Regio- and stereoselective synthesis of vinyl sulfides via PhSeBr-catalyzed hydrothiolation of alkynes

Article abstract of DOI:10.1016/j.tetlet.2007.05.076

We present here a simple and mild method of hydrothiolation of internal and terminal alkynes under PhSeBr-catalyzed reaction in the absence of solvent at room temperature. The reaction tolerates a wide variety of substituents on thiol, and provides the co

Full text of DOI:10.1016/j.tetlet.2007.05.076

Tetrahedron Letters 48 (2007) 4805–4808
Regio- and stereoselective synthesis of vinyl sulfides via
PhSeBr-catalyzed hydrothiolation of alkynes
´
Flavia Manarin, Juliano A. Roehrs, Marina Prigol, Diego Alves,
Cristina W. Nogueira and Gilson Zeni*
ˆ
Laborato´rio de Sı´ntese, Reatividade, Avaliac¸a˜o Farmacolo´gica e Toxicidade de Organocalcogenios, CCNE, UFSM,
Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
Received 11 April 2007; revised 14 May 2007; accepted 14 May 2007
Available online 18 May 2007
Abstract—We present here a simple and mild method of hydrothiolation of internal and terminal alkynes under PhSeBr-catalyzed
reaction in the absence of solvent at room temperature. The reaction tolerates a wide variety of substituents on thiol, and provides
the corresponding product in good yield and selectivity.
Ó 2007 Elsevier Ltd. All rights reserved.
Many different classes of organochalcogen compounds
have been prepared and studied to date. In this way,
vinylic sufides play an important role in the synthesis
of organochalcogen compounds, especially in the devel-
opment of many convenient methods for the stereoselec-
tive preparation of functionalized alkenes. Although
various methods are mentioned for the preparation of
vinylic sulfides, the more useful procedures have cen-
tered on the thiol addition to terminal or internal alk-
ynes and transition-metal-catalyzed hydrothiolation.1
In addition to their utility in the field of organic chemis-
try, toxicological, and pharmacological aspects of
organochalcogen compounds have also been recently
reviewed.2 Our continuing interest in the synthesis3
and application4 of vinylic chalcogenides in organic syn-
thesis prompted us to develop a new method for a con-
venient and efficient preparation of vinylic sulfides via
PhSeBr-catalyzed hydrothiolation of terminal and inter-
nal alkynes in a very short reaction time, at a room tem-
perature and under solvent-free conditions (Scheme 1).
R
H
PhSeBr (1mol%)
R2SH
R
YR1
+
0 oC
R2S
YR1
r.t., 30 min.
1a- R= C8H17, YR1= SMe; 1b- R= C6H5, YR1= SMe; 1c- R= C8H17, YR1= SPh;
1d- R= C8H17, YR1= SeMe; 1e- R= Ph, YR1= TeBu
Scheme 1.
results of the reactions with the variation in the temper-
ature, time, and the presence or absence of solvents are
summarized in Table 1.
In this procedure, the reaction carried out in solvents
such as THF and CH2Cl2 afforded moderate yields even
after heating the reaction mixture for a long period
(Table 1, entries 2–5). Gratifyingly, the absence of sol-
vent resulted in the vinyl sulfide product in 75% yield
(Table 1, entry 1). It is important to note that when
the amount of catalyst is reduced from 10 to 1 mol %
an increase in the yield was observed (Table 1, entries
1 and 7–9), while the increase to 1 equiv did not improve
the yields (Table 1, entry 6), in fact traces of product was
obtained, probably due to the direct electrophilic addi-
tion of PhSeBr to alkynes to give side products.5 As
shown in Table 1, other catalysts such as PhSeCl, ICl
and I2 gave the product in moderate yield (Table 1,
entries 11–13).
Since our initial studies have focused on the develop-
ment of an optimum set of reaction conditions, we have
initially chosen alkynyl methyl sulfide 1a and benzeneth-
iol as standard starting materials. In this way, the benz-
enethiol (1.1 mmol) was added at 0 °C to a solution of
compound 1a (1 mmol) and PhSeBr (1 mol %). The
The analysis of the optimized reactions demonstrated
that the optimal condition for this procedure was the
addition of PhSeBr (1 mol %) to a solution of alkynyl
Keywords: Vinylic sulfides; Hydrothiolation; Selenium.
*
Corresponding author. E-mail: gzeni@quimica.ufsm.br
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.076

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F. Manarin et al. / Tetrahedron Letters 48 (2007) 4805–4808
Table 1. Optimization of the reaction conditions
Table 2. Hydrothiolation of functionalized alkynes
Entry Thiol Product
C8H17
Entry
Catalysts (mol %)
Solvent
Yielda (%)
Yielda (%)
77
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhSeBr (10)
PhSeBr (10)
PhSeBr (10)
PhSeBr (10)
PhSeBr (10)
PhSeBr (1 equiv)
PhSeBr (5)
PhSeBr (3)
PhSeBr (1)
PhSeBr (1)
PhSeCl (1)
ICl (1)
—
75
H
CH2Cl2
THF
THF
THF
—
—
—
—
—
56b
69b
56b
51c
Traces
66
1
PhSH
S
SCH3
2a
C8H17
H
2
3
p-OMePhSH
p-ClPhSH
75
52
MeO
Cl
SCH3
S
67
77
74d
60
50
35
45
2b
C8H17
S
H
—
—
—
SCH3
I2(1)
—
2c
C8H17
S
H
a Yields are given for isolated products.
b The reaction was performed with 2 mL of solvent and heating at
4
5
o-ClPhSH
m-ClPhSH
83
74
SCH3
H
2d
50 °C.
Cl
c 20 mL of THF.
d 2 equiv of benzenethiol was used.
C8H17
S
SCH3
2e
methyl sulfide 1a (1 mmol) and benzenethiol (1.1 mmol)
at 0 °C. After the addition, the reaction mixture was stir-
red for 1 h at room temperature. This reaction condition
was systematically applied to other substrates to demon-
strate the efficiency of this method, and the results are
summarized in Table 2.6
Cl
Cl
C8H17
S
H
SCH3
6
ClPhCH2SH
55
2f
Ph
H
Inspection of Table 2 shows that the reaction worked
well for a variety of thiols and functionalized alkynes.
A detailed analysis of the results revealed that the reac-
tion is not sensitive to the electronic nature of functional
groups present in the thiols (Table 2, entries 1–6). Either
electron donating or electron withdrawing groups were
applied leading to corresponding vinyl sulfide in good
yield. Concerning the structure of thiols, we found some
limitations in this methodology, for example, no reac-
tion was observed with thiols bearing an alkyl group.
7
8
PhSH
70
58
S
SCH3
2g
Ph
H
OMePhSH
MeO
Cl
S
SCH3
2h
Ph
H
9
p-ClPhSH
30
S
SCH3
2i
We also investigated the influence of substituent at the
alkynes, where alkyl and aryl groups were compared.
Satisfactorily, all alkynes tested were effective, although
moderate yields were observed in the aryl alkynes (Table
2, entries 7–9). We have also performed a series of reac-
tions to test whether unsymmetrical internal alkynes
bearing a heteroatom such as Se, Te, and Sn would react
in the same fashion with thiols (Table 2, entries 13 and
14). As a result, the internal selenoalkyne 1d did not
react under our standard condition; however changing
the amount of PhSeBr from 1 to 10 mol % the desired
product was obtained in moderate yield (Table 2, entry
13). The hydrothiolation did not proceed satisfactorily
with unsymmetrical internal alkynes bearing a tellurium
group 1e bonded directly at the triple bond. In these
cases we observed only traces of products.
C8H17
S
H
10
11
PhSH
62
51
SPh
2j
C8H17
H
p-OMePhSH
MeO
Cl
S
SPh
2k
C8H17
H
12
13
14
p-ClPhSH
PhSH
65
S
SPh
2l
C8H17
S
H
40b
SeMe
2m
On the other hand, the reaction of thiol with alkynes
bearing an organotin group 1f gave a mixture of E
and Z vinylic compounds. Based on these results and
with the knowledge that the carbon–tin bond exhibits
an easier heterolytic cleavage towards nucleophilic
reagents than the carbon–sulfur and carbon–selenium
Ph
S
H
PhSH
Trace
TeBu
2n
a Yields are given for isolated products.
b Reaction performed in presence of PhSeBr (10 mol%).

F. Manarin et al. / Tetrahedron Letters 48 (2007) 4805–4808
4807
1
Analysis of the H and 13C NMR spectra showed that
all vinylic sulfides prepared presented data in full agree-
ment with their assigned structures. The regio- and ste-
reochemistries of trisubstituted vinylic sulfides were
determined by NOE and NOESY experiments (for more
details see Supporting data). The analysis of spectra
showed that the hydrothiolation proceeds by the addi-
tion of thiol in an anti-fashion stereoselectively affording
the corresponding Z vinylic sulfide.
Table 3. Hydrothiolation of terminal and internal alkynes
Entry Alkyne
Product
Yield (%)
Ph
Ph
OH
1
50
1f
PhS
2o
OH
HO
2
NR
OH
1g
1h
1i
SPh
2p
TsO
In summary, we have developed a new application of
PhSeBr in a highly selective catalyzed reaction of ben-
zenethiols to terminal and internal alkynes to give viny-
lic sulfides. The importance of the chemistry described
here lies in the established new synthetic method to pre-
pare vinylic sulfides in a short reaction time, mild reac-
tion conditions (room temperature) in the absence of
base, solvent, and transition metals.
3
4
5
6
7
NR
OTs
O
SPh
2q
O
NR
SPh
2r
Ph
Ph
62 (E/Z = 90/10)
76 (E/Z = 25/75)
70 (E/Z = 17/83)
1j
SPh
2s
2t
Ph
Ph
Ph
Ph
Acknowledgements
1j
1j
S(p-OMePh)
We are grateful to CNPq, CAPES(SAUX 2007) and
FAPERGS, for financial support. CNPq is also
acknowledged for a fellowship (to G.Z. and Manarin).
S(p-ClPh)
2u
Bu
PhS
Bu
Bu
SPh
Supplementary data
8
55
1k
Bu
2v
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.05.076.
triple bonds, due to the large volume and greater ionic
character of the tin atom and the easy polarization of
the bonds, we assumed that the terminal alkyne was
formed as an intermediate, which reacts with thiol to
give the mixture of isomers (Scheme 2).
References and notes
1. (a) Sridhar, R.; Surendra, K.; Krishnaveni, N. S.; Srinivas,
B.; Rao, K. R. Synlett 2006, 3495–3497; (b) Cao, C. S.;
Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127,
17614–17615; (c) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao,
T. J. Am. Chem. Soc. 1999, 121, 5108–5114; (d) Ananikov,
V. P.; Orlov, N. V.; Beletskaya, I. P. Organometallics 2006,
25, 1970–1977; (e) Kondoh, A.; Takami, K.; Yorimitsu, H.;
Oshima, K. J. Org. Chem. 2005, 70, 6468–6473.
Next we decided to expand the scope of this methodol-
ogy to include simple terminal and internal alkynes. As
shown in Table 3, all the propargyl alcohols were found
not effective, even the protected one. However, the use
of 3-phenylprop-2-yn-1-ol gave the desired product in
low yield (Table 3, entry 1). We also observed that the
regioselectivity control was governed by the effective
participation of the hydroxyl group from alkynol. In
addition, only one isomer was obtained with alkynes
containing hydroxyl group (Table 3, entry 1). Con-
versely, alkynes with no hydroxyl group gave a mixture
of isomers (Table 3, entries 5–7).
2. Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev.
2004, 104, 6255–6286.
3. (a) Zeni, G.; Stracke, M. P.; Nogueira, C. W.; Braga, A. L.;
Menezes, P. H.; Stefani, H. A. Org. Lett. 2004, 6, 1135–
1138; (b) Moro, A. V.; Nogueira, C. W.; Barbosa, N. B. V.;
Menezes, P. H.; Rocha, J. B. T.; Zeni, G. J. Org. Chem.
2005, 70, 5257–5268; (c) Zeni, G.; Barros, O. S. D.; Moro,
A. V.; Braga, A. L.; Peppe, C. Chem. Commun. 2003, 1258–
Ph
S
H
SH
SnBu3
Ph
SnBu3
+
PhSeBr (1mol%)
r.t., 30 min.
0 oC
SPh
1f
Ph
30%
(E/Z= 42/58)
Scheme 2.

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F. Manarin et al. / Tetrahedron Letters 48 (2007) 4805–4808
1259; (d) Barros, O. S. D.; Lang, E. S.; Peppe, C.; Zeni, G.
Synlett 2003, 1725–1727.
mixture was stirred at room temperature for 30 min. After
this time the reaction mixture was treated with CH2Cl2 and
concentrated under vacuum. The residue was purified by
flash chromatography and eluted with hexane to afford the
addition product 2a (0.226 g, 77%) as a yellow oil.
4. (a) Zeni, G.; Ludtke, D. S.; Panatieri, R. B.; Braga, A. L.
Chem. Rev. 2006, 106, 1032–1076; (b) Prediger, P.; Moro,
A. V.; Nogueira, C. W.; Savegnago, L.; Menezes, P. H.;
Rocha, J. B. T.; Zeni, G. J. Org. Chem. 2006, 71, 3786–
3792; (c) Barros, O. S. D.; Nogueira, C. W.; Stangherlin, E.
C.; Menezes, P. H.; Zeni, G. J. Org. Chem. 2006, 71, 1552–
1557.
Selected spectral and analytical data for 1-methylthio-2-
1
phenylthiodeca-1-ene (2a): Yield: 0.226 g (77%). H NMR:
(CDCl3, 200 MHz) d (ppm): 7.33–7.12 (m, 5H), 6.31 (s,
1H), 2.31 (s, 3H), 2.18 (t, J = 7.05 Hz, 2H), 1.50 (t,
J = 7.05 Hz, 2H), 1.21 (m, 10H), 0.86 (t, J = 7.1 Hz, 3H).
13C NMR: (CDCl3, 50 MHz), d (ppm): 134.18, 133.27,
130.23, 129.68, 128.70, 126.16, 37.19, 31.72, 29.17, 29.10,
28.72, 28.44, 22.54, 17.01, 14.00. MS (EI, 70 eV) m/z
(relative intensity): 294 (100), 185 (82), 170 (32), 155 (35),
140 (39), 125 (33), 109 (40), 88 (15), 77 (43), 29 (12). HRMS
Calcd for C17H26S2: 294.1475. Found: 294.1479.
5. Iwaoka, M.; Komatsu, H.; Katsuda, T.; Tomoda, S. J. Am.
Chem. Soc. 2004, 126, 5309.
6. Typical procedure for the preparation of the vinyl sulfides: To
a Schlenk 10 mL tube under argon atmosphere containing
PhSeBr (0.023 g, 1 mol %) was added alkynyl methyl sulfide
1a (0.184 g, 1 mmol). After stirring the mixture at 0 °C,
benzenethiol (0.121 g, 1.1 mmol) was added. The reaction