Synthesis of vinyl sulfides via hydrothiolation of alkynes using Al2O3/KF under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2008.01.093

We present here a clean, solvent-free hydrothiolation of alkynes using solid supported catalyst (Al₂O₃/KF). This efficient and improved method selectively furnishes the corresponding anti-Markovnikov vinyl sulfides in good to excellent yields. The method is applicable for aliphatic and aromatic thiols and the catalytic system can be re-used up to two times without previous treatment and with comparable activity.

Full text of DOI:10.1016/j.tetlet.2008.01.093

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1927–1930
Synthesis of vinyl sulfides via hydrothiolation of alkynes
using Al2O3/KF under solvent-free conditions
´
´
Marcio S. Silva, Renata G. Lara, Junior M. Marczewski, Raquel G. Jacob,
Eder J. Lenardao, Gelson Perin *
˜
ˆ
Instituto de Quı´mica e Geociencias, LASOL, Universidade Federal de Pelotas, UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil
Received 8 November 2007; revised 21 January 2008; accepted 24 January 2008
Available online 30 January 2008
Abstract
We present here a clean, solvent-free hydrothiolation of alkynes using solid supported catalyst (Al2O3/KF). This efficient and
improved method selectively furnishes the corresponding anti-Markovnikov vinyl sulfides in good to excellent yields. The method is
applicable for aliphatic and aromatic thiols and the catalytic system can be re-used up to two times without previous treatment and with
comparable activity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Solvent-free reaction; Hydrothiolation; Vinyl sulfide
Vinyl sulfides have been found to be a very useful tool in
organic synthesis, since sulfur-containing groups serve as
important auxiliary function in synthetic sequences.1 In
this way, various methods are mentioned for the prepara-
tion of vinyl sulfides and the most common protocols
involve the addition of thiol, or the respective anions, to
terminal or internal alkynes.2,3 Most of the described meth-
ods make use of toxic organic solvents and are catalyzed by
transition-metals2a,b or promoted by base.2c–e More
recently, some improvements on selective preparation of
vinyl sulfides have been described.3 These comprise the
use of catalytic phenylselenenyl bromide3a or nickel3b
under solvent-free conditions, b-cyclodextrin in the pres-
ence of water and acetone3c or under catalyst-free condi-
tions.3d In recent years, the use of potassium fluoride
supported on alumina (Al2O3/KF) as a green catalytic sys-
tem for a number of transformations has been increased.4
By using Al2O3/KF, the products can be easily isolated
by filtration and the generation of large amounts of salts
at the end of the synthesis, as well as the use of stoichio-
metric strong bases, can be avoided.
Our major research goal has been the development of
new and cleaner protocols for the preparation and syn-
thetic applications of organochalcogenium compounds.5
More recently, we have described several efficient
approaches using Al2O3/KF.6 In continuation to these
studies, we describe here the results of the hydrothiola-
tion of alkynes 1 using Al2O3/KF without any solvent
(Scheme 1).7,8
Initially, we chose propargyl alcohol (1a) and phenyl-
thiol (2a) as standard starting materials. We examined
the temperature, amount of Al2O3/KF (40%) and the use
of N2 atmosphere. It was found that stirring a mixture of
SR1
Al2O3/KF (40%)
+
H
R1S
+
H
R
SR1
R
60 oC, N2
R
1a-g
2a-c
(Z
)-3a-p
(E)-3a-p
OH
R = CH2OH, C(CH3)C2H5OH, CH2CH2OH, C(CH3)2OH, C6H5, C5H11
,
R1 = C6H5,
p
-ClC6H4, C12H25
*
Corresponding author. Tel./fax: +55 5332757354.
Scheme 1.
E-mail address: gelson_perin@ufpel.edu.br (G. Perin).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.093

1928
M. S. Silva et al. / Tetrahedron Letters 49 (2008) 1927–1930
1a (2 mmol) and 2a (1 mmol) in the presence of 0.08 g
(51 mol %) of Al2O3/KF (40%) at room temperature, the
products of hydrothiolation (3a) were obtained in an over-
all yield of 25% after 3.5 h, together with a great amount of
diphenyldisulfide. On the other hand, when the same pro-
tocol was performed at gentle heating (60 °C) and under
N2 atmosphere, the yield increased to 63% yield (Table 1,
entry 1). Using 0.120 g (77 mol %) of the catalyst or pro-
longed time (24 h) did not significantly increase the vinyl
sulfides yields. It was also observed that the catalytic sys-
tem can be re-used for 2 cycles, just by washing it with ethyl
acetate and drying under vacuum.
Using the optimized conditions, the protocol was
extended to other alkynyl alcohols and thiols (Table 1,
entries 2–12).8 Concerning the stereochemistry of products,
for all the studied examples, the anti-Markovnikov adduct
3 was obtained in higher amount than the Markovnikov
one. The formation of a Z and E mixture of 3 was also
observed (determined by 1H NMR) and the selectivity
was influenced by the substituent at alkynes (see Table
1). Thus, for example, Z-3a was obtained preferentially
from the reaction of propargyl alcohol (1a) with 2a (63%
yield, Z:E ratio = 86:14, entry 1), while E-3h was the major
obtained isomer for the reaction of 1-ethynylcyclohexanol
Table 1
Hydrothiolation of alkynes using Al2O3/KF under solvent-free condition
Entry
1
Alkyne 1
Thiol 2
Product 3
Time (h)
3.5
Ratioa (Z):(E)
Yieldb (%)
63 (64:36)c
C6H5S
OH
+
C6H5S
C6H5SH 2a
86:14
1a
OH
OH
(Z )-3a
(
E
)-3a
p-ClC6H4S
+
2
3
4
1a
1a
p-ClC6H4SH 2b
CH3(CH2)11SH 2c
C6H5SH 2a
1
4
4
75:25
55:45
31:69
57 (51:49)c
65 (92:8)c
90 (93:7)c
OH
p-ClC6H4S
OH
(
Z
)-3b
(E)-3b
C
12H25S
OH
+
C
12H25S
OH
(Z )-3c
(E )-3c
C6H5S
+
C6H5S
OH
1b
OH
(Z
)-3d
(
E
)-3d
OH
p
-ClC6H4S
+
p
- C lC6H4S
5
6
1b
p-ClC6H4SH 2b
C6H5SH 2a
3
23:77
60:40
88 (96:4)c
OH
(Z
)-3e
(E )-3e
OH
C6H5S
+
C6H5S
2.5
70 (86:14)c
OH
1c
OH
(Z)-3f
(E
)-3f OH
p
-ClC6H4S
+
p
-ClC6H4S
7
8
1c
p-ClC6H4SH 2b
C6H5SH 2a
3
3
29:71
13:87
74 (96:4)c
56 (94:6)c
OH
(
Z
)-3g
(
E
)-3g OH
C6H5S
C6H5S
+
HO
Z )-3h
HO
1d
OH
(
(
E
)-3h
p
-ClC6H4S
p
-ClC6H4S
+
9
1d
1d
p-ClC6H4SH 2b
CH3(CH2)11SH 2c
C6H5SH 2a
5
20:80
2:98
63 (93:7)c
86 (92:8)c
62 (92:8)c
HO
HO
(Z
)-3i
(E
)-3i
C
12H25
S
C12H25
S
+
10
11
6.5
2
HO
HO
(
Z )-3j
(E )-3j
C6H5S
(
OH
C6H5S
OH
+
53:47
OH
1e
(Z )-3k
E
)-3k

M. S. Silva et al. / Tetrahedron Letters 49 (2008) 1927–1930
1929
Table 1 (continued)
Entry
Alkyne 1
Thiol 2
Product 3
Time (h)
2
Ratioa (Z):(E)
Yieldb (%)
p
-ClC6H4S
(
p
-ClC6H4S
50:50
55 (54:46)c
12
1e
p-ClC6H4SH 2b
OH
+
OH
(Z
)-3l
E
)-3l
C6H5S
C5H11
+
13
C6H5SH 2a
C6H5S
C5H11
(Z )-3m
5.5
48:52
52 (100:00)c
C5H11
1f
(
E
)-3m
p
-ClC6H4S
+
14
15
1f
p-ClC6H4SH 2b
C6H5SH 2a
7
1
45:55
80:20
53 (100:00)c
90 (100:00)c
p
-ClC6H4S
C5H11
C5H11
(Z )-3n
(E )-3n
C6H5S
+
C6H5
C6H5S
C6H5
1g
C6H5
(Z )-3o
(E
)-3o
p
-ClC6H4S
+
16
1g
p-ClC6H4SH 2b
1
63:37
95 (100:00)c
p
-ClC6H4S
C6H5
C6H5
(Z )-3p
(E )-3p
a
Determined by 1H NMR of the crude reaction mixture and confirmed after isolation of pure products.
Yields of pure products isolated by column chromatography (hexanes/AcOEt) and identified by mass spectrometry, 1H and 13C NMR.2,3
The regioselectivity of the hydrothiolation (the ratio of anti-Markovnikov: Markovnikov product).
b
c
(1d) with 2a (56% yield, Z:E ratio = 13:87, entry 8). The
scope of our methodology was successfully expanded to
aromatic and aliphatic alkynes (Table 1, entries 13–16).
We observed that for these alkynes the reaction afforded
exclusively the respective anti-Markovnikov adducts
3m–p in good yields (52%–95%). Besides, the possible inter-
ference of the light in the stereoselectivity of the reaction
was also studied. Thus, when 1a and 2a reacted in the dark,
we observed the same results described above for the
preparation of 3a (Table 1, entry 1).
We also observed that, for some alkynes, the hydrothio-
lation with phenylthiol took place even in the absence of a
catalyst. Thus, for example, when a mixture of thiol 2b and
alkynols 1c or 1d was stirred at 60 °C for 3.5 h, the respec-
tive vinyl sulfides 3f and 3h were obtained in good yields
(68% and 55%). For the reaction of propargyl alcohol
(1a), however, the respective vinyl sulfide 3b was obtained
only in 23% yield. The hydrothiolation without Al2O3/
KF did not proceed satisfactorily for the reaction of 1-hep-
tyne (1f) with thiols. Similar result was observed for the
reactions with dodecanethiol (2c).
References and notes
1. For the synthetic utility of vinyl sulfides, see, for example: (a) Aucagne,
V.; Lorin, C.; Tatiboue¨t, A.; Rollin, P. Tetrahedron Lett. 2005, 46,
4349; (b) Muraoka, N.; Mineno, M.; Itami, K.; Yoshida, J.-I. J. Org.
Chem. 2005, 70, 6933; (c) Woodland, C. A.; Crawley, G. C.; Hartley,
R. C. Tetrahedron Lett. 2004, 45, 1227; (d) McReynolds, M. D.;
Dougherty, J. M.; Hanson, P. R. Chem. Rev. 2004, 104, 2239; (e) Oae,
S. Organic Sulfur Chemistry: Structure and Mechanism; CRC Press:
Boca Raton, FL, 1991; (f) Cremlyn, R. J. An Introduction to
Organosulfur Chemistry; Wiley & Sons: New York, 1996.
2. (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205; (b) Cao, C.;
Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127, 17614; (c)
Kondoh, A.; Takami, K.; Yorimitsu, H.; Oshima, K. J. Org. Chem.
2005, 70, 6468; (d) Waters, M. S.; Cowen, J. A.; McWilliams, J. C.;
Maligres, P. E.; Askin, D. Tetrahedron Lett. 2000, 41, 141; (e)
Wadsworth, D. H.; Detty, M. R. J. Org. Chem. 1980, 45, 4611.
3. (a) Manarin, F.; Roehrs, J. A.; Prigol, M.; Alves, D.; Nogueira, C. W.;
Zeni, G. Tetrahedron Lett. 2007, 48, 4805; (b) Ananikov, V. P.; Orlov,
N. V.; Beletskaya, I. P. Organometallics 2006, 25, 1970; (c) Sridhar, R.;
Surendra, K.; Krishnaveni, N. S.; Srinivas, B.; Rao, K. R. Synlett 2006,
3495; (d) Schneider, C. C.; Godoi, B.; Prigol, M.; Nogueira, C. W.;
Zeni, G. Organometallics 2007, 26, 4252.
4. For a review on Al2O3/KF in organic synthesis, see: Blass, B. E.
Tetrahedron 2002, 58, 9301.
In conclusion, several vinyl sulfides could be prepared
directly under solvent-free conditions using Al2O3/KF,
which can be re-used up to two times. The method is gen-
eral for the reaction of several alkynes with aromatic and
aliphatic thiols. This method consists in low consumption
of solvent in the overall protocol, short reaction time, mild
reaction conditions, good yields and simplicity, with non-
aqueous workup.
5. (a) Lenardao, E. J.; Mendes, S. R.; Ferreira, P. C.; Perin, G.; Silveira,
˜
C. C.; Jacob, R. G. Tetrahedron Lett. 2006, 47, 7439; (b) Perin, G.;
Jacob, R. G.; Dutra, L. G.; Azambuja, F.; Santos, G. F. F.; Lenardao,
˜
E. J. Tetrahedron Lett. 2006, 47, 935; (c) Perin, G.; Mendes, S. R.;
Silva, M. S.; Lenardao, E. J.; Jacob, R. G.; Santos, P. C. Synth.
˜
Commun. 2006, 36, 2587; (d) Perin, G.; Jacob, R. G.; Azambuja, F.;
Botteselle, G. V.; Siqueira, G. M.; Freitag, R. A.; Lenardao, E. J.
˜
Tetrahedron Lett. 2005, 46, 1679.
6. (a) Lenardao, E. J.; Ferreira, P. C.; Jacob, R. G.; Perin, G.; Leite, F. P.
˜
L. Tetrahedron Lett. 2007, 48, 6763; (b) Lenardao, E. J.; Lara, R. G.;
˜
Silva, M. S.; Jacob, R. G.; Perin, G.; Leite, F. P. L. Tetrahedron Lett.
2007, 48, 7668; (c) Perin, G.; Jacob, R. G.; Botteselle, G. V.; Kublik, E.
Acknowledgements
L.; Lenardao, E. J.; Cella, R.; Santos, P. C. S. J. Brazil Chem. Soc.
˜
2005, 16, 857.
This project is funded by CNPq, CAPES and
FAPERGS. Professor C. C. Silveira (UFSM/Brazil) is
7. Preparation of alumina supported potassium fluoride:9 Alumina (6.0 g of
Al2O3 90, 0.063–0.200 mm, Merck), KFÁ2H2O (5.2 g) and water
(10 mL) were mixed in a 50 mL beaker and the suspension stirred at
1
acknowledged for the H and 13C NMR analysis.

1930
M. S. Silva et al. / Tetrahedron Letters 49 (2008) 1927–1930
65 °C for 1 h. The resulting solid was dried at 80 °C for 1 h and
The solvent was evaporated under reduced pressure and the residue
was purified by column chromatography over silica gel eluting with
hexanes, yielding a mixture of Z- and E-3o (0.191 g, 90%, Z:E
subsequently for 4 h at 300 °C in an oven and finally cooled to
room temperature in a desiccator. The content of KF is about
40% (m/m).
1
ratio = 80:20). H NMR (200 MHz, CDCl3) d (ppm) (Z+E) 7.20–7.56
8. General procedure for the synthesis of vinyl sulfides: To a mixture of
phenyl acetylene (1g; 0.424 g; 2 mmol) and phenylthiol (2a; 0.110 g;
1 mmol) under N2 atmosphere, Al2O3/KF (0.08 g, obtained as
described above) was added at room temperature. Then, the temper-
ature was slowly raised to 60 °C. The reaction progress was followed by
TLC, and after 1 h (see Table 1) ethyl acetate (10 mL) was added and
the organic solution was separated of the aluminum oxide by filtration.
(m, 10H); E isomer: 6.88 (d, J = 15.4 Hz, 1H); 6.72 (d, J = 15.4 Hz,
1H); Z isomer: 6.59 (d, J = 10.6 Hz, 1H); 6.48 (d, J = 10.6 Hz, 1H); 13C
NMR (50 MHz, CDCl3) d (ppm) E isomer: 123.2, 125.9, 126.7, 127.4,
128.5, 129.0, 129.6, 131.6, 135.1, 136.3; Z isomer: 125.9, 127.0, 127.1,
127.2, 128.2, 128.7, 129.1, 130.0, 136.1, 136.4.3a
9. Saikia, D.; Khanuja, S. P. S.; Kahol, A. P.; Gupta, S. C.; Kumar, S.
Curr. Sci. 2001, 80, 1264.