Catalytic reductive cleavage of methyl α-d-glucoside acetals to ethers using hydrogen as a clean reductant

Article abstract of DOI:10.1039/c4ra09350j

The palladium-catalysed reductive cleavage of methyl glucoside acetals has been studied using hydrogen as a clean reducing agent. The reaction proceeds at 120 °C in cyclopentyl methyl ether (CPME) without acid co-catalyst. Under these conditions, the corresponding methyl glucoside monoethers were obtained with poor to good isolated yields (37-81%) and high selectivities (86-99%). This journal is

Full text of DOI:10.1039/c4ra09350j

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Catalytic reductive cleavage of methyl a-D-
glucoside acetals to ethers using hydrogen as a
Cite this: RSC Adv., 2014, 4, 50653
clean reductant†
Charlotte Gozlan,ab Romain Lafon,a Nicolas Duguet,a Andreas Redlb
a
*
and Marc Lemaire
Received 27th August 2014
Accepted 1st October 2014
The palladium-catalysed reductive cleavage of methyl glucoside acetals has been studied using hydrogen
as a clean reducing agent. The reaction proceeds at 120 ꢀC in cyclopentyl methyl ether (CPME) without acid
co-catalyst. Under these conditions, the corresponding methyl glucoside monoethers were obtained with
poor to good isolated yields (37–81%) and high selectivities (86–99%).
DOI: 10.1039/c4ra09350j
www.rsc.org/advances
retention by the bacteria cell. On the downside, even if carbo-
hydrate alkyl ethers present adequate features (a sugar moiety
Introduction
and a linear chain) for biodegradability, they could lead to
higher bioaccumulation than their ester derivatives.
Over the last century, environmental issues and ecological
impact awareness have increased the necessity to use nontoxic
and biodegradable surfactants.1 In this context, carbohydrate-
derived surfactants have recently been gaining much attention
due to their innocuous nature and the fact that they could be
obtained from renewable resources in bulk quantities.2,3
Sucrose esters,4 alkyl glucosides5 and polyglucosides (APGs)6
and sorbitan esters7,8 are representatives of these bio-based
surfactants that are commercially produced.9 For instance, they
are employed in many applications like emulsiers in the food
industry and in polymerization, detergents, cosmetics and
cleaning products. APGs are quite stable under neutral and
basic conditions and usually exhibit high hydrophilic–lipo-
philic balances (HLB's) which make them perfectly adequate for
detergent applications. For other applications requiring lower
HLB's such as emulsiers, carbohydrate fatty acid esters are
usually preferred. However, these surfactants are vulnerable
under acidic and basic conditions. As a result, the pH-window
of their optimal utilization is relatively narrow. Carbohydrate
alkyl ethers have been proposed as alternatives – with similar
HLB's – since ethers exhibit higher stability towards hydrolysis
and are not affected by esterases. For example, methyl 6-O-
dodecanyl-a-D-glucopyranoside has an enhanced antimicrobial
activity compared to the corresponding ester against Staphylo-
coccus aureus10,11 and Listeria spp.,12 probably due to its greater
The chemical syntheses of sugar ethers are notoriously
laborious and most approaches rely on multi-step preparation
including protection/deprotection steps due to the poly-
hydroxylated nature of the carbohydrates. The use of such
strategies results in a very high production cost which is not
acceptable for widespread industrial applications. Moreover,
sugar ethers are usually prepared using polar expensive and/or
toxic solvents such as dimethylsulfoxide (DMSO), dime-
thylformamide (DMF) and dimethylacetamide (DMA). In order
to install the ether functionality, traditional methods usually
rely on the Williamson synthesis using a strong base and an
alkyl halide or pseudo-halide.13 For obvious selectivity reasons,
this protocol requires multi-step protection/deprotection strat-
egies, resulting in a low atom-economy and the production of
large quantities of waste. When carrying out using prior
protections, the reaction affords low selectivity and moderate
yields. In carbohydrate chemistry, the direct functionalization
of individual hydroxyl group by an alkyl chain is very attractive
but also challenging due to the great difference of polarity
between the sugar and the aliphatic moiety. However, some
interesting synthetic routes have been reported in the literature.
Queneau et al. have studied the catalytic etherication of
sucrose with a fatty terminal epoxide using various tertiary
amines or a strongly basic anion-exchange resin as catalysts.14
The reaction requires an excess of sucrose and the use of DMSO
as solvent. These conditions afforded mixtures of sugar mono-
ethers with moderate yields and the formation of diethers could
not be avoided. Mortreux et al. have reported a sucrose-buta-
diene telomerization reaction using a palladium catalyst in
water.15 However, the scope is limited to the access to mono-
and dioctadienyl ethers. Moreover, the use of expensive
homogeneous catalysts makes difficult the industrialization of
a
`
Laboratoire de Catalyse Synthese et Environnement (CASYEN), Institut de Chimie et
´
´
´
Biochimie Moleculaires et Supramoleculaires (ICBMS), CNRS, UMR-5246, Universite
ˆ
Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, Bat. Curien/CPE,
69622, Villeurbanne, France. E-mail: marc.lemaire.chimie@univ-lyon1.fr; Fax: +33-
472-43-14-08; Tel: +33-472-43-14-07
bTereos Syral SAS, Z.I et Portuaire B.P.32, 67390 Marckolsheim, France. E-mail:
andreas.redl@tereos.com; Tel: +33-388-58-16-15
† Electronic supplementary information (ESI) available: GC method, general
procedures and characterization data of products. See DOI: 10.1039/c4ra09350j
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this methodology. The main problem of these methods is not protocol was also extended to the preparation of sugar ethers
the regioselectivity of the substitution (that is not necessarily from the corresponding sugar acetals.27 Even if hydrosiloxanes
required for a commercial surfactant) but the possibility to form are safer to use, they are expensive and the work-up could be
polysubstituted products. In fact, their presence could difficult especially on the large scale. The reductive cleavage of
dramatically change the physicochemical properties as they acetals to ethers could also be carried out by catalytic hydro-
could exhibit very different polarities (mono-, di-, and poly- genolysis.20b,28–31 In carbohydrate chemistry, the hydrogenolysis
ethers) and HLB's.
of acetals is mainly used for protection purposes and the
For several years, our group has been interested in devel- resulting ethers should be easily removed at the end of the
oping green methodologies for the catalytic direct reductive N- reaction sequence. That is the reason why, most reported
or O-alkylation of weak nucleophiles such as anilines,16 procedures described the hydrogenolysis of benzylidene acetals.
amides,17 ureas,18 alcohols19 and glycerol20 using hydrogen as a However, to the best of our knowledge, such methodologies
clean reducing agent. This method seemed particularly attrac- have never been described on sugar derivatives bearing long
tive for the alkylation of carbohydrates since no salts are alkyl chain acetals that are notoriously more stable and more
produced, water is obtained as the by-product and the atom difficult to reduce.
economy is usually very high. To the best of our knowledge, only
We now report here an efficient two-step procedure for the
one patent has described the direct reductive alkylation on preparation of methyl glucoside ethers from methyl glucoside
sugar derivatives to give the corresponding ethers. Indeed, through catalytic hydrogenolysis of the corresponding acetals.
Tulchinsky et al. have reported the alkylation of sorbitol using a By comparison with the direct reductive alkylation, this method
range of aldehydes to give sorbitan ethers upon dehydratation provides sugar monoethers with improved yields and higher
of sorbitol.21 However, we noticed a lack of reproducibility when selectivities.
repeating this protocol on sorbitol but also on other substrates
such as methyl glucoside, and the results obtained were not
satisfying (<5% GC yields). This result corroborates well with
our own ndings. Indeed, the yield of methyl glucoside ethers
were very low when carrying out the direct reductive alkylation
of methyl glucoside with a range of aldehydes under our
Results and discussion
Preparation of methyl glucoside acetals
The preparation of methyl glucoside acetals 2a–e has been
carried out by acetalisation of unprotected methyl glucoside 1
using a range of linear alkyl aldehydes. For this purpose, we
previously optimized conditions [polyol (40 equiv.), aldehyde (1
equiv.), 5%-Pd/C (0.5 mol% in Pd) and CSA (10 wt%) under
have adapted our previously reported conditions27 in which
hydrogen atmosphere]. Consequently, we turned our attention
DMF and (1R)-10-camphorsulfonic acid (CSA) were used as
solvent and acid catalyst, respectively. Indeed, DMF has been
to the development of a two-step procedure involving the
preparation of methyl glucoside acetals and their subsequent
replaced by a less toxic solvent32 (tetrahydrofuran, THF) and
reductive cleavage to the corresponding ethers (Scheme 1).
CSA was substituted by an ion-exchange resin (Amberlyst-15).
Thus, methyl a-D-glucoside 1 (2 equiv.) was treated with one
equivalent of aldehyde in dry THF using Amberlyst-15 (20 wt%/
If the acetalisation of sugar or sugar derivatives is relatively
well documented, the reductive cleavage of acetals to ethers has
been, by far, less studied. It is usually carried out using
sodium,22 aluminum,23 or boron hydrides,24 and hydrosilanes.25
Nevertheless, these hydride sources are very reactive towards air
and moisture and require safety precautions. Their hydrolysis
should be carefully performed and gives large quantities of
salts. In this context, we have recently developed a regioselective
cleavage of acetals using hydrosiloxanes such as tetrame-
thyldisiloxane (TMDS) with metal triates as catalysts.26 This
aldehyde) as a catalyst in the presence of Na2SO4 (1.5 equiv.)
(Fig. 1). Under these conditions, methyl glucoside acetals 2a–e
were obtained with poor to moderate yields (26–44%) aer
purication by column chromatography. It should be noted that
this improved procedure allowed the synthesis of these acetals
on a medium laboratory scale (up to 100 mmol).
Scheme 1 Synthesis of methyl glucoside monoethers 3 and 4 directly
from methyl glucoside 1 (top) and from a two-step procedure via an
acetal derivative 2 (bottom).
Fig. 1 Preparation of methyl 4,6-O-alkylidene-a-D-glucoside 2a–e.
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Optimization of the reductive cleavage of acetals
We have recently shown that glycerol acetals were formed as
intermediates in the direct reductive alkylation of glycerol with
aldehydes and could be converted to their corresponding ethers
with low to moderate yields in the presence of an acid co-cata-
lyst.20b Thus, the hydrogenolysis of methyl glucoside acetals was
rst investigated using these previously optimized conditions
and methyl 4,6-O-decanylidene-a-D-glucopyranoside 2d was
selected as a model substrate for the optimization of reaction
parameters.
Scheme 2 Potential routes to the formation of ethoxydecane by-
product.
corresponding methyl glucoside ethers 3d and 4d were formed
in a 80 : 20 ratio with 5% overall yield (Table 1, Entry 2). Further
decrease of the acid loading to 1.7 mol% led to the formation of
the desired ethers with 16% yield in a 69 : 31 ratio (Table 1,
Entry 3). These promising results prompted us to eliminate the
acid co-catalyst. Under these conditions, methyl glucoside
ethers 3d and 4d were obtained with an improved global yield of
32% (Table 1, Entry 4). On the downside, the regioselectivity of
the ring-opening was slightly altered and methyl 6-O-decylglu-
coside 3d was obtained as the major regioisomer in a 63 : 37
ratio. The inuence of the solvent was next probed.
Acid catalyst loading
Methyl 4,6-O-decanylidene-a-D-glucopyranoside 2d (0.1 M in dry
EtOH) was rst treated under 20 bar of hydrogen in the presence
of 5%-Pd/C (5 mol% in Pd) and camphorsulfonic acid (CSA, 5
mol%) as a co-catalyst. The reaction was performed at 120 ꢀC for
15 hours (Table 1). Under these conditions, sugar acetal 2d was
fully converted but no traces of the desired ethers 3d and/or 4d
was detected by GC aer derivatization33 of the crude reaction
mixture (Table 1, Entry 1).
However, the only product detected by GC and conrmed by
1H NMR was found to be ethoxydecane. The formation of this
product was probably resulting from the hydrolysis of the
starting material 2d to the corresponding methyl glucoside 1
Solvent screening
and decanal, following by its hydrogenation to decanol and In order to determine the best solvent for optimum yield and
subsequent etherication with EtOH under acidic conditions selectivity, a set of experiments was performed for the reduction
(Scheme 2, path a). Moreover, decanal could also undergo direct of acetal 2d using various polar protic, polar non-protic and
catalytic etherication with EtOH in the presence of hydrogen non-polar solvents (Table 2). First, methyl glucoside acetal 2d
and Pd/C. The presence of methyl glucoside 1 could also be (0.1 M) was reduced under hydrogen (20 bar) with 5%-Pd/C (5
explained by transacetalization of the starting material 2d with mol% in Pd) using dry MeOH as solvent. The reaction was
EtOH, leading to the formation of decanal diethylacetal and carried out at 120 ꢀC for 15 hours and gave a complete
ethoxydecane aer hydrogenolysis (Scheme 2, path b).
conversion of 2d (Table 2, Entry 1). Similarly to the result
We hypothesized that the acid co-catalyst accelerates the obtained in EtOH (Table 2, Entry 2), methyl glucoside ethers 3d
degradation of the acetal in the presence of traces of water. This and 4d were isolated with a low yield (9%) and methoxydecane
favours the formation of ethoxydecane, releasing one molecule was obtained as the major product. MeOH or EtOH was
t
of water and thus causing more hydrolysis of the starting replaced by a less nucleophilic alcohol such as BuOH in order
material. As a consequence, the reductive cleavage of acetal 2d to limit the formation of side products. Under these conditions,
was carried out using only 3.5 mol% of CSA and the the desired ethers were formed with an improved yield of 44%
Table 1 Influence of an acid co-catalyst on the hydrogenolysis of methyl 4,6-O-decylidene glucoside 2da
Entry
CSA (mol%)
Conv.b (2d, %)
Yieldc (3d + 4d, %)
Ratio (3d : 4d)c
1
2
3
4
5
100
100
99
0
5
16
32
—
3.5
1.7
0
80 : 20
69 : 31
63 : 37
100
a
Experimental conditions: methyl glucoside acetal 2d (0.33 g), 5%-Pd/C (5 mol% Pd), H2 (20 bar), dry EtOH (10 mL), 120 ꢀC, 15 h, stirring speed ¼
800 rpm. Conversions were determined by 1H NMR. Yields and ratio of 3d and 4d were determined by GC aer derivatization of the crude
b
c
reaction mixture.
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Table 2 Influence of the solvent in the hydrogenolysis of methyl 4,6-O-decylidene glucoside 2da
Yieldsc (%)
Selectivityc
Entry
Solvent
log P
Conv.b (%)
Ether 3d
Ether 4d
Ethers 3d + 4d
MeGlu 1
(6-ether 3d/4-ether 4d)
1
2
3
4
5
6
7
8
MeOH
EtOH
ꢁ0.77
ꢁ0.31
0.35
ꢁ0.18
0.94
0.46
1.20
1.4
98
100
89
14
94
69
87
83
83
60
65
9
20
22
0
18
22
19
37
44
32
27
0
12
22
5
16
21
23
21
26
19
30
9
32
44
5
34
43
42
58
70
51
57
2
—
31
0
9
8
11
20
6
9
5
n.d.
63 : 37
50 : 50
n.d.
53 : 47
51 : 49
45 : 55
64 : 36
63 : 37
62 : 38
47 : 53
tBuOH
TMP
MTBE
THF
2Me-THF
DBE
CPME
Heptane
Dodecane
9
10
11
1.59
4.66
6.82
a
Experimental conditions: methyl glucoside acetal 2d (0.33 g), 5%-Pd/C (5 mol% Pd), H2 (20 bar), dry solvent (10 mL), 120 ꢀC, 15 h, stirring speed ¼
800 rpm. Conversions were determined by 1H NMR. Yields and ratio of 3d and 4d were determined by GC aer derivatization of the crude
b
c
reaction mixture. TMP ¼ 1,2,3-trimethoxypropane, MTBE ¼ methyl-tert-butylether, DBE ¼ dibutylether, CPME ¼ cyclopentylmethylether.
but no selectivity in 3d or 4d was obtained (Table 2, Entry 3). We conversion (Table 2, Entry 9). It should be noted that CPME
next focused our attention on non-protic solvents with medium has been proposed as a safer alternative to other ether solvents
polarities such as ethereal solvents. The utilization of our home- due to its narrower explosibility range and greater resistance
made glycerol-based 1,2,3-trimethoxypropane34 (TMP) gave a to peroxide formation.35 Moreover, its high hydrophobicity,
ꢀ
low conversion of 2d (14%) and a very low yield of the desired limited miscibility in water (1.1 g per 100 g at 23 C) and low
ethers (5%) (Table 2, Entry 4). However, when the reaction was vaporization energy allow its use as a potential process solvent
performed in methyl-tert-butylether (MTBE), tetrahydrofuran that could be recovered and reused. In addition, CPME has a
(THF) or 2-methyltetrahydrofuran (2Me-THF), the conversion low toxicity and has been considered negative for genotoxicity
was much more satisfying (69–94%) and the best yield (43%) of and mutagenicity.36
ethers 3d and 4d was obtained using THF as solvent (Table 2,
Entries 5–7).
It should be noted that the formation of methyl glucoside 1
was signicantly reduced compared to the result obtained with
tert-butanol. Increasing the hydrophobic character of the
solvent had a positive effect on the reaction outcome. Indeed,
the reductive cleavage of acetal 2d gave the corresponding
ethers with 58% yield when the reaction was conducted in di-
Drying agent
As can be seen from this set of results (Table 2), the main
limitation of the product yield was due to the production of
methyl glucoside 1 from the hydrolysis of the starting material.
Considering that traces of water are relatively difficult to avoid,
methyl glucoside acetal 2d was pre-dried using MgSO4 as a
butylether (DBE) (Table 2, Entry 8). The best result was
dehydrating agent and submitted to the previously optimized
obtained using cyclopentylmethylether (CPME) as solvent.
conditions [2d (0.1 M in dry CPME), 20 bar H2, 5%-Pd/C (5
Under these conditions, the conversion of 2d reached 83% and
methyl decyl glucoside 3d and 4d were obtained with 70%
combined yield (Table 2, Entry 9). Interestingly, a moderate
63% selectivity was obtained for the 6-ether regioisomer 3d.
ꢀ
mol%), 120 C, 15 h]. Under these conditions, the conversion
was maintained (82%) and the global yield of 3d and 4d was
slightly improved to 72% (Scheme 3).
The use of non-polar solvents was also investigated. Using
heptane or dodecane, the conversion dropped to 60 and 65%
and ethers 3d and 4d were recovered with 51 and 57% yields,
respectively (Table 2, Entries 10–11). These results could be
explained by the lower solubility of the sugar acetal 2d in these
non-polar solvent. Finally, CPME was selected as the best
solvent for the reductive cleavage of acetal 2d as it offers a good
compromise which preserves high selectivity with a satisfying
Scheme 3 Hydrogenolysis of 2d with pre-drying.
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ꢀC as it gave a 77% yield. However, this result could not be
improved since the conversion is complete at this temperature.
When the selectivity in 3d and 4d is taken into account, the best
Catalyst loading
The inuence of the catalyst loading was next probed but the
nature of the metal and its support was not investigated in this
paper. Indeed, previous studies have already shown that Pd/C
was one of the best catalysts to perform the reductive ether-
ication of alcohols with aldehydes or ketones.20d,37 Thus, using
1 mol% of Pd (5% on charcoal), the conversion of 2d reached
18% but no traces of sugar ethers 3d or 4d has been detected by
GC (Table 3, Entry 1). Increasing the catalyst loading to 5 and 10
mol% had a benecial effect on the conversion and the desired
ethers were formed with 72% yield in both cases (Table 3,
Entries 2–3). Considering the fact that the starting material was
not totally converted when using 5 mol% of a 5%-Pd/C catalyst
(Table 3, Entry 2), the overall selectivity was better in this case
and reached 88%.
It should be noted that the hydrolysis of the acetal 2d seems
to be promoted by Pd/C since more methyl glucoside by-product
1 was produced at high catalyst loading. In order to determine
the role of the support, the hydrogenolysis of 2d was also carried
out using 5 mol% of a 10%-Pd/C catalyst (Table 3, Entry 4).
Under these conditions, the conversion was improved to 90%
but the overall yield was only 55% and the hydrolysis could not
be avoided. Finally, the use of 5 mol% of a 5%-Pd/C was found
optimum for both the yield and the selectivity.
ꢀ
result (88%) is obtained at 120 C. Moreover, the 72% yield of
methyl glucoside ethers could be further improved as the
conversion was not complete under these conditions. Finally, a
ꢀ
temperature of 120 C was selected for further optimization.
Inuence of the pressure
Considering the difficulties encountered to obtain a complete
conversion in acetal 2d while preserving a high selectivity, the
inuence of the H2 pressure was next studied. Indeed, the
reductive cleavage of an acetal requires the breaking of a C–O
bond and the efficiency of this process is directly linked to the
hydrogen availability. Thus, the hydrogenolysis of methyl
glucoside acetal 2d (dry on MgSO4, 0.1 M in dry CPME) was
performed using 5%-Pd/C (5 mol%) at 120 ꢀC for 15 hours
under different hydrogen pressure (Table 5).
When the hydrogen pressure was increased from 10 to 30
bar, the conversion of the starting material 2d increased grad-
ually from 61 to 94% (Table 5, Entries 1–3). A similar trend was
observed for the global yield of the desired ethers 3d and 4d that
reached a maximum (79%) for a hydrogen pressure of 30 bar
(Table 5, Entry 3). It should be noted that the hydrolysis side-
reaction was slightly amplied at such pressure. No attempt to
further increase the hydrogen pressure was made for technical
and safety reasons. Then, the reaction was carried out at 135 ꢀC
under 30 bar of hydrogen (Table 5, Entry 4). Under these
conditions, the conversion of acetal 2d was complete but more
by-products were observed and the desired ethers were only
obtained with 64% yield. Finally, a pressure of 30 bar of
Inuence of the temperature
The inuence of the temperature was next studied using 2d (dry
on MgSO4, 0.1 M in dry CPME) and 5%-Pd/C (5 mol%) under 20
bar of hydrogen for 15 hours (Table 4).
When the temperature was increased from 100 to 135 ꢀC, the
conversion of methyl glucoside acetal 2d increased gradually
from 65 to >99% (Table 4, Entries 1–3). A similar trend was
observed for the yield of the desired ethers 3d and 4d and a
ꢀ
hydrogen at 120 C was selected for further optimization.
Mechanical stirring
ꢀ
maximum yield of 77% was obtained at 135 C (Table 4, Entry
3). At a higher temperature (150 ꢀC), the conversion was For convenience, the optimization of the reductive cleavage of
surprisingly not complete (83%) and the sugar ethers 3d and 4d methyl glucoside acetal 2d was carried out using a 30 mL
were recovered with only 71% yield (Table 4, Entry 4). If the yield stainless steel autoclave using magnetic stirring. Even if this set-
is only taken into account, the best temperature seems to be 135 up is not perfectly adequate for a tri-phasic system (liquid, solid
Table 3 Influence of the Pd/C loadinga
Entry
Pd catalyst (loading)
Conv.b (2d, %)
Yieldc (3d + 4d, %)
Yieldc (1, %)
1
2
3
4
5%-Pd/C (1 mol%)
5%-Pd/C (5 mol%)
5%-Pd/C (10 mol%)
10%-Pd/C (5 mol%)
18
82
>99
90
0
0
10
13
10
72 (63 : 37)
72 (60 : 40)
55 (64 : 36)
a
Experimental conditions: methyl glucoside acetal 2d (0.33 g, dried on MgSO4), 5%-Pd/C, H2 (20 bar), dry CPME (10 mL), 120 ꢀC, 15 h, stirring speed
¼ 800 rpm. Conversions were determined by 1H NMR. Yields and ratio of 3d and 4d were determined by GC aer derivatization of the crude
b
c
reaction mixture.
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Table 4 Hydrogenolysis of methyl 4,6-O-decylidene glucoside 2d at different temperaturesa
Entry
Temperature (ꢀC)
Conv.b (2d, %)
Yieldc (3d + 4d, %)
Selectivityc (3d + 4d, %)
Yieldc (1, %)
1
2
3
4
100
120
135
150
65
82
>99
83
33 (60 : 40)
72 (63 : 37)
77 (65 : 35)
71 (63 : 37)
51
88
78
86
0
10
13
12
a
Experimental conditions: methyl glucoside acetal 2d (0.33 g, dried on MgSO4), 5%-Pd/C (5 mol%), H2 (20 bar), dry CPME (10 mL), 15 h, stirring
speed ¼ 800 rpm. b Conversions were determined by 1H NMR. c Yield, selectivity and ratio of 3d and 4d were determined by GC aer derivatization
of the crude reaction mixture.
and gas), it allowed a rapid screening of the reaction parameters and the reaction time was increased to 48 h in order to obtain
and led to the preparation of methyl glucoside ethers 3d and 4d better conversion.
with a satisfying yield of 79%. Conversely, the utilization of a
The hydrogenolysis of methyl 4,6-O-pentylidene glucoside 2a
300 mL stainless steel autoclave tted with a mechanic stirrer afforded the corresponding mixture of methyl 4-pentyl- and 6-
was found more appropriate for preparative purposes. Indeed, pentyl-glucoside ethers 3a and 4a in a moderate 38% isolated
the hydrogenolysis of 2d (1.0 g, 0.1 M in dry CPME) using a yield (Table 6, Entry 1). A similar yield (37%) of ethers 3b and 4b
perfectly stirred autoclave (800 rpm) under the previously opti- was obtained when starting from methyl 4,6-O-hexylidene
mized conditions [5%-Pd/C (5 mol%), H2 (30 bar), 120 ꢀC, 15 glucoside 2b (Table 6, Entry 2). Starting from acetals with a
hours] afforded the desired ethers 3d and 4d with an improved longer alkyl chain such as 2c and 2e, the yield of the desired
81% GC-yield (Scheme 4).
ethers increased to 40 and 51%, respectively (Table 6, Entries 3–
Under these conditions, methyl 6-decyl glucoside 3d was 4). This observation could be explained by the fact that
obtained as the major regioisomer with 68% selectivity and the hydrogen is more soluble in a non-polar medium, provided here
formation of methyl glucoside 1 was strongly minimized (5%). by the presence of the lipophilic alkyl chain. It should be added
that the ratio between 4-alkyl- and 6-alkyl-regioisomers was
barely affected with the increase of the alkyl chain length.
However, the conversions of the starting materials were not
complete even aer 48 hours at 120 C. Ethers 3a–e and 4a–e
have been isolated as the only products of the reaction and no
traces of side products, such as methyl glucoside 1, has been
detected under these conditions. This observation is well
translated if the selectivities are taken into account. Indeed, the
Scope of methyl glucoside acetals
ꢀ
In order to evaluate the scope and the limitations of the
method, the optimized conditions were applied to a range of
methyl glucoside-4,6-O-acetals 2 bearing different alkyl chain
length (Table 6). The reductive cleavage of these acetals was
carried out on the large scale without prior drying on MgSO4
Table 5 Hydrogenolysis of methyl 4,6-O-decylidene glucoside 2d at different H2 pressurea
Entry
Temp. (ꢀC)
H2 (bar)
Conv.b (2d, %)
Yieldc (3d + 4d, %)
Yieldc (1, %)
1
2
3
4
120
120
120
135
10
20
30
30
61
82
94
50 (62 : 38)
72 (63 : 37)
79 (59 : 41)
64 (62 : 38)
10
10
14
13
>99
a
Experimental conditions: methyl glucoside 2d (0.33 g, dried on MgSO4), 5%-Pd/C (5 mol%), H2 dry CPME (10 mL), 15 h, stirring speed ¼ 800 rpm.
b
c
Conversions were determined by 1H NMR. Yield, selectivity and ratio of 3d and 4d were determined by GC aer derivatization of the crude
reaction mixture.
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Scheme 4 Hydrogenolysis of 2d under optimized conditions with
mechanic stirring.
Fig. 2 Proposed mechanism for the preferential ring cleavage of
acetals.
desired ethers were formed with good to excellent selectivites
ranging from 86 to >99% (Table 6, Entries 1–4).
that breaks to furnish methyl 6-alkyl glucoside as the major
regioisomer.
Mechanistic considerations
Conclusions
Contrary to our previous works20 on the reductive alkylation of
glycerol with aldehydes, the reductive cleavage of methyl In conclusion, we have developed a cheap and environmentally-
glucoside acetals 2a–e proceeds in the absence of an acid co- friendly access to methyl glucoside ethers through the catalytic
catalyst. Indeed, in the latter case, the presence of CSA was hydrogenolysis of the corresponding acetals. The reductive
found deleterious for the product yield as it also promotes the cleavage of these acetals proceeds in the presence of Pd/C using
hydrolysis of the starting material (see Table 1). Thus, we hydrogen as a clean reducing agent and CPME as solvent. Under
hypothesized that the acidity of the Pd/C catalytic system is these conditions, the desired methyl glucoside ethers were
enough to activate the acetal and to promote the hydrogenolysis formed with poor to good yields (37–81%) and high selectivities
of the C–O bond. This hypothesis is supported by the works of (86–99%). Moreover, we have also shown that the presence of an
Kita37a and Marecot37b who have shown that the support acidity acid co-catalyst was not necessary and, contrary to our previous
has a crucial role in the reductive alkylation of alcohols without reports, could be deleterious for the overall process. It should be
acid co-catalyst. Consequently, a mechanistic rationale was added that methyl glucoside ethers have been obtained as a
proposed to account for the formation of methyl 6-alkyl gluco- mixture of regioisomers with a preference for the 6-alkyl
side ethers 3a–e as the major regioisomers (Fig. 2). The acetal regioisomer. A mechanism has been proposed to account for
function could be activated by Pd with the assistance of the 3- this regioselectivity. Current investigations are now focused
hydroxyl group of methyl glycoside. In this conguration, upon expanding the scope to other sugars or sugar derivatives
hydrogen could be preferentially delivered to the C–O(4) bond and increasing the regioselectivity of this method.
Table 6 Scope of methyl glucoside acetalsad
Selectivity
(3 + 4, %)
Entry
1
Substrate 2
Conv.b (2, %)
Product ratio
Yieldc (3 + 4, %)
3a : 4a
(70 : 30)
42
38
90
3b : 4b
(72 : 28)
2
3
37
42
59
37
40
51
>99
95
3c : 4c
(75 : 25)
3e : 4e
(73 : 27)
4
86
a
Experimental conditions: methyl glucoside acetal 2a–e (20 mmol), 5%-Pd/C (5 mol%), H2 (30 bar), dry CPME (200 mL), 120 ꢀC, 15 h, stirring speed
¼ 800 rpm. b Conversions were determined by 1H NMR. c Isolated yields. d Ratio of 3a–e and 4a–e were determined by GC aer derivatization of the
crude reaction mixture.
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Experimental
Acknowledgements
General information
The authors would like to thank the company TEREOS SYRAL
Methyl a-D-glucoside 1 (>98% purity) was purchased from SAS and the Association Nationale de la Recherche et de la
Sigma-Aldrich or Alfa-Aesar and Pd/C (5 or 10%, Pd on activated Technologie (ANRT) for nancial support through a CIFRE
carbon, reduced and dry, Escat 1431) from Strem Chemicals. grant (2011/1660) for C.G.
Valeraldehyde, hexanal, octanal, decanal and dodecanal were
supplied by Sigma-Aldrich or Alfa-Aesar. Amberlyst 15 dry was
bought from Rohm and Haas. All other reagents and solvents
Notes and references
were used as received without further purication. NMR spectra
were acquired on a Bruker 300 (1H, 300 MHz; 13C, 75 MHz)
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(TLC) was carried out on aluminum sheets coated with silica gel
Merck 60 F254 (0.25 mm) revealed with a solution of sulfuric
acid at 2.5 v/v% in ethanol. Flash column chromatography was
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numbers (n max) are expressed in cmꢁ1. Melting points were
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