A novel method for the reduction of sulfoxides and pyridine N-oxides with the system silane/MoO2Cl2

Article abstract of DOI:10.1016/j.tet.2006.07.077

A novel method for the reduction of sulfoxides and pyridine N-oxides using a silane and a catalytic amount of MoO₂Cl₂ in excellent yields and with a wide functional group tolerance is reported. A green protocol for this reaction was

Full text of DOI:10.1016/j.tet.2006.07.077

Tetrahedron 62 (2006) 9650–9654
A novel method for the reduction of sulfoxides and pyridine
N-oxides with the system silane/MoO2Cl2
*
Ana C. Fernandes and Carlos C. Romao
~
´
Instituto de Tecnologia Quımica e Biologica da Universidade Nova de Lisboa, Quinta do Marques, EAN, Apt 127,
ꢀ
^
2781-901 Oeiras, Portugal
Received 12 June 2006; revised 18 July 2006; accepted 25 July 2006
Available online 17 August 2006
Abstract—A novel method for the reduction of sulfoxides and pyridine N-oxides using a silane and a catalytic amount of MoO2Cl2 in
excellent yields and with a wide functional group tolerance is reported. A green protocol for this reaction was developed in water with the
air-stable catalytic system PMHS/MoO2Cl2(H2O)2.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Several studies have shown that Mo(VI)O2 complexes cata-
lyze the oxygen atom transfer reaction from the sulfoxides or
aromatic N-oxides to a phosphine, yielding the correspond-
ing sulfides or amines and the oxidized phosphine.5,9,18–20
The reduction (or deoxygenation) of sulfoxides and amine
N-oxides to the corresponding sulfides and amines is an
important organic and biological reaction. Over the years, sev-
eral methods have been developed to reduce sulfoxides1–8
and amine N-oxides,9–15 however, many of these trans-
formations are limited by side reactions, low yields, lack
of chemoselectivity or harsh conditions. For example, the
use of hydrogen halides is somewhat restricted with acid-
sensitive substrates, the reductions with the strong hydride
systems LiAlH4–TiCl4 and NaBH4–CoCl2 are incompatible
with several functional groups, and the reactions with phos-
phorus reagents, in most cases, require elevated temperature
and/or prolonged reaction times.
Recently, we have demonstrated that the high valent molyb-
denum-dioxo complex, MoO2Cl2, is an effective catalyst for
organic reductions, such as hydrosilylation of aldehydes and
ketones,21 and reduction of imines22 and esters.23 These
results confirm the new role of oxo complexes in catalytic re-
ductions, which unexpectedly adds to their well-established
abilities to catalyze oxygen-transfer reactions to olefins,
phosphines, and sulfites.
During the course of our studies on the reaction of esters
with the system PhSiH3/MoO2Cl2, we observed the reduc-
tion of both sulfinyl and carboxyl groups of methyl(phenyl-
sulfinyl)acetate, giving the 2-(phenylthio)ethanol in 75%
yield (Scheme 1). This result suggested the extension of
the system silane/MoO2Cl2 for the reduction of other sulf-
oxides. In this work, we investigated the deoxygenation of
sulfoxides and pyridine N-oxides using the catalysts
MoO2Cl2 and MoO2Cl2(H2O)2 in the presence of a silane
in organic and aqueous solvents.
Among the variety of metal complexes that have been used
as catalysts for the deoxygenation of sulfoxides and amine
N-oxides, molybdenum complexes have attracted consider-
able interest. This metal is found in a class of enzymes
that are commonly referred to as mononuclear molybdo-
enzymes or oxotransferases, such as dimethyl sulfoxide
reductases, that catalyze oxygen atom transfer to or from a
physiological donor/acceptor.16,17
Scheme 1.
Keywords: Reduction; Sulfoxides; Pyridine N-oxides; Dioxomolybdenum dichloride.
* Corresponding author. Tel.: +351 214469758; fax: +351 214411277; e-mail: anacris@itqb.unl.pt
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.077

A. C. Fernandes, C. C. Roma~o / Tetrahedron 62 (2006) 9650–9654
9651
a
Table 2. Reduction of sulfoxide with the system PhSiH3/MoO2Cl2
2. Results and discussion
Entry
1
Sulfoxide
Sulfide
Time Yieldb
To optimize the reaction conditions, we first studied the re-
duction of methyl phenyl sulfoxide 1 with several silanes
and solvents as summarized in Table 1. This sulfoxide was
completely reduced with phenylsilane (PhSiH3) in the pres-
ence of 5 mol % of MoO2Cl2 in refluxing tetrahydrofuran
after 2 h (entry 1). At room temperature, the reaction re-
quired significantly longer reaction times (20 h) and sulfide
2 was obtained in only 66% conversion (entry 2).
(h)
(%)
2
97
2
2
97
Table 1. Reduction of methyl phenyl sulfoxide 1 catalyzed by MoO2Cl2
3
4
20
7
96
92
Entry Silanea
Solvent
Temperature Time Conversionb
(ꢀC)
(h)
(%)
5
6
2
96
1
2
3
4
5
6
7
8
9
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PMHS
DMPHS THF
Et3SiH
Ph3SiH
THF
THF
Toluene 110
CH2Cl2
CH3CN
THF
67
rt
2
20
2
2
2
20
24
24
48
100
66
100
95
21
100
65
35
40
80
67
67
67
67
2.5 96
THF
THF
No reaction
7
2
92
a
The reactions were carried out with 100 mol % of PhSiH3, DMPHS,
Et3SiH or Ph3SiH and with 0.3 mol % of PMHS.
Conversion was determined by 1H NMR.
b
a
All reactions were carried out in refluxing THF with 1.0 mmol of sulf-
oxide, 1.0 mmol of PhSiH3, using 5 mol % of MoO2Cl2.
Isolated yield.
b
To evaluate the effect of solvents, the reduction of sulfoxide
1 was carried out in tetrahydrofuran, toluene, dichloro-
methane, and acetonitrile. Sulfide 2 was obtained in 100%
conversion in THF and toluene (entries 1 and 3), in 95% con-
version in dichloromethane (entry 4), but in acetonitrile it
was obtained in only 21% conversion (entry 5).
Attempted reduction of phenyl sulfone and 4-fluorophenyl
methyl sulfone resulted in only the recovery of starting
material.
The reduction of sulfoxides was also carried out with the
complex MoO2Cl2(H2O)2, which was easily prepared by ex-
traction from a hydrochloric acid solution of Na2MoO4 with
diethyl ether.19
This reaction was also investigated with several silanes.
With the polymethylhydrosiloxane (PMHS), sulfoxide 1
was completely reduced (entry 6) and with dimethylphenyl-
silane (DMPHS) and triethylsilane (Et3SiH), sulfide 2 was
obtained in 65% and 35% conversion, respectively (entries
7 and 8). No catalysis was observed with the triphenylsilane
(entry 9).
The catalytic activity of MoO2Cl2(H2O)2 was studied with
the silanes PhSiH3 and PMHS. The reduction of the sub-
strates, methyl phenyl sulfoxide, phenyl sulfoxide, and
benzyl sulfoxide with the system PhSiH3/MoO2Cl2(H2O)2
(5 mol %) in refluxing THF, afforded the corresponding sul-
fides in 95%, 96%, and 95%, respectively (Table 3, entries 1,
4, and 7). These yields and the reaction times are comparable
to those obtained with the system PhSiH3/MoO2Cl2 (Table 2,
entries 1–3).
To explore the scope of this catalytic reaction, the reduction
of a variety of sulfoxides with the system PhSiH3/MoO2Cl2
(5 mol %), in refluxing tetrahydrofuran, was investigated
(Table 2). As shown in Table 2, the sulfoxides were reduced
in excellent yields. This catalytic reaction is suitable for the
deoxygenation of aromatic and aliphatic sulfoxides, in par-
ticular, for the reduction of benzyl sulfoxide (entry 3), since
several methods fail completely with this substrate or only
provide poor yields of benzyl sulfide. This reaction is also
compatible with other functional groups such as halo,
carboxyl, and vinyl (entries 5–7). The chemoselective re-
duction of methyl(phenylsulfinyl)acetate, in 97% yield
(Table 2, entry 6), was possible in THF, contrary to the
reduction of both sulfinyl and carboxyl groups observed in
refluxing toluene (Scheme 1) and reported in our previous
work.23
The reaction of sulfoxides with PMHS in the presence of
5 mol % of MoO2Cl2(H2O)2, in refluxing methanol, was car-
ried out in air and produced the sulfides in excellent yields
(Table 3). The chemoselective reduction of methyl(phenyl-
sulfinyl)acetate was also possible in this reaction conditions
in good yield (entry 12).
Finally, we tried the reduction of sulfoxides with the system
PMHS/MoO2Cl2(H2O)2 in water at 80 ꢀC (Table 3). This
green system reduced the methyl phenyl sulfoxide in 52%

9652
A. C. Fernandes, C. C. Roma~o / Tetrahedron 62 (2006) 9650–9654
a
Table 3. Reduction of sulfoxides catalyzed by MoO2Cl2(H2O)2
it is easily handled, stable to air and water, inexpensive,
and non-toxic. However, the reductions with PMHS required
longer reaction times.
Entry
Sulfoxide
Silane
Solventb
Time Yield
(h)
(%)c
1
2
3
PhSiH3 THF
PMHS Methanol
1.5
2
20
95
95
52
The easy and inexpensive preparation of ether solution of
MoO2Cl2(H2O)2 and its air stability make this catalyst an
excellent alternative to MoO2Cl2, which has a difficult prep-
aration and a great air instability.
PMHS H2Od
4
5
6
PhSiH3 THF 2
PMHS Methanol 20
20
96
96
92
Other important advantage of the system PMHS/
MoO2Cl2(H2O)2 is related to the environmental concerns
and increased restrictions on the use of hazardous organic
solvents. With this system, the reduction, in water, was pos-
sible for some sulfoxides in moderate to good yields.
PMHS H2Od
7
8
PhSiH3 THF
20
95
95
PMHS Methanol 20
PMHS Methanol 20
20
9
10
95
50
PMHS H2Od
In this work, we also performed a brief investigation of the
deoxygenation of pyridine N-oxides with the silanes PhSiH3
and PMHS catalyzed by MoO2Cl2 and MoO2Cl2(H2O)2
(Table 4). As shown in Table 4, the catalytic systems
PhSiH3/MoO2Cl2, PhSiH3/MoO2Cl2(H2O)2, and PMHS/
MoO2Cl2(H2O)2 reduced the 3- and 4-methylpyridine
N-oxides in good yields in organic solvents. As observed
in the reduction of sulfoxides, the reaction with PMHS
required longer reaction times than with PhSiH3. Due
to the wide functional group tolerance verified in the reduc-
tion of sulfoxides, we believe that this novel method can be
suitable for the deoxygenation of other pyridine N-oxides.
Unfortunately, the pyridine N-oxides were not reduced in
water with the system PMHS/MoO2Cl2(H2O)2.
11
PMHS Methanol 20
PMHS Methanol 20
94
90
12
a
All reactions were carried out with 1.0 mmol of sulfoxide, 100 mol % of
PhSiH3 or 0.3 mol % of PMHS, using 5 mol % of MoO2Cl2(H2O)2.
Reflux temperature.
Isolated yield.
The reaction was carried out at 80 ꢀC.
b
c
d
In order to verify that MoO2Cl2 plays an active role in the de-
oxygenation process, we carried out the reaction of sulfoxide
1 with an excess of phenylsilane without catalyst and the
reaction of sulfoxide 1 with 5 mol % of MoO2Cl2 without
phenylsilane in refluxing THF during 2 h. In both cases, sulf-
oxide 1 was not reduced. These results suggest that MoO2Cl2
catalyzes the reaction by activation of the silane, producing
a hydride species (Mo-H).
yield, the phenyl sulfoxide in 92% yield, and the 4-chloro-
phenyl sulfoxide in 50% yield (Table 3, entries 3, 6, and
10). The benzyl sulfoxide and butyl sulfoxide did not react
in water.
The analysis of the 1H NMR spectrum of the reaction mix-
ture obtained in the reduction of the phenyl vinyl sulfoxide
with the system PMHS/MoO2Cl2(H2O)2 in methanol or in
water showed that the double bond was affected.
In the reaction of the complex MoO2Cl2(Bz2SO)2, prepared
by the addition of benzyl sulfoxide to the ether solution of
MoO2Cl2(H2O)2,19 with 1 equiv of the phenylsilane in
refluxing THF was observed the reduction of the sulfoxide,
The system PMHS/MoO2Cl2(H2O)2 proved to be very effi-
cient for the reduction of sulfoxides in organic solvents.
The use of PMHS is more attractive than PhSiH3 because
a
Table 4. Deoxygenation of pyridine N-oxides catalyzed by MoO2Cl2 or MoO2Cl2(H2O)2
Entry
R
Silane
Catalyst
Solventb
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
4-CH3
PhSiH3
PhSiH3
PMHS
PMHS
PhSiH3
PhSiH3
PMHS
PMHS
MoO2Cl2
THF
THF
3
3
20
20
3
3
20
20
85
84
MoO2Cl2(H2O)2
MoO2Cl2(H2O)2
MoO2Cl2(H2O)2
MoO2Cl2
MoO2Cl2(H2O)2
MoO2Cl2(H2O)2
MoO2Cl2(H2O)2
Methanol
86
No reaction
85
83
85
No reaction
H2Od
THF
3-CH3
THF
Methanol
H2Od
a
All reactions were carried out with 1.0 mmol of pyridine N-oxide, 100 mol % of PhSiH3 or 0.3 mol % of PMHS using 5 mol % of catalyst.
Reflux temperature.
Isolated yield.
The reaction was carried out at 80 ꢀC.
b
c
d

A. C. Fernandes, C. C. Roma~o / Tetrahedron 62 (2006) 9650–9654
9653
Scheme 2.
giving the benzyl sulfide (Scheme 2). A similar result was
obtained when the benzyl sulfoxide was reduced with the
system PhSiH3/MoO2Cl2(H2O)2 (Table 3, entry 7). This
result suggests the initial activation of the sulfoxide by the
oxygen coordination to the molybdenum, yielding the com-
plex MoO2Cl2(sulfoxide)2. This complex weakens the S–O
bond and renders the sulfur atom more susceptible to the
reduction. After the addition of the silane, the complex
MoO2Cl2(sulfoxide)2 is reduced with elimination of the
sulfide and a siloxane.
4.2. General procedures
4.2.1. General procedure for the reduction of sulfoxides
and pyridine N-oxides with the system PhSiH3/MoO2Cl2.
To a solution of MoO2Cl2 (5 mol %) in dry THF (5 ml) was
added the sulfoxide or the pyridine N-oxide (1.0 mmol) and
PhSiH3 (1.0 mmol) under nitrogen atmosphere. The reaction
mixture was stirred at reflux temperature (the reaction times
are indicated in Tables 2 and 4) and monitored periodically
by TLC. Upon completion, the reaction mixture was evapo-
rated and purified by silica gel column chromatography with
the appropriate mixture of n-hexane and ethyl acetate to
afford the sulfides and pyridines, which are all known
compounds.
3. Conclusion
In summary, we have developed a novel method for the
reduction of sulfoxide and pyridine N-oxides to the corre-
sponding sulfides and pyridines using the silane PhSiH3 in
the presence of a catalytic amount of MoO2Cl2 in excellent
yields and with a wide functional group tolerance. This cat-
alytic system can be a useful alternative to the traditional
methods for the reduction of sulfoxides, especially, in natu-
ral products and pharmaceutical synthesis, which require
mild conditions, selectivity, and functional group tolerance.
4.2.2. Green protocol for the reduction of sulfoxides with
the system PMHS/MoO2Cl2(H2O)2. To a solution of the
sulfoxide (1.0 mmol) in water (5 ml) or in methanol (3 ml)
were added the ether solution of MoO2Cl2(H2O)2 (5 mol %)
and PMHS (0.3 mol %). The reaction mixture was stirred at
reflux temperature in methanol or at 80 ꢀC in water (the reac-
tion times are indicated in Table 3). Upon completion, the re-
action mixture was extracted with diethyl ether (3ꢁ20 ml),
dried over sodium sulfate, evaporated, and purified by silica
gel column chromatography with the appropriate mixture of
n-hexane and ethyl acetate.
A green protocol for the reduction of sulfoxides was also de-
veloped with the system PMHS/MoO2Cl2(H2O)2 in water or
methanol. This novel, air-stable catalyst system reduced
sulfoxides in moderate to excellent yields. The simplicity
and environmental-friendly conditions of this protocol
make this novel method suitable for large-scale reductions.
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~