Synthesis of (Z)-organylthioenynes using KF/Al2O 3/solvent as recyclable system

Article abstract of DOI:10.1016/j.tetlet.2010.11.009

PEG-400 and glycerol were successfully used as recyclable solvents for the synthesis of several organylthioenynes in good to excellent yields and high selectivity using solid supported catalyst (KF/Al₂O₃). This easy, general and impr

Full text of DOI:10.1016/j.tetlet.2010.11.009

Tetrahedron Letters 52 (2011) 133–135
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (Z)-organylthioenynes using KF/Al2O3/solvent as recyclable system
Diego Alves a, Maraisa Sachini a, Raquel G. Jacob a, Eder J. Lenardão a, Maria E. Contreira a,
Lucielli Savegnago b, Gelson Perin a,
⇑
a Instituto de Química e Geociências, LASOL, Universidade Federal de Pelotas, UFPel, 96010-900, Pelotas-RS, Brazil
b Centro de Desenvolvimento Tecnológico, CDTec, Universidade Federal de Pelotas, UFPel, 96010-900 Pelotas-RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
PEG-400 and glycerol were successfully used as recyclable solvents for the synthesis of several organyl-
thioenynes in good to excellent yields and high selectivity using solid supported catalyst (KF/Al2O3). This
easy, general and improved method furnishes the corresponding alkenyl sulfides preferentially with Z
configuration. The catalytic system and the glycerol or PEG-400 can be reused up to three times without
previous treatment with comparable activity.
Received 14 September 2010
Revised 29 October 2010
Accepted 1 November 2010
Available online 5 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
PEG-400
Glycerol
Thioenynes
Vinyl sulfides are a valuable tool in organic reactions, acting as
key intermediate in organic synthesis.1 Besides, vinyl sulfides are
present in natural occurring compounds such as griseoviridin, a
type A streptogramin antibiotic, firstly isolated from Streptomyces
graminofaciens2 and benzylthiocredillidone, a yellow pigment iso-
lated from the brightly red colored sponge Crella spinulata.3 The
most common methods for the preparation of vinyl sulfides in-
increased in the last few years.11 Despite several advantages, the
solvent-free methods are restricted to systems where at least one
of the reagents is a liquid at room temperature, while the use of
ILs has some drawbacks, such as the high cost and the liberation
of hazardous HF during recycling. In this line, the use of PEG and
glycerol as promising media for organic reactions was recently
demonstrated by us12,13 and others.14–18
Recently, we have described several efficient approaches using
KF/Al2O3.19 As a continuation of our studies we report herein the
results of the hydrothiolation of 1,4-diorganyl-1,3-butadiynes 1
using KF/Al2O3 and PEG-400 or glycerol as recyclable solvents for
this reaction (Scheme 1).20,21
Initially, we chose 1,4-diphenyl-1,3-butadiyne 1a and benzene-
thiol 2a as standard starting materials in the presence of 3.0 mL of
PEG-400. We examined the temperature, amount of KF/Al2O3 (50%)
and the use of N2 atmosphere. It was found that stirring a mixture
of 1a (1.0 mmol) and 2a (1.0 mmol) in the presence of 0.07 g of KF/
Al2O3 (50%) at room temperature, a mixture of (Z)- and (E)-1,4-di-
phenyl-2-(phenylthio)but-1-en-3-ynes 3a was obtained in an
overall yield of 34% after 26 h, together with a great amount of
diphenyl disulfide (Table 1, entry 1).
Best results were obtained using 0.14 g and 0.28 g of KF/Al2O3,
but long reaction times were required (Table 1, entries 2 and 3).
On the other hand, when the same protocol was performed using
0.07 g of KF/Al2O3 on gentle heating (60 °C) the product was
volve the addition of thiol, or thiolate anions, to alkynes.4–6
A
drawback of most of these protocols is the use of toxic organic sol-
vents, transition-metals catalysts4 or stoichiometric amounts of
base.5 More recently, some improvements on selective preparation
of vinyl sulfides have been described under solvent-free or cata-
lyst-free conditions.6–8 Among the vinyl sulfides, organylthioeny-
nes are very useful synthons in organic synthesis, because they
can be used as precursor to enediynes and other functionalized
olefins. However, the number of methodologies for accessing
thioenynes is limited and the development of protocols for
rigorous regio- and stereochemical controlled synthesis of these
compounds remains yet a challenge.5b,6,9
The use of potassium fluoride supported on alumina (KF/Al2O3)
as a green catalytic system for a number of transformations has
been increased.10 By using KF/Al2O3, the products can be easily iso-
lated by filtration and the generation of large amounts of salts at
the end of the synthesis, as well as the use of stoichiometric strong
bases, can be avoided. On the other hand, the development of envi-
ronmentally benign and clean synthetic methods, including those
involving solvent-free or the use of alternative solvents, such as
water, ionic liquids (ILs), and polyethylene glycol (PEG), has
R
KF/Al2O3, glycerol 90 ºC, N2
R2S
R1
+
R2S
H
R
or PEG-400, 60 ºC
2a-d
1a-d
R1
3a-g
⇑
Corresponding author. Tel./fax: +55 5332757354.
E-mail address: perin@pq.cnpq.br (G. Perin).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.009

134
D. Alves et al. / Tetrahedron Letters 52 (2011) 133–135
Table 1
Besides, the use of glycerol as a solvent was evaluated. However,
Optimization of the synthesis of thiobut-1-en-3-yne 3aa,b
when the reactions were performed in the presence of glycerol at
the same temperature (60 °C), 3a was formed in poor yield (Table 1,
entry 8). To our satisfaction, by increasing the temperature to 90 °C
the reaction proceeds smoothly, furnishing the product 3a in satis-
factory yield (Z:E ratio = 95:5, Table 1, entry 9). When the temper-
ature was increased to 120 °C, poor yields were obtained (Table 1,
entry 10). In an optimized reaction, 1,4-dipheny-1,3-butadiyne 1a
(1.0 mmol) was dissolved in glycerol (3 mL) and reacted with ben-
zenethiol 2a (1.0 equiv) at 90 °C during 6 h under N2 atmosphere,
yielding 3a in 64% yield (Scheme 1).
Entry
Solvent
KF/Al2O3 (g)
Temp. (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
Glycerol
Glycerol
Glycerol
0.07
0.14
0.28
0.07
0.06
0.04
None
0.07
0.07
0.07
rt
rt
rt
60
60
60
60
60
90
120
26
26
26
1.5
7
8
2
6
6
34
52
87
93
85
74
13
8
64
45
10
6
Using the optimized conditions,21 the protocol was extended to
other thiols and symmetric conjugated butadiynes to produce
organothioenynes 3b–f in good to excellent yields (Table 2). The
small yield observed when glycerol was used can be attributed
to a competition between the hydrothiolation reaction and the
thiol oxidation to afford the respective disulfides. For all the stud-
ied examples, a variable amount of disulfide was isolated. This is in
agreement with a recent report of our group describing the clean
oxidation of thiols to disulfide in the presence of KF/Al2O3.19b
a
Reaction conditions: Diyne 1a (1.0 mmol); benzenethiol 2a (1.0 mmol).
For all the tested examples, a little amount of (E)-3a was also formed.
b
obtained in 93% yield after only 1.5 h (Z:E ratio = 92:8, Table 1, en-
try 4). When smaller amounts of the catalyst were used, the prod-
uct 3a was obtained in lower yields (entries 5 and 6). In the
absence of the catalytic system, 3a was obtained only in 13% yield
and with a loss of selectivity (Z:E ratio = 75:25, Table 1, entry 7).
Table 2
Hydrothiolation of butadiynes using KF/Al2O3 and glycerol or PEG as solvent
Entry
Butadiyne 1
Thiol 2
Product 3
Time (h)
1.5
Solvent
PEG
Ratioa (Z):(E)
Yieldb (%)
C6H5
92:8
93
C6H5S
C6H5
(89:11)c
(89)c
+
1
C6H5
C6H5
C6H5
C6H5
C6H5
(90:10)d
(92)d
C6H5S
C6H5SH 2a
1a
1a
1a
1a
C6H5
C6H5
(
Z
)-3a
( )-3a
E
2
3
1a
2a
(Z)-3a + (E)-3a
1.5
Glycerole
95:5
64
C6H5
4-ClC6H4S
C6H5
+
C6H5
4-ClC6H4S
p-ClC6H4SH 2b
2
2
PEG
89:11
88:12
86
79
C6H5
C6H5
(
Z
)-3b
(E)-3b
4
5
1a
2b
(Z)-3b + (E)-3b
Glycerole
SC4H9S
C6H5
C6H5
+
SC4H9S
SC4H9SH 2c
1
PEG
95:5
93:7
95
39
C6H5
C6H5
C6H5
(Z )-3c
(Z)-3c + (E)-3c
C6H5
(E)-3c
6
1a
2c
2.5
Glycerole
4-CH3OC6H4S
C6H5
+
C6H5
4-CH3OC6H4S
7
8
p-CH3OC6H4SH 2d
2.5
3
PEG
100:0
100:0
78
62
C6H5
C6H5
(Z )-3d
(E)-3d
1a
2d
(Z)-3d + (E)-3d
Glycerole
C6H5S
HO
HO
+
9
HO
OH
C6H5SH 2a
2
PEG
100:0
100:0
83
88
C6H5S
1b
OH
OH
(Z )-3e
(
E
)-3e
10
1b
2a
(Z)-3e + (E)-3e
1.5
Glycerole
C6H5S
HO
HO
+
HO
11
12
C6H5SH 2a
2
2
PEG
100:0
100:0
97
98
C6H5S
OH
OH
OH
(Z)-3f
(E)-3f
1c
1c
2a
(Z)-3f + (E)-3f
Glycerole
C6H5S
HO
HO
+
13
C6H5SH 2a
2
PEG
100:0
92
HO
C6H5
C6H5S
1d
C6H5
C6H5
(Z )-3g
(E )-3g
a
b
c
Determined by GC and 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.5b,9
Reaction performed in a 5 mmol scale.
d
e
Reaction was performed in the presence of the hydroquinone.
Reaction was performed under N2 atmosphere.

D. Alves et al. / Tetrahedron Letters 52 (2011) 133–135
135
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Satisfactory results were achieved using alkyl thiols and aryl thiols
containing electron donating or electron withdrawing groups
(Table 2, entries 1–8). The use of diynols afforded good to excellent
yields of desired products (Table 2, entries 9–12). Additionally,
when the unsymmetrical 2-methyl-6-phenylhexa-3,5-diyn-2-ol
1d reacted with benzenethiol 2a, we observed exclusively the for-
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study of the solvent/catalytic system was carried out for the reac-
tion.22 After completion of hydrothiolation, the reaction mixture
was diluted with hexane/ethyl acetate (90:10) and the product
was isolated. The remaining PEG or glycerol/KF/Al2O3 mixture
was directly reused for further reactions. It was observed that a
good level of efficiency was maintained even after three cycles.
Thus, the product 3a was obtained in 93%, 89%, 80% yields using
PEG as solvent, while using glycerol, the isolated yields were
64%, 55%, and 48% after successive cycles.
Concerning the stereochemistry of products, the formation of
(Z)-enyne was preferential for all the tested examples. Thus, Z-3a
was obtained preferentially from the reaction of 1,4-diorganyl-
1,3-butadiyne 1a with benzenethiol 2a (Z:E ratio = 92:8, Table 2,
entry 1), while 4-methoxybenzenethiol 2d afforded exclusively
the respective (Z)-adduct 3d (entries 7 and 8). A similar 100% ste-
reoselectivity was observed when the diynols 1b and 1c were used,
giving exclusively the respective adducts 3e and 3f with Z config-
uration (Table 2, entries 9–12). Comparable result was obtained
using a radical inhibitor. Thus, the reaction of 1a with 2a was per-
formed in the presence of the hydroquinone affording the product
3a in 92% yield and with a Z:E ratio = 90:10 (Table 2, entry 1). This
result is in according with a probable anionic mechanism.
In summary, an efficient and clean protocol was developed for
the selective synthesis of thiobutenynes. The reaction is promoted
by KF/Al2O3 and can be performed using glycerol or PEG as sol-
vents. The reactions proceeds easily and the products were ob-
tained in good to excellent yields. The use of glycerol as a
renewable, non-toxic, and recyclable solvent opens new possibili-
ties for future applications of glycerol in green and sustainable
chemistry.
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Chem. Soc. 2009, 20, 93; (b) Lenardão, E. J.; Silva, M. S.; Sachini, M.; Lara, R. G.;
Jacob, R. G.; Perin, G. ARKIVOC 2009, xi, 221; (c) Perin, G.; Mello, L. G.; Radatz, C.
S.; Savegnago, L.; Alves, D.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2010,
51, 4354.
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20. Preparation of alumina supported potassium fluoride:23 Alumina (4.0 g of
Al2O3 90, 0.063–0.200 mm, Merck), KF.2H2O (6.0 g) and water (10 mL) were
mixed in a 50 mL beaker and the suspension stirred at 65 °C for 1 h. The
resulting solid was dried at 80 °C for 1 h and subsequently 4 h at 300 °C in an
oven and finally cooled to room temperature in a desiccator. The content of KF
is about 50% (m/m).
Acknowledgments
We are grateful to FINEP, CAPES, CNPq, and FAPERGS/PRONEX
(10/0005-1 and 10/0130-3) for the financial support.
21. General procedure for the synthesis of thiobutenynes 3: To a mixture of 1,4-
diphenyl-1,3-butadiyne (1a; 0.202 g; 1 mmol), benzenethiol (2a; 0.110 g;
1 mmol) and PEG or glycerol (3 mL), KF/Al2O3 (0.07 g, obtained as described
above) was added at room temperature. The reaction mixture was allowed to
stir at 60 °C for the time indicated in Table 2. After that, the reaction mixture
was washed with a mixture of hexane/ethyl acetate (90:10; 3 Â 5 mL) and the
upper organic phase was separated from the PEG or glycerol containing the
supported catalyst, dried with MgSO4 and evaporated under reduced pressure.
The product was isolated by column chromatography using hexane as eluent,
yielding a mixture of Z-3a and E-3a (0.290 g, 93%, Z:E ratio = 92:8). 1H NMR
(200 MHz, CDCl3) d (Z + E) 7.43–7.55 (m, 4H); 7.05–7.33 (m, 11H); (Z isomer)
6.33 (s, 1H); (E isomer) 5.30 (s, 1H). MS m/z (rel. int.,%) 312 (M+, 100.0), 202
(99.7), 121 (50.0), 77 (19.5).
References and notes
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22. Reuse: To a round-bottomed flask containing 1,4-diphenyl-1,3-butadiyne 1a
(1.0 mmol), benzenethiol 2a (1.0 mmol) and solvent (3 mL) was added Al2O3/
KF. The reaction mixture was allowed to stir at 60 °C (using PEG-400) or at
90 °C (using glycerol) for 1.5 h. After that, the reaction mixture was washed
with
a
mixture of hexane/ethyl acetate (90:10; 3 Â 5 mL) and the upper
organic phase was separated from solvent/KF/Al2O3. The product was isolated
according procedure above. The mixture solvent/KF/Al2O3 was dried under
vacuum and reused for further reactions.
23. Wang, S.-X.; Li, J.-T.; Yang, W.-Z.; Li, T.-S. Ultrason. Sonochem. 2002, 9, 159.