Indium-catalyzed reductive sulfidation of aromatic carboxylic acids and aldehydes with elemental sulfur to prepare symmetrical benzyl sulfides

Article abstract of DOI:10.1002/ejoc.201403567

Described herein is a direct approach to symmetrical thioethers from either aromatic carboxylic acids or aromatic aldehydes with elemental sulfur (S₈) by using a reducing system combined with InI₃ and 1,1,3,3-tetramethyldisiloxane (TMDS). This sulfidation does not require functionalized sulfur reagents, such as sulfides, disulfides, or metal sulfides, and it simultaneously forms two carbon-sulfur bonds in a single catalytic system. The coupling reaction of either aromatic carboxylic acids or aromatic aldehydes with elemental sulfur in the presence of a catalytic amount of InI₃ and TMDS effectively produced the corresponding symmetrical benzyl sulfide derivatives.

Full text of DOI:10.1002/ejoc.201403567

FULL PAPER
DOI: 10.1002/ejoc.201403567
Indium-Catalyzed Reductive Sulfidation of Aromatic Carboxylic Acids and
Aldehydes with Elemental Sulfur to Prepare Symmetrical Benzyl Sulfides
Takahiro Miyazaki,[a] Kota Nishino,[a] Shunsuke Yoshimoto,[a] Yohei Ogiwara,[a] and
Norio Sakai*[a]
Keywords: Indium / Thioethers / Carboxylic acids / Aldehydes / Sulfur
Described herein is a direct approach to symmetrical thio-
ethers from either aromatic carboxylic acids or aromatic alde-
hydes with elemental sulfur (S8) by using a reducing system
combined with InI3 and 1,1,3,3-tetramethyldisiloxane
(TMDS). This sulfidation does not require functionalized
sulfur reagents, such as sulfides, disulfides, or metal sulfides,
and it simultaneously forms two carbon–sulfur bonds in a sin-
gle catalytic system.
(path E). However, these transformations, including our re-
ported reaction, typically involve either the use of thiols or
an emission of hydrogen sulfide with an unpleasant odor,
which leads to difficulties in handling in a laboratory set-
ting.
Introduction
As thioether derivatives consisting of a C–S bond show
biological and pharmacological activity, the development of
a convenient and effective method for the synthesis of thio-
ethers is an important goal.[1] Thus far, the Williamson-type
synthesis from alkyl halides and thiolate anions[2] and the
Ullmann-type coupling of aryl halides and thiols by using
metal catalysts, such as copper,[3] palladium,[4] and nickel,[5]
have been studied as representative preparations (path A in
Scheme 1). Also, a facile preparation from alcohols and thi-
ols by using zirconium tetrachloride and silica gel has been
reported (path B).[6] As another approach to the prepara-
tion of thioethers, reductive sulfidation from aldehydes or
ketones and thiols has been reported (path C). For example,
the preparation of thioethers from either aldehydes or
ketones and thiols by using a pyridine–borane complex in
a strong acid solvent was reported by Kikugawa.[7] Olah
and co-workers also reported that aldehydes or ketones ini-
tially reacted with thiols to give S,O-acetals, followed by
treatment of the intermediate with Et3SiH in the presence
of BF3·H2O to afford thioethers.[8] Moreover, in 2011 Roth
Scheme 1. Diverse approaches to thioethers.
Thus, we focused our attention on the practical use of
et al. developed the reductive sulfidation of either aldehydes elemental sulfur, because elemental sulfur has several ad-
or ketones and thiols with a combination of Et3SiH and a vantages: stability at ambient temperature, ready commer-
Brønsted acid, such as CF3SO3H.[9] In this context, we also cial availability, and easy handling of an odorless com-
reported an indium-catalyzed reductive sulfidation from pound on the laboratory scale. In previous synthetic ap-
carboxylic acids and thiols (path D).[10] As an alternative proaches to thioethers using elemental sulfur, Ogawa and
sulfur source instead of thiols, several approaches co-workers reported that S8 acted as a reducing agent to
using metal sulfides, such as Na2S,[11a] (Me3Si)2S,[11b] produce a metal sulfide, such as S(SmI2)2, which reacted
(Bu3Sn)2S,[11c,11d] or (Ph3Pb)2S,[11d] have been investigated with alkyl halides to give symmetrical thioethers.[12] In
2009, Jiang, Ma, and co-workers reported that an aryl thiol,
[a] Department of Pure and Applied Chemistry,
which was formed from elemental sulfur and an aryl iodide,
reacted with an alkyl halide to produce an unsymmetrical
thioether.[13] Also, recent reports have described the prepa-
ration of diaryl sulfides[14] or trifluoromethyl thioethers[15]
by using elemental sulfur. However, a one-pot, single-step
preparation of thioethers from carbonyl compounds, such
Faculty of Science and Technology,
Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
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.201403567.
Eur. J. Org. Chem. 2015, 1991–1994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1991

T. Miyazaki, K. Nishino, S. Yoshimoto, Y. Ogiwara, N. Sakai
FULL PAPER
as carboxylic acids or aldehydes, and elemental sulfur has ity and were converted into the corresponding thioethers
not been studied extensively. Herein, we describe the details 2f–2i in relatively moderate to excellent yields (entries 5–8).
on the first example of a reductive preparation of thioethers
Table 2. InI3-catalyzed reductive sulfidation of aromatic carboxylic
from elemental sulfur and either carboxylic acids or alde-
hydes by using a reducing system that combines an indium
acids 1 with elemental sulfur.[a]
catalyst and a hydrosilane by double C–S bond formation
(path F).
Results and Discussion
Entry
Ar
Product
Yield [%][b]
Initially, we examined the reaction of p-toluic acid (1a)
with elemental sulfur (S8)[16] by using a hydrosilane in the
presence of an indium catalyst (Table 1). When a reaction
was conducted with InBr3 and (EtO)3SiH with 1,2-di-
chloroethene (1,2-DCE) as a solvent, the desired thioether
2a was not detected by GC analysis (entry 1). A similar
result was observed when using an InBr3/Et3SiH system
(entry 2), but PhMe2SiH underwent the expected sulfid-
ation to give the symmetrical thioether 2a in 15% yield (en-
try 3). In a similar manner, 1,1,3,3-tetramethyldisiloxane
(TMDS), which showed good results for the coupling of
carboxylic acids with thiols reported by our group,[10] also
improved the product yield slightly to 27% (entry 4). It is
noteworthy that, when InBr3 was changed to a stronger
Lewis acid, InI3, the yield of 2a was improved significantly
to 74% (entry 5). Further examinations for the optimal
conditions, such as solvent screening and temperature con-
trol, were ineffective and afforded the product in lower
yields.[17,18]
1
2
3
4
5
6
7
8
2-MeC6H4
3-MeC6H4
3-PhOC6H4
Ph
4-ClC6H4
3-ClC6H4
2-BrC6H4
2-IC6H4
2b
2c
2d
2e
2f
2g
2h
2i
66
73
24
80
87
51
51
80
[a] Reaction conditions: 1 (0.6 mmol), S8 (0.3 mmol of S atom),
InI3 (0.03 mmol), TMDS (1.8 mmol), 1,2-DCE (0.6 mL), 80 °C,
20 h. [b] Isolated yield based on carboxylic acid 1.
Moreover, we envisioned that the reductive sulfidation
using elemental sulfur could be applied to the reaction with
aldehydes instead of carboxylic acids. Examination of sev-
eral benzaldehydes 3 was then conducted (Table 3). When
4-methylbenzaldehyde (3a) was treated with S8 in the pres-
ence of InI3 and TMDS in 1,2-DCE at 80 °C, the desired
sulfide 2a was obtained in 81% isolated yield (entry 1). The
sulfidation of benzaldehydes with an electron-donating
group, a methyl or a methoxy group at the 2- or 3-position,
afforded the corresponding thioethers in moderate yields
(entries 2–3). Also, unsubstituted benzaldehyde (3e) was
converted into benzyl sulfide (2e) in 54% yield (entry 4).
Reactions of aldehydes bearing an electron-withdrawing
group, such as a chlorophenyl or a bromophenyl group,
proceeded mostly smoothly to give the corresponding thio-
ether in moderate to excellent yields (entries 5–9). Espe-
cially, in the case of a reaction using 4-chlorobenzaldehyde
Table 1. Optimization for the reductive sulfidation of p-toluic acid
(1a) with elemental sulfur.[a]
Entry
InX3
Silane
Yield [%][b]
1
2
3
4
5
InBr3
InBr3
InBr3
InBr3
InI3
(EtO)3SiH
Et3SiH
PhMe2SiH
TMDS[d]
TMDS[d]
n.d.[c]
n.d.[c]
15
Table 3. InI3-catalyzed reductive sulfidation of aromatic aldehydes
3 with elemental sulfur.[a]
27
74 (56)[e]
[a] Reaction conditions: 1a (0.6 mmol), S8 (0.3 mmol of S atom),
InX3 (0.03 mmol), silane (3.6 mmol), 1,2-DCE (0.6 mL), 80 °C,
20 h. [b] GC yield based on carboxylic acid 1a. [c] Not detected.
[d] 1.8 mmol. [e] Isolated yield.
Entry
Ar
Time [h]
Product
Yield [%][b]
The results of sulfidation with several benzoic acids 1 are
summarized in Table 2. Carboxylic acids bearing a methyl
group at the 2- or 3-position were useful for the conversion,
and the corresponding thioethers 2b and 2c were obtained
in practical yields (entries 1–2). In the case with 3-phenoxy-
substituted benzoic acid 1d, a low conversion was observed,
but benzoic acid (1e) gave benzyl sulfide (2e) in good yield
(entries 3–4). In the case of the low product yield, no forma-
tion of a problematic byproduct, such as a benzylthiol de-
rivative, was observed (entry 3). Substrates containing halo-
1
2
3
4
5
6
7
8
9
4-MeC6H4
2-MeC6H4
3-MeOC6H4
Ph
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
24
20
20
20
2
4
8
2a
2b
2j
2e
2f
81
33
46
54
99
47
60
70
43
2g
2k
2l
8
20
2h
[a] Reaction conditions: 3 (0.6 mmol), S8 (0.3 mmol of S atom),
InI3 (0.03 mmol), TMDS (1.8 mmol), 1,2-DCE (0.6 mL), 80 °C. [b]
gen atoms on the phenyl group also showed a high reactiv- Isolated yield based on aldehyde 3.
1992 Eur. J. Org. Chem. 2015, 1991–1994
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Indium-Catalyzed Reductive Sulfidation of Aromatic Acids and Aldehydes
(3f) as substrate, the sulfidation proceeded faster and a by an indium catalyst, is reduced by a Si–H species, giving
higher yield of thioether 2f was obtained, relative to that silyl acetal B through silyl ester A with the liberation of
obtained by the reaction of carboxylic acid 1f (Table 2, en- H2.[23] A further reduction of B to silyl ether C is followed
try 5, and Table 3, entry 5). These results imply that this by substitution at a benzylic carbon from a C–O bond to a
application has the potential utility to supplement the re- C–S bond with a disilathiane, affording silyl thioether D.
sults on the sulfidation of carboxylic acids.
Finally, silyl thioether D undergoes either a cross-condensa-
In order to further explain the sulfidation, we next con- tion with a silyl ether, or a self-condensation with a silyl
ducted the mechanistic studies shown in Scheme 2. When thioether, producing the corresponding thioether 2 along
S8 reacted with InI3 and PhMe2SiH in the absence of a carb- with the regeneration of the indium catalyst. When using
oxylic acid, the generation of a disilathiane, (PhMe2Si)2S, aldehydes 3 instead of carboxylic acids, hydrosilylation of 3
was detected, and the product was finally identified by initially occurs to give silyl ether C, and several transforma-
HRMS (EI) analysis [Equation (1) in Scheme 2].[19] Also, tions from C to 2 proceed in a similar manner to that with
treatment of carboxylic acid 1a or aldehyde 3a with a disila- carboxylic acids 1 shown in Scheme 4.
thiane, (Me3Si)2S, and TMDS in the presence of InI3 for a
few hours gave the corresponding thioether 2a in good
yields [Equation (2) in Scheme 2]. These results suggest that
the disilathiane could be an intermediate and could func-
tion as a sulfur source in the sulfidation series.
Scheme 2. Generation and reactivity of a disilathiane.
Scheme 4. A plausible mechanism for the indium-catalyzed re-
ductive sulfidation of carboxylic acids or aldehydes.
When a coupling reaction of a benzyl silyl ether with
1 equiv. of a silyl thioether in the presence of InI3 was then
performed in 1,2-DCE at 80 °C for 1 h, the formation of
Conclusions
three thioethers was observed by GC analysis (Scheme 3).
Unsymmetrical thioether 4, which was derived from a cross-
condensation of the silyl ether and the silyl thioether, was
obtained as a major product in 55% yield.[20,21] Symmetri-
cal products 2f and 2e, through self-condensation, were also
obtained in 32 and 13% yields. On the basis of these results,
we assumed that the thioether would be formed through
either a coupling reaction between a silyl ether and a silyl
thioether or through the self-condensation of a silyl thio-
ether.[22]
We have demonstrated a direct one-pot synthesis of thio-
ethers from elemental sulfur and either aromatic carboxylic
acids or aromatic aldehydes by using a reducing system
combined with InI3 and TMDS. The typical sulfidation
method necessitates difficult-to-handle compounds such as
odorous thiols and strong reducing agents. By contrast, our
sulfidation protocol does not require such reagents and of-
fers a novel, easy procedure to produce symmetrical sulf-
ides. Mechanistic investigations of the sulfidation and prep-
aration of further unsymmetrical sulfides from two different
carbonyl compounds are now in progress.
Experimental Section
General Method: All reactions were carried out under a N2 atmo-
sphere, unless otherwise noted. 1,2-Dichloroethane (1,2-DCE) was
freshly distilled from P2O5 prior to use. All indium compounds
were commercially available and were used without further purifi-
cation. Hydrosilanes were used without further purification. Reac-
tions were monitored by thin-layer chromatography (TLC) analysis
Scheme 3. Formation of unsymmetrical and symmetrical thioethers
from a silyl ether and a silyl thioether.
of reaction aliquots. TLC was performed with silica gel 60 F254
,
and the components were located by observation under UV light.
Column chromatography was also performed with silica gel. 1H
NMR spectra were measured at 500 MHz with tetramethylsilane as
Although the details of the reaction are as yet unclear, a
possible mechanism for the sulfidation of carboxylic acids
is shown in Scheme 4. Benzoic acid derivative 1, activated an internal standard (δ = 0.00 ppm). 13C{1H} NMR spectra were
Eur. J. Org. Chem. 2015, 1991–1994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1993

T. Miyazaki, K. Nishino, S. Yoshimoto, Y. Ogiwara, N. Sakai
FULL PAPER
7397; e) T. Itoh, T. Mase, Org. Lett. 2004, 6, 4587; f) K. J.
Miller, M. M. Abu-Omar, Eur. J. Org. Chem. 2003, 1294; g) M.
Kosugi, T. Ogata, M. Terada, H. Sano, T. Migita, Bull. Chem.
Soc. Jpn. 1985, 58, 3657.
measured at 125 MHz with the center peak of chloroform (δ =
77.0 ppm) as reference. High-resolution mass spectra were mea-
sured with NBA (3-nitrobenzylalcohol) as a matrix.
General Procedure for the Synthesis of Sulfides: To a freshly distilled
dichloroethane solution (0.60 mL) in a screw-capped vial under a
N2 atmosphere were successively added a magnetic stirrer bar, carb-
oxylic acid 1 (0.60 mmol) or aldehyde 3 (0.60 mmol), elemental sul-
fur (0.30 mmol of S atoms, 9.6 mg), InI3 (0.030 mmol, 15 mg), and
TMDS (1.8 mmol, 3.2ϫ102 μL). The vial was sealed with a cap
that contained a PTFE septum. While heating the reaction mixture
at 80 °C (bath temperature), the reaction was monitored by TLC
until the starting carboxylic acid (or aldehyde) was consumed. Af-
ter the reaction, the resulting mixture was filtered through a Celite
pad and then concentrated under reduced pressure. The crude
product was purified by preparative TLC (SiO2, 99:1 = hexane/
EtOAc) to give the corresponding sulfide 2.
[5] For example see: a) S. Jammi, P. Barua, L. Rout, P. Saha, T.
Punniyamurthy, Tetrahedron Lett. 2008, 49, 1484; b) Y. Yatsu-
monji, O. Okada, A. Tsubouchi, T. Takeda, Tetrahedron 2006,
62, 9981; c) Y. Zhang, K. C. Ngeow, J. Y. Ying, Org. Lett. 2007,
9, 3495.
[6] H. Firouzabadi, N. Iranpoor, M. Jafarpour, Tetrahedron Lett.
2006, 47, 93.
[7] Y. Kikugawa, Chem. Lett. 1981, 10, 1157.
[8] G. A. Olah, Q. Wang, N. J. Trivedi, G. K. Surya Prakash, Syn-
thesis 1992, 465.
[9] B. A. Gellert, N. Kahlcke, M. Feurer, S. Roth, Chem. Eur. J.
2011, 17, 12203.
[10] N. Sakai, T. Miyazaki, T. Sakamoto, T. Yatsuda, T. Moriya,
R. Ikeda, T. Konakahara, Org. Lett. 2012, 14, 4366.
[11] a) J. Alvarez-Builla, J. J. Vaquero, J. L. Garcia Navio, J. F. Cab-
ello, C. Sunkel, M. Fau de Casa-Juana, F. Dorrego, L. Santos,
Tetrahedron 1990, 46, 967; b) W. Ando, T. Furuhata, H. Tsu-
maki, A. Sekiguchi, Synth. Commun. 1982, 12, 627; c) D. N.
Harpp, M. Gingras, Tetrahedron Lett. 1987, 28, 4373; d) M.
Gingras, T. H. Chan, D. N. Harpp, J. Org. Chem. 1990, 55,
2078.
Bis(2-iodobenzyl) Sulfide (2i): White solid (114.8 mg, 80%); m.p.
74–75 °C. 1H NMR (500 MHz, CDCl3): δ = 3.80 (s, 4 H, CH2),
6.94 (t, J = 7.5 Hz, 2 H, ArH), 7.30 (t, J = 7.5 Hz, 2 H, ArH), 7.36
(d, J = 7.5 Hz, 2 H, ArH), 7.84 (d, J = 7.5 Hz, 2 H, ArH) ppm.
13C NMR (125 MHz, CDCl3): δ = 41.4, 100.9, 128.3, 128.8, 130.1,
139.8, 140.2 ppm. MS (EI): m/z = 466 [M]+. HRMS (ESI): calcd.
for C14H12I2S [M + Na]+ 488.8647; found 488.8641.
[12] A. Ogawa, N. Takami, M. Sekiguchi, N. Sonoda, T. Hirao,
Heteroat. Chem. 1998, 9, 581.
[13] Y. Jiang, Y. Qin, S. Xie, X. Zhang, J. Dong, D. Ma, Org. Lett.
2009, 11, 5250.
[14] M. Arisawa, T. Ichikawa, M. Yamaguchi, Org. Lett. 2012, 14,
5318.
[15] a) C. Chen, Y. Xie, L. Chu, R.-W. Wang, X. Zhang, F.-L. Qing,
Angew. Chem. Int. Ed. 2012, 51, 2492; Angew. Chem. 2012, 124,
2542; b) C. Chen, L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012,
134, 12454.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data
for the products prepared by this method and copies of 1H and 13
NMR spectra of the products.
C
Acknowledgments
[16] When the reaction was carried out with the powder form of
elemental sulfur, a satisfactory result was obtained. However,
using the crystalline form reduced the yield of the thioether.
[17] When the reaction of 1a with S8 and TMDS in the presence of
a catalytic amount of InI3 was conducted at 80 °C for 20 h
using various solvents, such as toluene, CH3CN, DMF, and
EtOH, thioether 2a was obtained in 38%, 0%, 0%, and 0%
yield, respectively.
This work was partially supported by by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) with a Grant-in-
Aid for Scientific Research (C) (No. 25410120). We deeply thank
Shin-Etsu Chemical Co., Ltd. for the gift of hydrosilanes.
[1] a) R. C. Larock in Comprehensive Organic Transformations,
2nd ed., Wiley-VCH, New York, 1999; b) C. P. Baird, C. M. [18] When a similar reaction was carried out with another Lewis
Rayner, J. Chem. Soc. Perkin Trans. 1 1998, 1973.
acid, such as a typical zinc(II) catalyst, no improvement of the
product yield was observed.
[2] I. Koval, Russ. J. Org. Chem. 2007, 43, 319.
[3] For example see: a) H.-J. Xu, Y.-Q. Zhao, T. Feng, Y.-S. Feng,
J. Org. Chem. 2012, 77, 2878; b) L. Rout, P. Saha, S. Jammi,
T. Punniyamurthy, Eur. J. Org. Chem. 2008, 640; c) E. Sperotto,
G. P. M. van Klink, J. G. de Vries, G. van Koten, J. Org. Chem.
2008, 73, 5625; d) A. K. Verma, J. Singh, R. Chaudhary, Tetra-
hedron Lett. 2007, 48, 7199; e) L. Rout, T. K. Sen, T. Punniya-
murthy, Angew. Chem. Int. Ed. 2007, 46, 5583; Angew. Chem.
2007, 119, 5679; f) X. Lv, W. Bao, J. Org. Chem. 2007, 72, 3863;
g) D. Zhu, L. Xu, F. Wu, B. Wan, Tetrahedron Lett. 2006, 47,
[19] For (PhMe2Si)2S, HRMS (EI): calcd. for C16H22SSi2 [M]+
302.0981; found 302.0955.
[20] For indium-catalyzed substitution of benzyl acetate with a
thiosilane leading to the preparation of thioether 4, see: Y. Ni-
shimoto, A. Okita, M. Yasuda, A. Baba, Org. Lett. 2012, 14,
1846.
[21] To improve the yield of unsymmetrical thioether 4, the reaction
was carried out with 4 equiv. of the benzyl silyl ether under the
same conditions. In contrast, the product yield was decreased.
5781; h) Y.-J. Chen, H. H. Chen, Org. Lett. 2006, 8, 5609; i) [22] When the sulfidation was carried out by using a benzyl alcohol
C. G. Bates, P. Saejueng, M. Q. Doherty, D. Venkataraman,
Org. Lett. 2004, 6, 5005; j) F. Y. Kwong, S. L. Buchwald, Org.
Lett. 2002, 4, 3517.
as substrate, the corresponding benzyl sulfide was obtained in
80% NMR yield. See Supporting Information for details.
[23] a) Y. Nishimoto, A. Okita, M. Yasuda, A. Baba, Angew. Chem.
Int. Ed. 2011, 50, 8623; Angew. Chem. 2011, 123, 8782; b) Y.
Inamoto, Y. Nishimoto, M. Yasuda, A. Baba, Chem. Lett.
2013, 42, 1551.
[4] For example see: a) P. H. Lee, Y. Park, S. Park, E. Lee, S. Kim,
J. Org. Chem. 2011, 76, 760; b) M. A. Fernandez-Rodriguez,
J. F. Hartwig, J. Org. Chem. 2009, 74, 1663; c) C. Mispelaere-
Canivet, J.-F. Spindler, S. Perrio, P. Beslin, Tetrahedron 2005,
61, 5253; d) M. Murata, S. L. Buchwald, Tetrahedron 2004, 60,
Received: December 3, 2014
Published Online: February 5, 2015
1994
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 1991–1994