Single-step thioetherification by indium-catalyzed reductive coupling of carboxylic acids with thiols

Article abstract of DOI:10.1021/ol302109v

Direct thioetherification from a variety of aromatic carboxylic acids and thiols using a reducing system combined with InBr₃ and 1,1,3,3-teramethyldisiloxane (TMDS) in a one-pot procedure is demonstrated. It was also found that a system combine

Full text of DOI:10.1021/ol302109v

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4366–4369
Single-Step Thioetherification
by Indium-Catalyzed Reductive Coupling
of Carboxylic Acids with Thiols
Norio Sakai,* Takahiro Miyazaki, Tomohiro Sakamoto, Takuma Yatsuda,
Toshimitsu Moriya, Reiko Ikeda, and Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
sakachem@rs.noda.tus.ac.jp
Received July 2, 2012
ABSTRACT
Direct thioetherification from a variety of aromatic carboxylic acids and thiols using a reducing system combined with InBr3 and 1,1,3,3-
teramethyldisiloxane (TMDS) in a one-pot procedure is demonstrated. It was also found that a system combined with InI3 and TMDS underwent
thioetherification of aliphatic carboxylic acids with thiols.
Thioethers (sulfides) have been utilized as an important
building block for the efficient preparation of naturally
occurring products and medicinal drugs.1 The typical
approach to thioethers involves the reduction of sulfoxides
and sulfones (path a in Scheme 1),2 the Williamson-type
thioether synthesis from thiolate anions and alkyl halides
in the presence of a base, and the condensation of thiols
with benzyl/allyl alcohols in the presence of a Lewis acid
(path b in Scheme 1).3 More recently, a modified Ullmann
condensation of thiols with aryl halides using a metal
catalyst, such as copper,4 palladium,5 nickel,6 and others,7
has been reported (path c in Scheme 1).
Moreover, as examples using a reducing agent, such as a
borane and a silane (path d in Scheme 1), Kikugawa has
reported the direct reductive thioetherification of alde-
hydes or ketones with thiols using a pyridineÀBH3 reduc-
ing system in trifluoroacetic acid.8 Several groups have
carried out the synthesis of thioethers from aldehydes or
(1) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd ed.;
WileyÀVCH; New York, 1999. (b) Baird, C. P.; Rayner, C. M. J. Chem. Soc.,
Perkin Trans. 1 1998, 1973.
(2) For example, see: (a) Hua, G.; Woollins, J. D. Tetrahedron Lett.
2007, 48, 3677. (b) Bahrami, K.; Khodaei, M. M.; Khedri, M. Chem.
Lett. 2007, 36, 1324. (c) Kikuchi, S.; Konishi, H.; Hashimoto, Y.
Tetrahedron 2005, 61, 3587. (d) Miller, S. J.; Collier, T. R.; Wu, W.
Tetrahedron Lett. 2000, 41, 3781. (e) Shimizu, M.; Shibuya, K.; Hayakawa,
R. Synlett 2000, 1437. (f) Wakisaka, M.; Hatanaka, M.; Nitta, H.;
Hatamura, M.; Ishimaru, T. Synthesis 1980, 67. (g) Gardner, J. N.; Kaiser,
S.; Krubiner, A.; Lucas, H. Can. J. Chem. 1973, 51, 1419.
(3) For example, see: (a) Han, X.; Wu, J. Org. Lett. 2010, 12, 5780. (b)
Han, X.; Zhang, Y.; Wu, J. J. Am. Chem. Soc. 2010, 132, 4104. (c)
Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L.
J. Am. Chem. Soc. 2009, 131, 1753. (d) Cozzi, P. G.; Zoli, L. Angew.
Chem., Int. Ed. 2008, 47, 4162. (e) Koval, I. Russ. J. Org. Chem. 2007, 43,
319 and references cited therein. (f) Guindon, Y.; Frenette, R.; Fortin,
R.; Rokach, J. J. Org. Chem. 1983, 48, 1357.
(4) For example, see: (a) Xu, H.-J.; Zhao, Y.-Q.; Feng, T.; Feng,
Y.-S. J. Org. Chem. 2012, 77, 2878. (b) Rout, L.; Saha, P.; Jammi, S.;
Punniyamurthy, T. Eur. J. Org. Chem. 2008, 640. (c) Sperotto, E.; van
Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org. Chem. 2008, 73,
5625. (d) Verma, A. K.; Singh, J.; Chaudhary, R. Tetrahedron Lett. 2007,
48, 7199. (e) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem., Int.
Ed. 2007, 46, 5583. (f) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863. (g)
Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett. 2006, 47, 5781. (h)
Chen, Y. J.; Chen, H. H. Org. Lett. 2006, 8, 5609. (i) Bates, C. G.;
Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6,
5005. (j) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(5) For example, see: (a) Lee, P. H.; Park, Y.; Park, S.; Lee, E.; Kim,
S. J. Org. Chem. 2011, 76, 760. (b) Fernandez-Rodriguez, M. A.;
Hartwig, J. F. J. Org. Chem. 2009, 74, 1663. (c) Mispelaere-Canivet,
C.; Spindler, J.-F.; Perrio, S.; Beslin, P. Tetrahedron 2005, 61, 5253. (d)
Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397. (e) Itoh, T.;
Mase, T. Org. Lett. 2004, 6, 4587. (f) Miller, K. J.; Abu-Omar, M. M.
Eur. J. Org. Chem. 2003, 1294. (g) Kosugi, M.; Ogata, T.; Terada, M.;
Sano, H.; Migita, T. Bull. Chem. Soc. Jpn. 1985, 58, 3657.
(6) For example, see: (a) Jammi, S.; Barua, P.; Rout, L.; Saha, P.;
Punniyamurthy, T. Tetrahedron Lett. 2008, 49, 1484. (b) Yatsumonji,
Y.; Okada, O.; Tsubouchi, A.; Takeda, T. Tetrahedron 2006, 62, 9981.
(c) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9, 3495.
(7) For example, see: (a) Reddy, V. P.; Swapna, K.; Kumar, A. V.;
Rao, K. R. J. Org. Chem. 2009, 74, 3189. (b) Wu, J.-R.; Lin, C.-H.; Lee,
C.-F. Chem. Commun. 2009, 4450. (c) Reddy, V. P.; Kumar, A. V.;
Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697. (d) Wong, Y.-C.;
Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613. (e) Bulman Page,
P. C.; Klair, S. S.; Brown, M. P.; Smith, C. S.; Maginn, S. J.; Mulley, S.
Tetrahedron 1992, 48, 5933.
(8) Kikugawa, Y. Chem. Lett. 1981, 10, 1157.
r
10.1021/ol302109v
Published on Web 08/28/2012
2012 American Chemical Society

ketones and thiols using a reducing system combined with
a Lewis or Brønsted acid and a hydrosilane.9 In this con-
text, during ongoing studies on a functional group conver-
sion using an InBr3ÀEt3SiH reducing system,10,11 we accom-
plished a direct reductive thioetherification of acetals with
disulfides.12 However, the substrate employed in these con-
tributions is generally limited to an aldehyde, a ketone, or an
acetal. As far as can be ascertained, the direct conversion
from carboxylic acids, which are relatively tolerant to a
reducing agent, and thiols to thioethers has not been studied
(path e in Scheme 1).13 Herein, we report the first example of
a single-step synthesis of thioethers by the indium-catalyzed
reductive coupling of carboxylic acids with thiols.
examined using a model reaction of benzoic acid with
p-toluenethiol in the presence of 5 mol % of indium trihalide
(Table 1). Use of the best hydrosilane, Et3SiH, in our
previous work was ineffective for the reductive conversion
(entries 1;3). Thus, in cases using InBr3, whenEt3SiH was
changed to another hydrosilane, PhSiH3, and a siloxane,
TMDS, the yield of thioether 1a was remarkably increased
(entries 4 and 5).14 After further adjustment, the reaction
conditions that consisted of 5 mol % of InBr3 or InI3 and
6 equiv (SiÀH) of TMDS in 1,2-dichloroethane at 80 °C
were determined to be the best for this thioetherification
(entries 6 and 7).
Table 1. Examinations of the Optimal Conditions for
Thioetherification from Benzoic Acid and p-Toluenethiol
Scheme 1. Diverse Approaches to Thioethers
silane
temp yield
entry
InX3
(SiÀH equiv)
solvent
CHCl3
(°C)
(%)a
1
2
3
4
5
6
7c
InBr3
InCl3
In(OTf)3
InBr3
InBr3
InBr3
InI3
Et3SiH (4)
Et3SiH (4)
Et3SiH (4)
PhSiH3 (12)
TMDSb (8)
TMDSb (6)
TMDSb (6)
60
60
60
60
60
80
80
4
CHCl3
7
CHCl3
11
59
69
(91)
(94)
CHCl3
CHCl3
CH2ClCH2Cl
CH2ClCH2Cl
Initially, tofind the optimalconditions, the solvent effect
and amount of a reducing reagent, a hydrosilane, were
a GC (isolated) yield. b TMDS = tetramethyldisiloxane. c Reaction
time: 4 h.
(9) (a) Gellert, B. A.; Kahlcke, N.; Feurer, M.; Roth, S. Chem.;Eur.
J. 2011, 17, 12203. (b) Wang, Q.; Li, X.-y.; Prakash, G. K. S.; Olah,
G. A.; Loker, D. P.; Loker, K. B. ARKIVOC 2001, 116. (c) Olah, G. A.;
Wang, Q.; Trivedi, N. J.; Surya Prakash, G. K. Synthesis 1992, 465. (d)
Sassaman, M. B.; Surya Prakash, G. K.; Olah, G. A.; Donald, P.; Loker,
K. B. Tetrahedron 1988, 44, 3771.
(10) (a) Sakai, N.; Usui, Y.; Ikeda, R.; Konakahara, T. Adv. Synth.
Catal. 2011, 353, 3397. (b) Sakai, N.; Nagasawa, K.; Ikeda, R.; Nakaike,
Y.; Konakahara, T. Tetrahedron Lett. 2011, 52, 3133. (c) Sakai, N.;
Kawana, K.; Ikeda, R.; Nakaike, Y.; Konakahara, T. Eur. J. Org. Chem.
2011, 3178. (d) Sakai, N.; Fujii, K.; Nabeshima, S.; Ikeda, R.; Konakahara,
T. Chem. Commun. 2010,46, 3173. (e) Sakai, N.; Moritaka, K.; Konakahara,
T. Eur. J. Org. Chem. 2009, 4123. (f) Sakai, N.; Moriya, T.; Fujii, K.;
Konakahara, T. Synthesis 2008, 3533. (g) Sakai, N.; Fujii, K.; Konakahara,
T. Tetrahedron Lett. 2008, 49, 6873. (h) Sakai, N.; Moriya, T.; Konakahara,
T. J. Org. Chem. 2007, 72, 5920. (i) Sakai, N.; Hirasawa, M.; Konakahara, T.
Tetrahedron Lett. 2005, 46, 6407.
(11) For selected papers of functional group conversion by an
indiumÀsilane reducing system, see: (a) Pehlivan, L.; Metay, E.;
Delbrayelle, D.; Mignani, G.; Lemaire, M. Tetrahedron 2012, 68,
3151. (b) Tsuchimoto, T.; Wagatsuma, T.; Aoki, K.; Shimotori, J.
Org. Lett. 2009, 11, 2129. (c) Babu, S. A.; Yasuda, M.; Baba, A. Org.
Lett. 2007, 9, 405. (d) Miura, K.; Tomita, M.; Yamada, Y.; Hosomi, A.
J. Org. Chem. 2007, 72, 787. (e) Benati, L.; Bencivenni, G.; Leardini, R.;
Nanni, D.; Minozzi, M.; Spagnolo, P.; Scialpi, R.; Zanardi, G. Org. Lett.
2006, 8, 2499. (f) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew.
Chem., Int. Ed. 2004, 43, 1414. (g) Shibata, I.; Kato, H.; Ishida, T.;
Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 711. (h) Hayashi,
N.; Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981. (i) Miura, K.; Yamada,
Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985.
(12) For selected papers of preparation of thioethers using O,O- or O,
S-acetals, see: (a) Mukaiyama, T.; Ohno, T.; Nishimura, T.; Han, J. S.;
Kobayashi, S. Bull. Chem. Soc. Jpn. 1991, 64, 2524. (b) Mukaiyama, T.;
Ohno, T.; Nishimura, T.; Han, J. S.; Kobayashi, S. Chem. Lett. 1990, 19,
2239. (c) Kim, S.; Ho Park, J.; Lee, S. Tetrahedron Lett. 1989, 30, 6697.
(13) (a) Reductive conversion from carboxylic acids to S,S-acetals
was reported; see: Kim, S.; Kim, S. S. Tetrahedron Lett. 1987, 28, 1913.
(b) For reduction of thioesters to sulfides with LiAlH4ÀAlCl3, see:
Bublitz, D. E. J. Org. Chem. 1967, 32, 1630.
With the optimal conditions that mainly used economi-
cal InBr3, the scope and limitationsofthethioetherification
of benzoic acids were examined with a variety of thiols
(Scheme 2). When the reaction was run with benzenethiols
having an electron-donating or -withdrawing group, the
corresponding thioethers 2aÀ5a were produced in good to
excellent yields. When the reaction with an aliphatic thiol,
such as thiobenzyl alcohol and 1-octanethiol, was also
carried out, the corresponding thioether derivatives 6a and
7a were obtained in good yields. When the reaction was
performed with 1,2-ethanedithiol, the cyclic thioacetal
derivatives 8a and 9a were obtained in good yields.15 Also
the electronic effect of a substituent on the benzoic acid did
not affect the reaction yield to afford the expected thiols
10aÀ17a. However, for the substrate with an iodo sub-
stituent, when the reaction was carried out with InI3, only
the expected thioether 16a was obtained in a yield of 82%.
When using InBr3, the formation of a trace amount of the
deiodinated product 1a was detected by GC. This result
implied that some part of the reaction series might involve
(14) To avoid a drastic decrease in the yield by polymerization of a
silane, the amount of the silane was adjusted in each case. Also an
In(OTf)3ÀTMDS reducing system did not produce the corresponding
thioether.
(15) Kim, S.; Kim, S. S.; Lim, S. T.; Shim, S. C. J. Org. Chem. 1987,
52, 2114.
Org. Lett., Vol. 14, No. 17, 2012
4367

a radical path. Unfortunately, the reductive thioetherifica-
tion of the aromatic carboxylic acids having the nitro
group, the nitrile group, and alkenes did not occur.
good to excellent yields (Scheme 3). When the subsequent
reaction of an aliphatic carboxylic acid with an aliphatic
thiol, 1-octanethiol, was carried out, formation of the
expected thioether derivatives 23aÀ25a and 27a was ob-
served in moderate to good yields. The reducing system did
not affect a halogen substituent or a hydroxy group to any
great extent. However, a primary amino group strongly
coordinated to the indium catalyst, retarding the expected
thioetherification. Use of 1,2-ethanedithiol gave the cyclic
thioacetal 28a as well as the case using an aromatic
carboxylic acid. Althoughthe unreactedsiloxane remained
in this case, further reduction to a linear thioether did
not occur (see Table 2 and Scheme 5). When the reaction of
a carboxylic acid with a more hindered aliphatic thiol,
2-methyl-2-butanethiol, was run, the thioetherifica-
tion proceeded smoothly to produce the corresponding
thioether derivative 29a in good yield. Moreover, the
reaction of the carboxylic acid having thiophene with the
bulky thiol as a heterocycle gave the desired thioether
30a in good yield. Only when using thiobenzyl alcohol
was the formation of the S,S-acetal 31b observed with the
thioether 31a.
Scheme 2. Synthesis of Thioethers from Aromatic Carboxylic
Acids and Thiols
a InI3 was used.
Scheme 3. Direct Synthesis of Thioethers from Aliphatic Car-
boxylic Acids and Thiols
When the optimal conditions using InBr3 and TMDS in
CH2ClCH2Cl were applied to the reaction of an aliphatic
carboxylic acid with a thiol, contrary to our expectations,
there was a decrease inthe yield ofthe thioether18aand the
formation of S,S-acetal 18b as a major product (entry 1 in
Table 2). Thus, when InI3 was used, the yield of thioether
18a was drastically improved to 60% (entry 2). Moreover,
when the amount of siloxane increased to 4 equiv, the
quantitative formation of thioether 18a was observed
without the production of thioacetal 18b (entry 3).
Table 2. Re-examination of the Reaction Conditions
yield (%)a
a Method A: InI3 (5 mol %), TMDS (8 equiv), CH2ClCH2Cl, 80 °C,
4 h. b Method B: InI3 (5 mol %), TMDS (6 equiv), CHCl3, 60 °C, 4 h.
c Yield of S,S-acetal 31b was in parentheses.
silane
entry
InX3
(SiÀH equiv)
18a
18b
1
2
3
InBr3
InI3
TMDS (8)
TMDS (6)
TMDS (8)
33
58
It was noteworthy that although a conventional
Williamson-type thioether synthesis using a bulky thiol
gave the expected thioether 32a in low yield, our method
produced the same thioether in a good yield (Scheme 4).
To understand the reaction pathway for thioetherifica-
tion, several control experiments were then conducted.
60
35
InI3
(97)
ND
a GC (Isolated) yield.
With the optimal conditions, when the reactions of
aliphatic carboxylic acids having a naphthylmethyl sub-
stituent, a benzyl substituent, a branched carbon chain, or
a linear carbon chain with p-toluenethiol were conducted,
the corresponding thioethers 19aÀ22a were obtained in
(16) A reductive CÀS bond cleavage of an S,S-acetal by a metal
hydride complex was reported; see: Ikeshita, K.-i.; Kihara, N.; Sonoda,
M.; Ogawa, A. Tetrahedron Lett. 2007, 48, 3025.
(17) Nishimoto, Y.; Okita, A.; Yasuda, M.; Baba, A. Org. Lett. 2012,
14, 1846.
4368
Org. Lett., Vol. 14, No. 17, 2012

Scheme 4. Comparison of the PresentMethod with a Williamson-
Type Thioether Synthesis
Scheme 6. Substitution of an in Situ Generated Silyl Ether with
1-Octanethiol
a Recovery of the alkyl chloride.
Scheme 7. Plausible Reaction Path of the Thioetherification
Whentheisolatedthioacetal23b was treated with 5 mol % of
InI3 and 1 equiv (SiÀH) of TMDS in CH2ClCH2Cl
at 80 °C, the S,S-acetal was smoothly consumed within 1 h
to produce the corresponding thioether 23a in a nearly
quantitative yield (Scheme 5). Additionally, when the reac-
tion of the silyl ether, which was in situ derived from
3-phenylpropionic acid and TMDS in CDCl3, with 1-octan-
ethiol was monitored in the presence of 5 mol % of InI3 by
13C NMR, no formation of thioether 23a was observed
(Scheme 6). Therefore, in this reaction system, nucleophilic
substitution of the corresponding silyl ether with a thiol did
not occur. Also these results showed that the S,S-acetal was
an intermediate in the thioetherification series (see Table 2).16
S,S-acetal was finally reduced by a siloxane to produce the
thioether with the formation of a thiosilane. The thiosilane,
which functions as an effective thiolate nucleophile,17
probably drove the catalytic cycle. As an alternative path,
there may be direct reduction from the O,S-acetal to the
thioether (path b).18À20
Scheme 5. Reductive Conversion of S,S-Acetal 23b to Thioether
23a
We have demonstrated direct thioetherification from a
variety of aliphatic or aromatic carboxylic acids and thiols
using a reducing system combined with either InBr3 or InI3
and an economical disiloxane in a one-pot procedure. This
simple catalytic system enabled the reductive introduction
of a nucleophile onto the carbonyl carbon in a carboxylic
acid under gentle conditions.
On the basis of these results, we present a plausible
mechanism for the thioetherification as shown in Scheme 7.
A carboxylic acid was reduced to the corresponding silyl
acetal by a siloxane with the liberation of H2. The formed
silyl acetal was subsequnetly reacted with two molecules
of a thiol to produce the expected S,S-acetal (path a). The
Acknowledgment. This work was partially supported
by a grant from the Japan Private School Promotion
Foundation supported by MEXT and by a grant from
the CCIS program supported by MEXT. The authors
thank Shin-Etsu Chemical Co., Ltd., for the gift of silanes.
(18) An O,S-acetal, which was prepared in situ by an aldehyde and a
thiosilane, was readily reduced to produce the corresponding thioether;
see: Glass, R. S. Synth. Commun. 1976, 6, 47. See also ref 9d.
(19) No formation of thioesters was observed under our optimal
conditions (entries 6 and 7 in Table 1) through the reaction series. Also,
the indium catalyst did not catalyze a formation of thioesters from the
corresponding carboxylic acids and thiols with condensation. See details
in Supporting Information.
(20) When a thioester was treated with the optimal conditions, the
corresponding thioether was obtained in goodyield; however, it required
a quite long time (>48 h) to complete the reaction. See details in
Supporting Information.
Supporting Information Available. Copies of the NMR
spectra of the new compounds are supplied. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4369