Rhenium-catalyzed regio- and stereoselective synthesis of γ-thio-α,β-unsaturated ketones via insertion of terminal alkynes into the C-S bond

Article abstract of DOI:10.1021/ol302810u

The reaction of α-thioketones and alkynes in the presence of a rhenium catalyst, [HRe(CO)₄]_n, gave γ-thio-α, β-unsaturated ketones in excellent yields. The alkynes were inserted into the carbon-sulfur bond of the α-thioketones, and isomerization of a double bond provided the products with high regio- and stereoselectivities. This reaction also proceeded in an intramolecular fashion.

Full text of DOI:10.1021/ol302810u

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6116–6118
Rhenium-Catalyzed Regio- and
Stereoselective Synthesis of
γ‑Thio-r,β-unsaturated Ketones
via Insertion of Terminal Alkynes
into the CÀS Bond
Mitsumi Nishi, Yoichiro Kuninobu,*,† and Kazuhiko Takai*
Division of Chemistry and Biotechnology, Graduate School of Natural Science and
Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku,
Okayama 700-8530, Japan
kuninobu@mol.f.u-tokyo.ac.jp; ktakai@cc.okayama-u.ac.jp
Received October 12, 2012
ABSTRACT
The reaction of R-thioketones and alkynes in the presence of a rhenium catalyst, [HRe(CO)4]n, gave γ-thio-R,β-unsaturated ketones in excellent
yields. The alkynes were inserted into the carbonÀsulfur bond of the R-thioketones, and isomerization of a double bond provided the products
with high regio- and stereoselectivities. This reaction also proceeded in an intramolecular fashion.
Regio- and stereoselective insertion of alkynes into the
single bond of organic substrates is a useful and important
strategy for synthesizing multisubstituted alkenes. Utiliza-
tion of transition metal catalysts for such transforma-
tions is a promising method for practical uses; however,
problems of regio- and stereoselectivities should first be
solved. Recently, several transformations with high regio-
and stereoselectivities have been reported1 including ours.2
Many natural products, drugs, and organic functional
materials contain sulfur atoms and are used as reagents,
oxidants, and leaving groups in synthetic organic chemis-
try. When organosulfur compounds are synthesized by
the above-mentioned insertion method, several difficulties
arise. For example, the formation of radical species by
homolytic cleavage of the carbonÀsulfur bond which can
sometimes react to produce regio- and stereoisomers, and
the organosulfur compounds can cause poisonining of
the transition metal catalysts. To overcome these difficul-
ties, rhodium, palladium, platinum, and gold salts (or
complexes) are usually employed as catalysts for insertion
of a molecule into a CÀS bond (carbothiolation),3 such as
† Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
(1) For recent examples, see: (a) Huffman, M. A.; Liebeskind, L. S.
J. Am. Chem. Soc. 1991, 113, 2771. (b) Huffman, M. A.; Liebeskind,
L. S.; Pennington, W. T. Organometallics 1992, 11, 255. (c) Nozaki, K.;
Sato, N.; Takaya, H. Bull. Chem. Soc. Jpn. 1996, 69, 1629. (d) Kondo, T.;
Nakamura, A.; Okada, T.; Suzuki, N.; Wada, K.; Mitsudo, T.-a. J. Am.
Chem. Soc. 2000, 122, 6319. (e) Kondo, T.; Taguchi, Y.; Kaneko, Y.;
Niimi, M.; Mitsudo, T.-a. Angew. Chem., Int. Ed. 2004, 43, 5369.
(f) Murakami, M.; Itahasi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124,
13976. (g) Nakao, Y.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126,
13904. (h) Nakamura, I.; Bajracharya, G. B.; Wu, H.; Oishi, K.;
Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 15423. (i) Nishihara, Y.; Inoue, Y.; Itazaki, M.; Takagi, K.
Org. Lett. 2005, 7, 2639. (j) Murakami, M.; Ashida, S.; Matsuda, T.
J. Am. Chem. Soc. 2005, 127, 6932. (k) Murakami, M.; Ashida, S. Chem.
Commun. 2006, 4599. (l) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T.
J. Am. Chem. Soc. 2007, 129, 2428. (m) Shibata, T.; Nishikawa, G.; Endo,
K. Synlett 2008, 765. (n) Watson, M. P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2008, 130, 12594. (o) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.;
Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874. (p) Dreis,
A. M.; Douglas, C. J. J. Am. Chem. Soc. 2009, 131, 412. (q) Chen, X.;
Chen, D.; Lu, Z.; Kong, L.; Zhu, G. J. Org. Chem. 2011, 76, 6338.
(2) (a) Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006,
128, 11368. (b) Kuninobu, Y.; Takata, H.; Kawata, A.; Takai, K. Org.
Lett. 2008, 10, 3133. (c) Kuninobu, Y.; Kawata, A.; Nishi, M.; Takata,
H.; Takai, K. Chem. Commun. 2008, 6360. (d) Kuninobu, Y.; Kawata,
A.; Nishi, M.; Yudha, S. S.; Chen, J.; Takai, K. Chem.;Asian J. 2009, 4,
1424. (e) Kuninobu, Y.; Matsuzaki, H.; Nishi, M.; Takai, K. Org. Lett.
2011, 13, 2959.
r
10.1021/ol302810u
Published on Web 11/12/2012
2012 American Chemical Society

alkynylthiolation,4 arylthiolation,5 alkenylthiolation,6 allyl-
thiolation,7 acylthiolation,8 iminothiolation,9 alkylthiola-
tion,10 intramolecular carbothiolation,11 and so on.12,13 We
report herein the first example of insertion of alkynes into
the CÀS bond of R-thioketones, followed by isomerization
of the olefin moiety to give γ-thio-R,β-unsaturated ketones
with high regio- and stereoselectivity using a rhenium
catalyst.
Treatment of R-thioketone 1a with 1.2 equiv of alkyne
2a in the presence of a catalytic amount of the rhenium
catalyst, [HRe(CO)4]n, in toluene at 100 °C for 12 h gave
γ-thio-R,β-unsaturated ketone 3a in 99% yield (eq 1).14À16
The single product 3a was obtained in excellent yield
among the possible regio- and stereoisomers.
90% yields, respectively (entries 1 and 2). The desired
reaction proceeded well without loss of the bromine atom
(entry 2). When R-thioketone 1d having a methyl group at
the R1 position was employed, the conversion was quanti-
tative; however, amixtureofthreeregio-andstereoisomers
3d, 4d, and 5d was formed (entry 3). The corresponding
γ-thio-R,β-unsaturated ketone 3e was obtained in 74%
yield using R-thioketone 1e bearing an aliphatic substitu-
ent at the R2 position (entry 4). In the case of using an
R-thioketone without a substituent at the R-position, 1f, a
mixture of three regio- and stereoisomers 3f, 4f, and 5f was
generated (entry 5). The desired reaction did not occur
when 2-methyl-1-phenyl-2-(phenylthio)-1-propanone and
ethyl 2-(methylthio)acetate were used. The insertion reac-
tion did not proceed when using 2-phenoxypropiophenone
and 2-phenoxyacetophenone (β-keto ethers) instead of
R-thioketones 1a and 1f.
Table 1. Reactions between Several R-Thioketones 1 and
Phenylacetylene (2a)a
First, we investigated the scope of R-thioketones
(Table 1). R-Thioketones with an electron-donating or -
withdrawing group on the aromatic ring at the R1 position
gave γ-thio-R,β-unsaturated ketones 3b and 3c in 97% and
(3) For a review, see: (a) Kuniyasu, H.; Kurosawa, H. Chem.;Eur. J.
2002, 8, 2660. (b) Kuniyasu, H.; Kambe, N. Chem. Lett. 2006, 35, 1320.
(c) Kuniyasu, H.; Kambe, N. J. Synth. Org. Chem. Jpn. 2009, 67, 701.
(4) (a) Arisawa, M.; Igarashi, Y.; Tagami, Y.; Yamaguchi, M.;
Kabuto, C. Tetrahedron Lett. 2011, 52, 920. (b) Iwasaki, M.; Fujino,
D.; Wada, T.; Kondoh, A.; Yorimitsu, H.; Oshima, K. Chem.;Asian J.
2011, 6, 3190.
(5) (a) Sugoh, K.; Kuniyasu, H.; Sugae, T.; Ohtaka, A.; Takai, Y.;
Tanaka, A.; Machino, C.; Kambe, N.; Kurosawa, H. J. Am. Chem. Soc.
2001, 123, 5108. (b) Hirai, T.; Kuniyasu, H.; Kambe, N. Chem. Lett.
2004, 33, 1148. (c) Toyofuku, M.; Fujiwara, S.-i.; Shin-ike, T.; Kuniyasu,
H.; Kambe, N. J. Am. Chem. Soc. 2005, 127, 9706. (d) Yamashita, F.;
Kuniyasu, H.; Terao, J.; Kambe, N. Org. Lett. 2008, 10, 101.
(6) Toyofuku, M.; Fujiwara, S.-i.; Shin-ike, T.; Kuniyasu, H.;
Kambe, N. J. Am. Chem. Soc. 2008, 130, 10504.
(7) Hua, R.; Takeda, H.; Onozawa, S.-y.; Abe, Y.; Tanaka, M. Org.
Lett. 2007, 9, 263.
(8) (a) Minami, Y.; Kuniyasu, H.; Kambe, N. Org. Lett. 2008, 10,
2469. (b) Minami, Y.; Kuniyasu, H.; Miyafuji, K.; Kambe, N. Chem.
Commun. 2009, 3080.
(9) Minami, Y.; Kuniyasu, H.; Sanagawa, A.; Kambe, N. Org. Lett.
2010, 12, 3744.
(10) (a) Choi, N.; Kabe, Y.; Ando, W. Tetrahedron Lett. 1991, 32,
4573. (b) Nakamura, I.; Sato, T.; Terada, M.; Yamamoto, Y. Org. Lett.
2008, 10, 2649.
(11) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
2006, 45, 4473. See also, refs 1h and 10b.
(12) (a) Hua, R.; Takeda, H.; Onozawa, S.-y.; Abe, Y.; Tanaka, M.
J. Am. Chem. Soc. 2001, 123, 2899. (b) Kamiya, I.; Kawakami, J.-i.;
Yano, S.; Nomoto, A.; Ogawa, A. Organometallics 2006, 25, 3562. (c)
Ozaki, T.; Nomoto, A.; Kamiya, I.; Kawakami, J.-i.; Ogawa, A. Bull.
Chem. Soc. Jpn. 2011, 84, 155.
a 2a (1.2 equiv). b The ratio of 3d, 4d, and 5d is given in square
brackets. c 135 °C. d 2a (2.0 equiv), 135 °C. e The ratio of 3f, 4f, and 5f is
given in square brackets.
(13) Another method to synthesize organosulfur compounds is in-
sertion of carbon monoxide or isocyanides into the CÀS bond; see: (a)
Khumtaveeporn, K.; Alper, H. J. Org. Chem. 1994, 59, 1414. (b) Tobisu,
M.; Ito, S.; Kitajima, A.; Chatani, N. Org. Lett. 2008, 10, 5223.
(14) Investigation of several catalysts (alkyne (2.4 equiv), 135 °C):
Re2(CO)10, >99%; ReBr(CO)5, 10%; [ReBr(CO)3(thf)]2, 28%; Mn2-
(CO)10, 11%; MnBr(CO)5, trace; and Pd(OAc)2, PtCl2, PtCl4; no
reaction.
(15) This reaction did not proceed under UV irradiation or in the
presence of azobisisobutyronitrile (AIBN, radical initiator) instead of
the rhenium catalyst. These results indicate that this reaction does not
proceed via a radical mechanism.
Next, the scope of alkynes was investigated (Table 2).
The corresponding γ-thio-R,β-unsaturated ketones 3g and
3h were provided in excellent yields when aryl alkynes with
an electron-donating or -withdrawing group at the para-
position, 2band2c, respectively, wereused(entries1and2).
Aryl acetylene bearing a bromine atom, 2d, afforded
γ-thio-R,β-unsaturated ketone 3i in 99% yield without loss
of the bromine atom (entry 3). The corresponding γ-thio-
R,β-unsaturated ketones 3j and 3k were produced when
aryl acetylenes having a methoxy group at the meta- or
(16) In this reaction, the carbonyl group of R-thioketone 1a is
necessary to promote the reaction. In fact, insertion of alkyne 2a into
the CÀS bond of phenethyl phenyl sulfide did not proceed.
Org. Lett., Vol. 14, No. 23, 2012
6117

Table 2. Reactions between R-Thioketone 1a and Several
Alkynes 2a
Scheme 1. Proposed Mechanism for the Formation of
γ-Thio-R,β-unsaturated Ketones 3 and 4
The insertion reaction also proceeded in an intramolec-
ular fashion (eq 2). By treating the R-thioketones having
a 5-hexynyl chain at the R-position, 6, with a catalytic
amount of the rhenium catalyst, intramolecular insertion
occurred and the corresponding cyclohexene derivative 7
was afforded in 60% yield.
a 2 (1.2 equiv). b 24 h. c 2g (2.0 equiv). d Single product was obtained.
However, the stereochemistry of 3n was not determined.
ortho-position, 2e and 2f, respectively, were used (entries 4
and 5). The insertion reaction also proceeded when a
terminal alkyne with a heteroaromatic ring, 2g, was em-
ployed as the substrate (entry 6). Enyne 2h and aliphatic
acetylene 2i also gave the corresponding γ-thio-R,β-
unsaturated ketones 3m and 3n in 92% and 78% yields,
respectively (entries 7 and 8). However, the desired reac-
tion did not proceed with the internal alkynes of di-
phenylacetylene, 1-phenyl-1-propyne, and 6-dodecyne, and
(triisopropylsilyl)acetylene even at a higher temperature.
Although insertion of unsaturated bonds into a CÀC
bond of β-keto sulfones was observed in previous work,17
the insertion occurred at the CÀS single bond based on the
structure of product 3a in eq 1.
The proposed mechanism for the formation of unsatu-
rated ketones 3 and 4 is as follows (Scheme 1): (1) oxidative
addition of R-thioketone 1 to the rhenium center (CÀS
bond activation);18 (2-a) insertion of alkyne 2 to the formed
ReÀS bond or (2-b) insertion of alkyne 2 to the formed
ReÀC bond; (3) reductive elimination to give γ-thio-R,β-
unsaturated ketone 4; (4) isomerization of the olefin moiety
of 4 to provide 3 and/or A; and (5) isomerization of A to 3
due to thermodynamic stability.
Insummary,wehavesucceededintherhenium-catalyzed
regio- and stereoselective synthesis ofγ-thio-R,β-unsaturated
ketones from R-thioketones and alkynes by insertion of
alkynes into the CÀS bond of R-thioketones. This is
the first example of carbothiolation of an alkyne by an
R-thioketone and subsequent isomerization. In addi-
tion, cyclic γ-thio-R,β-unsaturated ketones could be
synthesized by the intramolecular reaction. We hope
that this reaction will become a useful method to synthe-
size organosulfur compounds.
Acknowledgment. This work was partially supported by
the Ministry of Education, Culture, Sports, Science, and
Technology of Japan.
Supporting Information Available. General experimen-
tal procedure and characterization data for γ-thio-R,β-
unsaturated ketones. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) In the case of β-keto sulfones instead of R-thioketones, alkynes
insert into a CÀC single bond of β-keto sulfones. See: ref 2e.
(18) For recent examples of transformations via oxidative addition to
a CÀS bond, see: (a) Arisawa, M.; Toriyama, F.; Yamaguchi, M. Chem.
Pharm. Bull. 2010, 58, 1349. (b) Arisawa, M.; Toriyama, F.; Yamaguchi,
M. Tetrahedron Lett. 2011, 52, 2344.
The authors declare no competing financial interest.
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