 148.6, 148.6,
1
1
35.0, 128.2, 121.6, 121.6, 77.4, 77.2, 77.0, 65.2 (d, J = 5.7 Hz),
6.6, 16.0 (d, J = 7.3 Hz). P NMR (243 MHz, CHLOROFORM-
3
1
1
29, 5962-5968. (b) Duechler, M.; Leszczynska, G.; Sochacka, E.; Nawrot,
D) δ 63.88. GC-MS: 292.
B. Nucleoside Modifications in the Regulation of Gene Expression: Focus
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ASSOCIATED CONTENT
Supporting Information
11. For selected articles and reviews, see: (a) Wenkert. E., Ferreira. T.,
Michelotti. E. Nickel -induced Conversion of Carbon-Sulphur into Carbon-
Carbon Bonds. One-step Transformations of Enol Sulphides into Olefins
and Benzenethiol Derivatives into Alkylarenes and Biaryls. J. Chem. Soc.,
Chem. Commun., 1979, 637-638. (b) Egi. M.; Liebeskind. L. S.
Hereroaromatic Thioether−Organostannane Cross-Coupling. Org. Lett.
The Supporting Information is available free of charge on the ACS
Publications website.
Solvent effect results in Figure S1. 1H NMR spectrum for
mechanistic study as shown in Figure S2 and Figure S3. Control
experiments for the mechanism verification as shown in Figure S4.
2
003, 5, 801-802. (c) Denmark, S. E.; Cresswell, A. J. Iron-Catalyzed
Cross-Coupling of Unactivated Secondary Alkyl Thio Ethers and Sulfones
with Aryl Grignard Reagents. J. Org. Chem., 2013, 78, 12593-12628. (d)
Li. J. -X.; An. Y. -N.; Yang. S. -R.; Wu. W.; Jiang. H.-F. Palladium-
catalyzed C–S Bond Activation and Functionalization of 3-Sulfenylindoles
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1594. (e) Kona, C. N.; Nishii, Y.; Miura, M. Thioether-Directed Selective
C4 C−H Alkenylation of Indoles under Rhodium Catalysis. Org. Let. 2018,
AUTHOR INFORMATION
Corresponding Author
*
cjxi@tsinghua.edu.cn
2
0, 4898-4901. (f) Zhu. D.; Shi. L. Ni-Catalyzed Cross-coupling of Aryl
Notes
Thioethers with Alkyl Grignard Reagents via C–S Bond Cleavage. Chem.
Commun. 2018, 54, 9313-9316. (g) Wang, L.; He, W.; Yu, Z. Transition-
The authors declare no competing financial interests.
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Page 6 of 7
metal Mediated Carbon–sulfur Bond Activation and Transformations.
2
Wang, S.; Xi, C. Recent Advances in Nucleophile-triggered CO -
Chem. Soc. Rev. 2013, 42, 599-621. (h) Modha, S. G.; Mehta, V. P.; Van
der Eycken, E. V. Transition Metal-catalyzed C–C Bond Formation via C–
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incorporated Cyclization Leading to Heterocycles. Chem. Soc. Rev. 2019,
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M.; Cantat, T. A Diagonal Approach to Chemical Recycling of Carbon
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2. (a) Ram. V. J.; Agarwal. N. Carbanion-induced Base-catalyzed
Synthesis of Unsymmetrical Biaryls from Suitably Functionalized 2H-
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