A practical and chemoselective Mo-catalysed sulfoxide reduction protocol using a 3-mercaptopropyl-functionalized silica gel (MPS)

Article abstract of DOI:10.1039/c6ra03106d

A convenient sulfoxide deoxygenation procedure using a mercaptopropyl-functionalized silica gel as the reducing agent is described. This new protocol based on a heterogeneous reagent displays broad scope and tolerance to reducible functional groups and, from an experimental point of view, enhances previous methods by simplifying the isolation of the sulfide to a simple filtration.

Full text of DOI:10.1039/c6ra03106d

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DOI: 10.1039/C6RA03106D
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Practical and Chemoselective Mo‐Catalysed Sulfoxide Reduction
Protocol using 3‐Mercaptopropyl‐functionalized Silica Gel (MPS)†
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
b
a
Nuría García, Manuel A. Fernández‐Rodríguez, Patricia García‐García, María R. Pedrosa,
a
a,
Francisco J. Arnáiz and Roberto Sanz *
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
convenient sulfoxide deoxygenation procedure using reduction of sulfoxides are still highly desirable. An ideal
mercaptopropyl‐functionalized silica gel as reducing agent is procedure should be selective, display high functional group
described. This new protocol based in a heterogeneous reagent tolerance, circumvent the employment of catalysts derived
displays broad scope and tolerance to reducible functional groups from precious metals as well as hazardous/toxic reagents, do
and, from an experimental point of view, enhances previous not generate side products and avoid arduous purification
methods by simplifying the isolation of the sulfide to a simple techniques.
filtration.
In this context, as part of our ongoing research in the
development of new redox protocols catalyzed by
5
a,9
The development of sustainable catalytic protocols for the
deoxygenation of organic compounds, frequently involved in
the synthesis of bioactive targets and in the production of
renewable fuels from vegetable oils, is an important goal for
chemists and engineers from both academia and industry.
Particularly, the deoxygenation of sulfoxides is of
extraordinary relevance in biological processes, to preclude
the oxidative damage of cells, as well as in organic synthesis
as a key step in several reaction sequences. Accordingly,
numerous catalytic methods have been developed in the past
dioxomolybenum(VI) complexes, we have recently reported
the use of alcohols such as pinacol (2,3‐dimethyl‐2,3‐
butanediol) and glycerol as environmentally benign reductants
10
in the chemoselective deoxygenation of sulfoxides. Notably,
these reactions were typically conducted in air and under
solvent free conditions and the corresponding sulfides were
isolated by a liquid‐liquid extraction to remove the catalyst,
the remaining alcohol and the water, acetone or formic acid
generated as by‐products.
1
2
Continuing with our interest in the development of sustainable
reductions protocols, we envisaged an expedient sulfoxide
3
decades to perform this transformation.
11
In this sense, considerable efforts have been done in the
catalyst development for sulfoxide reduction and, therefore,
significant achievements have been accomplished including
deoxygenation procedure using a solid supported reducing
agent that would simplify the reaction work‐up to just
filtration and solvent evaporation. To this aim we selected 3‐
mercaptopropyl‐functionalized silica gel (MPS) as reducing
agent. This heterogeneous reagent has been mainly used to
4
the use of non‐metal or abundant, inexpensive and non toxic
5
6
7
8
Mo, Zn, Cu or Fe based catalysts. These procedures
encompass the use of stoichiometric or excess amounts of
silanes, boranes, hydrogen or phosphorous(III)‐based reagents
as oxygen‐acceptors. So, most of them are limited by side
reactions, poor yields and/or selectivities, harsh reaction
conditions and the requirement of laborious purification
processes due to the generation of toxic by‐products difficult
to remove from the reaction mixture. Therefore, more
sustainable catalytic protocols for the chemoselective
1
2
13
support catalysts or as heavy metal scavenger and,
although the ability of thiols as oxygen acceptors in sulfoxide
1
4
reductions is well known, as far as we are aware, the use of
MPS as reductant was unexplored.
Considering our experience with other reducing agents, the
deoxygenation of bis(p‐tolyl)sulfoxide in the presence of
catalytic amounts of MoO Cl (dmf) (2 mol%) under
1
0
2
2
2
microwave irradiation was chosen as model reaction to assess
the reduction ability of MPS (1.1 equiv.) Initial experiments
.
conducted in toluene at different temperatures showed that
heating at 130 C was necessary to reach complete conversion
to the corresponding sulfide in 20 min, whereas at lower
temperatures or under solvent‐free conditions low
conversions were observed (Table 1, entries 1-3). The reaction
time could be cut by half by just increasing the temperature to
a.
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza.
Misael Bañuelos s/n, 09001‐Burgos, Spain. Fax: (+34) 947258831; E‐mail:
rsd@ubu.es
b.
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá.
28871, Alcalá de Henares, Madrid, Spain.
†
Electronic Supplementary Information (ESI) available: Experimental details and
NMR spectra of all the experiments. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2016
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1
40

C (entry 4). In this essay, bis(p‐tolyl)sulfide was obtained Table 1. Optimization of the reaction conditions for the Mo‐catalyseVdiewdeAorxtiycgleenOantilionne
in almost quantitative yield (97%) and in pure form after of bis(p‐tolyl)sulfoxide with mercaptopropyl‐functionalized silica gel (MPS) as reducing
simple filtration of the reaction mixture and solvent
DOI: 10.1039/C6RA03106D
a
agent.
evaporation. At this point, a parallel reaction with not linked 3‐
mercaptopropyl trimethoxysilane instead of MPS was
performed. As a result, complete conversion to the sulfide was
also detected supporting the role of the thiol entity as
b
entry
[Mo]
solvent
Toluene
Toluene

T (°C) t (min) yield (%)
functional group reducing agent (entry 5). Notably, in this case
column chromatography purification was required to remove
the subproducts formed in stoichiometric amounts derived
from the reductant. Consequently, in this homogeneous
conditions, besides the need of a time and resource consuming
purification step, a significant decrease in the yield compared
with the reaction under heterogeneous conditions was
observed (entries 4 vs 5), proving the advantageous use of the
solid‐supported reagent.
1
2
3
4
MoO
MoO
MoO
MoO
MoO
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
(dmf)
2
(dmf)
2
(dmf)
2
(dmf)
2
(dmf)
2
2
2
2
2
120
130
130
140
140
140
140
140
140
140
140
140
110
170
140
170
30
20
20
10
10
10
10
10
10
10
10
10
420
60
10
60
(30)
(100)
(40)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Mesitylene
Ethanol
Ethanol
(100)
(100)
(0)
c
5
6
7
8
9

Next, the influence of the catalyst was examined. As expected,
no appreciable reaction took place without catalyst (entry 6),
whereas other dioxomolybdenum(VI) complexes such as
MoO
2
Cl
2
(dmso)
2
(100)
(100)
(100)
(100)
(100)
(100)
(100)
(100)
(100)
(100)
2
MoO (acac)
2
MoO Cl (dmso) ,
MoO (acac) ,
2
MoO (dipic)(dmso),
2
2
2
2
2
2
MoO (dipic)(dmso)
MoO Cl (OPPh ) , MoO Br (dmso) or commercially available
2
2
3 2
2
2
2
1
0
1
MoO
2
Cl
2
(OPPh
3
)
2
MoO Cl also worked as active catalysts for this transformation
2
2
15
(
entries 7
-12). The cleanest reaction and the highest yield
1
MoO
2 2
Br (dmso)
2
was obtained with easily prepared and highly stable
5
a
12
2 2
MoO Cl
MoO Cl (dmf) complex and so, it was selected as catalyst for
2
2
2
d
the following experiments.
13
MoO
MoO
MoO
MoO
2
Cl
2
Cl
2
Cl
2
Cl
2
(dmf)
2
(dmf)
2
(dmf)
2
(dmf)
2
2
2
2
As we are aware that numerous synthetic labs do not have
access to microwave reactors, and intending to extend the
applicability of the reported reduction procedure to all the
research community, we have also studied the model reaction
under conventional heating techniques. Thus, after screening
several reaction parameters, we found that bis(p‐
tolyl)sulfoxide was completely transformed in the
corresponding sulfide in the presence of 1.1 equivalents of
d
14
15
d,e
16
a
All reactions were performed with 0.25 mmol of sulfoxide under microwave
irradiaꢀon (maximum waꢁage 300 W; see ESI† for details) unless otherwise
Based on the starting bis(p‐tolyl)sulfoxide; in brackets conversion
estimated by H NMR (300 MHz) from the crude reaction mixture after filtration.
Reaction performed under homogeneous conditions using 3‐mercaptopropyl
trimethoxysilane (1.1 equiv.) as reducing agent. Reactions conducted under
b
stated.
1
c
MPS and 2 mol% of MoO Cl (dmf) by heating them in toluene
2
2
2
d
at reflux for 7 h or in mesitylene at 170
4).

C for 1 h (entries 13
-
e
conventional heating. Reaction conducted in a sealed tube.
1
Further tests, performed under both microwave irradiation
and conventional heating, increasing the amount of supported
reducing agent led to no improvements in yield or reaction
time, whereas incomplete conversions were observed by
lowering the catalyst loading. In addition, the hydrocarbon
solvents (toluene or mesitylene) could be replaced by a more
sustainable solvent such as ethanol, although slightly lower
yields were obtained and the use of a sealed tube under
conventional heating was mandatory due to the lower boiling
Once we had demonstrated the viability of employing MPS as
solid‐supported reducing agent of sulfoxides, the scope of this
Mo‐catalyzed deoxygenation was explored. These reactions
were conducted using the optimal conditions determined, that
is, 1.1 equivalents of MPS, MoO Cl (dmf) (2.0 mol%) as
2
2
2
catalyst in toluene at 140 C for 10 min under microwave
irradiation. The results have been summarized in Table 2.
Reactions of a variety of representative diaryl, aryl‐alkyl (either
linear or branched), as well as dialkyl sulfoxides efficiently
occurred to give the corresponding thioethers (entries 1, 4, 6
and 8–11). Moreover, the suitability of the alternative protocol
under conventional heating was demonstrated for a few
examples (entries 3, 5, 7). Interestingly, although most of the
reactions were conducted starting with 0.5 mmol of the
sulfoxide, increasing the scale to 3 mmol with the model
substrate did not affect the outcome of the process (entry 2).
point of the solvent (entries 15
Furthermore, it should be noted that same results were
-16).
1
6
achieved with both commercial available Quadrasil® MP,
with a reported loading in the range of 1.0 to 1.5 mmol/g, and
1
7
synthesized MPS, with an equivalent 1.2 mmol/g loading,
indistinctly employed as supported reagent along the study.
2
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Table 2. Mo‐catalysed deoxygenation of sulfoxides using mercaptopropyl‐
functionalized silica gel (MPS) as reducing agent.
MoO
2 2 2
ew Article Online
Cl (dmf) (3.5 mg, 2.0 mol%) in tolueneVi(1 mL) was
a
irradiated in a sealed tube in the microwDO
I
:
10
.1
0
3
9/
C6
RA
0
3106
D
a
v
e
cavit
y
at
1
4
0 °C
for 10 min. Then, the reaction mixture was cooled to room
temperature and the silica gel was removed by filtration and
washed with Et O (2 x 5 mL). The solvents of the filtrate were
2
removed under reduced pressure to yield bis(p‐tolyl)sulfide in
yield
yield
(%)
pure form (104 mg, 97% yield).
Considering our previous results in this field, we postulate a
entry
product
b
entry
14
product
b
(%)
10
1
97
96
94
mechanism that would start with reaction of the
dioxomolybdenum(VI) catalyst with the thiol leading to the
c
2
3
71
d
thiolate complex
I (Scheme 1). At this point, reductive
4
5
94
91
elimination of an heterogeneous sulfenic acid derivative would
lead to the reduction of the dioxomolybenum(VI) catalyst to a
formal monooxomolybdenum(IV) species II, which would be
able to deoxygenate the sulfoxide to the corresponding
sulphide regenerating the active catalyst (Scheme 1).
d
15
67
85
87
86
S
6
89
91
Me
16
d
7
O
O
8
9
93
89
17
18
S
Ph
p-Tol
10
11
12
91
69
88
19
20
21
87
81
92
13
91
22
87
a
All reactions were conducted with 0.5 mmol of sulfoxide under microwave
irradiaꢀon (maximum waꢁage 300 W; see ESI† for details) unless otherwise
b
c
d
stated. Based on the starting sulfoxide. Reaction conducted at 3 mmol scale.
Reactions conducted at 170 °C in mesitylene under conventional heating for 1 h.
Scheme 1 Proposed catalytic cycle for the molybdenum-catalyzed
deoxygenation of sulfoxides
Next, reductions of a wide range of sulfoxides possessing the
most representative potentially reducible functionalities such
as halogens, C-C multiple bonds, aldehyde, ketone, ester,
Conclusions
In summary, we have developed a convenient protocol for the
Mo‐catalysed sulfoxide deoxygenation based on the unknown
use of mercaptopropyl‐functionalized silica gel (MPS) as
reducing agent. The improved strategy reduces the work‐up of
the reaction to just a simple filtration of the solid waste
without affecting the scope or tolerance to potential reducible
functional groups that has been demonstrated to be extremely
cyano or nitro groups were analyzed in order to evaluate the
chemoselectivity of the developed reduction procedure.
Notably, the deoxygenation of all these substrates gave
exclusively the corresponding sulfides with the additional
functional group unaltered (entries 12–22). It should be noted
that this Mo‐catalyzed reduction with MPS as reducing agent
displayed, in general, an excellent 90% average yield. Even the
inferior yields, around 70%, observed with dibutylsulfoxide and
sulfoxides bearing an olefin or an alkyne moiety are
synthetically useful, considering the simplicity of the protocol.
To summarize, under the developed protocol using microwave
irradiation all the sulfides were obtained in good yields from
the corresponding sulfoxides in less than 30 minutes, including
both reaction set‐up and work‐up, in pure form by a simple
filtration, without the need of further purification techniques.
In a representative experiment, a mixture of 458 mg of the
silica gel‐supported reagent (Quadrasil® MP or synthesized
high.
Therefore,
purification
protocols
including
chromatography and liquid‐liquid extractions, which are time
consuming and difficult to scale up, are not required.
Moreover, the reactions are performed in air using easily
available and environmentally friendly MoO Cl (dmf) as
catalyst and the products are obtained in good to excellent
yields from the corresponding starting materials in a few
minutes.
2
2
2
Acknowledgements
MPS), bis(p‐tolyl)sulfoxide (115 mg,
1
mmol) and
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We are grateful to the Ministerio de Economía
Competitividad (MINECO) and FEDER (CTQ2013‐48937‐C2‐1P)
y
M. A. Fernández‐Rodríguez, D. García, M. R. Pedrosa, F. J.
Arnáiz and R. Sanz, Green Chem., 2013, 15, 999–1005.
View Article Online
DOI: 10.1039/C6RA03106D
and Junta de Castilla y León (BU237U13) for financial support. 11 For the use of solid supported reagents in synthesis see: (a)
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