Indium-Catalyzed Reductive Sulfidation of Esters by Using Thiols: An Approach to the Diverse Synthesis of Sulfides

Article abstract of DOI:10.1002/ejoc.201501559

A new reductive preparation of unsymmetrical sulfides from esters and thiols in the presence of InI₃ and either 1,1,3,3-tetramethyldisiloxane (TMDS) or PhSiH₃ as the reductant was developed. This protocol was applied to not only benzoic acid esters that have a methoxy, methyl, chloro, bromo, iodo, or trifluoromethyl group on the aromatic ring but also aliphatic acid esters with either aromatic or aliphatic thiols. A reaction mechanism is proposed by using Hammett plot results and several control experiments. The reductive preparation of unsymmetrical sulfides from esters and thiols by using InI₃ and either 1,1,3,3-tetramethyldisiloxane (TMDS) or PhSiH₃ was developed. Several mechanistic studies support that the present transformation proceeds through O,S-and S,S-acetals as the reaction intermediates. TMDS = 1,1,3,3-tetramethyldisiloxane, R = aliphatic group.

Full text of DOI:10.1002/ejoc.201501559

DOI: 10.1002/ejoc.201501559
Full Paper
Reductive Sulfidation
Indium-Catalyzed Reductive Sulfidation of Esters by Using
Thiols: An Approach to the Diverse Synthesis of Sulfides
Takahiro Miyazaki,[a] Shinsei Kasai,[a] Yohei Ogiwara,[a] and Norio Sakai*[a]
Abstract: A new reductive preparation of unsymmetrical sulf- or trifluoromethyl group on the aromatic ring but also aliphatic
ides from esters and thiols in the presence of InI3 and either
1,1,3,3-tetramethyldisiloxane (TMDS) or PhSiH3 as the reductant
was developed. This protocol was applied to not only benzoic
acid esters that have a methoxy, methyl, chloro, bromo, iodo,
acid esters with either aromatic or aliphatic thiols. A reaction
mechanism is proposed by using Hammett plot results and sev-
eral control experiments.
Introduction
tion, we envision using esters as substrates for a reductive
sulfidation reaction with thiols, as similar O,S- or S,S-acetal inter-
mediates could be generated from esters. To the best of our
knowledge, this reductive approach to thioethers from esters
and thiols is unexplored.
Carbon–sulfur bond formation is an important area of organic
chemistry because of the synthetic versatility of the products,
including sulfides (thioethers), the structure of which is found in
biologically and pharmacologically active compounds.[1] Thiols
(mercaptans) are one of the more popular sulfidation reagents,
and a variety of synthetic methods that use them for C–S bond
formation have been developed.[2] Typically, C-sulfidation reac-
tions that use thiols involve the substitution of alkyl halides
or pseudo-halides by “RS” nucleophiles, which is known as a
Williamson-type sulfide synthesis.[3] The coupling of aryl or alk-
enyl halides with thiols by using transition metals, an Ullmann-
type reaction, is also known as a powerful strategy for thioether
preparation, particularly an Caryl-sulfidation.[4] The addition of
the S–H bond of thiols to unsaturated C–C bonds of alkenes,[5]
alkynes,[6] or allenes[7] is another procedure that is used for thio-
ether formation. This type of reaction offers one of the most
efficient routes to prepare sulfides in terms of atom economy.
Carbonyl compounds can also be employed as substrates for
thioetherification reactions with thiols. Recently, decarboxyl-
ative C–S cross-coupling reactions between carboxylic acids
and thiols with a transition-metal catalyst were developed to
form thioethers.[8] Several research groups have employed a re-
ductive approach to thioethers by using thiols and carbonyl
compounds, such as aldehydes[9] or ketones.[10] In 2012, we re-
ported that carboxylic acids are also available for this type of
transformation when used with an indium/hydrosilane reducing
system.[11] In this reaction, a variety of aromatic/aliphatic carb-
oxylic acids can be used to produce sulfides, which are formed
from the corresponding O,S- or S,S-acetal key intermediates
(Figure 1). On the basis of a plausible mechanism of the reac-
Figure 1. Reductive preparation of sulfides from (a) carboxylic acids with thi-
ols and (b) esters with thiols.
We disclose, herein, the full details of a new reductive cata-
lytic construction of thioethers from esters and thiols. This
present reaction is efficiently promoted by InI3 with either
1,1,3,3-tetramethyldisilazane (TMDS) or PhSiH3 as a reducing re-
agent to afford a variety of sulfides from aromatic/aliphatic
carboxylic acid esters and aryl/alkyl thiols (Figure 1). In addition,
several mechanistic investigations have suggested that either
an O,S- or S,S-acetal is formed during the reaction as an inter-
mediate, and a negative slope in the Hammett plot indicates
the existence of a cationic intermediate in the rate-limiting step.
Results and Discussion
[a] Department of Pure and Applied Chemistry,
Faculty of Science and Technology, Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
1. Aromatic Esters and Aromatic Thiols as Substrates
E-mail: sakachem@rs.noda.tus.ac.jp
http://www.rs.tus.ac.jp/sakaigroup/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501559.
The optimization of the reaction conditions for the sulfidation
was carried out by using methyl benzoate and p-toluenethiol
(1.2 equiv.) as model substrates in 1,2-dichloroethane (1,2-DCE)
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at 80 °C. First, we screened for the hydrosilane in the reaction methyl benzoate had only a slight effect on the transformation,
(Table 1). When InBr3 was combined with Et3SiH, the sulfidation and corresponding thioethers 6–8 were produced in relatively
was ineffective (Table 1, Entry 1). When hydrosilanes such as good yields (Table 2, Entries 5–7). Also, methyl benzoates that
Me2PhSiH and MePh2SiH were used, the desired thioether 1 contain a chlorine atom gave thioethers 9–11 in moderate
was formed in low yield (Table 1, Entries 2 and 3). However, yields, regardless of the position of the chloro group, whereas
thioether 1 was obtained in a 41 % yield when PhSiH3 was em- the use of o-bromobenzoate led to a decrease in the yield of
ployed in the reaction (Table 1, Entry 4). Interestingly, when the 12 (Table 2, Entries 8–11). Ethyl benzoate with an iodine atom
hydrosiloxane 1,1,3,3-tetramethyldisiloxane (TMDS) was used as at the para position was also compatible with the reaction and
the reducing reagent, thioether 1 was obtained in 86 % yield produced thioether 13 in 66 % yield (Table 2, Entry 12). How-
(Table 1, Entry 5). Next, change of the Lewis acid to aluminum ever, the sulfidation reaction with methyl o-iodobenzoate led
bromide did not result in the desired sulfidation reaction to a low conversion into thioether 14 along with a 16 % genera-
(Table 1, Entry 6).[12] Also, zinc bromide had a lower catalytic tion of sulfide 1, which indicates that deiodination had occurred
activity than indium bromide (Table 1, Entry 7). Using the non- as a side reaction (Table 2, Entry 13). When the reaction was
polar solvent toluene in the sulfidation reaction provided thio- carried out with aromatic esters that have the strong electron-
ether 1 in a 72 % yield (Table 1, Entry 8), whereas using aceto- withdrawing trifluoromethyl group, the formation of the corre-
nitrile did not allow for the expected sulfidation to proceed and sponding thioether 15 was rather low (Table 2, Entry 14).
resulted in the recovery of the starting ester (Table 1, Entry 9).
Table 2. Reaction of methyl benzoates with aryl mercaptans.[a]
Gratifyingly, the use of InI3, a stronger Lewis acid, improved the
product yield to 89 % without the recovery of the starting ester
(Table 1, Entry 10). Moreover, when the amount of TMDS was
increased to 8 equiv. (Si–H), the amount of thioether 1 in-
creased to an almost quantitative yield (Table 1, Entry 11).
Table 1. Optimization for reductive condensation of an ester with a thiol.[a]
Entry
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
H
H
H
H
p-MeO
p-Cl
p-Br
2
3
4
5
6
7
8
9
10
11
12
13
14
15
72
29
68
36
81
72
67
60
55
57
34
66
35[d]
40
o-Br
p-Me
p-MeO
m-PhO
p-Cl
m-Cl
o-Cl
o-Br
p-I
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-Me
Entry
Catalyst
Silane
Conversion [%][b]
Yield [%][b]
1
2
InBr3
InBr3
InBr3
InBr3
InBr3
AlBr3
ZnBr2
InBr3
InBr3
InI3
Et3SiH
Me2PhSiH
MePh2SiH
PhSiH3
TMDS
TMDS
TMDS
TMDS
TMDS
48
74
70
70
86
11
24
77
0
18
6
41
86
0
20
72
9
3[c]
4
10
11
12[c]
13
14
5
6
7
o-I
p-CF3
8[c]
9[d]
10
11[e]
[a] Reagents and conditions: methyl ester (0.6 mmol), thiol (0.72 mmol), InI3
(0.03 mmol), TMDS (2.4 mmol), 1,2-DCE (0.6 mL), 80 °C, 20 h. [b] Isolated
yields. [c] An ethyl ester was used as a substrate. [d] Deiodination occurred
as a side reaction, and product 1 was also generated in a 16 % GC yield.
<1
>99
>99
0
89
TMDS
TMDS
InI3
96 (90)[f]
[a] Reagents and conditions: methyl benzoate (0.6 mmol), p-toluenethiol
(0.72 mmol), InI3 (0.03 mmol), TMDS (1.8 mmol), 1,2-DCE (0.6 mL), 80 °C, 20 h.
[b] Determined by GC analysis. [c] Toluene was used as the solvent. [d] MeCN
was used as the solvent at 60 °C. [e] TMDS (Si–H, 8 equiv.) was used. [f] Iso-
lated yield in parentheses.
2. Aromatic Esters and Aliphatic Thiols as Substrates
The sulfidation of aromatic esters with aliphatic thiols, instead
To expand the generality of the sulfidation, the reaction was of aromatic thiols, was examined next (Scheme 1). For instance,
then carried out with various aromatic esters and aromatic thi- when methyl benzoate was treated with 1-octanethiol under
ols under the optimal conditions (Table 2). The reaction of our optimized reaction conditions, the desired thioether 16 was
methyl benzoate with p-methoxybenzenethiol gave the corre- obtained in 60 % yield. The reactions between esters that con-
sponding thioether 2 in 72 % yield (Table 2, Entry 1). On the tain an electron-donating group such as a methyl or methoxy
other hand, the use of p-chlorobenzenethiol led to thioether 3 group and octanethiol gave thioethers 17 and 18 in good
in a decreased yield (Table 2, Entry 2). Bromo-substituted yields. On the other hand, when methyl p-chlorobenzoate was
benzenethiols were also employed, but the reaction with the used, the yield of thioether 19 decreased to 39 %. As an exten-
ortho-substituted derivative was more influenced by steric fac- sion, benzylthiol (benzyl mercaptan) or tert-butylthiol (tert-butyl
tors than that of the para-substituted benzenethiol (Table 2, mercaptan) gave expected thioethers 20 and 21 in 50 and 38 %
Entries 3 and 4). A substituent on the benzene ring of the yield, respectively.
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In the case of p-methoxybenzenethiol, the expected product 23
was formed in moderate yield under both reaction conditions
(Table 3, Entries 3 and 4). On the other hand, when benzenethi-
ols with a bromine atom at either the para or ortho position
were subjected to conditions A, the yields of sulfides 24 and
25 highly improved to 92 and 88 % yield, respectively (Table 3,
Entries 5 and 7). In contrast, using conditions B resulted in re-
markably decreased yields of the same sulfides (Table 3, En-
tries 6 and 8). Aryl esters that have a naphthyl group on the
aliphatic acid portion were also subjected to both sets of reac-
tion conditions to give the corresponding thioether 26 in yields
of 59 and 57 %, respectively (Table 3, Entries 9 and 10).
Scheme 1. Reaction of methyl benzoates with alkyl mercaptans. Regents and
conditions: methyl ester (0.6 mmol), thiol (0.72 mmol), InI3 (0.06 mmol), TMDS
(1.8 mmol), 1,2-DCE (0.6 mL), 80 °C, 20 h.
4. Aliphatic Esters and Aliphatic Thiols as Substrates
3. Aliphatic Esters and Aromatic Thiols as Substrates
The one-pot preparation of thioether derivatives from the
methyl or phenyl aliphatic esters and aliphatic thiols was then
investigated as another application (Scheme 2). In most cases,
the desired sulfidation reaction proceeded smoothly to produce
the corresponding thioethers in good to excellent yields. The
reactions of the phenylacetic acid ester derivatives with 1-oc-
tanethiol gave the desired thioethers 27–30 in yields of 28–
78 %. In addition, the esters of an aliphatic acid that contains a
branched carbon chain or PhS moiety were employed to the
sulfidation with 1-octanethiol to afford 31 and 32. Combina-
tions of 3-phenylpropionic acid esters with several aliphatic thi-
ols gave sulfides 33–36 in relatively good yields. When the
The sulfidation reaction between aliphatic esters and aromatic
thiols was then investigated (Table 3). On the basis of the previ-
ous results, we conducted the reaction of methyl 3-phenyl-
propionate with p-toluenethiol under the optimal conditions,
and, contrary to our expectations, the formation of the desired
thioether 22 was not observed (see Table S1). We then antici-
pated that the aryl esters of an aliphatic acid could be em-
ployed, as aryloxy is a better leaving group than methoxy. After
investigating the reaction conditions several times, we found
that with regard to the aryl esters of 3-phenylpropionic acid,
the use of either p-chlorophenyl ester and PhSiH3 (conditions A)
or phenyl ester and TMDS (conditions B) effectively improved
the sulfidation reaction and gave corresponding thioether 22
in yields of 76 and 74 % (Table 3, Entries 1 and 2), respectively.
Table 3. Reaction of aliphatic esters with aryl mercaptans.[a]
[a] Reagents and conditions A: p-chlorophenyl ester (ArO = p-ClC6H4O,
0.6 mmol), thiol (0.72 mmol), InI3 (0.06 mmol), PhSiH3 (1.2 mmol), 1,2-DCE
(0.6 mL), 80 °C, 20 h. Reagents and conditions B: phenyl ester (ArO = PhO,
0.6 mmol), thiol (0.72 mmol), InI3 (0.03 mmol), TMDS (1.8 mmol), 1,2-DCE
(0.6 mL), 80 °C, 20 h. [b] Isolated yields. [c] NMR yield.
Scheme 2. Reaction of aliphatic esters with alkyl mercaptans. Reagents and
conditions: ester (0.6 mmol), thiol (0.72 mmol), InI3 (0.03 mmol), TMDS
(1.8 mmol), 1,2-DCE (0.6 mL), 80 °C, 20 h. [a] GC yield. [b] InBr3 (5 mol-%) and
TMDS (1.8 mmol) were employed over 4 h.
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cyclic ester hydrocoumarin was used as the substrate, InBr3
functioned as a better catalyst than InI3 to give ring-opened
sulfide 37. Unfortunately, this sulfidation approach could not
be applied to an ester such as methyl cinnamate, which has a
conjugated alkene system.
(3)
methyl benzoates with p-toluenethiol in the presence of InI3
and TMDS in CDCl3 were determined by H NMR spectroscopic
1
5. Mechanistic Studies of the Reductive Thioetherification
analysis. The results (Hammett plot) appear in Figure 2, and the
negative ρ value (ρ = –1.31) implies that a cationic intermediate
is involved in the rate-limiting step.
Our 2012 report of an indium-catalyzed reductive thioetherifi-
cation of carboxylic acids with thiols revealed the reaction inter-
mediates to be either O,S- or S,S-acetals.[11] The same mecha-
nism is expected to generate similar intermediates from esters.
To further understand this transformation, several control ex-
periments were conducted with either the O,S- or S,S-acetal as
the starting substrate. The reaction of a benzylic O,S-acetal with
0.5 equiv. of TMDS in CHCl3 in the presence of a catalytic
amount of InBr3, a weaker Lewis acid than InI3, at 60 °C for 0.5 h
produced thioether 1 and the corresponding S,S-acetal 1′ in 55
and 16 % yield, respectively [Equation (1)]. Thioether 1 was also
smoothly generated in quantitative yield from S,S-acetal 1′ and
an InBr3/TMDS system [Equation (2)].
(1)
Figure 2. Hammet plot for the InI3-catalyzed reductive sulfidation of the p-
substituted methyl benzoates p-RC6H4CO2Me (R = Me, H, Cl, CF3).
(2)
A plausible pathway is shown in Scheme 4. The observation
of S,S-acetals and the reactivity of both O,S- and S,S-acetals
suggest that these species constitute the intermediates in this
sulfidation reaction series. These intermediates can be formed
by the initial hydrosilylation of the ester activated by an indium
compound to produce silyl acetal A. The elimination of an alk-
oxide anion from the acetal proceeds to generate the corre-
sponding intermediate B, which undergoes a substitution with
a thiosilane, generated from a thiol and hydrosilane, to produce
O,S-acetal C.[13] The departure of the alkoxide leaving group
Similar studies were then conducted by using a combination
of 3-phenylpropionic acid ester and an alkylthiol. Consequently,
both the corresponding S,S-acetal 33′ and 36′ along with thio-
ether 33 and 36, respectively, were observed under the stand-
ard reaction conditions (Scheme 3). Moreover, the reductive
conversion of S,S-acetal 33′ into thioether 33 proceeded
smoothly by using an InI3/TMDS system [Equation (3)]. These
results strongly indicate that O,S- and S,S-acetals are relevant
intermediates.
Scheme 3. Control experiments.
To further explore the reaction mechanism, the relative rates
for the reductive sulfidation reactions of several p-substituted
Scheme 4. Plausible reaction mechanism.
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2 H), 7.57 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ =
21.0, 39.3, 92.4, 129.7, 130.7, 131.0, 131.7, 136.9, 137.6 ppm. HRMS
(EI): calcd. for C14H13IS [M]+ 339.9783; found 339.9778.
from acetal C produces cationic intermediate D, which can pro-
ceed through two possible reaction pathways: (1) one leads to
final sulfide E by a second hydrosilylation and (2) the other
leads to S,S-acetal F through the thiosilane. Either cationic inter-
mediate B or D can appear in the rate-limiting step on the basis
of the negative slope of the Hammett plot.
4-Methoxyphenyl 3-Phenylpropyl Sulfide (23): 1H NMR
(500.2 MHz, CDCl3): δ = 1.89 (quint, J = 7.5 Hz, 2 H), 2.72 (t, J =
7.5 Hz, 2 H), 2.81 (t, J = 7.5 Hz), 3.78 (s, 3 H), 6.83 (d, J = 8.5 Hz, 2
H), 7.14–7.19 (m, 3 H), 7.26 (t, J = 7.5 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2
H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 30.7, 34.5, 35.1, 55.3,
114.5, 125.9, 126.4, 128.3, 128.4, 133.1, 141.4, 158.8 ppm. HRMS (EI):
calcd. for C16H18OS [M]+ 258.1078; found 258.1079.
Conclusions
We have demonstrated an unprecedented sulfidation reaction
between esters and thiols through a new reductive system.
Compared with conventional methods for sulfidation, our de-
veloped procedure uses easily handled reagents, such as esters,
2-Bromophenyl 3-Phenylpropyl Sulfide (25): 1H NMR (500.2 MHz,
CDCl3): δ = 2.02 (quint, J = 7.5 Hz, 2 H), 2.79 (t, J = 7.5 Hz, 2 H),
2.92 (t, J = 7.5 Hz, 2 H), 6.70 (t, J = 7.5 Hz, 1 H), 7.14 (d, J = 8.0 Hz,
1 H), 7.18–7.24 (m, 4 H), 7.29 (t, J = 7.5 Hz, 2 H), 7.53 (d, J = 8.0 Hz,
indium iodide, and a hydrosilane, and enables a practical and 1 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 29.9, 32.0, 34.7, 123.3,
126.1, 126.3, 127.64, 127.65, 128.4, 128.5, 132.9, 138.1, 141.0 ppm.
straightforward sulfidation under milder reaction conditions.
Methyl benzoates that contain a methyl, methoxy, halogen, or
trifluoromethyl group can tolerate the present reduction sys-
tem, with the exception of methyl 2-iodobenzoate. The ap-
proach can be applied to not only aromatic esters and aromatic
thiols but also aliphatic esters and aliphatic thiols. Moreover, the
use of aryl esters, instead of methyl esters, led to an increase in
product yields and the elimination of thioacetal byproducts.
Work regarding further applications of this method and a fur-
ther explanation of the reaction mechanism is ongoing in our
laboratory.
HRMS (EI): calcd. for C15H15BrS [M]+ 306.0078; found 306.0076.
1
2-(p-Methoxyphenyl)ethyl Octyl Sulfide (28): H NMR (500 MHz,
CDCl3): δ = 0.88 (t, J = 7.5 Hz, 3 H), 1.27–1.38 (m, 10 H), 1.58 (quint,
J = 7.5 Hz, 2 H), 2.52 (t, J = 7.5 Hz, 2 H), 2.73 (t, J = 7.5 Hz, 2 H),
2.82 (t, J = 7.5 Hz, 2 H), 3.78 (s, 3 H), 6.84 (d, J = 8.5 Hz, 2 H), 7.12
(d, J = 8.5 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6,
28.9, 29.17, 29.18, 29.6, 31.8, 32.3, 33.9, 35.4, 55.2, 113.8, 129.4,
132.8, 158.0 ppm. HRMS (EI): calcd. for C17H28OS [M]+ 280.1861;
found 280.1860.
2-(p-Chlorophenyl)ethyl Octyl Sulfide (29): 1H NMR (500 MHz,
CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.27–1.36 (m, 10 H), 1.57 (quint,
J = 7.5 Hz, 2 H), 2.51 (t, J = 7.0 Hz, 2 H), 2.74 (t, J = 7.5 Hz, 2 H),
2.85 (t, J = 7.5 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz,
2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6, 28.9, 29.2, 29.6,
31.8, 32.3, 33.5, 35.6, 128.5, 129.8, 132.0, 139.0 ppm. HRMS (EI):
calcd. for C16H25ClS [M]+ 284.1365; found 284.1361.
Experimental Section
General Methods: All reactions were carried out under N2, unless
otherwise noted. 1,2-Dichloroethane was freshly distilled from P2O5
prior to use. All indium compounds were commercially available
and used without further purification. The hydrosilanes were used
without further purification. The reaction progress was monitored
by TLC analysis of reaction aliquots. Column chromatography was
2-(1-Naphthyl)ethyl Octyl Sulfide (30): 1H NMR (500 MHz, CDCl3):
δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.27–1.37 (m, 10 H), 1.57 (quint, J =
7.5 Hz, 2 H), 2.51 (t, J = 7.0 Hz, 2 H), 2.74 (t, J = 7.5 Hz, 2 H), 2.85 (t,
J = 7.5 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6, 28.9, 29.17, 29.18,
29.7, 31.8, 32.4, 32.9, 33.7, 123.4, 125.50, 125.52, 126.0, 126.3, 127.1,
128.9, 131.6, 133.9, 136.7 ppm. HRMS (EI): calcd. for C20H28S [M]+
300.1912; found 300.1913.
1
performed with silica gel. The H NMR spectroscopic data were re-
corded at 500 (or 300) MHz with tetramethylsilane as an internal
standard (δ = 0.00 ppm). The 13C NMR spectroscopic data were
measured at 125 (or 75) MHz by using the center peak of deuter-
ated chloroform (δ = 77.0 ppm) as the internal standard. High-reso-
lution mass spectra were measured by using NBA (3-nitrobenzyl
alcohol) as a matrix.
Octyl 2-Phenylbutyl Sulfide (31): 1H NMR (500 MHz, CDCl3): δ =
0.79 (t, J = 7.0 Hz, 3 H), 0.88 (t, J = 7.0 Hz, 3 H), 1.25–1.32 (m, 10 H),
1.51 (quint, J = 7.5 Hz, 2 H), 1.57–1.63 (m, 1 H), 1.88–1.93 (m, 1 H),
2.40 (t, J = 7.5 Hz, 2 H), 2.62–2.68 (m, 1 H), 2.73–2.80 (m, 2 H), 7.17–
7.23 (m, 3 H), 7.29–7.32 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 12.0, 14.1, 22.6, 28.3, 28.9, 29.2, 29.6, 31.8, 32.8, 39.1, 48.0, 126.4,
127.6, 128.3, 144.2 ppm. HRMS (FAB): calcd. for C18H31S [M]+
279.2146; found 279.2142.
General Procedure for the Synthesis of Sulfides from Aromatic
Esters and Aromatic Thiols: To a freshly distilled 1,2-dichloro-
ethane solution (0.60 mL) in a screw-capped vial under N2 were
successively added
a magnetic stir bar, an aromatic ester
(0.60 mmol), an aromatic thiol (0.72 mmol), InI3 (0.030 mmol,
15 mg), and TMDS (2.4 mmol, 4.2 × 102 μL). The vial was sealed
with a cap that contained a polytetrafluoroethylene (PTFE) septum.
The reaction mixture was heated at 80 °C (bath temperature), and
the progress was monitored by TLC analysis until the starting carb-
oxylic acid was consumed. Upon completion, the reaction was
quenched with H2O (3.0 mL), and the aqueous layer was extracted
with CHCl3 (3 × 5.0 mL). The combined organic phases were dried
with anhydrous Na2SO4, filtered, and then concentrated under re-
duced pressure. The crude product was purified by silica gel column
chromatography (hexane/AcOEt, 99:1) to give the corresponding
sulfide.
1
2-(Octylthio)ethyl Phenyl Sulfide (32): H NMR (500 MHz, CDCl3):
δ = 0.88 (t, J = 7.5 Hz, 3 H), 1.26–1.35 (m, 10 H), 1.54 (quint, J =
7.5 Hz, 2 H), 2.52 (t, J = 7.5 Hz, 2 H), 2.70–2.74 (m, 2 H), 3.08–3.11
(m, 2 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 2 H), 7.36 (d,
J = 8.0 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 22.6,
28.8, 29.1, 29.6, 31.4, 31.8, 32.0, 33.9, 126.4, 129.0, 129.8, 135.4 ppm.
HRMS (EI): calcd. for C16H26S [M]+ 282.1476; found 282.1495.
General Procedure for the Synthesis of Methyl Esters: A carb-
oxylic acid (5 mmol), sulfuric acid (1 mL), and a magnetic stir bar
were successively added to distilled methanol (20 mL). The solution
was stirred and heated at reflux for 2 h. Upon completion of the
reaction, the solution was neutralized with an aqueous NaHCO3 so-
p-Iodobenzyl p-Tolyl Sulfide (13): 1H NMR (500.2 MHz, CDCl3): δ =
2.30 (s, 3 H), 3.96 (s, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 7.06 (d, J = 8.5 Hz,
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[3] a) M. E. Cain, M. B. Evans, D. F. Lee, J. Chem. Soc. 1962, 1694–1699; b)
A. W. Herriott, D. Picker, J. Am. Chem. Soc. 1975, 97, 2345–2349; c) Y.
Guindon, R. Frenette, R. Fortin, J. Rokach, J. Org. Chem. 1983, 48, 1357–
1359; d) M. Ouertani, J. Collin, H. B. Kagan, Tetrahedron 1985, 41, 3689–
3693; e) B. M. Trost, T. S. Scanlan, Tetrahedron Lett. 1986, 27, 4141–4144;
f) P. C. Bulman Page, S. S. Klair, M. P. Brown, M. M. Harding, C. S. Smith,
S. J. Maginn, S. Mulley, Tetrahedron Lett. 1988, 29, 4477–4480; g) L. S.
Richter, J. C. Marsters, T. R. Gadek, Tetrahedron Lett. 1994, 35, 1631–1634;
h) C. Goux, P. Lhoste, D. Sinou, Tetrahedron Lett. 1992, 33, 8099–8102; i)
J. Yin, C. Pidgeon, Tetrahedron Lett. 1997, 38, 5953–5954; j) T. Kondo, Y.
Morisaki, S. Uenoyama, K. Wada, T.-A. Mitsudo, J. Am. Chem. Soc. 1999,
121, 8657–8658; k) A. Kawada, K. Yasuda, H. Abe, T. Harayama, Chem.
Pharm. Bull. 2002, 50, 380–383; l) Y. Inada, Y. Nishibayashi, M. Hidai, S.
Uemura, J. Am. Chem. Soc. 2002, 124, 15172–15173; m) B. C. Ranu, R.
Jana, Adv. Synth. Catal. 2005, 347, 1811–1818; n) Z.-P. Zhan, J.-L. Yu, H.-
J. Liu, Y.-Y. Cui, R.-F. Yang, W.-Z. Yang, J.-P. Li, J. Org. Chem. 2006, 71,
8298–8301; o) H. Firouzabadi, N. Iranpoor, M. Jafarpour, Tetrahedron Lett.
2006, 47, 93–97; p) Y. Yatsumonji, Y. Ishida, A. Tsubouchi, T. Takeda, Org.
Lett. 2007, 9, 4603–4606; q) A. B. Zaitsev, H. F. Caldwell, P. S. Pregosin,
L. F. Veiros, Chem. Eur. J. 2009, 15, 6468–6477; r) X. Han, J. Wu, Org.
Lett. 2010, 12, 5780–5782; s) S. Tanaka, P. Kanti Pradhan, Y. Maegawa, M.
Kitamura, Chem. Commun. 2010, 46, 3996–3998; t) A. Saha, B. C. Ranu,
Tetrahedron Lett. 2010, 51, 1902–1905; u) K. Bahrami, M. Mehdi Khodaei,
N. Khodadoustan, Synlett 2011, 2206–2210; v) P. Nath Chatterjee, S. Roy,
Tetrahedron 2012, 68, 3776–3785; w) S. Biswas, J. S. M. Samec, Chem.
Asian J. 2013, 8, 974–981.
[4] a) M. Kosugi, T. Shimizu, T. Migita, Chem. Lett. 1978, 7, 13–14; b) H.
Suzuki, H. Abe, A. Osuka, Chem. Lett. 1980, 9, 1363–1364; c) H. J. Cristau,
B. Chabaud, A. Chene, H. Christol, Synthesis 1981, 892–894; d) N. Zheng,
J. C. McWilliams, F. J. Fleitz, J. D. Armstrong III, R. P. Volante, J. Org. Chem.
1998, 63, 9606–9607; e) G. Y. Li, G. Zheng, A. F. Noonan, J. Org. Chem.
2001, 66, 8677–8681; f) F. Y. Kwong, S. L. Buchwald, Org. Lett. 2002, 4,
3517–3520; g) C. G. Bates, R. K. Gujadhur, D. Venkataraman, Org. Lett.
2002, 4, 2803–2806; h) M. Murata, S. L. Buchwald, Tetrahedron 2004, 60,
7397–7403; i) T. Itoh, T. Mase, Org. Lett. 2004, 6, 4587–4590; j) C. G. Bates,
P. Saejueng, M. Q. Doherty, D. Venkataraman, Org. Lett. 2004, 6, 5005–
5008; k) C. Mispelaere-Canivet, J.-F. Spindler, S. Perrio, P. Beslin, Tetrahe-
dron 2005, 61, 5253–5259; l) M. A. Fernández-Rodríguez, Q. Shen, J. F.
Hartwig, J. Am. Chem. Soc. 2006, 128, 2180–2181; m) M. A. Fernández-
Rodríguez, Q. Shen, J. F. Hartwig, Chem. Eur. J. 2006, 12, 7782–7796; n)
Y.-C. Wong, T. T. Jayanth, C.-H. Cheng, Org. Lett. 2006, 8, 5613–5616; o)
Y.-J. Chen, H.-H. Chen, Org. Lett. 2006, 8, 5609–5612; p) B. C. Ranu, A.
Saha, R. Jana, Adv. Synth. Catal. 2007, 349, 2690–2696; q) A. Correa, M.
Carril, C. Bolm, Angew. Chem. Int. Ed. 2008, 47, 2880–2883; Angew. Chem.
2008, 120, 2922–2925; r) S. Bhadra, B. Sreedhar, B. C. Ranu, Adv. Synth.
Catal. 2009, 351, 2369–2378; s) M. A. Fernández-Rodríguez, J. F. Hartwig,
J. Org. Chem. 2009, 74, 1663–1672; t) C. C. Eichman, J. P. Stambuli, J. Org.
Chem. 2009, 74, 4005–4008; u) X. Ku, H. Huang, H. Jiang, H. Liu, J. Comb.
Chem. 2009, 11, 338–340; v) J. She, Z. Jiang, Y. Wang, Tetrahedron Lett.
2009, 50, 593–596; w) V. P. Reddy, K. Swapna, A. V. Kumar, K. R. Rao, J.
Org. Chem. 2009, 74, 3189–3191; x) V. P. Reddy, A. V. Kumar, K. Swapna,
K. R. Rao, Org. Lett. 2009, 11, 1697–1700; y) J.-R. Wu, C.-H. Liu, C.-F. Lee,
Chem. Commun. 2009, 4450–4452; z) S. Kovács, Z. Novák, Org. Biomol.
Chem. 2011, 9, 711–716.
lution. The aqueous layer was extracted with AcOEt (10 mL), and
the organic phase was dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure to afford the corresponding
methyl ester.
General Procedure for the Synthesis of Phenyl Esters: A carb-
oxylic acid (5 mmol), phenol (5.0 mmol, 4.7 × 102 mg), 4-(dimethyl-
amino)pyridine (5.0 mmol, 7.6 × 10 mg), and a magnetic stir bar
were successively added to distilled 1,2-dichloromethane. N,N′-Di-
cyclohexylcarbodiimide (5.0 mmol, 1.0 × 103 mg) was added, and
the solution was stirred at 0 °C to room temperature overnight.
Upon completion of the reaction, the mixture was filtered, and the
filtrate was then concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography (hexane/
AcOEt, 9:1) to afford the corresponding phenyl ester.
Synthesis of the O,S-Acetal [Methoxy(p-tolylthio)methyl]benz-
ene: To freshly distilled toluene (0.5 mL) in a screw-capped vial
under N2 were successively added a magnetic stirrer bar, LiBr
(0.40 mmol, 3.5 × 10 mg), benzaldehyde dimethyl acetal (2.0 mmol,
3.0 × 102 mg), and p-toluenethiol (2.6 mmol, 3.2 × 102 mg). The
contents of the vial were stirred at room temperature for 25 h. Upon
completion of the reaction, the solution was neutralized with an
aqueous NaOH solution. The aqueous layer was extracted with
AcOEt (10 mL), and the organic phase was dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography
(hexane/AcOEt, 99:1) to give the corresponding O,S-acetal, [meth-
oxy(p-tolylthio)methyl]benzene. 1H NMR (500.2 MHz, CDCl3): δ =
2.30 (s, 3 H), 3.51 (s, 3 H), 5.65 (s, 1 H), 7.03 (d, J = 8.0 Hz, 2 H),
7.22–7.27 (m, 7 H) ppm. 13C NMR (125.8 MHz, CDCl3): δ = 21.1, 56.5,
91.4, 126.2, 127.8, 128.0, 129.1, 129.4, 134.1, 137.9, 139.4 ppm.
HRMS (EI): calcd. for C14H13S [M – CH3O]+ 213.0738; found 213.0746.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (C) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) (no. 25410120). We deeply
thank Shin-Etsu Chemical Co., Ltd. for a gift of hydrosilanes.
Keywords: Synthetic methods · Carboxylic acids · Sulfur ·
Indium · Silanes
[1] a) R. L. Beard, D. F. Colon, T. K. Song, P. A. Davies, D. M. Kochhar, R. S.
Chandraratna, J. Med. Chem. 1996, 39, 3556–3563; b) S. W. Kaldor, V. J.
Kalish, J. F. Davies, B. V. Shetty, J. E. Fritz, K. Appelt, J. A. Burgess, K. M.
Campanale, N. Y. Chirgadze, D. K. Clawson, B. A. Dressman, S. D. Hatch,
D. A. Khalil, M. B. Kosa, P. P. Lubbehusen, M. A. Muesing, A. K. Patick, S. H.
Reich, K. S. Su, J. H. Tatlock, J. Med. Chem. 1997, 40, 3979–3985; c) G. Liu,
J. T. Link, Z. Pei, E. B. Reilly, S. Leitza, B. Nguyen, K. C. Marsh, G. F. Okasin-
ski, T. W. von Geldern, M. Ormes, K. Fowler, M. Gallatin, J. Med. Chem.
2000, 43, 4025–4040; d) G. Liu, J. R. Huth, E. T. Olejniczak, R. Mendoza,
P. DeVries, S. Leitza, E. B. Reilly, G. F. Okasinski, S. W. Fesik, T. W. von Geld-
ern, J. Med. Chem. 2001, 44, 1202–1210; e) P. Johannesson, G. Lindeberg,
A. Johansson, G. V. Nikiforovich, A. Gogoll, B. Synnergren, M. Le Grèves,
F. Nyberg, A. Karlén, A. Hallberg, J. Med. Chem. 2002, 45, 1767–1777; f)
G. De Martino, M. C. Edler, G. La Regina, A. Coluccia, M. C. Barbera, D.
Barrow, R. I. Nicholson, G. Chiosis, A. Brancale, E. Hamel, M. Artico, R.
Silvestri, J. Med. Chem. 2006, 49, 947–954.
[5] a) K. Griesbaum, Angew. Chem. Int. Ed. Engl. 1970, 9, 273–287; Angew.
Chem. 1970, 82, 276–290; b) T. Mukaiyama, T. Izawa, K. Saigo, H. Takei,
Chem. Lett. 1973, 2, 355–356; c) C. G. Screttas, M. Micha-Screttas, J. Org.
Chem. 1979, 44, 713–719; d) P. Kumar, P. K. Pandey, V. R. Hegde, Synlett
1999, 1921–1922; e) S. Kanagasabapathy, A. Sudalai, B. C. Benicewicz,
Tetrahedron Lett. 2001, 42, 3791–3794; f) E. V. Sirazieva, V. A. Startseva,
L. E. Nikitina, V. V. Plemenkov, V. V. Klochkov, B. I. Khairutdinov, Chem.
Nat. Compd. 2004, 40, 478–481; g) C. Brouwer, R. Rahaman, C. He, Synlett
2007, 1785–1789; h) B. C. Ranu, T. Mandal, Synlett 2007, 925–928; i) S. A.
Delp, C. Munro-Leighton, L. A. Goj, M. A. Ramírez, T. B. Gunnoe, J. L.
Petersen, P. D. Boyle, Inorg. Chem. 2007, 46, 2365–2367; j) C. Rissing, D. Y.
Son, Organometallics 2008, 27, 5394–5397; k) B. Movassagh, M. Navidi,
ARKIVOC (Gainesville, FL, U.S.) 2008, 47–53; l) C. C. Silveira, S. R. Mendes,
F. M. Líbero, Synlett 2010, 790–792; m) S. Banerjee, J. Das, S. Santra,
Tetrahedron Lett. 2009, 50, 124–127; n) E. D. Goddard-Borger, M. B. Tro-
pak, S. Yonekawa, C. Tysoe, D. J. Mahuran, S. G. Withers, J. Med. Chem.
[2] a) I. V. Koval', Russ. J. Org. Chem. 2007, 43, 319–346; b) I. P. Beletskaya,
V. P. Ananikov, Chem. Rev. 2011, 111, 1596–1636; c) R. Castarlenas, A.
Di Giuseppe, J. J. Pérez-Torrente, L. A. Oro, Angew. Chem. Int. Ed. 2013,
52, 211–222; Angew. Chem. 2013, 125, 223–234.
Eur. J. Org. Chem. 2016, 1043–1049
www.eurjoc.org
1048
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2012, 55, 2737–2745; o) L. Lázár, M. Csávás, M. Herczeg, P. Herczegh, A.
Borbás, Org. Lett. 2012, 14, 4650–4653; p) J. R. Cabrero-Antonino, A.
Leyva-Pérez, A. Corma, Adv. Synth. Catal. 2012, 354, 678–687; q) A. Mal-
one, E. M. Scanlan, Org. Lett. 2013, 15, 504–507; r) M. Claudino, M. Jons-
son, M. Johansson, RSC Adv. 2013, 3, 11021–11034; s) L. Lázár, M. Csávás,
A. Hadházi, M. Herczeg, M. Tóth, L. Somsák, T. Barna, P. Herczegh, A.
Borbás, Org. Biomol. Chem. 2013, 11, 5339–5350; t) M. A. Savolainen, J.
Wu, Org. Lett. 2013, 15, 3802–3804; u) T. Tamai, A. Ogawa, J. Org. Chem.
2014, 79, 5028–5035.
a) A. Kondoh, K. Takami, H. Yorimitsu, K. Oshima, J. Org. Chem. 2005, 70,
6468–6473; b) C. Cao, L. R. Fraser, J. A. Love, J. Am. Chem. Soc. 2005, 127,
17614–17615; c) R. Sridhar, K. Surendra, N. S. Krishnaveni, B. Srinivas, K. R.
Rao, Synlett 2006, 3495–3497; d) D. A. Malyshev, N. M. Scott, N. Marion,
E. D. Stevens, V. P. Ananikov, I. P. Beletskaya, S. P. Nolan, Organometallics
2006, 25, 4462–4470; e) L. R. Fraser, J. Bird, Q. Wu, C. Cao, B. O. Patrick,
J. A. Love, Organometallics 2007, 26, 5602–5611; f) A. Sabarre, J. Love,
Org. Lett. 2008, 10, 3941–3944; g) J. Yang, A. Sabarre, L. R. Fraser, B. O.
Patrick, J. A. Love, J. Org. Chem. 2009, 74, 182–187; h) C. J. Weiss, S. D.
Wobser, T. J. Marks, J. Am. Chem. Soc. 2009, 131, 2062–2063; i) C. J. Weiss,
T. J. Marks, J. Am. Chem. Soc. 2010, 132, 10533–10546; j) A. Di Giuseppe,
R. Castarlenas, J. J. Pérez-Torrente, M. Crucianelli, V. Polo, R. Sancho, F. J.
Lahoz, L. A. Oro, J. Am. Chem. Soc. 2012, 134, 8171–8183; k) Y. Yang, R. M.
Rioux, Green Chem. 2014, 16, 3916–3925; l) N. Rajesh, D. Prajapati, RSC
Adv. 2014, 4, 32108–32112.
Chem. 1996, 61, 4161–4163; d) Menggenbateer, M. Narsireddy, G. Ferrara,
N. Nishina, T. Jin, Y. Yamamoto, Tetrahedron Lett. 2010, 51, 4627–4629; e)
A. B. Pritzius, B. Breit, Angew. Chem. Int. Ed. 2015, 54, 3121–3125; Angew.
Chem. 2015, 127, 3164–3168.
[8] Z. Duan, S. Ranjit, P. Zhang, X. Liu, Chem. Eur. J. 2009, 15, 3666–3669.
[9] R. S. Glass, Synth. Commun. 1976, 6, 47–51.
[10] a) Y. Kikugawa, Chem. Lett. 1981, 10, 1157–1158; b) T. Mukaiyama, T.
Ohno, T. Nishimura, J. S. Han, S. Kobayashi, Bull. Chem. Soc. Jpn. 1991,
64, 2524–2527; c) G. A. Olah, Q. Wang, N. J. Trivedi, G. K. S. Prakash,
Synthesis 1992, 465–466; d) Q. Wang, X.-y. Li, G. K. S. Prakash, G. A. Olah,
D. P. Loker, K. B. Locker, ARKIVOC (Gainesville, FL, U.S.) 2001, 116–128; e)
B. A. Gellert, N. Kahlcke, M. Feurer, S. Roth, Chem. Eur. J. 2011, 17, 12203–
12209.
[11] N. Sakai, T. Miyazaki, T. Sakamoto, T. Yatsuda, T. Moriya, R. Ikeda, T. Konak-
ahara, Org. Lett. 2012, 14, 4366–4369.
[12] When the model reaction shown in Scheme 1 was carried out with other
Lewis acids, such as B(C6F5)3 and CuBr2, the expected sulfide was ob-
tained in small amounts. Also, when FeCl3 was used, the sulfidation did
not proceed.
[6]
[13] a) D. J. Harrison, D. R. Edwards, R. McDonald, L. Rosenberg, Dalton Trans.
2008, 3401–3411; b) Y. Nishimoto, Y. Inamoto, T. Saito, M. Yasuda, A.
Baba, Eur. J. Org. Chem. 2010, 3382–3386; c) Y. Inamoto, Y. Nishimoto, M.
Yasuda, A. Baba, Org. Lett. 2012, 14, 1168–1171; d) Y. Nishimoto, A. Okita,
M. Yasuda, A. Baba, Org. Lett. 2012, 14, 1846–1849.
[7] a) T. L. Jacobs, G. E. Illingworth, J. Org. Chem. 1963, 28, 2692–2698; b) K.
Griesbaum, A. A. Oswald, E. R. Quiram, W. Naegele, J. Org. Chem. 1963,
28, 1952–1957; c) A. Ogawa, J. Kawakami, N. Sonoda, T. Hirao, J. Org.
Received: December 11, 2015
Published Online: January 15, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim