Synthesis of thioethers by ini3-catalyzed substitution of siloxy group using thiosilanes

Article abstract of DOI:10.3390/molecules21101330

The substitution of a siloxy group using thiosilanes smoothly occurred in the presence of InI₃ catalyst to yield the corresponding thioethers. InI₃was a specifically effective catalyst in this reaction system, while other typical Lew

Full text of DOI:10.3390/molecules21101330

molecules
Communication
Synthesis of Thioethers by InI3-Catalyzed
Substitution of Siloxy Group Using Thiosilanes
Yoshihiro Nishimoto 1,*, Aya Okita 2, Akio Baba 2 and Makoto Yasuda 2,
*
1
Frontier Research Base for Global Young Researchers, Center for Open Innovation Research and Education
(COiRE), Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Osaka 565-0871,
Japan; ayaokita@chem.eng.osaka-u.ac.jp (A.O.); baba@chem.eng.osaka-u.ac.jp (A.B.)
Correspondence: nishimoto@chem.eng.osaka-u.ac.jp (Y.N.); yasuda@chem.eng.osaka-u.ac.jp (M.Y.);
Tel.: +81-6-6879-7386 (Y.N.); +81-6-6879-7384 (M.Y.)
2
*
Academic Editor: Mitsuo Kira
Received: 6 September 2016; Accepted: 3 October 2016; Published: 6 October 2016
Abstract: The substitution of a siloxy group using thiosilanes smoothly occurred in the presence of
InI3 catalyst to yield the corresponding thioethers. InI3 was a specifically effective catalyst in this
reaction system, while other typical Lewis acids such as BF3 OEt2, AlCl3, and TiCl4 were ineffective.
·
Various silyl ethers such as primary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic, and
propargylic types were applicable. In addition, bulky OSitBuMe2 and OSiiPr3 groups, other than the
OSiMe3 group, were successfully substituted. The substitution reaction of enantiopure secondary
benzylic silyl ether yielded the corresponding racemic thioether product, which suggested that the
reaction of tertiary alkyl, secondary alkyl, benzylic, and propargylic silyl ethers would proceed via a
SN1 mechanism.
Keywords: indium; silyl ethers; thiosilanes; thioethers
1. Introduction
Organosulfur compounds are important building blocks in organic synthesis because many
natural and pharmaceutical products contain sulfur [
useful compound [ ]. Therefore, there are various types of synthetic methods to produce thioethers
such as hydrothiolation of alkenes [ ], Chan-Lam-Evans coupling using thiols [10], and transition
metal-catalyzed coupling between aryl halides and thiols [11 12]. The substitution reaction of alkyl
halides with sulfur nucleophiles is one of the most typical and practical methods in the synthesis
of alkyl thioethers (Scheme 1A) [13 18]. However, the use of alkyl halides has an inherent problem;
1–5]. In particular, a thioether is a popular and
1–5
6–9
,
–
that is, the potential toxicity of alkyl halides and metal halides as by-products. Recently, alcohol
derivatives such as alkyl ethers, alkyl acetates, alkyl carbonates, and silyl ethers have been suggested
as promising substrates that could solve the problem. In particular, silyl ethers are one of the most
useful alcohol derivatives because they are often used as protected alcohols in the syntheses of complex
organic compounds such as natural products, drugs, and agrichemicals [19,20]. However, there are
few reports about the synthesis of thioethers via the direct use of silyl ethers, due to the very poor
leaving ability of the siloxy group [21]. Although the coupling reaction between alkenyl silyl ethers
and thiosilanes has been reported, a stoichiometric amount of BF3
·
OEt2 was required [22]. Electrolysis
with a thiosilane using only an -acylamino silyl ether was also reported [23]. Therefore, in general,
α
a multi-step sequence involving deprotection and transformation of the siloxy group is required in
order to transform silyl ethers to thioethers (Scheme 1B). Therefore, the establishment of a direct
transformation of silyl ethers to thioethers would be ideal in terms of step-economy. Herein, we
report the direct substitution of a siloxy group with thiosilanes catalyzed by InI3 to synthesize a
Molecules 2016, 21, 1330; doi:10.3390/molecules21101330
www.mdpi.com/journal/molecules

Molecules 2016, 21, 1330
2 of 7
variety of thioethers (Scheme 1C). A disiloxane generated as a by-product has low toxicity, is inert,
and is easily removed, so the present substitution reaction is a very practical synthetic method for
producing thioethers.
Scheme 1. Synthetic methods for producing a thioether. (Mt = metal, R1 = alkyl, R2 = alkyl or aryl).
2. Results
First, the effect of the catalyst was investigated in the reaction of the primary alkyl silyl ether
1a with trimethyl(phenylthio)silane (2a) (Table 1). Recently, we studied the moderate Lewis acidity
of indium salts in order to develop the catalytic coupling reactions of alcohols and their derivatives
with various nucleophiles [24–34]. Therefore, a substitution reaction in the presence of InI3 at room
temperature was carried out and produced the desired thioether 3aa with a 27% yield (Entry 1).
The InI3-catalyzed reaction at 80 ◦C moderately proceeded to produce 3aa with a 53% yield (Entry 2).
By contrast, InCl3 did not mediate this substitution reaction (Entry 3), and InBr3 gave only a 27%
yield (Entry 4). Typical Lewis acids such as BF3 OEt2, AlCl3, and TiCl4 showed no catalytic activity
·
(Entries 5–7). The use of nonpolar solvents such as toluene and hexane resulted in low yields (Entries 8
and 9). Polar tetrahydrofuran (THF) solvent was not suitable (Entry 10). Finally, the InI3-catalyzed
reaction carried out in ClCH2CH2Cl at 80 ◦C for 8 h produced the highest yield (Entry 11).
Table 1. Optimization of conditions in the reaction of silyl ether 1a with thiosilane 2a a.
Yield (%) b
Entry
Catalyst (10 mol %)
Solvent
Conditions
1
2
3
4
5
6
7
8
9
InI3
InI3
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
Toluene
RT c, 2 h
27
53
0
27
0
0
0
30
17
0
◦
80 C, 2 h
◦
InCl3
InBr3
BF3·OEt2
AlCl3
TiCl4
InI3
80 C, 2 h
◦
80 C, 2 h
◦
80 C, 2 h
◦
80 C, 2 h
◦
80 C, 2 h
◦
80 C, 2 h
◦
InI3
InI3
InI3
Hexane
68 C, 2 h
◦
THF d
10
11
a
66 C, 2 h
◦
ClCH2CH2Cl
80 C, 8 h
67
1a (1.2 equiv.), 2a (1 equiv.), catalyst (0.1 equiv.), solvent (1 M); b Yields were determined by 1H-NMR; c RT =
room temperature; d THF = Tetrahydrofuran.
The scope of the silyl ethers is listed in Table 2. The reaction of secondary alkyl silyl ether 1b
resulted in only a 32% yield of thioether 3ba (Entry 1). On the other hand, tertiary alkyl and secondary
benzyl silyl ethers (1c and 1d) gave very high yields even at room temperature (Entries 2 and 3).
Primary benzylic substrates were also suitable for this system, and both electron-rich and electron-poor
benzyl silyl ethers produced the corresponding thioethers 3ea, 3fa, and 3ga in high yields (Entries 4–6).

Molecules 2016, 21, 1330
3 of 7
The substitution reaction of propargylic silyl ether 1h smoothly occurred at room temperature without
an allenylic thioether product being generated in a rearrangement reaction (Entry 7). Additionally, the
primary alkyl silyl ether 1i, which bears an olefin moiety, was applicable to this reaction (Entry 8).
Table 2. Scope of the silyl ethers 1b–i in the InI3-catalyzed substitution reaction using thiosilane 2a a.
Yield (%) b
Entry
R1OSiMe3
Conditions
Product
ClCH2CH2Cl
80 C, 8 h
1
32
◦
1b
1c
3ba
3ca
CH2Cl2
RT, 2 h
2
3
99 (95) c
CH2Cl2
RT, 2 h
98
3da
3ea
1d
1e
ClCH2CH2Cl
80 C, 2 h
4
5
85
88
◦
CH2Cl2
RT, 2 h
1f
3fa
ClCH2CH2Cl
80 C, 2 h
6
83
◦
1g
3ga
CH2Cl2
RT, 2 h
7
8
67
36
1h
1i
3ha
3ia
ClCH2CH2Cl
◦
80 C, 2 h
a 1 (1.2 equiv.), 2a (1 equiv.), InI3 (0.1 equiv.), solvent (1 M); b Yields were determined by 1H-NMR; c Isolated yield.
Various types of thiosilanes were examined in this reaction system (Scheme 2). Arylthiosilanes
bearing electron-withdrawing and electron-donating groups produced the desired products 3eb and
3ec in high yields, respectively. An alkyl thiosilane, other than an aryl type, was also applicable to the
present substitution reaction. The reaction of benzyl silyl ether 1e with trimethyl(dodecylthio)silane
(2d) smoothly occurred to produce the corresponding dialkyl thioether 3ed with 92% yield.
Scheme 2. Substitution reaction using different types of thiosilanes.

Molecules 2016, 21, 1330
4 of 7
Bulky silyl groups are generally more useful and robust protecting groups compared with the
trimethylsilyl group in organic synthesis. We examined OSitBuMe2, OSiiPrMe2, and OSiiPr3 groups
for the substitution reaction (Scheme 3). Despite the large steric hindrance, the bulky silyl ethers 1j
, 1k,
and 1l reacted with thiosilane 2a to produce the corresponding thioether 3aa in high yields.
Scheme 3. Substitution of bulky siloxy groups. RT: room temperature.
The excellent results given by the reaction using tertiary alkyl and benzylic thioethers suggested
that the substitution reaction using these thioethers occurred via the SN1 mechanism involving a
carbocation intermediate. Actually, the reaction of the enantiopure benzyl silyl ether (R)-1d catalyzed
by InI3 produced a racemic mixture of 3aa (Scheme 4, upper line) [35]. The reaction using the allyl
silyl ether 1m exclusively0yielded thioether 3mb-1 without producing the thioether 3mb-2 through
allylic rearrangement (SN2 mechanism) (Scheme 4, lower line). This result showed that the reaction of
a primary allylic silyl ether involves a SN2 mechanism.
Scheme 4. Mechanistic study.
Plausible reaction mechanisms are illustrated in Scheme 5. From the result of Equation 1, the
substitution reactions of tertiary alkyl, secondary alkyl, benzylic, and propargylic silyl ethers would
proceed via the SN1 mechanism (Scheme 5A). A siloxy group coordinates to InI3 (
cleavage of the C–O bond generates a carbocation intermediate. The nucleophilic attack of the thiosilane
to the carbocation intermediate gives thioether and Me3SiOSiMe3, and InI3 regenerates. On the
4), and then the
2
3
other hand, the reaction of a primary alkyl silyl ether would proceed via a SN2-type mechanism
(Scheme 5B), because a primary alkyl cation is not easily generated. First, the coordination of a siloxy
group to InI3 enhances polarization of the C–O bond. Then, an SN2 reaction of the InI3-activated silyl
ether
4 with thiosilane 2 occurs. The reaction of a primary allyl silyl ether also involves this type
of mechanism (Scheme 4, lower line). Generally, transmetalation between a metal salt (MtXn) and
thiosilane (R2S-SiMe3) may occur to generate a metal thiolate (MtXn-y(SR2)y). Actually, AlCl3 and
BF3 OEt2 transmetalate with thiosilane 2a to form thioaluminum and thioborane, respectively [36].
·
On the other hand, the transmetalation between InI3 and thiosilane 2a does not occur, which allows
InI3 to work as a Lewis acid catalyst in the present substitution reaction [36]. A disiloxane by-product
has low toxicity and is easily removed by column chromatography on silica gel, which enhances the
utility of this reaction system in organic synthesis.

Molecules 2016, 21, 1330
5 of 7
Scheme 5. Plausible reaction mechanisms.
3. Experimental Section
Typical Procedure: Silyl ether 1c (0.135 g, 0.6 mmol) was added to a suspended solution of
thiosilane 2a (0.089 g, 0.5 mmol) and InI3 (0.026 g, 0.05 mmol) in dichloromethane (0.5 mL). The reaction
mixture was stirred at room temperature for 2 h and was then quenched by a saturated aqueous solution
of NaHCO3. The crude product was extracted with dichloromethane. The combined organic layer
was dried over MgSO4, and concentrated under reduced pressure. The NMR yield was determined by
1H-NMR (1H-NMR spectra were recorded on a JMTC-400/54/SS instrument at 400 MHz (JEOL Ltd.,
Tokyo, Japan), using 1,1,2,2-tetrachloroethane as an internal standard. The crude product was purified
by flash chromatography (Hexane/EtOAc = 95:5, spherical silica gel 60 µm, 30 g, diameter 2.7 cm,
Shoko Scientific Co., Ltd., Kanagawa, Japan) to afford the corresponding thioether 3ca (0.119 g, 95%).
4. Conclusions
We have developed an InI3-catalyzed coupling reaction of silyl ethers with thiosilanes. A variety
of silyl ethers and thiosilanes are applicable to the present coupling reaction. In particular, the scope
of silyl ethers is significantly broad, and primary alkyl, secondary alkyl, tertiary alkyl, benzylic, and
propargylic silyl ethers are feasible substrates. In addition, the substitution of OSiMe3 as well as
OSitBuMe2 and OSiiPr3 groups smoothly occurred. InI3 specifically achieved this catalytic substitution
reaction unlike other typical Lewis acids. This was possible because the transmetalation between InI3
and thiosilane does not occur, and InI3 sufficiently activates silyl ether due to its moderate Lewis acidity.
Acknowledgments: This work was supported by JSPS KAKENHI Grant Numbers JP15H05848 in Middle
Molecular Strategy and JP16K05719. Yoshihiro Nishimoto thanks the Tonen General Sekiyu Research and
Development Encouragement Foundation and the Tokuyama Science Foundation for financial support. Yoshihiro
Nishimoto acknowledges support from the Frontier Research Base for Global Young Researchers, Osaka University,
on the Program of MEXT.
Author Contributions: Yoshihiro Nishimoto, Akio Baba, and Makoto Yasuda conceived and designed the
experiments and wrote the paper. Yoshihiro Nishimoto and Aya Okita performed the experiments.
Conflicts of Interest: The authors declare no conflict of interest.
References and Notes
1.
2.
Peach, M.E. The Chemistry of the Thiol Group; Patai, S., Ed.; John Wiley & Sons: London, UK, 1979; pp. 721–756.
Damani, L.A. Metabolism of Sulfur Functional Groups. In Sulfur-Containing Drugs and Related Organic
Compounds: Chemistry, Biochemistry, and Toxicology; Ellis Horwood Ltd.: Chichester, UK, 1989; Volume 1,
Part A.
3.
Oae, S. Organic Sulfur Chemistry: Structure and Mechanism; Doi, J.T., Ed.; CRC Press: Boca Raton, FL,
USA, 1991.

Molecules 2016, 21, 1330
6 of 7
4.
5.
Cremlyn, R.J. An Introduction to Organosulfur Chemistry; John Wiley & Sons: New York, NY, USA, 1996.
McReynolds, M.D.; Doughtery, J.M.; Hanson, P.R. Synthesis of Phosphorus and Sulfur Heterocycles via
Ring-Closing Olefin Metathesis. Chem. Rev. 2004, 104, 2239–2258. [CrossRef] [PubMed]
Ranu, B.C.; Mandal, T. Water-promoted highly selective anti-Markovnikov addition of thiols to unactivated
alkenes. Synlett 2007, 925–928. [CrossRef]
Lenardão, E.J.; Ferreira, P.C.; Jacob, R.G.; Perin, G.; Leite, F.P.L. Solvent-free conjugated addition of
thiols to citral using KF/alumina: Preparation of 3-thioorganylcitronellals, potential antimicrobial agents.
Tetrahedron Lett. 2007, 48, 6763–6766. [CrossRef]
6.
7.
8.
9.
Lenardão, E.J.; Jacob, R.G.; Mesquita, K.D.; Lara, R.G.; Webber, R.; Martinez, D.M.; Savegnago, L.;
Mendes, S.R.; Alves, D.; Perin, G. Glycerol as a promoting and recyclable medium for catalyst-free synthesis
of linear thioethers: New antioxidants from eugenol. Green Chem. Lett. Rev. 2013, 6, 269–276.
Movassagh, B.; Navidi, M. Water promoted catalyst-free anti-Markovnikov addition of thiols to styrenes.
Arkivoc 2008, 47–53.
10. See a recent review: Ley, S.V.; Thomas, A.W. Modern synthetic methods for copper-mediated C(aryl)–O,
C(aryl)–N, and C(aryl)–S Bond Formation. Angew. Chem. Int. Ed. 2003, 42, 5400–5449.
11. See a review: Kondo, T.; Mitsudo, T. Metal-catalyzed carbon-sulfur bond formation. Chem. Rev. 2000, 100,
3205–3220. [CrossRef]
12. See a review: Lee, C.F.; Liu, Y.C.; Badsara, S.S. Transition-metal-catalyzed C-S bond coupling reaction.
Chem. Asian J. 2014, 9, 706–722.
13. Parham, W.E.; Wynberg, H. Diethyl mercaptoacetal. Org. Synth. 1963, 4, 295.
14. Boscato, J.F.; Catala, J.M.; Franta, E.; Brossas, J. Action of elementary sulfur onto carbanions: A new route to
dialkylpolysulfides. Tetrahedron Lett. 1980, 21, 1519–1520. [CrossRef]
15. Hundscheid, F.J.A.; Tandon, V.K.; Rouwette, P.H.A.M.; van Leusen, A.M. Synthesis of chiral sulfonylmethyl
isocyanides, and comparison of their propensities in asymmetric induction reactions with acetophenones.
Tetrahedron 1987, 43, 5073–5088. [CrossRef]
16. Malmstrom, J.; Gupta, V.; Engman, L. Novel antioxidants: unexpected rearrangements in the radical
cyclization approach to 2,3-dihydrobenzo[b]thiophene-5-ol derivatives. J. Org. Chem. 1998, 63, 3318–3323.
[CrossRef]
17. Blanchard, P.; Jousselme, B.; Frere, P.; Roncali, J. 3- and 3,4-Bis(2-cyanoethylsulfanyl)thiophenes as building
blocks for functionalized thiophene-based
[CrossRef] [PubMed]
π-conjugated systems. J. Org. Chem. 2002, 67, 3961–3964.
18. Ranu, B.C.; Jana, R. Ionic liquid as catalyst and reaction medium: A simple, convenient and green procedure
for the synthesis of thioethers, thioesters and dithianes using an inexpensive ionic liquid, [pmIm]Br.
Adv. Synth. Catal. 2005, 347, 1811–1818. [CrossRef]
19. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; John Wiley & Sons: New York, NY,
USA, 1991; pp. 68–87.
20. Wuts, P.G.M.; Greene, T.W. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons: New York, NY,
USA, 2007; pp. 165–221.
21. The substitution reaction of silyl ethers with Ph3P(SCN)2: Iranpoor, N.; Firouzabadi, H.; Shaterian, H.
Efficient conversion of silyl ethers to thiocyanates with Ph3P(SCN)2. Synlett 2000, 65–66.
22. Degl’Innocenti, A.; Ulivi, P.; Capperucci, A.; Mordini, A.; Reginato, G.; Ricci, A. Thiosilanes in organic
synthesis: A novel approach to vinyl sulphides. Synlett 1992, 499–501. [CrossRef]
23. Inokuchi, T.; Yamashita, H.; Date, T.; Torii, S. Generation and Michael reaction of 1,3-bis(trimethylsiloxy)-
isoindoles by reduction of N-alkylphthalimides with a Zn-Me3SiCl-lutidine system. Synth. Commun. 1989
19, 267–274. [CrossRef]
,
24. Nishimoto, Y.; Okita, A.; Yasuda, M.; Baba, A. Synthesis of a wide range of thioethers by indium triiodide
catalyzed direct coupling between alkyl acetates and thiosilanes. Org. Lett. 2012, 14, 1846–1849. [CrossRef]
[PubMed]
25. Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. InCl3/Me3SiBr-catalyzed direct coupling between silyl ethers
and enol acetates. Org. Lett. 2011, 13, 2762–2765. [CrossRef] [PubMed]
26. Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A. InI3/Me3SiI-catalyzed direct alkylation of enol acetates using
alkyl acetates or alkyl ethers. Chem. Lett. 2011, 40, 1223–1225. [CrossRef]

Molecules 2016, 21, 1330
7 of 7
27. Nishimoto, Y.; Saito, T.; Yasuda, M.; Baba, A. Indium-catalyzed coupling reaction between silyl enolates and
alkyl chlorides or alkyl ethers. Tetrahedron 2009, 65, 5462–5471. [CrossRef]
28. Nishimoto, Y.; Onishi, Y.; Yasuda, M.; Baba, A. α-Alkylation of carbonyl compounds by direct addition of
alcohols to enol acetates. Angew. Chem. Int. Ed. 2009, 48, 9131–9134. [CrossRef] [PubMed]
29. Nishimoto, Y.; Kajioka, M.; Saito, T.; Yasuda, M.; Baba, A. Direct coupling of alcohols with alkenylsilanes
catalyzed by indium trichloride or bismuth tribromide. Chem. Commun. 2008, 6396–6398. [CrossRef]
[PubMed]
30. Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. InCl3/I2-catalyzed cross-coupling of alkyl trimethylsilyl ethers
and allylsilanes via an in situ derived combined Lewis acid of InCl3 and Me3SiI. J. Org. Chem. 2007, 72,
8588–8590. [CrossRef] [PubMed]
31. Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. Direct coupling reaction between alcohols and silyl compounds:
Enhancement of Lewis acidity of Me3SiCl using InCl3. J. Org. Chem. 2006, 71, 8516–8522. [CrossRef]
[PubMed]
32. Saito, T.; Yasuda, M.; Baba, A. Indium-silicon combined Lewis acid catalyst for direct allylation of alcohols
with allyltrimethylsilane in non-halogenated solvent. Synlett 2005, 1737–1739. [CrossRef]
33. Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Direct substitution of the hydroxyl group in alcohols with silyl
nuculeophiles catalyzed by indium trichloride. Angew. Chem. Int. Ed. 2004, 43, 1414–1416. [CrossRef]
[PubMed]
34. Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A. Indium-catalyzed direct chlorination of alcohols using
chlorodimethylsilane-benzil as a selective and mild system. J. Am. Chem. Soc. 2004, 126, 7186–7187.
[CrossRef] [PubMed]
35. Enantiopure silyl ether (R)-1d was synthesized by the silylation of (R)-1-phenylethanol (97% enantiomeric
excess, purchased from Wako Pure Chemical Industries, Ltd., Osaka, Japan) using trimethylsilyl chloride
and Et3N.
36. NMR studies showed that AlCl3 and BF3 OEt2 transmetalated with thiosilane 2a to generate Me3SiCl and
·
Me3SiF, respectively. In contrast, when an equivalent amount of InI3 and thiosilane 2a was mixed, no
transmetalation was observed by 13C-NMR. See reference 24.
Sample Availability: Not available.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).