Highly regioselective double hydrothiolation of terminal acetylenes with thiols catalyzed by palladium diacetate

Article abstract of DOI:10.1246/bcsj.20100311

Treatment of terminal acetylenes 1 with two equivalents of thiols 2 in the presence of Pd(OAc)₂ catalyst and H₂O causes regioselective double hydrothiolation of 1, leading to the corresponding dithioketals 3 in moderate to good yields.

Full text of DOI:10.1246/bcsj.20100311

Short Articles
Bull. Chem. Soc. Jpn. Vol. 84, No. 4, 413–415 (2011)
413
Table 1. The Reaction of 1-Octyne (1a) with Benzenethiol (2a)a)
cat. Pd(OAc)2
PhSH (2a), H2O
Highly Regioselective Double
Hydrothiolation of Terminal
Acetylenes with Thiols Catalyzed
by Palladium Diacetate
SPh
(CH2)5CH3
PhS SPh
(CH2)5CH3
(CH2)5CH3
+
solvent
40 °C, 20 h
1a
3a
4a
Entry
Solvent
Yield of 3a/%b)
Yield of 4a/%b)
1
THF
80
72
71
ND
73
83
84
66
66
17
ND
ND
3
69
3
ND
ND
ND
ND
28
2c)
3d)
4e)
5f)
6
THF
THF
THF
THF
Takenori Mitamura, Masayuki Daitou,
Akihiro Nomoto, and Akiya Ogawa*
Acetone
EtOH
CH3CN
CHCl3
Benzene
Department of Applied Chemistry, Graduate School
of Engineering, Osaka Prefecture University,
1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531
7
8
9
10
Received November 8, 2010
E-mail: ogawa@chem.osakafu-u.ac.jp
a) Reaction conditions: 1-octyne (1a, 0.5 mmol), benzenethiol
(2a, 1.0 mmol), Pd(OAc)2 (5 mol % based on 1a), solvent
(0.5 mL), H2O (ca. 1 equiv based on 1a), 40 °C, 20 h. b)
1
Determined by H NMR. c) The reaction was carried out for
Treatment of terminal acetylenes 1 with two equivalents
of thiols 2 in the presence of Pd(OAc)2 catalyst and H2O
causes regioselective double hydrothiolation of 1, leading to
the corresponding dithioketals 3 in moderate to good yields.
16 h. d) AcOH (1 equiv based on 1a) was used in place of H2O.
e) The reaction was carried out in the absence of H2O. f) The
reaction was carried out for 40 h in the absence of H2O.
(Entry 3). When we examined the Pd(OAc)2-catalyzed reaction
of 1a with 2a in the absence of H2O, the Pd(OAc)2-catalyzed
reaction provided only vinyl sulfide 4a as a single hydro-
thiolation product (Entry 4). However, when the Pd(OAc)2-
catalyzed reaction of 1a with 2a in the absence of H2O was
conducted for 40 h, dithioketal 3a was obtained in 73% yield
(Entry 5). Thus, these results suggest that the addition of H2O
or AcOH promotes the double hydrothiolation of terminal
acetylenes. The Pd(OAc)2-catalyzed double hydrothiolation of
1a was also examined in several solvents. In the cases of
acetone and ethanol, the corresponding dithioketal 3a was
obtained in 83% and 84% yields, respectively (Entries 6 and 7).
In acetonitrile or chloroform, 3a was also produced in moderate
yields (Entries 8 and 9). In contrast, when benzene was used as
a nonpolar solvent, a mixture of vinyl sulfide 4a and dithioketal
3a was formed with lower conversion (Entry 10).
We next examined the Pd(OAc)2-catalyzed reaction of
several terminal acetylenes 1 with thiols 2 (Table 2). 1-Hexyne
(1b) and 5-methyl-1-hexyne (1c) provided the corresponding
dithioketals 3b and 3c in good to high yields (Entries 2 and 3).
Hydroxy, carboxy, and chloro substituents were tolerated under
these double hydrothiolation conditions, affording 3d, 3e, and
3f in moderate to good yields, respectively (Entries 4-6). In the
cases of 5-hexynenitrile (1g) and methyl propargyl ether (1h),
moderate yields of 3g and 3h were obtained (Entries 7 and 8).
Unfortunately, propargyl chloride (1i) or bromide (1j) were not
suitable substrates for this double hydrothiolation, and instead,
the oligomerization of 1i or 1j took place (Entries 9 and 10).
In the case of phenylacetylene (1k), the reaction led to 3k
successfully when the reaction mixture was treated in two steps
(Entry 11).8 We also attempted using several arenethiols. 4-
Fluorobenzenethiol (2b) and 4-chlorobenzenethiol (2c) pro-
duced dithioketals 3l and 3m in 70% and 55% isolated yields,
respectively (Entries 12 and 13). In contrast, the reactions with
Organosulfur compounds are a useful class of compounds in
pharmaceutical science, materials science, and organic syn-
thesis, because of their bioactivity, material functionalities, and
synthetic utilities as reaction intermediates.1 Although transi-
tion-metal-catalyzed addition reactions of organosulfur com-
pounds, e.g., thiols, to C-C unsaturated bonds are expected to be
efficient methods for the synthesis of organosulfur compounds
including the formation of new C-S bonds, the development of
these methods is thought to be challenging due to poisoning of
transition-metal catalysts by sulfur.2 We have recently revealed
the palladium-catalyzed addition of organic disulfides or thiols
to acetylenes3 or allenes,4 leading to the corresponding vinyl
sulfides selectively. Very recently, we and other groups have
also subsequently achieved several addition reactions of
organosulfur compounds to unsaturated bonds mediated by
transition-metal catalysts.5,6 During the course of our research
extending the transition-metal-catalyzed addition reactions of
thiols to unsaturated bonds, we have found that thiols add
duplicately to acetylenes. Herein, we wish to report a Pd(OAc)2-
catalyzed regioselective double hydrothiolation of terminal
acetylenes with thiols to give the corresponding dithioketals in
the presence of H2O or AcOH (eq 1).7
cat. Pd(OAc)2
R2S SR2
R1
R2SH
+
R1
ð1Þ
H2O or AcOH
3
1
2
We examined the Pd(OAc)2-catalyzed reaction of 1-octyne
(1a) with 2 equivalents of benzenethiol (2a) in THF at 40 °C
in the presence of H2O (Table 1). 1-Octyne (1a) underwent
the double hydrothiolation with 2a to afford dithioketal 3a
selectively (Entries 1 and 2). In addition, the use of AcOH in
place of H2O was effective for this double hydrothiolation
Published on the web April 7, 2011; doi:10.1246/bcsj.20100311

414
Bull. Chem. Soc. Jpn. Vol. 84, No. 4 (2011)
© 2011 The Chemical Society of Japan
SPh
Table 2. Double Hydrothiolation of Terminal Acetylenes 1
with Thiols 2a)
+
PhSH
3a
THF, 40 °C, 20 h
4a, 0.15 mmol
2a, 1 equiv
cat. Pd(OAc)2
R2S SR2
R1
R1
condition = Pd(OAc)2 (5 mol%)/H2O (1 equiv)
80%
R2SH
+
Pd(OAc)2 (5 mol%)/AcOH (1 equiv) 93%
Pd(OAc)2 (5 mol%)/no additive
no catalyst/AcOH (1 equiv)
80%
ND
1
2
3
Entry 1 R1
2
R2
3
Yield/%b)
* Determined by 1H NMR.
1
2
3
4
5
6
7
8
9
1a CH3(CH2)5-
1b CH3(CH2)3-
1c (CH3)2CH(CH2)2- 2a Ph-
1d HO(CH2)2-
1e HO2C(CH2)3-
1f Cl(CH2)3-
1g NC(CH2)3-
1h CH3OCH2-
1i ClCH2-
2a Ph-
2a Ph-
3a 72 (67)
3b 67 (57)
3c 82 (73)
3d 60 (43)
3e 69 (33)
Scheme 1. Reactions of vinyl sulfide 4a.
Generation of Palladium Sulfide Species
2a Ph-
2a Ph-
2a Ph-
2a Ph-
2a Ph-
2a Ph-
2a Ph-
2a Ph-
2b 4-F-C6H4-
2c 4-Cl-C6H4- 3m 70 (55)
2d 4-CH3-C6H4- 3n 20 (8)
2e 2-CH3-C6H4- 3o 23 (®)
2f C6H11-
2g CH3(CH2)11- 3q ND
R2SH (2)
Pd(SR2)2Ln
Pd(OAc)2
3f
54 (45)
−2 AcOH
3g 36 (21)
3h 36 (28)
Palladium-Catalyzed Double Hydrothiolation
R2S SR2
3i
5
R1
10 1j BrCH2-
11c) 1k Ph-
3j ND
3k 53 (52)
R1
3
1
12 1a CH3(CH2)5-
13 1a CH3(CH2)5-
14d) 1a CH3(CH2)5-
15d) 1a CH3(CH2)5-
16e) 1a CH3(CH2)5-
17 1a CH3(CH2)5-
3l
93 (70)
R2SH (2)
R1
Pd(SR2)2Ln
R2S SR2
PdLn
Pd(SR2)2Ln
R1
3p 25 (25)
R1
R2S
PdSR2Ln
a) Reaction conditions: acetylene (1, 0.5 mmol), thiol (2,
1.0 mmol), Pd(OAc)2 (5 mol % based on 1), THF (0.5 mL),
H2O (ca. 1 equiv based on 1), 40 °C, 16 h. b) Yields were
determined by 1H NMR. Values in parentheses are isolated
yields. c) This reaction was conducted by the following two
steps: (1) phenylacetylene (1k, 0.25 mmol), benzenethiol (2a,
0.25 mmol), Pd(OAc)2 (5 mol %), acetone (0.25 mL), 40 °C,
16 h; (2) benzenethiol (2a, 0.25 mmol), AcOH (0.25 mmol),
40 °C, 16 h. The yield shown in Entry 11 was calculated after
the two steps reaction. d) The corresponding vinyl sulfide 4
was obtained mainly. e) Most of the starting material 1a was
recovered unchanged.
R1
R2S
H
R2SH (2)
4
Scheme 2. A plausible reaction pathway.
vinylpalladium species. Protonolysis of vinylpalladium species
with thiols produced the vinyl sulfide 4 with regeneration of the
palladium sulfide complex. Further thiopalladation and proto-
nolysis with thiols afforded dithioketals 3. H2O or AcOH may
contribute to accelerating the addition of thiols to unsaturated
bonds by protonolysis or coordinate to the catalyst to prevent
the clustering of palladium complex with sulfur species.
We also examined the reaction using PhSD or D2O to gain
mechanistic insights (Scheme 3).9 When 1a was treated with
PhSD (68%D) in the presence of H2O, the reaction formed 3a,
d1-3a, and d2-3a in 35%, 21%, and 15% yields. In addition, the
reaction of 4a with PhSH in the presence of D2O was also
carried out, which afforded 3a and d1-3a in 35% and 36%
yields. These observations suggest that H2O (or AcOH)
promotes protonation in the generation of dithioketals.
In summary, we have developed the palladium diacetate-
catalyzed double hydrothiolation of terminal acetylenes with
thiols in the presence of H2O or AcOH, leading to the
corresponding dithioketals selectively. We also revealed that
this palladium-catalyzed double hydrothiolation took place via
the formation of vinyl sulfides and the additives, i.e., H2O or
AcOH, promoted the addition of thiols to unsaturated bonds.
4-toluenethiol (2d), 2-toluenethiol (2e), and cyclohexanethiol
(2f) afforded low yields of 3n, 3o, and 3p (Entries 14-16), and
dodecanethiol (2g) did not give 3q (Entry 17).
To elucidate the reaction pathway for the palladium
diacetate-catalyzed double hydrothiolation of terminal acety-
lenes with thiols, we focused on vinyl sulfides as a plausible
intermediate. When vinyl sulfide 4a was treated with 2a and
H2O in the presence of Pd(OAc)2 as a catalyst, hydrothiolation
of 4a proceeded to afford the dithioketal 3a in 80% yield
(Scheme 1). AcOH was also efficient for the hydrothiolation of
4a, providing an excellent yield of 3a. In addition, the reaction
of 4a in the absence of additives also provided 3a in 80% yield.
On the other hand, no reaction took place by use of AcOH in
the absence of Pd(OAc)2. These results strongly suggest that
the double hydrothiolation proceeds via the formation of vinyl
sulfides and is catalyzed by palladium species in both first
addition of thiols to terminal acetylenes and second addition to
vinyl sulfides.
Experimental
A plausible reaction pathway for the reaction is proposed in
Scheme 2. Ligand exchange of acetate groups of Pd(OAc)2
with R2S groups generated Pd(SR2)2Ln and AcOH (Scheme 2).
The coordination of alkyne to the palladium sulfide complex
and syn-thiopalladation of alkyne formed ¢-cis-thio-substituted
General Procedure for the Palladium Diacetate-Cata-
lyzed Double Hydrothiolation of Terminal Acetylenes. To a
solution of 1-octyne (1a, 0.5 mmol) and palladium diacetate
(5 mol %) in THF (0.5 mL) were added benzenethiol (2a,
1.0 mmol) and H2O (ca. 1 equiv based on 1a), and the mixture

T. Mitamura et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 4 (2011)
415
Pd(OAc)2 (5 mol%)
H2O (ca. 1 equiv)
2006, 35, 1320.
a) H. Kuniyasu, A. Ogawa, S. Miyazaki, I. Ryu, N. Kambe, N.
3
1a
+
PhSD (68%D)
1 equiv
Sonoda, J. Am. Chem. Soc. 1991, 113, 9796. b) H. Kuniyasu, A. Ogawa,
K. Sato, I. Ryu, N. Kambe, N. Sonoda, J. Am. Chem. Soc. 1992, 114,
5902. c) A. Ogawa, T. Ikeda, K. Kimura, T. Hirao, J. Am. Chem. Soc.
1999, 121, 5108.
THF
40 oC, 16 h
PhS SPh
PhS SPh
+
PhS SPh
(CH2)5CH3
d2-3a, 15%
+
4
a) A. Ogawa, J. Kawakami, N. Sonoda, T. Hirao, J. Org. Chem.
H3C
(CH2)5CH3 DH2C
(CH2)5CH3 D2HC
1996, 61, 4161. b) S. Kodama, E. Nishinaka, A. Nomoto, M. Sonoda, A.
Ogawa, Tetrahedron Lett. 2007, 48, 6312.
3a, 35%
d1-3a, 21%
Pd(OAc)2 (5 mol%)
5
For recent advances in bisthiolation, see: a) T. Kondo, S.
Uenoyama, K. Fujita, T. Mitsudo, J. Am. Chem. Soc. 1999, 121, 482. b)
M. Arisawa, M. Yamaguchi, Org. Lett. 2001, 3, 763. c) V. P. Ananikov,
M. A. Kabeshov, I. P. Beletskaya, G. G. Aleksandrov, I. L. Eremenko,
J. Organomet. Chem. 2003, 687, 451. d) V. P. Ananikov, I. P. Beletskaya,
G. G. Aleksandrov, I. L. Eremenko, Organometallics 2003, 22, 1414. e)
S. Usugi, H. Yorimitsu, H. Shinokubo, K. Oshima, Org. Lett. 2004, 6,
601. f) V. P. Ananikov, I. P. Beletskaya, Org. Biomol. Chem. 2004, 2,
284. g) V. P. Ananikov, M. A. Kabeshov, I. P. Beletskaya, Synlett 2005,
1015. h) V. P. Ananikov, M. A. Kabeshov, I. P. Beletskaya, V. N.
Khrustalev, M. Y. Antipin, Organometallics 2005, 24, 1275. i) M.
Arisawa, K. Fujimoto, S. Morinaka, M. Yamaguchi, J. Am. Chem. Soc.
2005, 127, 12226. j) I. P. Beletskaya, V. P. Ananikov, Pure Appl. Chem.
2007, 79, 1041. k) I. P. Beletskaya, V. P. Ananikov, Eur. J. Org. Chem.
2007, 3431. l) M. Cai, Y. Wang, W. Hao, Green Chem. 2007, 9, 1180. m)
V. P. Ananikov, K. A. Gayduk, I. P. Beletskaya, V. N. Khrustalev, M. Y.
Antipin, Chem.®Eur. J. 2008, 14, 2420. n) V. P. Ananikov, N. V. Orlov,
M. A. Kabeshov, I. P. Beletskaya, Z. A. Starikova, Organometallics
2008, 27, 4056. o) H. Kuniyasu, K. Takekawa, F. Yamashita, K.
Miyafuji, S. Asano, Y. Takai, A. Ohtaka, A. Tanaka, K. Sugoh, H.
Kurosawa, N. Kambe, Organometallics 2008, 27, 4788. p) M. Wang, L.
Cheng, B. Hong, Z. Wu, Organometallics 2009, 28, 1506. q) N.
Taniguchi, Tetrahedron 2009, 65, 2782. r) Y. Nishiyama, H. Ohnishi, Y.
Koguma, Bull. Chem. Soc. Jpn. 2009, 82, 1170. s) A. Nomoto, G.
Shiino, A. Ogawa, Res. Chem. Intermed. 2009, 35, 965. t) V. P.
Ananikov, K. A. Gayduk, I. P. Beletskaya, V. N. Khrustalev, M. Y.
Antipin, Eur. J. Inorg. Chem. 2009, 1149. u) V. P. Ananikov, K. A.
Gayduk, N. V. Orlov, I. P. Beletskaya, V. N. Khrustalev, M. Y. Antipin,
Chem.®Eur. J. 2010, 16, 2063.
4a +
PhSH
1 equiv
THF, D2O (ca. 1 equiv)
40 oC, 20 h
PhS SPh
PhS SPh
DH2C (CH2)5CH3
d1-3a, 36%
* Determined by 1H NMR.
+
H3C
(CH2)5CH3
3a, 35%
Scheme 3. The reaction using PhSD or D2O.
was stirred at 40 °C for 16 h. After the reaction, the mixture was
filtered through a Celite pad (eluent: AcOEt) and the filtrate
was concentrated under reduced pressure. The crude mixture
was purified by PTLC (Hex:AcOEt = 99:1) to give 2,2-
bis(phenylsulfanyl)octane (3a, 0.335 mmol, 67%) as slightly
yellow oil.
2,2-Bis(phenylsulfanyl)octane (3a): 1H NMR (400 MHz,
CDCl3): ¤ 0.87 (t, J = 6.6 Hz, 3H), 1.15-1.34 (m, 6H), 1.37 (s,
3H), 1.55-1.74 (m, 4H), 7.27-7.39 (m, 6H), 7.58-7.68 (m, 4H);
13C NMR (100 MHz, CDCl3): ¤ 14.0, 22.5, 24.7, 28.1, 29.2,
31.7, 41.5, 64.2, 128.4, 128.9, 132.1, 136.8; MS (EI) m/z 330
(M+, 100).
This work is supported by Grant-in-Aid for Scientific
Research on Scientific Research (B, No. 19350095), from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. T. M. also thanks the Japan Society for the
Promotion of Science (JSPS) for the Research Fellowship for
Young Scientists.
6
For recent advances in hydrothiolation, see: a) W.-J. Xiao, H.
Alper, J. Org. Chem. 2001, 66, 6229. b) I. Kamiya, E. Nishinaka, A.
Ogawa, J. Org. Chem. 2005, 70, 696. c) V. P. Ananikov, D. A. Malyshev,
I. P. Beletskaya, G. G. Aleksandrov, I. L. Eremenko, Adv. Synth. Catal.
2005, 347, 1993. d) C. Cao, L. R. Fraser, J. A. Love, J. Am. Chem. Soc.
2005, 127, 17614. e) V. P. Ananikov, N. V. Orlov, I. P. Beletskaya,
Organometallics 2006, 25, 1970. f) D. A. Malyshev, N. M. Scott, N.
Marion, E. D. Stevens, V. P. Ananikov, I. P. Beletskaya, S. P. Nolan,
Organometallics 2006, 25, 4462. g) V. P. Ananikov, N. V. Orlov, I. P.
Beletskaya, V. N. Khrustalev, M. Y. Antipin, T. V. Timofeeva, J. Am.
Chem. Soc. 2007, 129, 7252. h) A. Kondoh, H. Yorimitsu, K. Oshima,
Org. Lett. 2007, 9, 1383. i) L. R. Fraser, J. Bird, Q. Wu, C. Cao, B. O.
Patrick, J. A. Love, Organometallics 2007, 26, 5602. j) S. Shoai, P.
Bichler, B. Kang, H. Buckley, J. A. Love, Organometallics 2007, 26,
5778. k) S. Kodama, A. Nomoto, M. Kajitani, E. Nishinaka, M. Sonoda,
A. Ogawa, J. Sulfur Chem. 2009, 30, 309. l) J. Yang, A. Sabarre, L. R.
Fraser, B. O. Patrick, J. A. Love, J. Org. Chem. 2009, 74, 182. m) A.
Corma, C. González-Arellano, M. Iglesias, F. Sánchez, Appl. Catal., A
2010, 375, 49.
Supporting Information
1
Experimental procedures, characterization data, and H and
13C NMR spectra for dithioketals. This material is available
free of charge on the web at http://www.csj.jp/journals/bcsj/.
References
1
a) T. Wirth, Angew. Chem., Int. Ed. 2000, 39, 3740. b) G.
Mugesh, W.-W. du Mont, H. Sies, Chem. Rev. 2001, 101, 2125. c) C. W.
Nogueira, G. Zeni, J. B. T. Rocha, Chem. Rev. 2004, 104, 6255. d) G.
Zeni, D. S. Lüdtke, R. B. Panatieri, A. L. Braga, Chem. Rev. 2006, 106,
1032. e) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534. f) G. Perin, E. J.
Lenardão, R. G. Jacob, R. B. Panatieri, Chem. Rev. 2009, 109, 1277. g)
Organosulfur Chemistry I in Topics in Current Chemistry, ed. by P. C. B.
Page, Springer, Berlin, 1999, Vol. 204. doi:10.1007/3-540-48956-8 h)
Organosulfur Chemistry II in Topics in Current Chemistry, ed. by P. C. B.
Page, Springer, Berlin, 1999, Vol. 205. doi:10.1007/3-540-48986-X
7
For the InBr3-catalyzed addition of thiols to acetylenes, leading
to dithioketals, see: J. S. Yadav, B. V. Subba Reddy, A. Raju, K.
Ravindar, G. Baishya, Chem. Lett. 2007, 36, 1474.
8
When the reaction of phenylacetylene (0.1 mmol) with benzene-
thiol (0.2 mmol) in the presence of Pd(OAc)2 (5 mol %) and H2O (ca.
0.1 mmol) in THF was conducted, a complex mixture of 1,1-bis(phen-
ylsulfanyl)ethylbenzene, 2-phenylsulfanylstyrene, and 1-phenylsulfanyl-
styrene was obtained.
2
a) A. Ogawa, J. Organomet. Chem. 2000, 611, 463. b) T. Kondo,
T. Mitsudo, Chem. Rev. 2000, 100, 3205. c) F. Alonso, I. P. Beletskaya,
M. Yus, Chem. Rev. 2004, 104, 3079. d) I. Beletskaya, C. Moberg,
Chem. Rev. 2006, 106, 2320. e) H. Kuniyasu, N. Kambe, Chem. Lett.
9
For the monohydrothiolation using deuterated thiol, see Ref. 3b.