Indium-catalyzed reductive three-component coupling reaction of aliphatic/aromatic carboxylic acids with t-butyl mercaptan leading to unsymmetrical dialkyl sulfides

Article abstract of DOI:10.1016/j.tetlet.2016.06.001

An InI₃–TMDS (1,1,3,3-tetramethyldisiloxane) reducing system efficiently catalyzed a sequential three-component coupling of aliphatic carboxylic acids, aromatic carboxylic acids, and t-butyl mercaptan (t-butylthiol), to produce unsymmetrical dialkyl sulfides. With this reducing system, t-butyl mercaptan became a new source of sulfidation via an alkyl t-butyl sulfide that functioned as the reaction intermediate.

Full text of DOI:10.1016/j.tetlet.2016.06.001

Tetrahedron Letters 57 (2016) 3117–3120
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium-catalyzed reductive three-component coupling reaction of
aliphatic/aromatic carboxylic acids with t-butyl mercaptan leading to
unsymmetrical dialkyl sulfides
⇑
Norio Sakai , Shunsuke Yoshimoto, Takahiro Miyazaki, Yohei Ogiwara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An InI3–TMDS (1,1,3,3-tetramethyldisiloxane) reducing system efficiently catalyzed a sequential three-
component coupling of aliphatic carboxylic acids, aromatic carboxylic acids, and t-butyl mercaptan (t-
butylthiol), to produce unsymmetrical dialkyl sulfides. With this reducing system, t-butyl mercaptan
became a new source of sulfidation via an alkyl t-butyl sulfide that functioned as the reaction
intermediate.
Received 5 May 2016
Revised 25 May 2016
Accepted 1 June 2016
Available online 2 June 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Reductive sulfidation
Indium
Unsymmetrical sulfide
Carboxylic acid
t-Butyl mercaptan
Introduction
using a sulfur source as a third component,6–8 that of dialkyl sul-
fides has not been studied extensively. Therefore, we anticipated
Multi-component coupling reactions are important and attrac-
tive procedures in synthetic organic chemistry. These procedures
offer several advantages, such as environmentally benign system
based on a reduction in the reaction process, a simultaneous for-
mation of more than one bond on products, and a one-pot prepa-
ration of highly valuable compounds.1 Dialkyl sulfides
(thioethers) that involve two C(sp3)–S bonds constitute the central
framework of sulfur-containing natural products that function as
biologically active substances and highly valuable molecules.2
However, the development of a facile approach to the preparation
of their structure has not been widely explored. As a representative
approach to dialkyl sulfides, a Williamson-type synthesis that
involves a substitution of alkyl halides, alcohols or their analogs
with alkyl thiols (mercaptans) in the presence of a promoter, such
as an acid or a base,3 is well-known. In these methods, however,
one substrate should involve a sulfur moiety, such as a thiol, in
its molecular structure. Thus far, the one-pot production of unsym-
metrical dialkyl sulfides has been limited to a three-component
coupling reaction using two alkyl sources and one sulfur source,
such as the coupling of alkyl halides, alcohols, and a thiourea
derivative as a sulfur source in the presence of NaH.4,5 Compared
with inter- or intramolecular preparations of alkyl aryl sulfides
that there is plenty of room for development of the novel prepara-
tion of dialkyl sulfides.
In this context, we previously reported the indium-catalyzed
sulfidation of aliphatic carboxylic acids with t-BuSH in the pres-
ence of a hydrosilane (Si-H) leading to alkyl sulfides (path a in
Scheme 1).9,10 During ongoing studies on sulfidation, however,
we found that when aromatic carboxylic acids were reacted with
the same reducing system, the corresponding dibenzyl sulfides
were selectively obtained (path b in Scheme 1).11 Therefore, we
anticipated that in the first sulfidation step, alkyl carboxylic acids
were treated with t-BuSH under an InI3–TMDS reducing system
to temporarily form an alkyl t-butyl sulfide, followed by the addi-
tion of an aromatic carboxylic acid to the reaction mixture, which
resulted in the preparation of an unsymmetrical sulfide (path c in
Scheme 1). Herein, we report the preliminary results of a sequen-
tial three-component coupling reaction of aliphatic carboxylic
acids, aromatic carboxylic acids, and t-butyl mercaptan as a sulfur
source, which led to unsymmetrical dialkyl sulfides.
Results and discussion
On the basis of our previous work, several examinations were
conducted to establish the optimal conditions for the preparation
of an unsymmetrical sulfide (Table 1).12 A mixture of 3-phenylpro-
pionic acid and t-BuSH was initially treated with 5 mol% of InI3 and
⇑
Corresponding author. Tel.: +81 4 7122 1092; fax: +81 4 7123 9890.
E-mail address: sakachem@rs.noda.tus.ac.jp (N. Sakai).
http://dx.doi.org/10.1016/j.tetlet.2016.06.001
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

3118
N. Sakai et al. / Tetrahedron Letters 57 (2016) 3117–3120
Table 2
Scope of aromatic carboxylic acids used in the second sulfidation stepa
Entry
Ar
Yield (%)
1
2a
Scheme 1. Approach to unsymmetrical dialkyl sulfides.
1
2
3
4
5
6
7b
8
9
Ph
1b
1c
1d
1e
1f
1g
1h
1i
80
85
47
67
65
54
46
67
nd
12
6
8
3
6
Trace
Trace
7
p-MeC6H4
o-MeC6H4
m-ClC6H4
o-ClC6H4
o-BrC6H4
p-IC6H4
TMDS (Si-H: 6 equiv) in 1,2-dichloroethane (1,2-DCE) at 80 °C for
4 h (the first sulfidation step), followed by the addition of both 4-
chlorobenzoic acid and TMDS and heating for 20 h (the second sul-
fidation step) to produce the expected unsymmetrical sulfide 1a in
a 62% yield (entry 1).13 Also, we observed the formations of sym-
metrical dibenzyl sulfide 3a and sulfides 2a and 4a containing t-
butyl mercaptan moiety. By-products 3a and 4a seems to be pro-
duced through coupling with the remaining t-butyl mercaptan in
the first step. Thus, to prevent the formation of these by-products,
the same reaction was then treated with a slightly excessive
p-CF3C6H4
p-NO2C6H4
1j
87
Reaction conditions: 3-phenylpropionic acid (0.75 mmol), tBuSH (0.6 mmol), an
aromatic carboxylic acid (0.75 mmol), TMDS (Si-H: 6 equiv) used in the first sulfi-
dation step, TMDS (Si-H: 6 equiv) used in the second sulfidation step.
a
b
1,2-DCE (1 mL).
t
amount of the aliphatic carboxylic acid (1.25 equiv for BuSH). As
the benzoic acid with an o-methyl-substituted group resulted in a
decrease in the product yield (entry 3). Benzoic acids with an elec-
tron-withdrawing group, such as a halogen substituent and a tri-
fluoromethyl group, regardless of the substituted position,
afforded the expected sulfides 1e–1i in modest to good yields
(entries 4–8). A p-iodo-substituted substrate encountered a solu-
bility problem that increased the solvent to 1 mL. On the other
hand, p-nitrobenzoic acid did not undertake the coupling at the
second step to recover the unreacted intermediate 2a, which was
formed in-situ in the first step in a high yield (entry 9). In most
cases, the formation of the intermediate sulfide 2a was detected.
As described in introduction, no aliphatic carboxylic acids could
be applied to the second sulfidation step.
a result, the formation of 3a and 4a was undetectable (entry 2).
In addition, the yield of sulfide 1a was improved to an 80% NMR
yield. An increase in the carboxylic acid to 2 equiv resulted in a
decrease in the product yield (entries 3 and 4). There is no clear
reason for these results at the present step. Conducting the same
reaction with 10 mol% of InI3 produced the best isolated yield of
unsymmetrical sulfide 1a, and the remaining of intermediate 2a
was restrained to only a 6% yield (entry 5).14
Next, we examined the scope and limitations of the present sul-
fidation of 3-phenylpropionic acid, t-butyl mercaptan, and a vari-
ety of aromatic carboxylic acids (Table 2). Benzoic acids with no
substituent or an electron-donating group, such as a methyl group,
at the para-position produced the corresponding unsymmetrical
sulfides 1b and 1c in relatively good yields (entries 1 and 2). Also,
This three-component coupling reaction could be applied to the
sulfidation of several aliphatic carboxylic acids (Table 3). The cou-
Table 1
Examinations of the reaction conditions
Table 3
Scope of the aliphatic carboxylic acids used in the first sulfidation stepa
Entry
InI3
PhCH2CH2CO2H
(equiv)
Yielda (%)
(mol%)
1a
2a
3a
4a
1
2
3
4
5
5
5
5
5
10
1.0
1.25
1.5
2.0
1.25
62
80
58
63
14
9
20
23
6
4
10
ND
ND
ND
ND
ND
ND
ND
ND
a
Reaction conditions: 3-phenylpropionic acid (0.75 mmol), tBuSH (0.6 mmol), an
84 (78)
aromatic carboxylic acid (0.75 mmol), TMDS (Si-H: 6 equiv) used in the first
sulfidation step, TMDS (Si-H: 6 equiv) used in the second sulfidation step.
a
NMR (isolated) yield.

N. Sakai et al. / Tetrahedron Letters 57 (2016) 3117–3120
3119
in Scheme 4. In the first sulfidation step, the reaction of a car-
boxylic acid with a hydrosilane occurred twice to produce silyl
acetal A.16 Then, the silyl acetal was reacted with a thiosilane,
which was derived from t-butyl mercaptan and a hydrosilane,17
to form O,S-acetal B. The acetal B was nucleophilically reduced
with a hydrosilane to afford the sulfide intermediate C. In the sec-
ond sulfidation step, an aromatic carboxylic acid was reduced to
produce the corresponding silyl ether D. The silyl ether D was cou-
pled with the previous sulfide intermediate C, finally leading to the
unsymmetrical sulfide with the release of isobutene and a silanol.
Scheme 2. Control experiment for sulfidation with the aromatic carboxylic acid.
Conclusions
We demonstrated that an indium(III)-hydrosilane reducing sys-
tem effectively catalyzed a three-component coupling reaction of
aliphatic carboxylic acids, aromatic carboxylic acids, and t-butyl
mercaptan, which led to a one-pot preparation of unsymmetrical
dialkyl sulfides. We also found that t-butyl mercaptan successfully
functioned as one sulfur source in the sulfide skeleton, and dis-
closed that an alkyl t-butyl sulfide was a key intermediate in this
sulfidation series.
Scheme 3. Control experiments for sulfidation with the benzyl silyl ether.
Acknowledgments
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (C) (No. 25410120) from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT), Japan. We deeply
thank Shin-Etsu Chemical Co., Ltd., for the gift of hydrosilanes. The
authors thank Mr. Kota Nishino for his experimental support.
Supplementary data
Supplementary data (copies of the 1H and 13C NMR spectra of
sulfides 1 that were produced by this procedure were supplied)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.06.001.
References and notes
1. Zhu, J.; Bienayme, H. Multicomponent Reactions; WILEY-VCH: Weinheim, 2000.
2. (a) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335–354; (b) Procter, D. J. J.
Chem. Soc., Perkin Trans. 1 2000, 835–871; (c) Block, E. Angew. Chem., Int. Ed.
1992, 31, 1135–1178.
Scheme 4. Plausible reaction mechanism for sulfidation.
3. For the selected review and papers on the basis of Williamson-type
thioetherification, see: (a) Koval, I. Russ. J. Org. Chem. 2007, 43, 319–346. and
the references cited therein; (b) Altimari, J. M.; Delaney, J. P.; Servinis, L.;
Squire, J. S.; Thornton, M. T.; Khosa, S. K.; Long, B. M.; Johnstone, M. D.; Fleming,
C. L.; Pfeffer, F. M.; Hickey, S. M.; Wride, M. P.; Ashton, T. D.; Fox, B. L.; Byrne,
N.; Henderson, L. C. Tetrahedron Lett. 2012, 53, 2035–2039; (c) Gohain, M.;
Marais, C.; Bezuidenhoudt, B. C. B. Tetrahedron Lett. 2012, 53, 1048–1050; (d)
Firouzabadi, H.; Iranpoor, N.; Jafarpour, M. Tetrahedron Lett. 2006, 47, 93–97;
(e) Falck, J. R.; Lai, J.-Y.; Cho, S.-D.; Yu, J. Tetrahedron Lett. 1999, 40, 2903–2906;
(f) Guindon, Y.; Frenette, R.; Fortin, R.; Rokach, J. J. Org. Chem. 1983, 48, 1357–
1359.
4. For selected papers of the preparation of unsymmetrical dialkyl sulfides, see:
(a) Eccles, K. S.; Elcoate, C. J.; Lawrence, S. E.; Maguire, A. R. ARKIVOC 2010, 9,
216–228; (b) Fujisaki, S.; Fujiwara, I.; Norisue, Y.; Kajigaeshi, S. Bull. Chem. Soc.
Jpn. 1985, 58, 2429–2430.
5. For selected papers of the preparation of symmetrical dialkyl sulfides, see: (a)
Miyazaki, T.; Katayama, M.; Yoshimoto, S.; Ogiwara, Y.; Sakai, N. Tetrahedron
Lett. 2016, 57, 676–679; (b) Ogawa, A.; Takami, N.; Sekiguchi, M.; Sonoda, N.;
Hirao, T. Heteroat. Chem 1998, 9, 581–584; (c) Steliou, K.; Salama, P.; Corriveau,
J. J. Org. Chem. 1985, 50, 4969–4971; (d) Gladysz, J. A.; Wong, V. K.; Jick, B. S.
Tetrahedron 1979, 35, 2329–2335.
6. For the recent selected papers of intermolecular preparations including a sulfur
source as a third component leading to alkyl aryl sulfides, see: (a) Rostami, A.;
Rostami, A.; Ghaderi, A. J. Org. Chem. 2015, 80, 8694–8704; (b) Jiang, Y.; Qin, Y.;
Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org. Lett. 2009, 11, 5250–5253; (c) Ham, J.;
Yang, I.; Kang, H. J. Org. Chem. 2004, 69, 3236–3239.
7. For the recent selected papers of intramolecular preparations including a sulfur
source as a third component leading to alkyl aryl sulfides, see: (a) Sangeetha, S.;
Muthupandi, P.; Sekar, G. Org. Lett. 2015, 17, 6006–6009; (b) Zhang, X.; Zeng,
W.; Yang, Y.; Huang, H.; Liang, Y. Org. Lett. 2014, 16, 876–879; (c) Qiao, Z.; Liu,
H.; Xiao, X.; Fu, Y.; Wei, J.; Li, Y.; Jiang, X. Org. Lett. 2013, 15, 2594–2597; (d)
pling of linear aliphatic carboxylic acids, such as propionic acid,
acetic acid, and 4-chlorophenylacetic acid, with t-butyl mercaptan
and benzoic acids proceeded in practical yields, and produced the
corresponding sulfides 1k–1m. Gratifyingly, although the product
yield was relatively low, the reducing system could be applied to
the sulfidation of an aliphatic carboxylic acid with a thiophene ring
to produce sulfide 1n.
To further understand the reaction pathway series, several con-
trol experiments were examined using the reaction intermediate,
sulfide 2a, and the results are summarized in Schemes 2 and 3. Ini-
tially, when the coupling of the prepared intermediate 2a with 4-
chlorobenzoic acid was treated under the optimal conditions com-
posed of InI3 and TMDS, the final sulfide 1a was obtained in a high
yield (91%) with the recovery of 2a (5%). Consequently, these
results show that a combination of both reagents is essential to
effectively promote the second-step of sulfidation. Also, when a
similar reaction of 2a with a benzyl silyl ether derivative derived
from an aromatic carboxylic acid and a hydrosilane was examined
with the catalytic system involving both InI3 and TMDS, sulfide 1b
was obtained in a moderate yield. In a similar manner, only the
indium catalyst also produced 1b in the same yield.
On the basis of the results of the control experiments,15 a plau-
sible pathway for the three-component coupling reaction is shown

3120
N. Sakai et al. / Tetrahedron Letters 57 (2016) 3117–3120
Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org. Chem. 2011, 76, 7546–
7550.
8. For selected papers of the preparation of diaryl sulfides using a sulfur source as
a third component, for example: (a) Taniguchi, N. Tetrahedron 2012, 68, 10510–
reaction vial. The mixture was heated at 80 °C for 20 h again. After the reaction,
the reaction resultant mixture was quenched by a saturated NaHCO3 aqueous
solution (3 mL). The aqueous layer was extracted with chloroform (3 mL Â 3).
The combined organic phase was dried over anhydrous Na2SO4, filtered, and
then evaporated under reduced pressure. The crude material was purified by
column chromatography (silica gel, 99/1 = hexane/EtOAc) to give the
corresponding dialkyl sulfide. The ratio of the remaining intermediate was
determined by NMR using 1,1,2,2-tetrachloroethane as an internal standard.
13. Although the use of other hydrosilanes, such as Et3SiH, PhSiH3, and MePh2SiH,
10515; (b) Ke, F.; Qu, Y.; Jiang, Z.; Li, Z.; Wu, D.; Zhou, X. Org. Lett. 2011, 13,
6a
454–457. See also Ref.
.
9. Sakai, N.; Miyazaki, T.; Sakamoto, T.; Yatsuda, T.; Moriya, T.; Ikeda, R.;
Konakahara, T. Org. Lett. 2012, 14, 4366–4369.
10. For the paper of indium-catalyzed thioetherification of aryl halides with thiols,
see: Reddy, V. P.; Swapna, K.; Kumar, A. V.; Rao, K. R. J. Org. Chem. 2009, 74,
3189–3191.
11. Sakai, N.; Miyazaki, T.; Sakamoto, T.; Yatsuda, T.; Fujii, K.; Moriya, T.; Ikeda, R.;
Konakahara, T. 59th Symposium on Organometallic Chemistry, Japan, Abstract,
P2C-24; Osaka University: Osaka (Japan), 2012.
was ineffective, Me2PhSiH shows
a relatively good effect for the similar
sulfidation to give the corresponding unsymmetrical sulfide in an 80% yield.
14. Unfortunately, the complete separation of the major product 1a from
intermediate 2a with common purifications was impossible.
15. Miyazaki, T.; Nishino, K.; Yoshimoto, S.; Ogiwara, Y.; Sakai, N. Eur. J. Org. Chem.
2015, 1991–1994.
12. General procedure for the preparation of dialkyl sulfides: To a freshly distilled
1,2-dichloroethane solution (0.6 mL) in
atmosphere were successively added
a
screw-capped tube under
a
N2
16. For the selected papers of a catalytic formation of a silyl acetal, see: (a) Bézier,
D.; Park, S.; Brookhart, M. Org. Lett. 2013, 15, 496–499; (b) Zheng, J.; Chevance,
S.; Darcel, C.; Sortais, J.-B. Chem. Commun. 2013, 49, 10010–10012; (c) Feghali,
E.; Jacquet, O.; Thuery, P.; Cantat, T. Sci. Technol. 2014, 4, 2230–2234.
17. For the selected paper of a substitution with a thiosilane, see: Nishimoto, Y.;
Okita, A.; Yasuda, M.; Baba, A. Org. Lett. 2012, 14, 1846–1849.
a
magnetic stirrer bar, an aliphatic
carboxylic acid (0.75 mmol), tBuSH (0.60 mmol, 54 mg), InI3 (0.060 mmol,
30 mg), and TMDS (1.8 mmol, 3.2 Â 102
lL). The reaction tube was heated at
80 °C for 4 h. After cooling to room temperature, an aromatic carboxylic acid
(0.75 mmol) and TMDS (1.8 mmol, 3.2 Â 102
lL) were then added to the