TMDS-Pd/C: A convenient system for the reduction of acetals to ethers

Article abstract of DOI:10.1016/j.tetlet.2011.01.038

A simple and practical procedure for the reduction of acetals to ethers is described. It is based on the use of a 1,1,3,3-tetramethyldisiloxane (TMDS)-Pd/C system in the presence of a Br?nsted acid as the co-catalyst. The reaction occurs under mild conditions and ethers are obtained in high yields.

Full text of DOI:10.1016/j.tetlet.2011.01.038

Tetrahedron Letters 52 (2011) 1281–1283
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Tetrahedron Letters
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TMDS–Pd/C: a convenient system for the reduction of acetals to ethers
Yan Shi a,b, Wissam Dayoub b, Guo-Rong Chen a, , Marc Lemaire b,
⇑
⇑
a Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, PR China
b Laboratoire de Catalyse et Synthèse Organique, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS UMR5246, Université Lyon 1, Bâtiment Curien-CPE,
3° étage, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and practical procedure for the reduction of acetals to ethers is described. It is based on the use
of a 1,1,3,3-tetramethyldisiloxane (TMDS)–Pd/C system in the presence of a Brønsted acid as the co-cat-
alyst. The reaction occurs under mild conditions and ethers are obtained in high yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 14 September 2010
Revised 7 January 2011
Accepted 10 January 2011
Available online 18 January 2011
Keywords:
1,1,3,3-Tetramethyldisiloxane (TMDS)
Pd/C
Reduction
Acetal
Reduction of C–O bond of acetals is a valuable method for the
straightforward synthesis of ethers. It is widely used not only as a
deprotecting strategy but also as a strategy for constructing build-
ing blocks in carbohydrate chemistry.1 Since Doukas and Fontaine
reduced acetals using LiAlH4 in the presence of HCl,2 numerous
other catalytic systems have been developed with different hydride
sources including, LiAlH4, NaH,3 DIBAL-H,4 NaBH3CN,5 BH3,6 Et3-
SiH,7 and PhSiH3.8 Among these hydride sources, silane derivatives
have emerged as attractive potent reducing reagents since some of
them are stable to air and moisture, easy to handle, and readily
available. However, most of the other methods suffer from serious
drawbacks such as incompatibility with sensitive functionalities,
and the need for a careful control of the reaction conditions as well
as the use of rigorously dry reagents and solvents.7a Thus, in the lit-
erature, different silane systems have been developed; Et3SiH–TFA,
Et3SiH–TfOH, Et3SiH–PhBCl2, Et3SiH–EtAlCl2, Et3SiH–BF3ÁEt2O. All of
these systems combine the alkyl-silane with stoichiometric
amount or excess of acid and the reduction reaction of acetals is
performed at low temperatures.7 To the best of our knowledge, only
one publication reported the reduction of acetals using a silane in
the presence of catalytic amount of metal complex.8a
Hydrosiloxane derivatives would constitute attractive promising
reducing agents that are, as the silanes, stable to air and mois-
ture.10 Moreover, when used, hydrosiloxanes give rise to polysilox-
anes as byproducts which is innocuous.11 In addition, when TMDS
is used a linear polymer easy to separate from the reaction medium
is generated. For several years now, our laboratory has been
exploring the potentialities of hydrosiloxane derivatives and their
use as substitutes to silanes in various reduction reactions. In fact,
we have already successfully developed and reported the reduction
of phosphine oxides to phosphines,12 nitriles to amines,13 and
amides to aldehydes,14 using the shortest chain polymer, the
1,1,3,3-tetramethyldisiloxane (TMDS) activated by titanium (IV)
isopropoxide. We also reported the reduction of nitro compounds
to amines activated by iron (III).15 Herein, we describe the use of
a new reducing system composed of TMDS as the solvent and
source of hydride, Pd/C as the catalyst, and camphorsulfonic acid
as the co-catalyst, for the reduction of acetals to ethers.
We began our investigation with the reduction of 2-phenethyl-
1,3-dioxane 1a that we chose as a model molecule following
Scheme 1. This molecule was synthesized in one step starting
from the commercially available 3-phenylpropanal and 1,3-
dihydroxypropane.
Although silane derivatives have many advantages as hydride
sources they are also known to generate, under certain conditions,
highly pyrophoric and toxic gas.9 Therefore, more convenient alter-
natives, that is, the use of new hydride sources must be explored.
The first experiment was conducted using a ruthenium metal
complex [RuCl2(PPh3)3] as the catalyst and TMDS as the hydride
O
metal catalyst
O
OH
O
siloxane
⇑
Corresponding authors. Tel.: +86 216 425 301 6;fax: +86 216 425 275 8 (G.R.C.);
tel.: +33 472 314 07; fax: +33 472 314 08 (M.L.).
E-mail addresses: mrs_guorongchen@ecust.edu.cn (G.-R. Chen), marc.lemaire@
univ-lyon1.fr (M. Lemaire).
1a
1b
Scheme 1. Acetal reduction.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.038

1282
Y. Shi et al. / Tetrahedron Letters 52 (2011) 1281–1283
Table 1
donor. Unfortunately, in this case, no reaction was observed after
Reduction of acetals with different TMDS-catalyst systems
24 h at 60 °C. This is probably due to the TMDS lack of reactivity.
Indeed, hydrosiloxane compounds are not sufficiently potent hy-
dride sources themselves and require activation. Therefore, TMDS
activated by titanium (IV) isopropoxide (Ti(OiPr)4) was then tried
for the reduction of 2-phenethyl-1,3-dioxane (1a). It should be
noted that this TMDS–Ti(OiPr)4 system has already been used in
our laboratory to reduce various nitriles and amides. In this case
too, no reaction had occurred (Table 1, entry 1). However, when
15 mol % of PdCl2 and 5 equiv of TMDS were employed, 29% of
the starting material was converted into the corresponding ether
1b (Table 1, entry 2). With 2.5 mol % of Pd/C and 2 equiv of TMDS,
75% of acetal 1a was converted into the corresponding ether 1b
after 48 h at 60 °C (Table 1, entry 4). After acidic work-up, and sol-
vent extraction, ether 1b could be obtained in 72% yield (Table 1,
entry 3).
Si Si
H
O
H
O
O
metal catalyst
O
OH
O
S
1a
1b
OH
O
O
Entrya Siloxane
(equiv)
Metal catalyst
(mol %)
Conversionb of 1a Yieldb 1b
(%)
(%)
1
TMDS, 5
TMDS, 5
TMDS, 2
Ti(OiPr)4, 100
PdCl2, 15
Pd/C, 2.5
0
41
75
0
29
72
2
3c
a
b
c
General conditions: 60 °C, 24 h.
Determined by 1H NMR based on starting material 1a.
Reaction time = 48 h. In this case, 53% of conversion was estimated by 1H NMR
after 24 h of reaction.
Although the best results were obtained using reasonable quan-
tities of Pd/C and TMDS (2.5 mol % Pd/C and 2 equiv TMDS), further
efforts were engaged to decrease these quantities while optimizing
the reaction conditions and testing new catalysts as well as new
hydride sources. The idea was to activate acetal 1a by the use of
a Brønsted acid, that is, camphorsulfonic acid (CSA) which would
enable us to decrease the amount of catalyst and/or the hydride
source. In fact, very recently, our group reported the synthesis of
glycerol mono-ethers (GME) by reductive alkylation of alcohols
and using Pd/C as the catalyst and camphorsulfonic acid as the
co-catalyst under hydrogen pressure.16 In this process the use of
CSA as the co-catalyst gave the best yields. In addition Bethmont
et al. reported the synthesis of ethers from aldehydes and linear
alcohols under hydrogen pressure. They showed that the acid func-
tion promotes ether formation from the ketal.17
Table 2
Reduction of acetals in the presence of camphorsulfonic acid
Entrya Siloxane
(equiv)
Metal catalyst
(mol %)
CSA
(wt %)
Conversionb of Yieldb
1a (%)
1b (%)
1
2
3
TMDS, 5
TMDS, 5
PMHS, 12
Pd/C, 1
Ru/C, 1
Pd/C, 1
5
5
5
47
12
0
46
9
0
a
General conditions: 60 °C, 24 h.
Determined by 1H NMR based on starting material 1a.
b
Table 3
Effect of different factorsa
Entry TMDS
(equiv)
Pd/C
CSA
Time
(h)
Conversionb of Yieldb1b
With 1 mol % of Pd/C, 5 equiv of TMDS, and 5 wt % of CSA, 47%
acetal 1a were converted after 24 h at 60 °C (Table 2, entry 1). After
acidic work-up, ether 1b could be obtained in 46% yield (Table 2,
entry 1). Under the same reaction conditions, but replacing Pd/C
by Ru/C catalyst, 9% of ether 1b was detected (Table 2, entry 2).
Surprisingly, when polymethylhydrosiloxane (PMHS) was used as
(mol %)
(wt %)
1a (%)
(%)
1
2
3
5
2
3
5
1
1
5
5
30
15
24
24
100
39
>99
27
91
90
a
General condition: 60 °C.
Determined by 1H NMR based on starting material 1a.
b
Table 4
Reduction of acetals to ethers under the optimized conditionsa
Entry
1
Acetal
Product
Conversionb (%)
100
Yieldb (%)
>99
O
O
2b
2a
O
OH
O
3b
4b
2c
3
100
100
95
87
3a
4a
5a
O
OH
OH
O
O
O
O
O
O
OH
OH
OH
4c
5
90
63
5b
O
OH
O
O
6a
HO
100
94d
6bHO
O
O
6c
HO
O
O
OH
HO
OH
O
7b
7ae
HO
6
87
87f
OH
7C
HO
O
HO
O
O
a
b
c
d
e
f
General conditions: 3 equiv TMDS, 1 mol % Pd/C, 30 wt % CSA, 60 °C, 24 h.
Detemined by 1H NMR based on starting materials.
10 wt % CSA.
Ratio between two products: 6b/6c = 6:5.
As detected by gas chromatography the ratio between six-membered ring acetals and five-membered ring acetals is 1:1.
Ratio between the two products: 7b/7c = 7:3.

Y. Shi et al. / Tetrahedron Letters 52 (2011) 1281–1283
1283
a hydride source under the same conditions as described above, no
References and notes
reaction had occurred (Table 2, entry 3). That might be due to the
lack of accessibility of the PMHS active sites because of the absence
of solvent and therefore of a good stirring. From these preliminary
results, we concluded that Pd/C is the best for the reduction reac-
tion and that the use of CSA as the co-catalyst is important for
decreasing the catalyst quantity.
In order to optimize the reaction conditions, we repeated the
reduction of acetal 1a with various amounts of TMDS, Pd/C and
CSA. As shown in Table 3, the best result for the reduction of acetal
1a was obtained with 5 equiv of TMDS, 5 mol % of Pd/C and 5 wt % of
CSA at 60 °C for 15 h. Under these conditions, ether 1b could be ob-
tained in quantitative yield (Table 3, entry 1). When decreasing the
quantities of TMDS (2 equiv) and Pd/C (1 mol %), lower yields were
detected when performing the reaction under the same conditions
as described for entry 1 in terms of temperature and CSA amount.
In this case, ether 1b was detected in 27% yield (Table 3, entry 2).
A better result could be obtained when 30 wt % of CSA were used
even with only 1 mol % of Pd/C. In this case ether 1b was detected
in 90% yield as estimated by 1H NMR (Table 3, entry 3).
From these results, we adopted the following conditions as the
optimized ones, for the rest of our investigations: 3 equiv TMDS,
1 mol % Pd/C, 30 wt %, 60 °C, 24 h.17 In order to test the versatility
of our approach we finally applied these conditions for the reduc-
tion of different acetals (Table 4). All linear and aromatic acetals
were reduced with good conversion rates. Thus the corresponding
ethers were obtained in high yields (Table 4, entries 1–6). It should
be noted that benzaldehyde acetals (3a, 5a) are more active than
other acetals, since only 10 wt % CSA were sufficient to reach good
conversion rates. Although all ethers were synthesized in good
yields, the selectivity of the reaction for glycerol derivatives re-
mained low between primary and secondary ethers (Table 4, en-
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tries
5 and 6). This drawback renders this method less
competitive than the one that uses H2.16,18 However, this method
would constitute a good alternative to the reductive alkylation
method since it avoids the reduction of the aromatic rings that
can occur when using H2.19
18. General procedure for reduction of acetals: In a screw-caped vial, 1 mmol acetal,
1 mol % Pd/C and 30 wt % CSA were introduced at room temperature under
Argon atmosphere. Then 0.54 ml (3 equiv) of TMDS was added and mixture
was stirred at 60 °C. After 24 h at this temperature, the reaction medium was
diluted with 5 ml of dichloromethane and filtered over Celite. The filtrate was
then mixed with 3 equiv HCl and the resulting solution stirred for 1 h at room
temperature. The organic layer was separated and the organic solvents
evaporated in vacuo. The resulting crude was finally analyzed by 1H NMR
with no further purification.
In summary, we reported in this Letter a convenient and
straightforward method to reduce acetals to ethers in high yields
and under mild conditions. This method uses TMDS as the hydride
source with catalytic quantity of Pd/C as the catalyst in the pres-
ence of camphorsulfonic acid as a promoter. Nevertheless, this
method has also its limitations in terms of chemoselectivity.
19. (a) Shi, Y.; Dayoub, W.; Favre-Réguillon, A.; Chen, G. R.; Lemaire, M. Tetrahedron
Lett. 2009, 50, 6891–6893; (b) Tulchinsky, M. L.; Briggs, J. R.; Rand, C. L. U.S.
Patent US 2010/0048940 A1, 2010.
Acknowledgments
The financial support allocated in the frame of the MIRA collab-
orative program between Région Rhône-Alpes and Shanghai City
(PR China) is warmly thanked. China Scholarship Council is also
gratefully acknowledged for Ph.D. grants to YS.