Regioselective hydrothiolation of terminal acetylene catalyzed by magnetite (Fe3O4) nanoparticles

Article abstract of DOI:10.1080/00397911.2016.1262421

Herein, we report a new and solvent-free methodology for the preparation of vinyl thioethers from terminal alkynes and thiols, using magnetite (Fe₃O₄) nanoparticles as a recyclable catalyst. With this greener method, the desired viny

Full text of DOI:10.1080/00397911.2016.1262421

Regioselective Hydrothiolation of Terminal Acetylene catalyzed by Magnetite
(Fe3O4) Nanoparticles
Manuela S. T. Rocha1, Jamal Rafique1, Sumbal Saba1,2, Juliano B. Azeredo3, Davi Back4,
Marcelo Godoi5, Antonio L. Braga1
1Universidade Federal de Santa Catarina, UFSC – Departamento de Química, SC, Brazil
2Department of chemistry, Shaheed Benazir Bhutto Women University, Peshawar, KPK,
Pakistan 3Universidade Federal do Pampa-UNIPAMPA, Uruguaiana, RS, Brazil
4Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS,
Brazil 5Escola de Química e Alimentos, Universidade Federal do Rio Grande –Campus
Santo Antônio da Patrulha, RS, Brazil
Corresponding author , E-mail: braga.antonio@ufsc.br (A.L. Braga)
Corresponding author E-mail: marcelogodoi@furg.br (M. Godoi)
Received 10 September 2016
Abstract
Herein, we report a new and solvent free methodology for the preparation of vinyl
thioethers from terminal alkynes and thiols, employing Fe3O4 nanoparticles as a
recyclable catalyst. With this greener method, the desired vinyl thioethers were achieved
in good yields and with good stereoselectivity. In addition, the catalyst was easily
recovered using a simple external magnet and reused for further catalytic reactions
without significant loss of activity up to the fifth cycle.
Graphical Abstract
KEYWORDS: nanoparticles, acetylenes, catalysis, thioethers, Magnetite (Fe3O4)
1

INTRODUCTION
Organosulphur compounds are of unique biological and pharmaceutical importance and
have been used as powerful intermediates in synthetic organic chemistry.[1,2] In this
context, vinyl thioethers have attracted considerable attention in recent years. For
instance, these types of compounds have become suitable synthetic intermediates in a
variety of transformations, including total synthesis.[3] They have also been employed as
privileged substrates in the preparation of a wide range of bioactive molecules.[4]
The most atom-economical and powerful pathway for the preparation of vinyl thioethers
is the hydrothiolation of alkynes, conveniently promoted by transition-metal or radical
initiators (Scheme 1). Basically, there are three possible products for this type of reaction:
Markovnikov A and anti-Markovnikov B and C, which can be formed with different
levels of stereo- and regio-selectivity.[5]
Several hydrothiolation reactions have furnished Markovnikov products employing
different transition metal catalysts,[6] including nickel,[7] palladium[8] and rhodium.[9]
Notably, the selective formation of vinyl thioethers via anti-Markovnikov products under
different conditions have also been described.[10] For example, these compounds have
been conventionally prepared employing either traditional radical inhibitor[11] or through
metal catalysis processes using copper,[12] palladium,[13] gold[14] and indium.[15]
2

Nevertheless, most of these protocols have some drawbacks, such as the employment of
expensive catalysts, the use of toxic solvents, air reactivity of some sulphur compounds
and long reaction times. Thus, the development of new protocols to obtain vinyl
thioethers in good yields and high level of stereo- and regio-selectivity under mild
conditions is highly desirable.
On the other hand, nanomaterials with reactive morphologies have become one of the
most applicable and powerful catalysts for the generation of new carbon-heteroatom
bonds.[16] In this context, nano-CuO has been applied as a catalyst for the cross-coupling
of thiols with vinyl halides.[17]
However, the magnetic nanocatalysts are preferred when compared to other nano
analogues mainly due to their unique features, such as easy recyclability and
recoverability of the catalyst by simple magnet force, avoiding the need for tedious work-
ups for the separation.[18] Ranu and co-workers have reported an elegant protocol for the
preparation of vinyl thioethers through the cross-coupling of disulphides and vinyl
halides catalysed by a bimetallic system of iron and copper, in the presence of base and
additive, employing water as a solvent.[19] Nonetheless, there is still the issue of lower
atom-economical as well as wastewater, which requires suitable treatment with a high
cost.[20] Thus, the development of a new eco-friendly methodology for the preparation of
vinyl thioethers associated with solvent-, base- and additive-free conditions represents a
promising challenge in this area.
3

More recently, that the combination of magnetically recoverable iron oxide and solvent-
free conditions was applied for the synthesis of sulphides and derivates as an
environmentally benign alternative in the field of organosulphur chemistry.[21] Despite
the good features of this eco-friendly system, the combination of nanocatalysis and
solvent-free conditions has not been previously explored for the stereoselectivity
synthesis of (Z)-vinyl thioethers through the hydrothiolation of alkynes.
Therefore, in accordance with our continuing interest in catalytic processes and eco-
friendly processes,[22] a stereoselectivity and greener method for the preparation of vinyl
thioethers employing Fe3O4 nanopowder as a recyclable catalyst is reported herein
(Scheme 1).
RESULTS AND DISCUSSION
In order to optimized the reaction conditions, we carried out the reaction using para-
methylbenzenethiol 1a and phenylacetylene 2a as model substrates (Table 1). Initially,
we evaluated the influence of several iron catalysts on the reaction system. Performing
the reaction employing 5 mol% of nano-Fe2O3 as a catalyst afforded the desired vinyl
thioether in reasonable yield with a Z:E ratio of 77:23 (entry 1). Noteworthy, when we
employed nano-Fe3O4 with particle size 50-100 nm as a catalyst the desired product was
achieved with 85% yield and with a similar stereoselectivity ratio (entry 2). However, the
yield value of 3a was decreased when the nano-Fe3O4 loading was decreased to 2.5 mol%
(entry 3).
4

Bulky oxides were less effective as catalysts when compared to their nanoparticle
analogues (compare entries 5 vs 1 and 4 vs 2). Other bulky catalysts also had an adverse
effect on the reaction system, affording product 3a in lower yields even with higher
reaction times (entries 6-8). Thus, to obtain compound 3a in good yield and with high
stereoselectivity, the best option found was the use of 5 mol% of catalyst, as shown in
entry 2.
Having identified the best catalyst, we then evaluated other reaction parameters, such as
temperature and time. On decreasing the reaction temperature from 25 to 0 °C we
observed a decrease in the yield values for product 3a (entries 9 and 10). No significant
change in the yield was observed when the temperature of the reaction was increased to
80 °C (entry 11). Finally, we investigated the influence of the reaction time and 10 min
proved to be the best option, since no improvement in the yield and selectivity was
obtained when this reaction parameter was evaluated (entries 12 and 13). Moreover, the
desired vinyl thioether 3a was obtained in reasonable yield in the absence of a catalyst
after 50 minutes with no stereoselectivity, since the corresponding isomers were
delivered in almost the same ratio (entry 14).
Having determined the best reaction conditions, we then evaluated the scope of our
protocol by testing a wide range of thiols and alkynes (Table 2). When the reaction was
carried out employing phenylacetylene and benzenethiol as substrates the corresponding
product 3b was delivered in 78% yield with good selectivity (entry 2).
5

Next, we evaluated the electronic effects of substituents attached to the para position of
the aromatic ring in the thiol. In this way, the reactions with either para-donating or
para-withdrawing substituents in the benzenethiol underwent a smooth hydrothiolation
reaction with very high stereoselectivity and in moderate to good yields (entries 3-5).
Further experiments indicated that either releasing or withdrawing substituents at ortho
position of aromatic ring could be tolerated, which afforded the corresponding products
in reasonable yields and in similar ratios of stereoselectivity (entries 6 and 7). We also
applied the same protocol for the preparation of a series of vinyl thioethers starting from
aliphatic thiols (entries 8-11). For instance, when benzyl mercaptan was used as a sulphur
source, the desired product 3h was obtained in good yield and high stereoselectivity
(entry 8).
Subsequently, the combination of structurally diverse alkynes with para-
methylbenzenethiol was also investigated (entries 12-18). Notably, when we treated
meta-chloro phenyl acetylene 2b with thiol 1a the desired product 3l was achieved in
87% yield with good stereoselectivity in only 6 minutes (entry 12). Similarly, when a
thiol with a CF3 group at the para position of the aromatic ring was employed, the
corresponding product was obtained in very high yield in a shorter reaction time (entry
13). However, the activity of acetylenes with electron releasing groups as substrates was
lower, affording the corresponding products in lower yields and similar stereoseletivity
(entries 14 and 15).
6

The aliphatic alkynes 3k and 3l were not efficient substrates for this transformation.
Nonetheless, when the aliphatic alkyne 2h was employed the respective product 3r was
delivered in reasonable yield and high Z:E ratio (entry 14).
We also studied the recyclability of the Fe3O4 nanoparticles to evaluate the sustainability
of the present protocol. The catalyst was recovered from the reaction medium with the
aid of an external magnet and reused for consecutive cycles under similar conditions.
Notably, the catalyst maintained its activity and high effectiveness for up to five cycles,
affording the desired vinyl thioether in good yield and with high selectivity (Table 3).
The TEM analysis of the Fe3O4 nanoparticles was performed before use and after an
additional five reaction runs (Figure 1). The experimental results obtained suggest that
the reaction involves a heterogeneous process via surface Fe3O4 nanoparticle catalysis.
CONCLUSIONS
In conclusion, we successful developed a solvent free and greener method for the
preparation of vinyl thioethers, employing Fe3O4 nanoparticles as a recyclable catalyst
under solvent-free conditions. In most cases, this new approach provided the desired
products in very good yields and with high stereoselectivity. Furthermore, the
nanocatalyst was highly efficient in this transformation and it was easily recovered from
the reaction by facile separation with an external magnet, and reused for further
experiments without significant loss of activity.
7

EXPERIMENTAL SECTION
General Procedure For The Preparation Of Vinyl Thioethers
The Fe3O4 nanopowder (0.025 mmol, 5 mol%) and terminal acetylene (0.6 mmol) were
placed in a round-bottom flask, followed by thiol (0.5 mmol). The reaction was stirred at
room temperature and the progress was monitored by TLC. After completion of the
reaction, diethyl ether was added and the resulting solution was transferred to a round-
bottom flask. The volatiles were removed under vacuum to afford the crude product.
Purification by flash chromatography with a mixture of ethyl acetate/hexane (1:99)
afforded the desired vinyl thioether.
Recyclability Of The Catalyst
After completion of the reaction, the Fe3O4 nanoparticles were collected on an external
magnet, washed with diethyl ether and dried under vacuum. The recovered catalyst was
reused directly for the next experiment.
SUPPORTING INFORMATION
All synthesized compounds were characterized by 1H NMR and 13C NMR; unknown
compounds were also characterized by high-resolution mass spectra. This material can be
found via the Supplementary Content section of this article’s webpage.
ACKNOWLEGMENTS
8

We are grateful to the CAPES, CNPq, FAPESC, INCT-Catálise, TWAS and FAPERGS
for financial support. CNPq is also acknowledged for the master’s scholarship awarded to
M. S. T. R. The authors are also grateful to LCME-UFSC for the TEM analysis.
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Table 1. Optimization of reaction conditionsa
Entry Catalyst
Time (min) Temp (°C) Yield (%)a Z:Eb
1
nano-Fe2O3 10
25
25
25
25
25
25
25
25
0
54
85
50
57
21
30
27
13
56
64
81
46
78
59
75:25
70:30
77:23
80:20
84:16
73:27
85:15
64:36
75:25
64:36
63:37
64:36
75:25
47:53
2
nano-Fe3O4 10
3c
4
nano-Fe3O4 10
Fe3O4
Fe2O3
Fe0
10
10
50
5
6
7
FeCl3.6H2O 50
FeCl3 50
8
9
nano-Fe3O4 10
nano-Fe3O4 10
nano-Fe3O4 10
10
11
12
13
14
10
80
25
25
25
nano-Fe3O4
nano-Fe3O4 15
50
5
-
a Isolated yield.
b Determined by 1H NMR spectroscopy.
c The reaction was carried out using 2.5 mol% of catalyst
12

Table 2. Synthesis of several vinyl thioethers
Entry Thiol
1
R1
Ph
2a
Time (min) Product
10
Yield(%)a Z:Eb
85
78
71
55
70:30
70:30
80:20
86:14
1a
3a
2
Ph
10
2a
1b
3b
3
Ph
7
2a
1c
3c
4
Ph
5
2a
1d
3d
5
Ph
8
56
68
60
83:17
76:24
73:27
2a
1e
3e
6
Ph
25
2a
3f
1f
7
Ph
120
2a
1g
3g
8
Ph
15
66
71:29
2a
1g
13

3h
3i
9
Ph
25
120
120
6
36
47
63
87
88
80:20
80:20
75:25
77:23
68:32
1h
1i
2a
10
11
12
13
Ph
2a
3j
3k
3l
Ph
2a
1j
m-ClPh
2b
1a
p-CF3Ph
5
2c
1a
3m
3n
14
p-MePh
8
66
82
77:23
73:27
2d
1a
1a
15c
p-MeOPh 36
2e
3o
3p
16
17
n-C6H13
40
40
----
----
----
----
2f
1a
1a
CH2OH
2g
3q
14

18
EtOCO
30
57
80:20
2h
1a
a Isolated yield.
3r
b Determined by 1H NMR spectroscopy.
cTemperature: 40 °C.
15

Table 3. Reusability of the catalyst
Cycles Yield (%)a Z:Eb
1
2
3
4
5
82
85
74
75
74
78:22
73:27
75:25
77:23
76:24
a Isolated yield.
b Determined by 1H NMR spectroscopy.
16

Scheme 1. Hydrothiolation of alkynes with thiols
17

Figure 1. TEM images of Fe3O4 nanoparticles. (a) Fresh Fe3O4 nanopowder. (b) Fe3O4
nanopowder recovered after fifth experiment.
18