Synthesis of a wide range of thioethers by indium triiodide catalyzed direct coupling between alkyl acetates and thiosilanes

Article abstract of DOI:10.1021/ol300450j

An indium triiodide-catalyzed substitution of the acetoxy group in alkyl acetates with thiosilanes provides access to a variety of thioethers. The method is efficient for a wide scope of acetates such as primary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic, and propargylic acetates.

Full text of DOI:10.1021/ol300450j

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1846–1849
Synthesis of a Wide Range of Thioethers
by Indium Triiodide Catalyzed Direct
Coupling between Alkyl Acetates and
Thiosilanes
Yoshihiro Nishimoto, Aya Okita, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received February 23, 2012
ABSTRACT
An indium triiodide-catalyzed substitution of the acetoxy group in alkyl acetates with thiosilanes provides access to a variety of thioethers. The
method is efficient for a wide scope of acetates such as primary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic, and propargylic acetates.
The development of the synthetic method for thioethers
is a significant issue because various organosulfur com-
pounds play important roles in organic synthesis, bio-
organic, and medicinal chemistry.1 The reaction between
alkyl halides and metal thiolates is a classical route to
thioethers.2 However, these methods have drawbacks such
as a requirement for a strong base and inherent byproduc-
tion of an equimolar amount of metal halides. To
overcome these problems, the replacement of alkyl halides
with other electrophiles, such as alkyl alcohols, ethers, or
esters, is promising because of their availability and stabil-
ity and the fact that they are environmentally benign.
(1) (a) Peach, M. E. In The Chemistry of the Thiol Group; Patai, S., Ed.;
John Wiley & Sons: London, 1979; pp 721À756. (b) Damani, L. A. In
Sulfur-Containing Drugs and Related Organic Compounds: Chemistry,
Biochemistry, and Toxicology; Ellis Horwood Ltd.: Chichester, UK, 1989;
Vol. 1, Part B: Metabolism of Sulfur Functional Groups. (c) Oae, S., Ed.
Organic Sulfur Chemistry: Structure and Mechanism; CRC Press: Boca
Raton, 1991. (d) Cremlyn, R. J. In An Introduction to Organosulfur
Chemistry; Wiley & Sons: New York, 1996. (e) McReynolds, M. D.;
Doughtery, J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239.
(2) (a) Parham, W. E.; Wynberg, H. Org. Synth. 1963, 4, 295. (b)
Boscato, J. F.; Catala, J. M.; Franta, E.; Brossas, J. Tetrahedron Lett.
1980, 21, 1519. (c) Hundscheid, F. J. A.; Tandon, V. K.; Rouwette, P. H.
A. M.; van Leusen, A. M. Tetrahedron 1987, 43, 5073. (d) Malmstrom,
J.; Gupta, V.; Engman, L. J. Org. Chem. 1998, 63, 3318. (e) Blanchard,
P.; Jousselme, B.; Frere, P.; Roncali, J. J. Org. Chem. 2002, 67, 3961. (f)
Ranu, B. C.; Jana, R. Adv. Synth. Catal. 2005, 1811.
(3) Lewis acid catalyzed reactions: (a) Guindon, Y. R.; Frenette, R.;
Fortin, J.; Rokach, J. J. Org. Chem. 1983, 48, 1357. (b) Ouertani, M.;
Collin, J.; Kagan, H. B. Tetrahedron 1985, 41, 3689. (c) Kawada, A.;
Yasuda, K.; Abe, H.; Harayama, T. Chem. Pharm. Bull. 2002, 50, 380.
(d) Ohmori, K.; Ushimaru, N.; Suzuki, K. Tetrahedron Lett. 2002, 43,
7753. (e) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y. Y.; Yang, R. F.; Yang,
W. Z.; Li, J. P. J. Org. Chem. 2006, 71, 8298. (f) Han, X.; Wu, J. Org.
Lett. 2010, 12, 5780.
Figure 1. Syntheses of thioethers by direct coupling using alkyl
acetates.
Several procedures have been presented, but they still
have a limitation in the scope of applicable electrophiles.3À7
In particular, the employment of alkyl acetates remains
relatively undeveloped despite their high convenience for
organic synthesis. Transition-metal-catalyzed reactions
are limited to allylic acetates because of the generation of
π-allylic metal intermediates.4dÀf While some Lewis acid
r
10.1021/ol300450j
Published on Web 03/19/2012
2012 American Chemical Society

catalyzed SN1 reactions were also reported, only benzylic
acetates, which easily generate the corresponding carbo-
cations, were used.3d,6j,6k There are only SN2 reactions using
specifically activated acetates such as β-nitro acetates,6b,c
β-acetoxy R-diazo carbonyl compounds,6h and R-amide R-
acetoxy esters.6g In these reaction systems, the scope of
applicable alkyl acetates was strictly limited by the reaction
mechanism. In addition, the substitution of simple alkyl
acetates, which requires harsh conditions, has not been
much developed because of the risk of undesired transfor-
mation of esters into thioesters. Herein, we present a
general route to thioethers in which a direct coupling
between alkyl acetates and thiosilanes was effectively
catalyzed by InI3. Various types of acetates such as pri-
mary, secondary, tertiary, allylic, benzylic, and propargylic
acetates were readily applicable. As far as we could ascer-
tain, the present reaction system has the widest scope of
alkyl acetates among reported procedures (Figure 1).
First, the screening of catalysts was carried out in the
model reaction of 2-acetoxyoctane 1a with trimethyl-
(phenylthio)silane 2a (Table 1). InI3 was found to promote
most effectively the direct substitution of the acetoxy
group by 2a at 90 °C in toluene, furnishing the desired
thioether 3aa in 77% yield (entry 1). InBr3 also showed a
moderate catalytic effect (entry 2).8 The use of InCl3 and
In(OTf)3 resulted in no reaction (entries 3 and 4). The
representative oxophilicLewisacids suchasBF3 OEt2 and
AlCl3 afforded no desired thioether (entries 5 and 7).
Interestingly, a stoichiometric amount of BF3 OEt2 or
3
3
AlCl3 promoted a type of transesterification to produce
silyl ether 4 and thioester 5 (entries 6 and 8). These results
strongly indicated a sharp contrast in activation mode of
acetoxy moiety between indium triiodide and the repre-
sentative Lewis acids. Moreover, the employment of ZnI2,
which was reported to be effective in the synthesis of
thioethers by the reaction between thiols and alcohols,3a
resulted in only 8% yield (entry 9). B(C6F5)3 and Bi(OTf)3
were ineffective, although they accelerated coupling reac-
tions of alkyl acetates with allylic silanes and silyl enolates,
respectively (entries 10 and 11).9,10 Sc(OTf)3 also gave no
product (entry 12). ClCH2CH2Cl and hexane were also
found to be suitable solvents (entries 13 and 14). In contrast,
coordinative solvents like acetonitrile and DMF did not
furnish the desired reaction (entries 15 and 16).
Table 1. Screening of Catalysts and Solventsa
yieldb (%)
(4) Transition-metal-catalyzed reactions: (a) Inomata, K.; Yamamoto,
T.; Kotake, H. Chem. Lett. 1981, 1357. (b) Trost, B. M.; Scanlan, T. S.
Tetrahedron Lett. 1986, 27, 4141. (c) Goux, C.; Lhoste, P.; Sinou, D.
Tetrahedron Lett. 1992, 33, 8099. (d) Kondo, T.; Morisaki, Y.; Uenoyama,
S.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc. 1999, 121, 8657. (e)
Nakagawa, H.; Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2004, 69, 3474. (f) Yatsumonji, Y.; Ishida, Y.; Tsubouchi, A.; Takeda,
T. Org. Lett. 2007, 9, 4603. (g) Tanaka, S.; Pradhan, P. K.; Maegawa,
Y.; Kitamura, M. Chem. Commun. 2010, 46, 3996.
entry
catalyst
InI3
3aa
4c
5
1
77
49
0
0
0
0
2
InBr3
0
0
3
InCl3
0
4
In(OTf)3
0
0
0
(5) Ruthenium-catalyzed propargylic substitution reaction:Inada,
Y.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002,
124, 15172.
5
BF3 OEt2
0
0
5
3
6d
7
BF3 OEt2
0
34
0
35
0
3
AlCl3
AlCl3
ZnI2
0
(6) SN2-type reaction using a strong base: (a) Carroll, F. I.; White,
J. D.; Wall, M. J. Org. Chem. 1963, 28, 1236. (b) Lehr, H.; Karlan, S.;
Goldberg, M. W. J. Med. Chem. 1963, 6, 136. (c) Carroll, F. I.; White,
J. D.; Wall, M. E. J. Org. Chem. 1963, 28, 1240. (d) Ono, N.; Kamimura,
A.; Kaji, A. Tetrahedron Lett. 1986, 27, 1595. (e) Selva, M.; Trotta, F.;
Tundo, P. J. Chem. Soc., Perkin Trans. 2 1992, 519. (f) Otera, J.;
Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron 1997, 53, 13633.
(g) Paulitz, C.; Steglich, W. J. Org. Chem. 1997, 62, 8474. (h) Xu, F.; Shi,
W.; Wang, J. J. Org. Chem. 2005, 70, 4191. (i) Kuroda, K.; Maruyama,
Y.; Hayashi, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2009, 82, 381. (j)
Lee, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6480. (k)
Saha, A.; Ranu, B. C. Tetrahedron Lett. 2010, 51, 1902.
8d
9
0
30
0
20
0
8
10
11
12
13e
14f
15g
16h
B(C6F5)3
Bi(OTf)3
Sc(OTf)3
InI3
0
0
0
0
0
0
0
0
0
66
64
0
0
0
InI3
0
0
InI3
0
0
InI3
0
0
0
(7) (a) Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 17, 1409. (b)
Mukaiyama, T.; Ikegai, K. Chem. Lett. 2004, 1522.
a 1a (1 mmol), 2a (2 mmol), catalyst (0.1 mmol), toluene (1 mL),
90 °C, 3 h. b Yields were determined by analysis of 1H NMR spectra of
product mixtures prior to purification. c The yield of 4 was determined
after the hydrolysis of 4 to 2-octanol with 1 M HCl aq. d Catalyst
(1 mmol). e 1,2-DCE solvent. f Hexane solvent. g CH3CN solvent. h DMF
solvent.
(8) (a) Yasuda, M.; Saito, T.; Ueba, M.; Baba, A. Angew. Chem., Int.
Ed. 2004, 43, 1414. (b) Saito, T.; Yasuda, M.; Baba, A. Synlett 2005,
1737. (c) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem.
2006, 71, 8516. (d) Huang, J.-M.; Wong, C.-M.; Xub, F.-X.; Loh, T.-P.
Tetrahedron Lett. 2007, 48, 3375. (e) Baba, A.; Yasuda, M.; Nishimoto,
Y.; Saito, T.; Onishi, Y. Pure Appl. Chem. 2008, 80, 845. (f) Nishimoto,
Y.; Kajioka, M.; Saito, T.; Yasuda, M.; Baba, A. Chem. Commun. 2008,
6396. (g) Nishimoto, Y.; Onishi, Y.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2009, 48, 9131. (h) Nishimoto, Y.; Saito, T.; Yasuda, M.;
Baba, A. Tetrahedron 2009, 65, 5462. (i) Nishimoto, Y.; Moritoh, R.;
Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2009, 48, 4577. (j)
Nishimoto, Y.; Inamoto, Y.; Saito, T.; Yasuda, M.; Baba, A. Eur. J.
Org. Chem. 2010, 3382. (k) Nishimoto, Y.; Ueda, H.; Inamoto, Y.;
Yasuda, M.; Baba, A. Org. Lett. 2010, 12, 3390. (l) Onishi, Y.;
Nishimoto, Y.; Yasuda, M.; Baba, A. Org. Lett. 2011, 13, 2762. (m)
Nishimoto, Y.; Okita, A.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed.
2011, 50, 8623. (n) Onishi, Y.; Nishimoto, Y.; Yasuda, M.; Baba, A.
Chem. Lett. 2011, 40, 1223.
We next surveyed the scope of applicable thioethers. As
Table 2 shows, a variety of alkyl acetates were employed
smoothly. Primary and tertiary alkyl acetates (1b and 1d)
(9) (a) Rubin, M.; Gevorgyan, V. Org. Lett. 2001, 3, 2705. (b)
Schwier, T.; Rubin, M.; Gevorgyan, V. Org. Lett. 2004, 6, 1999.
(10) (a) Rubenbauer, P.; Bach, T. Tetrahedron Lett. 2008, 49, 1305.
(b) Rubenbauer, P.; Herdtweck, E.; Strassner, T.; Bach, T. Angew.
Chem., Int. Ed. 2008, 47, 10106.
Org. Lett., Vol. 14, No. 7, 2012
1847

as well as a secondary substrate 1c were utilized to give the
corresponding thioethers in high yields (entries 1À3). The
reaction of 1-adamantyl acetate 1e proceeded in excellent
yield despite possessing significant steric hindrance (entry 4).
Benzylic acetates bearing both electron-donating and -with-
drawing groups were found to be reactive electrophiles
(entries 5À9). This reaction system was applicable for
large-scale synthesis (entry 6). (2-Thienyl)methyl acetate 1j
furnished the desired product 3ja in 87% yield (entry 10).
The substitutions of allylic and propargylic acetoxy groups
(1k and 1l) were achieved (entries 11 and 12). R-Acetoxy
ketone 1m was also applicable to furnish the corresponding
R-thio ketone 3ma in 67% yield (entry 13). Ferrocene,
alkene, and phthalimide moieties tolerated the reaction
conditions (entries 14À16).11 It was notable that the acetoxy
group was substituted in preference to the chloro group to
give 5-chloropentyl phenyl thioether 3qa in 49% yield in the
reaction using 5-chloropentyl acetate 1q, although a 10%
yield of 1,5-bis(phenylthio)pentane 6 was observed (entry
17). The intramolecular competitive reaction using com-
pound 1r showed that the tertiary alkyl acetate has a higher
reactivity than the primary counterpart (entry 18).
Table 2. Substitution of OAc Group in Various Alkyl Acetates 1
with Thiosilane 2aa
Scheme 1 shows the effect of substituentsinthiosilanes2.
In the reaction with benzylic acetate 1f, both arylthiosilanes
bearing electron-donating and withdrawing groups gave
satisfying results at room temperature (3fb and 3fc).
Primary- and secondary alkyl thiosilanes also furnished
the corresponding thioethers in high yields, respectively, at
90 °C (3fd and 3fe). The difference in reaction temperature
indicated the higher reactivity of arylthiosilanes as com-
pared to alkylthiosilanes.
The reaction using optically active alkyl acetate, (S)-
2-acetoxyoctane (S)-1a, proceeded with racemization to give
the thioether 3aa in only 4% ee, which suggested that the
reaction is likely proceeding through an SN1 mechanism
via a carbocation intermediate (eq 1). However, the effec-
tive reaction using primary alkyl acetates and R-acetoxy
ketone, which cannot be expected to generate a stable
carbocation, is consistent with the reaction proceeding
through an SN2 mechanism. Therefore, the reaction mech-
anism would depend on the type of alkyl acetates.
The mixture of InI3, n-hexyl acetate 1s, and thiosilane 2a
in toluene-d8 solvent was monitored by 13C NMR at room
temperature, in which these conditions caused no substitu-
tion reaction of 1s with 2a. The considerable change of
signals of both acetate 1s and thiosilane 2a were observed,
which indicated that InI3 interacts with both alkyl acetate
and thiosilane.12 In addition, no transmetalation between
thiosilane 2a and InI3 was detected.13 In contrast, AlCl3
a 1 (1 mmol), 2a (2 mmol), InI3 (0.1 mmol), toluene (1 mL), room
temperature, 3 h. b Yields of crude products determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as the internal standard.
Values in parentheses are yields of isolated products. c The reaction was
carried out at 90 °C. d Large-scale synthesis 1 (20 mmol), 2a (40 mmol),
InI3 (2 mmol), toluene (20 mL). Isolated yield is shown. e The reaction
was carried out from 0 °C to room temperature. f InI3 (0.2 mmol).
(11) The difference between an NMR yield and an isolated yield was
caused by the difficult separation of the product from byproduct,
PhSSPh.
(12) See the Supporting Information for details of the NMR study.
(13) When an equivalent amount of InI3 and thiosilane 2a was mixed
in toluene-d8, no transmetalation was observed by 13C NMR.
1848
Org. Lett., Vol. 14, No. 7, 2012

produced with regeneration of InI3. InI3 brings alkyl
acetate 1 close to thiosilane 2 in complex 7, which would
contribute to the widespread scope of alkyl acetates. The
Lewis acidity of the indium center is not decreased due to
no transmetalation between InI3 and thiosilane to activate
alkyl acetate 2 effectively.
Scheme 1. Examination for Scope of Thiosilane 2.a
To expand the present procedure, the reaction of lac-
tones with thiosilane 2 was examined (Scheme 3).15 γ-
Butyrolactone 7 smoothly underwent the ring-opening
reaction to give the corresponding thiocarboxylic acid 10
in 73% yield. δ-Valerolactone 8 and ε-caprolactone 9 also
furnished the desired products 11 and 12 in excellent yields,
respectively.
a Reaction conditions: 1f (1 mmol), 2 (2 mmol), InI3 (0.1 mmol),
toluene (1 mL), 3 h. Yield of products after purification. b At room
temperature. c At 90 °C.
Scheme 3. Ring-Opening Reactions of Lactones with
Thiosilane 2aa
Scheme 2. Tentative Mechanism
a Yield of products after purification.
In conclusion, we have developed an effective and prac-
tical synthesis of thioethers by the InI3-catalyzed substitu-
tion reaction between alkyl acetates and thiosilanes. The
generality of alkyl acetates is remarkably widespread: pri-
mary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic,
and propargylic acetates, and R-acetoxy ketones were all
applicable. This reaction system was compatible with a
diverse range of functional groups including alkene, alkyne,
ferrocene, phthalimide, and ketone groups. Mechanistic
studies revealed the interesting feature of InI3 that acceler-
ates both mechanisms of SN1 and SN2 types.
and BF3 OEt2 easily transmetalated with 2a to generate
3
thioaliminum and thioborane, respectively.14 These metal
thiolates may cause a type of transesterification to give
thioesters (Table 1, entries 6 and 8).
On the basis of the above controlled studies, a tentative
mechanism is presented in Scheme 2. InI3 is coordinated by
both the carbonyl oxygen of alkyl acetate 1 and the sulfur
atom of thiosilane 2 to form complex 6. In the case of
secondary alkyl, tertiary alkyl, benzylic, propargylic, and
allylic acetates, an SN1-type substitution proceeds. On the
other hand, reactions of primary alkyl acetates and R-
acetoxy carbonyl compounds occur in SN2-type mecha-
nisms because of instability of the corresponding carbo-
cation. Finally, thioether 3 and trimethylsilyl acetate are
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Innovative Areas (No.
22106527 and No. 23105525) and Challenging Exploratory
Research (No. 23655083) from the Ministry of Education,
Culture, Sports, Science and Technology (Japan).
Supporting Information Available. Experimental pro-
cedures and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Node, M.; Nishide, K.; Ochiai, M.; Fuji, K.; Fujita, E. J. Org.
Chem. 1981, 46, 5163.
(14) NMR studies showed that AlCl3 and BF3 OEt2 transmetalated
3
with 2a to generate Me3SiCl and Me3SiF, respectively. See the Support-
ing Information for details.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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